Chaotic Strings in AdS/CFT.

Holographic theories with classical gravity duals are maximally chaotic; i.e., they saturate the universal bound on the rate of growth of chaos [J. Maldacena, S. H. Shenker, and D. Stanford, J. High Energy Phys. 08 (2016) 106JHEPFG1029-847910.1007/JHEP08(2016)106]. It is interesting to ask whether this property is true only for leading large N correlators or if it can show up elsewhere. In this Letter, we consider the simplest setup to tackle this question: a Brownian particle coupled to a thermal ensemble. We find that the four-point out-of-time-order correlator that diagnoses chaos initially grows at an exponential rate that saturates the chaos bound, i.e., with a Lyapunov exponent λ_{L}=2π/β. However, the scrambling time is parametrically smaller than for plasma excitations, t_{*}∼βlogsqrt[λ] instead of t_{*}∼βlogN^{2}. Our result shows that, at least in certain cases, maximal chaos can be attained in the probe sector without the explicit need of gravitational degrees of freedom.Funded by SCOAP3

Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving

Influence of the gender on the relationship between heart rate and blood pressure

Blood Pressure (BP) and Heart Rate (HR) provide information on clin-ical condition along 24h. Both signals present circadian changes due to sympa-thetic/parasympathetic control system that influence the relationship between them. Moreover, also the gender could modify this relation, acting on both con-trol systems. Some studies, using office measurements examined the BP/HR re-lation, highlighting a direct association between the two variables, linked to sus-pected coronary heart disease. Nevertheless, till now such relation has not been studied yet using ambulatory technique that is known to lead to additional prog-nostic information about cardiovascular risks. In order to examine in a more ac-curate way this relation, in this work we evaluate the influence of gender on the BP/HR relationship by using hour-to-hour 24h ambulatory measurements. Data coming from 122 female and 50 male normotensive subjects were recorded using a Holter Blood Pressure Monitor and the parameters of the linear regression fit-ting BP/HR were calculated. Results confirmed those obtained in previous stud-ies using punctual office measures in males and underlined a significant relation between Diastolic BP and HR during each hour of the day in females; a different trend in the BP/HR relation between genders was found only during night-time. Moreover, the circadian rhythm of BP/HR is similar in both genders but with different values of HR and BP at different times of the day

Arginase attenuates inhibitory nonadrenergic noncholinergic nerve-induced nitric oxide generation and airway smooth muscle relaxation

BACKGROUND: Recent evidence suggests that endogenous arginase activity potentiates airway responsiveness to methacholine by attenuation of agonist-induced nitric oxide (NO) production, presumably by competition with epithelial constitutive NO synthase for the common substrate, L-arginine. Using guinea pig tracheal open-ring preparations, we now investigated the involvement of arginase in the modulation of neuronal nitric oxide synthase (nNOS)-mediated relaxation induced by inhibitory nonadrenergic noncholinergic (iNANC) nerve stimulation. METHODS: Electrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5 – 16 Hz)-induced relaxation was measured in tracheal preparations precontracted to 30% with histamine, in the presence of 1 μM atropine and 3 μM indomethacin. The contribution of NO to the EFS-induced relaxation was assessed by the nonselective NOS inhibitor L-NNA (0.1 mM), while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor nor-NOHA (10 μM). Furthermore, the role of substrate availability to nNOS in EFS-induced relaxation was measured in the presence of various concentrations of exogenous L-arginine. RESULTS: EFS induced a frequency-dependent relaxation, ranging from 6.6 ± 0.8% at 0.5 Hz to 74.6 ± 1.2% at 16 Hz, which was inhibited with the NOS inhibitor L-NNA by 78.0 ± 10.5% at 0.5 Hz to 26.7 ± 7.7% at 8 Hz (P < 0.01 all). In contrast, the arginase inhibitor nor-NOHA increased EFS-induced relaxation by 3.3 ± 1.2-fold at 0.5 Hz to 1.2 ± 0.1-fold at 4 Hz (P < 0.05 all), which was reversed by L-NNA to the level of control airways in the presence of L-NNA (P < 0.01 all). Similar to nor-NOHA, exogenous L-arginine increased EFS-induced airway relaxation (P < 0.05 all). CONCLUSION: The results indicate that endogenous arginase activity attenuates iNANC nerve-mediated airway relaxation by inhibition of NO generation, presumably by limiting L-arginine availability to nNOS

Arginase strongly impairs neuronal nitric oxide-mediated airway smooth muscle relaxation in allergic asthma

BACKGROUND: Using guinea pig tracheal preparations, we have recently shown that endogenous arginase activity attenuates inhibitory nonadrenergic noncholinergic (iNANC) nerve-mediated airway smooth muscle relaxation by reducing nitric oxide (NO) production – due to competition with neuronal NO-synthase (nNOS) for the common substrate, L-arginine. Furthermore, in a guinea pig model of allergic asthma, airway arginase activity is markedly increased after the early asthmatic reaction (EAR), leading to deficiency of agonist-induced, epithelium-derived NO and subsequent airway hyperreactivity. In this study, we investigated whether increased arginase activity after the EAR affects iNANC nerve-derived NO production and airway smooth muscle relaxation. METHODS: Electrical field stimulation (EFS; 150 mA, 4 ms, 4 s, 0.5 – 16 Hz)-induced relaxation was measured in tracheal open-ring preparations precontracted to 30% with histamine in the presence of 1 μM atropine and 3 μM indomethacin. The contribution of NO to EFS-induced relaxation was assessed by the nonselective NOS inhibitor N(ω)-nitro-L-arginine (L-NNA, 100 μM), while the involvement of arginase activity in the regulation of EFS-induced NO production and relaxation was investigated by the effect of the specific arginase inhibitor N(ω)-hydroxy-nor-L-arginine (nor-NOHA, 10 μM). Furthermore, the role of substrate availability to nNOS was measured in the presence of exogenous L-arginine (5.0 mM). RESULTS: At 6 h after ovalbumin-challenge (after the EAR), EFS-induced relaxation (ranging from 3.2 ± 1.1% at 0.5 Hz to 58.5 ± 2.2% at 16 Hz) was significantly decreased compared to unchallenged controls (7.1 ± 0.8% to 75.8 ± 0.7%; P < 0.05 all). In contrast to unchallenged controls, the NOS inhibitor L-NNA did not affect EFS-induced relaxation after allergen challenge, indicating that NO deficiency underlies the impaired relaxation. Remarkably, the specific arginase inhibitor nor-NOHA normalized the impaired relaxation to unchallenged control (P < 0.05 all), which effect was inhibited by L-NNA (P < 0.01 all). Moreover, the effect of nor-NOHA was mimicked by exogenous L-arginine. CONCLUSION: The results clearly demonstrate that increased arginase activity after the allergen-induced EAR contributes to a deficiency of iNANC nerve-derived NO and decreased airway smooth muscle relaxation, presumably via increased substrate competition with nNOS

Nonlinear Supersymmetry as a Hidden Symmetry

Ver abstrac

Resuming Work After Cancer: A Prospective Study of Occupational Register Data

Introduction Long-term employment rates have been studied in cancer survivors, but little is known about the return to work of cancer patients. This study investigated return to work (RTW) within 2 years after the diagnosis of different types of cancer. Methods This prospective study investigated the associations of demographics (age, gender, socioeconomic status, and residential region) and occupational factors (occupation, duration of employment, and company size) of employees absent from work due to cancer with the time to partial RTW, defined as working at least 50% of the earnings before sickness absence. Likewise, the associations of demographics and occupational factors with full RTW at equal earnings as before sickness absence were investigated. Results The cohort included 5,234 employees who had been absent from work due to cancer between January 2004 and December 2006. The time to partial RTW was shortest among employees with skin cancer (median 55 days) and longest among employees with lung cancer (median 377 days). There were no significant associations between RTW and demographics. With regard to the occupational factors, employees in high occupational classes started working earlier than those in low occupational classes, but the time to full RTW did not differ significantly across occupational classes. Employees working in large companies returned to work earlier than those working in small companies. Conclusion RTW after different types of cancer depended on occupational factors rather than demographics

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST)

Background: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. Aims: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. Methods: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. Baseline results: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. Conclusion: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856)

On-line electrochemistry–bioaffinity screening with parallel HR-LC-MS for the generation and characterization of modified p38α kinase inhibitors

In this study, an integrated approach is developed for the formation, identification and biological characterization of electrochemical conversion products of p38α mitogen-activated protein kinase inhibitors. This work demonstrates the hyphenation of an electrochemical reaction cell with a continuous-flow bioaffinity assay and parallel LC-HR-MS. Competition of the formed products with a tracer (SKF-86002) that shows fluorescence enhancement in the orthosteric binding site of the p38α kinase is the readout for bioaffinity. Parallel HR-MSn experiments provided information on the identity of binders and non-binders. Finally, the data produced with this on-line system were compared to electrochemical conversion products generated off-line. The electrochemical conversion of 1-{6-chloro-5-[(2R,5S)-4-(4-fluorobenzyl)-2,5-dimethylpiperazine-1-carbonyl]-3aH-indol-3-yl}-2-morpholinoethane-1,2-dione resulted in eight products, three of which showed bioaffinity in the continuous-flow p38α bioaffinity assay used. Electrochemical conversion of BIRB796 resulted, amongst others, in the formation of the reactive quinoneimine structure and its corresponding hydroquinone. Both products were detected in the p38α bioaffinity assay, which indicates binding to the p38α kinase