Targeting oxidative stress after percutaneous coronary intervention

Percutaneous coronary intervention (PCI) improves the blood supply to the heart by unblocking narrowed coronary arteries. Implantation of a coronary stent is usually required to scaffold the artery and improve long-term vessel patency. Drug-eluting stents (DES) have been developed to decrease the incidence of stent renarrowing, known as in-stent restenosis (ISR), the main limitation of bare metal stents (BMS). DES release potent drugs into the artery wall to inhibit cell division and attenuate ISR. However, this strategy can also impair vascular healing and increase the risk of stent thrombosis, which is a serious concern. Novel approaches to this problem are urgently required. Oxidative stress reflects a state in which reactive oxygen species (ROS) prevail over antioxidant defences. PCI causes a major release of ROS from the injured artery wall and these molecules appear to play an important role in critical signalling pathways involved in vascular repair. Numerous animal studies have found that oral antioxidants may reduce ISR and improve healing, yet these strategies have not been effective in humans. Stent-based delivery of antioxidants may offer more efficacious, targeted protection against oxidative stress than oral administration. The role of oxidative stress in endothelial repair mediated by bone marrow-derived endothelial progenitor cells (EPCs) in patients with coronary heart disease is also poorly defined. The main aims of this thesis were: to determine the in vitro effects of oxidative stress on key aspects of thrombosis and vascular healing; to evaluate a novel antioxidant-eluting stent in an in vivo porcine model; and to examine the relationship between oxidised low-density lipoprotein (oxLDL), EPCs and coronary endothelial function in patients with stable angina. Oxidative stress, generated by the xanthine/xanthine oxidase reaction, inhibited whole blood aggregation in a concentration-dependent fashion. This was probably due to an excess of ROS which impaired, rather than stimulated, thrombosis. Healthy endothelial cells (ECs) also inhibited whole blood aggregation, but this was not mitigated by oxidative stress. EC migration was assessed using an in vitro endothelial wound scratch assay. Oxidative stress was highly toxic to ECs and inhibited migratory activity. Nitrone D, a novel spin trapping antioxidant, was evaluated for its suitability as a novel DES coating. Nitrone D displayed weak antithrombotic effects, but markedly inhibited EC migration. Nitrone D was therefore unsuitable for a DES that was intended to improve re-endothelialisation. Oral probucol has established efficacy in animal models of restenosis, but not in humans. Probucol has been successfully incorporated as a dual DES coating with rapamycin in clinical trials. Succinobucol is a novel derivative of probucol with more potent antioxidant, anti-inflammatory and antiproliferative effects. A novel polymer-free succinobucol-eluting stent (SES) and succinobucol/rapamycin-eluting stent (SRES) were developed and compared to a commercially available polymer-free rapamycin-eluting stent (RES) and BMS. Pharmacokinetic studies demonstrated optimal drug elution from the SES. However, in a porcine coronary model, the SES significantly increased neointimal thickness and aggravated ISR. The RES reduced neointimal thickness non-significantly, whereas the SRES caused no difference in neointimal thickness, compared with the BMS. The SES was associated with greater inflammation and persistent fibrin deposition around the stent struts, which are signs of defective healing. There were no significant differences in endothelial regeneration between the groups. Subsequent cell culture studies found that succinobucol was toxic to ECs and smooth muscle cells. In the clinical study, circulating levels of EPCs were strongly correlated with coronary endothelial function, which is a novel finding. Plasma oxLDL levels were not correlated with EPCs or coronary endothelial function. In conclusion, ROS reflect a large array of molecules released after PCI that are multi-faceted regulators of platelets and vascular cells. As such, they represent a complex target for novel DES technologies. Excessive ROS may inhibit thrombus formation and delay re-endothelialisation. However, potent antioxidants delivered to injured arterial tissue after PCI may not necessarily encourage the physiological processes required to accelerate vascular repair. At high dose, local delivery of antioxidants may actually promote inflammation and aggravate ISR. Although oxLDL is known to induce endothelial dysfunction, it is not correlated with the number of circulating EPCs. These findings underline the complicated role of oxidative stress in vascular repair after PCI. Further studies are required to clarify whether antioxidants will ever provide advantages over existing options in the rapidly evolving field of interventional cardiology

Radial versus femoral access for rotational atherectomy: A UK observational study of 8622 patients

Background—Rotational atherectomy (RA) is an important interventional tool for heavily calcified coronary lesions. We compared the early clinical outcomes in patients undergoing RA using radial or femoral access. Methods and Results—We identified all patients in England and Wales who underwent RA between January 1, 2005, and March 31, 2014. Eight thousand six hundred twenty-two RA cases (3069 radial and 5553 femoral) were included in the analysis. The study primary outcome was 30-day mortality. Propensity scores were calculated to determine the factors associated with treatment assignment to radial or femoral access. Multivariable logistic regression analysis, using the calculated propensity scores, was performed. Thirty-day mortality was 2.2% in the radial and 2.3% in the femoral group (P=0.76). Radial access was associated with equivalent 30-day mortality (adjusted odds ratio [OR], 1.06; 95% confidence interval [CI], 0.77–1.46; P=0.71), procedural success (OR, 1.04; 95% CI, 0.84–1.29; P=0.73), major adverse cardiac and cerebrovascular events (OR, 1.05; 95% CI, 0.80–1.38; P=0.72), and net adverse clinical events (OR, 0.90; 95% CI, 0.71–1.15; P=0.41), but lower rates of in-hospital major bleeding (OR, 0.62; 95% CI, 0.40–0.98; P=0.04) and major access site complications (OR, 0.05; 95% CI, 0.01–0.38; P=0.004), compared with femoral access. Conclusions—In this large real-world study of patients undergoing RA, radial access was associated with equivalent 30-day mortality and procedural success, but reduced major bleeding and access site complications, compared with femoral access

Personality Profiling: How informative are social media profiles in predicting personal information?

Personality profiling has been utilised by companies for targeted advertising, political campaigns and vaccine campaigns. However, the accuracy and versatility of such models still remains relatively unknown. Consequently, we aim to explore the extent to which peoples' online digital footprints can be used to profile their Myers-Briggs personality type. We analyse and compare the results of four models: logistic regression, naive Bayes, support vector machines (SVMs) and random forests. We discover that a SVM model achieves the best accuracy of 20.95% for predicting someones complete personality type. However, logistic regression models perform only marginally worse and are significantly faster to train and perform predictions. We discover that many labelled datasets present substantial class imbalances of personal characteristics on social media, including our own. As a result, we highlight the need for attentive consideration when reporting model performance on these datasets and compare a number of methods for fixing the class-imbalance problems. Moreover, we develop a statistical framework for assessing the importance of different sets of features in our models. We discover some features to be more informative than others in the Intuitive/Sensory (p = 0.032) and Thinking/Feeling (p = 0.019) models. While we apply these methods to Myers-Briggs personality profiling, they could be more generally used for any labelling of individuals on social media.Comment: 8 pages, 6 figures. Dataset available at https://figshare.com/articles/dataset/Self-Reported_Myers-Briggs_Personality_Types_on_Twitter/2362055

Mapping and explaining the productivity of Pinus radiata in New Zealand

Mapping Pinus radiata productivity for New Zealand not only provides useful information for forest owners, industry stakeholders and policy managers, but also enables current and future plantations to be visualised, quantified, and planned. Using an extensive set of permanent sample plots, split into fitting (n = 1,146) and validation (n = 618) datasets, models of P. radiata 300 Index (an index of volume mean annual increment) and Site Index (an index of height growth) were developed using a regression kriging technique. Spatial predictions were accurate and accounted for 61% and 70% of the variance for 300 Index and Site Index, respectively. Productivity predicted from these surfaces for the entire plantation estate averaged 27.4 m³ ha⁻¹ yr⁻¹ for the 300 Index and 30.4 m for Site Index. Surfaces showed wide regional variation in this productivity, which was attributable mainly to variation in air temperature and root-zone water storage from site to site

DIMINUTIVE SUFFIXES IN THE GREEK NEW TESTAMENT: A CROSS-LINGUISTIC STUDY

Abstract: Diminuted word forms in the Greek New Testament have much in common with their counterparts in other languages, and typically convey smallness, slightness, affection, or derogation. In some cases their meanings are "faded" or "bleached" and do not convey anything different from the base form of the word, as happens also in other languages. Diminutive usage can express solidarity and common values in certain speech communities, and may be doing so in some New Testament passages. (Article

The relationship between oxidised LDL, endothelial progenitor cells and coronary endothelial function in patients with CHD

Objective The balance between coronary endothelial dysfunction and repair is influenced by many protective and deleterious factors circulating in the blood. We studied the relationship between oxidised low-density lipoprotein (oxLDL), circulating endothelial progenitor cells (EPCs) and coronary endothelial function in patients with stable coronary heart disease (CHD). Methods 33 patients with stable CHD were studied. Plasma oxLDL was measured using ELISA, coronary endothelial function was assessed using intracoronary acetylcholine infusion and EPCs were quantified using flow cytometry for CD34+/KDR+ cells. Results Plasma oxLDL correlated positively with the number of EPCs in the blood (r=0.46, p=0.02). There was a positive correlation between the number of circulating EPCs and coronary endothelial function (r=0.42, p=0.04). There was no significant correlation between oxLDL and coronary endothelial function. Conclusions Plasma levels of oxLDL are associated with increased circulating EPCs in the blood of patients with CHD, which may reflect a host-repair response to endothelial injury. Patients with stable CHD had a high prevalence of coronary endothelial dysfunction, which was associated with lower numbers of circulating EPCs, suggesting a mechanistic link between endothelial dysfunction and the pathogenesis of atherosclerosis

Statistics of Solar Wind Electron Breakpoint Energies Using Machine Learning Techniques

Solar wind electron velocity distributions at 1 au consist of a thermal "core" population and two suprathermal populations: "halo" and "strahl". The core and halo are quasi-isotropic, whereas the strahl typically travels radially outwards along the parallel and/or anti-parallel direction with respect to the interplanetary magnetic field. With Cluster-PEACE data, we analyse energy and pitch angle distributions and use machine learning techniques to provide robust classifications of these solar wind populations. Initially, we use unsupervised algorithms to classify halo and strahl differential energy flux distributions to allow us to calculate relative number densities, which are of the same order as previous results. Subsequently, we apply unsupervised algorithms to phase space density distributions over ten years to study the variation of halo and strahl breakpoint energies with solar wind parameters. In our statistical study, we find both halo and strahl suprathermal breakpoint energies display a significant increase with core temperature, with the halo exhibiting a more positive correlation than the strahl. We conclude low energy strahl electrons are scattering into the core at perpendicular pitch angles. This increases the number of Coulomb collisions and extends the perpendicular core population to higher energies, resulting in a larger difference between halo and strahl breakpoint energies at higher core temperatures. Statistically, the locations of both suprathermal breakpoint energies decrease with increasing solar wind speed. In the case of halo breakpoint energy, we observe two distinct profiles above and below 500 km/s. We relate this to the difference in origin of fast and slow solar wind.Comment: Published in Astronomy & Astrophysics, 11 pages, 10 figure

Non-Traditional Vectors for Paralytic Shellfish Poisoning

Paralytic shellfish poisoning (PSP), due to saxitoxin and related compounds, typically results from the consumption of filter-feeding molluscan shellfish that concentrate toxins from marine dinoflagellates. In addition to these microalgal sources, saxitoxin and related compounds, referred to in this review as STXs, are also produced in freshwater cyanobacteria and have been associated with calcareous red macroalgae. STXs are transferred and bioaccumulate throughout aquatic food webs, and can be vectored to terrestrial biota, including humans. Fisheries closures and human intoxications due to STXs have been documented in several non-traditional (i.e. non-filter-feeding) vectors. These include, but are not limited to, marine gastropods, both carnivorous and grazing, crustacea, and fish that acquire STXs through toxin transfer. Often due to spatial, temporal, or a species disconnection from the primary source of STXs (bloom forming dinoflagellates), monitoring and management of such non-traditional PSP vectors has been challenging. A brief literature review is provided for filter feeding (traditional) and non-filter feeding (non-traditional) vectors of STXs with specific reference to human effects. We include several case studies pertaining to management actions to prevent PSP, as well as food poisoning incidents from STX(s) accumulation in non-traditional PSP vectors

Accurately characterising the importance of wave-particle interactions in radiation belt dynamics: the pitfalls of statistical wave representations

Wave-particle interactions play a crucial role in energetic particle dynamics in the Earth's radiation belts. However the relative importance of different wave-modes in these dynamics is poorly understood. Typically this is assessed during geomagnetic storms using statistically averaged empirical wave models as a function of geomagnetic activity in advanced radiation belt simulations. However statistical averages poorly characterise extreme events such as geomagnetic storms in that storm-time ULF wave power is typically larger than that derived over a solar cycle and Kp is a poor proxy for storm-time wave power