bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Ambient Turbulence on Interleaving at a Baroclinic Front
Authors: Smyth William D. , Ruddick Barry
Published: November 2009

In this paper the authors investigate the action of ambient turbulence on thermohaline interleaving using both theory and numerical calculations in combination with observations from Meddy Sharon and the Faroe Front. The highly simplified models of ambient turbulence used previously are improved upon by allowing turbulent diffusivities of momentum, heat, and salt to depend on background gradients and to evolve as the instability grows.

Previous studies have shown that ambient turbulence, at typical ocean levels, can quench the thermohaline interleaving instability on baroclinic fronts. These findings conflict with the observation that interleaving is common in baroclinic frontal zones despite ambient turbulence. Another challenge to the existing theory comes from numerical experiments showing that the Schmidt number for sheared salt fingers is much smaller than previously assumed. Use of the revised value in an interleaving calculation results in interleaving layers that are both weaker and thinner than those observed. This study aims to resolve those paradoxes.

The authors show that, when turbulence has a Prandtl number greater than unity, turbulent momentum fluxes can compensate for the reduced Schmidt number of salt fingering. Thus, ambient turbulence determines the vertical scale of interleaving. In typical oceanic interleaving structures, the observed property gradients are insufficient to predict interleaving growth at an observable level, even when improved turbulence models are used. The deficiency is small, though: gradients sharper by a few tens of percent are sufficient to support instability. The authors suggest that this is due to the efficiency of interleaving in erasing those property gradients.

A new class of mechanisms for interleaving, driven by flow-dependent fluctuations in turbulent diffusivities, is identified. The underlying mechanism is similar to the well-known Phillips layering instability; however, because of Coriolis effects, it has a well-defined vertical scale and also a tilt angle opposite to that of finger-driven interleaving.
NAM–SCA: A Nonhydrostatic Anelastic Model with Segmentally Constant Approximations
Authors: Yano Jun-Ichi , Bénard Pierre , Couvreux Fleur , Lahellec Alain
Published: November 2009

An atmospheric convective system may be modeled as an ensemble of discrete plume elements. A representation of decomposited plumes provides the basis for mass-flux convective parameterization. A dry version of such a prototype model is constructed in a two-dimensional horizontally periodic domain. Each discrete plume element is approximated by a horizontally homogeneous segment such that the whole system is given by segmentally constant approximations (SCA) in the horizontal direction for each vertical level in a nonhydrostatic anelastic model (NAM). The distribution of constant segments is highly inhomogeneous in space and evolves with time in a highly adaptive manner.

The basic modeling strategy from a physical point of view is to activate new segments vertically upward with time when a convective plume is growing and to deactivate segments when a plume event is over. The difference in physical values crossing segment interfaces is used as a criterion for numerically implementing this strategy. Whenever a large difference is found, the given interface is stretched vertically by subdividing an existing segment into two. In turn, when a segment interface difference is found below the threshold, the given interface is removed, thereby merging the two segments into one.

This nonhydrostatic anelastic model with segmentally constant approximations (NAM–SCA) is tested on an idealized atmospheric convective boundary layer. It successfully simulates the evolution of convective plumes with a relatively limited number of segments (i.e., high compression) and with a much scarcer distribution of segments over nonplume environments (i.e., extremely inhomogeneous distribution of segments). Overall, this method compresses the size of the model up to 5 times compared to a standard NAM with homogeneous grid distribution without substantially sacrificing numerical accuracy.
Ensemble Kalman Filter Data Assimilation in a 1D Numerical Model Used for Fog Forecasting
Authors: Rémy Samuel , Bergot Thierry
Published: November 2009

Because poor visibility conditions have a considerable influence on airport traffic, a need exists for accurate and updated fog and low-cloud forecasts. Couche Brouillard Eau Liquide (COBEL)-Interactions between Soil, Biosphere, and Atmosphere (ISBA), a boundary layer 1D numerical model, has been developed for the very short-term forecast of fog and low clouds. This forecast system assimilates local observations to produce initial profiles of temperature and specific humidity. The initial conditions have a great impact on the skill of the forecast.

In this work, the authors first estimated the background error statistics; they varied greatly with time, and cross correlations between temperature and humidity in the background were significant. This led to the implementation of an ensemble Kalman filter (EnKF) within COBEL-ISBA. The new assimilation system was evaluated with temperature and specific humidity scores, as well as in terms of its impact on the quality of fog forecasts. Simulated observations were used and focused on the modeling of the atmosphere before fog formation and also on the simulation of the life cycle of fog and low clouds. For both situations, the EnKF brought a significant improvement in the initial conditions and the forecasts. The forecast of the onset and burn-off times of fogs was also improved. The EnKF was also tested with real observations and gave good results. The size of the ensemble did not have much impact when simulated observations were used, thanks to an adaptive covariance inflation algorithm, but the impact was greater when real observations were used.
The Role of Polymorphisms Within Paraoxonases (192 Gln/Arg in PON1 and 311Ser/Cys in PON2) in the Modulation of Cardiovascular Risk: A Pilot Study
Authors: Gluba Anna , Pietrucha Tadeusz , Banach Maciej , Piotrowski Grzegorz , Rysz Jacek
Published: November 2009

Paraoxonases (PONs) may exert anti-atherogenic action by reducing lipid peroxidation. We evaluated the influence of 2 polymorphisms within PON1 (192 Gln/ Arg) and PON2 (311 Ser/Cys) genes in 407 young Poles: 273 patients who experienced a first myocardial infarction (MI) under the age of 45 (study group) and 134 healthy volunteers (control group) with a HEART Score ≤2 (low risk). Paraoxonase 1 polymorphism 192Gln/Arg influenced the risk of premature MI (P = .0054). A positive family history of coronary artery disease (CAD) was associated with the 192Arg allele (P = .0107). The association between PON1 genotype (192 Gln/Arg) and low-density lipoprotein cholesterol (LDL-C) (P = .036) levels was also observed. However, we did not find any relationship between polymorphism 311Ser/Cys and CAD risk (P = .418). PON1 polymorphism 192Gln/Arg influenced the risk of premature MI. The association between PON1 genotype (192 Gln/Arg) and serum LDL-C levels may be explained by PON participation in reverse cholesterol transport.
Chronic Kidney Disease as a Predictor of Coronary Lesion Morphology
Authors: Kilickesmez Kadriye Orta , Abaci Okay , Okcun Baris , Kocas Cuneyt , Baskurt Murat , Arat Alev , Ersanli Murat , Gurmen Tevfik
Published: November 2009

Coronary artery disease (CAD) is the main cause of death in patients with chronic kidney disease (CKD). We investigated whether CKD stage affected coronary lesion morphology in patients with established CAD. Coronary angiograms of 264 patients were evaluated. Chronic kidney disease was staged using the estimated glomerular filtration rate (eGFR) from the serum creatinine prior to coronary angiography. Patients were divided into 3 groups: dialysis or severe decrease in GFR <30 mL/min per 1.73 m2 (group 1; n = 60), patients with moderate kidney failure (group 2; n = 116), and patients with normal renal function or mild decrease in GFR (group 3; n = 88). The likelihood of CAD and lesion complexity increased with decreasing eGFR (P = .001). Patients with CKD also had more significant CAD. The risk of significant coronary obstruction and lesion complexity increased progressively with decreasing eGFR. The eGFR may predict lesion complexity among patients with CKD undergoing coronary angiography.
Cardiac Adaptive Responses After Hypoxia in an Experimental Model
Authors: Bin-Jaliah Ismaeel , Ammar Hania I. , Mikhailidis Dimitri P. , Dallak Mohammed A. , Al-Hashem Fahaid H. , Haidara Mohamed A. , Yassin Hanaa Z. , Bahnasi Abeer A. , Rashed Laila A. , Isenovic Esma R.
Published: November 2009

The role of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in mediating hypoxic preconditioning under the acute intermittent hypoxic condition (AIH) was investigated in this study. Male Wistar rats were randomly assigned and kept in normoxic conditions, (Nx) or in AIH conditions and subjected to brief cycles hypoxia/reoxygenation. Hearts were isolated, perfused, and subjected to in vitro global ischemia followed by reperfusion. During and at the end of reperfusion, left ventricular developed pressure (LVDP); LV end diastolic pressure (LVEDP); rate pressure product (RPP); peak left ventricular pressure rise (ΔP/Δt max ) and heart rate (HR) were measured. Hearts subjected to AIH displayed a significant higher LVDP (P < .001), RPP (P < .001), and ΔP/Δt max (P < .001). Expression of VEGF and EPO were significantly increased at 3, 8, and 24 hours after AIH. Hypoxic training could provide a new approach to enhance endogenous cardioprotective mechanisms.
Endogenous Oil Rents
Authors: Dunning Thad
Published: November 2009

Oil rents may at times fall like “manna from heaven” into the fiscal coffers of the state. Yet politicians also make decisions that can increase or decrease the extent to which oil rents accrue to the central government. Though counterintuitive, various evidence suggests that politicians sometimes do not seek to maximize the state’s claim on rents. In this article, the author substantiates this observation with evidence from Venezuela and then develops a formal model of the relationship between electoral competition and rent choice. The author argues that the model can explain why politicians allowed the central government’s share of rents to decline in Venezuela beginning in the 1990s, even though a decline in rents plausibly contributed to the destabilization of Venezuelan democracy. The argument illuminates patterns of rent capture in other cases, whereas the model may be useful in many settings in which the gains from economic investment are realized over several electoral terms.
History and the Critique of Social Concepts
Authors: Epstein Brian
Published: November 2009

Many theorists have regarded genealogy as an important technique for social criticism. But it has been unclear how genealogy can go beyond the accomplishments of other, more mundane, critical methods. I propose a new approach to understanding the critical potential of history. I argue that theorists have been misled by the assumption that if a claim is deserving of criticism, it is because the claim is false. Turning to the criticism of concepts rather than criticism of claims, I expand on the distinction between “descriptive semantics” and “foundational semantics” to show that genealogy can be uniquely qualified to explore the foundations of concepts, and hence to criticize concepts that are problematic in nonobvious ways.
Reclaiming Davidson’s Methodological Rationalism as Galilean Idealization in Psychology
Authors: Lee Carole J.
Published: November 2009

In his early experimental work with Suppes, Davidson adopted rationality assumptions, not as necessary constraints on interpretation, but as practical conceits in addressing methodological problems faced by experimenters studying decision making under uncertainty. Although the content of their theory has since been undermined, their methodological approach—a Galilean form of methodological rationalism—lives on in contemporary psychological research.This article draws on Max Weber’s verstehen to articulate an account of Galilean methodological rationalism; explains how anomalies faced by Davidson’s early experimental work gave rise to his later, canonical claims about rationality and interpretation; and reclaims this Galilean framework for use in contemporary psychological research.
Cartwright on “Economics”
Authors: Boland Lawrence
Published: November 2009

Nancy Cartwright claims that “Causality is a hot topic today both in philosophy and economics.” She may be right about philosophers, but not when it comes to economists. Cartwright talks about “economics” but nothing she says about it corresponds to what is taught in economics classes. Today, economics is dominated by model builders—but not all models involve econometrics. While all model builders do respect an endogenous-exogenous distinction between variables, this distinction will not be on the basis of which type of variable “causes” which, but on which variables are “determined” (and hence explained) by the model and those which are not.
Conceptual Exclusion and Public Reason
Authors: Morgan-Olsen Brandon
Published: November 2009

Deliberative democratic theorists typically use accounts of public reason— that is, constraints on the types of reasons one can invoke in public, political discourse—as a tool to resist political exclusion; at its most basic level, the aim of a theory of public reason is to prevent situations in which powerful majority groups are able to justify policy choices based on reasons that are not even assessable by minority groups. However, I demonstrate here that a type of exclusion I call “conceptual exclusion” complicates this picture. I argue that the possibility of conceptual exclusion creates the potential for public reason constraints to further exclude already marginalized groups— contrary to the standard view—and thus that taking conceptual exclusion seriously requires both a revision of traditional accounts of public reason and a reconceptualization of our civic obligations.
Investigation of the Pharmacokinetic Interactions of Deferasirox, a Once‐Daily Oral Iron Chelator, With Midazolam, Rifampin, and Repaglinide in Healthy Volunteers
Authors: Skerjanec Andrej , Wang Jixian , Maren Kelly , Rojkjaer Lisa
Published: November 2009

Deferasirox, a newly developed iron chelator, was coadministered orally with either a known inducer of drug metabolism or with cosubstrates for cytochrome P450 (CYP) to characterize the potential for drug‐drug interactions. In the induction assessment, single‐dose deferasirox pharmacokinetics were obtained in the presence and absence of a repeated‐dose regimen of rifampin. In the CYP3A interaction evaluation, midazolam and its active hydroxylated metabolite were assessed after single doses of midazolam in the presence and absence of steady‐state concentrations of deferasirox. To test for interaction at the level of CPY2C8, single‐dose repaglinide pharmacokinetics/pharmacodynamics were determined with and without repeated‐dose administration of deferasirox. After rifampin, a significant reduction (44%) in plasma exposure (AUC) to deferasirox was observed. Upon coadministration of midazolam, there was a modest reduction of up to 22% in midazolam exposure (AUC, Cmax), suggesting a modest induction of CYP3A4/5 by deferasirox. Deferasirox caused increases in repaglinide plasma Cmax and AUC of 1.5‐fold to over 2‐fold, respectively, with little change in blood glucose measures. Specific patient prescribing recommendations were established when coadministering deferasirox with midazolam, repaglinide, and rifampin. These recommendations may also apply to other substrates of CYP3A4/5 and CYP2C8 or potent inducers of glucuronidation.
Subcutaneous Bioavailability of Golimumab at 3 Different Injection Sites in Healthy Subjects
Authors: Xu Zhenhua , Wang Qingmin , Zhuang Yanli , Frederick Bart , Yan Hong , Bouman‐Thio Esther , Marini Joseph C. , Keen Monica , Snead David , Davis Hugh M. , Zhou Honghui
Published: November 2009

This study characterized the pharmacokinetics (PK) of golimumab, an antitumor necrosis factor alpha human IgG1k monoclonal antibody, after a single intravenous (IV) or subcutaneous (SC) administration in healthy subjects and determined the absolute bioavailability of SC golimumab delivered at 3 different anatomical regions. Seventy‐eight healthy adult males were randomly assigned to receive a single dose of golimumab 100 mg by IV (30‐minute infusion, n = 23) or SC administration at different sites (upper arm, n = 18; abdomen, n = 18; thigh, n = 19). Serial blood samples were collected for PK characterization. Following IV administration, the mean maximum observed serum golimumab concentration (Cmax) and the mean area under the concentration versus time curves from time zero to infinity (AUC0‐∞) were 29.5 ± 5.8 μg/mL and 195.9 ± 48.9 μg·d/mL, respectively. After SC administration, the mean values of Cmax and AUC0‐∞ were 6.3 ± 2.8 μg/mL and 100.1 ± 29.2 μg·d/mL, respectively. The median terminal half‐life was similar for SC and IV administration (10.9 and 11.8 days, respectively). The overall mean bioavailability of SC golimumab was 51%, and absorption was similar for the 3 injection sites. Golimumab 100 mg was generally well tolerated in this study. Results support the flexibility in the choice of an injection site for SC administration of golimumab.
An Integrated Glucose‐Insulin Model to Describe Oral Glucose Tolerance Test Data in Healthy Volunteers
Authors: Silber Hanna E. , Frey Nicolas , Karlsson Mats O.
Published: November 2009

The extension of the previously developed integrated models for glucose and insulin (IGI) to include the oral glucose tolerance test (OGTT) in healthy volunteers could be valuable to better understand the differences between healthy individuals and those with type 2 diabetes mellitus (T2DM). Data from an OGTT in 23 healthy volunteers were used. Analysis was based on the previously developed intravenous model with extensions for glucose absorption and incretin effect on insulin secretion. The need for additional structural components was evaluated. The model was evaluated by simulation and a bootstrap. Multiple glucose and insulin concentration peaks were observed in most individuals as well as hypoglycemic episodes in the second half of the experiment. The OGTT data were successfully described by the extended basic model. An additional control mechanism of insulin on glucose production improved the description of the data. The model showed good predictive properties, and parameters were estimated with good precision. In conclusion, a previously presented integrated model has been extended to describe glucose and insulin concentrations in healthy volunteers following an OGTT. The characterization of the differences between the healthy and diabetic stages in the IGI model could potentially be used to extrapolate drug effect from healthy volunteers to T2DM.
Pharmacokinetics and Safety of Ginsenoside Rd Following a Single or Multiple Intravenous Dose in Healthy Chinese Volunteers
Authors: Zeng Xing , Deng Yuanhui , Feng Yi , Liu Yiming , Yang Liu , Huang Yu , Sun Jing , Liang Weixiong , Guan Yongyuan
Published: November 2009

The pharmacokinetics and safety of ginsenoside Rd (Rd) were assessed in healthy Chinese volunteers. In the single‐dose study, a randomized, open‐label, 3‐way crossover design was used. Participants were assigned to receive 10, 45, or 75 mg Rd by intravenous infusion, with a 2‐week washout period between dosing periods. Plasma levels of Rd were found to be proportional to dose, with the mean Cmaxand AUC0‐∞ranging from 2.8 to 19.3 mg/L and 27.9 to 212.5 mg·h/L over the dose range studied. Ginsenoside Rd was slowly cleared from plasma (t1/2Z= 17.7–19.3 hours). In the multiple‐dose study, 10 mg Rd was administered once daily for 6 days. Slight drug accumulation was noted. The mean steady‐state Cmax, AUC0‐∞, and AUCsswere 4.0 mg/L, 51.7 mg·h/L, and 26.4 mg·h/L, respectively. The t1/2Zwas 20.5 hours, which was similar to the single‐dose value. Ginsenoside Rd was well tolerated with no pattern of dose‐related adverse events. It had a favorable pharmacokinetic and safety profile that enables the drug to be explored in future clinical studies that target patients with acute ischemic stroke.
Esophageal Mucosal Injury With Low‐Dose Aspirin and Its Prevention by Rabeprazole
Authors: Sugimoto Mitsushige , Nishino Masafumi , Kodaira Chise , Yamade Mihoko , Ikuma Mutsuhiro , Tanaka Tatsuo , Sugimura Haruhiko , Hishida Akira , Furuta Takahisa
Published: November 2009

Aspirin is used widely as an antithrombotic drug for the prevention of cardiovascular and cerebrovascular events. Although aspirin increases the risk for gastrointestinal mucosal injury, the effect on esophageal mucosa is unclear. This study investigates whether aspirin induces esophageal mucosal injury and whether a proton‐pump inhibitor can prevent such injury in relation to CYP2C19 genotypes. Fifteen healthy Japanese volunteers are dosed for 7 days in a 5‐way randomly crossover trial: placebo, aspirin 100 mg, rabeprazole 10 mg, and aspirin 100 mg plus rabeprazole 10 mg either once daily or 4 times per day. All subjects undergo endoscopy and 24‐hour intragastric pH monitoring on day 7. With the aspirin regimen, esophageal mucosal disorders occur in 7 patients (46.7%) (5, grade M; 2, grade A). The median 24‐hour pH differs significantly among subjects who develop grade M or A gastroesophageal reflux disease and those who do not develop gastroesophageal reflux disease; the median pH in grade A gastroesophageal reflux disease is significantly lower (1.5 [range, 1.1–1.9]) than that in patients without gastroesophageal reflux disease (5.6 [range, 0.8–8.4], P = .04). Rabeprazole significantly inhibits acid secretion irrespective of CYP2C19 genotypes and decreases the incidence of aspirin‐related esophageal injury and symptoms according to increasing pH value. Aspirin induces esophageal mucosal injury in an acid‐dependent manner. Concomitant proton‐pump inhibitor therapy may prevent advanced effects of low‐dose aspirin.
Effects of Online Health Sources on Credibility and Behavioral Intentions
Authors: Hu Yifeng , Shyam Sundar S.
Published: November 2009

Online health information comes from a variety of online sources. Based on a typology of online sources, this research examines the direct and combined influences of original sources (doctors vs. laypersons) and selecting sources (Web sites vs. bulletin boards vs. blogs vs. personal home pages vs. Internet) on perceived credibility of—and behavioral intentions toward—health information. A large 2 (message) × 2 (original source) × 5 (selecting source) full-factorial online experiment revealed that respondents ( N = 555) were more likely to take action based on the information sourced from a Web site than from a blog or a personal home page. The effect was mediated by perceived level of gatekeeping and perceived information completeness. The analysis also yielded a three-way interaction between message, original source, and selecting source on perceived credibility, suggesting the operation of an appropriateness heuristic when evaluating source combinations for less relevant health topics. Theoretical and practical implications are discussed, leading to the proposal of a new online source typology.
Examining the Relation Between Racial Identity Attitude Clusters and Psychological Health Outcomes in African American College Students
Authors: Whittaker Valene A. , Neville Helen A.
Published: November 2009

Using Cross’s expanded Nigrescence theory, this study examined the relation between patterns of racial identity attitudes and mental health outcomes among a sample of 317 Black American college students. Racial identity attitudes were operationalized using the Cross Racial Identity Scale, and the mental health outcomes assessed included subjective well-being, hardiness, and general psychological health. Results from a cluster analysis indicated a five-cluster solution (Low Race Salience, Multiculturalist, Self-Hatred, Immersion, and Afrocentric), which for the most part is consistent with previous research. In addition, differential associations were found between cluster groups and psychological health outcomes, where participants in the Multiculturalist cluster reported greater levels of psychological well-being and those in the Immersion cluster group reported the lowest levels. The implications for these findings with respect to future research are discussed.
Statutory Union Recognition Provisions as Stimulants to Employer Anti-Unionism in Three Anglo-Saxon Countries
Authors: Gall Gregor
Published: November 2009

This article examines why employer opposition is stimulated by the introduction of statutory union recognition provisions in Britain, Ireland and the US. It examines the impact of the provisions for encouraging union organizing, which in turn stimulates employer anti-unionism, which then negates the intention of the provisions.
The effect of Diprivan (propofol) on phosphorylcholine surfaces during cardiopulmonary bypass — an in vitro investigation
Authors: Myers Gerard J , Voorhees Cheri , Eke Bob , Johnstone RenRen
Published: November 2009

It is well known that extracorporeal surfaces have the ability to bind such drugs as fentanyl, nitroglycerine and propofol. Adsorption of the injectable anesthetic agent Diprivan® (propofol) onto uncoated and heparin-coated extracorporeal surfaces during cardiopulmonary bypass (CPB) has been previously investigated; however, propofol adsorption onto synthetic-coated extracorporeal surfaces has not been published previously. The focus of this investigation was on the interaction of propofol and the synthetic biomimetic coating from the Sorin Group called Mimesys® (phosphorylcholine (PC)). A randomized series of six in vitro experiments were done with propofol using both PC-coated circuits without arterial filters and those with arterial filters. The circuits were identical in all experiments and priming remained the same, with 750 mls of normal saline and 1250 mls of fresh bovine blood (hematocrit 41.0 ± 1.0%). After circulation and collection of baseline samples, the first (low) dose of 4 mg (4000 mcg) of Diprivan 1% was added to the perfusate, followed by the second (high) dose of 40 mg (40,000 mcg) and the final challenge (extreme dose) of 356 mg (356,000 mcg) of Diprivan.

Drug assay was done by an independent laboratory, using the standardized method of High Performance Liquid Chromatography (HPLC). Measurements of total propofol were done at baseline, 20 minutes, 40 minutes and 60 minutes after each injection. Oxygenator performance was also measured prior to the addition of propofol and repeated after exposure to 4 mg, 40mg and 356 mg propofol for 60 min, 120 min and 180 minutes of circulation. Results indicate that phosphorylcholine coating does not prevent the adsorption of propofol during extracorporeal circulation and the oxygenator’s gas exchange ability is not affected by prolonged exposure to an extreme dose of the medication during high flow extracorporeal circulation.
Pharmacodynamic and pharmacokinetic effects of the intravenous CB1 receptor agonist Org 26828 in healthy male volunteers
Authors: Zuurman L , Passier P CCM , de Kam M L , Kleijn H J , Cohen A F , van Gerven J MA
Published: November 2009

An ideal drug for outpatient treatments under conscious sedation would have both sedative and analgesic properties. CB1/CB2 agonists are expected to have sedative, amnestic, analgesic and anti-emetic properties. The main objective of this first study in humans was to assess the sedative properties of intravenous Org 26828. In addition, pharmacokinetics, amnestic properties, postural stability, and behavioural and cardiovascular effects were studied. Midazolam intravenous 0.1 mg/kg and placebo were used as controls. The pharmacokinetic parameters (Cmax and AUC0-inf) of the main metabolite Org 26761 were proportional to dose. No effects were observed after doses up to 0.3 μg/kg of Org 26828. Dose-related effects were observed at higher doses. Although subjects reported subjective sedation after administration of Org 26828 at 3 and 6 μg/kg, the observed sedation was considerably less than after midazolam. Doses higher than the maximum tolerated dose of 1 μg/kg of Org 26828 caused unpleasant central nervous system effects (anxiety, paranoia, hallucinations). Therefore, Org 26828 is not suitable for providing sedation for outpatient surgical procedures.
Harms associated with psychoactive substances: findings of the UK National Drug Survey
Authors: Morgan Celia JA , Muetzelfeldt Leslie , Muetzelfeldt Mark , Nutt David J , Curran H. Valerie
Published: November 2009

Nutt and colleagues’ ‘rational’ scale to assess the harms of commonly used drugs was based on ratings by a panel of experts. This survey aimed to assess drug users’ views of the harms of drugs using the same scale. As users’ drug choices are not solely based on harms, we additionally assessed perceived benefits. The survey was hosted at http://www.nationaldrugsurvey.org. UK residents reported their experience of 20 commonly used substances; those with direct experience of a substance rated its physical, dependence-related and social harms as well as benefits. A total of 1501 users completed the survey. There was no correlation between the classification of the 20 drugs under the Misuse of Drugs Act and ranking of harms by users. Despite being unclassified substances, alcohol, solvents and tobacco were rated within the top ten most harmful drugs. There was a remarkably high correlation (r = 0.896) overall between rankings by users’ and by experts. Ecstasy, cannabis and LSD were ranked highest by users on both acute and chronic benefits. These findings imply that users are relatively well informed about the harms associated with the drugs they use. They also suggest that the current UK legal classification system is not acting to inform users of the harms of psychoactive substances.
Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania
Authors: Valvassori Samira S , Elias Guilherme , de Souza Bruna , Petronilho Fabrícia , Dal-Pizzol Felipe , Kapczinski Flávio , Trzesniak Clarissa , Tumas Vitor , Dursun Serdar , Nisihara Chagas Marcos Hortes , Hallak Jaime EC , Zuardi Antonio W , Quevedo João , Crippa José AS
Published: November 2009

Cannabidiol (CBD), a Cannabis sativa constituent, may present a pharmacological profile similar to mood stabilizing drugs, in addition to anti-oxidative and neuroprotective properties. The present study aims to directly investigate the effects of CBD in an animal model of mania induced by d-amphetamine (d-AMPH). In the first model (reversal treatment), rats received saline or d-AMPH (2 mg/kg) once daily intraperitoneal (i.p.) for 14 days, and from the 8th to the 14th day, they were treated with saline or CBD (15, 30 or 60 mg/kg) i.p. twice a day. In the second model (prevention treatment), rats were pretreated with saline or CBD (15, 30, or 60 mg/kg) regime i.p. twice a day, and from the 8th to the 14th day, they also received saline or d-AMPH i.p. once daily. In the hippocampus CBD (15 mg/kg) reversed the d-AMPH-induced damage and increased (30 mg/kg) brain-derived neurotrophic factor (BDNF) expression. In the second experiment, CBD (30 or 60 mg/kg) prevented the d-AMPH-induced formation of carbonyl group in the prefrontal cortex. In the hippocampus and striatum the d-AMPH-induced damage was prevented by CBD (15, 30 or 60 mg/kg). At both treatments CBD did not present any effect against d-AMPH-induced hyperactivity. In conclusion, we could not observe effects on locomotion, but CBD protect against d-AMPH-induced oxidative protein damage and increased BDNF levels in the reversal model and these effects vary depending on the brain regions evaluated and doses of CBD administered.
Double-blind, placebo-controlled comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR
Authors: Hewett Karen , Gee Michelle D , Krishen Alok , Wunderlich Hans-Peter , Le Clus Alfred , Evoniuk Gary , Modell Jack G
Published: November 2009

Bupropion, a noradrenaline/dopamine reuptake inhibitor, and venlafaxine, a serotonin/noradrenaline reuptake inhibitor, are both established antidepressants with proven efficacy in randomized controlled clinical trials. The objective of this double-blind, randomized, placebo- and active-controlled, eight-week, flexible-dose study was to evaluate the efficacy and tolerability of the once-daily extended-release formulations of these two antidepressants compared with placebo. Patients with major depressive disorder were randomized to once-daily treatment with bupropion XR 150 mg (n = 204), the extended-release formulation of venlafaxine (venlafaxine XR) 75 mg (n = 198) or placebo (n = 189) during weeks 1 to 4, with the option to double the dose at week 5 if response was inadequate. In this study, bupropion XR did not demonstrate statistically significant evidence of greater improvement from baseline compared with placebo on week 8 Montgomery Asberg Depression Rating scale scores (primary endpoint) or on secondary endpoints including CGI, HAM-A and responder and remitter analyses. Descriptive statistics for venlafaxine XR indicated separation versus placebo on MADRS total scores at week 8 and other intermediate time points, and on other endpoints including CGI, HAM-A and responder and remitter analyses. Both active treatments elicited improvement on the Sheehan Disability Scale and its subscales and were generally well tolerated at the doses studied. Rates of nausea, dry mouth, dizziness, hyperhidrosis, insomnia, constipation, tremor, anorexia and male sexual dysfunction were elevated in the venlafaxine XR group, consistent with its mixed serotonergic/noradrenergic mechanism. Rates of dry mouth, insomnia and hyperhidrosis were elevated in the bupropion XR group, consistent with its catecholaminergic mechanism.
Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus
Authors: dos Santos Lucinéia , de Andrade Telma GCS , Graeff Frederico G
Published: November 2009

The present work aimed to evaluate the effects of social separation for 14 days (chronic stress) and of withdrawal from a 14-day treatment with diazepam (acute stress) on the exploratory behaviour of male rats in the elevated plus-maze and on serotonin (5-hydroxytryptamine) turnover in different brain structures. Social separation had an anxiogenic effect, evidenced by fewer entries into, and less time spent on the open arms of the elevated plus-maze. Separation also selectively increased 5-hydroxytryptamine turnover in the hippocampus and median raphe nucleus. Diazepam withdrawal had a similar anxiogenic effect in grouped animals and increased 5-hydroxytryptamine turnover in the same brain structures. Chronic treatment with imipramine during the 14 days of separation prevented the behavioural and neurochemical changes caused by social separation. It is suggested that the increase in anxiety determined by both acute and chronic stress is mediated by the activation of the median raphe nucleus-hippocampal 5-hydroxytryptamine pathway.
Review: The biological basis of antipsychotic response in schizophrenia
Authors: Stone James M. , Raffin Marie , Morrison Paul , McGuire Philip K.
Published: November 2009

Schizophrenia is a severe mental illness affecting approximately 1% of the population worldwide. Antipsychotic drugs are effective in symptom control in up to two-thirds of patients, but in at least one-third of patients the response is poor. The reason for this is not clear, but one possibility is that good and poor responders have different neurochemical pathologies, and may therefore benefit from different treatment approaches. In this selective review we summarise research findings investigating the biological differences between patients with schizophrenia who show a good or a poor response to treatment with antipsychotic drugs.
Sex differences in affective response to opioid withdrawal during adolescence
Authors: Hodgson Stephen R , Hofford Rebecca S , Roberts Kris W , Eitan Dvora , Wellman Paul J , Eitan Shoshana
Published: November 2009

Drug withdrawal is suggested to play a role in precipitating mood disorders in individuals with familial predisposition. Age-related differences in affective responses to withdrawal might explain the increased risk of mental illnesses when drug use begins during adolescence. Recently we observed that, in contrast to adult male mice, adolescent males exhibited a decrease in immobility in the forced swim test on the third day of withdrawal, as compared with controls. Thus, the present study examined forced swim test behaviors of adolescent female mice during opioid withdrawal. Similar to the male study, adolescent female mice were injected with two morphine regimens which differed in dosage. Three and nine days following discontinuation of morphine administration, forced swim test immobility time and locomotion were evaluated. In contrast to males, which exhibited a decrease in immobility, no significant differences in immobility were observed in female adolescents undergoing withdrawal as compared with saline-injected controls. This sex difference in forced swim test behaviors was not due to changes in overall motor activity, since differences in locomotion were not observed in either male or female adolescent mice. Thus, this study demonstrates sex differences in forced swim test behavior during opioid withdrawal. Forced swim test behaviors are classically used to evaluate mood in rodents, thus this study suggests that opioid withdrawal might affect mood differentially across sexes.
Electrophysiological evidence of nicotine’s distracter-filtering properties in non-smokers
Authors: Knott Verner , Heenan Adam , Shah Dhrasti , Bolton Kiley , Fisher Derek , Villeneuve Crystal
Published: November 2009

Nicotine-enhanced attentional functions are purported to underlie improvements in behavioral performance in cognitive tasks but it is unclear as to whether these effects involve selective attention or attentional control under conditions of distraction. Behavioral and event-related potential measures were used to examine the effects of nicotine on distractibility in 21 non-smokers who were instructed to ignore task-irrelevant auditory stimuli while they performed a visual discrimination task. In a randomized, double-blind, placebo-controlled cross-over design, nicotine gum (6 mg) shortened overall reaction times but failed to prevent increased response slowing and errors caused by deviant sounds. Relative to placebo, nicotine did not modulate the early pre-attentive detection of deviants as reflected in the mismatch negativity but it attenuated the amplitude of the deviant-elicited P3a, an event-related potential component indexing the involuntary shifting of attention. Nicotine also enhanced attentional re-focusing back on to task-relevant stimuli following distraction as evidenced by an increased amplitude of the re-orienting negativity. These findings and the behavioral–electrophysiological dissociation seen with nicotine are discussed in relation to theories of attention and smoking motivation.
Combined treatment with quetiapine and sertindole in therapy refractory insomnia after clozapine discontinuation
Authors: Hanisch F , Friedemann J , Pillmann F
Published: November 2009

Insomnia associated with chronic schizophrenia and after clozapine discontinuation represents a common, but mostly not predominant, complaint and often does not respond sufficiently to classical hypnotics. We report the case of a 46-year-old patient with schizophrenia who developed a rebound insomnia confirmed by polysomnography after discontinuation of long-term treatment with clozapine and changing to sertindole therapy. Zolpidem, zolpiclone and chloral hydrate only led to short-term improvement of subjective sleep quality. An add-on therapy with 300 mg quetiapine resulted in improved subjective quality of sleep regarding sleep latency and the number of nocturnal awakenings. The combination of the two neuroleptics did not lead to increased QTc intervals (normal QTc < 450 ms) or metabolic side effects. In conclusion, the combination of sertindole and quetiapine might be a safe and effective combination in therapy-refractory insomnia after clozapine discontinuation in schizophrenia.
Effects of tyrosine/phenylalanine depletion on electrophysiological correlates of memory in healthy volunteers
Authors: Linssen Anke MW , Riedel Wim J , Sambeth Anke
Published: November 2009

Dopamine is well known for involvement in reinforcement, motor control and frontal lobe functions, such as attention and memory. Tyrosine/phenylalanine depletion (TPD) lowers dopamine synthesis and can therefore be used as a model to study the effects of low dopamine levels. This is the first study to assess the effect of TPD on memory performance and its electrophysiological correlates. In a double blind placebo (PLA)-controlled crossover design, 17 healthy volunteers (six males, 11 females) aged between 18 and 25 were tested after TPD and PLA. Working memory was assessed using a Sternberg memory scanning task (SMS) and episodic memory using the Visual Verbal Learning Test (VVLT). Simultaneously, event-related potentials (ERPs) were measured. The tyrosine and phenylalanine ratio was significantly reduced after TPD and increased after PLA. Working memory performance was not affected by TPD. However, ERP measures were affected by the treatment, indicating that TPD impaired stimulus processing during working memory performance. Episodic memory was not impaired after TPD. Again, alterations in ERP measures suggested adverse effects of TPD on memory-related processing. These results suggest that dopamine is involved in both working memory and episodic memory-related processing, although the effects are too small to be detected by performance measures.
Glucose enhancement of memory is modulated by trait anxiety in healthy adolescent males
Authors: Smith Michael A , Hii Hilary L , Foster Jonathan K , van Eekelen JAM
Published: November 2009

Glucose administration is associated with memory enhancement in healthy young individuals under conditions of divided attention at encoding. While the specific neurocognitive mechanisms underlying this ‘glucose memory facilitation effect’ are currently uncertain, it is thought that individual differences in glucoregulatory efficiency may alter an individual’s sensitivity to the glucose memory facilitation effect. In the present study, we sought to investigate whether basal hypothalamic–pituitary–adrenal axis function (itself a modulator of glucoregulatory efficiency), baseline self-reported stress and trait anxiety influence the glucose memory facilitation effect. Adolescent males (age range = 14–17 years) were administered glucose and placebo prior to completing a verbal episodic memory task on two separate testing days in a counter-balanced, within-subjects design. Glucose ingestion improved verbal episodic memory performance when memory recall was tested (i) within an hour of glucose ingestion and encoding, and (ii) one week subsequent to glucose ingestion and encoding. Basal hypothalamic–pituitary–adrenal axis function did not appear to influence the glucose memory facilitation effect; however, glucose ingestion only improved memory in participants reporting relatively higher trait anxiety. These findings suggest that the glucose memory facilitation effect may be mediated by biological mechanisms associated with trait anxiety.
During pregnancy, recreational drug-using women stop taking ecstasy (3,4-methylenedioxy-N-methylamphetamine) and reduce alcohol consumption, but continue to smoke tobacco and cannabis: initial findings from the Development and Infancy Study
Authors: Moore Derek G , Turner John D , Parrott Andrew C , Goodwin Julia E , Fulton Sarah E , Min Meeyoung O , Fox Helen C , Braddick Fleur MB , Axelsson Emma L , Lynch Stephanie , Ribeiro Helena , Frostick Caroline J , Singer Lynn T
Published: November 2009

While recreational drug use in UK women is prevalent, to date there is little prospective data on patterns of drug use in recreational drug-using women immediately before and during pregnancy. A total of 121 participants from a wide range of backgrounds were recruited to take part in the longitudinal Development and Infancy Study (DAISY) study of prenatal drug use and outcomes. Eighty-six of the women were interviewed prospectively while pregnant and/or soon after their infant was born. Participants reported on use immediately before and during pregnancy and on use over their lifetime. Levels of lifetime drug use of the women recruited were high, with women reporting having used at least four different illegal drugs over their lifetime. Most users of cocaine, 3,4-methylenedioxy-N-methylamphetamine (MDMA) and other stimulants stopped using these by the second trimester and levels of use were low. However, in pregnancy, 64% of the sample continued to use alcohol, 46% tobacco and 48% cannabis. While the level of alcohol use reduced substantially, average tobacco and cannabis levels tended to be sustained at pre-pregnancy levels even into the third trimester (50 cigarettes and/or 11 joints per week). In sum, while the use of ‘party drugs’ and alcohol seems to reduce, levels of tobacco and cannabis use are likely to be sustained throughout pregnancy. The data provide polydrug profiles that can form the basis for the development of more realistic animal models.
Evaluation of Rhodiola rosea L. extract on affective and physical signs of nicotine withdrawal in mice
Authors: Mattioli Laura , Perfumi Marina
Published: November 2009

The aim of the present study was to investigate the effects of a Rhodiola rosea L. extract on the prevention of the development of nicotine dependence and for the reduction of abstinence suffering following nicotine cessation in mice. Dependence was induced in mice by subcutaneous injections of nicotine (2 mg/kg, 4 times/day) for eight days. Spontaneous abstinence syndrome was evaluated 20 h after the last nicotine administration, by analysis of withdrawal signs, as affective (anxiety-like behaviour) and physical (somatic signs and locomotor activity). Rhodiola rosea L. extract was administered orally during nicotine treatment (10, 15 and 20 mg/kg) or during nicotine withdrawal (20 mg/kg). Results show that both affective and somatic signs (head shaking, paw tremors, body tremors, ptosis, jumping, piloerection and chewing) induced by nicotine withdrawal are abolished by administration of Rhodiola rosea L. extract in a dose-dependent fashion, during both nicotine exposure and nicotine cessation. In conclusion, our data encourage additional studies to define the use of R. rosea L. as a therapeutic approach in the treatment of smoking cessation.
Recognizing emotions in faces: effects of acute tryptophan depletion and bright light
Authors: aan het Rot Marije , Coupland Nicholas , Boivin Diane B , Benkelfat Chawki , Young Simon N
Published: November 2009

In healthy never-depressed individuals, acute tryptophan depletion (ATD) may selectively decrease the accurate recognition of fearful facial expressions. Here we investigated the perception of facial emotions after ATD in more detail. We also investigated whether bright light, which can reverse ATD’s mood-lowering effect, can also reverse its effect on the perception of facial emotions. On two separate test days, spent in a room that was either bright (n = 14) or dim (n = 16), healthy never-depressed women completed a facial emotion perception task six hours after ingesting tryptophan-deficient and balanced amino acid mixtures. Treatments were administered double blind and in randomized order using a crossover design. In dim light ATD decreased recognition accuracy of anger, disgust, and surprise. The labeling of fear and sadness was not affected. In bright light no effects of ATD were seen. Bright light was identified as a potential confounding factor in task performance. The effects of ATD on facial emotion perception may be less emotion-specific than thought previously, and occurred in a direction opposite to what might be expected based on theories of mood-congruent bias.