Effect of Arginase Inhibition on Pulmonary L-Arginine Metabolism in Murine Pseudomonas Pneumonia

Rationale: Infection of the lung with Pseudomonas aeruginosa results in upregulation of nitric oxide synthases (NOS) and arginase expression, and both enzymes compete for L-arginine as substrate. Nitric oxide (NO) production may be regulated by arginase as it controls L-arginine availability for NOS. We here studied the effect of systemic arginase inhibition on pulmonary L-arginine metabolism in Pseudomonas pneumonia in the mouse. Methods: Mice (C57BL/6, 8–10 weeks old, female) underwent direct tracheal instillation of Pseudomonas (PAO-1)-coated agar beads and were treated by repeated intra-peritoneal injections of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) or PBS until lungs were harvested on day 3 of the infection. L-arginine metabolites were quantified using liquid chromatography-tandem mass spectrometry, NO metabolites nitrate and nitrite by Griess reagent and cytokines by ELISA. Results: NO metabolite concentrations (48.5±2.9 vs. 10.9±2.3 µM, p<0.0001), as well as L-ornithine (29.6±1.7 vs 2.3±0.4 µM, p<0.0001), the product of arginase activity, were increased in Pseudomonas infected lungs compared to naïve controls. Concentrations of the NOS inhibitor asymmetric dimethylarginine (ADMA) were also increased (0.44±0.02 vs. 0.16±0.01 µM, p<0.0001). Arginase inhibition in the infected animals resulted in a significant decrease in L-ornithine (14.6±1.6 µM, p<0.0001) but increase in L-arginine concentration (p<0.001), L-arginine/ADMA ratio (p<0.001), L-arginine availability for NOS (p<0.001), and NO metabolite concentrations (67.3±5.7 µM, p<0.05). Arginase inhibitor treatment also resulted in an increase in NO metabolite levels in animals following intratracheal injection of LPS (p = 0.015). Arginase inhibition was not associated with an increase in inflammatory markers (IFN-γ, IL-1β, IL-6, MIP-2, KC or TNF-α) in lung. Concentrations of the L-ornithine-dependent polyamines putrescine, spermidine and spermine were increased in Pseudomonas infected lungs (p<0.001, respectively) but were unaffected by ABH treatment. Conclusions: Systemic arginase inhibition with ABH during Pseudomonas pneumonia in mice results in an increase in pulmonary NO formation but no pro-inflammatory effect

Health-related quality of life in young adults born small for gestational age : a prospective cohort study

Background Individuals born small for gestational age (SGA) have an increased risk of several adverse health outcomes, but their health-related quality of life (HRQoL) across young adulthood has yet to be studied. The main aim of this study was to investigate if being born SGA at term is associated with poor HRQoL at 32 years of age. A second aim was to explore longitudinal changes in HRQoL from age 20 to 32 years. Methods In the prospective NTNU Low Birth Weight in a Lifetime Perspective study, 56 participants born SGA and 68 non-SGA control participants completed the Short Form 36 Health Survey (SF-36) at age 32 years to assess HRQoL. The SF-36 was also administrated at age 20 and 28 years. Longitudinal changes in the eight SF-36 domains and the two component summaries from 20 to 32 years were analyzed by linear mixed models. In total, 82 adults born SGA and 98 controls participated at least once and were included in the longitudinal analyses. Results At age 32 years the participants born SGA scored 14.8 (95% CI 4.7 to 25.3) points lower in the SF-36 role-physical domain compared with the control group, i.e. more problems with work or other daily activities due to physical health problems. The longitudinal analyses showed significant group differences from 20 to 32 years in the role-emotional domain, and in the physical and mental component summaries. Among participants born SGA, the physical component summary decreased from age 20 to 28 years (-3.2, 95% CI -5.0 to -1.8), while the mental component summary (6.0, 95% CI 2.9 to 8.6) and role-emotional domain score (19.3, 95% CI 9.9 to 30.3) increased, but there were no further changes from 28 to 32 years. There were no longitudinal changes in the control group from 20 to 32 years. Conclusion Overall, individuals born SGA at term reported similar HRQoL at age 32 years compared with non-SGA controls. Self-perceived mental health improved during young adulthood among individuals born SGA, while self-perceived physical health deteriorated. The latter findings warrant further investigation.Peer reviewe

Hemispheric asymmetries in resting-state EEG and fMRI are related to approach and avoidance behaviour, but not to eating behaviour or BMI

Much of our behaviour is driven by two motivational dimensions-approach and avoidance. These have been related to frontal hemispheric asymmetries in clinical and resting-state EEG studies: Approach was linked to higher activity of the left relative to the right hemisphere, while avoidance was related to the opposite pattern. Increased approach behaviour, specifically towards unhealthy foods, is also observed in obesity and has been linked to asymmetry in the framework of the right-brain hypothesis of obesity. Here, we aimed to replicate previous EEG findings of hemispheric asymmetries for self-reported approach/avoidance behaviour and to relate them to eating behaviour. Further, we assessed whether resting fMRI hemispheric asymmetries can be detected and whether they are related to approach/avoidance, eating behaviour and BMI. We analysed three samples: Sample 1 (n = 117) containing EEG and fMRI data from lean participants, and Samples 2 (n = 89) and 3 (n = 152) containing fMRI data from lean, overweight and obese participants. In Sample 1, approach behaviour in women was related to EEG, but not to fMRI hemispheric asymmetries. In Sample 2, approach/avoidance behaviours were related to fMRI hemispheric asymmetries. Finally, hemispheric asymmetries were not related to either BMI or eating behaviour in any of the samples. Our study partly replicates previous EEG findings regarding hemispheric asymmetries and indicates that this relationship could also be captured using fMRI. Our findings suggest that eating behaviour and obesity are likely to be mediated by mechanisms not directly relating to frontal asymmetries in neuronal activation quantified with EEG and fMRI.Peer reviewe

Proposal for a unified nomenclature for target site mutations associated with resistance to fungicides

Evolved resistance to fungicides is a major problem limiting our ability to control agricultural, medical and veterinary pathogens and is frequently associated with substitutions in the amino acid sequence of the target protein. The convention for describing amino-acid substitutions is to cite the wild type amino acid, the codon number and the new amino acid, using the one letter amino acid code. It has frequently been observed that orthologous amino acid mutations have been selected in different species by fungicides from the same mode of action class, but the amino acids have different numbers. These differences in numbering arise from the different lengths of the proteins in each species. The purpose of the current paper is to propose a system for unifying the labelling of amino acids in fungicide target proteins. To do this we have produced alignments between fungicide target proteins of relevant species fitted to a well-studied “archetype” species. Orthologous amino acids in all species are then assigned numerical “labels” based on the position of the amino acid in the archetype protein

Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease

Background No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. Results 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O 2 -saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O 2 -saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. Conclusions Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013)

A Federated Database for Obesity Research:An IMI-SOPHIA Study

Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.</p

A Melodic Contour Repeatedly Experienced by Human Near-Term Fetuses Elicits a Profound Cardiac Reaction One Month after Birth

Human hearing develops progressively during the last trimester of gestation. Near-term fetuses can discriminate acoustic features, such as frequencies and spectra, and process complex auditory streams. Fetal and neonatal studies show that they can remember frequently recurring sounds. However, existing data can only show retention intervals up to several days after birth.Here we show that auditory memories can last at least six weeks. Experimental fetuses were given precisely controlled exposure to a descending piano melody twice daily during the 35(th), 36(th), and 37(th) weeks of gestation. Six weeks later we assessed the cardiac responses of 25 exposed infants and 25 naive control infants, while in quiet sleep, to the descending melody and to an ascending control piano melody. The melodies had precisely inverse contours, but similar spectra, identical duration, tempo and rhythm, thus, almost identical amplitude envelopes. All infants displayed a significant heart rate change. In exposed infants, the descending melody evoked a cardiac deceleration that was twice larger than the decelerations elicited by the ascending melody and by both melodies in control infants.Thus, 3-weeks of prenatal exposure to a specific melodic contour affects infants 'auditory processing' or perception, i.e., impacts the autonomic nervous system at least six weeks later, when infants are 1-month old. Our results extend the retention interval over which a prenatally acquired memory of a specific sound stream can be observed from 3-4 days to six weeks. The long-term memory for the descending melody is interpreted in terms of enduring neurophysiological tuning and its significance for the developmental psychobiology of attention and perception, including early speech perception, is discussed

Distinction between Climate and Stream Piracy from a paleohydrologic reconstruciton

International audienc

(Not) Lost in Translation: Psychological Adaptation Occurs During Speech Translation

While language style is considered to be automatic and relatively stable, its plasticity has not yet been studied in translations that require the translator to “step into the shoes of another person.” In the present study, we propose a psychological model of language adaptation in translations. Focusing on an established interindividual difference marker of language style, that is, gender, we examined whether translators assimilate to the original gendered style or implicitly project their own gendered language style. In a preregistered study, we investigated gender differences in language use in TED Talks ( N = 1,647) and their translations ( N = 544) in same- versus opposite-gender speaker/translator dyads. The results showed that translators assimilated to gendered language styles even when in mismatch to their own gender. This challenges predominating views on language style as fixed and fosters a more dynamic view of language style as also being shaped by social context