Role of inorganic nitrate and nitrite in driving nitric oxide-cGMP-mediated inhibition of platelet aggregation in vitro and in vivo

This is the peer reviewed version of the article, which has been published in final form at [doi: 10.1111/jth.12711. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.Nitric oxide (NO) is a critical negative regulator of platelets that is implicated in the pathology of thrombotic diseases. Platelets generate NO, but the presence and functional significance of NO synthase (NOS) in platelets is unclear. Inorganic nitrate/nitrite is increasingly being recognized as a source of bioactive NO, although its role in modulating platelets during health and vascular dysfunction is incompletely understood. METHODS: We investigated the functional significance and upstream sources of NO-cGMP signaling events in platelets by using established methods for assessing in vitro and in vivo platelet aggregation, and assessed the bioconversion of inorganic nitrate to nitrite during deficiency of endothelial NOS (eNOS). RESULTS: The phosphodiesterase 5 (PDE5) inhibitor sildenafil inhibited human platelet aggregation in vitro. This inhibitory effect was abolished by a guanylyl cyclase inhibitor and NO scavengers, but unaffected by NOS inhibition. Inorganic nitrite drove cGMP-mediated inhibition of human platelet aggregation in vitro and nitrate inhibited platelet function in eNOS(-/-) mice in vivo in a model of thromboembolic radiolabeled platelet aggregation associated with an enhanced plasma nitrite concentration as compared with wild-type mice. CONCLUSIONS: Platelets generate transient, endogenous cGMP signals downstream of NO that are primarily independent of NOS and may be enhanced by inhibition of PDE5. Furthermore, nitrite can generate transient NO-cGMP signals in platelets. The absence of eNOS leads to enhanced plasma nitrite levels following nitrate administration in vivo, which negatively impacts on platelet function. Our data suggest that inorganic nitrate exerts an antiplatelet effect during eNOS deficiency, and, potentially, that dietary nitrate may reduce platelet hyperactivity during endothelial dysfunction.British Pharmacological Society Integrative Pharmacology Fund Pump Priming Grant

Improving a Fundamental Measure of Lexical Association

Pointwise mutual information (PMI), a simple measure of lexical association, is part of several algorithms used as models of lexical semantic memory. Typically, it is used as a component of more complex distributional models rather than in isolation. We show that when two simple techniques are applied—(1) down-weighting co-occurrences involving low-frequency words in order to address PMI’s so-called “frequency bias,” and (2) defining co-occurrences as counts of “events in which instances of word1 and word2 co-occur in a context” rather than “contexts in which word1 and word2 co-occur”—then PMI outperforms default parameterizations of word embedding models in terms of how closely it matches human relatedness judgments. We also identify which down-weighting techniques are most helpful. The results suggest that simple measures may be capable of modeling certain phenomena in semantic memory, and that complex models which incorporate PMI might be improved with these modifications.Cambridge Centre for Digital Knowledg

Exponential Random Graph Modeling for Complex Brain Networks

Exponential random graph models (ERGMs), also known as p* models, have been utilized extensively in the social science literature to study complex networks and how their global structure depends on underlying structural components. However, the literature on their use in biological networks (especially brain networks) has remained sparse. Descriptive models based on a specific feature of the graph (clustering coefficient, degree distribution, etc.) have dominated connectivity research in neuroscience. Corresponding generative models have been developed to reproduce one of these features. However, the complexity inherent in whole-brain network data necessitates the development and use of tools that allow the systematic exploration of several features simultaneously and how they interact to form the global network architecture. ERGMs provide a statistically principled approach to the assessment of how a set of interacting local brain network features gives rise to the global structure. We illustrate the utility of ERGMs for modeling, analyzing, and simulating complex whole-brain networks with network data from normal subjects. We also provide a foundation for the selection of important local features through the implementation and assessment of three selection approaches: a traditional p-value based backward selection approach, an information criterion approach (AIC), and a graphical goodness of fit (GOF) approach. The graphical GOF approach serves as the best method given the scientific interest in being able to capture and reproduce the structure of fitted brain networks

An intervention modelling experiment to change GP's intentions to implement evidence-based practice : using theory-based interventions to promote GP management of upper respiratory tract infection without prescribing antibiotics #2

Background: Psychological theories of behaviour may provide a framework to guide the design of interventions to change professional behaviour. Behaviour change interventions, designed using psychological theory and targeting important motivational beliefs, were experimentally evaluated for effects on the behavioural intention and simulated behaviour of GPs in the management of uncomplicated upper respiratory tract infection (URTI). Methods: The design was a 2 × 2 factorial randomised controlled trial. A postal questionnaire was developed based on three theories of human behaviour: Theory of Planned Behaviour; Social Cognitive Theory and Operant Learning Theory. The beliefs and attitudes of GPs regarding the management of URTI without antibiotics and rates of prescribing on eight patient scenarios were measured at baseline and post-intervention. Two theory-based interventions, a "graded task" with "action planning" and a "persuasive communication", were incorporated into the post-intervention questionnaire. Trial groups were compared using co-variate analyses. Results: Post-intervention questionnaires were returned for 340/397 (86%) GPs who responded to the baseline survey. Each intervention had a significant effect on its targeted behavioural belief: compared to those not receiving the intervention GPs completing Intervention 1 reported stronger self-efficacy scores (Beta = 1.41, 95% CI: 0.64 to 2.25) and GPs completing Intervention 2 had more positive anticipated consequences scores (Beta = 0.98, 95% CI = 0.46 to 1.98). Intervention 2 had a significant effect on intention (Beta = 0.90, 95% CI = 0.41 to 1.38) and simulated behaviour (Beta = 0.47, 95% CI = 0.19 to 0.74). Conclusion: GPs' intended management of URTI was significantly influenced by their confidence in their ability to manage URTI without antibiotics and the consequences they anticipated as a result of doing so. Two targeted behaviour change interventions differentially affected these beliefs. One intervention also significantly enhanced GPs' intentions not to prescribe antibiotics for URTI and resulted in lower rates of prescribing on patient scenarios compared to a control group. The theoretical frameworks utilised provide a scientific rationale for understanding how and why the interventions had these effects, improving the reproducibility and generalisability of these findings and offering a sound basis for an intervention in a "real world" trial. Trial registration: Clinicaltrials.gov NCT00376142This study is funded by the European Commission Research Directorate as part of a multi-partner program: Research Based Education and Quality Improvement (ReBEQI): A Framework and tools to develop effective quality improvement programs in European healthcare. (Proposal No: QLRT-2001-00657)

Hypoxia and adipose tissue function and dysfunction in obesity

The rise in the incidence of obesity has led to a major interest in the biology of white adipose tissue. The tissue is a major endocrine and signalling organ, with adipocytes, the characteristic cell type, secreting a multiplicity of protein factors – the adipokines. Increases in the secretion of a number of adipokines occurs in obesity, underpinning inflammation in white adipose tissue and the development of obesity-associated diseases. There is substantial evidence, particularly from animal studies, that hypoxia develops in adipose tissue as the tissue mass expands, and the reduction in pO2 is considered to underlie the inflammatory response. Exposure of white adipocytes to hypoxic conditions in culture induces changes in the expression of >1,000 genes. The secretion of inflammation-related adipokines is up-regulated by hypoxia, and there is a switch from oxidative metabolism to anaerobic glycolysis. Glucose utilisation is increased in hypoxic adipocytes with corresponding increases in lactate production. Importantly, hypoxia induces insulin resistance in fat cells and leads to the development of adipose tissue fibrosis. Many of the responses of adipocytes to hypoxia are initiated at pO2 levels above the normal physiological range for adipose tissue. The other cell types within the tissue also respond to hypoxia, with the differentiation of preadipocytes to adipocytes being inhibited and preadipocytes being transformed into leptin-secreting cells. Overall, hypoxia has pervasive effects on the function of adipocytes and appears to be a key factor in adipose tissue dysfunction in obesity

Elucidating the aetiology of human Campylobacter coli infections

Peer reviewedPublisher PD

Target Zones in History and Theory: Lessons from an Austro-Hungarian Experiment (1896-1914)

The first known experiment with an exchange rate band took place in Austria- Hungary between 1896 and 1914. The rationale for introducing this policy rested on precisely those intuitions that the modern literature has emphasized: the band was designed to secure both exchange rate stability and monetary policy autonomy. However, unlike more recent experiences, such as the ERM, this policy was not undermined by credibility problems. The episode provides an ideal testing ground for some important ideas in modern macroeconomics: specifically, can formal rules, when faithfully adhered to, provide policy makers with some advantages such as short term autonomy? First, we find that a credible band has a "microeconomic" influence on exchange rate stability. By reducing uncertainty, a credible fluctuation band improves the quality of expectations, a channel that has been neglected in the modern literature. Second, we show that the standard test of the basic target zone model is flawed and develop an alternative methodology. We believe that these findings shed a new light on the economics of exchange rate bands

The development of path integration: combining estimations of distance and heading

Efficient daily navigation is underpinned by path integration, the mechanism by which we use self-movement information to update our position in space. This process is well-understood in adulthood, but there has been relatively little study of path integration in childhood, leading to an underrepresentation in accounts of navigational development. Previous research has shown that calculation of distance and heading both tend to be less accurate in children as they are in adults, although there have been no studies of the combined calculation of distance and heading that typifies naturalistic path integration. In the present study 5-year-olds and 7-year-olds took part in a triangle-completion task, where they were required to return to the startpoint of a multi-element path using only idiothetic information. Performance was compared to a sample of adult participants, who were found to be more accurate than children on measures of landing error, heading error, and distance error. 7-year-olds were significantly more accurate than 5-year-olds on measures of landing error and heading error, although the difference between groups was much smaller for distance error. All measures were reliably correlated with age, demonstrating a clear development of path integration abilities within the age range tested. Taken together, these data make a strong case for the inclusion of path integration within developmental models of spatial navigational processing

Fluoroquinolone resistance during 2000–2005 : An observational study

<p>Abstract</p> <p>Background</p> <p>Moxifloxacin is a respiratory fluoroquinolone with a community acquired pneumonia indication. Unlike other fluoroquinolones used in our healthcare system, moxifloxacin's urinary excretion is low and thus we hypothesized that increased use of moxifloxacin is associated with an increase in fluoroquinolone resistance amongst gram negative uropathogens.</p> <p>Methods</p> <p>All antibiograms for Gram negative bacteria were obtained for 2000 to 2005. The defined daily dose (DDD) for each fluoroquinolone was computed according to World Health Organization criteria. To account for fluctuation in patient volume, DDD/1000 bed days was computed for each year of study. Association between DDD/1000 bed days for each fluoroquinolone and the susceptibility of Gram negative bacteria to ciprofloxacin was assessed using Pearson's Correlation Coefficient, r.</p> <p>Results</p> <p>During the study period, there were 48,261 antibiograms, 347,931 DDD of fluoroquinolones, and 1,943,338 bed days. Use of fluoroquinolones among inpatients decreased from 237.2 DDD/1000 bed days in 2000 to 115.2 DDD/1000 bed days in 2005. With the exception of <it>Enterobacter aerogenes</it>, moxifloxacin use was negatively correlated with sensitivity among all 13 Gram negative species evaluated (r = -0.07 to -0.97). When the sensitivities of all Gram negative organisms were aggregated, all fluoroquinolones except moxifloxacin were associated with increased sensitivity (r = 0.486 to 1.000) while moxifloxacin was associated with decreased sensitivity (r = -0.464).</p> <p>Conclusion</p> <p>Moxifloxacin, while indicated for empiric treatment of community acquired pneumonia, may have important negative influence on local antibiotic sensitivities amongst Gram negative organisms. This effect was not shared by other commonly used members of the fluoroquinolone class.</p

Studying Fake News via Network Analysis: Detection and Mitigation

Social media for news consumption is becoming increasingly popular due to its easy access, fast dissemination, and low cost. However, social media also enable the wide propagation of "fake news", i.e., news with intentionally false information. Fake news on social media poses significant negative societal effects, and also presents unique challenges. To tackle the challenges, many existing works exploit various features, from a network perspective, to detect and mitigate fake news. In essence, news dissemination ecosystem involves three dimensions on social media, i.e., a content dimension, a social dimension, and a temporal dimension. In this chapter, we will review network properties for studying fake news, introduce popular network types and how these networks can be used to detect and mitigation fake news on social media.Comment: Submitted as a invited book chapter in Lecture Notes in Social Networks, Springer Pres