Citrulline a More Suitable Substrate than Arginine to Restore NO Production and the Microcirculation during Endotoxemia

BACKGROUND: Impaired microcirculation during endotoxemia correlates with a disturbed arginine-nitric oxide (NO) metabolism and is associated with deteriorating organ function. Improving the organ perfusion in endotoxemia, as often seen in patients with severe infection or systemic inflammatory response syndrome (SIRS) is, therefore, an important therapeutic target. We hypothesized that supplementation of the arginine precursor citrulline rather than arginine would specifically increase eNOS-induced intracellular NO production and thereby improve the microcirculation during endotoxemia. METHODOLOGY/PRINCIPAL FINDINGS: To study the effects of L-Citrulline and L-Arginine supplementation on jejunal microcirculation, intracellular arginine availability and NO production in a non-lethal prolonged endotoxemia model in mice. C57/Bl6 mice received an 18 hrs intravenous infusion of endotoxin (LPS, 0.4 µg • g bodyweight(-1) • h(-1)), combined with either L-Citrulline (6.25 mg • h-1), L-Arginine (6.25 mg • h(-1)), or L-Alanine (isonitrogenous control; 12.5 mg • h(-1)) during the last 6 hrs. The control group received an 18 hrs sterile saline infusion combined with L-Alanine or L-Citrulline during the last 6 hrs. The microcirculation was evaluated at the end of the infusion period using sidestream dark-field imaging of jejunal villi. Plasma and jejunal tissue amino-acid concentrations were measured by HPLC, NO tissue concentrations by electron-spin resonance spectroscopy and NOS protein concentrations using Western blot. CONCLUSION/SIGNIFICANCE: L-Citrulline supplementation during endotoxemia positively influenced the intestinal microvascular perfusion compared to L-Arginine-supplemented and control endotoxemic mice. L-Citrulline supplementation increased plasma and tissue concentrations of arginine and citrulline, and restored intracellular NO production in the intestine. L-Arginine supplementation did not increase the intracellular arginine availability. Jejunal tissues in the L-Citrulline-supplemented group showed, compared to the endotoxemic and L-Arginine-supplemented endotoxemic group, an increase in degree of phosphorylation of eNOS (Ser 1177) and a decrease in iNOS protein level. In conclusion, L-Citrulline supplementation during endotoxemia and not L-Arginine reduced intestinal microcirculatory dysfunction and increased intracellular NO production, likely via increased intracellular citrulline and arginine availability

Black hole spin: theory and observation

In the standard paradigm, astrophysical black holes can be described solely by their mass and angular momentum - commonly referred to as `spin' - resulting from the process of their birth and subsequent growth via accretion. Whilst the mass has a standard Newtonian interpretation, the spin does not, with the effect of non-zero spin leaving an indelible imprint on the space-time closest to the black hole. As a consequence of relativistic frame-dragging, particle orbits are affected both in terms of stability and precession, which impacts on the emission characteristics of accreting black holes both stellar mass in black hole binaries (BHBs) and supermassive in active galactic nuclei (AGN). Over the last 30 years, techniques have been developed that take into account these changes to estimate the spin which can then be used to understand the birth and growth of black holes and potentially the powering of powerful jets. In this chapter we provide a broad overview of both the theoretical effects of spin, the means by which it can be estimated and the results of ongoing campaigns.Comment: 55 pages, 5 figures. Published in: "Astrophysics of Black Holes - From fundamental aspects to latest developments", Ed. Cosimo Bambi, Springer: Astrophysics and Space Science Library. Additional corrections mad

Binary systems and their nuclear explosions

Peer ReviewedPreprin

Relativistic Binaries in Globular Clusters

Galactic globular clusters are old, dense star systems typically containing 10\super{4}--10\super{7} stars. As an old population of stars, globular clusters contain many collapsed and degenerate objects. As a dense population of stars, globular clusters are the scene of many interesting close dynamical interactions between stars. These dynamical interactions can alter the evolution of individual stars and can produce tight binary systems containing one or two compact objects. In this review, we discuss theoretical models of globular cluster evolution and binary evolution, techniques for simulating this evolution that leads to relativistic binaries, and current and possible future observational evidence for this population. Our discussion of globular cluster evolution will focus on the processes that boost the production of hard binary systems and the subsequent interaction of these binaries that can alter the properties of both bodies and can lead to exotic objects. Direct {\it N}-body integrations and Fokker--Planck simulations of the evolution of globular clusters that incorporate tidal interactions and lead to predictions of relativistic binary populations are also discussed. We discuss the current observational evidence for cataclysmic variables, millisecond pulsars, and low-mass X-ray binaries as well as possible future detection of relativistic binaries with gravitational radiation.Comment: 88 pages, 13 figures. Submitted update of Living Reviews articl

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

LOFAR 144-MHz follow-up observations of GW170817

ABSTRACT We present low-radio-frequency follow-up observations of AT 2017gfo, the electromagnetic counterpart of GW170817, which was the first binary neutron star merger to be detected by Advanced LIGO–Virgo. These data, with a central frequency of 144 MHz, were obtained with LOFAR, the Low-Frequency Array. The maximum elevation of the target is just 13${_{.}^{\circ}}$7 when observed with LOFAR, making our observations particularly challenging to calibrate and significantly limiting the achievable sensitivity. On time-scales of 130–138 and 371–374 d after the merger event, we obtain 3σ upper limits for the afterglow component of 6.6 and 19.5 mJy beam−1, respectively. Using our best upper limit and previously published, contemporaneous higher frequency radio data, we place a limit on any potential steepening of the radio spectrum between 610 and 144 MHz: the two-point spectral index $\alpha ^{610}_{144} \gtrsim$ −2.5. We also show that LOFAR can detect the afterglows of future binary neutron star merger events occurring at more favourable elevations.</jats:p

Gedrag van Bacillus cereus in het maag-darmkanaal

Dit rapport presenteert een wiskundig dynamisch model waarmee het gedrag van Bacillus cereus in het maag-darmkanaal beschreven wordt. Microbiologische processen en processen in het maag/darmkanaal vormen samen de basis voor dit mechanistische model. Variabiliteit in groeikarakteristieken en fysieke eigenschappen van B. cereus-stammen komen tot uitdrukking in de parameterwaarden verkregen uit experimenten. Met het model zijn verschillende hypothesen getest betreffende initiele inname van B. cereus microben en daaropvolgende "in vivo" processen welke tot een potentiele infectie kunnen leiden. Modeluitkomsten laten het lot van vegetatieve cellen en/of sporen in de maag en dunne darm tijdens de vertering van een maaltijd met B. cereus-microben zien. Hieruit blijkt dat de maag weinig invloed heeft op het uiteindelijke aantal vegetatieve cellen in de dunne darm. Een "milde" blootstelling [10ˆ3 kolonievormende eenheden (kve) gˆ-1] geeft nog steeds een verhoogde kans op een toxico-infectie wanneer 100 g voedsel wordt geconsumeerd met daarin, tenminste, licht mesofiele B. cereus stammen. Blootstellingsnivo's juist boven de Nederlandse gestelde norm van < 10ˆ5 kve gˆ-1 vormen volgens dit model altijd een potentieel gevaar. Verder geeft dit model inzicht in de onzekerheid van bepaalde parameterwaarden welke nader experimenteel onderzocht zouden moeten worden om tot een betere risicobeoordeling te kunnen komen. Integratie van experimentele data in een dynamisch model met daarin de belangrijkste componenten voor voedselinfectie zal uiteindelijk leiden tot verbeterde suggesties voor voedselmicrobiologische criteria.This report presents a mathematical dynamical model for the behaviour of Bacillus cereus in the gastro-intestinal tract. Biological processes and system dynamics are simultaneously incorporated in this mechanistic model. Variability in growth characteristics and physical traits of different B. cereus strains are expressed through the incorporation of a range of reasonable parameter values obtained from experiments. Different hypotheses concerning initial ingestion of B. cereus microbes and subsequent in vivo processes leading to a potential infection are tested. Model outputs show the course of (attached) vegetative cells and/or spores in the stomach and small intestine during the digestion of food containing B. cereus microbes. Results show the minor influence of the stomach on the ultimate number of vegetative cells in the small intestine. A "mild" exposure (10ˆ3 cfu gˆ-1) still causes an increased probability on food intoxication when 100 g of food containing, at least, slightly mesophilic B. cereus strains is consumed. Exposure to levels just above the Dutch standard (set at < 10ˆ5 cfu gˆ-1) will, according to this model, always form a food hazard problem. Furthermore, this model gives insight in the uncertainty of some parameter values that need elaborated experimental investigation to come to an improved hazard characterisation and, with that, to improved suggestions for food microbiological criteria.VW

Gedrag van Bacillus cereus in het maag-darmkanaal

This report presents a mathematical dynamical model for the behaviour of Bacillus cereus in the gastro-intestinal tract. Biological processes and system dynamics are simultaneously incorporated in this mechanistic model. Variability in growth characteristics and physical traits of different B. cereus strains are expressed through the incorporation of a range of reasonable parameter values obtained from experiments. Different hypotheses concerning initial ingestion of B. cereus microbes and subsequent in vivo processes leading to a potential infection are tested. Model outputs show the course of (attached) vegetative cells and/or spores in the stomach and small intestine during the digestion of food containing B. cereus microbes. Results show the minor influence of the stomach on the ultimate number of vegetative cells in the small intestine. A "mild" exposure (10^3 cfu g^-1) still causes an increased probability on food intoxication when 100 g of food containing, at least, slightly mesophilic B. cereus strains is consumed. Exposure to levels just above the Dutch standard (set at < 10^5 cfu g^-1) will, according to this model, always form a food hazard problem. Furthermore, this model gives insight in the uncertainty of some parameter values that need elaborated experimental investigation to come to an improved hazard characterisation and, with that, to improved suggestions for food microbiological criteria.Dit rapport presenteert een wiskundig dynamisch model waarmee het gedrag van Bacillus cereus in het maag-darmkanaal beschreven wordt. Microbiologische processen en processen in het maag/darmkanaal vormen samen de basis voor dit mechanistische model. Variabiliteit in groeikarakteristieken en fysieke eigenschappen van B. cereus-stammen komen tot uitdrukking in de parameterwaarden verkregen uit experimenten. Met het model zijn verschillende hypothesen getest betreffende initiele inname van B. cereus microben en daaropvolgende "in vivo" processen welke tot een potentiele infectie kunnen leiden. Modeluitkomsten laten het lot van vegetatieve cellen en/of sporen in de maag en dunne darm tijdens de vertering van een maaltijd met B. cereus-microben zien. Hieruit blijkt dat de maag weinig invloed heeft op het uiteindelijke aantal vegetatieve cellen in de dunne darm. Een "milde" blootstelling [10^3 kolonievormende eenheden (kve) g^-1] geeft nog steeds een verhoogde kans op een toxico-infectie wanneer 100 g voedsel wordt geconsumeerd met daarin, tenminste, licht mesofiele B. cereus stammen. Blootstellingsnivo's juist boven de Nederlandse gestelde norm van < 10^5 kve g^-1 vormen volgens dit model altijd een potentieel gevaar. Verder geeft dit model inzicht in de onzekerheid van bepaalde parameterwaarden welke nader experimenteel onderzocht zouden moeten worden om tot een betere risicobeoordeling te kunnen komen. Integratie van experimentele data in een dynamisch model met daarin de belangrijkste componenten voor voedselinfectie zal uiteindelijk leiden tot verbeterde suggesties voor voedselmicrobiologische criteria