Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

New Findings What is the central question of this study? The Notch signalling pathway plays an important role in muscle regeneration, and activation of the pathway has been shown to enhance muscle regeneration in aged mice. It is unknown whether Notch activation will have a similarly beneficial effect on muscle regeneration in the context of Duchenne muscular dystrophy (DMD). What is the main finding and its importance? Although expression of Notch signalling components is altered in both mouse models of DMD and in human DMD patients, activation of the Notch signalling pathway does not confer any functional benefit on muscles from dystrophic mice, suggesting that other signalling pathways may be more fruitful targets for manipulation in treating DMD. Abstract In Duchenne muscular dystrophy (DMD), muscle damage and impaired regeneration lead to progressive muscle wasting, weakness and premature death. The Notch signalling pathway represents a central regulator of gene expression and is critical for cellular proliferation, differentiation and apoptotic signalling during all stages of embryonic muscle development. Notch activation improves muscle regeneration in aged mice, but its potential to restore regeneration and function in muscular dystrophy is unknown. We performed a comprehensive examination of several genes involved in Notch signalling in muscles from dystrophin-deficient mdx and dko (utrophin- and dystrophin-null) mice and DMD patients. A reduction of Notch1 and Hes1 mRNA in tibialis anterior muscles of dko mice and quadriceps muscles of DMD patients and a reduction of Hes1 mRNA in the diaphragm of the mdx mice were observed, with other targets being inconsistent across species. Activation and inhibition of Notch signalling, followed by measures of muscle regeneration and function, were performed in the mouse models of DMD. Notch activation had no effect on functional regeneration in C57BL/10, mdx or dko mice. Notch inhibition significantly depressed the frequency-force relationship in regenerating muscles of C57BL/10 and mdx mice after injury, indicating reduced force at each stimulation frequency, but enhanced the frequency-force relationship in muscles from dko mice. We conclude that while Notch inhibition produces slight functional defects in dystrophic muscle, Notch activation does not significantly improve muscle regeneration in murine models of muscular dystrophy. Furthermore, the inconsistent expression of Notch targets between murine models and DMD patients suggests caution when making interspecies comparisons.

G-CSF does not influence C2C12 myogenesis despite receptor expression in healthy and dystrophic skeletal muscle

Granulocyte-colony stimulating factor (G-CSF) increases recovery of rodent skeletal muscles after injury, and increases muscle function in rodent models of neuromuscular disease. However, the mechanisms by which G-CSF mediates these effects are poorly understood. G-CSF acts by binding to the membrane spanning G-CSFR and activating multiple intracellular signaling pathways. Expression of the G-CSFR within the haematopoietic system is well known, but more recently it has been demonstrated to be expressed in other tissues. However, comprehensive characterization of G-CSFR expression in healthy and diseased skeletal muscle, imperative before implementing G-CSF as a therapeutic agent for skeletal muscle conditions, has been lacking. Here we show that the G-CSFR is expressed in proliferating C2C12 myoblasts, differentiated C2C12 myotubes, human primary skeletal muscle cell cultures and in mouse and human skeletal muscle. In mdx mice, a model of human Duchenne muscular dystrophy (DMD), G-CSF mRNA and protein was down-regulated in limb and diaphragm muscle, but circulating G-CSF ligand levels were elevated. G-CSFR mRNA in the muscles of mdx mice was up-regulated however steady-state levels of the protein were down-regulated. We show that G-CSF does not influence C2C12 myoblast proliferation, differentiation or phosphorylation of Akt, STAT3, and Erk1/2. Media change alone was sufficient to elicit increases in Akt, STAT3, and Erk1/2 phosphorylation in C2C12 muscle cells and suggest previous observations showing a G-CSF increase in phosphoprotein signaling be viewed with caution. These results suggest that the actions of G-CSF may require the interaction with other cytokines and growth factors in vivo, however these data provides preliminary evidence supporting the investigation of G-CSF for the management of muscular dystrophy.

Radiotherapy in the Barwon South Western Region: a rural perspective

Introduction: Cancer-related mortality rates are higher in rural areas compared with urban regions. Whether there are corresponding geographical variations in radiotherapy utilisation rates (RURs) is the subject of this study. Methods: RURs for the regional centre of Geelong and rural areas of the Barwon South Western Region were calculated using a population-based database (2009). Results: Lower RURs were observed for rural patients compared with the Geelong region for prostate cancer (15.7% vs 25.8%, P = 0.02), rectal cancer (32.8% vs 44.7%, P = 0.11), lymphoma (9.4% vs 26.2%, P = 0.05), and all cancers overall (25.6% vs 28.9%, P = 0.06). This lower rate was significant in men (rural, 19.9%; Geelong, 28.3%; P = 0.00) but not in women (rural, 33.6%; Geelong, 29.7%; P = 0.88). Time from diagnosis to radiotherapy was not significantly different for patients from the two regions. Tumour staging within the rural and Geelong regions was not significantly different for the major tumour streams of rectal, prostate and lung cancer (P = 0.61, P = 0.79, P = 0.43, respectively). A higher proportion of tumours were unstaged or unstageable in the rural region for lung (44% vs 18%, P < 0.01) and prostate (73% vs 57%, P < 0.01) cancer. Conclusion: Lower RURs were observed in our rural region. Differences found within tumour streams and in men suggest a complexity of relationships that will require further study.

Parental influences on the diets of 2- to 5-year-old children: systematic review of qualitative research

Parents have a major influence on young children's diets, food choices and habit formation. However, research concerning parental influence on children's diets is limited. Qualitative research informs quantitative research with a narrative of 'what works' and is a valuable tool to inform intervention design and practice. This article presents a systematic review of qualitative research with parents of preschool children and their influence on their child's diet. Nine studies were identified. Findings highlight the need to promote culturally tailored programmes to combat specific cultural differences such as attitudes; perceptions and concerns; address common barriers to providing healthy foods and challenges faced by lower income families; the use of food to shape a child's behaviour; that children will grow out of excess weight; common misconceptions such as a heavier child is healthier and depriving a child's food request could result in starvation. Research on parental understanding of healthy diets and feeding practices is lacking. Further insights into how to positively influence children's diets will come from research examining parent feeding practices and nutrition knowledge. © The Author(s) 2013.

Time and spatial resolution of slip and twinning in a grain embedded within a magnesium polycrystal

Plastic yielding in magnesium alloys frequently involves the initiation of both slip and twinning events. A proper understanding of the phenomenon at the grain level requires knowledge of how these two mechanisms progress and interact over both time and space and what the local resolved stresses are. To date, simultaneous collection of such information has not been achievable. To address this shortfall, we have developed a modified Laue based in situ micro X-ray diffraction technique with an unprecedented combination of time and spatial resolution. A ten-fold reduction in data collection times is realized by the refinement of rapid polychromatic Laue "single-shot" mapping. From single Laue patterns, we extract grain depth information, detect onset of yielding and achieve 2 × 10-4 lattice strain resolution. The technique is employed to examine yielding and twinning in a magnesium grain embedded ∼200 μm below the sample surface. We examine 13 time steps and reveal the following behaviour: initial onset of basal slip, subsequent onset of twinning, development of further accommodation slip and evolution of twin shape and size; along with the corresponding values of local resolved shear stresses. © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Associations of television viewing time with adults' well-being and vitality

Television (TV) viewing, a common leisure-time sedentary behaviour, is associated adversely with cardio-metabolic health, fatigue, depression and mental health. However, associations of TV viewing time with health-related quality of life attributes are less well understood. We examined associations of TV viewing time with physical well-being, mental well-being and vitality in a large population-based sample of Australian adults.

Hoarding in attention deficit hyperactivity disorder: Understanding the comorbidity

Abstract
Hoarding disorder has a frequent co-occurrence with attention-deficit/hyperactivity disorder (ADHD). An accurate understanding of the comorbidity between hoarding disorder and ADHD remains unclear but is essential to inform appropriate assessment, prevention and treatment approaches. This paper will provide a review of potential comorbidity models and aetiological mechanisms implicated in both disorders in order to inform understanding of the nature of the comorbidity between hoarding disorder and ADHD. A correlated liabilities model is identified that implicates genetic, neurological, and executive functioning factors in the development and maintenance of hoarding symptoms in individuals with ADHD.

Healthy weight regulation and eating disorder prevention in high school students: a universal and targeted web-based intervention

Background: Given the rising rates of obesity in children and adolescents, developing evidence-based weight loss or weight maintenance interventions that can be widely disseminated, well implemented, and are highly scalable is a public health necessity. Such interventions should ensure that adolescents establish healthy weight regulation practices while also reducing eating disorder risk.

Objective: This study describes an online program, StayingFit, which has two tracks for universal and targeted delivery and was designed to enhance healthy living skills, encourage healthy weight regulation, and improve weight/shape concerns among high school adolescents.

Methods: Ninth grade students in two high schools in the San Francisco Bay area and in St Louis were invited to participate. Students who were overweight (body mass index [BMI] >85th percentile) were offered the weight management track of StayingFit; students who were normal weight were offered the healthy habits track. The 12-session program included a monitored discussion group and interactive self-monitoring logs. Measures completed pre- and post-intervention included self-report height and weight, used to calculate BMI percentile for age and sex and standardized BMI (zBMI), Youth Risk Behavior Survey (YRBS) nutrition data, the Weight Concerns Scale, and the Center for Epidemiological Studies Depression Scale.

Results: A total of 336 students provided informed consent and were included in the analyses. The racial breakdown of the sample was as follows: 46.7% (157/336) multiracial/other, 31.0% (104/336) Caucasian, 16.7% (56/336) African American, and 5.7% (19/336) did not specify; 43.5% (146/336) of students identified as Hispanic/Latino. BMI percentile and zBMI significantly decreased among students in the weight management track. BMI percentile and zBMI did not significantly change among students in the healthy habits track, demonstrating that these students maintained their weight. Weight/shape concerns significantly decreased among participants in both tracks who had elevated weight/shape concerns at baseline. Fruit and vegetable consumption increased for both tracks. Physical activity increased among participants in the weight management track, while soda consumption and television time decreased.

Conclusions: Results suggest that an Internet-based, universally delivered, targeted intervention may support healthy weight regulation, improve weight/shape concerns among participants with eating disorders risk, and increase physical activity in high school students. Tailored content and interactive features to encourage behavior change may lead to sustainable improvements in adolescent health.

Obesity prevention in early life: an opportunity to better support the role of Maternal and Child Health Nurses in Australia

BACKGROUND: Because parents with young children access primary health care services frequently, a key opportunity arises for Maternal and Child Health (MCH) nurses to actively work with families to support healthy infant feeding practices and lifestyle behaviours. However, little is known regarding the extent to which MCH nurses promote obesity prevention practices and how such practices could be better supported. METHODS: This mixed methods study involved a survey of 56 MCH nurses (response rate 84.8 %), 16 of whom participated in semi-structured qualitative interviews. Both components aimed to examine the extent to which nurses addressed healthy infant feeding practices, healthy eating, active play and limiting sedentary behavior during routine consultations with young children 0-5 years. Key factors influencing such practices and how they could be best supported were also investigated. All data were collected from September to December 2013. Survey data were analysed descriptively and triangulated with qualitative interview findings, the analysis of which was guided by grounded theory principles. RESULTS: Although nurses reported measuring height/length and weight in most consultations, almost one quarter (22.2 %) reported never/rarely using growth charts to identify infants or children at risk of overweight or obesity. This reflected a reluctance to raise the issue of weight with parents and a lack of confidence in how to address it. The majority of nurses reported providing advice on aspects of infant feeding relevant to obesity prevention at most consultations, with around a third (37 %) routinely provided advice on formula preparation. Less than half of nurses routinely promoted active play and only 30 % discussed limiting sedentary behaviour such as TV viewing. Concerns about parental receptiveness and maintaining rapport were key barriers to more effective implementation. CONCLUSION: While MCH nurses are well placed to address obesity prevention in early life, there is currently a missed public health opportunity. Improving nurse skills in behaviour change counseling will be key to increasing their confidence in raising sensitive lifestyle issues with parents to better integrate obesity prevention practices into normal MCH service delivery.

Development of a laboratory-based transmission diffraction technique for in situ deformation studies of Mg alloys

A laboratory-based transmission X-ray diffraction technique was developed to measure elastic lattice strains parallel to the loading direction during in situ tensile deformation. High-quality transmission X-ray diffraction data were acquired in a time frame suitable for in situ loading experiments by application of a polycapillary X-ray optic with a conventional laboratory Cu X-ray source. Based on the measurement of two standard reference materials [lanthanum hexaboride (NIST SRM 660b) and silicon (NIST SRM 640c)], precise instrumental alignment and calibration of the transmission diffraction geometry were realized. These results were also confirmed by the equivalent data acquired using the standard Bragg-Brentano measurement geometry. An empirical Caglioti function was employed to describe the instrumental broadening, while an axis of rotation correction was used to measure and correct the specimen displacement from the centre of the goniometer axis. For precise Bragg peak position and hkil intensity information, a line profile fitting methodology was implemented, with Pawley refinement used to measure the sample reference lattice spacings (d o (hkil)). It is shown that the relatively large X-ray probe size available (7 × 714mm) provides a relatively straightforward approach for improving the grain statistics for the study of metal alloys, where grain sizes in excess of 114μm can become problematic for synchrotron-based measurements. This new laboratory-based capability was applied to study the lattice strain evolution during the elastic-plastic transition in extruded and rolled magnesium alloys. A strain resolution of 2 × 10-4 at relatively low 2θ angles (20-65° 2θ) was achieved for the in situ tensile deformation studies. In situ measurement of the elastic lattice strain accommodation with applied stress in the magnesium alloys indicated the activation of dislocation slip and twin deformation mechanisms. Furthermore, measurement of the relative change in the intensity of 0002 and 10 3 was used to quantify {10 2} 011 tensile twin onset and growth with applied load.

Functionalism, co-operation, good faith, and the making of the "daily-preventive justice" in contract law theory and practice. A contribution to a rational understanding of good faith and to its future reseasonable developments. Evaluations from

The thoughts and observations contained in this paper were first presented in a preliminary form at the Staff Seminar that I gave at the University of Cape Town (UCT) - Department of Private Law, on Tuesday May 8 2012. The organizers generously offered me a free choice of subject. Such an offer always poses a problem to imaginative people like myself. I finally chose as my subject the role of good faith in contract law theory and practice and then entitled the Seminar “Good Faith & Contracts - Brothers in Arms”. The aim of the talk was to briefly describe what I see behind the doctrine of good faith (and, more broadly, behind the general course of the parties’ behavior before and after the conclusion of an agreement), to then explain the need of its protection and future reasonable developments by challenging the limitations of both traditional and current legal approaches to contract law theory and practice. By adopting a comparative modus investigandi, it emerged that especially in the area of contract law a new law-finding process is emerging in the European continent and it is leading to re-conceive the meta-national legislative interventions by challenging the limits of Hobbes’s Leviathan. As asserted, we ought to not take this process for granted because although there are many forms of social organization, contract is the most pervasive and the law of contract still is the most important vehicle to support and supplement private arrangements. However, the point of departure for theorizing about private law is based on experience. Consequently, despite the growing emphasis on the convergence of national legal systems in Europe, conducting research on private law theory and practice requires that imagination and creativity be matched with prudence. Proficiency has to be aligned with what we have learned from history.