Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120

BACKGROUND: The blood brain barrier (BBB) is the first line of defence of the central nervous system (CNS) against circulating pathogens, such as HIV. The cytotoxic HIV protein, gp120, damages endothelial cells of the BBB, thereby compromising its integrity, which may lead to migration of HIV-infected cells into the brain. Fibroblast growth factor 2 (FGF2), produced primarily by astrocytes, promotes endothelial cell fitness and angiogenesis. We hypothesized that treatment of human umbilical vein endothelial cells (HUVEC) with FGF2 would protect the cells from gp120-mediated toxicity via endothelial cell survival signalling. RESULTS: Exposure of HUVEC to gp120 resulted in dose- and time-dependent cell death; whereas, pre-treatment of endothelial cells with FGF2 protected cells from gp120 angiotoxicity. Treatment of HUVEC with FGF2 resulted in dose- and time-dependent activation of the extracellular regulated kinase (ERK), with moderate effects on phosphoinositol 3 kinase (PI3K) and protein kinase B (PKB), also known as AKT, but no effects on glycogen synthase kinase 3 (GSK3β) activity. Using pharmacological approaches, gene transfer and kinase activity assays, we show that FGF2-mediated angioprotection against gp120 toxicity is regulated by crosstalk among the ERK, PI3K-AKT and PKC signalling pathways. CONCLUSIONS: Taken together, these results suggest that FGF2 may play a significant role in maintaining the integrity of the BBB during the progress of HIV associated cerebral endothelial cell damage

Alterations in the Notch4 pathway in cerebral endothelial cells by the HIV aspartyl protease inhibitor, nelfinavir

<p>Abstract</p> <p>Background</p> <p>Aspartyl protease inhibitors (PIs) used to treat HIV belong to an important group of drugs that influence significantly endothelial cell functioning and angiogenic capacity, although specific mechanisms are poorly understood. Recently, PIs, particularly Nelfinavir, were reported to disrupt Notch signaling in the HIV-related endothelial cell neoplasm, Kaposi's sarcoma. Given the importance of maintaining proper cerebral endothelial cell signaling at the blood brain barrier during HIV infection, we considered potential signaling pathways such as Notch, that may be vulnerable to dysregulation during exposure to PI-based anti-retroviral regimens. Notch processing by γ-secretase results in cleavage of the notch intracellular domain that travels to the nucleus to regulate expression of genes such as vascular endothelial cell growth factor and NFκB that are critical in endothelial cell functioning. Since, the effects of HIV PIs on γ-secretase substrate pathways in cerebral endothelial cell signaling have not been addressed, we sought to determine the effects of HIV PIs on Notch and amyloid precursor protein.</p> <p>Results</p> <p>Exposure to reported physiological levels of Saquinavir, Indinavir, Nelfinavir and Ritonavir, significantly increased reactive oxygen species in cerebral endothelial cells, but had no effect on cell survival. Likewise, PIs decreased Notch 4-protein expression, but had no effect on Notch 1 or amyloid precursor protein expression. On the other hand, only Nelfinavir increased significantly Notch 4 processing, Notch4 intracellular domain nuclear localization and the expression of notch intracellular domain targets NFκB and matrix metalloproteinase 2. Pre-treatment with the antioxidant Vitamin E prevented PI-induced reactive oxygen species generation and partially prevented Nelfinavir-induced changes in both Notch 4 processing, and cellular localization patterns. Moreover, in support of increased expression of pro-angiogenic genes after Nelfinavir treatment, Nelfinavir did not inhibit angiogenic capacity.</p> <p>Conclusion</p> <p>Nelfinavir affects Notch 4 processing that results in induction of expression of the pro-angiogenic genes NFκB and matrix metalloproteinase 2 in cerebral endothelial cells.</p

A physical activity, nutrition and oral health intervention in nursery settings:Process evaluation of the NAP SACC UK feasibility cluster RCT

Background The nutrition and physical activity self-assessment for childcare (NAP SACC) intervention has demonstrated effectiveness in the USA. A feasibility randomised controlled trial was conducted in England to adapt the intervention to the UK context. An embedded process evaluation focused on three key questions. 1. Was it feasible and acceptable to implement the intervention as planned? 2. How did the intervention affect staff and parent mediators? 3. Were the trial design and methods acceptable? Methods Twelve nurseries in south-west England were recruited and randomised to intervention or control. The intervention comprised: NAP SACC UK Partner (Health Visitor) support to nurseries to review practice and policies against best practice, and then set goals to improve physical activity, nutrition and oral health; two staff training workshops; and a web-based parent support element. The process evaluation comprised: observations of Partner training (n = 1), Partner/manager meetings (n = 5) and staff workshops (n = 10); semi-structured interviews with Partners (n = 4), managers (n = 12), staff (n = 4) and parents (n = 20); analysis of self-assessment forms, goal setting forms and Partner logbooks; and assessment of staff and parent knowledge, motivation and self-efficacy mediators. Results Overall, NAP SACC UK was feasible to implement and acceptable to nursery staff, managers, Partners and parents. The intervention was implemented as planned in five of the six intervention nurseries. Partners and managers appreciated the opportunity to review and improve nursery practices and valued the relationship forged between them. Staff rated the training workshops highly, despite attending outside of working hours. Most goals set by nurseries were achieved. However, Partners raised concerns about Health Visitors’ capacity to deliver the intervention in any subsequent roll out. Mediator scores improved in all but two areas in intervention staff and parents, with decreases or minimal changes in the control group. The web-based parent element was not well used and should be removed from any subsequent trial. The trial methods were acceptable to managers, staff, Partners and parents. Conclusions Implementing and evaluating a physical activity and nutrition intervention in nursery settings is feasible and acceptable. A full RCT of NAP SACC UK (with appropriate modifications) is warranted

Agribusiness Sheep Updates - 2004 - Part 1

Proceedings of the Agribusiness Sheep Updates - 2004 Forward Dr Mark Dolling Manager, Sheep Industries and Pasture, Department of Agriculture Western Australia Keynotes Australian Wool Innovation Limited DR LEN STEPHENS AUSTRALIAN WOOL INNOVATION LIMITED (AWI) Commercialisation of Sheepmeat Eating Quality Outcomes, David Thomason, General Manger Marketing Meat & livestock Australia Limited PLENARY The Fitness of the Future Merino, Norm Adams and Shimin Liu, CSIRO Livestock Industries Ovine Johne’s Disease – Managing the Disease, Managing the Issues, PETER BUCKMAN, CHIEF VETERINARY OFFICER, DEPARTMENT OF AGRICULTURE WESTERN AUSTRALIA Animal Welfare – Changes in Latitudes Changes in Attitudes, Michael Paton and Dianne Evans, Department of Agriculture Western Australian. Live Sheep Exports, JOHN EDWARDS. CHAIRMAN, WESTERN AUSTRALIAN LIVE SHEEP EXPORTERS ASSOCIATION MeCustomising to the Needs of the Customer – Insights from the New Zealand Merino Experience, DR SCOTT CHAMPION, RESEARCH, DEVELOPMENT AND PRODUCT INNOVATION MANAGER, THE NEW ZEALAND MERINO COMPANY LIMITED Agribusiness Sheep Updates Conference -Economic and Financial Market Update Alan Langford, Economist, BankWest Concurrent sessions - Meeting the Market Breeding Wool to Address Consumer Requirements in Fabrics A.C. SCHLINK CSIRO Livestock Industries, J.C. GREEFF AND M. E. LADYMAN Department of Agriculture Western Australia Fibre Contribution to Retail Demand for Knitwear Melanie LadymanA and John StantonAB ADepartment of Agriculture Western Australia and BCurtin University of Technology Sustainable Merino, is this the Future for Merino? Stuart Adams, iZWool International P/L Meeting lamb Market Specs from Crossbred Ewes Dr. Neal Fogarty, NSW Agriculture and the Australian Sheep Industry CRC Use of Serial Body Weight Measurements in Prime Lamb Finishing Systems Matthew Kelly, CSIRO Livestock Industries, James Skerritt, Ian McFarland Department of Agriculture Western Australia, Australian Sheep Industry CR

Le Forum, Vol. 43 #4

https://digitalcommons.library.umaine.edu/francoamericain_forum/1102/thumbnail.jp

PINCH is an independent prognostic factor in rectal cancer patients without preoperative radiotherapy - a study in a Swedish rectal cancer trial of preoperative radiotherapy

<p>Abstract</p> <p>Background</p> <p>The clinical significance between particularly interesting new cysteine-histidine rich protein (PINCH) expression and radiotherapy (RT) in tumours is not known. In this study, the expression of PINCH and its relationship to RT, clinical, pathological and biological factors were studied in rectal cancer patients.</p> <p>Methods</p> <p>PINCH expression determined by immunohistochemistry was analysed at the invasive margin and inner tumour area in 137 primary rectal adenocarcinomas (72 cases without RT and 65 cases with RT). PINCH expression in colon fibroblast cell line (CCD-18 Co) was determined by western blot.</p> <p>Results</p> <p>In patients without RT, strong PINCH expression at the invasive margin of primary tumours was related to worse survival, compared to patients with weak expression, independent of TNM stage and differentiation (<it>P </it>= 0.03). No survival relationship in patients with RT was observed (<it>P </it>= 0.64). Comparing the non-RT with RT subgroup, there was no difference in PINCH expression in primary tumours (invasive margin (<it>P </it>= 0.68)/inner tumour area (<it>P </it>= 0.49). In patients with RT, strong PINCH expression was related to a higher grade of LVD (lymphatic vessel density) (<it>P </it>= 0.01)</p> <p>Conclusions</p> <p>PINCH expression at the invasive margin was an independent prognostic factor in patients without RT. RT does not seem to directly affect the PINCH expression.</p

Associations of context-specific sitting time with markers of cardiometabolic risk in Australian adults

BACKGROUND: High volumes of sitting time are associated with an elevated risk of type 2 diabetes and cardiovascular disease, and with adverse cardiometabolic risk profiles. However, previous studies have predominately evaluated only total sitting or television (TV) viewing time, limiting inferences about the specific cardiometabolic health impacts of sitting accumulated in different contexts. We examined associations of sitting time in four contexts with cardiometabolic risk biomarkers in Australian adults. METHODS: Participants (n = 3429; mean +/- SD age 58 +/- 10 years) were adults without clinically diagnosed diabetes or cardiovascular disease from the 2011-2012 Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Multiple linear regressions examined associations of self-reported context-specific sitting time (occupational, transportation, TV-viewing and leisure-time computer use) with a clustered cardiometabolic risk score (CMR) and with individual cardiometabolic risk biomarkers (waist circumference, BMI, resting blood pressure, triglycerides, HDL- and LDL-cholesterol, and fasting and 2-h post-load plasma glucose). RESULTS: Higher CMR was significantly associated with greater TV-viewing and computer sitting time (b [95%CI] = 0.07 [0.04, 0.09] and 0.06 [0.03, 0.09]), and tended to be associated with higher occupational and transport sitting time (0.01 [- 0.01, 0.03] and 0.03 [- 0.00, 0.06]), after adjustment for potential confounders. Furthermore, keeping total sitting time constant, accruing sitting via TV-viewing and computer use was associated with significantly higher CMR (0.05 [0.02, 0.08] and 0.04 [0.01, 0.06]), accruing sitting in an occupational context was associated with significantly lower CMR (- 0.03 [- 0.05, - 0.01]), while no significant association was seen for transport sitting (0.00 [- 0.03, 0.04]). Results varied somewhat between the respective biomarkers; however, higher sitting time in each domain tended to be associated detrimentally with individual biomarkers except for fasting glucose (non-significant associations) and systolic blood pressure (a beneficial association was observed). Overall, associations were stronger for TV-viewing and computer use, and weaker for occupational sitting. CONCLUSIONS: Higher context-specific sitting times tended to be detrimentally associated, albeit modestly, with CMR and several cardiometabolic risk biomarkers. There was some evidence suggesting that the context in which people sit is relevant above and beyond total sitting time. Methodological issues notwithstanding, these findings may assist in identifying priorities for sitting-reduction initiatives, in order to achieve optimal cardiometabolic health benefits

Child-care self-assessment to improve physical activity, oral health and nutrition for 2- to 4-year-olds:a feasibility cluster RCT

Background: The Nutrition And Physical Activity Self Assessment for Child Care (NAP SACC) intervention has shown evidence of effectiveness in the USA but not been adapted or assessed for effectiveness in the UK. Objectives: To evaluate the feasibility and acceptability of implementing NAP SACC in the UK. Design: Adaptation and development of NAP SACC and feasibility cluster randomised controlled trial (RCT) including process and economic evaluations. Substudies assessed mediator questionnaire test–retest reliability and feasibility of food photography methods. Setting: Nurseries, staff and parents in North Somerset, Cardiff, Gloucestershire and Bristol. Participants: Development – 15 early years/public health staff and health visitors, 12 nursery managers and 31 parents. RCT – 12 nurseries and 31 staff, four partners and 168 children/parents. Mediator substudy – 82 parents and 69 nursery staff. Food photography substudy – four nurseries, 18 staff and 51 children. Intervention: NAP SACC UK partners supported nurseries to review policies and practices and set goals to improve nutrition, oral health and physical activity (PA) over 5 months. Two workshops were delivered to nursery staff by local experts. A home component [website, short message service (SMS) and e-mails] supported parents. The control arm continued with usual practice. Main outcome measures: Feasibility and acceptability of the intervention and methods according to prespecified criteria. Data sources: Qualitative data to adapt the intervention. Measurements with children, parents and staff at baseline and post intervention (8–10 months after baseline). Interviews with nursery managers, staff, parents and NAP SACC UK partners; observations of training, workshops and meetings. Nursery environment observation, nursery Review and Reflect score, and resource log. Child height and weight, accelerometer-determined PA and sedentary time, screen time and dietary outcomes using the Child and Diet Evaluation Tool. Staff and parent questionnaires of knowledge, motivation and self-efficacy. Child quality of life and nursery, family and health-care costs. Food photography of everything consumed by individual children and staff questionnaire to assess acceptability. Results: Thirty-two per cent (12/38) of nurseries and 35.3% (168/476) of children were recruited; no nurseries withdrew. The intervention was delivered in five out of six nurseries, with high levels of fidelity and acceptability. Partners found it feasible but had concerns about workload. The child loss to follow-up rate was 14.2%. There was suggestion of promise in intervention compared with control nurseries post intervention for snacks, screen time, proportion overweight or obese and accelerometer-measured total PA and moderate to vigorous PA. Many parental and nursery knowledge and motivation mediators improved. The average cost of delivering the intervention was £1184 per nursery excluding partner training, and the average cost per child was £27. Fourteen per cent of parents used the home component and the mediator questionnaire had good internal consistency and test–retest reliability. Photography of food was acceptable and feasible. Limitations: Following nursery leavers was difficult. Accelerometer data, diet data and environmental assessment would have been more reliable with 2 days of data. Conclusions: The NAP SACC UK intervention and methods were found to be feasible and acceptable to participants, except for the home component. There was sufficient suggestion of promise to justify a definitive trial. Future work: A multicentre cluster randomised controlled trial to evaluate the effectiveness and cost-effectiveness of NAP SACC UK has been funded by NIHR and will start in July 2019 (PHR NIHR 127551). Trial registration: Current Controlled Trials ISRCTN16287377

Protocol to evaluate the effectiveness and cost-effectiveness of an environmental nutrition and physical activity intervention in nurseries (Nutrition and Physical Activity Self Assessment for Child Care - NAP SACC UK): a multicentre cluster randomised controlled trial

Background: One in seven UK children have obesity when starting school, with higher prevalence associated with deprivation. Most pre-school children do not meet UK recommendations for physical activity and nutrition. Formal childcare settings provide opportunities to deliver interventions to improve nutritional quality and physical activity to the majority of 3–4-year-olds. The nutrition and physical activity self-assessment for childcare (NAP SACC) intervention has demonstrated effectiveness in the USA with high acceptability in the UK. The study aims to evaluate the effectiveness and cost-effectiveness of the NAP SACC UK intervention to increase physical activity, reduce sedentary time and improve nutritional intake. Methods: Multi-centre cluster RCT with process and economic evaluation. Participants are children aged 2 years or over, attending UK early years settings (nurseries) for ≥ 12 h/week or ≥ 15 h/week during term time and their parents, and staff at participating nurseries. The 12-month intervention involves nursery managers working with a Partner (public health practitioner) to self-assess policies and practices relating to physical activity and nutrition; nursery staff attending one physical activity and one nutrition training workshop and setting goals to be achieved within 6 months. The Partner provides support and reviews progress. Nursery staff receive a further workshop and new goals are set, with Partner support for a further 6 months. The comparator is usual practice. Up to 56 nurseries will be stratified by area and randomly allocated to intervention or comparator arm with minimisation of differences in level of deprivation. Primary outcomes: accelerometer-assessed mean total activity time on nursery days and average total energy (kcal) intake per eating occasion of lunch and morning/afternoon snacks consumed within nurseries. Secondary outcomes: accelerometer-assessed mean daily minutes of moderate-to-vigorous physical activity and sedentary time per nursery day, total physical activity on nursery days compared to non-nursery days, average serving size of lunch and morning/afternoon snacks in nursery per day, average percentage of core and non-core food in lunch and morning/afternoon snacks, zBMI, proportion of children who are overweight/obese and child quality-of-life. A process evaluation will examine fidelity, acceptability, sustainability and context. An economic evaluation will compare costs and consequences from the perspective of the local government, nursery and parents. Trial registration: ISRCTN33134697, 31/10/2019