Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver

Purpose: Although oral fluoropyrimidine pro-drugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally designed drug in 16 patients with advanced solid cancers. Method: Crossover pharmacokinetic study of oral (400 or 800 mg) and intravenous (250 mg/m 2) OGT 719. Results: Linear pharmacokinetics and oral bioavailability of approximately 25% were observed at the dose levels used in this study. Like other 5-FU prodrugs, considerable interpatient variability was observed in bioavailability following oral dosing. The mean half-life for oral doses was 4 h. OGT 719 was well tolerated. No objective tumour responses were demonstrated. Conclusion: The systemic bioavailability and half-life of oral OGT 719 are sufficient to merit dose escalation studies with frequent daily dosing. Subsequent efficacy studies should be performed in patients with primary and secondary liver malignancies.

The use of acoustic indices to determine avian species richness in audio-recordings of the environment

Interpreting acoustic recordings of the natural environment is an increasingly important technique for ecologists wishing to monitor terrestrial ecosystems. Technological advances make it possible to accumulate many more recordings than can be listened to or interpreted, thereby necessitating automated assistance to identify elements in the soundscape. In this paper we examine the problem of estimating avian species richness by sampling from very long acoustic recordings. We work with data recorded under natural conditions and with all the attendant problems of undefined and unconstrained acoustic content (such as wind, rain, traffic, etc.) which can mask content of interest (in our case, bird calls). We describe 14 acoustic indices calculated at one minute resolution for the duration of a 24 hour recording. An acoustic index is a statistic that summarizes some aspect of the structure and distribution of acoustic energy and information in a recording. Some of the indices we calculate are standard (e.g. signal-to-noise ratio), some have been reported useful for the detection of bioacoustic activity (e.g. temporal and spectral entropies) and some are directed to avian sources (spectral persistence of whistles). We rank the one minute segments of a 24 hour recording in descending order according to an "acoustic richness" score which is derived from a single index or a weighted combination of two or more. We describe combinations of indices which lead to more efficient estimates of species richness than random sampling from the same recording, where efficiency is defined as total species identified for given listening effort. Using random sampling, we achieve a 53% increase in species recognized over traditional field surveys and an increase of 87% using combinations of indices to direct the sampling. We also demonstrate how combinations of the same indices can be used to detect long duration acoustic events (such as heavy rain and cicada chorus) and to construct long duration (24 h) spectrograms.

The obesity epidemic : both energy intake and physical activity contribute

Recent data from Australia, the United States and Europe show increased self-reported energy intake associated with obesity, in contrast to earlier suggestions that the obesity epidemic has occurred despite minimal or no increase in per capita energy intake from food. The effect of increased energy intake is compounded by sedentary lifestyles. Both physical activity and nutrition must be addressed to reduce the prevalence of obesity and improve the health of Australians.

Market turbulence, temporal orientation and firm performance

This study investigates the role of environmental dynamics (i.e., market turbulence) as a factor influencing an organisation’s top management temporal orientation, and the impact of temporal orientation on innovative and financial performance. Results show that firm’s operating in highly turbulent markets exhibit higher degrees of future orientation, as opposed to present orientation. Future-oriented (rather than present-oriented) firms also experience higher levels of both incremental and radical innovations, which in turn generate financial performance. The study highlights the important role of shared strategic mindset (which is contextually influenced) as a driving factor behind the firm innovative and financial performance.

A phase II study of Caelyx, liposomal doxorubicin : lack of activity in patients with advanced gastric cancer

Purpose A phase II study was designed to assess the efficacy and safety of Caelyx (liposomal doxorubicin) in patients with advanced or metastatic gastric cancer. Methods A total of 25 patients with gastric adenocarcinoma were treated with Caelyx 45 mg/m2 every 28 days as first-line therapy for advanced disease. Patients were treated until tumour progression or unacceptable toxicity. Results One patient was withdrawn from the study after experiencing a severe infusion reaction. Of the 24 evaluable patients, 1 had a partial response, 7 had stable disease and the others progressed. Side effects, in particular palmar-plantar erythrodysaesthesia and haematological toxicity, were minor. Conclusions We conclude that while this dose and schedule of Caelyx in this patient group is acceptable, further studies with this regimen cannot be recommended due to the lack of antitumour activity seen.

Biomechanical characteristics of peripheral diabetic neuropathy : a systematic review and meta-analysis of findings from the gait cycle, muscle activity and dynamic barefoot plantar pressure

Background: Diabetic peripheral neuropathy is an important cause of foot ulceration and limb loss. This systematic review and meta-analysis investigated the effect of diabetic peripheral neuropathy on gait, dynamic electromyography and dynamic plantar pressures. Methods: Electronic databases were searched systematically for articles reporting the effect of diabetic peripheral neuropathy on gait, dynamic electromyography and plantar pressures. Searches were restricted to articles published between January 2000 and April 2012. Outcome measures assessed included spatiotemporal parameters, lower limb kinematics, kinetics, muscle activation and plantar pressure. Meta-analyses were carried out on all outcome measures reported by ≥3 studies. Findings: Sixteen studies were included consisting of 382 neuropathy participants, 216 diabetes controls without neuropathy and 207 healthy controls. Meta-analysis was performed on 11 gait variables. A high level of heterogeneity was noted between studies. Meta-analysis results suggested a longer stance time and moderately higher plantar pressures in diabetic peripheral neuropathy patients at the rearfoot, midfoot and forefoot compared to controls. Systematic review of studies suggested potential differences in the biomechanical characteristics (kinematics, kinetics, EMG) of diabetic neuropathy patients. However these findings were inconsistent and limited by small sample sizes.; Interpretation: Current evidence suggests that patients with diabetic peripheral neuropathy have elevated plantar pressures and occupy a longer duration of time in the stance-phase during gait. Firm conclusions are hampered by the heterogeneity and small sample sizes of available studies. Interpretation: Current evidence suggests that patients with diabetic peripheral neuropathy have elevated plantar pressures and occupy a longer duration of time in the stance-phase during gait. Firm conclusions are hampered by the heterogeneity and small sample sizes of available studies.

Correlating flow induced shear stress and chondrocytes activity in micro-porous scaffold using computational fluid dynamics and rapid prototyping

Flow induced shear stress plays an important role in regulating cell growth and distribution in scaffolds. This study sought to correlate wall shear stress and chondrocytes activity for engineering design of micro-porous osteochondral grafts based on the hypothesis that it is possible to capture and discriminate between the transmitted force and cell response at the inner irregularities. Unlike common tissue engineering therapies with perfusion bioreactors in which flow-mediated stress is the controlling parameter, this work assigned the associated stress as a function of porosity to influence in vitro proliferation of chondrocytes. D-optimality criterion was used to accommodate three pore characteristics for appraisal in a mixed level fractional design of experiment (DOE); namely, pore size (4 levels), distribution pattern (2 levels) and density (3 levels). Micro-porous scaffolds (n=12) were fabricated according to the DOE using rapid prototyping of an acrylic-based bio-photopolymer. Computational fluid dynamics (CFD) models were created correspondingly and used on an idealized boundary condition with a Newtonian fluid domain to simulate the dynamic microenvironment inside the pores. In vitro condition was reproduced for the 3D printed constructs seeded by high pellet densities of human chondrocytes and cultured for 72 hours. The results showed that cell proliferation was significantly different in the constructs (p<0.05). Inlet fluid velocity of 3×10-2mms-1 and average shear stress of 5.65×10-2 Pa corresponded with increased cell proliferation for scaffolds with smaller pores in hexagonal pattern and lower densities. Although the analytical solution of a Poiseuille flow inside the pores was found insufficient for the description of the flow profile probably due to the outside flow induced turbulence, it showed that the shear stress would increase with cell growth and decrease with pore size. This correlation demonstrated the basis for determining the relation between the induced stress and chondrocyte activity to optimize microfabrication of engineered cartilaginous constructs.

Physical activity and health-related quality of life among physiotherapists : a cross sectional survey in an Australian hospital and health service

Background Physiotherapists are a professional group with a high rate of attrition and at high risk of musculoskeletal disorders. The purpose of this investigation was to examine the physical activity levels and health-related quality of life of physiotherapists working in metropolitan clinical settings in an Australian hospital and health service. It was hypothesized that practicing physiotherapists would report excellent health-related quality of life and would already be physically active. Such a finding would add weight to a claim that general physical activity conditioning strategies may not be useful for preventing musculoskeletal disorders among active healthy physiotherapists, but rather, future investigations should focus on the development and evaluation of role specific conditioning strategies. Methods A questionnaire was completed by 44 physiotherapists from three inpatient units and three ambulatory clinics (63.7% response rate). Physical activity levels were reported using the Active Australia Survey. Health-related quality of life was examined using the EQ-5D instrument. Physical activity and EQ-5D data were examined using conventional descriptive statistics; with domain responses for the EQ-5D presented in a frequency histogram. Results The majority of physiotherapists in this sample were younger than 30 years of age (n = 25, 56.8%) consistent with the presence of a high attrition rate. Almost all respondents exceeded minimum recommended physical activity guidelines (n = 40, 90.9%). Overall the respondents engaged in more vigorous physical activity (median = 180 minutes) and walking (median = 135 minutes) than moderate exercise (median = 35 minutes) each week. Thirty-seven (84.1%) participants reported no pain or discomfort impacting their health-related quality of life, with most (n = 35,79.5%) being in full health. Conclusions Physical-conditioning based interventions for the prevention of musculoskeletal disorders among practicing physiotherapists may be better targeted to role or task specific conditioning rather than general physical conditioning among this physically active population. It is plausible that an inherent attrition of physiotherapists may occur among those not as active or healthy as therapists who cope with the physical demands of clinical practice. Extrapolation of findings from this study may be limited due to the sample characteristics. However, this investigation addressed the study objectives and has provided a foundation for larger scale longitudinal investigations in this field.

Strategies for developing and delivering a parental physical activity intervention : answers to the what and how

Background Parents are at risk for physical inactivity; however, few studies have designed physical activity (PA) interventions specifically applied to individuals with young children. To ensure the effectiveness of interventions, it may be useful to first elicit the needs from the target population and incorporate salient strategies identified to the design and delivery of a resultant intervention. We aimed to explore strategies for what to include in and how to best deliver a program designed to increase parental PA. Methods Twelve parents (6 mothers, 6 fathers) of children younger than 5 years participated in focus group discussions exploring strategies for an intervention program designed to increase parental PA. Results A range of themes such as Focus on the Children and Flexible Life/Family Plans imbedded in strategies such as persuasion and information, problem-solving, skill building, and environmental approaches were identified. In addition, a range of strategies for how to best deliver a parental PA intervention evidenced in emerging themes such as Diverse and Brief and Individualized Approach was discussed. Conclusions Future research should continue to adopt a ground up, community-based approach to the development and implementation of interventions for this at-risk group to ensure sustained involvement in regular PA.

Urinary biomarkers of physical activity : candidates and clinical utility

Chronic physical inactivity is a major risk factor for a number of important lifestyle diseases, while inappropriate exposure to high physical demands is a risk factor for musculoskeletal injury and fatigue. Proteomic and metabolomic investigations of the physical activity continuum - extreme sedentariness to extremes in physical performance - offer increasing insight into the biological impacts of physical activity. Moreover, biomarkers, revealed in such studies, may have utility in the monitoring of metabolic and musculoskeletal health or recovery following injury. As a diagnostic matrix, urine is non-invasive to collect and it contains many biomolecules, which reflect both positive and negative adaptations to physical activity exposure. This review examines the utility and landscape of biomarkers of physical activity with particular reference to those found in urine.

Breast cancer cells induce osteolytic bone lesions in vivo through a reduction in osteoblast activity in mice

Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients.

Large-scale analysis of formations in soccer

Due to the demand for better and deeper analysis in sports, organizations (both professional teams and broadcasters) are looking to use spatiotemporal data in the form of player tracking information to obtain an advantage over their competitors. However, due to the large volume of data, its unstructured nature, and lack of associated team activity labels (e.g. strategic/tactical), effective and efficient strategies to deal with such data have yet to be deployed. A bottleneck restricting such solutions is the lack of a suitable representation (i.e. ordering of players) which is immune to the potentially infinite number of possible permutations of player orderings, in addition to the high dimensionality of temporal signal (e.g. a game of soccer last for 90 mins). Leveraging a recent method which utilizes a "role-representation", as well as a feature reduction strategy that uses a spatiotemporal bilinear basis model to form a compact spatiotemporal representation. Using this representation, we find the most likely formation patterns of a team associated with match events across nearly 14 hours of continuous player and ball tracking data in soccer. Additionally, we show that we can accurately segment a match into distinct game phases and detect highlights. (i.e. shots, corners, free-kicks, etc) completely automatically using a decision-tree formulation.

Psychological determinants and outcomes of sedentary and physical activity behaviours

There is now a large body of literature that supports the protective role of physical activity for both physical and psychological health. Sedentary behaviour was previously considered the functional opposite of physical activity, but 10 years ago, Owen and colleagues highlighted the need to study physical activity and sedentary behaviour as two distinct modes of behaviour that can independently influence health [1]. Since then, there has been growing evidence that participation in sedentary behaviours such as television viewing, computer use and sitting at work are associated with higher risk of chronic disease outcomes (type 2 diabetes, obesity), and leisure-time sitting has recently been associated with increased mortality [2]. Growing research points to the possible synergistic effects of physical activity and sedentary behaviours in contributing to health outcomes

Activity, motivation and games for young children

The research described in this paper examines the extent to which very young children were able to use the Stomp platform (a floor-based gaming system designed to provide new, active participatory experiences) to engage in game play. We are interested in how children's engagement in different activities within the game world influences their motivation to play games. We map activity to motivational needs of competence, autonomy and relatedness. A detailed examination of two Stomp experiences demonstrates how this type of analysis is useful in identifying the strengths and weaknesses of the games for this audience.

The baby boomers and beyond report : physical activity levels of older Western Australians 2006

Participation in sufficient levels of physical activity provides significant health benefits, particularly in older adults. The monitoring of physical activity levels in the Western Australian population is therefore necessary for developing and implementing strategies and programs for increasing participation. The Premier’s Physical Activity Taskforce (PATF) conducted a survey in 2006 to measure physical activity levels among Western Australian adults to follow-up the 1999 and 2002 state physical activity surveys. There is now widespread agreement that many health problems of older life – including the onset of frailty and disability – can be postponed or delayed by adopting health-enhancing habits such as physical activity. Adults over 65 years are the most rapidly growing age group and will continue to rise as more persons turn 65. If older adults could be encouraged to be more active as they age, frailty and disability associated with falls would be reduced, and function and physical and mental health in older people would be improved thereby reducing the burden of disease and injury. Given that physical inactivity is one of the most important and modifiable risk factors contributing to ill health, particularly for people as they age, the overall aim of this study was to examine patterns of physical activity in those aged 45 years and over – referred to hereafter as baby boomers+ – in more detail.