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1.  Systemic Administration of 8-OH-DPAT and Eticlopride, but not SCH23390, Alters Loss-Chasing Behavior in the Rat 
Neuropsychopharmacology  2013;38(6):1094-1104.
Gambling to recover losses is a common gaming behavior. In a clinical context, however, this phenomenon mediates the relationship between diminished control over gambling and the adverse socioeconomic consequences of gambling problems. Modeling loss-chasing through analogous behaviors in rats could facilitate its pharmacological investigation as a potential therapeutic target. Here, rats were trained to make operant responses that produced both food rewards, and unpredictably, imminent time-out periods in which rewards would be unavailable. At these decision points, rats were offered choices between waiting for these time-out periods to elapse before resuming responding for rewards (‘quit' responses), or selecting risky options with a 0.5 probability of avoiding the time-outs altogether and a 0.5 probability of time-out periods twice as long as signaled originally (‘chase' responses). Chasing behavior, and the latencies to chase or quit, during sequences of unfavorable outcomes were tested following systemic administration of the 5-HT1A receptor agonist, 8-OH-DPAT, the D2 receptor antagonist, eticlopride, and the D1 receptor antagonist, SCH23390. 8-OH-DPAT and eticlopride significantly reduced the proportion of chase responses, and the mean number of consecutive chase responses, in a dose-dependent manner. 8-OH-DPAT also increased latencies to chase. Increasing doses of eticlopride first speeded, then slowed, latencies to quit while SCH23390 had no significant effects on any measure. Research is needed to identify the precise cognitive mechanisms mediating these kinds of risky choices in rats. However, our data provide the first experimental demonstration that 5-HT1A and D2, but not D1, receptor activity influence a behavioral analog of loss-chasing in rats.
doi:10.1038/npp.2013.8
PMCID: PMC3629409  PMID: 23303072
5-HT1A receptors; addiction & substance abuse; behavioral science; D2 receptors; gambling; loss-chasing; neurotransmitters; psychiatry & behavioral sciences; gambling; loss-chasing; dopamine; serotonin; 5-HT1A receptors; D2 receptors
2.  I Want to Help You, But I Am Not Sure Why: Gaze-Cuing Induces Altruistic Giving 
Detecting subtle indicators of trustworthiness is highly adaptive for moving effectively amongst social partners. One powerful signal is gaze direction, which individuals can use to inform (or deceive) by looking toward (or away from) important objects or events in the environment. Here, across 5 experiments, we investigate whether implicit learning about gaze cues can influence subsequent economic transactions; we also examine some of the underlying mechanisms. In the 1st experiment, we demonstrate that people invest more money with individuals whose gaze information has previously been helpful, possibly reflecting enhanced trust appraisals. However, in 2 further experiments, we show that other mechanisms driving this behavior include obligations to fairness or (painful) altruism, since people also make more generous offers and allocations of money to individuals with reliable gaze cues in adapted 1-shot ultimatum games and 1-shot dictator games. In 2 final experiments, we show that the introduction of perceptual noise while following gaze can disrupt these effects, but only when the social partners are unfamiliar. Nonconscious detection of reliable gaze cues can prompt altruism toward others, probably reflecting the interplay of systems that encode identity and control gaze-evoked attention, integrating the reinforcement value of gaze cues.
doi:10.1037/a0033677
PMCID: PMC3970851  PMID: 23937180
gaze; joint attention; altruism
3.  A Quantitative Comparison of Human HT-1080 Fibrosarcoma Cells and Primary Human Dermal Fibroblasts Identifies a 3D Migration Mechanism with Properties Unique to the Transformed Phenotype 
PLoS ONE  2013;8(12):e81689.
Here, we describe an engineering approach to quantitatively compare migration, morphologies, and adhesion for tumorigenic human fibrosarcoma cells (HT-1080s) and primary human dermal fibroblasts (hDFs) with the aim of identifying distinguishing properties of the transformed phenotype. Relative adhesiveness was quantified using self-assembled monolayer (SAM) arrays and proteolytic 3-dimensional (3D) migration was investigated using matrix metalloproteinase (MMP)-degradable poly(ethylene glycol) (PEG) hydrogels (“synthetic extracellular matrix” or “synthetic ECM”). In synthetic ECM, hDFs were characterized by vinculin-containing features on the tips of protrusions, multipolar morphologies, and organized actomyosin filaments. In contrast, HT-1080s were characterized by diffuse vinculin expression, pronounced β1-integrin on the tips of protrusions, a cortically-organized F-actin cytoskeleton, and quantitatively more rounded morphologies, decreased adhesiveness, and increased directional motility compared to hDFs. Further, HT-1080s were characterized by contractility-dependent motility, pronounced blebbing, and cortical contraction waves or constriction rings, while quantified 3D motility was similar in matrices with a wide range of biochemical and biophysical properties (including collagen) despite substantial morphological changes. While HT-1080s were distinct from hDFs for each of the 2D and 3D properties investigated, several features were similar to WM239a melanoma cells, including rounded, proteolytic migration modes, cortical F-actin organization, and prominent uropod-like structures enriched with β1-integrin, F-actin, and melanoma cell adhesion molecule (MCAM/CD146/MUC18). Importantly, many of the features observed for HT-1080s were analogous to cellular changes induced by transformation, including cell rounding, a disorganized F-actin cytoskeleton, altered organization of focal adhesion proteins, and a weakly adherent phenotype. Based on our results, we propose that HT-1080s migrate in synthetic ECM with functional properties that are a direct consequence of their transformed phenotype.
doi:10.1371/journal.pone.0081689
PMCID: PMC3857815  PMID: 24349113
4.  White matter alterations in antipsychotic- and mood stabilizer-naïve individuals with bipolar II/NOS disorder☆ 
NeuroImage : Clinical  2013;3:271-278.
Structural magnetic resonance imaging (MRI) studies using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) have been inconsistent in demonstrating impairments in gray matter (GM) and white matter (WM) structures in bipolar disorder (BD). This may be a consequence of significant confounding effects of medication, illness history and selection of controls in existing studies. Study of bipolar II or not-otherwise-specified (BD II/NOS) disorder provides a solution to these confounds and a bridge to unipolar cases across the affective spectrum.
Thirty-eight euthymic, antipsychotic- and mood stabilizer-naïve young adults (mean age = 20.9 years) with BD II/NOS and 37 age-, cognitive ability- and gender-matched healthy controls (HCs) underwent MRI. Voxel-wise and regional gray matter volume comparisons were conducted using voxel-based morphometry (VBM). Tract-based spatial statistics (TBSS) were used to assess whole-brain WM, as indexed using fractional anisotropy (FA), mean diffusivity (MD), parallel and perpendicular diffusion values. No between-group differences were observed for whole-brain VBM comparisons. By contrast, in comparison to HCs, participants with BD II/NOS had significant widespread reductions in FA and increased MD and perpendicular diffusion values in virtually all the major cortical white matter tracts.
These data suggest pathophysiological involvement of WM microstructures – but not GM macrostructures – in high functioning BD II/NOS patients at an early age and before significant clinical adversity has been recorded. We propose that white matter development is a valid candidate target for understanding genetic and environmental antecedents to bipolar disorder and mood disorder more generally.
Highlights
•Antipsychotic- and mood stabilizer-naïve bipolar II/NOS participants underwent MRI.•Data analysis included tract-based spatial statistics and voxel-based morphometry.•Bipolar II/NOS participants had widespread reductions in fractional anisotropy.•We report alterations in white – but not gray – matter structures in bipolar II/NOS.
doi:10.1016/j.nicl.2013.08.005
PMCID: PMC3814955  PMID: 24273712
Bipolar II disorder; Bipolar disorder NOS; Diffusion tensor imaging; Voxel-based morphometry; Mood stabilizers; Antipsychotics
5.  Dopamine Modulates Risk-Taking as a Function of Baseline Sensation-Seeking Trait 
The Journal of Neuroscience  2013;33(32):12982-12986.
Trait sensation-seeking, defined as a need for varied, complex, and intense sensations, represents a relatively underexplored hedonic drive in human behavioral neuroscience research. It is related to increased risk for a range of behaviors including substance use, gambling, and risky sexual practice. Individual differences in self-reported sensation-seeking have been linked to brain dopamine function, particularly at D2-like receptors, but so far no causal evidence exists for a role of dopamine in sensation-seeking behavior in humans. Here, we investigated the effects of the selective D2/D3 agonist cabergoline on performance of a probabilistic risky choice task in healthy humans using a sensitive within-subject, placebo-controlled design. Cabergoline significantly influenced the way participants combined different explicit signals regarding probability and loss when choosing between response options associated with uncertain outcomes. Importantly, these effects were strongly dependent on baseline sensation-seeking score. Overall, cabergoline increased sensitivity of choice to information about probability of winning; while decreasing discrimination according to magnitude of potential losses associated with different options. The largest effects of the drug were observed in participants with lower sensation-seeking scores. These findings provide evidence that risk-taking behavior in humans can be directly manipulated by a dopaminergic drug, but that the effectiveness of such a manipulation depends on baseline differences in sensation-seeking trait. This emphasizes the importance of considering individual differences when investigating manipulation of risky decision-making, and may have relevance for the development of pharmacotherapies for disorders involving excessive risk-taking in humans, such as pathological gambling.
doi:10.1523/JNEUROSCI.5587-12.2013
PMCID: PMC3735881  PMID: 23926253
6.  Reduced Subjective Response to Acute Ethanol Administration Among Young Men with a Broad Bipolar Phenotype 
Neuropsychopharmacology  2012;37(8):1808-1815.
Elevated lifetime prevalence rates of alcohol use disorders (AUDs) are a feature of bipolar disorder (BD). Individuals at-risk for AUDs exhibit blunted subjective responses to alcohol (low levels of response), which may represent a biomarker for AUDs. Thus, individuals at-risk for BD may exhibit low responses to alcohol. Participants were 20 unmedicated adult males who reported high rates of hypomanic experiences (bipolar phenotype participants; BPPs), aged 18 to 21 years, and 20 healthy controls matched on age, gender, IQ, BMI, and weekly alcohol intake. Subjective and pharmacokinetic responses to acute alcohol (0.8 g/kg) vs placebo administration were collected in a randomized, double-blind, cross-over, placebo-controlled, within-subjects design. BPP participants reported significantly lower subjective intoxication effects (‘feel high': F=14.2, p=0.001; ‘feel effects': F=8.1, p=0.008) across time, but did not differ in their pharmacokinetic, stimulant, or sedative responses. Paradoxically, however, the BPP participants reported significantly higher expectations of the positive effects of alcohol than controls. Our results suggest that unmedicated young males with previous hypomanic experiences exhibit diminished subjective responses to alcohol. These blunted alcohol responses are not attributable to differences in weekly alcohol intake, pharmacokinetic effects (eg, absorption rates), or familial risk of AUDs. These observations suggest that the dampened intoxication may contribute to the increased rates of alcohol misuse in young people at-risk for BD, and suggest possible shared etiological factors in the development of AUDs and BD.
doi:10.1038/npp.2012.45
PMCID: PMC3376329  PMID: 22491350
alcohol abuse/dependence; bipolar disorder; adolescence; hypomania; mood; ethanol; alcohol and alcoholism; mood/anxiety/stress disorders; depression; unipolar/bipolar; psychopharmacology; adolescence; hypomania; mood; ethanol; bipolar disorder; alcohol use disorders
7.  Effect of Genetic Variation in LRRTM3 on Risk of Alzheimer Disease 
Archives of neurology  2012;69(7):894-900.
Objective
To explore the role of leucine-rich repeat transmembrane 3 (LRRTM3) in late-onset Alzheimer disease (AD) by independent genetic epidemiologic and functional studies.
Methods
First, we explored associations between LRRTM3 single-nucleotide polymorphisms and AD in the National Institute on Aging Late-Onset Alzheimer’s Disease case-control data set (993 patients and 884 control subjects) and a cohort of Caribbean Hispanics (549 patients and 544 controls) using single-marker and haplo-type analyses. Then we explored the effect of LRRTM3 small-hairpin RNAs on amyloid precursor protein processing.
Results
One single-nucleotide polymorphism in the promoter region (rs16923760; C allele: odds ratio,−0.74, P=.03), and a block of 4 single-nucleotide polymorphisms in intron 2 (rs1925608, C allele: 0.84, P=.04; rs7082306, A allele: 0.75, P=.04; rs1925609, T allele: 1.2, P=.03; and rs10997477, T allele: 0.88, P=.05) were associated with AD in the National Institute on Aging Late-Onset Alzheimer’s Disease data set or the Caribbean His-panic data set. The corresponding haplotypes were also associated with AD risk (.01< P<.05). In addition, LRRTM3 knockdown with small-hairpin RNAs caused a significant decrease in amyloid precursor protein processing (P<.05 to P<.01) compared with the scrambled small-hairpin RNA condition.
Conclusions
These complementary findings support the notions that genetic variation in LRRTM3 is associated with AD risk and that LRRTM3 may modulate γ-secretase processing of amyloid precursor protein. Additional studies are needed to determine whether the specific alleles associated with differential risk for AD indeed confer this risk through an effect of LRRTM3 expression levels that in turn modulates amyloid precursor protein processing.
doi:10.1001/archneurol.2011.2463
PMCID: PMC3391336  PMID: 22393166
8.  Dopamine Modulates Reward Expectancy During Performance of a Slot Machine Task in Rats: Evidence for a ‘Near-miss' Effect 
Neuropsychopharmacology  2011;36(5):913-925.
Cognitive accounts of gambling suggest that the experience of almost winning—so-called ‘near-misses'—encourage continued play and accelerate the development of pathological gambling (PG) in vulnerable individuals. One explanation for this effect is that near-misses signal imminent winning outcomes and heighten reward expectancy, galvanizing further play. Determining the neurochemical processes underlying the drive to gamble could facilitate the development of more effective treatments for PG. With this aim in mind, we evaluated rats' performance on a novel model of slot machine play, a form of gambling in which near-miss events are particularly salient. Subjects responded to a series of three flashing lights, loosely analogous to the wheels of a slot machine, causing the lights to set to ‘on' or ‘off'. A winning outcome was signaled if all three lights were illuminated. At the end of each trial, rats chose between responding on the ‘collect' lever, resulting in reward on win trials, but a time penalty on loss trials, or starting a new trial. Rats showed a marked preference for the collect lever when both two and three lights were illuminated, indicating heightened reward expectancy following near-misses similar to wins. Erroneous collect responses were increased by amphetamine and the D2 receptor agonist quinpirole, but not by the D1 receptor agonist SKF 81297 or receptor subtype selective antagonists. These data suggest that dopamine modulates reward expectancy following the experience of almost winning during slot machine play, via activity at D2 receptors, and this may result in an enhancement of the near-miss effect and facilitate further gambling.
doi:10.1038/npp.2010.230
PMCID: PMC3077261  PMID: 21209612
amphetamine; D2 receptor; extinction; gambling; quinpirole; reinstatement; dopamine; psychopharmacology; animal models; psychostimulants; gambling; extinction; reinstatement; amphetamine; quinpirole
9.  The Roles of Dopamine and Serotonin in Decision Making: Evidence from Pharmacological Experiments in Humans 
Neuropsychopharmacology  2010;36(1):114-132.
Neurophysiological experiments in primates, alongside neuropsychological and functional magnetic resonance investigations in humans, have significantly enhanced our understanding of the neural architecture of decision making. In this review, I consider the more limited database of experiments that have investigated how dopamine and serotonin activity influences the choices of human adults. These include those experiments that have involved the administration of drugs to healthy controls, experiments that have tested genotypic influences upon dopamine and serotonin function, and, finally, some of those experiments that have examined the effects of drugs on the decision making of clinical samples. Pharmacological experiments in humans are few in number and face considerable methodological challenges in terms of drug specificity, uncertainties about pre- vs post-synaptic modes of action, and interactions with baseline cognitive performance. However, the available data are broadly consistent with current computational models of dopamine function in decision making and highlight the dissociable roles of dopamine receptor systems in the learning about outcomes that underpins value-based decision making. Moreover, genotypic influences on (interacting) prefrontal and striatal dopamine activity are associated with changes in choice behavior that might be relevant to understanding exploratory behaviors and vulnerability to addictive disorders. Manipulations of serotonin in laboratory tests of decision making in human participants have provided less consistent results, but the information gathered to date indicates a role for serotonin in learning about bad decision outcomes, non-normative aspects of risk-seeking behavior, and social choices involving affiliation and notions of fairness. Finally, I suggest that the role played by serotonin in the regulation of cognitive biases, and representation of context in learning, point toward a role in the cortically mediated cognitive appraisal of reinforcers when selecting between actions, potentially accounting for its influence upon the processing salient aversive outcomes and social choice.
doi:10.1038/npp.2010.165
PMCID: PMC3055502  PMID: 20881944
dopamine; serotonin; psychiatry and behavioral sciences; value; choice; social; dopamine; serotonin; psychiatry and behavioral sciences; cognition; decision making; value; choice; social; risk
10.  Serotonin and Dopamine Play Complementary Roles in Gambling to Recover Losses 
Neuropsychopharmacology  2010;36(2):402-410.
Continued gambling to recover losses—‘loss chasing'—is a prominent feature of social and pathological gambling. However, little is known about the neuromodulators that influence this behavior. In three separate experiments, we investigated the role of serotonin activity, D2/D3 receptor activity, and beta-adrenoceptor activity on the loss chasing of age and IQ-matched healthy adults randomized to treatment or an appropriate control/placebo. In Experiment 1, participants consumed amino-acid drinks that did or did not contain the serotonin precursor, tryptophan. In Experiment 2, participants received a single 176 μg dose of the D2/D3 receptor agonist, pramipexole, or placebo. In Experiment 3, participants received a single 80 mg dose of the beta-adrenoceptor blocker, propranolol, or placebo. Following treatment, participants completed a computerized loss-chasing game. Mood and heart rate were measured at baseline and following treatment. Tryptophan depletion significantly reduced the number of decisions made to chase losses, and the number of consecutive decisions to chase, in the absence of marked changes in mood. By contrast, pramipexole significantly increased the value of losses chased and diminished the value of losses surrendered. Propranolol markedly reduced heart rate, but produced no significant changes in loss-chasing behavior. Loss chasing can be thought of as an aversively motivated escape behavior controlled, in part, by the marginal value of continued gambling relative to the value of already accumulated losses. Serotonin and dopamine appear to play dissociable roles in the tendency of individuals to gamble to recover, or to seek to ‘escape' from, previous losses. Serotonergic activity seems to promote the availability of loss chasing as a behavioral option, whereas D2/D3 receptor activity produces complex changes in the value of losses judged worth chasing. Sympathetic arousal, at least as mediated by beta-adrenoceptors, does not play a major role in laboratory-based loss-chasing choices.
doi:10.1038/npp.2010.170
PMCID: PMC3055672  PMID: 20980990
serotonin; dopamine; loss chasing; gambling; persistence; value; addiction and substance abuse; behavioral science; dopamine; serotonin; gambling; loss chasing; persistence; value
11.  Impact of Genetic Variation in SORCS1 on Memory Retention 
PLoS ONE  2011;6(10):e24588.
Objective
We previously reported that genetic variants in SORCS1 increase the risk of AD, that over-expression of SorCS1 reduces γ-secretase activity and Aβ levels, and that SorCS1 suppression increases γ-secretase processing of APP and Aβ levels. We now explored the effect of variation in SORCS1 on memory.
Methods
We explored associations between SORCS1-SNPs and memory retention in the NIA-LOAD case control dataset (162 cases,670 controls) and a cohort of Caribbean Hispanics (549 cases,544 controls) using single marker and haplotype analyses.
Results
Three SNPs in intron 1, were associated with memory retention in the NIA-LOAD dataset or the Caribbean Hispanic dataset (rs10884402(A allele:β = −0.15,p = 0.008), rs7078098(C allele:β = 0.18,p = 0.007) and rs950809(C allele:β = 0.17,p = 0.008)) and all three SNPs were significant in a meta-analysis of both datasets (0.002
Conclusions
Variation in intron 1 in SORCS1 is associated with memory changes in AD.
doi:10.1371/journal.pone.0024588
PMCID: PMC3202519  PMID: 22046233
Journal of General Internal Medicine  2010;25(10):1071-1077.
BACKGROUND
Given increasing interest in helping consumers choose high-performing (higher quality, lower cost) physicians, one approach chosen by several large employers is to provide assistance in the form of a telephonic “health coach” — a registered nurse who assists with identifying appropriate and available providers.
OBJECTIVE
To evaluate the health coach’s influence on provider choice and the quality of the user experience in the early introduction of this service.
DESIGN
Cross-sectional survey of 3490 employees and covered dependents of a large national firm that offered health coach services to all employees and covered dependents. The survey began in September 2007 with proportionate stratified sampling of 1750 employees and covered dependents who used the services between October 2007 and February 2008, and 1740 non-users.
PARTICIPANTS
Insured adults (ages 21–64) employed by a large national firm or covered dependents of employees.
MEASUREMENTS
Awareness of the service, reason for using service, visits to providers recommended by service, use of health advice provided by service, user satisfaction.
MAIN RESULTS
The primary reason for using the service was to obtain provider referrals (73%). Fifty-two percent of users sought a specialist referral, 33% a PCP referral and 9% a hospital referral. Eighty-nine percent of users seeking a provider referral were referred in-network; 81% of those referred visited the referred provider. Measures of satisfaction with both the service and the care delivered by recommended providers were over 70%.
CONCLUSIONS
Customers largely follow the provider recommendation of the health coach. Users express general satisfaction with existing health coach services, but differences in performance between vendors highlight the need for the services to be well implemented.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-010-1428-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s11606-010-1428-4
PMCID: PMC2955479  PMID: 20556533
health coach; physician referral; physician performance data; employee assistance program; survey
The Journal of infectious diseases  2010;202(2):302-312.
HIV-infected patients are at increased risk for development of pulmonary complications, including chronic obstructive pulmonary disease (COPD). Inflammation associated with sub-clinical infection has been postulated to promote COPD. Persistence of Pneumocystis (Pc) is associated with HIV and COPD, although a causal relationship has not been established. We used a simian/human immunodeficiency virus (SHIV) model of HIV infection to study pulmonary effects of Pc colonization. SHIV-infected/Pc-colonized monkeys developed progressive obstructive pulmonary disease characterized by increased emphysematous tissue and bronchial-associated lymphoid tissue. Elevated Th2 cytokines and pro-inflammatory mediators in bronchoalveolar lavage fluid coincided with Pc colonization and pulmonary function decline. These results support the concept that an infectious agent contributes to development of HIV-associated lung disease and suggests that Pc colonization may be a risk factor for the development of HIV-associated COPD. Furthermore, this model allows examination of early host responses important to disease progression thus identifying potential therapeutic targets for COPD.
doi:10.1086/653485
PMCID: PMC2946196  PMID: 20533880
Pneumocystis; COPD; SHIV; AIDS; HIV
Psychopharmacology  2005;189(4):505-516.
Rationale
A number of studies have compared ecstasy users to control groups on various measures of neuropsychological function in order to determine whether ecstasy use results in lasting cognitive deficits. However, few of those studies controlled adequately for non-ecstasy illicit drug use.
Objective
The aim of this study was to investigate neuropsychological function in chronic ecstasy users while controlling for polydrug use.
Methods
Neuropsychological function was assessed in four groups—30 current 3,4-methylenedioxymethamphetamine (MDMA) users with a little history of illicit drug use other than ecstasy and cannabis, 30 polydrug controls, 30 drug-naïve controls and 20 ex-MDMA users—using a battery of well-validated, computerized neuropsychological tests. The battery focused on memory, executive function, impulsivity and risk-taking.
Results
Few differences were apparent between the groups, and on no measure were the current MDMA users impaired significantly relative to the polydrug controls. However, within the current MDMA users, questionnaire-measured impulsivity correlated with performance on a number of tests—a relationship that was not apparent in the controls.
Conclusions
These data highlight the complexity in understanding the current ecstasy literature and suggest that some individuals may be particularly vulnerable to cognitive impairment following chronic use. Although no differences were identified between the current MDMA users and the controls, trait impulsiveness was significantly correlated with impairment on a number of neuropsychological outcome measures in the MDMA users, but not in the controls. These data suggest that impulsive individuals may be those most at risk for the development of cognitive impairment following chronic ecstasy use.
doi:10.1007/s00213-005-0101-9
PMCID: PMC2653936  PMID: 16163532
3,4-Methylenedioxymethamphetamine (MDMA); Ecstasy; Neuropsychology; Polydrug use; Executive function; Memory; Decision-making; Risk-taking; Impulsivity
Psychopharmacology  2006;188(2):213-227.
Rationale
3, 4-Methylenedioxymethamphetamine (MDMA or “ecstasy”) is a popular drug of abuse known to result in depletions of the serotonin (5-HT) system. A number of studies have reported that ecstasy users differ from controls on a variety of measures of cognitive function. However, the literature is not consistent and many negative findings were also reported. One reason for such inconsistency might be interindividual variance in vulnerability to the deleterious effects of ecstasy due to a number of factors, both genetic and environmental.
Objectives
To investigate the hypothesis that carriers of the s allele at the 5-HT transporter gene-linked polymorphic region (5-HTTLPR), which was associated with reduced serotonergic neurotransmission relative to the l allele, would be most vulnerable to the effects of ecstasy on cognitive function.
Methods
We assessed memory, decision-making, and executive function in ecstasy users and controls, stratifying by genotype at the 5-HTTLPR.
Results
We observed that the 5-HTTLPR genotype groups differed on a number of measures in both the ecstasy users and the controls. While performing a risky decision-making task, ss and ls controls attended to differences in the probability of winning chosen gambles to a greater extent than the ll controls. However, this difference was dramatically attenuated in the ss ecstasy users. Furthermore, independent of ecstasy use, volunteers of the ss genotype outperformed the ll genotype on a visual planning task.
Conclusions
The results are consistent with the hypothesis that cognitive impairment in ecstasy users may depend on genetic variation at the 5-HTTLPR.
doi:10.1007/s00213-006-0495-z
PMCID: PMC2585286  PMID: 16941121
Ecstasy (MDMA); Decision-making; Serotonin transporter-linked polymorphic region (5-HTTLPR); Neuropsychology; Memory; Executive function
Rationale: COPD is associated with reduced life expectancy.
Objectives: To determine the association between small airway pathology and long-term survival after lung volume reduction in chronic obstructive pulmonary disease (COPD) and the effect of corticosteroids on this pathology.
Methods: Patients with severe (GOLD-3) and very severe (GOLD-4) COPD (n = 101) were studied after lung volume reduction surgery. Respiratory symptoms, quality of life, pulmonary function, exercise tolerance, chest radiology, and corticosteroid treatment status were assessed preoperatively. The severity of luminal occlusion, wall thickening, and the presence of small airways containing lymphoid follicles were determined in resected lung tissue. Kaplan-Meier survival analysis and Cox proportional hazards models were used to determine the relationship between survival and small airway pathology. The effect of corticosteroids on this pathology was assessed by comparing treated and untreated groups.
Measurements and Main Results: The quartile of subjects with the greatest luminal occlusion, adjusted for covariates, died earlier than subjects who had the least occlusion (hazard ratio, 3.28; 95% confidence interval, 1.55–6.92; P = 0.002). There was a trend toward a reduction in the number of airways containing lymphoid follicles (P = 0.051) in those receiving corticosteroids, with a statistically significant difference between the control and oral ± inhaled corticosteroid–treated groups (P = 0.019). However, corticosteroid treatment had no effect on airway wall thickening or luminal occlusion.
Conclusions: Occlusion of the small airways by inflammatory exudates containing mucus is associated with early death in patients with severe emphysema treated by lung volume reduction surgery. Corticosteroid treatment dampens the host immune response in these airways by reducing lymphoid follicles without changing wall thickening and luminal occlusion.
doi:10.1164/rccm.200612-1772OC
PMCID: PMC1976540  PMID: 17556723
premature death in COPD; airway remodeling; mucosal immune response; corticosteroids
Brain imaging and behavior  2007;1(3-4):43-57.
To achieve greater understanding of the brain mechanisms underlying nicotine craving in female smokers, we examined the influence of nicotine non-abstinence vs. acute nicotine abstinence on cue-elicited activation of the ventral striatum. Eight female smokers underwent an event-related functional magnetic resonance imaging (fMRI) paradigm presenting randomized sequences of smoking-related and non-smoking related pictures. Participants were asked to indicate by a key press the gender of individuals in smoking-related and non-smoking related pictures (gender discrimination task), to maintain and evaluate attention to the pictures. There was a significant effect of smoking condition on reaction times (RT) for a gender discrimination task intended to assess and maintain attention to the photographs—suggesting a deprivation effect of acute nicotine abstinence and a statistical trend indicating greater RTs for smoking cues than neutral cues. BOLD contrast (smoking vs. non-smoking cues) was greater in the non-abstinent vs. acutely abstinent conditions in the ventral striatum including the nucleus accumbens (VS/NAc). Moreover, a significant positive correlation was observed between baseline cigarette craving prior to scanning and VS/NAc activation (r=0.84, p=0.009), but only in the non-abstinent condition. These results may either be explained by ceiling effects of nicotine withdrawal in the abstinent condition or, may indicate reduced relative activation (smoking vs. neutral contrast) in the VS/NAc in the abstinent vs. non-abstinent conditions in this group of female smokers.
doi:10.1007/s11682-007-9004-1
PMCID: PMC2367252  PMID: 18458752
fMRI; Smoking; Tobacco; Cue reactivity; Ventral striatum; Nucleus accumbens
Applied Microbiology  1972;23(2):423-424.
Sodium nitrite formed by nitrate reduction produced a false-negative reaction in the detection of indole formation when both tests were conducted in one medium.
PMCID: PMC380356  PMID: 4552894
Journal of Clinical Investigation  1970;49(2):335-345.
The instantaneous uptake of CO in the lungs was measured with a water-filled body plethysmograph in normal man. First, control measurements of plethysmograph pressure were made while the subject held his breath for 7 sec after breathing gas mixtures prepared to bring his alveolar PO2 and PCO2 close to mixed venous levels. Then, CO uptake measurements were made while he held his breath after inhaling the same gas mixtures with added CO (2.0%). The change in lung volume on CO minus the change in lung volume during the control measurement was a measure of the CO uptake in the lungs. Cardiopneumatic changes in lung gas volume were subtracted electrically. All of five subjects showed pulsatile CO uptake. The mean CO uptake was 103 ml/min. A peak uptake of 2.0 (range 1.6-2.3) times the mean uptake occurred 0.3-0.4 sec after the R wave of the EKG and a minimum uptake of 0.4 (range 0.2-0.5) times the mean uptake occurred during the tenth of a second before the R wave of the EKG. These results suggest that pulmonary capillary blood volume is pulsatile during the cardiac cycle.
PMCID: PMC322475  PMID: 5411784
Psychological Science  2014;25(7):1303-1313.
How do people sustain resources for the benefit of individuals and communities and avoid the tragedy of the commons, in which shared resources become exhausted? In the present study, we examined the role of serotonin activity and social norms in the management of depletable resources. Healthy adults, alongside social partners, completed a multiplayer resource-dilemma game in which they repeatedly harvested from a partially replenishable monetary resource. Dietary tryptophan depletion, leading to reduced serotonin activity, was associated with aggressive harvesting strategies and disrupted use of the social norms given by distributions of other players’ harvests. Tryptophan-depleted participants more frequently exhausted the resource completely and also accumulated fewer rewards than participants who were not tryptophan depleted. Our findings show that rank-based social comparisons are crucial to the management of depletable resources, and that serotonin mediates responses to social norms.
doi:10.1177/0956797614527830
PMCID: PMC4230382  PMID: 24815611
social behavior; social influences; neurotransmitters
Journal of Clinical Investigation  1968;47(12):2569-2579.
Airway conductance is known to increase with an increase in the lung volume at which it is measured, owing to a change in transpulmonary pressure and lung tissue tension. We investigated the effect of surgical resection of lung tissue on functional residual capacity and airway conductance in patients with localized lung disease (i.e., carcinoma or tuberculosis) and in patients with lung cysts or bullous emphysema. In four out of five of the patients who had resection of one or more lobes of the lung to remove localized disease there was a reduction both in the airway conductance and in the functional residual capacity with relatively little change in the conductance volume ratio.
By contrast, in all patients who underwent bullectomy, there was a decrease in functional residual capacity but an increase in airway conductance, and an increase in the conductance/volume ratio. This change was sustained in patients who had had localized cysts removed. However, the measurements gradually reverted toward preoperative values in those patients who had generalized emphysema.
The increase in airway conductance after resection of blebs and bullae presumably was due to improved lung elastic pressure causing the airways to increase in diameter and conductance. In addition, some patients may have experienced relief of compression of neighboring airways.
PMCID: PMC297427  PMID: 5725275

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