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

Impact of carbohydrate restriction with and without fatty acid loading on myocardial 18F-FDG uptake during PET: A randomized controlled trial

Low-carbohydrate (LC) and high-fat, low-carbohydrate (HFLC) dietary preparations may enhance 18F-FDG-PET-based imaging of small, inflamed structures near the heart by suppressing myocardial FDG signal. We compared myocardial 18F-FDG uptake in patients randomized to LC, HFLC, and unrestricted (UR) preparations prior to 18F-FDG-PET. We randomized 63 outpatients referred for oncologic 18F-FDG-PET to LC, HFLC, or UR dietary preparations (1:1:1 allocation) starting the evening before PET. After eating dinner according to instructions, UR and LC patients fasted until FDG injection (mean time 745 minutes for UR, 899 minutes for LC), and HFLC patients drank a fatty drink 60-70 minutes prior to FDG injection. Attenuation-corrected PET imaging was performed 60 minutes after FDG administration. Maximal myocardial standard uptake values (MyoSUVmax) were systematically measured in axial view and compared between the three groups. Using UR patients as reference, mean MyoSUVmax was lower in LC patients (3.3 ± 2.7 vs 6.2 ± 5.2, P = .03) but not in HFLC patients (5.5 ± 4.2, P = .63). Ratios of MyoSUVmax to liver SUVmax, calculated to control for background uptake, were not significantly different amongst the groups (1.9 ± 2.1 LC, 2.6 ± 2.3 HFLC, 3.6 ± 3.5 UR). In this small randomized controlled trial using UR diet as reference, LC dietary preparation followed by extended fasting resulted in significant myocardial uptake suppression

Tuberculosis in UK cities: workload and effectiveness of tuberculosis control programmes

<p>Abstract</p> <p>Background</p> <p>Tuberculosis (TB) has increased within the UK and, in response, targets for TB control have been set and interventions recommended. The question was whether these had been implemented and, if so, had they been effective in reducing TB cases.</p> <p>Methods</p> <p>Epidemiological data were obtained from enhanced surveillance and clinics. Primary care trusts or TB clinics with an average of > 100 TB cases per year were identified and provided reflections on the reasons for any change in their local incidence, which was compared to an audit against the national TB plan.</p> <p>Results</p> <p>Access to data for planning varied (0-22 months). Sputum smear status was usually well recorded within the clinics. All cities had TB networks, a key worker for each case, free treatment and arrangements to treat HIV co-infection. Achievement of targets in the national plan correlated well with change in workload figures for the commissioning organizations (Spearman's rank correlation R = 0.8, P < 0.01) but not with clinic numbers. Four cities had not achieved the target of one nurse per 40 notifications (Birmingham, Bradford, Manchester and Sheffield). Compared to other cities, their loss to follow-up during treatment was usually > 6% (χ²= 4.2, P < 0.05), there was less TB detected by screening and less outreach. Manchester was most poorly resourced and showed the highest rate of increase of TB. Direct referral from radiology, sputum from primary care and outreach workers were cited as important in TB control.</p> <p>Conclusion</p> <p>TB control programmes depend on adequate numbers of specialist TB nurses for early detection and case-holding.</p> <p>Please see related article: <url>http://www.biomedcentral.com/1741-7015/9/127</url></p

Plasma acylcarnitine concentrations reflect the acylcarnitine profile in cardiac tissues

Funding Information: This study was supported by the Latvian National Research Program BIOMEDICINE. E. Liepinsh was supported by the FP7 project InnovaBalt [grant Nr. 316149]. We would like to thank Dr. Reinis Vilskersts and Gita Dambrova for help with the isolated skeletal muscle experiments. Publisher Copyright: © 2017 The Author(s).Increased plasma concentrations of acylcarnitines (ACs) are suggested as a marker of metabolism disorders. The aim of the present study was to clarify which tissues are responsible for changes in the AC pool in plasma. The concentrations of medium- and long-chain ACs were changing during the fed-fast cycle in rat heart, muscles and liver. After 60 min running exercise, AC content was increased in fasted mice muscles, but not in plasma or heart. After glucose bolus administration in fasted rats, the AC concentrations in plasma decreased after 30 min but then began to increase, while in the muscles and liver, the contents of medium- and long-chain ACs were unchanged or even increased. Only the heart showed a decrease in medium- and long-chain AC contents that was similar to that observed in plasma. In isolated rat heart, but not isolated-contracting mice muscles, the significant efflux of medium- and long-chain ACs was observed. The efflux was reduced by 40% after the addition of glucose and insulin to the perfusion solution. Overall, these results indicate that during fed-fast cycle shifting the heart determines the medium- and long-chain AC profile in plasma, due to a rapid response to the availability of circulating energy substrates.publishersversionPeer reviewe

First Impressions of HIV Risk: It Takes Only Milliseconds to Scan a Stranger

Research indicates that many people do not use condoms consistently but instead rely on intuition to identify sexual partners high at risk for HIV infection. The present studies examined neural correlates for first impressions of HIV risk and determined the association of perceived HIV risk with other trait characteristics. Participants were presented with 120 self-portraits retrieved from a popular online photo-sharing community (www.flickr.com). Factor analysis of various explicit ratings of trait characteristics yielded two orthogonal factors: (1) a ‘valence-approach’ factor encompassing perceived attractiveness, healthiness, valence, and approach tendencies, and (2) a ‘safeness’ factor, entailing judgments of HIV risk, trustworthiness, and responsibility. These findings suggest that HIV risk ratings systematically relate to cardinal features of a high-risk HIV stereotype. Furthermore, event-related brain potential recordings revealed neural correlates of first impressions about HIV risk. Target persons perceived as risky elicited a differential brain response in a time window from 220–340 ms and an increased late positive potential in a time window from 350–700 ms compared to those perceived as safe. These data suggest that impressions about HIV risk can be formed in a split second and despite a lack of information about the actual risk profile. Findings of neural correlates of risk impressions and their relationship to key features of the HIV risk stereotype are discussed in the context of the ‘risk as feelings’ theory

Age, period, and cohort analysis of regular dental care behavior and edentulism: A marginal approach

<p>Abstract</p> <p>Background</p> <p>To analyze the regular dental care behavior and prevalence of edentulism in adult Danes, reported in sequential cross-sectional oral health surveys by the application of a marginal approach to consider the possible clustering effect of birth cohorts.</p> <p>Methods</p> <p>Data from four sequential cross-sectional surveys of non-institutionalized Danes conducted from 1975-2005 comprising 4330 respondents aged 15+ years in 9 birth cohorts were analyzed. The key study variables were seeking dental care on an annual basis (ADC) and edentulism. For the analysis of ADC, survey year, age, gender, socio-economic status (SES) group, denture-wearing, and school dental care (SDC) during childhood were considered. For the analysis of edentulism, only respondents aged 35+ years were included. Survey year, age, gender, SES group, ADC, and SDC during childhood were considered as the independent factors. To take into account the clustering effect of birth cohorts, marginal logistic regressions with an independent correlation structure in generalized estimating equations (GEE) were carried out, with PROC GENMOD in SAS software.</p> <p>Results</p> <p>The overall proportion of people seeking ADC increased from 58.8% in 1975 to 86.7% in 2005, while for respondents aged 35 years or older, the overall prevalence of edentulism (35+ years) decreased from 36.4% in 1975 to 5.0% in 2005. Females, respondents in the higher SES group, in more recent survey years, with no denture, and receiving SDC in all grades during childhood were associated with higher probability of seeking ADC regularly (<it>P </it>< 0.05). The interaction of SDC and age (<it>P </it>< 0.0001) was significant. The probabilities of seeking ADC were even higher among subjects with SDC in all grades and aged 45 years or older. Females, older age group, respondents in earlier survey years, not seeking ADC, lower SES group, and not receiving SDC in all grades were associated with higher probability of being edentulous (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>With the use of GEE, the potential clustering effect of birth cohorts in sequential cross-sectional oral health survey data could be appropriately considered. The success of Danish dental health policy was demonstrated by a continued increase of regular dental visiting habits and tooth retention in adults because school dental care was provided to Danes in their childhood.</p

Changing Patterns of Microhabitat Utilization by the Threespot Damselfish, Stegastes planifrons, on Caribbean Reefs

Background: The threespot damselfish, Stegastes planifrons (Cuvier), is important in mediating interactions among corals, algae, and herbivores on Caribbean coral reefs. The preferred microhabitat of S. planifrons is thickets of the branching staghorn coral Acropora cervicornis. Within the past few decades, mass mortality of A. cervicornis from white-band disease and other factors has rendered this coral a minor ecological component throughout most of its range. Methodology/Principal Findings: Survey data from Jamaica (heavily fished), Florida and the Bahamas (moderately fished), the Cayman Islands (lightly to moderately fished), and Belize (lightly fished) indicate that distributional patterns of S. planifrons are positively correlated with live coral cover and topographic complexity. Our results suggest that speciesspecific microhabitat preferences and the availability of topographically complex microhabitats are more important than the abundance of predatory fish as proximal controls on S. planifrons distribution and abundance. Conclusions/Significance: The loss of the primary microhabitat of S. planifrons—A. cervicornis—has forced a shift in the distribution and recruitment of these damselfish onto remaining high-structured corals, especially the Montastraea annulari

Nonlinearity and Topology

The interplay of nonlinearity and topology results in many novel and emergent properties across a number of physical systems such as chiral magnets, nematic liquid crystals, Bose-Einstein condensates, photonics, high energy physics, etc. It also results in a wide variety of topological defects such as solitons, vortices, skyrmions, merons, hopfions, monopoles to name just a few. Interaction among and collision of these nontrivial defects itself is a topic of great interest. Curvature and underlying geometry also affect the shape, interaction and behavior of these defects. Such properties can be studied using techniques such as, e.g. the Bogomolnyi decomposition. Some applications of this interplay, e.g. in nonreciprocal photonics as well as topological materials such as Dirac and Weyl semimetals, are also elucidated

Bloodstream-To-Eye Infections Are Facilitated by Outer Blood-Retinal Barrier Dysfunction

This work was funded by National Institutes of Health (NIH; http://www.nih.gov) Grants R01EY024140 and R21EY022466 (to M.C.C.) and R01EY019494 (to M.H.E.). Our research is also funded in part by NIH Core Grant P30EY021725 (to Robert E. Anderson, OUHSC) and an unrestricted grant from Research to Prevent Blindness Inc. (http://www.rpbusa.org) to the Dean A. McGee Eye Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.We thank Bolanle Adebayo (Cameron University, Lawton OK), Craig Land (Oklahoma State University, Stillwater OK), Nathan Jia (Oklahoma Christian University, Edmond OK), Kobbe Wiafe (Oklahoma School of Science and Mathematics, Oklahoma City OK), and Amanda Roehrkasse and Madhu Parkunan (OUHSC) for intellectual discussions and technical assistance. The authors also acknowledge thank Nanette Wheatley, Dr. Feng Li, and Mark Dittmar (OUHSC Live Animal Imaging Core, P30EY021725) for their invaluable technical assistance.This work was presented in part at the 2014 Association for Research in Vision and Ophthalmology Annual Conference in Orlando FL.The blood-retinal barrier (BRB) functions to maintain the immune privilege of the eye, which is necessary for normal vision. The outer BRB is formed by tightly-associated retinal pigment epithelial (RPE) cells which limit transport within the retinal environment, maintaining retinal function and viability. Retinal microvascular complications and RPE dysfunction resulting from diabetes and diabetic retinopathy cause permeability changes in the BRB that compromise barrier function. Diabetes is the major predisposing condition underlying endogenous bacterial endophthalmitis (EBE), a blinding intraocular infection resulting from bacterial invasion of the eye from the bloodstream. However, significant numbers of EBE cases occur in non-diabetics. In this work, we hypothesized that dysfunction of the outer BRB may be associated with EBE development. To disrupt the RPE component of the outer BRB in vivo, sodium iodate (NaIO3) was administered to C57BL/6J mice. NaIO3-treated and untreated mice were intravenously injected with 108 colony forming units (cfu) of Staphylococcus aureus or Klebsiella pneumoniae. At 4 and 6 days postinfection, EBE was observed in NaIO3-treated mice after infection with K. pneumoniae and S. aureus, although the incidence was higher following S. aureus infection. Invasion of the eye was observed in control mice following S. aureus infection, but not in control mice following K. pneumoniae infection. Immunohistochemistry and FITC-dextran conjugate transmigration assays of human RPE barriers after infection with an exoprotein-deficient agr/sar mutant of S. aureus suggested that S. aureus exoproteins may be required for the loss of the tight junction protein, ZO-1, and for permeability of this in vitro barrier. Our results support the clinical findings that for both pathogens, complications which result in BRB permeability increase the likelihood of bacterial transmigration from the bloodstream into the eye. For S. aureus, however, BRB permeability is not required for the development of EBE, but toxin production may facilitate EBE pathogenesis.Yeshttp://www.plosone.org/static/editorial#pee