Synthetic and computational studies on the tricarboxylate core of 6,7-dideoxysqualestatin H5 involving a carbonyl ylide cycloaddition–rearrangement

Reaction of diazodiketoesters 17 and 28 with methyl glyoxylate in the presence of catalytic rhodium(II) acetate generates predominantly the 6,8-dioxabicyclo[3.2.1]octanes 29 and 30, respectively. Acid-catalysed rearrangement of the corresponding alcohol 31 favours, at equilibrium, the 2,8-dioxabicyclo[3.2.1]octane skeleton 33 of the squalestatins–zaragozic acids. Force field calculations on the position of the equilibrium gave misleading results. DFT calculations were correct in suggesting that the energy difference between 31 and 33 should be small, but did not always suggest the right major product. Calculation of the NMR spectra of the similar structures could be used to assign the isomers with a high level of confidence

Chronic nitrite treatment activates adenosine monophosphate-activated protein kinase-endothelial nitric oxide synthase pathway in human aortic endothelial cells

Endothelial dysfunction, with impaired bioavailability and/or bioactivity of the vasoprotective molecule, nitric oxide, appears to be a vital step in the initiation of atherosclerosis. Several studies have shown that dietary nitrate/nitrite can have significant benefits on human cardiovascular homeostasis. Although serum nitrite concentrations can reach micromolar levels, the physiological significance of nitrate/nitrite in normal tissues has not been fully elucidated. We investigated in vitro the chronic effects of nitrate/nitrite on endothelial nitric oxide synthase (eNOS) to determine the potential vasoprotective effects of nitrate/nitrite and the underlying molecular mechanisms. Our results demonstrate the expression of phosphorylated eNOS at Ser1177 and phosphorylated adenosine monophosphate activated protein kinase (AMPK) at Thr172 in human aortic endothelial cells were increased after nitrite treatment. We suggest that nitrite stimulation may enhance eNOS activation, which is due, in part, to AMPK activation. The AMPK–eNOS activation by nitrite may be a possible molecular mechanism underlying the vascular protective effects of dietary nitrate

Enzymatically modified isoquercitrin improves endothelial function in volunteers at risk of cardiovascular disease

A higher intake of food rich in flavonoids such as quercetin can reduce the risk of CVD. Enzymatically modified isoquercitrin (EMIQ®) has a bioavailability 17-fold higher than quercetin aglycone and has shown potential CVD moderating effects in animal studies. The present study aimed to determine whether acute ingestion of EMIQ® improves endothelial function, blood pressure (BP) and cognitive function in human volunteers at risk of CVD. Twenty-five participants (twelve males and thirteen females) with at least one CVD risk factor completed this randomised, controlled, crossover study. In a random order, participants were given EMIQ® (2 mg aglycone equivalent)/kg body weight or placebo alongside a standard breakfast meal. Endothelial function, assessed by flow-mediated dilatation (FMD) of the brachial artery was measured before and 1·5 h after intervention. BP, arterial stiffness, cognitive function, BP during cognitive stress and measures of quercetin metabolites, oxidative stress and markers of nitric oxide (NO) production were assessed post-intervention. After adjustment for pre-treatment measurements and treatment order, EMIQ® treatment resulted in a significantly higher FMD response compared with the placebo (1·80 (95 % CI 0·23, 3·37) %; P = 0·025). Plasma concentrations of quercetin metabolites were significantly higher (P \u3c 0·001) after EMIQ® treatment compared with the placebo. No changes in BP, arterial stiffness, cognitive function or biochemical parameters were observed. In this human intervention study, the acute administration of EMIQ® significantly increased circulating quercetin metabolites and improved endothelial function. Further clinical trials are required to assess whether health benefits are associated with long-term EMIQ® consumption

Dietary flavonoids and the prevalence and 15-y incidence of age-related macular degeneration

Background: The majority of research performed to date has examined the effects of commonly known antioxidants such as vitamins C, E, and A and carotenoids on age-related macular degeneration (AMD) risk and progression. To date, there is limited research on promising phytochemicals with antioxidant and anti-inflammatory properties, including flavonoids. Objective: In this exploratory study, we aimed to assess the independent associations between dietary intake of total flavonoids and common flavonoid classes with the prevalence and 15-y incidence of AMD. Design: In this population-based cohort study, 2856 adults aged ≥49 y at baseline and 2037 followed up 15 y later were included in prevalence and incidence analyses, respectively. Dietary intake was assessed by using a semiquantitative food-frequency questionnaire (FFQ). Estimates of the flavonoid content of foods in the FFQ were assessed by using the USDA Flavonoid, Isoflavone, and Proanthocyanidin databases. AMD was assessed from retinal photographs. Results: In cross-sectional analysis, each 1-SD increase in total overall flavonoid intake was associated with a reduced likelihood of any AMD (multivariable-adjusted OR: 0.76; 95% CI: 0.58, 0.99). Each 1-SD increase in dietary intake of total flavonols and total flavanones was associated with reduced odds of the prevalence of any AMD [multivariable-adjusted OR (95% CI): 0.75 (0.58, 0.97) and 0.77 (0.60, 0.99), respectively]. A marginally significant trend (P = 0.05) was observed between increasing the intake of total flavanone and hesperidin (from the first to the fourth quartile) and reduced likelihood of incident late AMD, after multivariable adjustment. Participants who reported ≥1 serving of oranges/d compared with those who never consumed oranges at baseline had a reduced risk of late AMD 15 y later (multivariable-adjusted OR: 0.39; 95% CI: 0.18, 0.85). Conclusions: Our findings suggest an independent and protective association between dietary intake of flavonoids and the likelihood of having AMD. Additional prospective cohort studies are needed to validate these findings

Evaluation of ‘Eyelander’: a video game designed to engage children and young people with homonymous visual field loss in compensatory training

Introduction: Rehabilitation can improve visual outcomes for adults with acquired homonymous visual field loss. However, it is unclear whether (re)habilitation improves visual outcomes for children because previous training schedules have been tiresome, uninteresting, and failed to keep them engaged. In this study we assessed whether children and young people with homonymous visual field loss would adhere to six weeks of unsupervised compensatory training using a specialised video game. Methods: Participants aged between 7 and 25 with homonymous visual field loss completed table-top assessments of visual search across four site visits. Two baseline assessments separated by four weeks evaluated spontaneous improvements before training began. Participants were then given a copy of the video game to use unsupervised at home for six weeks. Two follow-up assessments separated by four weeks were then conducted to evaluate immediate and acutely maintained effects of training. Results. 15 candidates met the inclusion-exclusion criteria, 9 participated, and 8 completed the study. Participants completed an average of 5.6 hours training unsupervised over the six weeks. Improvements on in-game metrics plateaued during week 3 of training. The time taken to find objects during table-top activities improved by an average of 24% (95% CI [2%, 46%]) after training. Discussion: The findings demonstrate that children and young people with homonymous visual field loss will engage with gamified compensatory training, and can improve visual outcomes with less time commitment than adults have required with non-gamified training in previous studies. Appropriately powered, randomised controlled trials are required to evaluate the validity and generalisability of observed training effects. Implications for practitioners: We conclude that (re)habilitation specialists can use specialist video games and gamification to engage children and young people with homonymous visual field loss in long-term unsupervised training schedules

Psychological distress and quality of life in asymptomatic adults following provision of imaging results for prevention of cardiovascular disease events: A scoping review

Aims Psychological distress and changes in health-related quality of life (HRQoL) may occur after screening for disease. Reporting outcomes related to potential benefits and harms of screening is a key recommendation in the guidelines for reporting high-quality trials or interventions. However, no reviews have directly investigated outcomes related to psychological distress and/or changes in HRQoL following imaging assessment of cardiovascular risk and communication of cardiovascular findings to asymptomatic adults. A scoping review was conducted to map research on psychological distress and/or HRQoL following screening. Methods and results Six electronic databases (MEDLINE, PsychINFO, Social Work Abstracts, Psychology and Behavioural Sciences Collection, CINAHL, and EMBASE) were searched for articles that assessed psychological distress and/or HRQoL following screening. Two investigators independently screened titles and abstracts for all records retrieved using predefined criteria. Studies were conducted among active smokers, military personnel, athletes, post-menopausal women, and high-risk individuals. Seven constructs related to psychological distress and HRQoL appeared across 11 articles (randomized controlled trials, n = 4 and non-randomized studies, n = 7). Worry, depression, perceived stress, anxiety, and quality of life were most prominent. Multiple-item measures of psychological distress (e.g. Taylor Anxiety Score and Beck Depression Inventory) were used in 5/9 (56%) studies. Key findings on psychological distress and/or changes in HRQoL following screening were mixed. Conclusions Findings support the need for multiple-item measures with better psychometric properties to examine the psychological responses to screening results in future studies. Strategies to support individuals during and following vascular screening to maximise potential benefits of screening and minimize harms are discussed

Association of dietary nitrate intake with the 15-year incidence of age-related macular degeneration

Background Dietary nitrate, found predominantly in green leafy vegetables and beetroot, is a precursor of nitric oxide. Under- or overproduction of nitric oxide is implicated in the etiology of several eye diseases. However, the potential influence of dietary nitrate intake on age-related macular degeneration (AMD) risk has not been assessed. Objective To investigate the temporal association between dietary nitrate intake (from both vegetable and nonvegetable sources) and the 15-year incidence of AMD, independent of potential confounders. Design A longitudinal cohort study conducted from 1992-1994 to 2007-2009. Participants/setting The Blue Mountains Eye Study is a population-based study of adults aged 49+ at baseline, from a region west of Sydney, Australia. At baseline, 2,856 participants with complete dietary data and AMD information were examined, and of these, 2,037 participants were re-examined 15 years later and thus included in incidence analysis. Main outcomes measured Incidence of AMD (main outcome) was assessed from retinal photographs. Dietary intake was assessed using a semiquantitative food-frequency questionnaire. Nitrate intake from vegetables and nonvegetable sources was calculated by use of a validated comprehensive database. Results After adjusting for age, sex, smoking, energy intake, fish consumption, and AMD risk alleles (complement factor H and age-related maculopathy susceptibility-2 single nucleotide polymorphisms), participants in the third quartile compared with those in the first quartile (reference group) of total nitrate and total vegetable nitrate intake had reduced risk of incident early AMD: odds ratio (OR) 0.61 (95% CI 0.41 to 0.90) and OR 0.65 (95% CI 0.44 to 0.96), respectively. Significant associations were not observed between the fourth vs first quartile of total nitrate and vegetable nitrate intake with incident early AMD: OR 0.74 (95% CI 0.51 to 1.08) and OR 0.69 (95% CI 0.47 to 1.00), respectively. Nonsignificant associations were also observed with 15-year incidence of late AMD and total nonvegetable nitrate intake. Conclusions These novel findings could have important implications, if the association between total nitrate intake and vegetable nitrate intake and 15-year incidence of early AMD is confirmed in other observational or intervention studies

Psychological distress and quality of life in asymptomatic adults following provision of imaging results for prevention of cardiovascular disease events: a scoping review

Aims: Psychological distress and changes in health-related quality of life (HRQoL) may occur after screening for disease. Reporting outcomes related to potential benefits and harms of screening is a key recommendation in the guidelines for reporting high-quality trials or interventions. However, no reviews have directly investigated outcomes related to psychological distress and/or changes in HRQoL following imaging assessment of cardiovascular risk and communication of cardiovascular findings to asymptomatic adults. A scoping review was conducted to map research on psychological distress and/or HRQoL following screening. Methods and results: Six electronic databases (MEDLINE, PsychINFO, Social Work Abstracts, Psychology and Behavioural Sciences Collection, CINAHL, and EMBASE) were searched for articles that assessed psychological distress and/or HRQoL following screening. Two investigators independently screened titles and abstracts for all records retrieved using predefined criteria. Studies were conducted among active smokers, military personnel, athletes, post-menopausal women, and high-risk individuals. Seven constructs related to psychological distress and HRQoL appeared across 11 articles (randomized controlled trials, n = 4 and non-randomized studies, n = 7). Worry, depression, perceived stress, anxiety, and quality of life were most prominent. Multiple-item measures of psychological distress (e.g. Taylor Anxiety Score and Beck Depression Inventory) were used in 5/9 (56%) studies. Key findings on psychological distress and/or changes in HRQoL following screening were mixed. Conclusions: Findings support the need for multiple-item measures with better psychometric properties to examine the psychological responses to screening results in future studies. Strategies to support individuals during and following vascular screening to maximise potential benefits of screening and minimize harms are discussed

Diets high in n-3 fatty acids are associated with lower arterial stiffness in patients with rheumatoid arthritis: a latent profile analysis

Supplementation with n-3 fatty acids can influence inflammation and markers of arterial stiffness that are increased in patients with rheumatoid arthritis (RA). However, it is unknown whether specific patterns of dietary fatty acid intake are similarly associated. In a longitudinal study, eighty-six RA patients reported their dietary intake and had arterial stiffness measured using the augmentation index (AIx) at baseline and 8 months. Latent profile analysis (LPA) was performed to characterise patterns of fatty acid intake using sixteen major fatty acids. Models for two to six profiles were compared using the Akaike and Bayesian information criteria. Associations between AIx and the profiles were adjusted for age, sex, disease activity, fish oil supplementation, medications, physical activity and socio-economic status. LPA identified five distinct profiles. Profile 1 subjects (n 7) reported significantly higher intake of palmitoleic acid (16 : 1), arachidonic acid (20 : 4n-6), EPA (20 : 5n-3), DHA (22 : 6n-3) and docosapentaenoic acid (22 : 5n-3) (