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1.  Fluorescent substrates for flow cytometric evaluation of efflux inhibition in ABCB1, ABCC1, and ABCG2 transporters 
Analytical biochemistry  2013;437(1):77-87.
ATP binding cassette (ABC) transmembrane efflux pumps such as P-glycoprotein (ABCB1), multidrug resistance protein 1 (ABCC1), and breast cancer resistance protein (ABCG2) play an important role in anti-cancer drug resistance. A large number of structurally and functionally diverse compounds act as substrates or modulators of these pumps. In vitro assessment of the affinity of drug candidates for multidrug resistance proteins is central to predict in vivo pharmacokinetics and drug–drug interactions. The objective of this study was to identify and characterize new substrates for these transporters. As part of a collaborative project with Life Technologies, 102 fluorescent probes were investigated in a flow cytometric screen of ABC transporters. The primary screen compared substrate efflux activity in parental cell lines with their corresponding highly expressing resistant counterparts. The fluorescent compound library included a range of excitation/emission profiles and required dual laser excitation as well as multiple fluorescence detection channels. A total of 31 substrates with active efflux in one or more pumps and practical fluorescence response ranges were identified and tested for interaction with eight known inhibitors. This screening approach provides an efficient tool for identification and characterization of new fluorescent substrates for ABCB1, ABCC1, and ABCG2.
PMCID: PMC3785545  PMID: 23470221
Efflux inhibition; ABCB1; ABCC1; ABCG2; Fluorescent substrate; Flow cytometry
2.  Conduct Disorder and Initiation of Substance Use: A Prospective Longitudinal Study 
To examine the influence of conduct disorder (CD) on substance initiation.
Community adolescents without CD (n= 1165, mean baseline age= 14.6), with CD (n= 194, mean baseline age= 15.3), and youth with CD recruited from treatment (n=268, mean baseline age= 15.7) were prospectively followed and re-interviewed during young adulthood (mean ages at follow-up respectively: 20, 20.8, and 24). Young adult retrospective reports of age of substance initiation for 10 substance classes were analyzed using Cox regression analyses. Hazard ratios of initiation for the CD cohorts (community without CD as the reference) at ages 15, 18, and 21 were calculated, adjusting for baseline age, gender, and race.
Among community subjects, CD was associated with elevated adjusted hazards for initiation of all substances, with comparatively greater hazard ratios of initiating illicit substances at age 15. By age 18, the adjusted hazard ratios remained significant except for alcohol. At age 21, the adjusted hazard ratios were significant only for cocaine, amphetamines, inhalants and club drugs. A substantial portion of community subjects without CD never initiated illicit substances. Clinical youth with CD demonstrated similar patterns, with comparatively larger adjusted hazard ratios.
CD confers increase risk for substance initiation across all substance classes at age 15 with greater relative risk for illicit substances compared to licit substances. This effect continues until age 18, with the weakest effect for alcohol. It further diminishes for other substances by 21; although, the likelihood of initiating cocaine, amphetamines, inhalants and club drugs among those who have not initiated yet continues to be highly elevated by 21.
PMCID: PMC3813459  PMID: 23622852
conduct disorder; substance use disorders
3.  A Selective ATP-binding Cassette Sub-family G Member 2 Efflux Inhibitor Revealed Via High-Throughput Flow Cytometry 
Chemotherapeutics tumor resistance is a principal reason for treatment failure and clinical and experimental data indicate that multidrug transporters such as ATP-binding Cassette (ABC) B1 and ABCG2 play a leading role by preventing cytotoxic intracellular drug concentrations. Functional efflux inhibition of existing chemotherapeutics by these pumps continues to present a promising approach for treatment. A contributing factor to the failure of existing inhibitors in clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We have identified selective efflux inhibitors by profiling multiple ABC transporters against a library of small molecules to find molecular probes to further explore such interactions. In our primary screening protocol using JC-1 as a dual-pump fluorescent reporter substrate we identified a piperazine substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused SAR-driven chemistry effort we describe compound 1 (CID44640177), an efflux inhibitor with selectivity toward ABCG2 over ABCB1. Compound 1 is also shown to potentiate the activity of mitoxantrone in vitro as well as preliminarily in vivo in an ABCG2 over-expressing tumor model. At least two analogs significantly reduce tumor size in combination with the chemotherapeutic topotecan. To our knowledge, low nanomolar chemoreversal activity coupled with direct evidence of efflux inhibition for ABCG2 is unprecedented.
PMCID: PMC3623016  PMID: 22923785
Multi-drug resistance; ABC Transporter; ABCG2; ABCB1; Efflux inhibition
4.  The effectiveness of police custody assessments in identifying suspects with intellectual disabilities and attention deficit hyperactivity disorder 
BMC Medicine  2013;11:248.
Intellectual Disabilities (ID) and Attention Deficit Hyperactivity Disorder (ADHD) are recognized psychological vulnerabilities in police interviews and court proceedings in England and Wales. The aims of this study were to investigate: (a) the prevalence of ID and/or ADHD among suspects detained at a large London metropolitan police station and their relationship with conduct disorder (CD), (b) the impact of their condition on police staff resources, (c) the effectiveness of current custody assessment tools in identifying psychological vulnerabilities, and (d) the use of ‘Appropriate Adults’ in interviews.
A total of 200 individuals in a police custody suite were interviewed and screened for ID, ADHD (current symptoms) and CD.
The screening rates for these three disorders were 6.7%, 23.5% and 76.3%, respectively. ADHD contributed significantly to increased requests being made of staff after controlling for CD and duration of time in custody. This is a novel finding. Reading and writing difficulties and mental health problems were often identified from the custody risk assessment tools, but they were not used effectively to inform on the need for the use of an Appropriate Adult. The frequency with which Appropriate Adults were provided to support detainees in police interviews (4.2%) remains almost identical to that found in a similar study conducted 20 years previously.
The current findings suggest that in spite of reforms recently made in custodial settings, procedures may not have had the anticipated impact of improving safeguards for vulnerable suspects. Detainees with ID and ADHD require an Appropriate Adult during police interviews and other formal custody procedures, which they commonly do not currently receive. The findings of the current study suggest this may be due, in large part, to the ineffective use of risk-assessment tools and healthcare professionals, which represent missed opportunities to identify such vulnerabilities.
PMCID: PMC3879086  PMID: 24261542
Intellectual disabilities; ADHD; Conduct disorder; IQ; Risk assessment; Police
5.  A non-randomised controlled trial of the R&R2MHP cognitive skills program in high risk male offenders with severe mental illness 
BMC Psychiatry  2013;13:267.
The growing popularity of offending behavior programs has led to the interest of whether such programs are effective with mentally disordered offenders. This study aimed to evaluate the effectiveness of the Reasoning and Rehabilitation program adapted for offenders with severe mental illness (R&R2 MHP).
A sample of 59 adult high risk males detained in a high secure hospital completed questionnaires at baseline and post treatment to assess violent attitudes, anger, coping processes and social problem-solving. An informant measure of social and psychological functioning, including disruptive behavior, was completed by staff at the same time. The data of 30 patients who participated in the group condition were compared using intention to treat analysis with 29 controls who received treatment as usual.
80% of group participants completed the program. In contrast to controls, significant medium-large treatment effects were found at outcome on self-reported measures of violent attitudes, social problem-solving and coping processes. Improvements were endorsed by informant ratings of disruptive behavior, social and psychological functioning.
The R&R2MHP had a comparatively low dropout rate and was effective in a sample of high risk mentally disordered offenders requiring detention in high security. Future research should use a randomized controlled design.
Trial registration
Current Controlled Trials ACTRN12613000216718.
PMCID: PMC3853927  PMID: 24498962
Mentally disordered offenders; Treatment outcome; Reasoning & Rehabilitation; Cognitive skills
6.  Behavioral Disinhibition and Sexual Risk Behavior among Adolescents and Young Adults in Malawi 
PLoS ONE  2013;8(9):e73574.
While behavioral factors such as early age of sexual debut, inconsistent use of condoms and multiple sexual partners have been studied in Africa, less is known about how characteristics such as impulsivity and externalizing behaviors relate to HIV-related sexual risk-taking in that region. The purpose of this study was to develop a culturally adapted behavioral disinhibition index in a sample of adolescents and young adults in Malawi. We then sought to examine the relationship between the index and sexual risk behavior as measured by multiple sexual partners and number of lifetime sexual partners.
Cross-sectional data were collected from 2342 participants in rural Malawi aged 15 to 29 years. We constructed a disinhibitory behavior score (DBS) using questions assessing disinhibitory behaviors. Bivariate analyses were conducted to assess the relationships among the individual DBS component behaviors. We utilized multivariable logistic regression to determine the association of the DBS with multiple sexual partners, and negative binomial regression to model the relationship between the DBS and number of lifetime sexual partners.
Nearly all the DBS component behaviors were significantly associated in the bivariate analyses. The DBS was associated with having multiple sexual partners (OR 1.97; 95% CI 1.57–2.48) in the multivariable logistic regression analysis. Further, negative binomial regression results demonstrated that the DBS was associated with an increased number of lifetime sexual partners (OR 1.11; 95% CI 1.07–1.16).
HIV preventive programs in Africa should take into consideration disinhibitory behaviors that may be associated with sexual risk-taking. The DBS can be used as a simple tool to identify those who may be more likely to engage in these behaviors and provide useful information regarding which groups of individuals particularly need to be targeted for behavior change interventions.
PMCID: PMC3767775  PMID: 24039987
Drug and alcohol dependence  2012;123(0 1):S52-S58.
The cross-drug relationship of subjective experiences between alcohol, tobacco, and marijuana and problem drug use behaviors were examined. Data were drawn from 3853 individuals between the ages of 11 and 30 years of age participating in the Colorado Center on Antisocial Drug Dependence [CADD]. Subjective experiences were assessed using a 13-item questionnaire that included positive and negative responses for alcohol, tobacco, and marijuana. Lifetime abuse and dependence on these three drugs was assessed using the Composite International Diagnostic Interview, Substance Abuse Module [CIDI-SAM].
Positive and negative subjective experience scales were similar for alcohol, tobacco, and marijuana, although the hierarchical ordering of items differed by drug. Subjective experience scales for each of the three drugs examined correlated significantly, with the strongest relationship being for alcohol and marijuana experiences. Significant associations were identified between how a person experienced a drug and abuse and dependence status for the same or different drug.
Cross-drug relationships provide evidence for a common liability or sensitivity towards responding in a similar manner to drugs of abuse within and across different pharmacological classes.
PMCID: PMC3729264  PMID: 22445481
Subjective effects; alcohol; tobacco; marijuana
8.  Genetic Etiology of the Common Liability to Drug Dependence: Evidence of Common and Specific Mechanisms for DSM-IV Dependence Symptoms 
Drug and Alcohol Dependence  2012;123S1:S24-S32.
We investigated the etiological nature of comorbid alcohol, tobacco, and cannabis DSM-IV dependence symptoms in late adolescence and young adulthood while accounting for gender differences in the magnitude of genetic and environmental influences.
Univariate and multivariate twin modeling was used to determine the heritability of each substance and the etiology of multiple drug problems in a sample of 2484 registrants of the Center for Antisocial Drug Dependence who provided data at the second wave of an ongoing longitudinal study. We report on mean and prevalence levels of whole-life DSM-IV dependence symptoms that were assessed with the Composite International Diagnostic Interview-Substance Abuse Module. Biometrical analyses were limited to age-adjusted DSM-IV dependence symptom counts from a subset of twins that reported using alcohol, tobacco, or cannabis in their lifetime.
Male and female alcohol, tobacco, and cannabis DSM-IV symptoms are indicators of a heritable unidimensional latent continuous trait. Additive genetic factors explain more than 60% of the common liability to drug dependence. A larger proportion of the variation in each substance is attributable to substance-specific genetic and environmental factors.
These data suggest that both common and substance-specific genetic and environmental factors contribute to individual differences in the levels of DSM-IV alcohol, tobacco, and cannabis dependence symptoms.
PMCID: PMC3342475  PMID: 22243758
Alcohol; Tobacco; Cannabis; Young Adulthood; Dependence; Heritability
9.  Externalizing Behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster 
Behavior genetics  2011;42(3):402-414.
There is strong evidence for shared genetic factors contributing to childhood externalizing disorders and substance abuse. Externalizing disorders often precede early substance experimentation, leading to the idea that individuals inherit a genetic vulnerability to generalized disinhibitory psychopathology. Genetic variation in the CHRNA5/CHRNA3/CHRNB4 gene cluster has been associated with early substance experimentation, nicotine dependence, and other drug behaviors. This study examines whether the CHRNA5/CHRNA3/CHRNB4 locus is correlated also with externalizing behaviors in three independent longitudinally assessed adolescent samples. We developed a common externalizing behavior phenotype from the available measures in the three samples, and tested for association with 10 SNPs in the gene cluster. Significant results were detected in two of the samples, including rs8040868, which remained significant after controlling for smoking quantity. These results expand on previous work focused mainly on drug behaviors, and support the hypothesis that variation in the CHRNA5/CHRNA3/CHRNB4 locus is associated with early externalizing behaviors.
PMCID: PMC3506120  PMID: 22042234
nicotinic receptor genes; externalizing behaviors; association study; disinhibition; drug behaviors
10.  Identification of a small molecule yeast TORC1 inhibitor with a flow cytometry-based multiplex screen 
ACS Chemical Biology  2012;7(4):715-722.
TOR (target of rapamycin) is a serine/threonine kinase, evolutionarily conserved from yeast to human, which functions as a fundamental controller of cell growth. The moderate clinical benefit of rapamycin in mTOR-based therapy of many cancers favors the development of new TOR inhibitors. Here we report a high throughput flow cytometry multiplexed screen using five GFP-tagged yeast clones that represent the readouts of four branches of the TORC1 signaling pathway in budding yeast. Each GFP-tagged clone was differentially color-coded and the GFP signal of each clone was measured simultaneously by flow cytometry, which allows rapid prioritization of compounds that likely act through direct modulation of TORC1 or proximal signaling components. A total of 255 compounds were confirmed in dose-response analysis to alter GFP expression in one or more clones. To validate the concept of the high throughput screen, we have characterized CID 3528206, a small molecule most likely to act on TORC1 as it alters GFP expression in all five GFP clones in an analogous manner to rapamycin. We have shown that CID 3528206 inhibited yeast cell growth, and that CID 3528206 inhibited TORC1 activity both in vitro and in vivo with EC50s of 150 nM and 3.9 μM, respectively. The results of microarray analysis and yeast GFP collection screen further support the notion that CID 3528206 and rapamycin modulate similar cellular pathways. Together, these results indicate that the HTS has identified a potentially useful small molecule for further development of TOR inhibitors.
PMCID: PMC3331904  PMID: 22260433
11.  Occupational issues of adults with ADHD 
BMC Psychiatry  2013;13:59.
ADHD is a common neurodevelopmental disorder that persists into adulthood. Its symptoms cause impairments in a number of social domains, one of which is employment. We wish to produce a consensus statement on how ADHD affects employment.
This consensus development conference statement was developed as a result of a joint international meeting held in July 2010. The consensus committee was international in scope (United Kingdom, mainland Europe, United Arab Emirates) and consisted of individuals from a broad range of backgrounds (Psychiatry, Occupational Medicine, Health Economists, Disability Advisors). The objectives of the conference were to discuss some of the occupational impairments adults with ADHD may face and how to address these problems from an inclusive perspective. Furthermore the conference looked at influencing policy and decision making at a political level to address impaired occupational functioning in adults with ADHD and fears around employing people with disabilities in general.
The consensus was that there were clear weaknesses in the current arrangements in the UK and internationally to address occupational difficulties. More so, Occupational Health was not wholly integrated and used as a means of making positive changes to the workplace, but rather as a superfluous last resort that employers tried to avoid. Furthermore the lack of cross professional collaboration on occupational functioning in adults with ADHD was a significant problem.
Future research needs to concentrate on further investigating occupational functioning in adults with ADHD and pilot exploratory initiatives and tools, leading to a better and more informed understanding of possible barriers to employment and potential schemes to put in place to address these problems.
PMCID: PMC3599848  PMID: 23414364
12.  The role of language in Concern and Disregard for others in the first years of life 
Developmental psychology  2012;49(2):197-214.
We examined the associations between language skills and Concern and Disregard for Others in young children assessed longitudinally at ages 14, 20, 24, and 36 months, testing the hypothesis that language skills have a specific role (distinct from that of general cognitive ability) in the development of Concern and Disregard for Others. We found that higher language skills predicted higher Concern for Others and lower Disregard for Others even after controlling for general cognitive ability, whereas the association between general cognitive ability and Concern/Disregard for Others was not significant after controlling for language skills. Language skills at 14 months predicted Concern for Others at 36 months, and results suggested that the relations between language skills and Concern and Disregard for Others begin early in development. Gender differences in Concern and Disregard for Others were at least partially explained by differences in language skills. These results support the specific role of language skills in Concern and Disregard for Others.
PMCID: PMC3410981  PMID: 22545842
empathy; hostility; concern for others; disregard for others; intelligence; verbal ability; language skills; sex differences
13.  Early concern and disregard for others as predictors of antisocial behavior 
Prediction of antisocial behavior is important given its adverse impact on both the individuals engaging in antisocial behavior and society. Additional research identifying early predictors of future antisocial behavior, or antisocial propensity, is needed. The present study tested the hypothesis that both concern for others and active disregard for others in distress in toddlers and young children predict antisocial behavior during middle childhood and adolescence.
A representative sample of same-sex twins (N = 956) recruited in Colorado was examined. Mother-rated and researcher-observed concern and disregard for others assessed at age 14 to 36 months were examined as predictors of parent- (age 4 to 12), teacher- (age 7 to 12), and self-reported (age 17) antisocial behavior.
Observed disregard for others predicted antisocial behavior assessed by three different informants (parents, teachers, and self), including antisocial behavior assessed 14 years later. It also predicted a higher-order antisocial behavior factor (β = .58, p < .01) after controlling for observed concern for others. Mother-rated disregard for others predicted parent-reported antisocial behavior. Contrary to predictions, neither mother-rated nor observed concern for others inversely predicted antisocial behavior. Results of twin analyses suggested that the covariation between observed disregard for others and antisocial behavior was due to shared environmental influences.
Disregard for others in toddlerhood/early childhood is a strong predictor of antisocial behavior in middle childhood and adolescence. The results suggest the potential need for early assessment of disregard for others and the development of potential interventions.
PMCID: PMC3547395  PMID: 23320806
antisocial behavior; empathy; concern for others; disregard for others
14.  Rates of undiagnosed attention deficit hyperactivity disorder in London drug and alcohol detoxification units 
BMC Psychiatry  2012;12:223.
ADHD is a common childhood onset mental health disorder that persists into adulthood in two-thirds of cases. One of the most prevalent and impairing comorbidities of ADHD in adults are substance use disorders. We estimate rates of ADHD in patients with substance abuse disorders and delineate impairment in the co-morbid group.
Screening for ADHD followed by a research diagnostic interview in people attending in-patient drug and alcohol detoxification units.
We estimated prevalence of undiagnosed ADHD within substance use disorder in-patients in South London around 12%. Those individuals with substance use disorders and ADHD had significantly higher self-rated impairments across several domains of daily life; and higher rates of substance abuse and alcohol consumption, suicide attempts, and depression recorded in their case records.
This study demonstrates the high rates of untreated ADHD within substance use disorder populations and the association of ADHD in such patients with greater levels of impairment. These are likely to be a source of additional impairment to patients and represent an increased burden on clinical services.
PMCID: PMC3537519  PMID: 23216993
15.  Strategies for characterizing complex phenotypes and environments: General and specific family environmental predictors of young adult tobacco dependence, alcohol use disorder, and co-occurring problems* 
Drug and alcohol dependence  2011;118(2-3):444-451.
Defining phenotypes in studies of tobacco and alcohol misuse is difficult because of the complexity of these behaviors and their strong association with each other and with other problem behaviors. The present paper suggests a strategy for addressing this issue by conceptualizing and partitioning variance in phenotypes into either general or substance/behavior-specific. The paper also applies the general or substance/behavior-specific conceptualization to environmental predictors of tobacco and alcohol misuse and other problem behaviors.
Data were drawn from the Seattle Social Development Project, a contemporary, ethnically diverse and gender balanced longitudinal panel including 808 participants. Latent variable modeling was used to partition variance in young adult (age 24) nicotine dependence, alcohol abuse and dependence, illicit drug abuse and dependence, involvement in crime, and engagement in HIV sexual risk behavior into general problem behavior and behavior-specific variance. Similarly, measures of general, drinking-specific, and smoking-specific adolescent family environment were constructed.
Consistent with expectations, more positive general family environment during adolescence was associated with lower levels of shared variance in problem behaviors at age 24, but not with unique variance in tobacco or alcohol use disorder. Higher levels of family smoking and drinking environments during adolescence, however, were positively associated with unique variance in tobacco and alcohol use disorder, respectively, but did not predict shared variance in problem behaviors.
Results support the utility of the proposed approach. Ways in which this approach might contribute to future molecular genetic studies are discussed.
PMCID: PMC3179565  PMID: 21636226
nicotine dependence; alcohol use disorder; phenotype definition; measuring environment for GxE research
16.  High-Throughput Screen for the Chemical Inhibitors of Antiapoptotic Bcl-2 Family Proteins by Multiplex Flow Cytometry 
The human Bcl-2 family includes six antiapoptotic members (Bcl-2, Bcl-B, Bcl-W, Bcl-XL, Bfl-1, and Mcl-1) and many proapoptotic members, wherein a balance between the two determines cell life or death in many physiological and disease contexts. Elevated expression of various antiapoptotic Bcl-2 members is commonly observed in cancers, and chemical inhibitors of these proteins have been shown to promote apoptosis of malignant cells in culture, in animal models, and in human clinical trials. All six antiapoptotic members bind a helix from the proapoptotic family member Bim, thus quenching Bim's apoptotic signal. Here, we describe the use of a multiplex, high-throughput flow cytometry assay for the discovery of small molecule modulators that disrupt the interaction between the antiapoptotic members of the Bcl-2 family and Bim. The six antiapoptotic Bcl-2 family members were expressed as glutathione-S-transferase fusion proteins and bound individually to six glutathione bead sets, with each set having a different intensity of red fluorescence. A fluorescein-conjugated Bcl-2 homology region 3 (BH3) peptide from Bim was employed as a universal ligand. Flow cytometry measured the amount of green peptide bound to each bead set in a given well, with inhibitory compounds resulting in a decrease of green fluorescence on one or more bead set(s). Hits and cheminformatically selected analogs were retested in a dose–response series, resulting in three “active” compounds for Bcl-B. These three compounds were validated by fluorescence polarization and isothermal titration calorimetry. We discuss some of the lessons learned about screening a chemical library provided by the National Institutes of Health Small Molecule Repository (∼195,000 compounds) using high-throughput flow cytometry.
PMCID: PMC3182036  PMID: 21561376
17.  Premetazoan Ancestry of the Myc–Max Network 
Molecular Biology and Evolution  2011;28(10):2961-2971.
The origin of metazoans required the evolution of mechanisms for maintaining differentiated cell types within a multicellular individual, in part through spatially differentiated patterns of gene transcription. The unicellular ancestor of metazoans was presumably capable of regulating gene expression temporally in response to changing environmental conditions, and spatial cell differentiation in metazoans may represent a co-option of preexisting regulatory mechanisms. Myc is a critical regulator of cell growth, proliferation, and death that is found in all metazoans but absent in other multicellular lineages, including fungi and plants. Homologs of Myc and its binding partner, Max, exist in two of the closest living relatives of animals, the choanoflagellate Monosiga brevicollis (Mb) and Capsaspora owczarzaki, a unicellular opisthokont that is closely related to metazoans and choanoflagellates. We find that Myc and Max from M. brevicollis heterodimerize and bind to both canonical and noncanonical E-boxes, the DNA-binding sites through which metazoan Myc proteins act. Moreover, in M. brevicollis, MbMyc protein can be detected in nuclear and flagellar regions. Like metazoan Max proteins, MbMax can form homodimers that bind to E-boxes. However, cross-species dimerization between Mb and human Myc and Max proteins was not observed, suggesting that the binding interface has diverged. Our results reveal that the Myc/Max network arose before the divergence of the choanoflagellate and metazoan lineages. Furthermore, core features of metazoan Myc function, including heterodimerization with Max, binding to E-box sequences in DNA, and localization to the nucleus, predate the origin of metazoans.
PMCID: PMC3203627  PMID: 21571926
Myc; Max; multicellularity; choanoflagellates; Monosiga brevicollis; Capsaspora owczarzaki; evolution
18.  Managing patient deterioration: a protocol for enhancing undergraduate nursing students’ competence through web-based simulation and feedback techniques 
BMC Nursing  2012;11:18.
To describe a funded proposal for the development of an on-line evidence based educational program for the management of deteriorating patients.
There are international concerns regarding the management of deteriorating patients with issues around the ‘failure to rescue’. The primary response to these issues has been the development of medical emergency teams with little focus on the education of primary first responders.
A mixed methods triangulated convergent design.
In this four phase proposal we plan to 1. examine nursing student team ability to manage deteriorating patients and based upon these findings 2. develop web based educational material, including interactive scenarios. This educational material will be tested and refined in the third Phase 3, prior to evaluation and dissemination in the final phase.
This project aims to enhance knowledge development for the management of deteriorating patients through rigorous assessment of team performance and to produce a contemporary evidence-based online training program.
PMCID: PMC3534359  PMID: 23020906
Education; Nursing; Patient deterioration; Simulation
19.  A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment 
BMC Medicine  2012;10:99.
In childhood, attention deficit/hyperactivity disorder (ADHD) is characterized by age-inappropriate levels of inattentiveness/disorganization, hyperactivity/impulsiveness, or a combination thereof. Although the criteria for ADHD are well defined, the long-term consequences in adults and children need to be more comprehensively understood and quantified. We conducted a systematic review evaluating the long-term outcomes (defined as 2 years or more) of ADHD with the goal of identifying long-term outcomes and the impact that any treatment (pharmacological, non-pharmacological, or multimodal) has on ADHD long-term outcomes.
Studies were identified using predefined search criteria and 12 databases. Studies included were peer-reviewed, primary studies of ADHD long-term outcomes published between January 1980 to December 2010. Inclusion was agreed on by two independent researchers on review of abstracts or full text. Published statistical comparison of outcome results were summarized as poorer than, similar to, or improved versus comparators, and quantified as percentage comparisons of these categories.
Outcomes from 351 studies were grouped into 9 major categories: academic, antisocial behavior, driving, non-medicinal drug use/addictive behavior, obesity, occupation, services use, self-esteem, and social function outcomes. The following broad trends emerged: (1) without treatment, people with ADHD had poorer long-term outcomes in all categories compared with people without ADHD, and (2) treatment for ADHD improved long-term outcomes compared with untreated ADHD, although not usually to normal levels. Only English-language papers were searched and databases may have omitted relevant studies.
This systematic review provides a synthesis of studies of ADHD long-term outcomes. Current treatments may reduce the negative impact that untreated ADHD has on life functioning, but does not usually 'normalize' the recipients.
PMCID: PMC3520745  PMID: 22947230
ADHD; adult; childhood; outcomes; psychiatry; systematic
20.  A Novel Flow Cytometric HTS Assay Reveals Functional Modulators of ATP Binding Cassette Transporter ABCB6 
PLoS ONE  2012;7(7):e40005.
ABCB6 is a member of the adenosine triphosphate (ATP)-binding cassette family of transporter proteins that is increasingly recognized as a relevant physiological and therapeutic target. Evaluation of modulators of ABCB6 activity would pave the way toward a more complete understanding of the significance of this transport process in tumor cell growth, proliferation and therapy-related drug resistance. In addition, this effort would improve our understanding of the function of ABCB6 in normal physiology with respect to heme biosynthesis, and cellular adaptation to metabolic demand and stress responses. To search for modulators of ABCB6, we developed a novel cell-based approach that, in combination with flow cytometric high-throughput screening (HTS), can be used to identify functional modulators of ABCB6. Accumulation of protoporphyrin, a fluorescent molecule, in wild-type ABCB6 expressing K562 cells, forms the basis of the HTS assay. Screening the Prestwick Chemical Library employing the HTS assay identified four compounds, benzethonium chloride, verteporfin, tomatine hydrochloride and piperlongumine, that reduced ABCB6 mediated cellular porphyrin levels. Validation of the identified compounds employing the hemin-agarose affinity chromatography and mitochondrial transport assays demonstrated that three out of the four compounds were capable of inhibiting ABCB6 mediated hemin transport into isolated mitochondria. However, only verteporfin and tomatine hydrochloride inhibited ABCB6’s ability to compete with hemin as an ABCB6 substrate. This assay is therefore sensitive, robust, and suitable for automation in a high-throughput environment as demonstrated by our identification of selective functional modulators of ABCB6. Application of this assay to other libraries of synthetic compounds and natural products is expected to identify novel modulators of ABCB6 activity.
PMCID: PMC3393737  PMID: 22808084
21.  A multi-site controlled trial of a cognitive skills program for mentally disordered offenders 
BMC Psychiatry  2012;12:44.
The effectiveness of offending behaviour programs in forensic mental health settings is not well established. Thus this study aimed to evaluate the Reasoning and Rehabilitation Mental Health program (R&R2 MHP) among a mentally disordered offender (MDO) population.
A sample of 121 adult males drawn from 10 forensic mental health sites completed questionnaires at baseline and post-treatment to assess violent attitudes, locus of control, social problem-solving and anger. An informant measure of social and psychological functioning, including disruptive behaviour, was completed by unit staff at the same time. At three month follow-up patients completed again the violent attitudes and locus of control questionnaires. The data of 67 patients who participated in the group condition were compared with 54 waiting-list controls who received treatment as usual.
78% of group participants completed the program. In contrast to controls, significant treatment effects were found at outcome on self-reported measures of violent attitudes, rational problem-solving and anger cognitions. Improvements were endorsed by informant ratings of social and psychological functioning within the establishments. At follow-up significant treatment effects were found for both violent attitudes and locus of control.
R&R2 MHP was effective in a sample of MDOs and had a comparatively low drop-out rate. Future research should use a randomized controlled design.
PMCID: PMC3464877  PMID: 22607165
Mentally disordered offenders; Treatment outcome; Reasoning & Rehabilitation; Cognitive skills
22.  The Association between Positive Parenting and Externalizing Behavior1 
Infant and child development  2011;21(1):85-106.
The present study examined the role of positive parenting on externalizing behaviors in a longitudinal, genetically informative sample. It often is assumed that positive parenting prevents behavior problems in children via an environmentally mediated process. Alternatively, the association may be due to either an evocative gene-environment correlation, in which parents react to children’s genetically-influenced behavior in a positive way, or a passive gene-environment correlation, where parents passively transmit a risk environment and the genetic risk factor for the behavioral outcome to their children. The present study estimated the contribution of these processes in the association between positive parenting and children’s externalizing behavior. Positive parenting was assessed via observations at ages 7, 9, 14, 24, and 36 months and externalizing behaviors were assessed through parent report at ages 4, 5, 7, 9, 10, 11, and 12 years. The significant association between positive parenting and externalizing behavior was negative, with children of mothers who showed significantly more positive parenting during toddlerhood having lower levels of externalizing behavior in childhood; however, there was not adequate power to distinguish whether this covariation was due to genetic, shared environmental, or nonshared environmental influences.
PMCID: PMC3347769  PMID: 22577341
23.  Drug Repurposing from an Academic Perspective 
Academia and small business research units are poised to play an increasing role in drug discovery, with drug repurposing as one of the major areas of activity. Here we summarize project status for a number of drugs or classes of drugs: raltegravir, cyclobenzaprine, benzbromarone, mometasone furoate, astemizole, R-naproxen, ketorolac, tolfenamic acid, phenothiazines, methylergonovine maleate and beta-adrenergic receptor drugs, respectively. Based on this multi-year, multi-project experience we discuss strengths and weaknesses of academic-based drug repurposing research. Translational, target and disease foci are strategic advantages fostered by close proximity and frequent interactions between basic and clinical scientists, which often result in discovering new modes of action for approved drugs. On the other hand, lack of integration with pharmaceutical sciences and toxicology, lack of appropriate intellectual coverage and issues related to dosing and safety may lead to significant drawbacks. The development of a more streamlined regulatory process world-wide, and the development of pre-competitive knowledge transfer systems such as a global healthcare database focused on regulatory and scientific information for drugs world-wide, are among the ideas proposed to improve the process of academic drug discovery and repurposing, and to overcome the “valley of death” by bridging basic to clinical sciences.
PMCID: PMC3285382  PMID: 22368688
24.  The Etiology of Observed Negative Emotionality from 14 to 24 Months 
We examined the magnitude of genetic and environmental influences on observed negative emotionality at age 14, 20, and 24 months. Participants were 403 same-sex twin pairs recruited from the Longitudinal Twin Study whose emotional responses to four different situations were coded by independent raters. Negative emotionality showed significant consistency across settings, and there was evidence of a latent underlying negative emotionality construct. Heritability decreased, and the magnitude of shared environmental influences increased, for the latent negative emotionality construct from age 14 to 24 months. There were significant correlations between negative emotionality assessed at age 14, 20, and 24 months, and results suggested common genetic and shared environmental influences affecting negative emotionality across age, and that age-specific influences are limited to non-shared environmental influences, which include measurement error.
PMCID: PMC3270250  PMID: 22303413
negative emotionality; neuroticism; development; genetic influences; environmental influences
25.  A Systematic Review of Global Publication Trends Regarding Long-Term Outcomes of ADHD 
There is increased global recognition of attention deficit hyperactivity disorder (ADHD) as a serious medical condition with long-term consequences. Although originally conceived of as a childhood disorder, ADHD is being increasingly recognized in adults. Individual geographic regions may have specific interests and objectives for the study of ADHD. A systematic review of long-term outcomes (LTOs) in ADHD was conducted to evaluate research on ADHD LTOs on a global scale. Studies that were at least 2 years in duration were examined. A total of 351 studies were identified in the final analysis. We identified nine outcomes of interest and classified studies by specific geographical regions, age groups studied and study design by region and over time. Published studies of LTOs in ADHD have increased in all geographical regions over the past three decades, with a peak number of 42 publications in 2008. This rise in publications on ADHD LTOs may reflect a rise in global interest and recognition of consequences and impairment associated with ADHD. Although many world regions have published on ADHD LTOs, the majority of studies have emerged from the US and Canada, followed by Europe. While investigators in the US and Canada were predominantly interested in drug addiction as a LTO, European researchers were more interested in antisocial behavior, and Eastern Asian investigators focused on both of these LTOs as well as self-esteem. Geographical differences in the focus of ADHD LTO studies may reflect regional variations in cultural values. Proportionally fewer prospective longitudinal studies and proportionally more retrospective and cross-sectional studies have been published in more recent decades. Finally, more studies focusing on ADHD in adolescents and adults have been conducted in recent years, and particularly adolescents in Eastern Asia. These changes in basic study design may reflect an increase in the recognition that ADHD is a lifetime chronic disorder. This systematic review analysis of publication trends in ADHD LTOs reflects geographically based interests that change over time.
PMCID: PMC3260478  PMID: 22279437
ADHD; attention deficit; hyperactivity; hyperkinetic; TDAH

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