Influence of homocysteine on the interaction between circulating monocytes and endothelial cells

Mild hyperhomocysteinemia is an independent risk factor for the development of coronary artery disease, cerebrovascular disease and peripheral arterial disease. The mechanisms by which hyperhomocysteinemia promotes vascular disease are not completely understood yet. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteine’s deleterious effects on the vasculature. Elevated levels of homocysteine lead to increased generation of superoxide anion in endothelial cells by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation rate of homocysteine and other aminothiols in the circulation. Furthermore, homocysteine has been shown to inhibit the activity of important cellular antioxidant enzymes, like the cellular isoform of glutathione peroxidase or superoxide dismutase, which may contribute to homocysteine’s induced oxidant stress. The resulting increase in reactive oxygen species leads to decreased bioavailability of the endothelium-derived signaling molecule nitric oxide via oxidative inactivation and thereby induces endothelial dysfunction. This seems to play a central role in the molecular mechanisms underlying the effects of homocysteine on vascular function. Hyperhomocysteinemia not only leads to endothelial dysfunction but also promotes the development and propagation of atherosclerotic lesion in atherosclerosis-prone animal models. As the recruitment of circulating monocytes to the vessel wall plays a crucial role in the process of atherosclerosis, the purpose of this study was to examine the influence of homocysteine on the interaction of endothelial cells with monocytes. Exposure of endothelial monolayers to D,L- and L-homocysteine resulted in a time- and dose-dependent increase in adherent THP-1 cells by upregulating ICAM-1 expression on endothelial cells. L-cysteine and D-homocysteine had no effects. This indicates that the stimulatory effect is specific for the naturally occurring L-stereoisomer and rather a biochemical than a chemical effect. The increased endothelial expression of ICAM-1 seems to be mediated by increased activation of the nuclear transcription factor NF-kB, as shown by increased nuclear translocation of NF-kB in homocysteine-incubated endothelial cells. In accordance, inhibition of NF-kB translocation by a synthetic inhibitor Bay 11-7082 significantly diminished homocysteine-induced ICAM-1 expression and adhesion of monocytes to endothelial cells. In addition, incubation of monocytes with D,L- homocysteine and L-homocysteine resulted in significant increase in the number of adhering monocytes to unstimulated endothelial monolayer by upregulating the expression of beta-2 integrins. Furthermore, homocysteine-incubation of endothelial cells and monocytes resulted in a dose-dependent and significant increase in the intracellular generation of reactive oxygen species. In support of the role of increased oxidant stress for the above mentioned effects, treatment of endothelial cells with the superoxide scavengers MnTBAP or Tiron together with homocysteine abolished homocysteine-induced monocyte adhesion, ICAM-1 expression and the nuclear translocation of NF-kB. Incubation of THP-1 monocytes with Tiron abolished homocysteine-induced beta-2 integrin expression on these cells and adhesion to unstimulated endothelial cells. These findings suggest that superoxide anion radicals mediate homocysteine’s effects on endothelium-monocyte interactions. In addition to previous studies that indicated that a significant source of reactive oxygen species in homocysteine-treated endothelial cells might be endothelial nitric oxide synthase, experiments using inhibitors of nitric oxide synthase in THP-1 cells indicated that nitric oxide synthase-dependent generation of superoxide anion also occurs in homocysteine-incubated THP-1 cells. This mechanism may contribute to homocysteine-induced oxidant stress. The information generated from these studies may be helpful in designing intervention strategies aimed at inhibiting the generation of reactive oxygen species in the vasculature that is associated with signaling events of monocyte recruitment and infiltration involved in atherosclerosis

Individualised sensory intervention to improve quality of life in people with dementia and their companions (SENSE-Cog trial): study protocol for a randomised controlled trial

Background: Hearing and vision impairments are highly prevalent in people with dementia and may have a negative impact on quality of life and other dementia-related outcomes. Intervening to optimise sensory impairment and support sensory function may be a means of improving dementia-related outcomes. The SENSE-Cog trial will test whether a home-based multi-part sensory intervention is effective in improving quality of life and other key outcomes in people with dementia and hearing or vision problems (or both) and their companions. Methods: This is an European, multi-centre, observer-blind, pragmatic, randomised controlled trial. Three hundred fifty four people with dementia and hearing or vision impairment (or both) and their companions will be randomly assigned to receive either "care as usual" or a multi-component sensory intervention including assessment and correction of hearing or vision impairments (or both), home-based (maximum 10 visits over 18 weeks), therapist-delivered sensory support (that is, adherence to devices; improving the sensory environment (that is, lighting), communication training, and sign-posting to other support agencies). Change from baseline to intervention end (18 weeks) and post-intervention (36 weeks) will be compared between the two arms in the following outcomes: quality of life (primary endpoint), sensory and cognitive functional ability, relationships, mental well-being, health resource utilisation and cost-effectiveness. Discussion: This is one of two articles outlining the SENSE-Cog trial. Here, we describe the protocol for the effectiveness of the SENSE-Cog intervention. A parallel and complementary process evaluation will be described elsewhere. If the SENSE-Cog trial demonstrates that the sensory intervention improves outcomes in dementia, we will make a toolkit of training materials, resources and information available to health and social care providers to implement the intervention in routine practice. This will be a significant contribution to the therapeutic management of people with dementia and sensory impairment. Trial registration: ISRCTN (Trial ID: ISRCTN17056211) on 19 February 2018

Trials

Background Optimising hearing and vision function may be important in improving a range of outcomes for people living with dementia (PwD) and their companions. The SENSE-Cog cross-national randomised controlled trial (RCT) is evaluating the effectiveness of a sensory intervention (SI) to improve quality of life for PwD with concurrent hearing and/or vision impairment, in five European countries. To ascertain how or why the intervention will, or will not, achieve its outcomes, we have designed a process evaluation to explore potential discrepancies between expected and observed outcomes. This will also help us to understand how context may influence the outcomes. Here we describe the protocol for this process evaluation, which is embedded within the RCT. Methods/design We will use a mixed methods approach with a theoretical framework derived from the UK Medical Research Council’s’ guidance on process evaluations. It will include the following: (1) evaluating how key aspects of the intervention will be delivered, which will be important to scale the intervention in real world populations; (2) characterising the contextual issues, which may shape the delivery and the impact of the intervention in different countries; and (3) investigating possible causal mechanisms through analyses of potential moderators and mediators. To avoid bias, we will analyse the process data before the analysis of the main effectiveness outcomes. Discussion This evaluation will provide insight into how the complex SENSE-Cog SI will be tailored, enacted and received across the different European contexts, all of which have unique health and social care economies. The findings will provide insight into the causal mechanisms effecting change, and will determine whether we should implement the intervention, if effective, on a wider scale for PwD and concurrent sensory impairment

Repair after myocardial infarction, between fantasy and reality: the role of chemokines

Despite considerable progress over the last decades, acute myocardial infarction continues to remain the major cause of morbidity and mortality worldwide. The present therapies include only cause-dependent interventions, which are not able to reduce myocardial necrosis and optimize cardiac repair following infarction. This review highlights the cellular and molecular processes after myocardial injury and focuses on chemokines, the main modulators of the inflammatory and reparatory events, as the most valuable drug targets

SENATOR: a novel software approach to prescribing optimisation in older people with multimorbidity

Background: The challenges of prescribing optimisation in the growing population of multi-morbid older people with complex polypharmacy are considerable. Since most people who prescribe medication for multi-morbid older patients do not have specific training or expertise in medication optimisation or complex polypharmacy, there is a need for a novel, systematic and reliable solution to address this challenge. Methods: In 2012, the SENATOR consortium (www.senator-project.eu) was funded under the EU’s FP7 programme to design and test by clinical trial a software engine specifically designed for drug/nondrug treatment optimisation in older people with multi-morbidity and associated complex polypharmacy. In partnership with a healthcare software SME , the SENATOR consortium has developed a software engine for this purpose. The consortium has also embarked on a randomised clinical trial (RCT) comparing the effects of SENATOR softwareguided prescribing optimisation in older multi-morbid patients hospitalised with acute illness with standard pharmaceutical care in 6 European centres, randomised into two groups of approximately 900 patients each. Outcome measures: The primary outcome measure is the proportion of patients experiencing one or more non-trivial ADR’s during their index hospitalisation. Other outcome measures include medication appropriateness, all-cause in-patient mortality, cost of composite healthcare utilization and quality of life at 12 weeks follow-up. The SENATOR RCT will be completed in 2017. Conclusions: The SENATOR software tool is designed to curtail polypharmacy, inappropriate prescribing and prevent non-trivial adverse drug reactions/events. The SENATOR RCT will determine its efficacy in acutely ill older multi-morbid patients cared for by clinicians other than geriatricians

Feral pigs facilitate hyperpredation by golden eagles and indirectly cause the decline of the island fox

Introduced species can compete with, prey upon or transmit disease to native forms, resulting in dev- astation of indigenous communities. A more subtle but equally severe effect of exotic species is as a supplemental food source for predators that allows them to increase in abundance and then overexploit native prey species. Here we show that the introduction of feral pigs (Sus scrofa) to the California Channel Islands has sustained an unnaturally large breeding population of golden eagles (Aquila chrysaetos), a native predator. The resulting increase in predation on the island fox (Urocyon lit- toralis) has caused the near extirpation of three subspecies of this endemic carnivore. Foxes evolved on the islands over the past 20,000 years, pigs were introduced in the 1850s and golden eagles, his- torically, were only transient visitors. Although these three species have been sympatric for the past 150 years, this predator–prey interaction is a recent phenomenon, occurring within the last decade. We hypothesize that this interaction ultimately stems from human-induced perturbations to the island, mainland and surrounding marine environmentsPeer reviewe