The effect of calcareous marine algae, with or without marine magnesium oxide, and sodium bicarbonate on rumen pH and milk production in mid-lactation dairy cows.

Two experiments were carried out to evaluate different dietary buffers and their influence on (1) rumen pH in dairy cows and (2) milk production in dairy cows. The supplements included were calcareous marine algae (CMA; Lithothamnion calcareum), with or without marine magnesium oxide (MM; precipitated magnesia derived from seawater), and sodium bicarbonate (SB). Dietary treatments in experiment 1 consisted of the control [32.9% starch and sugar, and 19.9% neutral detergent fiber from forage per kg of dry matter (DM)] including no dietary buffer (CON); the control plus 0.45% DM CMA (CMA); the control plus 0.45% DM CMA and 0.11% DM MM (CMA+MM); the control plus 0.9% DM SB (SB). Diets were formulated to a dry matter intake (DMI) of 18 kg per cow/d. Dietary treatments in experiment 2 also consisted of CON (28.3% starch and sugar, and 23% neutral detergent fiber from forage per kg of DM), CMA, CMA+MM, and SB and were formulated to achieve identical intakes of experimental ingredients (80 g of CMA, 80 g of CMA plus 20 g MM, and 160 g of SB per cow/d) with a DMI of 22.6 kg per cow/d. Experiment 1 used 4 rumen-cannulated dairy cows in a 4 × 4 Latin square design. Rumen pH was measured over five 2-h periods, following feeding, using rumen pH probes. In experiment 2, 52 multiparous and 4 primiparous cows (62.7 ± 3.4 d in milk) were assigned to 4 experimental treatments for 80 d. Both CMA treatments maintained a greater mean rumen pH than the CON during 4 of the 5 periods following feeding and the CON had a greater number of hours below rumen pH 5.5 compared with all other treatments. Dry matter intakes tended to be higher on the SB compared with CON. The CMA treatment increased the production of milk fat and protein yield (kg/d) compared with all other treatments. Both CMA and CMA+MM increased milk fat yield compared with CON but were similar to each other and SB. Protein yield was highest in the CMA treatment compared with CON, CMA+MM, and SB. All 3 buffer treatments increased milk fat concentration compared with CON but did not differ from each other. The SB treatment reduced milk protein concentration and milk production efficiency, energy-corrected milk per kilogram of DMI. Results indicate that the addition of CMA can benefit milk fat and protein production when included in diets based on typical feedstuffs of the northern European region. The use of CMA when compared with SB, in such diets, can increase milk protein production and milk production efficiency.

Implementation fidelity of a self-management course for epilepsy: method and assessment.

BACKGROUND: Complex interventions such as self-management courses are difficult to evaluate due to the many interacting components. The way complex interventions are delivered can influence the effect they have for patients, and can impact the interpretation of outcomes of clinical trials. Implementation fidelity evaluates whether complex interventions are delivered according to protocol. Such assessments have been used for one-to-one psychological interventions; however, the science is still developing for group interventions. METHODS: We developed and tested an instrument to measure implementation fidelity of a two-day self-management course for people with epilepsy, SMILE(UK). Using audio recordings, we looked at adherence and competence of course facilitators. Adherence was assessed by checklists. Competence was measured by scoring group interaction, an overall impression score and facilitator "didacticism". To measure "didacticism", we developed a novel way to calculate facilitator speech using computer software. Using this new instrument, implementation fidelity of SMILE(UK) was assessed on three modules of the course, for 28% of all courses delivered. RESULTS: Using the instrument for adherence, scores from two independent raters showed substantial agreement with weighted Kappa of 0.67 and high percent agreement of 81.2%. For didacticism, the results from both raters were highly correlated with an intraclass coefficient of 0.97 (p < 0.0001). We found that the courses were delivered with a good level of adherence (> 50% of scored items received the maximum of 2 points) and high competence. Groups were interactive (mean score: 1.9-2.0 out of 2) and the overall impression was on average assessed as "good". Didacticism varied from 42% to 93% of total module time and was not associated with the other competence scores. CONCLUSION: The instrument devised to measure implementation fidelity was reproducible and easy to use. The courses for the SMILE(UK) study were delivered with a good level of adherence to protocol while not compromising facilitator competence. TRIAL REGISTRATION: ISRCTN57937389 .

Whey protein gel composites in the diet of goats increased the omega-3 and omega-6 content of milk fat.

Previously, feeding whey protein gels containing polyunsaturated fatty acids (PUFA) reduced their rumen biohydrogenation and increased their concentration in milk fat of Holstein cows. Our objective was to test the efficacy of whey protein isolate (WPI) gels produced in a steam tunnel as a method to alter the fatty acid (FA) composition of the milk lipids. Four primiparous Lamancha goats in midlactation were fed three diets in a 3 × 4 Latin square design. The WPI gels were added to a basal concentrate mix that contained one of three lipid sources: (i) 100% soya bean oil (S) to create (WPI/S), (ii) a 1:1 (wt/wt) mixture of S and linseed (L) oil to create (WPI/SL), or (iii) 100% L to create (WPI/L). Periods were 22 days with the first 10 days used as an adjustment phase followed by a 12-day experimental phase. During the adjustment phase, all goats received a rumen available source of lipid, yellow grease, to provide a baseline for milk FA composition. During the experimental phase, each goat received its assigned WPI. Milk FA concentration of C18:2 n-6 and C18:3 n-3 reached 9.3 and 1.64 g/100 g FA, respectively, when goats were fed WPI/S. Feeding WPI/SL increased the C18:2 n-6 and C18:3 n-3 concentration to 6.22 and 4.36 g/100 g FA, and WPI/L increased C18:2 n-6 and C18:3 n-3 to 3.96 and 6.13 g/100 g FA respectively. The adjusted transfer efficiency (%) of C18:3 n-3 to milk FA decreased significantly as dietary C18:3 n-3 intake increased. Adjusted transfer efficiency for C18:2 n-6 did not change with increasing intake of C18:2 n-6. The WPI gels were effective at reducing rumen biohydrogenation of PUFA; however, we observed a change in the proportion increase of C18:3 n-3 in milk FA suggesting possible regulation of n-3 FA to the lactating caprine mammary gland.

Randomized clinical trial of sacral versus percutaneous tibial nerve stimulation in patients with faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) is a well established therapy for faecal incontinence (FI). Percutaneous tibial nerve stimulation (PTNS) is a newer, less invasive, treatment. The effectiveness and acceptability of these treatments have not been compared systematically. METHODS: An investigator-blinded randomized pilot trial of PTNS versus SNS with a parallel qualitative study was performed. Quantitative clinical outcomes and qualitative data from patient interviews were collected for both interventions. RESULTS: Forty patients (39 women; mean age 59 years) met the eligibility criteria; 23 were randomized to receive SNS and 17 to PTNS. Fifteen patients progressed to permanent SNS implantation and 16 received a full course of PTNS. Within-group effect sizes were marginally greater for SNS than for PTNS on available-case analysis. Mean(s.d.) FI episodes per week at baseline, and 3 and 6 months of follow-up were: 11·4(12·0), 4·0(4·0) and 4·9(6·9) respectively for SNS compared with 10·6(11·2), 5·8(6·9) and 6·3(6·9) for PTNS. Mean(s.d.) Cleveland Clinic Incontinence Score values at baseline, and 3 and 6 months were: 16·2(3·0), 11·1(5·2) and 10·4(5·6) for SNS versus 15·1(2·7), 11·7(4·4) and 12·1(5·2) for PTNS. Improvement of at least 50 per cent in FI episodes per week at 6 months was seen in 11 of 18 patients in the SNS group compared with seven of 15 in the PTNS group. Effect estimates for SNS with chronic implanted stimulation were larger (10 of 15 patients at 6 months). Disease-specific and generic quality-of-life improvements complemented clinical outcome data. Qualitative analysis of interview data suggested that both treatments had high acceptability amongst patients. CONCLUSION: In the short term, both SNS and PTNS provide some clinical benefit to patients with FI. Registration numbers: 2010-018728-15 and 10479 (http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=10479).

Effect of feeding calcareous marine algae to Holstein cows prepartum or postpartum on serum metabolites and performance.

Thirty-six multiparous Holstein cows and 12 springing heifers were used in a 9-wk randomized design trial to determine the response of cows fed calcareous marine algae (CMA) beginning 3wk prepartum or after parturition through 6wk postpartum on dry matter intake (DMI), blood and urine metabolites, and milk yield and composition. Within parity and expected calving date, cows were assigned randomly to 1 of 4 treatments with a 2×2 factorial arrangement. Prepartum diets were supplemented with calcium carbonate (CON) or 50g/d of CMA with a resulting dietary cation-anion difference of -5.17 and -3.99mEq/100g, respectively. Postpartum diets were formulated to provide either 317g/d of sodium bicarbonate and calcium carbonate (NBC) or 100g/d of CMA, providing a dietary cation-anion difference of 35.58 and 15.64mEq/100g, based on 25kg/d of DMI, respectively. No differences were observed in prepartum DMI or postpartum DMI, milk yield, percentage of milk fat, protein, lactose, and solids-not fat among treatments. Milk protein yield was higher for cows fed CMA prepartum compared with CON. Interactions of prepartum treatment and week were observed for yield of milk fat and energy-corrected milk because of higher yields for cows fed CMA during wk 2 and 6 compared with CON. Serum Na concentrations were greater for cows fed CON prepartum or NBC postpartum compared with CMA. Postpartum urinary concentrations of Na exhibited an interaction among treatments and were higher for CON-NBC and CMA-NBC compared with CON-CMA and CMA-CMA. Similar interactions of treatments were also observed for serum urea N and creatinine postpartum. Postpartum urinary K concentrations were higher for cows fed CMA postpartum compared with NBC. Results of this trial indicate that feeding cows CMA prepartum does not affect DMI or serum metabolites prepartum, but does support higher milk protein yield. Performance and serum metabolite concentrations of cows fed CMA postpartum were comparable with that of cows fed NBC, except for changes in serum and urinary concentration of Na, which was a function of dietary Na intake.

Tomato seeds as a novel by-product feed for lactating dairy cows.

Whole tomato seeds, a novel by-product feedstuff, were fed to lactating Holstein cows to determine the nutritive value of whole tomato seeds by replacing whole cottonseed in the total mixed ration. Four primiparous and 4 multiparous Holstein cows were used in a 4×4 Latin square design and fed 1 of 4 total mixed rations. Whole tomato seeds replaced whole cottonseed on a weight-to-weight basis for lipid. The proportion of whole tomato seeds to whole cottonseed in the diets were 100:0, 50:50, 25:75, and 0:100 on a lipid basis. Thus, tomato seeds were 4.0, 2.4, 1.1, and 0% of the ration dry matter, respectively. Milk yield and the concentrations and yields of protein, lactose, and solids-not-fat did not differ for the effect of diet. However, milk fat concentration decreased and milk fat yield tended to decrease as whole tomato seeds replaced whole cottonseed. Intakes of dry matter, lipid, and crude protein did not differ. Whole-tract apparent digestibility of dry matter and ash-free neutral detergent fiber did not differ, but digestibility of total fatty acids and crude protein decreased with increasing proportion of whole tomato seeds. Urea concentration in milk and plasma both decreased with increasing whole tomato seeds. Fecal concentration of linoleic and α-linolenic acids increased with increasing whole tomato seeds, suggesting that seeds were passing out of the digestive tract undigested. The concentrations of C18:2n-6 and C18:3n-3 in milk fat had small increases, but their yields were not different, suggesting that only a small amount of whole-tomato-seed lipid might have been digested postruminally. Amounts of trans C18:1 fatty acids in milk fat were higher with increasing whole cottonseed, which might suggest a shift in rumen biohydrogenation pathways. At the level of feeding used in the current study, whole tomato seeds replaced whole cottonseed in the diet of lactating dairy cows without a change in production.

Interventions to improve exercise behaviour in sedentary people living with and beyond cancer: a systematic review.

BACKGROUND: To systematically review the effects of interventions to improve exercise behaviour in sedentary people living with and beyond cancer. METHODS: Only randomised controlled trials (RCTs) that compared an exercise intervention to a usual care comparison in sedentary people with a homogeneous primary cancer diagnosis, over the age of 18 years were eligible. The following electronic databases were searched: Cochrane Central Register of Controlled Trials MEDLINE; EMBASE; AMED; CINAHL; PsycINFO; SportDiscus; PEDro from inception to August 2012. RESULTS: Fourteen trials were included in this review, involving a total of 648 participants. Just six trials incorporated prescriptions that would meet current recommendations for aerobic exercise. However, none of the trials included in this review reported intervention adherence of 75% or more for a set prescription that would meet current aerobic exercise guidelines. Despite uncertainty around adherence in many of the included trials, the interventions caused improvements in aerobic exercise tolerance at 8-12 weeks (SMD=0.73, 95% CI=0.51-0.95) in intervention participants compared with controls. At 6 months, aerobic exercise tolerance is also improved (SMD=0.70, 95% CI=0.45-0.94), although four of the five trials had a high risk of bias; hence, caution is warranted in its interpretation. CONCLUSION: Expecting the majority of sedentary survivors to achieve the current exercise guidelines is likely to be unrealistic. As with all well-designed exercise programmes, prescriptions should be designed around individual capabilities and frequency, duration and intensity or sets, repetitions, intensity of resistance training should be generated on this basis.

Systematic review of tibial nerve stimulation to treat faecal incontinence.

BACKGROUND: Two forms of tibial nerve stimulation are used to treat faecal incontinence (FI): percutaneous (PTNS) and transcutaneous (TTNS) tibial nerve stimulation. This article critically appraises the literature on both procedures. METHODS: A systematic review was performed adhering to the PRISMA framework. A comprehensive literature search was conducted, with systematic methodological quality assessment and data extraction. Summary measures for individual outcome variables are reported. RESULTS: Twelve articles met eligibility criteria; six related to PTNS, five to TTNS, and one to both procedures. These included ten case series and two randomized clinical trials (RCTs). Case series were evaluated using the National Institute for Health and Care Excellence quality assessment for case series, scoring 3-6 of 8. RCTs were evaluated using the Jadad score, scoring 4 of a possible 5 marks, and the Cochrane Collaboration bias assessment tool. From one RCT and case series reports, the success rate of PTNS, based on the proportion of patients who achieved a reduction in weekly FI episodes of at least 50 per cent, was 63-82 per cent, and that of TTNS was 0-45 per cent. In an RCT of TTNS versus sham, no patient had a reduction in weekly FI episodes of 50 per cent or more, whereas in an RCT of PTNS versus TTNS versus sham, 82 per cent of patients undergoing PTNS, 45 per cent of those having TTNS, and 13 per cent of patients in the sham group had treatment success. CONCLUSION: PTNS and TTNS result in significant improvements in some outcome measures; however, TTNS was not superior to sham stimulation in a large, adequately powered, RCT. As no adequate RCT of PTNS versus sham has been conducted, conclusions cannot be drawn regarding this treatment.

Mechanical load applied by Intraosseous Transcutaneous Amputation Prosthesis (ITAP) during walking on level and sloped treadmill: A case study.

This proof of concept study presents a method to collect and analyse kinetic data from one participant with a transfemoral amputation fitted with a percutaneous osseointegrated implant walking on a level and sloped treadmill. We describe the construction of and results from a bespoke wireless six axis load cell built into one participant's prosthetic assembly. The load cell does not clinically compromise the participant in any way and is an initial milestone in the development of a light-weight wireless load cell for use with percutaneous osseointegrated implants. In this case, it is the first time that kinetic data from a participant fitted with an Intraosseous Transcutaneous Amputation Prosthesis has been published. We propose that the data can be used to model the load transfer to the host bone, with several clinically significant applications. The raw dynamic data are made available and quasi-static load cases for each functional phase of gait are presented. Peak forces obtained in the medio-lateral (X), cranio-caudal (Y) and antero-posterior (Z) axes over level ground respectively were -243.8 N (0.24 BW), 1321.5 N (1.31 BW) and -421.8 N (0.42 BW); uphill were -141.0 N (0.14 BW), 1604.2 N (1.59 BW), -498.1 N (0.49 BW); downhill were -206.0 N (0.20 BW), 1103.9 N (1.09 BW), -547.2 N (0.54 BW). The kinetics broadly followed able bodied gait patterns with some gait strategies consistent in participants with other implant designs or prosthetic socket connections, for example offloading the artificial limb downhill.

Understanding the processes underpinning IMPlementing IMProved Asthma self-management as RouTine (IMP2ART) in primary care: study protocol for a process evaluation within a cluster randomised controlled implementation trial.

BACKGROUND: Providing supported self-management for people with asthma can reduce the burden on patients, health services and wider society. Implementation, however, remains poor in routine clinical practice. IMPlementing IMProved Asthma self-management as RouTine (IMP2ART) is a UK-wide cluster randomised implementation trial that aims to test the impact of a whole-systems implementation strategy, embedding supported asthma self-management in primary care compared with usual care. To maximise opportunities for sustainable implementation beyond the trial, it is necessary to understand how and why the IMP2ART trial achieved its clinical and implementation outcomes. METHODS: A mixed-methods process evaluation nested within the IMP2ART trial will be undertaken to understand how supported self-management was implemented (or not) by primary care practices, to aid interpretation of trial findings and to inform scaling up and sustainability. Data and analysis strategies have been informed by mid-range and programme-level theory. Quantitative data will be collected across all practices to describe practice context, IMP2ART delivery (including fidelity and adaption) and practice response. Case studies undertaken in three to six sites, supplemented by additional interviews with practice staff and stakeholders, will be undertaken to gain an in-depth understanding of the interaction of practice context, delivery, and response. Synthesis, informed by theory, will combine analyses of both qualitative and quantitative data. Finally, implications for the scale up of asthma self-management implementation strategies to other practices in the UK will be explored through workshops with stakeholders. DISCUSSION: This mixed-methods, theoretically informed, process evaluation seeks to provide insights into the delivery and response to a whole-systems approach to the implementation of supported self-management in asthma care in primary care. It is underway at a time of significant change in primary care in the UK. The methods have, therefore, been developed to be adaptable to this changing context and to capture the impact of these changes on the delivery and response to research and implementation processes.

Genomic collinearity and the genetic architecture of floral differences between the homoploid hybrid species Iris nelsonii and one of its progenitors, Iris hexagona.

Hybrid speciation represents a relatively rapid form of diversification. Early models of homoploid hybrid speciation suggested that reproductive isolation between the hybrid species and progenitors primarily resulted from karyotypic differences between the species. However, genic incompatibilities and ecological divergence may also be responsible for isolation. Iris nelsonii is an example of a homoploid hybrid species that is likely isolated from its progenitors primarily by strong prezygotic isolation, including habitat divergence, floral isolation and post-pollination prezygotic barriers. Here, we used linkage mapping and quantitative trait locus (QTL) mapping approaches to investigate genomic collinearity and the genetic architecture of floral differences between I. nelsonii and one of its progenitor species I. hexagona. The linkage map produced from this cross is highly collinear with another linkage map produced between I. fulva and I. brevicaulis (the two other species shown to have contributed to the genomic makeup of I. nelsonii), suggesting that karyotypic differences do not contribute substantially to isolation in this homoploid hybrid species. Similar to other studies of the genetic architecture of floral characteristics, at least one QTL was found that explained >20% variance in each color trait, while minor QTLs were detected for each morphological trait. These QTLs will serve as hypotheses for regions under selection by pollinators.

Implementing psychological interventions delivered by respiratory professionals for people with COPD. A stakeholder interview study.

Implementing psychological interventions in healthcare services requires an understanding of the organisational context. We conducted an interview study with UK National Health Service stakeholders to understand the barriers and facilitators for implementing psychological interventions for people with chronic obstructive pulmonary disorder (COPD). We used TANDEM as an exemplar intervention; a psychological intervention recently evaluated in a randomised controlled trial. Twenty participants providing care and/or services to people with COPD were purposively sampled from NHS primary/secondary care, and commissioning organisations. Participants were recruited via professional networks and referrals. Verbatim transcripts of semi-structured interviews were analysed using thematic analysis. Four themes were identified: (1) Living with COPD and emotional distress affects engagement with physical and psychological services; (2) Resource limitations affects service provision in COPD; (3) Provision of integrated care is important for patient well-being; and (4) Healthcare communication can be an enabler or a barrier to patient engagement. People need support with physical and psychological symptoms inherent with COPD and healthcare should be provided holistically. Respiratory healthcare professionals are considered able to provide psychologically informed approaches, but resources must be available for training, staff supervision and service integration. Communication between professionals is vital for clear understanding of an intervention's aims and content, to facilitate referrals and uptake. There was widespread commitment to integrating psychological and physical care, and support of respiratory healthcare professionals' role in delivering psychological interventions but significant barriers to implementation due to concerns around resources and cost efficiency. The current study informs future intervention development and implementation.

Technology for mobility in SCI 10 years from now.

OBJECTIVES: To identify technological advances and that are likely to have a great impact on the quality of life and participation in individuals with spinal cord injury (SCI). METHODS: In this paper we use the International Classification of Function to frame a discussion on how technology is likely to impact SCI in 10 years. In addition, we discuss the implication of technological advances on future research. RESULTS/CONCLUSION: Although technology advances are exciting, a large challenge for the research community will be how to effectively apply and deploy this technology. Advances occurring in the next 10 years that reduce cost of technology may be more important to the population with SCI than brand new technologies. Social context is everything. As a research community we must advocate for better systems of care. Advocating now for better care will lead to a world in 2020 that is ready to adopt new technologies that are truly transformative.

The cell cycle and c-Src.

The activity of the proto-oncogene encoded c-Src product is tightly regulated in vivo. In recent years, a model has emerged of how this regulation is achieved. In particular, protein kinases and phosphatases that are potential regulators of c-Src activity in the cell cycle have been identified and characterized.

Design and characterization of a novel permanent magnet synchronous motor used in a growing prosthesis for young patients with bone cancer.

Approximately 50 child sarcomas are treated with limb salvage surgery each year in the United Kingdom. These children need an extendable implant that can be lengthened periodically to keep pace with the growth in the opposite limb. Surgically, invasive devices have been used for the past 30 years with intrinsic problems of infection and long-term recurrent trauma to the patient. To eliminate problems associated with the invasive device, a noninvasive extendable prosthesis was developed. The magnetically coupled drive technology used for this prosthesis was a synchronous motor with a gear-driven telescoping shaft. In this design the motor configuration was in two parts: a rotating magnet (rotor) that fitted inside the prosthesis where space was limited and the stator, which was an external device used to extend the prosthesis remotely as the patient grew. This compact external drive produced a focused magnetic flux that required no cooling and operated on a single-phase power supply. The extending mechanism in the implant was able to overcome up to 1300 N force, which is the tension force exerted by the soft tissues during the lengthening procedure. The device has been successfully implanted in 50 patients.

Evaluation of a pharmacist-led, medicines education program for Aboriginal Health Workers.

INTRODUCTION: The health of Indigenous Australians is exceptionally poor compared with that of non-Indigenous Australians. Cardiovascular diseases are the leading cause of death, the death rate being at least 2.7 times higher than the total Australian population. Indigenous Australians also experience underutilisation and reduced quality use of medicines. Aboriginal Health Workers (AHWs) are appropriate members of the healthcare team to provide information about medicines to the Indigenous community. However, despite having an expanding role in medicines management, AHWs have reported they do not have adequate appropriate education to support this role. Community pharmacists in localities with high Indigenous populations are well placed to provide medicines education to AHWs; however, to be successful in this role they need to develop their cultural awareness. The purpose of this study was to evaluate a culturally appropriate, pharmacist-led cardiovascular medicines education program for AHWs. Research questions included: What was the impact of the program on the pharmacists? What were the barriers and facilitators? Was the program useful and acceptable to the AHWs? METHODS: Four educational units were developed in collaboration with AHWs. A purposive sample of community pharmacists from western New South Wales (NSW) attended training involving instruction in the delivery of the program and cultural awareness training. The pharmacists then recruited local AHWs and delivered the program. Evaluation, with respect to the pharmacists, involved a repeated measures, three-phase questionnaire and semi-structured, face-to-face, in-depth interview post-program. Feedback was obtained from the AHWs in the form of a brief survey, and an audit of the attendance at each session was performed. RESULTS: Twelve pharmacists in 10 localities throughout western NSW delivered the program to a total of 47 AHWs. Statistically significant differences in the questionnaire responses, as a result of delivering the education, indicated the pharmacists felt better equipped to deal with Indigenous health issues (p = 0.002, Mann-Whitney U-test); they knew more AHWs in their area (p = 0.005, Mann-Whitney U-test); they felt more confident as educators of AHWs (p = 0.007, Mann-Whitney U-test); and more confident that they had the necessary resources to deliver this education (p = 0.005, Mann-Whitney U-test). The semi-structured interviews revealed that the experience of delivering the education improved pharmacists' confidence as educators and motivated them to develop sustainable relationships with AHWs. A significant barrier lay in the challenges associated with organizing the AHW education sessions, while an important facilitator was prior established relationships with local Aboriginal health services. Evaluation with respect to the AHWs revealed the program reached 80% (n = 47/59) of AHWs within the western NSW region. In total, 46% (n = 27) of AHW participants attended all four educational units and attendance at each educational unit was above 78% (n = 37) throughout. The AHWs reported that they found the program interesting and relevant and were enthusiastic for future collaboration with the pharmacists. CONCLUSIONS: The desire to develop sustainable relationships was seen by all participants as the most positive aspect of the program.

Exercise training as a novel primary treatment for localised prostate cancer: a multi-site randomised controlled phase II study.

Alternative management strategies for localised prostate cancer are required to reduce morbidity and overtreatment. The aim of this study was to evaluate the feasibility, safety and acceptability of exercise training (ET) with behavioural support as a primary therapy for low/intermediate risk localised prostate cancer. Men with low/intermediate-risk prostate cancer were randomised to 12 months of ET or usual care with physical activity advice (UCwA) in a multi-site open label RCT. Feasibility included acceptability, recruitment, retention, adherence, adverse events and disease progression. Secondary outcomes included quality of life and cardiovascular health indices. Of the 50 men randomised to ET (n = 25) or UCwA (n = 25), 92% (n = 46) completed 12 month assessments. Three men progressed to invasive therapy (two in UCwA). In the ET group, men completed mean: 140 mins per week for 12 months (95% CI 129,152 mins) (94% of target dose) at 75% Hrmax. Men in the ET group demonstrated improved body mass (mean reduction: 2.0 kg; 95% CI -2.9,-1.1), reduced systolic (mean: 13 mmHg; 95%CI 7,19) and diastolic blood pressure (mean:8 mmHg; 95% CI 5,12) and improved quality of life (EQ.5D mean:13 points; 95% CI 7,18). There were no serious adverse events. ET in men with low/intermediate risk prostate cancer is feasible and acceptable with a low progression rate to radical treatment. Early signals on clinically relevant markers were found which warrant further investigation.

Cell cycle-dependent activation of Ras.

BACKGROUND: Ras proteins play an essential role in the transduction of signals from a wide range of cell-surface receptors to the nucleus. These signals may promote cellular proliferation or differentiation, depending on the cell background. It is well established that Ras plays an important role in the transduction of mitogenic signals from activated growth-factor receptors, leading to cell-cycle entry. However, important questions remain as to whether Ras controls signalling events during cell-cycle progression and, if so, at which point in the cell-cycle it is activated. RESULTS: To address these questions we have developed a novel, functional assay for the detection of cellular activated Ras. Using this assay, we found that Ras was activated in HeLa cells, following release from mitosis, and in NIH 3T3 fibroblasts, following serum-stimulated cell-cycle entry. In each case, peak Ras activation occurred in mid-G1 phase. Ras activation in HeLa cells at mid-G1 phase was dependent on RNA and protein synthesis and was not associated with tyrosine phosphorylation of Shc proteins and their binding to Grb2. Significantly, activation of Ras and the extracellular-signal regulated (ERK) sub-group of mitogen-activated protein kinases were not temporally correlated during G1-phase progression. CONCLUSIONS: Activation of Ras during mid-G1 phase appears to differ in many respects from its rapid activation by growth factors, suggesting a novel mechanism of regulation that may be intrinsic to cell-cycle progression. Furthermore, the temporal dissociation between Ras and ERK activation suggests that Ras targets alternate effector pathways during G1-phase progression.

Myristylation is required for Tyr-527 dephosphorylation and activation of pp60c-src in mitosis.

The chicken proto-oncoprotein c-Src is phosphorylated by p34cdc2 during mitosis concomitant with increased c-Src tyrosine kinase activity. On the basis of indirect evidence, we previously suggested that this is caused by partial dephosphorylation at Tyr-527, the phosphorylation of which suppresses c-Src kinase activity. In support of this hypothesis, we now show that treatment of cells with a protein tyrosine phosphatase inhibitor, sodium vanadate, blocks the mitotic increase in Src kinase activity. Also, we show that an amino-terminal mutation that prevents myristylation (and membrane localization) of c-Src does not interfere with the p34cdc2-mediated phosphorylations but blocks both mitotic dephosphorylation of Tyr-527 (in kinase-defective Src) and stimulation of c-Src kinase activity. Furthermore, in unsynchronized cells, the kinase activity of nonmyristylated c-Src is suppressed by 60% relative to wild-type c-Src, presumably because of increased Tyr-527 phosphorylation. Consistent with this, the Tyr-527 dephosphorylation rate measured in cell homogenates is much higher for wild-type, myristylated c-Src than for nonmyristylated c-Src. Tyr-527 phosphatase activity was primarily associated with the nonsoluble subcellular fraction. These findings suggest that the phosphatase(s) that acts on Tyr-527 is membrane bound and indicate that membrane localization of c-Src is necessary for its mitotic activation by dephosphorylation of Tyr-527.