CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein

The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.

Small animal bone healing models : standards, tips, and pitfalls results of a consensus meeting

Small animal fracture models have gained increasing interest in fracture healing studies. To achieve standardized and defined study conditions, various variables must be carefully controlled when designing fracture healing experiments in mice or rats. The strain, age and sex of the animals may influence the process of fracture healing. Furthermore, the choice of the fracture fixation technique depends on the questions addressed, whereby intra- and extramedullary implants as well as open and closed surgical approaches may be considered. During the last few years, a variety of different, highly sophisticated implants for fracture fixation in small animals have been developed. Rigid fixation with locking plates or external fixators results in predominantly intramembranous healing in both mice and rats. Locking plates, external fixators, intramedullary screws, the locking nail and the pin-clip device allow different degrees of stability resulting in various amounts of endochondral and intramembranous healing. The use of common pins that do not provide rotational and axial stability during fracture stabilization should be discouraged in the future. Analyses should include at least biomechanical and histological evaluations, even if the focus of the study is directed towards the elucidation of molecular mechanisms of fracture healing using the largely available spectrum of antibodies and gene-targeted animals to study molecular mechanisms of fracture healing. This review discusses distinct requirements for the experimental setups as well as the advantages and pitfalls of the different fixation techniques in rats and mice.

Determinants of rapid weight gain during infancy: Baseline results from the NOURISH randomised controlled trial.

Background: Rapid weight gain in infancy is an important predictor of obesity in later childhood. Our aim was to determine which modifiable variables are associated with rapid weight gain in early life. Methods: Subjects were healthy infants enrolled in NOURISH, a randomised, controlled trial evaluating an intervention to promote positive early feeding practices. This analysis used the birth and baseline data for NOURISH. Birthweight was collected from hospital records and infants were also weighed at baseline assessment when they were aged 4-7 months and before randomisation. Infant feeding practices and demographic variables were collected from the mother using a self administered questionnaire. Rapid weight gain was defined as an increase in weight-for-age Z-score (using WHO standards) above 0.67 SD from birth to baseline assessment, which is interpreted clinically as crossing centile lines on a growth chart. Variables associated with rapid weight gain were evaluated using a multivariable logistic regression model. Results: Complete data were available for 612 infants (88% of the total sample recruited) with a mean (SD) age of 4.3 (1.0) months at baseline assessment. After adjusting for mother's age, smoking in pregnancy, BMI, and education and infant birthweight, age, gender and introduction of solid foods, the only two modifiable factors associated with rapid weight gain to attain statistical significance were formula feeding [OR=1.72 (95%CI 1.01-2.94), P= 0.047] and feeding on schedule [OR=2.29 (95%CI 1.14-4.61), P=0.020]. Male gender and lower birthweight were non-modifiable factors associated with rapid weight gain. Conclusions: This analysis supports the contention that there is an association between formula feeding, feeding to schedule and weight gain in the first months of life. Mechanisms may include the actual content of formula milk (e.g. higher protein intake) or differences in feeding styles, such as feeding to schedule, which increase the risk of overfeeding. Trial Registration: Australian Clinical Trials Registry ACTRN12608000056392

Influences on student learning in engineering : some results from case study fieldwork

This paper closely examines factors affecting students’ progression in their engineering programs through fieldwork conducted at three Australian universities. To extract clues on how specific teaching methods can be used to maximize learning, the investigation considered factors such as understanding how students take in, process and present information. A number of focus groups were conducted with students and the data gathered was combined with survey results of students’ and academics’ learning styles. The paper reports on the process followed, and provides some analysis of the gathered data, as part of an Australian Learning and Teaching Council, ALTC, Associate Fellowship program.

Some empirical results for neo-Piagetian reasoning in novice programmers and the relationship to code explanation questions

Recent research on novice programmers has suggested that they pass through neo-Piagetian stages: sensorimotor, preoperational, and concrete operational stages, before eventually reaching programming competence at the formal operational stage. This paper presents empirical results in support of this neo-Piagetian perspective. The major novel contributions of this paper are empirical results for some exam questions aimed at testing novices for the concrete operational abilities to reason with quantities that are conserved, processes that are reversible, and properties that hold under transitive inference. While the questions we used had been proposed earlier by Lister, he did not present any data for how students performed on these questions. Our empirical results demonstrate that many students struggle to answer these problems, despite the apparent simplicity of these problems. We then compare student performance on these questions with their performance on six explain in plain English questions.

The nonprofit board as a team : pilot results and initial insights

There is a growing desire for boards of nonprofits to deliver better governance to the organizations they control. Consequently, self-evaluation has become an important tool for nonprofit boards to meet these expectations and demonstrate that they are discharging their responsibilities effectively. This article describes initial results aimed at developing a psychometrically sound, survey-based board evaluation instrument, based on the Team Development Survey (TDS), that assesses the team attributes of an organization’s board. Our results indicate that while constructs applicable to teams generally appear to apply to boards, there are also important differences. We highlight how a perception of board objective clarity, appropriate skills mix, resource availability, and psychological safety were positively and significantly associated with measures of board, management and organizational performance.

Driving for work : a series of organisational audit results

Previous research has indicated that road crashes are the most common form of work related fatalities (Haworth et al., 2000). Historically, industry has often taken a “silver bullet” approach developing and implementing a single countermeasure to address all their work related road safety issues, despite legislative requirements to discharge obligations through minimising risk and enhancing safety. This paper describes the results and implications from a series of work related road safety audits that were undertaken across five organisations to determine deficiencies in each organisation‟s safe driving management and practice. Researchers conducted a series of structured interviews, reviewed documentation relating to work related driving, and analysed vehicle related crash and incident records to determine each organisation‟s current situation in the management of work related road safety and driver behaviour. A number of consistent themes and issues across each organisation were identified relating to managing driver behaviour, organisational policies, incident recording and reporting, communication and education, and formalisation of key work related road safety strategies. Although organisations are required to undertake risk reduction strategies for all work related driving, the results of the research suggest that many organisations fail to systematically manage driver behaviour and mitigate work related road safety risk. Future improvements in work related road safety will require organisations to firstly acknowledge the high risk associated with drivers driving for work and secondly adopt comprehensive risk mitigation strategies in a similar manner to managing other workplace hazards.

Has increasing the age for child passengers to wear child restraints improved the extent to which they are used? Results from an Australian focus group and survey study.

Acknowledgement that many children in Australia travel in restraints that do not offer them the best protection has led to recent changes in legislation such that the type of restraint for children under 7 years is now specified. This paper reports the results of two studies (observational; focus group/ survey) carried out in the state of Queensland to evaluate the effectiveness of these changes to the legislation. Observations suggested that almost all of the children estimated as aged 0-12 years were restrained (95%). Analysis of the type of restraint used for target-aged children (0-6 year olds) suggests that the proportion using an age-appropriate restraint has increased by an estimated 7% since enactment of the legislation. However, around 1 in 4 children estimated as aged under 7 years were using restraints too large for good fit. Results from the survey and focus group suggested parents were supportive of the changes in legislation. Non-Indigenous parents agreed that the changes had been necessary, were effective at getting children into the right restraints, were easy to understand as well as making it clear what restraint to use with children. Moreover, they did not see the legislation as too complicated or too hard to comply with. Indigenous parents who participated in a focus group also regarded the legislation as improving children’s safety. However, they identified the cost of restraints as an important barrier to compliance. In summary, the legislation appears to have had a positive effect on compliance levels and on raising parental awareness of the need to restrain children child-specific restraints for longer. However, it would seem that an important minority of parents transition their children into larger restraints too early for optimal protection. Intervention efforts should aim to better inform these parents about appropriate ages for transition, especially from forward facing childseats. This could potentially be through use of other important transitions that occur at the same age, such as starting school. The small proportion of parents who do not restrain their children at all are also an important community sector to target. Finally, obtaining restraints presents a significant barrier to compliance for parents on limited incomes and interventions are needed to address this.