Nitric Oxide and Infection: Another View

Nitric oxide (NO) has been nicknamed "murderer” and "mediator” because it has toxic and signaling properties. We review these two aspects of NO synthesis from the perspective of the clinical infectious disease specialist by considering the potential of NO as an endothelium-derived relaxing factor (EDRF) in inflammation and sepsis and its potential as an antimicrobial system. We deviate from observations in recent authoritative reviews and point to important speciesdifferences that make it unlikely that NO serves as an EDRF mediating inflammatory vasodilatation in humans or that NO synthesized by human phagocytes has an antimicrobial function.We propose that in humans, NOsynthesis is moreconfined and compartmentalized than in certain other animal species, and therefore, unwelcome toxicity, vasodilatation, or disturbance of paracrine signaling mechanisms (i.e., modulation of phagocytic cell functions) are avoided during inflammatio

Nitrite Generation in Interleukin-4—Treated Human Macrophage Cultures Does Not Involve the Nitric Oxide Synthase Pathway

The search continues for high-output nitric oxide biosynthesis in human macrophages analogous to murine phagocytes. Recently, generation of nitrite in culture supernatants of human macrophages exposed to interferon-γ and interleukin-4 (IFN-γ/IL-4) was reported. The present study reproduces these findings and shows that L-arginine is not consumed and L-citrulline is not produced during this process. Furthermore, the biosynthesis of the obligatory cofactor tetrahydrobiopterin is not coinduced. These biochemical data provide support against a nitric oxide synthase contribution to nitrite accumulation. Nitrite was generated from nitrate salts even in cell-free media. Nitric oxide synthase activity but not nitrate reduction depended on molecular oxygen. Nitrite accumulation in experiments with IFN-γ/IL-4 in human monocytes appears to be an in vitro artifact produced by nitrate-reducing activities contained in cytokine preparation

Экономический анализ способов транспортировки нефтегазовых ресурсов при освоении Арктического шельфа

Объектом исследования является транспортная составляющая в проектах освоения углеводородных ресурсов арктического шельфа. Цель работы – разработка методического инструментария для экономической оценки и выбора способа транспортировки углеводородов при освоении нефтегазовых ресурсов арктического шельфа России. В процессе исследования проведен анализ научной литературы по соответствующей тематике. Основой для анализа послужили публикации отечественных и зарубежных авторов, посвященные вопросам транспортировки углеводородов с арктического шельфа России, в том числе выбору экономически целесообразных способов транспортировки добытых углеводородов на мировые рынки сбыта. В результате исследования была выбрана и обоснована наилучшая организационная схема транспортировки углеводородов с участков российского арктического шельфа. Область применения: информационно-аналитическое руководство при подготовке рекомендаций по выбору схемы транспортировки углеводородов с арктического шельфа; справочный материал по вопросам освоения углеводородных ресурсов российского шельфа и способах их транспортировки на мировые энергетические рынки. Экономическая эффективность/значимость работы заключается в разработке предложений и материалов по формированию научно-методического аппарата выбора экономически целесообразных способов транспортировки углеводородных ресурсов с арктического шельфа.The object of study is the transport component in the projects of development of hydrocarbon resources of the Arctic shelf. The aim of this work is to develop methodological tools for the economic evaluation and choice of mode of transport of hydrocarbons in oil and gas resources development of the Russian Arctic shelf. During the study, the analysis of the scientific literature on the relevant topics. The basis for the analysis was the publication of domestic and foreign authors, devoted to the transportation of hydrocarbons from the Arctic shelf of Russia, including the selection of economically viable ways of transporting produced hydrocarbons to the world markets. The study has been selected and justified the best organizational scheme of transportation of hydrocarbons from areas of the Russian Arctic shelf. Scope: information and analytical leadership in the preparation of recommendations on the selection of scheme for transportation of hydrocarbons from the Arctic shelf; reference material for the development of hydrocarbon resources on the Russian shelf and their transportation to the world energy markets. Economic efficiency and significance of the work lies in the development of proposals and materials for the formation of the scientifically-methodical device of the selection of economically viable ways of transporting hydrocarbon resources from the Arctic shelf

Implementation of standard testbeds for numerical relativity

We discuss results that have been obtained from the implementation of the initial round of testbeds for numerical relativity which was proposed in the first paper of the Apples with Apples Alliance. We present benchmark results for various codes which provide templates for analyzing the testbeds and to draw conclusions about various features of the codes. This allows us to sharpen the initial test specifications, design a new test and add theoretical insight.Comment: Corrected versio

Triptans and troponin: a case report

This case report describes for the first time acute coronary syndrome in a 67-year old patient after oral intake of naratriptan for migraine. So far in the literature, only sumatriptan, zolmitriptan and frovatriptan have been described to cause acute coronary syndromes

Carnitine reduces the lipoperoxidative damage of the membrane and apoptosis after induction of cell stress in experimental glaucoma

The pathological damage caused by glaucoma is associated to a high intraocular pressure. The ocular hypertone is most likely due to a defective efflux of aqueous humor from the anterior chamber of the eye. Ocular hypertension causes apoptotic death of retinal ganglion cells and overexpression of molecular markers typical of cell stress response and apoptosis. In this work, we report on the neuroprotective, antiapoptotic and antioxidant action of a natural substance, -carnitine. This compound is known for its ability to improve the mitochondrial performance. We analyze a number of cellular and molecular markers, typical of ocular hypertension and, in general, of the cell stress response. In particular, -carnitine reduces the expression of glial fibrillary acidic protein, inducible nitric oxide synthase, ubiquitin and caspase 3 typical markers of cell stress. In addition, the morphological analysis of the optic nerve evidenced a reduction of the pathological excavation of the optic disk. This experimental hypertone protocol induces a severe lipoperoxidation, which is significantly reduced by -carnitine. The overall interpretation is that mortality of the retinal cells is due to membrane damage

IL-17A Synergizes with IFN-γ to Upregulate iNOS and NO Production and Inhibit Chlamydial Growth

IFN-γ-mediated inducible nitric oxide synthase (iNOS) expression is critical for controlling chlamydial infection through microbicidal nitric oxide (NO) production. Interleukin-17A (IL-17A), as a new proinflammatory cytokine, has been shown to play a protective role in host defense against Chlamydia muridarum (Cm) infection. To define the related mechanism, we investigated, in the present study, the effect of IL-17A on IFN-γ induced iNOS expression and NO production during Cm infection in vitro and in vivo. Our data showed that IL-17A significantly enhanced IFN-γ-induced iNOS expression and NO production and inhibited Cm growth in Cm-infected murine lung epithelial (TC-1) cells. The synergistic effect of IL-17A and IFN-γ on Chlamydia clearance from TC-1 cells correlated with iNOS induction. Since one of the main antimicrobial mechanisms of activated macrophages is the release of NO, we also examined the inhibitory effect of IL-17A and IFN-γ on Cm growth in peritoneal macrophages. IL-17A (10 ng/ml) synergizes with IFN-γ (200 U/ml) in macrophages to inhibit Cm growth. This effect was largely reversed by aminoguanidine (AG), an iNOS inhibitor. Finally, neutralization of IL-17A in Cm infected mice resulted in reduced iNOS expression in the lung and higher Cm growth. Taken together, the results indicate that IL-17A and IFN-γ play a synergistic role in inhibiting chlamydial lung infection, at least partially through enhancing iNOS expression and NO production in epithelial cells and macrophages

Neurons are MHC Class I-Dependent Targets for CD8 T Cells upon Neurotropic Viral Infection

Following infection of the central nervous system (CNS), the immune system is faced with the challenge of eliminating the pathogen without causing significant damage to neurons, which have limited capacities of renewal. In particular, it was thought that neurons were protected from direct attack by cytotoxic T lymphocytes (CTL) because they do not express major histocompatibility class I (MHC I) molecules, at least at steady state. To date, most of our current knowledge on the specifics of neuron-CTL interaction is based on studies artificially inducing MHC I expression on neurons, loading them with exogenous peptide and applying CTL clones or lines often differentiated in culture. Thus, much remains to be uncovered regarding the modalities of the interaction between infected neurons and antiviral CD8 T cells in the course of a natural disease. Here, we used the model of neuroinflammation caused by neurotropic Borna disease virus (BDV), in which virus-specific CTL have been demonstrated as the main immune effectors triggering disease. We tested the pathogenic properties of brain-isolated CD8 T cells against pure neuronal cultures infected with BDV. We observed that BDV infection of cortical neurons triggered a significant up regulation of MHC I molecules, rendering them susceptible to recognition by antiviral CTL, freshly isolated from the brains of acutely infected rats. Using real-time imaging, we analyzed the spatio-temporal relationships between neurons and CTL. Brain-isolated CTL exhibited a reduced mobility and established stable contacts with BDV-infected neurons, in an antigen- and MHC-dependent manner. This interaction induced rapid morphological changes of the neurons, without immediate killing or impairment of electrical activity. Early signs of neuronal apoptosis were detected only hours after this initial contact. Thus, our results show that infected neurons can be recognized efficiently by brain-isolated antiviral CD8 T cells and uncover the unusual modalities of CTL-induced neuronal damage

Nitric Oxide and Infection: Another View

Nitric oxide (NO) has been nicknamed "murderer” and "mediator” because it has toxic and signaling properties. We review these two aspects of NO synthesis from the perspective of the clinical infectious disease specialist by considering the potential of NO as an endothelium-derived relaxing factor (EDRF) in inflammation and sepsis and its potential as an antimicrobial system. We deviate from observations in recent authoritative reviews and point to important speciesdifferences that make it unlikely that NO serves as an EDRF mediating inflammatory vasodilatation in humans or that NO synthesized by human phagocytes has an antimicrobial function.We propose that in humans, NOsynthesis is moreconfined and compartmentalized than in certain other animal species, and therefore, unwelcome toxicity, vasodilatation, or disturbance of paracrine signaling mechanisms (i.e., modulation of phagocytic cell functions) are avoided during inflammatio