Amyloid beta peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation

Background: Amyloid beta (A beta)-induced vascular dysfunction significantly contributes to the pathogenesis of Alzheimer\u27s disease (AD). A beta is known to impair endothelial nitric oxide synthase (eNOS) activity, thus inhibiting endothelial nitric oxide production (NO). Method: In this study, we investigated A beta-effects on heat shock protein 90 (HSP90) interaction with eNOS and Akt in cultured vascular endothelial cells and also explored the role of oxidative stress in this process. Results: Treatments of endothelial cells (EC) with A beta promoted the constitutive association of HSP90 with eNOS but abrogated agonist (vascular endothelial growth factor (VEGF))-mediated HSP90 interaction with Akt. This effect resulted in blockade of agonist-mediated phosphorylation of Akt and eNOS at serine 1179. Furthermore, A beta stimulated the production of reactive oxygen species in endothelial cells and concomitant treatments of the cells with the antioxidant N-acetyl-cysteine (NAC) prevented A beta effects in promoting HSP90/eNOS interaction and rescued agonist-mediated Akt and eNOS phosphorylation. Conclusions: The obtained data support the hypothesis that oxidative damage caused by A beta results in altered interaction of HSP90 with Akt and eNOS, therefore promoting vascular dysfunction. This mechanism, by contributing to A beta-mediated blockade of nitric oxide production, may significantly contribute to the cognitive impairment seen in AD patients

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Association between diet-quality scores, adiposity, total cholesterol and markers of nutritional status in European adults: findings from the Food4Me study

Diet-quality scores (DQS), which are developed across the globe, are used to define adherence to specific eating patterns and have been associated with risk of coronary heart disease and type-II diabetes. We explored the association between five diet-quality scores (Healthy Eating Index,HEI; Alternate Healthy Eating Index, AHEI; MedDietScore, MDS; PREDIMED Mediterranean DietScore, P-MDS; Dutch Healthy Diet-Index, DHDI) and markers of metabolic health (anthropometry,objective physical activity levels (PAL), and dried blood spot total cholesterol (TC), total carotenoids,and omega-3 index) in the Food4Me cohort, using regression analysis. Dietary intake was assessed using a validated Food Frequency Questionnaire. Participants (n= 1480) were adults recruited from seven European Union (EU) countries. Overall, women had higher HEI and AHEI than men (p< 0.05), and scores varied significantly between countries. For all DQS, higher scores were associated with lower body mass index, lower waist-to-height ratio and waist circumference, and higher total carotenoids and omega-3-index (p trends < 0.05). Higher HEI, AHEI, DHDI, and P-MDS scores were associated with increased daily PAL, moderate and vigorous activity, and reduced sedentary behaviour (p trend < 0.05). We observed no association between DQS and TC. To conclude,higher DQS, which reflect better dietary patterns, were associated with markers of better nutritional status and metabolic health

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Would you use it with a seal of approval? Important attributes of 2,4-dinitrophenol (2,4-DNP) as a hypothetical pharmaceutical product

Background2,4-Dinitrophenol (2,4-DNP) is an effective but highly dangerous fat burner, not licensed for human consumption. Death cases reported for 2,4-DNP overdose, particularly among young adults, have raised concerns about the ineffective regulatory control, lack of education and risks associated with impurity, and the unknown concentration of 2,4-DNP purchased on the Internet.MethodsUsing a sequential mixed method design and based on a hypothetical scenario as if 2,4-DNP was a licensed pharmaceutical drug, first we conducted a qualitative study to explore what product attributes people consider when buying a weight-loss aid. Focus group interviews with six females and three males (mean age = 21.6 ± 1.8 years) were audiorecorded, transcribed verbatim, and subjected to thematic analysis. Sixteen attributes were identified for the Best–Worst Scale (BWS) in the quantitative survey with 106 participants (64% female, mean age = 27.1 ± 11.9 years), focusing on 2,4-DNP. Demographics, weight satisfaction, and risk for eating disorder data were collected.ResultsIn contrast to experienced users such as bodybuilders, our study participants approached 2,4-DNP cautiously. Attributes of 2,4-DNP as a hypothetical weight-loss drug comprised a range of desirable and avoidable features. Of the 16 selected attributes, BWS suggested that long-term side effects were the most and branding was the least important attribute. Effectiveness and short-term side effects were also essential. Those in the &gt;25 year group showed least concerns for legality. Neutral BWS scores for cost, treatment, degree of lifestyle changes required, and specificity required for the hypothetical weight-loss drug to be effective were likely caused by disagreement about their importance among the participants, not indifference.ConclusionWith advances in research, 2,4-DNP as a pharmaceutical drug in the future for treating neurodegenerative diseases and potentially for weight loss is not inconceivable. Caution is warranted for interpreting the BWS scores. Owing to the difference in what data represent at individual vs. population levels, with pooled data, the method correctly identifies attributes by which most people are satisfied but misrepresents attributes that are individually very important but not universally agreed. Whilst this may be an advantage in marketing applications, it limits the utility of BWS as a research tool

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam

The effect of the apolipoprotein E genotype on response to personalized dietary advice intervention: findings from the Food4Me randomized controlled trial

Background: The apolipoprotein E (APOE) risk allele (ɛ4) is associated with higher total cholesterol (TC), amplified response to saturated fatty acid (SFA) reduction, and increased cardiovascular disease. Although knowledge of gene risk may enhance dietary change, it is unclear whether ɛ4 carriers would benefit from gene-based personalized nutrition (PN). Objectives: The aims of this study were to 1) investigate interactions between APOE genotype and habitual dietary fat intake and modulations of fat intake on metabolic outcomes; 2) determine whether gene-based PN results in greater dietary change than do standard dietary advice (level 0) and nongene-based PN (levels 1–2); and 3) assess the impact of knowledge of APOE risk (risk: E4+, nonrisk: E4−) on dietary change after gene-based PN (level 3). Design: Individuals (n = 1466) recruited into the Food4Me pan-European PN dietary intervention study were randomly assigned to 4 treatment arms and genotyped for APOE (rs429358 and rs7412). Diet and dried blood spot TC and ω-3 (n–3) index were determined at baseline and after a 6-mo intervention. Data were analyzed with the use of adjusted general linear models. Results: Significantly higher TC concentrations were observed in E4+ participants than in E4− (P < 0.05). Although there were no significant differences in APOE response to gene-based PN (E4+ compared with E4−), both groups had a greater reduction in SFA (percentage of total energy) intake than at level 0 (mean ± SD: E4+, −0.72% ± 0.35% compared with −1.95% ± 0.45%, P = 0.035; E4−, −0.31% ± 0.20% compared with −1.68% ± 0.35%, P = 0.029). Gene-based PN was associated with a smaller reduction in SFA intake than in nongene-based PN (level 2) for E4− participants (−1.68% ± 0.35% compared with −2.56% ± 0.27%, P = 0.025). Conclusions: The APOE ɛ4 allele was associated with higher TC. Although gene-based PN targeted to APOE was more effective in reducing SFA intake than standard dietary advice, there was no difference between APOE “risk” and “nonrisk” groups. Furthermore, disclosure of APOE nonrisk may have weakened dietary response to PN