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1.  Emergency supply of prescription-only medicines to patients by community pharmacists: a mixed methods evaluation incorporating patient, pharmacist and GP perspectives 
BMJ Open  2015;5(7):e006934.
To evaluate and inform emergency supply of prescription-only medicines by community pharmacists (CPs), including how the service could form an integral component of established healthcare provision to maximise adherence.
Mixed methods. 4 phases: prospective audit of emergency supply requests for prescribed medicines (October–November 2012 and April 2013); interviews with CPs (February–April 2013); follow-up interviews with patients (April–May 2013); interactive feedback sessions with general practice teams (October–November 2013).
22 community pharmacies and 6 general practices in Northwest England.
27 CPs with experience of dealing with requests for emergency supplies; 25 patients who received an emergency supply of a prescribed medicine; 58 staff at 6 general practices.
Clinical audit in 22 pharmacies over two 4-week periods reported that 526 medicines were requested by 450 patients. Requests peaked over a bank holiday and around weekends. A significant number of supplies were made during practice opening hours. Most requests were for older patients and for medicines used in long-term conditions. Difficulty in renewing repeat medication (forgetting to order, or prescription delays) was the major reason for requests. The majority of medicines were ‘loaned’ in advance of a National Health Service (NHS) prescription. Interviews with CPs and patients indicated that continuous supply had a positive impact on medicines adherence, removing the need to access urgent care. General practice staff were surprised and concerned by the extent of emergency supply episodes.
CPs regularly provide emergency supplies to patients who run out of their repeat medication, including during practice opening hours. This may aid adherence. There is currently no feedback loop, however, to general practice. Patient care and interprofessional communication may be better served by the introduction of a formally structured and funded NHS emergency supply service from community pharmacies, with ongoing optimisation of repeat prescribing.
PMCID: PMC4499725  PMID: 26163029
2.  Substituted N-(Biphenyl-4′-yl)methyl (R)-2-Acetamido-3-methoxypropionamides: Potent Anticonvulsants That Affect Frequency (Use) Dependence and Slow Inactivation of Sodium Channels 
Journal of Medicinal Chemistry  2014;57(14):6165-6182.
We prepared 13 derivatives of N-(biphenyl-4′-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound’s whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.
PMCID: PMC4111400  PMID: 25004277
3.  Do Ethnicity and Gender Moderate the Influence of Posttraumatic Stress Disorder on Time to Smoking Lapse? 
Addictive behaviors  2014;39(7):1163-1167.
Following a smoking cessation attempt, smokers with posttraumatic stress disorder (PTSD) experience smoking relapse at a higher and faster rate. Black ethnicity and female gender are also associated with lower success rates following smoking cessation. No study to date has prospectively examined how ethnicity and gender may moderate the effect of PTSD on smoking relapse. It was hypothesized that female gender and Black ethnicity would significantly predict early lapse after quitting; further, it was predicted that ethnicity and gender would moderate the effect of PTSD on relapse rate. Smokers with PTSD (n = 48) and without PTSD (n = 56) completed ecological momentary assessment (EMA) the week after a quit date, and self-initiated EMA entries after smoking lapse. Smoking abstinence was biologically verified. The sample included Black (62%) and White (38%) participants, and was 50% female. Study hypotheses were tested with Cox proportional hazards regression modeling time to first smoking lapse. Study results confirmed the main hypothesis, with a significant PTSD X Ethnicity interaction emerging. The effect of PTSD on smoking relapse was significant for White participants but not for Black participants. No significant gender moderation was found. Taken together, study results support previous research, and suggest that the relationship between smoking and PTSD is stronger for White smokers than for minorities. This study has significant implications for research in smoking and mental disease, as well as for smoking cessation treatments for Black smokers.
PMCID: PMC4064680  PMID: 24727113
Tobacco control; smoking cessation; ethnic minorities; African Americans; posttraumatic stress disorder = PTSD; health disparities
4.  Understanding Public Perceptions of the HPV Vaccination Based on Online Comments to Canadian News Articles 
PLoS ONE  2015;10(6):e0129587.
Given the variation in human papillomavirus (HPV) vaccine coverage across Canada, and debate regarding delivery of HPV vaccines in Catholic schools, we studied online comments on Canadian news websites to understand public perceptions of HPV and HPV vaccine.
We searched English- and French-language Canadian news websites for 2012 articles that contained the terms “HPV” or “human papillomavirus.” Articles about HPV vaccinations that contained at least one comment were included. Two researchers independently coded comments, analyzing them for emerging themes.
We identified 3073 comments from 1198 individuals in response to 71 news articles; 630 (52.6%) individuals expressed positive sentiments about HPV vaccination (2.5 comments/individual), 404 (33.7%) were negative (3.0 comments/individual), 34 (2.8%) were mixed (1.5 comments/individual) and 130 (10.8%) were neutral (1.6 comments/individual). Vaccine-supportive commenters believed the vaccine is safe and effective. Common themes in negative comments included concerns regarding HPV vaccine safety and efficacy, distrust of pharmaceutical companies and government, and belief that school-age children are too young for HPV vaccine. Many comments focused on whether the Catholic Church has the right to inform health policy for students, and discussion often evolved into debates regarding HPV and sexual behaviour. We noted that many individuals doubted the credibility of vaccine safety information.
The majority of commenters do not appear to be against HPV vaccination, but public health messaging that focuses on both the vaccine’s safety profile, and its use as a means to prevent cancer rather than sexually transmitted HPV infection may facilitate its acceptance.
PMCID: PMC4460033  PMID: 26053866
5.  The Role of Daily Hassles and Distress Tolerance in Predicting Cigarette Craving During a Quit Attempt 
Nicotine & Tobacco Research  2014;16(6):872-875.
Ecological momentary assessment (EMA) has shown that smoking behavior is linked to transient variables in the smoker’s immediate context. Such research suggests that daily hassles (e.g., losing one’s keys) may be more likely to lead to cigarette craving and eventual lapse than infrequent, large-scale stressors (e.g., death of a loved one) among individuals attempting to quit smoking. However, individual differences in distress tolerance (DT) may moderate the relationship between daily hassles and daily cigarette craving during a quit attempt.
A sample of 56 veterans and community members drawn from a larger smoking-cessation study completed structured interviews and paper-and-pencil questionnaires during an initial laboratory visit and, directly following a quit attempt, were monitored via EMA. Multilevel modeling was used to examine the relationship between daily hassles and daily cigarette craving and to determine whether DT moderated this relationship.
Daily hassles were positively associated with daily cigarette craving, and this association was moderated by individual differences in DT, such that the lower one’s DT, the stronger the relationship between daily hassles and daily cigarette craving. This model explained 13% of the intraindividual variability and 8% of the interindividual variability in daily cigarette craving.
Smoking-cessation interventions may be strengthened by targeting smokers’ individual responses to contextual factors, such as by helping smokers develop skills to cope more effectively with distress prior to and during the quit phase.
PMCID: PMC4015097  PMID: 24474304
6.  Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy 
PLoS ONE  2015;10(6):e0127791.
Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, β = -0.06, p = 1.1 x 10-7). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10-7. Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.
PMCID: PMC4452656  PMID: 26030142
7.  Diverse perspectives on developments in epilepsy surgery 
Seizure  2010;19(10):659-668.
The objective of this article is to review the dramatic changes that have occurred in the field of epilepsy surgery since the founding of Epilepsy Action in 1950. We have chosen to consider these advances from the biomedical perspective (the physician and basic scientist), and the behavioral perspective (the psychologist and the patient). Both of these viewpoints are equally important in understanding the evolution of epilepsy surgery over the past 60 years, but may not always be well synchronized.
PMCID: PMC4425445  PMID: 21093313
history; epilepsy surgery; seizure outcome; cognition; psychosocial; quality of life
8.  Religious coping among women with obstetric fistula in Tanzania 
Global public health  2014;9(5):516-527.
Religion is an important aspect of Tanzanian culture, and is often used to cope with adversity and distress. This study aimed to examine religious coping among women with obstetric fistulae. Fifty-four women receiving fistula repair at a Tanzanian hospital completed a structured survey. RCOPE assessed positive and negative religious coping strategies. Analyses included associations between negative religious coping and key variables (demographics, religiosity, depression, social support and stigma). Forty-five women also completed individual in-depth interviews where religion was discussed. Although participants utilised positive religious coping strategies more frequently than negative strategies (p<.001), 76% reported at least one form of negative religious coping. In univariate analysis, negative religious coping was associated with stigma, depression and low social support. In multivariate analysis, only depression remained significant, explaining 42% of the variance in coping. Qualitative data confirmed reliance upon religion to deal with fistula-related distress, and suggested that negative forms of religious coping may be an expression of depressive symptoms. Results suggest that negative religious coping could reflect cognitive distortions and negative emotionality, characteristic of depression. Religious leaders should be engaged to recognise signs of depression and provide appropriate pastoral/spiritual counseling and general psychosocial support for this population.
PMCID: PMC4046104  PMID: 24735435
obstetric fistula; Tanzania; religion; gender; maternal health
9.  Silencing of odorant receptor gene expression by G protein βγ signaling ensures the expression of one odorant receptor per olfactory sensory neuron 
Neuron  2014;81(4):847-859.
Olfactory sensory neurons express just one out of a possible ~1000 odorant receptor genes, reflecting an exquisite mode of gene regulation. In one model, once an odorant receptor is chosen for expression, other receptor genes are suppressed by a negative feedback mechanism, ensuring a stable functional identity of the sensory neuron for the lifetime of the cell. The signal transduction mechanism subserving odorant receptor gene silencing remains obscure, however. Here we demonstrate in the zebrafish that odorant receptor gene silencing is dependent on receptor activity. Moreover, we show that signaling through G protein βγ subunits is both necessary and sufficient to suppress the expression of odorant receptor genes, and likely acts through histone methylation to maintain the silenced odorant receptor genes in transcriptionally inactive heterochromatin. These results provide new insights linking receptor activity with the epigenetic mechanisms responsible for ensuring the expression of one odorant receptor per olfactory sensory neuron.
PMCID: PMC4412037  PMID: 24559675
10.  Multi-Ancestral Analysis of Inflammation-Related Genetic Variants and C-Reactive Protein in the Population Architecture using Genomics and Epidemiology (PAGE) Study 
C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.
Methods and Results
We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40,473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected p<3.1×10−3 for replication, p<2.0×10−4 for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (p=2.0×10−6) and rs646776 (p=3.1×10−5).
We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and LDL cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups, and of looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
PMCID: PMC4104750  PMID: 24622110
genetic epidemiology; inflammation; C-reactive protein; race and ethnicity; single nucleotide polymorphism; pleiotropy
11.  Why we scratch an itch: the molecules, cells and circuits of itch 
Nature neuroscience  2014;17(2):175-182.
Itch is described as an irritating sensation that triggers a desire to scratch. However, this definition hardly seems fitting for the millions of people who suffer from intractable itch. Indeed, the Buddhist philosopher Nāgārjuna more aptly stated, “There is pleasure when an itch is scratched. But to be without an itch is more pleasurable still.” Chronic itch is widespread and very difficult to treat. In this review we focus on the molecules, cells and circuits in the peripheral and central nervous systems that drive acute and chronic itch transmission. Understanding the itch circuitry is critical to developing new therapies for this intractable disease.
PMCID: PMC4364402  PMID: 24473265
12.  Psychological intervention reduces self-reported performance anxiety in high school music students 
Music performance anxiety (MPA) can be distressing for many young people studying music, and may negatively impact upon their ability to cope with the demands and stressors of music education. It can also lead young people to give up music or to develop unhealthy coping habits in their adult music careers. Minimal research has examined the effectiveness of psychological programs to address MPA in young musicians. Sixty-two adolescents were pseudo-randomized to a cognitive behavioral (CB) group-delivered intervention or a waitlist condition. The intervention consisted of psychoeducation, cognitive restructuring and relaxation techniques, identification of strengths, goal-setting, imagery and visualization techniques to support three solo performances in front of judges. Significant reductions in self-rated MPA were found in both groups following the intervention and compared to their baseline MPA. This reduction was maintained at 2-months follow-up. There appeared to be inconsistent effects of the intervention upon judge-rated MPA, however the presence of floor effects precluded meaningful reductions in MPA. There appeared to be no effect of the intervention upon judge-rated performance quality. This study highlights the potential for group-based CB programs to be delivered within school music curricula to help young musicians develop skills to overcome the often debilitating effects of MPA.
PMCID: PMC4347450  PMID: 25784885
performance anxiety; music; adolescents; psychological intervention; performance psychology
13.  Antiviral Mechanisms of Human Defensins 
Journal of molecular biology  2013;425(24):10.1016/j.jmb.2013.09.038.
Defensins are an effector component of the innate immune system with broad antimicrobial activity. Humans express two types of defensins, α- and β-defensins, which have antiviral activity against both enveloped and non-enveloped viruses. The diversity of defensin-sensitive viral species reflects a multitude of antiviral mechanisms. These include direct defensin targeting of viral envelopes, glycoproteins, and capsids in addition to inhibition of viral fusion and post-entry neutralization. Binding and modulation of host cell surface receptors and disruption of intracellular signaling by defensins can also inhibit viral replication. In addition, defensins can function as chemokines to augment and alter adaptive immune responses, revealing an indirect antiviral mechanism. Nonetheless, many questions regarding the antiviral activities of defensins remain. Although significant mechanistic data is known for α-defensins, molecular details for β-defensin inhibition are mostly lacking. Importantly, the role of defensin antiviral activity in vivo has not been addressed due to the lack of a complete defensin knockout model. Overall, the antiviral activity of defensins is well established as are the variety of mechanisms by which defensins achieve this inhibition; however, additional research is needed to fully understand the role of defensins in viral pathogenesis.
PMCID: PMC3842434  PMID: 24095897
virus; defensin; antimicrobial peptides; innate immunity
14.  Detection of Pleiotropy through a Phenome-Wide Association Study (PheWAS) of Epidemiologic Data as Part of the Environmental Architecture for Genes Linked to Environment (EAGLE) Study 
PLoS Genetics  2014;10(12):e1004678.
We performed a Phenome-wide association study (PheWAS) utilizing diverse genotypic and phenotypic data existing across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC), and accessed by the Epidemiological Architecture for Genes Linked to Environment (EAGLE) study. We calculated comprehensive tests of association in Genetic NHANES using 80 SNPs and 1,008 phenotypes (grouped into 184 phenotype classes), stratified by race-ethnicity. Genetic NHANES includes three surveys (NHANES III, 1999–2000, and 2001–2002) and three race-ethnicities: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We identified 69 PheWAS associations replicating across surveys for the same SNP, phenotype-class, direction of effect, and race-ethnicity at p<0.01, allele frequency >0.01, and sample size >200. Of these 69 PheWAS associations, 39 replicated previously reported SNP-phenotype associations, 9 were related to previously reported associations, and 21 were novel associations. Fourteen results had the same direction of effect across more than one race-ethnicity: one result was novel, 11 replicated previously reported associations, and two were related to previously reported results. Thirteen SNPs showed evidence of pleiotropy. We further explored results with gene-based biological networks, contrasting the direction of effect for pleiotropic associations across phenotypes. One PheWAS result was ABCG2 missense SNP rs2231142, associated with uric acid levels in both non-Hispanic whites and Mexican Americans, protoporphyrin levels in non-Hispanic whites and Mexican Americans, and blood pressure levels in Mexican Americans. Another example was SNP rs1800588 near LIPC, significantly associated with the novel phenotypes of folate levels (Mexican Americans), vitamin E levels (non-Hispanic whites) and triglyceride levels (non-Hispanic whites), and replication for cholesterol levels. The results of this PheWAS show the utility of this approach for exposing more of the complex genetic architecture underlying multiple traits, through generating novel hypotheses for future research.
Author Summary
The Epidemiological Architecture for Genes Linked to Environment (EAGLE) study performed a Phenome-Wide Association Study (PheWAS) to investigate comprehensive associations between a wide range of phenotypes and single-nucleotide polymorphisms using the diverse genotypic and phenotypic data that exists across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC). In this study, we replicated known genotype-phenotype associations, identified genotypes associated with phenotypes related to previously reported associations, and most importantly, identified a series of novel genotype-phenotype associations. We also identified potential pleiotropy; that is, SNPs associated with more than one phenotype. We explored the features of these PheWAS results, characterizing any potential functionality of the SNPs of this study, determining association results that were found in more than one racial/ethnic group for the same SNP and phenotype, identifying novel direction of effect relationships for SNPs demonstrating potential pleiotropy, and investigating the association results in the context of gene-based biological networks. Through considering the SNP associations on multiple phenotypic outcomes, as well as through exploring pleiotropy, we may be able to leverage the results of PheWAS to uncover more of the complex underlying genomic architecture of complex traits.
PMCID: PMC4256091  PMID: 25474351
15.  The Epithelial Cell-derived Atopic Dermatitis Cytokine TSLP Activates Neurons to Induce Itch 
Cell  2013;155(2):285-295.
Atopic dermatitis (AD) is a chronic itch and inflammatory disorder of the skin that affects one in ten people. Patients suffering from severe AD eventually progress to develop asthma and allergic rhinitis, in a process known as the “atopic march.” Signaling between epithelial cells and innate immune cells via the cytokine Thymic Stromal Lymphopoietin (TSLP) is thought to drive AD and the atopic march. Here we report that epithelial cells directly communicate to cutaneous sensory neurons via TSLP to promote itch. We identify the ORAI1/NFAT calcium signaling pathway as an essential regulator of TSLP release from keratinocytes, the primary epithelial cells of the skin. TSLP then acts directly on a subset of TRPA1-positive sensory neurons to trigger robust itch behaviors. Our results support a new model whereby calcium-dependent TSLP release by keratinocytes activates both primary afferent neurons and immune cells to promote inflammatory responses in the skin and airways.
PMCID: PMC4041105  PMID: 24094650
16.  Carbamazepine Potentiates the Effectiveness of Morphine in a Rodent Model of Neuropathic Pain 
PLoS ONE  2014;9(9):e107399.
Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7–14 and absent at PID21–28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7–28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential therapeutic use of morphine and CBZ as a combinational treatment for neuropathic pain.
PMCID: PMC4164621  PMID: 25221944
17.  Gender moderates the influence of psychosocial factors and drug use on HAART adherence in the context of HIV and childhood sexual abuse 
AIDS care  2014;26(8):959-967.
This study aimed to examine gender moderation within a stress and coping model of HIV medication adherence in adults with a history of childhood sexual abuse (CSA). Sequelae of CSA, including negative coping, psychological distress, and drug use, interfere with adherence to highly active antiretroviral treatment (HAART). These obstacles to adherence are likely moderated by gender. Gender may particularly influence the mediational effect of drug use on adherence. Participants included 206 adults living with HIV/AIDS and CSA. Categorical/continuous variable methodology (CVM) in a structural equation modeling (SEM) framework was used to test a multigroup model with women and men. Gender significantly moderated several effects in the model. For women, the effect of psychological distress on HAART adherence was mediated by drug use, and the effect of drug use on viral load was mediated by HAART adherence. Among men, drug use did not significantly impact adherence. Since gender appears to moderate the effect of drug use on medication adherence, it is particularly important to address drug use within the context of HIV disease management in women with a history of CSA. Further, interventions to increase HAART adherence should take trauma history, gender, and drug abuse into account when assessing efficacy.
PMCID: PMC4156823  PMID: 24410324
medication adherence; CSA = childhood sexual abuse; HIV = human immunodeficiency virus; drug abuse; SEM = structural equation modeling; gender difference
18.  Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations 
American Journal of Epidemiology  2013;178(5):780-790.
Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993–2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987–1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991–1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10−5) and inversely associated with percentage of calories derived from carbohydrate (βmeta = −0.2796 (standard error, 0.0709); P = 8 × 10−5). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)2) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m2, 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake.
PMCID: PMC3755639  PMID: 23820787
energy intake; fat mass and obesity-associated (FTO) gene; obesity; percent calories from fat; race/ethnicity
19.  Pharmacy Students’ Perceptions of Natural Science and Mathematics Subjects 
Objective. To determine the level of importance pharmacy students placed on science and mathematics subjects for pursuing a career in pharmacy.
Method. Two hundred fifty-four students completed a survey instrument developed to investigate students’ perceptions of the relevance of science and mathematics subjects to a career in pharmacy. Pharmacy students in all 4 years of a master of pharmacy (MPharm) degree program were invited to complete the survey instrument.
Results. Students viewed chemistry-based and biology-based subjects as relevant to a pharmacy career, whereas mathematics subjects such as physics, logarithms, statistics, and algebra were not viewed important to a career in pharmacy.
Conclusion. Students’ experience in pharmacy and year of study influenced their perceptions of subjects relevant to a pharmacy career. Pharmacy educators need to consider how they can help students recognize the importance of scientific knowledge earlier in the pharmacy curriculum.
PMCID: PMC4140484  PMID: 25147390
science; mathematics; pharmacy students; career
20.  (Biphenyl-4-yl)methylammonium Chlorides: Potent Anticonvulsants That Modulate Na+ Currents 
Journal of medicinal chemistry  2013;56(14):10.1021/jm4007092.
We have reported that compounds containing a bi-aryl linked unit (Ar-X-Ar′) modulated Na+ currents by promoting slow inactivation and fast inactivation processes and by inducing frequency (use)-dependent inhibition of Na+ currents. These electrophysiological properties have been associated with the mode of action of several antiepileptic drugs. In this study, we demonstrate that the readily accessible (biphenyl-4-yl)methylammonium chlorides (compound class B) exhibited a broad range of anticonvulsant activities in animal models and in the maximal electroshock seizure test the activity of (3′-trifluoromethoxybiphenyl-4-yl)methylammonium chloride (8) exceeded that of phenobarbital and phenytoin upon oral administration to rats. Electrophysiological studies of 8 using mouse catecholamine A– differentiated cells and rat embryonic cortical neurons confirmed that 8 promoted slow and fast inactivation in both cell types but did not affect the frequency (use)-dependent block of Na+ currents.
PMCID: PMC3842382  PMID: 23772678
21.  Defensins and Viral Infection: Dispelling Common Misconceptions 
PLoS Pathogens  2014;10(7):e1004186.
PMCID: PMC4102581  PMID: 25033215
22.  The genetic basis of music ability 
Music is an integral part of the cultural heritage of all known human societies, with the capacity for music perception and production present in most people. Researchers generally agree that both genetic and environmental factors contribute to the broader realization of music ability, with the degree of music aptitude varying, not only from individual to individual, but across various components of music ability within the same individual. While environmental factors influencing music development and expertise have been well investigated in the psychological and music literature, the interrogation of possible genetic influences has not progressed at the same rate. Recent advances in genetic research offer fertile ground for exploring the genetic basis of music ability. This paper begins with a brief overview of behavioral and molecular genetic approaches commonly used in human genetic analyses, and then critically reviews the key findings of genetic investigations of the components of music ability. Some promising and converging findings have emerged, with several loci on chromosome 4 implicated in singing and music perception, and certain loci on chromosome 8q implicated in absolute pitch and music perception. The gene AVPR1A on chromosome 12q has also been implicated in music perception, music memory, and music listening, whereas SLC6A4 on chromosome 17q has been associated with music memory and choir participation. Replication of these results in alternate populations and with larger samples is warranted to confirm the findings. Through increased research efforts, a clearer picture of the genetic mechanisms underpinning music ability will hopefully emerge.
PMCID: PMC4073543  PMID: 25018744
music; music ability; music perception; music production; genetic; genome; review
23.  Predictors of Lapse in First Week of Smoking Abstinence in PTSD and Non-PTSD Smokers 
Nicotine & Tobacco Research  2012;15(6):1122-1129.
Retrospective research suggests smokers with posttraumatic stress disorder (PTSD) lapse more quickly after their quit date. Ecological momentary assessment (EMA) research is needed to confirm the presence of early smoking lapse in PTSD and form conceptualizations that inform intervention.
Smokers with (n = 55) and without (n = 52) PTSD completed alarm-prompted EMA of situational and psychiatric variables the week before and after a quit date, and self-initiated EMA following smoking lapses. Blood samples at baseline and on the quit date allowed assessment of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA(S)).
PTSD was related to shorter time to lapse (hazard ratio [HR] = 1.677, 95% CI: 1.106–2.544). Increased smoking abstinence self-efficacy was related to longer time to lapse (HR = 0.608, 95% CI: 0.430–0.860). Analyses of participants’ real-time reports revealed that smokers with PTSD were more likely to attribute first-time lapses to negative affect ( = 5.412, p = .020), and trauma reminders (Fisher’s exact p = .003**). Finally, the quit date decrease in DHEA(S) was related to shorter time to lapse (HR = 1.009, 95% CI: 1.000–1.018, p < .05).
Results provide evidence of shorter time to first smoking lapse in PTSD, and add to evidence that early lapse occasions are more strongly related to trauma reminders, negative affect, and cravings in smokers with PTSD.
PMCID: PMC3646653  PMID: 23178322
24.  Lack of Associations of Ten Candidate Coronary Heart Disease Risk Genetic Variants and Subclinical Atherosclerosis in Four U.S. Populations: the Population Architecture using Genomics and Epidemiology (PAGE) Study 
Atherosclerosis  2013;228(2):390-399.
A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.
Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.
None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3,809 AA, and 5,353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10−5), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).
We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
PMCID: PMC3717342  PMID: 23587283
ankle brachial index; carotid artery intima-media thickness; carotid plaque; coronary heart disease; genetic association study; multiethnic populations; subclinical atherosclerosis
25.  SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons 
Channels  2013;7(3):153-159.
The axon/dendrite specification collapsin response mediator protein 2 (CRMP2) bidirectionally modulates N-type voltage-gated Ca2+ channels (CaV2.2). Here we demonstrate that small ubiquitin-like modifier (SUMO) protein modifies CRMP2 via the SUMO E2-conjugating enzyme Ubc9 in vivo. Removal of a SUMO conjugation site KMD in CRMP2 (K374A/M375A/D376A; CRMP2AAA) resulted in loss of SUMOylated CRMP2 without compromising neurite branching, a canonical hallmark of CRMP2 function. Increasing SUMOylation levels correlated inversely with calcium influx in sensory neurons. CRMP2 deSUMOylation by SUMO proteases SENP1 and SENP2 normalized calcium influx to those in the CRMP2AAA mutant. Thus, our results identify a novel role for SUMO modification in CRMP2/CaV2.2 signaling pathway.
PMCID: PMC3710342  PMID: 23510938
SUMO; CRMP2; Ubc9; CaV2.2; calcium influx; sensory neurons

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