Dietary nitrate and population health: a narrative review of the translational potential of existing laboratory studies

BACKGROUND: Dietary inorganic nitrate (NO(3)(−)) is a polyatomic ion, which is present in large quantities in green leafy vegetables and beetroot, and has attracted considerable attention in recent years as a potential health-promoting dietary compound. Numerous small, well-controlled laboratory studies have reported beneficial health effects of inorganic NO(3)(−) consumption on blood pressure, endothelial function, cerebrovascular blood flow, cognitive function, and exercise performance. Translating the findings from small laboratory studies into ‘real-world’ applications requires careful consideration. MAIN BODY: This article provides a brief overview of the existing empirical evidence basis for the purported health-promoting effects of dietary NO(3)(−) consumption. Key areas for future research are then proposed to evaluate whether promising findings observed in small animal and human laboratory studies can effectively translate into clinically relevant improvements in population health. These proposals include: 1) conducting large-scale, longer duration trials with hard clinical endpoints (e.g. cardiovascular disease incidence); 2) exploring the feasibility and acceptability of different strategies to facilitate a prolonged increase in dietary NO(3)(−) intake; 3) exploitation of existing cohort studies to explore associations between NO(3)(−) intake and health outcomes, a research approach allowing larger samples sizes and longer duration follow up than is feasible in randomised controlled trials; 4) identifying factors which might account for individual differences in the response to inorganic NO(3)(−) (e.g. sex, genetics, habitual diet) and could assist with targeted/personalised nutritional interventions; 5) exploring the influence of oral health and medication on the therapeutic potential of NO(3)(−) supplementation; and 6) examining potential risk of adverse events with long term high- NO(3)(−) diets. CONCLUSION: The salutary effects of dietary NO(3)(−) are well established in small, well-controlled laboratory studies. Much less is known about the feasibility and efficacy of long-term dietary NO(3)(−) enrichment for promoting health, and the factors which might explain the variable responsiveness to dietary NO(3)(−) supplementation between individuals. Future research focussing on the translation of laboratory data will provide valuable insight into the potential applications of dietary NO(3)(−) supplementation to improve population health

Interleukin-17 Stimulates C-Reactive Protein Expression in Hepatocytes and Smooth Muscle Cells via p38 MAPK and ERK1/2-Dependent NF-κB and C/EBPβ Activation

Elevated systemic levels of the acute phase C-reactive protein (CRP) are predictors of future cardiovascular events. There is evidence that CRP may also play a direct role in atherogenesis. Here we determined whether the proinflammatory interleukin (IL)-17 stimulates CRP expression in hepatocytes (Hep3B cell line and primary hepatocytes) and coronary artery smooth muscle cells (CASMC). Our results demonstrate that IL-17 potently induces CRP expression in Hep3B cells independent of IL-1β and IL-6. IL-17 induced CRP promoter-driven reporter gene activity that could be attenuated by dominant negative IκBα or C/EBPβ knockdown and stimulated both NF-κB and C/EBP DNA binding and reporter gene activities. Targeting NF-κB and C/EBPβ activation by pharmacological inhibitors, small interfering RNA interference and adenoviral transduction of dominant negative expression vectors blocked IL-17-mediated CRP induction. Overexpression of wild type p50, p65, and C/EBPβ stimulated CRP transcription. IL-17 stimulated p38 MAPK and ERK1/2 activation, and SB203580 and PD98059 blunted IL-17-mediated NF-κB and C/EBP activation and CRP transcription. These results, confirmed in primary human hepatocytes and CASMC, demonstrate for the first time that IL-17 is a potent inducer of CRP expression via p38 MAPK and ERK1/2-dependent NF-κB and C/EBPβ activation and suggest that IL-17 may mediate chronic inflammation, atherosclerosis, and thrombosis

Solution-Phase Combinatorial Chemistry in Lead Discovery

Solution-phase approaches in combinatorial chemistry complement solid-phase approaches and each can be used to advantage in particular circumstances. Solution-phase synthesis of pools of compounds, whilst allowing successful identification of a selection of good lead structures for medicinal chemistry programmes, also reinforced a number of the disadvantages of such an approach. Solution-phase parallel synthesis of discrete compounds has, however, proved to be a very useful and popular approach both for lead generation and in lead optimisation work. The range of chemistry suitable for use in such approaches is expanding rapidly and some of these chemistries are discussed. The current focus is on enhancing the quality of compounds prepared in array formats, and we describe a number of useful approaches which are being developed to that end

Design approaches in technology enhanced learning

Design is a critical to the successful development of any interactive learning environment (ILE). Moreover, in technology enhanced learning (TEL), the design process requires input from many diverse areas of expertise. As such, anyone undertaking tool development is required to directly address the design challenge from multiple perspectives. We provide a motivation and rationale for design approaches for learning technologies that draws upon Simon's seminal proposition of Design Science (Simon, 1969). We then review the application of Design Experiments (Brown, 1992) and Design Patterns (Alexander et al., 1977) and argue that a patterns approach has the potential to address many of the critical challenges faced by learning technologists

Analysis of the recombination landscape of hexaploid bread wheat reveals genes controlling recombination and gene conversion frequency

Background: Sequence exchange between homologous chromosomes through crossing over and gene conversion is highly conserved among eukaryotes, contributing to genome stability and genetic diversity. A lack of recombination limits breeding efforts in crops; therefore, increasing recombination rates can reduce linkage drag and generate new genetic combinations. Results: We use computational analysis of 13 recombinant inbred mapping populations to assess crossover and gene conversion frequency in the hexaploid genome of wheat (Triticum aestivum). We observe that high-frequency crossover sites are shared between populations and that closely related parents lead to populations with more similar crossover patterns. We demonstrate that gene conversion is more prevalent and covers more of the genome in wheat than in other plants, making it a critical process in the generation of new haplotypes, particularly in centromeric regions where crossovers are rare. We identify quantitative trait loci for altered gene conversion and crossover frequency and confirm functionality for a novel RecQ helicase gene that belongs to an ancient clade that is missing in some plant lineages including Arabidopsis. Conclusions: This is the first gene to be demonstrated to be involved in gene conversion in wheat. Harnessing the RecQ helicase has the potential to break linkage drag utilizing widespread gene conversions

CD4(+) T follicular helper and IgA(+) B cell numbers in gut biopsies from HIV-infected subjects on antiretroviral therapy are similar to HIV-uninfected individuals

BACKGROUND: Disruption of gastrointestinal tract epithelial and immune barriers contribute to microbial translocation, systemic inflammation, and progression of HIV-1 infection. Antiretroviral therapy (ART) may lead to reconstitution of CD4(+) T cells in gut-associated lymphoid tissue (GALT), but its impact on humoral immunity within GALT is unclear. Therefore, we studied CD4(+) subsets, including T follicular helper cells (Tfh), as well as resident B cells that have switched to IgA production, in gut biopsies, from HIV(+) subjects on suppressive ART compared to HIV-negative controls (HNC). METHODS: Twenty-three HIV(+) subjects on ART and 22 HNC undergoing colonoscopy were recruited to the study. Single-cell suspensions were prepared from biopsies from left colon (LC), right colon (RC), and terminal ileum (TI). T and B lymphocyte subsets, as well as EpCAM(+) epithelial cells, were accurately enumerated by flow cytometry, using counting beads. RESULTS: No significant differences in the number of recovered epithelial cells were observed between the two subject groups. However, the median TI CD4(+) T cell count/10(6) epithelial cells was 2.4-fold lower in HIV(+) subjects versus HNC (19,679 versus 47,504 cells; p = 0.02). Similarly, median LC CD4(+) T cell counts were reduced in HIV(+) subjects (8,358 versus 18,577; p = 0.03) but were not reduced in RC. Importantly, we found no significant differences in Tfh or IgA(+) B cell counts at either site between HIV(+) subjects and HNC. Further analysis showed no difference in CD4(+), Tfh, or IgA(+) B cell counts between subjects who commenced ART in primary compared to chronic HIV-1 infection. Despite the decrease in total CD4 T cells, we could not identify a selective decrease of other key subsets of CD4(+) T cells, including CCR5(+) cells, CD127(+) long-term memory cells, CD103(+) tissue-resident cells, or CD161(+) cells (surrogate marker for Th17), but there was a slight increase in the proportion of T regulatory cells. CONCLUSION: While there were lower absolute CD4(+) counts in the TI and LC in HIV(+) subjects on ART, they were not associated with significantly reduced Tfh cell counts or IgA(+) B cells, suggesting that this important vanguard of adaptive immune defense against luminal microbial products is normalized following ART.John Zaunders, Mark Danta, Michelle Bailey, Gerald Mak, Katherine Marks, Nabila Seddiki, Yin Xu, David J. Templeton, David A. Cooper, Mark A. Boyd, Anthony D. Kelleher and Kersten K. Koelsc

Estimating Household and Community Transmission of Ocular Chlamydia trachomatis

Trachoma is a major cause of blindness worldwide and results from ocular infection with the bacterium Chlamydia trachomatis. Mass distribution of antibiotics in communities is part of the strategy to eliminate blindness due to trachoma. Targeted treatment of infected households could be more efficient, but the success of such a strategy will depend on the extent of transmission of infection between members of the same household and between members of the community. In this work, we estimated the magnitude of household and community transmission in four populations, two from The Gambia and two from Tanzania. We found that, in general, transmission of the bacteria within households is very efficient. In three of the four populations, persistent infection within households was predicted by the high level of household transmission (a phenomenon observed in longitudinal studies of trachoma). In all of the studied populations, individuals who live in households with more individuals contribute more to the number of new infections in the community than those who live with fewer individuals. Further studies are required to identify and examine household-targeted approaches to treatment

Different Measures, Different Outcomes? A Systematic Review of Performance-Based versus Self-Reported Measures of Health Literacy and Numeracy

BACKGROUND Health literacy (HL) and numeracy are measured by one of two methods: performance on objective tests or self-report of one’s skills. Whether results from these methods differ in their relationship to health outcomes or use of health services is unknown. METHODS We performed a systematic review to identify and evaluate articles that measured both performance-based and self-reported HL or numeracy and examined their relationship to health outcomes or health service use. To identify studies, we started with an AHRQ-funded systematic review of HL and health outcomes. We then looked for newer studies by searching MEDLINE from 1 February 2010 to 9 December 2014. We included English language studies meeting pre-specified criteria. Two reviewers independently assessed abstracts and studies for inclusion and graded study quality. One reviewer abstracted information from included studies while a second checked content for accuracy. RESULTS We identified four “fair” quality studies that met inclusion criteria for our review. Two studies measuring HL found no differences between performance-based and self-reported HL for association with self-reported outcomes (including diabetes, stroke, hypertension) or a physician-completed rheumatoid arthritis disease activity score. However, HL measures were differentially related to a patient-completed health assessment questionnaire and to a patient’s ability to interpret their prescription medication name and dose from a medication bottle. Only one study measured numeracy and found no difference between performance-based and self-reported measures of numeracy and colorectal cancer (CRC) screening utilization. However, in a moderator analysis from the same study, performance-based and self-reported numeracy were differentially related to CRC screening utilization when stratified by certain patient–provider communication behaviors (e.g., the chance to always ask questions and get the support that is needed). DISCUSSION Most studies found no difference in the relationship between results of performance-based and self-reported measures and outcomes. However, we identified few studies using multiple instruments and/or objective outcomes

Risk factors for race-day fatality in flat racing Thoroughbreds in Great Britain (2000 to 2013)

A key focus of the racing industry is to reduce the number of race-day events where horses die suddenly or are euthanased due to catastrophic injury. The objective of this study was therefore to determine risk factors for race-day fatalities in Thoroughbred racehorses, using a cohort of all horses participating in flat racing in Great Britain between 2000 and 2013. Horse-, race- and course-level data were collected and combined with all race-day fatalities, recorded by racecourse veterinarians in a central database. Associations between exposure variables and fatality were assessed using logistic regression analyses for (1) all starts in the dataset and (2) starts made on turf surfaces only. There were 806,764 starts in total, of which 548,571 were on turf surfaces. A total of 610 fatalities were recorded; 377 (61.8%) on turf. In both regression models, increased firmness of the going, increasing racing distance, increasing average horse performance, first year of racing and wearing eye cover for the first time all increased the odds of fatality. Generally, the odds of fatality also increased with increasing horse age whereas increasing number of previous starts reduced fatality odds. In the ‘all starts’ model, horses racing in an auction race were at 1.46 (95% confidence interval (CI) 1.06–2.01) times the odds of fatality compared with horses not racing in this race type. In the turf starts model, horses racing in Group 1 races were at 3.19 (95% CI 1.71–5.93) times the odds of fatality compared with horses not racing in this race type. Identification of novel risk factors including wearing eye cover and race type will help to inform strategies to further reduce the rate of fatality in flat racing horses, enhancing horse and jockey welfare and safety