114 research outputs found
Short-term beneficial effects of methylene blue on kidney damage in septic shock patients
Contains fulltext :
71022.pdf (publisher's version ) (Closed access)OBJECTIVE: We previously demonstrated that upregulation of renal inducible nitric oxide synthase (iNOS) is associated with proximal tubule injury during systemic inflammation in humans. In this study we investigated the short-term effect of methylene blue (MB), an inhibitor of the NO pathway, on kidney damage and function in septic shock patients. DESIGN AND SETTING: A prospective clinical study conducted in an intensive care unit. PATIENTS: Nine patients (four men, five women, mean age 71 +/- 3 years) with confirmed or suspected bacterial infection and with refractory septic shock defined as a mean arterial pressure or = 0.2 microg/kg per minute. INTERVENTIONS: A 4 h continuous intravenous infusion of 1 mg/kg MB per hour. MEASUREMENTS AND RESULTS: The urinary excretion of NO metabolites decreased with median 90% (range 75-95%) from baseline to 6 h after MB administration. The first 24 h creatinine clearance improved by 51% (18-173%) after MB treatment but was still strongly impaired. During the first 6 h after the start of MB treatment both the urinary excretion of cytosolic glutathione S-transferase A1-1 and P1-1, markers for proximal and distal tubule damage, respectively, decreased by 45% (10-70%) and 70% (40-85) vs. baseline. After termination of the MB infusion the NO metabolites and markers of tubular injury returned to pretreatment levels. CONCLUSIONS: In septic patients with refractory shock short-term infusion of MB is associated with a decrease in NO production and an attenuation of the urinary excretion of renal tubular injury markers
Lattice Boltzmann simulations of soft matter systems
This article concerns numerical simulations of the dynamics of particles
immersed in a continuum solvent. As prototypical systems, we consider colloidal
dispersions of spherical particles and solutions of uncharged polymers. After a
brief explanation of the concept of hydrodynamic interactions, we give a
general overview over the various simulation methods that have been developed
to cope with the resulting computational problems. We then focus on the
approach we have developed, which couples a system of particles to a lattice
Boltzmann model representing the solvent degrees of freedom. The standard D3Q19
lattice Boltzmann model is derived and explained in depth, followed by a
detailed discussion of complementary methods for the coupling of solvent and
solute. Colloidal dispersions are best described in terms of extended particles
with appropriate boundary conditions at the surfaces, while particles with
internal degrees of freedom are easier to simulate as an arrangement of mass
points with frictional coupling to the solvent. In both cases, particular care
has been taken to simulate thermal fluctuations in a consistent way. The
usefulness of this methodology is illustrated by studies from our own research,
where the dynamics of colloidal and polymeric systems has been investigated in
both equilibrium and nonequilibrium situations.Comment: Review article, submitted to Advances in Polymer Science. 16 figures,
76 page
Cognitive Bias in Ambiguity Judgements:Using Computational Models to Dissect the Effects of Mild Mood Manipulation in Humans
Positive and negative moods can be treated as prior expectations over future delivery of rewards and punishments. This provides an inferential foundation for the cognitive (judgement) bias task, now widely-used for assessing affective states in non-human animals. In the task, information about affect is extracted from the optimistic or pessimistic manner in which participants resolve ambiguities in sensory input. Here, we report a novel variant of the task aimed at dissecting the effects of affect manipulations on perceptual and value computations for decision-making under ambiguity in humans. Participants were instructed to judge which way a Gabor patch (250ms presentation) was leaning. If the stimulus leant one way (e.g. left), pressing the REWard key yielded a monetary WIN whilst pressing the SAFE key failed to acquire the WIN. If it leant the other way (e.g. right), pressing the SAFE key avoided a LOSS whilst pressing the REWard key incurred the LOSS. The size (0-100 UK pence) of the offered WIN and threatened LOSS, and the ambiguity of the stimulus (vertical being completely ambiguous) were varied on a trial-by-trial basis, allowing us to investigate how decisions were affected by differing combinations of these factors. Half the subjects performed the task in a 'Pleasantly' decorated room and were given a gift (bag of sweets) prior to starting, whilst the other half were in a bare 'Unpleasant' room and were not given anything. Although these treatments had little effect on self-reported mood, they did lead to differences in decision-making. All subjects were risk averse under ambiguity, consistent with the notion of loss aversion. Analysis using a Bayesian decision model indicated that Unpleasant Room subjects were ('pessimistically') biased towards choosing the SAFE key under ambiguity, but also weighed WINS more heavily than LOSSes compared to Pleasant Room subjects. These apparently contradictory findings may be explained by the influence of affect on different processes underlying decision-making, and the task presented here offers opportunities for further dissecting such processes
Erythropoietic protoporphyria without skin symptoms-you do not always see what they feel
Erythropoietic protoporphyria (EPP) is an inherited disorder of the porphyrin metabolism that often remains undiagnosed in children. We report on a 4-year-old girl who had been suffering for 1 year from recurrent painful crises affecting her hands, feet, and nose following sun exposure. Objective skin lesions were absent until the age of 6. Porphyrin analysis revealed elevated free erythrocyte protoporphyrin (FEP) levels confirming the diagnosis of EPP. This illustrates that skin lesions might be completely absent in children affected with EPP, a fact that has only been reported once previously. Because EPP can manifest with few and unspecific cutaneous symptoms or no skin lesions at all, like in this patient, the diagnosis of EPP might be delayed or missed. EPP should be excluded in all photosensitive children, especially when discomfort is disproportionate to the extent of the cutaneous lesions. The clinic, pathophysiology, diagnosis, complications, and therapy of EPP are discussed
Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype
Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development
Electrical and Mechanical Ventricular Activation During Left Bundle Branch Block and Resynchronization
Cardiac resynchronization therapy (CRT) aims to treat selected heart failure patients suffering from conduction abnormalities with left bundle branch block (LBBB) as the culprit disease. LBBB remained largely underinvestigated until it became apparent that the amount of response to CRT was heterogeneous and that the therapy and underlying pathology were thus incompletely understood. In this review, current knowledge concerning activation in LBBB and during biventricular pacing will be explored and applied to current CRT practice, highlighting novel ways to better measure and treat the electrical substrate
Characterization of an Nmr Homolog That Modulates GATA Factor-Mediated Nitrogen Metabolite Repression in Cryptococcus neoformans
Nitrogen source utilization plays a critical role in fungal development, secondary metabolite production and pathogenesis. In both the Ascomycota and Basidiomycota, GATA transcription factors globally activate the expression of catabolic enzyme-encoding genes required to degrade complex nitrogenous compounds. However, in the presence of preferred nitrogen sources such as ammonium, GATA factor activity is inhibited in some species through interaction with co-repressor Nmr proteins. This regulatory phenomenon, nitrogen metabolite repression, enables preferential utilization of readily assimilated nitrogen sources. In the basidiomycete pathogen Cryptococcus neoformans, the GATA factor Gat1/Are1 has been co-opted into regulating multiple key virulence traits in addition to nitrogen catabolism. Here, we further characterize Gat1/Are1 function and investigate the regulatory role of the predicted Nmr homolog Tar1. While GAT1/ARE1 expression is induced during nitrogen limitation, TAR1 transcription is unaffected by nitrogen availability. Deletion of TAR1 leads to inappropriate derepression of non-preferred nitrogen catabolic pathways in the simultaneous presence of favoured sources. In addition to exhibiting its evolutionary conserved role of inhibiting GATA factor activity under repressing conditions, Tar1 also positively regulates GAT1/ARE1 transcription under non-repressing conditions. The molecular mechanism by which Tar1 modulates nitrogen metabolite repression, however, remains open to speculation. Interaction between Tar1 and Gat1/Are1 was undetectable in a yeast two-hybrid assay, consistent with Tar1 and Gat1/Are1 each lacking the conserved C-terminus regions present in ascomycete Nmr proteins and GATA factors that are known to interact with each other. Importantly, both Tar1 and Gat1/Are1 are suppressors of C. neoformans virulence, reiterating and highlighting the paradigm of nitrogen regulation of pathogenesis
Heat treatment following surface silanization in rebonded tribochemical silica-coated ceramic brackets: shear bond strength analysis
Psychometric properties of the osteoporosis assessment questionnaire (OPAQ) 2.0: results from the multiple outcomes of raloxifene evaluation (MORE) study
- …