Effects of oxidized low density lipoprotein, lipid mediators and statins on vascular cell interactions

The integrin heterodimer CD11b/CD18 (alpha M beta 2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive! and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet alpha llb beta 3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac,mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro,indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs

Contribution of particulate nitrate to airborne measurements of total reactive nitrogen

Simultaneous measurements of speciated, total reactive nitrogen (NOy) and particulate NO3 (particle diameter <1.3 μm) were made on board the NASA P-3B aircraft over the western Pacific in February-April 2001 during the Transport and Chemical Evolution over the Pacific (TRACE-P) experiment. Gas-phase and particulate NOy was measured using a gold tube catalytic converter. For the interpretation of particulate NOy, conversion efficiencies of particulate NH4NO3, KNO3, NaNO3, and Ca(NO3)2 were measured in the laboratory. Only NH4NO3 showed quantitative conversion, and its conversion efficiency was as high as that for HNO3. NOy measured on board the aircraft was found to be systematically higher by 10-30% than the sum of the individual NOy gas components (Σ(NOy)i) at 0-4 km. Particulate NO3- concentrations measured by a particle-into-liquid sampler (PILS) were nearly equal to NOy - Σ(NOy)i under low-dust-loading conditions. The PILS data showed that the majority of the particulate NO3- was in the form of NH4NO3 under these conditions, suggesting that NH4NO3 particles were quantitatively converted to detectable NO by the NOy converter, consistent with the laboratory experiments. The contribution of particulate NO3- to NOy was most important at 0-2 km, where NO3- constituted 10-30% of NOy during TRACE-P. On average, the amounts of particulate NO3- and gas-phase HNO3 were comparable in this region. Copyright 2005 by the American Geophysical Union

The UK register of HIV seroconverters: Methods and analytical issues

A Register of HIV-infected persons who have had a negative antibody test within 3 years of their first antibody positive test (seroconverters) is being set up in the UK to monitor the distribution of times from HIV seroconversion to AIDS (the incubation period) and to death. It will also provide a national resource for use by those designing studies in this group of individuals. Clinicians caring for HIV-positive persons in Genito-Urinary Medicine, Infectious Disease and other departments throughout the UK were asked to participate by providing information on eligible subjects. Most laboratories undertaking HIV antibody testing were also contacted and asked to provide the name of the attending clinician for all seroconverters identified through the HIV laboratory reporting systems of the PHLS Communicable Disease Surveillance Centre (CDSC) and the Scottish Centre for Infection and Environmental Health (SCIEH) and for any other seroconverters known to them but not identified by CDSC or SCIEH. Data items sought for the Register include: sex, ethnic group, probable route of HIV transmission, annual CD4 counts, details of therapy and prophylaxis prescribed, AIDS-defining events and vital status. Follow up information is collected annually. Wherever possible, all seroconverters known to a clinic have been identified, whether currently alive or dead, either from clinic records or laboratory reporting or both. The objective is to establish and update a complete register of seroconverters on a long-term basis to provide reliable estimates of the incubation period on which future projections of AIDS cases in the UK can be made

Impacts of biomass burning in Southeast Asia on ozone and reactive nitrogen over the western Pacific in spring

Aircraft measurements of ozone (O3) and its precursors (reactive nitrogen, CO, nonmethane hydrocarbons) were made over the western Pacific during the Transport and Chemical Evolution Over the Pacific (TRACE-P) campaign, which was conducted during February-April 2001. Biomass burning activity was high over Southeast Asia (SEA) during this period (dry season), and convective activity over SEA frequently transported air from the boundary layer to the free troposphere, followed by eastward transport to the sampling region over the western Pacific south of 30°N. This data set allows for systematic investigations of the chemical and physical processes in the outflow from SEA. Methyl chloride (CH3Cl) and CO are chosen as primary and secondary tracers, respectively, to gauge the degree of the impact of emissions of trace species from biomass burning. Biomass burning is found to be a major source of reactive nitrogen (NO x, PAN, HNO3, and nitrate) and O3 in this region from correlations of these species with the tracers. Changes in the abundance of reactive nitrogen during upward transport are quantified from the altitude change of the slopes of the correlations of these species with CO. NOx decreased with altitude due to its oxidation to HNO3. On the other hand, PAN was conserved during transport from the lower to the middle troposphere, consistent with its low water solubility and chemical stability at low temperatures. Large losses of HNO3 and nitrate, which are highly water soluble, occurred in the free troposphere, most likely due to wet removal by precipitation. This has been shown to be the major pathway of NOy loss in the middle troposphere. Increases in the mixing ratios of O3 and its precursors due to biomass burning in SEA are estimated using the tracers. Enhancements of CO and total reactive nitrogen (NOy), which are directly emitted from biomass burning, were largest at 2-4 km. At this altitude the increases in NOy and O3 were 810 parts per trillion by volume (pptv) and 26 parts per billion by volume (ppbv) above their background values of 240 pptv and 31 ppbv, respectively. The slope of the O3-CO correlation in biomass burning plumes was similar to those observed in fire plumes in northern Australia, Africa, and Canada. The O3 production efficiency (OPE) derived from the O3-CO slope and NOx/CO emission ratio (ER) is shown to be positively correlated with the C2H4 /NOx ER, indicating that the C2H4/NO x ER is a critical parameter in determining the OPE. Comparison of the net O3 flux across the western Pacific region and total O3 production due to biomass burning in SEA suggests that about 70% of O3 produced was transported to the western Pacific. Copyright 2004 by the American Geophysical Union

Quantum Memories. A Review based on the European Integrated Project "Qubit Applications (QAP)"

We perform a review of various approaches to the implementation of quantum memories, with an emphasis on activities within the quantum memory sub-project of the EU Integrated Project "Qubit Applications". We begin with a brief overview over different applications for quantum memories and different types of quantum memories. We discuss the most important criteria for assessing quantum memory performance and the most important physical requirements. Then we review the different approaches represented in "Qubit Applications" in some detail. They include solid-state atomic ensembles, NV centers, quantum dots, single atoms, atomic gases and optical phonons in diamond. We compare the different approaches using the discussed criteria.Comment: 22 pages, 12 figure

Visual parameter optimisation for biomedical image processing

Background: Biomedical image processing methods require users to optimise input parameters to ensure high quality output. This presents two challenges. First, it is difficult to optimise multiple input parameters for multiple input images. Second, it is difficult to achieve an understanding of underlying algorithms, in particular, relationships between input and output. Results: We present a visualisation method that transforms users’ ability to understand algorithm behaviour by integrating input and output, and by supporting exploration of their relationships. We discuss its application to a colour deconvolution technique for stained histology images and show how it enabled a domain expert to identify suitable parameter values for the deconvolution of two types of images, and metrics to quantify deconvolution performance. It also enabled a breakthrough in understanding by invalidating an underlying assumption about the algorithm. Conclusions: The visualisation method presented here provides analysis capability for multiple inputs and outputs in biomedical image processing that is not supported by previous analysis software. The analysis supported by our method is not feasible with conventional trial-and-error approaches

Proteomic analysis of early diabetic retinopathy reveals mediators of neurodegenerative brain diseases

© 2018 The Authors. PURPOSE. Current evidence suggests that retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy. Our main goal was to examine whether, in the diabetic human retina, common proteins and pathways are shared with brain neurodegenerative diseases. METHODS. A proteomic analysis was performed on three groups of postmortem retinas matched by age: nondiabetic control retinas (n = 5), diabetic retinas without glial activation (n = 5), and diabetic retinas with glial activation (n = 5). Retinal lysates from each group were pooled and run on an SDS-PAGE gel. Bands were analyzed sequentially by liquid chromatography-mass spectrometry (LC/MS) using an Orbitrap Mass Spectrometer. RESULTS. A total of 2190 proteins were identified across all groups. To evaluate the association of the identified proteins with neurological signaling, significant signaling pathways belonging to the category ‘‘Neurotransmitters and Other Nervous System Signaling” were selected for analysis. Pathway analysis revealed that ‘‘Neuroprotective Role of THOP1 in Alzheimer’s Disease” and ‘‘Unfolded Protein Response” pathways were uniquely enriched in control retinas. By contrast, ‘‘Dopamine Degradation” and ‘‘Parkinson’s Signaling” were enriched only in diabetic retinas with glial activation. The ‘‘Neuregulin Signaling,” “Synaptic Long Term Potentiation,” and “Amyloid Processing” pathways were enriched in diabetic retinas with no glial activation. CONCLUSIONS. Diabetes-induced retinal neurodegeneration and brain neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, share common pathogenic pathways. These findings suggest that the study of neurodegeneration in the diabetic retina could be useful to further understand the neurodegenerative processes that occur in the brain of persons with diabetes