Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide

Nitric oxide (NO) is a vasodilator and independent modulator of cardiac remodelling. Commonly, in cardiac disease (e.g. heart failure) endothelial dysfunction (synonymous with NO-deficiency) has been implicated in increased blood pressure (BP), cardiac hypertrophy and fibrosis. Currently no effective therapies replacing NO have succeeded in the clinic. Inorganic nitrate (NO3 - ), through chemical reduction to nitrite and then NO, exerts potent BP-lowering but whether it might be useful in treating undesirable cardiac remodelling is unknown. In a nested age- and sex-matched case-control study of hypertensive patients +/- left ventricular hypertrophy (NCT03088514) we show that lower plasma nitrite concentration and vascular dysfunction accompany cardiac hypertrophy and fibrosis in patients. In mouse models of cardiac remodelling, we also show that restoration of circulating nitrite levels using dietary nitrate improves endothelial dysfunction through targeting of xanthine oxidoreductase (XOR)-driven H2 O2 and superoxide, and reduces cardiac fibrosis through NO-mediated block of SMAD-phosphorylation leading to improvements in cardiac structure and function. We show that via these mechanisms dietary nitrate offers easily translatable therapeutic options for treatment of cardiac dysfunction

Evaluating conceptual modelling practices: Composites, things, properties

This chapter examines how ontological theory can be used to predict how alternative conceptual modelling representations affect end-user understanding of these representations. Specifically, it examines how ontological theory can be used to show how part-whole relations (composites) and things and properties can be best represented to enhance understanding of these real-world phenomena. We report the outcomes of two experiments that provide evidence to support the ontologically sound representation of part-whole relations and things and properties. We also discuss the outcomes of a cognitive process tracing study that explains why the ontologically sound representation of things and properties is more easily understood. In essence, our empirical research provides evidence to support the use of ontology as a theoretical basis to guide conceptual modelling practices.

Representing part-whole relationships in conceptual modeling: An empirical evaluation

The part-of or part-whole construct is a fundamental element of many conceptual modeling grammars that is used to associate one thing (a component) with another thing (a composite). Substantive theoretical issues surrounding the part-whole construct remain to be resolved, however. For instance, contrary to widespread claims, the relationship between components and composites is not always transitive. Moreover, how the part-whole construct should be represented in a conceptual schema diagram remains a contentious issue. Some analysts argue composites should be represented as a relationship or association. Others argue they should be represented as an entity. In this paper we use an ontological theory to support our arguments that composites should be represented as entities and not relationships or associations. We also describe an experiment that we undertook to test whether representing composites as relationships or entities enables users to understand a domain better. Our results support our arguments that using entities to represent composites enables users to better understand a domain

Representing part–whole relations in conceptual modeling : an empirical evaluation

The part-of construct is a fundamental element of many conceptual modeling grammars that is used to associate one thing (a component) with another thing (a composite). Substantive theoretical issues surrounding the part-of construct remain to be resolved, however. For instance, contrary to widespread claims, some researchers now argue the relationship between components and composites is not always transitive. Moreover, how the part-of construct should be represented in a conceptual schema diagram remains a contentious issue. Some analysts argue composites should be represented as a relationship or association. Others argue they should be represented as an entity. ory to support our arguments that composites should be represented as entities and not relationships or associations. We also describe an experiment that we undertook to test whether representing composites as relationships or entities enables users to understand a domain better. Our results support our arguments that using entities to represent composites enables users to better understand a domain

Retrospective observational study on the use of acetyl-l-carnitine in ALS

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage