The mitochondrial and autosomal mutation landscapes of prostate cancer

BACKGROUND: Prostate cancer (PCa) is the most common cancer in men. PCa is strongly age associated; low death rates in surveillance cohorts call into question the widespread use of surgery, which leads to overtreatment and a reduction in quality of life. There is a great need to increase the understanding of tumor characteristics in the context of disease progression.

OBJECTIVE: To perform the first multigenome investigation of PCa through analysis of both autosomal and mitochondrial DNA, and to integrate exome sequencing data, and RNA sequencing and copy-number alteration (CNA) data to investigate how various different tumor characteristics, commonly analyzed separately, are interconnected.

DESIGN, SETTING, AND PARTICIPANTS: Exome sequencing was applied to 64 tumor samples from 55 PCa patients with varying stage and grade. Integrated analysis was performed on a core set of 50 tumors from which exome sequencing, CNA, and RNA sequencing data were available.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Genes, mutated at a significantly higher rate relative to a genomic background, were identified. In addition, mitochondrial and autosomal mutation rates were correlated to CNAs and proliferation, assessed as a cell cycle gene expression signature.

RESULTS AND LIMITATIONS: Genes not previously reported to be significantly mutated in PCa, such as cell division cycle 27 homolog (Saccharomyces cerevisiae) (CDC27), myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3), lysine (K)-specific demethylase 6A (KDM6A), and kinesin family member 5A (KIF5A) were identified. The mutation rate in the mitochondrial genome was 55 times higher than that of the autosomes. Multilevel analysis demonstrated a tight correlation between high reactive-oxygen exposure, chromosomal damage, high proliferation, and in parallel, a transition from multiclonal indolent primary PCa to monoclonal aggressive disease. As we only performed targeted sequence analysis; copy-number neutral rearrangements recently described for PCa were not accounted for.

CONCLUSIONS: The mitochondrial genome displays an elevated mutation rate compared to the autosomal chromosomes. By integrated analysis, we demonstrated that different tumor characteristics are interconnected, providing an increased understanding of PCa etiology.

Gender-specific profiling in SCN1A polymorphisms and time-to-recurrence in patients with stage II/III colorectal cancer treated with adjuvant 5-fluoruracil chemotherapy

This study was designed to analyze the gender-related association between SCN1A polymorphisms (voltage-gated sodium channels; α-subunit) and time-to-recurrence (TTR) in patients with colorectal cancer (CRC) treated with 5-fluoruracil (5-FU)-based adjuvant chemotherapy. We enrolled from a prospective database patients with stage II and III CRC treated with adjuvant 5-FU-based chemotherapy. Genotypes for SCN1A rs3812718 and rs229877 were determined by direct DNA sequencing. One hundred twenty-seven males and 107 females were included in the study. In the univariate and multivariate analysis, the shortest TTR was associated with female patients carrying the rs3812718-TT genotype (hazard ratio (HR): 2.26 (95% confidence interval (CI): 0.89, 5.70), P=0.039) but with male patients carrying the rs3812718-CC genotype (HR: 0.49 (95% CI: 0.18, 1.38), P=0.048). For rs229877 the CT genotype was associated with a trend for shorter TTR in both gender populations. The study validated gender-dependent association between genomic SCN1A rs3812718 polymorphism and TTR in CRC patients treated with adjuvant 5-FU-based chemotherapy. This study confirms that voltage-gated Na+ channels may be a potential therapeutic target and a useful predictive biomarker before 5-FU infusion.

Transplantation tolerance induced by regulatory T cells: in vivo mechanisms and sites of action.

The mechanisms by which CD4(+)CD25(+)Foxp3(+) T (Treg) cells regulate effector T cells in a transplantation setting and their in vivo homeostasis still remain to be clarified. Using a mouse adoptive transfer model, we analyzed the in vivo expansion, trafficking, and effector function of alloreactive T cells and donor-specific Treg cells, in response to a full-thickness skin allograft. Fluorescent-labeled CD4(+)CD25(-) and antigen-specific Treg cells were transferred alone or co-injected into syngeneic BALB/c-Nude recipients transplanted with skins from (C57BL/6 x BALB/c) F1 donors. Treg cells divided in vivo, migrated and accumulated in the allograft draining lymph nodes as well as within the graft. The co-transfer of Treg cells did not modify the early activation and homing of CD4(+)CD25(-) T cells in secondary lymphoid organs. However, in the presence of Treg cells, alloreactive CD4(+)CD25(-) T cells produced significantly less IFN-gamma and were present in reduced numbers in the secondary lymphoid organs. Furthermore, time-course studies showed that Treg cells were recruited into the allograft at a very early stage after transplantation and effectively prevented the infiltration of effector T cells. In conclusion, suppression of rejection requires the early recruitment to the site of antigenic challenge of donor-specific Treg cells, which then mainly regulate the effector arm of T cell alloresponses.

A physical activity intervention in a workplace setting

Physical inactivity poses a huge burden on Canada's health care system and is detrimental to the health of Canadians (Katzmarzyk & Janssen, 2004). Walking is a viable option for individuals to become physically active on a daily basis and is in fact the most commonly reported leisure time physical activity. It has been associated with many health benefits including weight loss/weight control, reduced risk of coronary artery disease and diabetes, lowered blood pressure, and improved psychological wellbeing (Brisson & Tudor-Locke, 2004). Specifically, individuals' stage of change, selfefficacy and health related quality of life (HRQL) are three psychological constructs that can be greatly improved with increased physical activity (Dishman, 1991; Penedo & Dahn, 2005; Poag & McAuley, 1992). Public health physical activity recommendations exist but many individuals find these difficult to meet due to overly busy lifestyles (Public Health Agency of Canada, 2003). Pedometers are inexpensive devices that can monitor individual bouts of walking so that the incorporation of physical activity into one's daily life is more plausible. They are also excellent tools for motivation, goalsetting, and immediate feedback (Brisson & Tudor-Locke, 2004). Since many people spend a large proportion of their time at their places of employment, workplaces have begun to be a common site for the development of physical activity interventions. These programs have been growing in popUlarity and have shown numerous benefits for both employees and employers (Voit, 2001). The purpose of the current study was to implement and evaluate the use of a pedometer-based physical activity intervention incorporating goal-setting and physical activity logs in a workplace setting, and to examine the relationship between different types of self-efficacy (task, barrier, and scheduling) and different phases of the intervention. Twenty male participants from a local steel manufacturing plant who exhibited health risk factors (e.g. hypertension, diabetes, etc.) were assigned to one of two groups (group A or group B). All participants were asked to wear pedometers on their waists, record their daily steps, set goals that were outlined on a step-tracking sheet (detennined by their baseline number of steps), and keep track of their work days, wakelbed time, sedentary time, and time spent doing other physical activity. Group A began the intervention immediately following the baseline measures, whereas group B continued with their regular routine for 4 weeks before beginning. Physiological measures (height, weight, blood pressure, relative body fat, waist and hip circumference, and body mass index) were taken and a battery of questionnaires that assessed barrier, task and scheduling self-efficacy, HRQL, and stage of change administered at baseline, week 5 (end of intervention for group A), week 9 (end of intervention for group B; follow-up for group A) and week 13 (follow-up for both groups). Results showed that this workplace physical activity intervention was successful at increasing the participants' daily steps, that task self-efficacy is a significant predictor of participants' exercise adherence during the initial stages of participation (intervention phase), and that the participants felt that this intervention was effective. Finally, further exploratory analyses showed that this intervention was effective for all participants, but most valuable for participants most in need of improvement - that is, those who were most sedentary prior to the intervention. This intervention is an inexpensive use of simple and effective tools (e.g. pedometers), has the potential to attract a wide variety of participants and become a pennanent part of any health promotion initiative.

Preparation and characterization of micro and nano fiber reinforced natural rubber composites by latex stage processing

Use of short fibers as reinforcing fillers in rubber composites is on an increasing trend. They are popular due to the possibility of obtaining anisotropic properties, ease of processing and economy. In the preparation of these composites short fibers are incorporated on two roll mixing mills or in internal mixers. This is a high energy intensive time consuming process. This calls for developing less energy intensive and less time consuming processes for incorporation and distribution of short fibers in the rubber matrix. One method for this is to incorporate fibers in the latex stage. The present study is primarily to optimize the preparation of short fiber- natural rubber composite by latex stage compounding and to evaluate the resulting composites in terms of mechanical, dynamic mechanical and thermal properties. A synthetic fiber (Nylon) and a natural fiber (Coir) are used to evaluate the advantages of the processing through latex stage. To extract the full reinforcing potential of the coir fibers the macro fibers are converted to micro fibers through chemical and mechanical means. The thesis is presented in 7 chapters

‘Did Ronald McDonald also tend to scare you as a child?’: working to emplace consumption, commodities, and citizen-students in a large classroom setting

So-called ‘radical’ and ‘critical’ pedagogy seems to be everywhere these days on the landscapes of geographical teaching praxis and theory. Part of the remit of radical/critical pedagogy involves a de-centring of the traditional ‘banking’ method of pedagogical praxis. Yet, how do we challenge this ‘banking’ model of knowledge transmission in both a large-class setting and around the topic of commodity geographies where the banking model of information transfer still holds sway? This paper presents a theoretically and pedagogically driven argument, as well as a series of practical teaching ‘techniques’ and tools—mind-mapping and group work—designed to promote ‘deep learning’ and a progressive political potential in a first-year large-scale geography course centred around lectures on the Geographies of Consumption and Material Culture. Here students are not only asked to place themselves within and without the academic materials and other media but are urged to make intimate connections between themselves and their own consumptive acts and the commodity networks in which they are enmeshed. Thus, perhaps pedagogy needs to be emplaced firmly within the realms of research practice rather than as simply the transference of research findings.

An integrated multi-stage model of knowledge management in international joint ventures: identifying a trigger for knowledge exploration and knowledge harvest

This paper examines the evolution of knowledge management from the initial knowledge migration stage, through adaptation and creation, to the reverse knowledge migration stage in international joint ventures (IJVs). While many studies have analyzed these stages (mostly focusing on knowledge transfer), we investigated the path-dependent nature of knowledge flow in IJVs. The results from the empirical analysis based on a survey of 136 Korean parent companies of IJVs reveal that knowledge management in IJVs follows a sequential, multi-stage process, and that the knowledge transferred from parents to IJVs must first be adapted within its new environment before it reaches the creation stage. We also found that only created knowledge is transferred back to parents.

PokerMapper: : mapping executive functions, poker playing ability and responsible gambling in online environments

Research objectives Poker and responsible gambling both entail the use of the executive functions (EF), which are higher-level cognitive abilities. The main objective of this work was to assess if online poker players of different ability show different performances in their EF and if so, which functions are the most discriminating ones. The secondary objective was to assess if the EF performance can predict the quality of gambling, according to the Gambling Related Cognition Scale (GRCS), the South Oaks Gambling Screen (SOGS) and the Problem Gambling Severity Index (PGSI). Sample and methods The study design consisted of two stages: 46 Italian active players (41m, 5f; age 32±7,1ys; education 14,8±3ys) fulfilled the PGSI in a secure IT web system and uploaded their own hand history files, which were anonymized and then evaluated by two poker experts. 36 of these players (31m, 5f; age 33±7,3ys; education 15±3ys) accepted to take part in the second stage: the administration of an extensive neuropsychological test battery by a blinded trained professional. To answer the main research question we collected all final and intermediate scores of the EF tests on each player together with the scoring on the playing ability. To answer the secondary research question, we referred to GRCS, PGSI and SOGS scores.  We determined which variables that are good predictors of the playing ability score using statistical techniques able to deal with many regressors and few observations (LASSO, best subset algorithms and CART). In this context information criteria and cross-validation errors play a key role for the selection of the relevant regressors, while significance testing and goodness-of-fit measures can lead to wrong conclusions.   Preliminary findings We found significant predictors of the poker ability score in various tests. In particular, there are good predictors 1) in some Wisconsin Card Sorting Test items that measure flexibility in choosing strategy of problem-solving, strategic planning, modulating impulsive responding, goal setting and self-monitoring, 2) in those Cognitive Estimates Test variables related to deductive reasoning, problem solving, development of an appropriate strategy and self-monitoring, 3) in the Emotional Quotient Inventory Short (EQ-i:S) Stress Management score, composed by the Stress Tolerance and Impulse Control scores, and in the Interpersonal score (Empathy, Social Responsibility, Interpersonal Relationship). As for the quality of gambling, some EQ-i:S scales scores provide the best predictors: General Mood for the PGSI; Intrapersonal (Self-Regard; Emotional Self-Awareness, Assertiveness, Independence, Self-Actualization) and Adaptability  (Reality Testing, Flexibility, Problem Solving) for the SOGS, Adaptability for the GRCS. Implications for the field Through PokerMapper we gathered knowledge and evaluated the feasibility of the construction of short tasks/card games in online poker environments for profiling users’ executive functions. These card games will be part of an IT system able to dynamically profile EF and provide players with a feedback on their expected performance and ability to gamble responsibly in that particular moment. The implementation of such system in existing gambling platforms could lead to an effective proactive tool for supporting responsible gambling. 

Health-related quality of life of overweight and obese children

Context: The negative effects of childhood overweight and obesity on quality of life (QOL) have been shown in clinical samples but not yet in population-based community samples.

Objective: To determine relationships between weight and health-related QOL reported by parent-proxy and child self-report in a population sample of elementary school children.

Design, Setting, and Participants: Cross-sectional data collected in 2000 within the Health of Young Victorians Study, a longitudinal cohort study commenced in 1997. Individuals were recruited via a random 2-stage sampling design from primary schools in Victoria, Australia. Of the 1943 children in the original cohort, 1569 (80.8%) were resurveyed 3 years later at a mean age of 10.4 years.

Main Outcome Measures: Health-related QOL using the PedsQL 4.0 survey completed by both parent-proxy and by child self-report. Summary scores for children'S total, physical, and psychosocial health and subscale scores for emotional, social, and school functioning were compared by weight category based on International Obesity Task Force cut points.

Results: Of 1456 participants, 1099 (75.5%) children were classified as not overweight; 294 (20.2%) overweight; and 63 (4.3%) obese. Parent-proxy and child self-reported PedsQL scores decreased with increasing child weight. The parent-proxy total PedsQL mean (SD) score for children who were not overweight was 83.1 (12.5); overweight, 80.0 (13.6); and obese, 75.0 (14.5); P < .001. The respective child self-reported total PedsQL mean (SD) scores were 80.5 (12.2), 79.3 (12.8), and 74.0 (14.2); P < .001. At the subscale level, child and parent-proxy reported scores were similar, showing decreases in physical and social functioning for obese children compared with children who were not overweight (all P < .001). Decreases in emotional and school functioning scores by weight category were not significant.

Conclusion: The effects of child overweight and obesity on health-related QOL in this community-based sample were significant but smaller than in a clinical sample using the same measure.

Pain beliefs and pain management of oncology patients

Cancer pain is estimated to occur in 30% to 70% of patients with early-stage cancer and 60% to 95% with advanced cancer. Current research shows that cancer pain continues to be undertreated despite the availability of analgesics and established guidelines to maximize their effectiveness. The purpose of this study was to describe oncology patients' pain experience during an episode of hospitalization with particular emphasis on exploring the relationship between oncology patients' beliefs about pain and the treatment they received. Consecutive patients (n = 126) were interviewed 48 hours after admission to an urban and a regional hospital in Australia; 47.6% of patients had experienced moderate to severe pain in the previous 24 hours but had only received 40.4% of available analgesic. Patients held varying beliefs about pain and pain treatments in particular, 41% held strong beliefs about the potential for addiction to narcotics. Patients who held this belief reported higher current pain, worst pain intensity, and higher average pain intensity in the previous 24 hours. Effective pain management in the inpatient oncology setting continues to be an important clinical issue, and patients do not receive all available pain treatment. There may be an important association between patients' beliefs about pain and pain management and the pain management they receive.

ACE-Obesity : priority setting for obesity prevention

The ACE-Obesity study uses an evidence-based approach to evaluate interventions aimed at reducing the prevalence of obesity in Australian youth. It informs decision-makers about the benefits of individual interventions and the packaging of a coherent strategy for obesity prevention and management. To avoid methodological confounding, the approach employs standardised methods including a two stage concept of benefit; a common comparator, setting and decision context; Australian data; and extensive probabilistic uncertainty testing. The technical cost-effectiveness results (cost per DALY) for each of the selected interventions will be reported. Modelling is undertaken to convert changes in behaviour to BMI outcomes and then to DALYs, and issues of the attribution of costs across multiple objectives arise. Due process is achieved by involving stakeholders on a Working Group, and by consideration of second stage filters (such as equity, acceptability and feasibility). The results are brought together in a 'league table' in which all the interventions are ranked in order of economic merit without the usual methodological concerns about results drawn from studies lacking in comparability. In packaging interventions to meet particular budget allocations, the divisibility, mutual exclusivity and returns to scale of individual interventions are considered, as well as issues of program logic, target group coverage and a range of settings.

Obesity prevention in the family day care setting : impact of the romp & chomp intervention on opportunities for children's physical activity and healthy eating

Background The Romp & Chomp intervention reduced the prevalence of overweight/obesity in pre-school children in Geelong, Victoria, Australia through an intervention promoting healthy eating and active play in early childhood settings. This study aims to determine if the intervention successfully created more health promoting family day care (FDC) environments.
Methods The evaluation had a cross-sectional, quasi-experimental design with the intervention FDC service in Geelong and a comparison sample from 17 FDC services across Victoria. A 45-item questionnaire capturing nutrition- and physical activity-related aspects of the policy, socio-cultural and physical environments of the FDC service was completed by FDC care providers (in 2008) in the intervention (n = 28) and comparison (n = 223) samples.
Results Select results showed intervention children spent less time in screen-based activities (P = 0.03), organized active play (P < 0.001) and free inside play (P = 0.03) than comparison children. There were more rules related to healthy eating (P < 0.001), more care provider practices that supported children’s positive meal experiences (P < 0.001), fewer unhealthy food items allowed (P = 0.05), higher odds of staff being trained in nutrition (P = 0.04) and physical activity (P < 0.001), lower odds of having set minimum times for outside (P < 0.001) and organized (P = 0.01) active play, and of rewarding children with food (P < 0.001).
Conclusions Romp & Chomp improved the FDC service to one that discourages sedentary behaviours and promotes opportunities for children to eat nutritious foods. Ongoing investment to increase children’s physical activity within the setting and improving the capacity and health literacy of care providers is required to extend and sustain the improvements.

Thai emergency nurses’ management of patients with severe traumatic brain injury: comparison of knowledge and clinical management with best available evidence

Background:
In Thailand, the rate of TBI-related hospitalisation is increasing, however, little is known about the evidence-based management of severe TBI in the developing world. The aim of this study was to explore Thai emergency nurses’ management of patients with severe TBI.

Methods:
An exploratory descriptive mixed method design was used to conduct this two stage study: survey methods were used to examine emergency nurses’ knowledge regarding management of patients with severe TBI (Stage 1) and observational methods were used to examine emergency nurses’ clinical management of patients with severe TBI (Stage 2). The study setting was the emergency department (ED) at a regional hospital in Southern Thailand.

Results:
34 nurses participated in Stage 1 (response rate 91.9%) and the number of correct responses ranged from 33.3% to 95.2%. In Stage 2, a total of 160 points of measurement were observed in 20 patients with severe TBI over 40 h. In this study there were five major areas identified for the improvement of care of patients with severe TBI: (i) end-tidal carbon dioxide (ETCO2) monitoring and targets; (ii) use of analgesia and sedation; (iii) patient positioning; (iv) frequency of nursing assessment; and (v) dose of Mannitol diuretic.

Conclusions:
There is variation in Thai nurses’ knowledge and care practices for patients with severe TBI. To increase consistency of evidence-based TBI care in the Thai context, a knowledge translation intervention that is ecologically valid, appropriate to the Thai healthcare context and acceptable to the multidisciplinary care team is needed.

Associations of obsessive-compulsive symptoms with clinical and neurocognitive features in schizophrenia according to stage of illness

This study aimed to investigate the association of obsessive-compulsive symptoms with clinical and neurocognitive features in patients with schizophrenia. This study enrolled 163 people with schizophrenia who were receiving risperidone monotherapy. Comorbid obsessive-compulsive symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale, and subjects with a score≥10 constituted the obsessive-compulsive symptom group (n=30, 18.4%). The learning index was significantly higher in patients with obsessive-compulsive symptoms than in those without such symptoms after adjusting for age, stage (early and chronic), duration of illness, and CDSS score. However, there was no significant interaction between obsessive-compulsive symptoms and stage of illness. Scores on Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Beck Depression Inventory were significantly higher in the obsessive-compulsive symptom group. In addition, the Subjective Well-being under Neuroleptic Treatment score was significantly lower in the obsessive-compulsive symptom group. In conclusion, comorbid obsessive-compulsive symptoms in patients with schizophrenia were associated with a higher learning ability without a significant interaction with stage of illness. However, schizophrenia patients with obsessive-compulsive symptoms had more severe psychotic and depressive symptoms and poorer quality of life.

Associations of obsessive-compulsive symptoms with clinical and neurocognitive features in schizophrenia according to stage of illness

This study aimed to investigate the association of obsessive-compulsive symptoms with clinical and neurocognitive features in patients with schizophrenia. This study enrolled 163 people with schizophrenia who were receiving risperidone monotherapy. Comorbid obsessive-compulsive symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale, and subjects with a score ≥ 10 constituted the obsessive-compulsive symptom group (n=30, 18.4%). The learning index was significantly higher in patients with obsessive-compulsive symptoms than in those without such symptoms after adjusting for age, stage (early and chronic), duration of illness, and CDSS score. However, there was no significant interaction between obsessive-compulsive symptoms and stage of illness. Scores on Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Beck Depression Inventory were significantly higher in the obsessive-compulsive symptom group. In addition, the Subjective Well-being under Neuroleptic Treatment score was significantly lower in the obsessive-compulsive symptom group. In conclusion, comorbid obsessive-compulsive symptoms in patients with schizophrenia were associated with a higher learning ability without a significant interaction with stage of illness. However, schizophrenia patients with obsessive-compulsive symptoms had more severe psychotic and depressive symptoms and poorer quality of life.