Monocyte dimethylarginine dimethylaminohydrolase 2 is regulated by pathological stress and plays a critical role in the immune response to sepsis

Background: Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase (NOS) and regulates the synthesis of nitric oxide (NO) in vivo. ADMA is metabolised by the enzymes dimethylarginine dimethylaminohydrolase 1 and 2 (DDAH 1 and 2), which have differing tissue distributions, with DDAH2 the only isoform found in immune cells. These studies tested the hypothesis that DDAH2 plays an important role in regulating the immune response to infection by modulating ADMA concentrations. Methods: In order to test this hypothesis, a series of experiments explored the regulation of murine and human monocyte DDAH2 in response to pathophysiological stressors. The impact of global and macrophage-specific DDAH2 knockout on the haemodynamic and immune response to sepsis and the resulting association with mortality was determined using transgenic animal models. Finally, the role of DDAH2 in human septic shock was determined by analysing plasma and DNA from patients enrolled in a randomised controlled trial of vasopressor therapy. Results: In isolated monocytes, DDAH2 was found to be regulated by both Interferon-γ and hypoxia, leading to reduced intracellular ADMA concentrations and exaggerated NO synthesis by immune cells. Both global and macrophage-specific knockout of DDAH2 led to significant impairment of immune cell function and increased mortality following caecal ligation and puncture in animal models. Increased plasma ADMA and SDMA levels were shown to be associated with risk of death in 215 patients with septic shock. However, when data were corrected for methylarginine clearance, ADMA was also found to play a protective role. In this population, the DDAH2 single nucleotide polymorphism rs805305 was associated with improved survival and increased ADMA:SDMA ratio. Conclusions: Considered as a whole, these data demonstrate that DDAH2 plays an important role in regulating the immune response to sepsis and the risk of death in human septic shock.Open Acces

Magnetic Field Induced Charge Instabilities in Weakly Coupled Superlattices

Using a time dependent selfconsistent model for vertical sequential tunneling,we study the appearance of charge instabilities that lead to the formation of electric field domains in a weakly coupled doped superlattice in the presence of high magnetic fields parallel to the transport direction. The interplay between the high non linearity of the system --coming from the Coulomb interaction-- and the inter-Landau-level scattering at the domain walls (regions of charge accumulation inside the superlattice) gives rise to new unstable negative differential conductance regions and extra stable branches in the sawtooth-like I-V curves.Comment: 5 pages, 4 postscript figure

Bench to bedside review: therapeutic modulation of nitric oxide in sepsis-an update.

Nitric oxide is a signalling molecule with an extensive range of functions in both health and disease. Discovered in the 1980s through work that earned the Nobel prize, nitric oxide is an essential factor in regulating cardiovascular, immune, neurological and haematological function in normal homeostasis and in response to infection. Early work implicated exaggerated nitric oxide synthesis as a potentially important driver of septic shock; however, attempts to modulate production through global inhibition of nitric oxide synthase were associated with increased mortality. Subsequent work has shown that regulation of nitric oxide production is determined by numerous factors including substrate and co-factor availability and expression of endogenous regulators. In sepsis, nitric oxide synthesis is dysregulated with exaggerated production leading to cardiovascular dysfunction, bioenergetic failure and cellular toxicity whilst at the same time impaired microvascular function may be driven in part by reduced nitric oxide synthesis by the endothelium. This bench to bedside review summarises our current understanding of the ways in which nitric oxide production is regulated on a tissue and cellular level before discussing progress in translating these observations into novel therapeutic strategies for patients with sepsis

2-Hydroxyglutarate Metabolism Is Altered in an in vivo Model of LPS Induced Endotoxemia.

The metabolic response to endotoxemia closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following lipopolysaccharide (LPS) administration in vivo, and in human septic patients. We further show that enhanced activation of the enzymes responsible for 2-HG degradation, D- and L-2-HGDH, underlie this effect. To determine the role of supplementation with 2HG, we carried out co-administration of LPS and 2HG. This co-administration in mice modulates a number of aspects of physiological responses to LPS, and in particular, protects against LPS-induced hypothermia. Our results identify a novel role for 2HG in endotoxemia pathophysiology, and suggest that this metabolite may be a critical diagnostic and therapeutic target for sepsis

Human Infection with G12 Rotaviruses, Germany

Rotavirus group A G12 genotypes were detected in 3 (1.5%) of 198 stool samples positive for human rotavirus. G12P[6] was present in 2 samples, and a mixed G3G12P[8] was found in 1 sample. Phylogenetic analysis of complete open reading frames of all 11 genomic RNA segments proved their Wa-like genogroup affiliation

Endothelial cell regulation of systemic haemodynamics and metabolism acts through the HIF transcription factors.

BackgroundThe vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory conditions. This study uses a series of transgenic murine models to explore for the first time the role of the hypoxia-inducible factors, HIF-1α and HIF-2α in the pulmonary and systemic circulations as potential regulators of systemic vascular function in normoxic or hypoxic conditions and in response to inflammatory stress. We developed a series of transgenic mouse models, the HIF-1α Tie2Cre, deficient in HIF1-α in the systemic and pulmonary vascular endothelium and the L1Cre, a pulmonary endothelium specific knockout of HIF-1α or HIF-2α. In vivo, arterial blood pressure and metabolic activity were monitored continuously in normal atmospheric conditions and following an acute stimulus with hypoxia (10%) or lipopolysaccharide (LPS). Ex vivo, femoral artery reactivity was assessed using wire myography.ResultsUnder normoxia, the HIF-1α Tie2Cre mouse had increased systolic and diastolic arterial pressure compared to litter mate controls over the day-night cycle under normal environmental conditions. VO2 and VCO2 were also increased. Femoral arteries displayed impaired endothelial relaxation in response to acetylcholine mediated by a reduction in the nitric oxide dependent portion of the response. HIF-1α L1Cre mice displayed a similar pattern of increased systemic blood pressure, metabolic rate and impaired vascular relaxation without features of pulmonary hypertension, polycythaemia or renal dysfunction under normal conditions. In response to acute hypoxia, deficiency of HIF-1α was associated with faster resolution of hypoxia-induced haemodynamic and metabolic compromise. In addition, systemic haemodynamics were less compromised by LPS treatment.ConclusionsThese data show that deficiency of HIF-1α in the systemic or pulmonary endothelium is associated with increased systemic blood pressure and metabolic rate, a pattern that persists in both normoxic conditions and in response to acute stress with potential implications for our understanding of the pathophysiology of vascular dysfunction in acute and chronic disease

The SOFA score-development, utility and challenges of accurate assessment in clinical trials.

The Sequential Organ Failure Assessment or SOFA score was developed to assess the acute morbidity of critical illness at a population level and has been widely validated as a tool for this purpose across a range of healthcare settings and environments.In recent years, the SOFA score has become extensively used in a range of other applications. A change in the SOFA score of 2 or more is now a defining characteristic of the sepsis syndrome, and the European Medicines Agency has accepted that a change in the SOFA score is an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis. The requirement to detect modest serial changes in a patients' SOFA score therefore means that increased clarity on how the score should be assessed in different circumstances is required.This review explores the development of the SOFA score, its applications and the challenges associated with measurement. In addition, it proposes guidance designed to facilitate the consistent and valid assessment of the score in multicentre sepsis trials involving novel therapeutic agents or interventions.ConclusionThe SOFA score is an increasingly important tool in defining both the clinical condition of the individual patient and the response to therapies in the context of clinical trials. Standardisation between different assessors in widespread centres is key to detecting response to treatment if the SOFA score is to be used as an outcome in sepsis clinical trials