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1.  Alternating layer addition approach to CdSe/CdS core/shell quantum dots with near-unity quantum yield and high on-time fractions 
We report single-particle photoluminescence (PL) intermittency (blinking) with high on-time fractions in colloidal CdSe quantum dots (QD) with conformal CdS shells of 1.4 nm thickness, equivalent to approximately 4 CdS monolayers. All QDs observed displayed on-time fractions > 60% with the majority > 80%. The high-on-time-fraction blinking is accompanied by fluorescence quantum yields (QY) close to unity (up to 98% in an absolute QY measurement) when dispersed in organic solvents and a monoexponential ensemble photoluminescence (PL) decay lifetime. The CdS shell is formed in high synthetic yield using a modified selective ion layer adsorption and reaction (SILAR) technique that employs a silylated sulfur precursor. The CdS shell provides sufficient chemical and electronic passivation of the QD excited state to permit water solubilization with greater than 60% QY via ligand exchange with an imidazole-bearing hydrophilic polymer.
PMCID: PMC4052982  PMID: 24932403
2.  The general population cohort in rural south-western Uganda: a platform for communicable and non-communicable disease studies 
The General Population Cohort (GPC) was set up in 1989 to examine trends in HIV prevalence and incidence, and their determinants in rural south-western Uganda. Recently, the research questions have included the epidemiology and genetics of communicable and non-communicable diseases (NCDs) to address the limited data on the burden and risk factors for NCDs in sub-Saharan Africa. The cohort comprises all residents (52% aged ≥13years, men and women in equal proportions) within one-half of a rural sub-county, residing in scattered houses, and largely farmers of three major ethnic groups. Data collected through annual surveys include; mapping for spatial analysis and participant location; census for individual socio-demographic and household socioeconomic status assessment; and a medical survey for health, lifestyle and biophysical and blood measurements to ascertain disease outcomes and risk factors for selected participants. This cohort offers a rich platform to investigate the interplay between communicable diseases and NCDs. There is robust infrastructure for data management, sample processing and storage, and diverse expertise in epidemiology, social and basic sciences. For any data access enquiries you may contact the director, MRC/UVRI, Uganda Research Unit on AIDS by email to or the corresponding author.
PMCID: PMC3600628  PMID: 23364209
Data resource profile; general population cohort; communicable and non-communicable diseases; Uganda
3.  Genetic variants influencing circulating lipid levels and risk of coronary artery disease 
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of LDL-c, HDL-c and triglycerides.
Methods and results
We combined genome-wide association data from eight studies, comprising up to 17,723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37,774 participants from eight populations and also in a population of Indian Asian descent. We also assessed the association between SNPs at lipid loci and risk of CAD in up to 9,633 cases and 38,684 controls.
We identified four novel genetic loci that showed reproducible associations with lipids (P values 1.6 × 10−8 to 3.1 × 10−10). These include a potentially functional SNP in the SLC39A8 gene for HDL-c, a SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-c and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with one or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (P values 1.1 × 10−3 to 1.2 × 10−9).
We have identified four novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-c, genetic loci mainly associated with circulating triglycerides and HDL-c are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
PMCID: PMC3891568  PMID: 20864672
lipids; lipoproteins; genetics; epidemiology
4.  Energy transfer mediated by asymmetric hydrogen-bonded interfaces† 
Amidine-appended ferrocene derivatives form a supramolecular assembly with Ru(ii)(bpy-COOH) (L)22+ complexes (bpy-COOH is 4-CO2H-4′-CH3-bpy and L = bpy, 2,2′-bipyridine or btfmbpy, 4,4′-bis (trifluoromethyl)-2,2′-bipyridine). Steady-state, time-resolved spectroscopy and kinetic isotope effects establish that the metal-to-ligand charge transfer excited states of the Ru(ii) complexes are quenched by proton-coupled energy transfer (PCEnT). These results show that proton motion can be effective in mediating not only electron transfer (ET) but energy transfer (EnT) as well.
PMCID: PMC3868475  PMID: 24363889
5.  The Association of Menopausal Status with Physical Function: The Study of Women’s Health Across the Nation (SWAN) 
Menopause (New York, N.Y.)  2012;19(11):1186-1192.
To determine if post-menopausal status is associated with self-reported limitations in physical function.
SWAN is a multi-site, multi-ethnic, longitudinal study of midlife women. Women aged 45–57 years (N=2,566) completed the Medical Outcomes Study Short-Form Physical Function Scale at visit 4 (2000–2001); scores created a 3-category variable of physical function limitations: none (86–100), moderate (51–85) and substantial (0–50). Menopausal status in SWAN is a 5-category list variable based on menstrual bleeding patterns and gynecological surgery. Pre-and peri-menopausal women using hormones (n=284) or missing physical function scores (n=46) were excluded. Multinomial logistic regression was used to relate physical function and menopausal status adjusting for age, ethnicity, site, education, body mass index (BMI), self-reported diabetes, hypertension, arthritis, depressive symptoms, smoking and hormone use among postmenopausal women.
Of 2,236 women, 8% were pre-, 51% early peri-, 12% late peri-, 24% natural post-, and 5% surgical post-menopausal status. In the full model, substantial limitations in physical function were higher in post-menopausal compared to pre-menopausal women whether it occurred naturally (OR 3.82; 95% CI: 1.46–10.0) or surgically (OR 3.54; 95% CI: 1.15–10.84). These associations were attenuated by higher BMI and depressive symptoms, but remained significant. Moderate limitations in physical function were not significantly related to menopausal status.
Women with surgical or naturally occurring post-menopause reported greater limitations in physical function than pre-menopausal women, independent of age, only partly explained by higher BMI and depressive symptoms. This suggests that physiologic changes of menopause could contribute directly to limitations in physical function.
PMCID: PMC3526111  PMID: 22760087
Physical functioning; Functional limitations; Menopause; Menopausal status; SF-36
6.  A qualitative study of predelivery counselling for extreme prematurity 
Paediatrics & Child Health  2012;17(8):432-436.
To ascertain from parents of neonates born before 27 weeks’ gestational age how to improve predelivery counselling for delivery room resuscitation.
Qualitative ethnographic study using semistructured, face-to-face interviews of 10 families. Data were analyzed using a constant comparative method.
Parents had no previous knowledge about prematurity. They would have preferred prioritized information during predelivery counselling focused on the immediate risks to their child. Resuscitation wishes were inconsistently sought. Opportunities for repeat discussions involving both parents were often missed. Parents agreed that the opportunity to explicitly state resuscitation wishes should be offered. Additional materials, such as pamphlets or videos, would improve counselling.
Information about prematurity should be offered when the pregnancy is deemed high risk, with repeat counselling opportunities for both parents to discuss options. Once the decision is made to resuscitate, parents want the neonatal team to convey a message of hope and compassion.
PMCID: PMC3474383  PMID: 24082803
Counselling; Informed consent; Prematurity; Resuscitation; Qualitative
7.  Inbreeding reveals mode of past selection on male reproductive characters in Drosophila melanogaster 
Ecology and Evolution  2013;3(7):2089-2102.
Directional dominance is a prerequisite of inbreeding depression. Directionality arises when selection drives alleles that increase fitness to fixation and eliminates dominant deleterious alleles, while deleterious recessives are hidden from it and maintained at low frequencies. Traits under directional selection (i.e., fitness traits) are expected to show directional dominance and therefore an increased susceptibility to inbreeding depression. In contrast, traits under stabilizing selection or weakly linked to fitness are predicted to exhibit little-to-no inbreeding depression. Here, we quantify the extent of inbreeding depression in a range of male reproductive characters and then infer the mode of past selection on them. The use of transgenic populations of Drosophila melanogaster with red or green fluorescent-tagged sperm heads permitted in vivo discrimination of sperm from competing males and quantification of characteristics of ejaculate composition, performance, and fate. We found that male attractiveness (mating latency) and competitive fertilization success (P2) both show some inbreeding depression, suggesting they may have been under directional selection, whereas sperm length showed no inbreeding depression suggesting a history of stabilizing selection. However, despite having measured several sperm quality and quantity traits, our data did not allow us to discern the mechanism underlying the lowered competitive fertilization success of inbred (f = 0.50) males.
PMCID: PMC3728949  PMID: 23919154
Attractiveness; Drosophila melanogaster; inbreeding depression; past selection; sperm competition; sperm length
8.  Identification and Characterisation of a Nuclear Localisation Signal in the SMN associated protein, Gemin4 
Gemin4 is a ubiquitously expressed multifunctional protein that is involved in U snRNP assembly, apoptosis, nuclear /cytoplasmic transportation, transcription, and RNAi pathways. Gemin4 is one of the core components of the Gemin-complex, which also contains survival motor neuron (SMN), the seven Gemin proteins (Gemin2–8), and Unrip. Mutations in the SMN1 gene cause the autosomal recessive disorder spinal muscular atrophy (SMA). Although the functions assigned to Gemin4 predominantly occur in the nucleus, the mechanisms that mediate the nuclear import of Gemin4 remain unclear. Here, using a novel panel of Gemin4 constructs we identify a canonical nuclear import sequence (NLS) in the N-terminus of Gemin4. The Gemin4 NLS is necessary and independently sufficient to mediate nuclear import of Gemin4. This is the first functional NLS identified within the SMN-Gemin complex.
PMCID: PMC3613997  PMID: 18675250
Gemin4; survival motor neuron; SMN; spinal muscular atrophy (SMA) nuclear localisation signal (NLS); import receptors
9.  Adverse Respiratory Symptoms and Environmental Exposures Among Children and Adolescents Following Hurricane Katrina 
Public Health Reports  2011;126(6):853-860.
Children and adolescents are especially vulnerable to environmental exposures and their respiratory effects. Following Hurricane Katrina in 2005, residents experienced multiple adverse environmental exposures. We characterized the association between upper respiratory symptoms (URS) and lower respiratory symptoms (LRS) and environmental exposures among children and adolescents affected by Hurricane Katrina.
We conducted a cross-sectional study following the return of the population to New Orleans after Hurricane Katrina (October 2005 and February 2006) among a convenience sample of children and adolescents attending New Orleans health facilities. We used uni-, bi-, and multivariable analyses to describe participants, exposures, and associations with URS/LRS.
Of 1,243 participants, 47% were Caucasian, 50% were male, and 72% were younger than 11 years of age. Multiple environmental exposures were identified during and after the storm and at current residences: roof/glass/storm damage (50%), outside mold (22%), dust (18%), and flood damage (15%). Self-reported URS and LRS (76% and 36%, respectively) were higher after the hurricane than before the hurricane (22% and 9%, respectively, p<0.0001). Roof/glass/storm damage at home was associated with URS (adjusted odds ratio [AOR] = 1.59, 95% confidence interval [CI] = 1.15, 2.21) and LRS (AOR=1.35, 95% CI 1.01, 1.80), while mold growth at home was associated with LRS (AOR=1.47, 95% CI 1.02, 2.12).
Children and adolescents affected by Hurricane Katrina experienced environmental exposures associated with increased prevalence of reported URS and LRS. Additional research is needed to investigate the long-term health impacts of Hurricane Katrina.
PMCID: PMC3185321  PMID: 22043101
10.  Education and levels of salivary cortisol over the day in U.S. adults 
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is hypothesized to be an important pathway linking socioeconomic position and chronic disease.
This paper tests the association between education and the diurnal rhythm of salivary cortisol.
Up to 8 measures of cortisol (mean of 5.38 per respondent) over two days were obtained from 311 respondents, aged 18–70, drawn from the 2001–2002 Chicago Community Adult Health Study. Multi-level models with linear splines were used to estimate waking level, rates of cortisol decline, and area-under-the-curve over the day, by categories of education.
Lower education (0–11 years) was associated with lower waking levels of cortisol, but not the rate of decline of cortisol, resulting in a higher area-under-the-curve for more educated respondents throughout the day.
This study found evidence of lower cortisol exposure among individuals with less education and thus does not support the hypothesis that less education is associated with chronic over-exposure to cortisol.
PMCID: PMC3486742  PMID: 20812036
11.  Environmental Factors Influencing Gene Transfer Agent (GTA) Mediated Transduction in the Subtropical Ocean 
PLoS ONE  2012;7(8):e43506.
Microbial genomic sequence analyses have indicated widespread horizontal gene transfer (HGT). However, an adequate mechanism accounting for the ubiquity of HGT has been lacking. Recently, high frequencies of interspecific gene transfer have been documented, catalyzed by Gene Transfer Agents (GTAs) of marine α-Proteobacteria. It has been proposed that the presence of bacterial genes in highly purified viral metagenomes may be due to GTAs. However, factors influencing GTA-mediated gene transfer in the environment have not yet been determined. Several genomically sequenced strains containing complete GTA sequences similar to Rhodobacter capsulatus (RcGTA, type strain) were screened to ascertain if they produced putative GTAs, and at what abundance. Five of nine marine strains screened to date spontaneously produced virus-like particles (VLP's) in stationary phase. Three of these strains have demonstrated gene transfer activity, two of which were documented by this lab. These two strains Roseovarius nubinhibens ISM and Nitratireductor 44B9s, were utilized to produce GTAs designated RnGTA and NrGTA and gene transfer activity was verified in culture. Cell-free preparations of purified RnGTA and NrGTA particles from marked donor strains were incubated with natural microbial assemblages to determine the level of GTA-mediated gene transfer. In conjunction, several ambient environmental parameters were measured including lysogeny indicated by prophage induction. GTA production in culture systems indicated that approximately half of the strains produced GTA-like particles and maximal GTA counts ranged from 10–30% of host abundance. Modeling of GTA-mediated gene transfer frequencies in natural samples, along with other measured environmental variables, indicated a strong relationship between GTA mediated gene transfer and the combined factors of salinity, multiplicity of infection (MOI) and ambient bacterial abundance. These results indicate that GTA-mediated HGT in the marine environment with the strains examined is favored during times of elevated bacterial and GTA abundance as well as in areas of higher salinity.
PMCID: PMC3419701  PMID: 22905268
12.  Demyelination Causes Synaptic Alterations in Hippocampi from Multiple Sclerosis Patients 
Annals of neurology  2011;69(3):445-454.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. While the clinical impact of gray matter pathology in MS brains is unknown, 30–40% of MS patients demonstrate memory impairment. The molecular basis of this memory dysfunction has not yet been investigated in MS patients.
To investigate possible mechanisms of memory impairment in MS patients, we compared morphological and molecular changes in myelinated and demyelinated hippocampi from postmortem MS brains.
Demyelinated hippocampi had minimal neuronal loss but significant decreases in synaptic density. Neuronal proteins essential for axonal transport, synaptic plasticity, glutamate neurotransmission, glutamate homeostasis and memory/learning were significantly decreased in demyelinated hippocampi, but not in demyelinated motor cortices from MS brains.
Collectively, these data support hippocampal demyelination as a cause of synaptic alterations in MS patients and establish that the neuronal genes regulated by myelination reflect specific functions of neuronal subpopulations.
PMCID: PMC3073544  PMID: 21446020
Multiple Sclerosis; hippocampus; demyelination; memory
13.  A Comparative PCET Study of a Donor-Acceptor Pair Linked by Ionized and Non-ionized Asymmetric Hydrogen-Bonded Interfaces 
A Zn(II) porphyrin-amidinium is the excited state electron donor (D) to a naphthalene diimide acceptor (A) appended with either a carboxylate or sulfonate functionality. The two-point hydrogen bond (---[H+]---) formed between the amidinium and carboxylate or sulfonate establishes a proton-coupled electron transfer (PCET) pathway for charge transfer. The two D---[H+]---A assemblies differ only by the proton configuration within the hydrogen bonding interface. Specifically, the amidinium transfers a proton to the carboxylate to form a non-ionized amidine-carboxylic acid two-point hydrogen network whereas the amidinium maintains both protons when bound to the sulfonate functionality forming an ionized amidinium-sulfonate two-point hydrogen network. These two interface configurations within the dyads thus allow for a direct comparison of PCET kinetics for the same donor and acceptor juxtaposed by an ionized and non-ionized hydrogen-bonded interface. Analysis of PCET kinetics ascertained from transient absorption and transient emission spectroscopy reveal that the ionized interface is more strongly impacted by the local solvent environment, thus establishing that the initial static configuration of the proton interface is a critical determinant to the kinetics of PCET.
PMCID: PMC3278395  PMID: 19489645
14.  Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease 
Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.
PMCID: PMC3166154  PMID: 21915365
Epidemiology; Genetics of cardiovascular disease; Risk factors; IGF1; IGFBP3
15.  The Influence of Menopausal Status and Postmenopausal Use of Hormone Therapy on Presentation of Major Depression in Women 
Menopause (New York, N.Y.)  2010;17(4):828-839.
The purpose of this study was to determine whether there are differences in depression characteristics among premenopausal, perimenopausal, and postmenopausal women with major depressive disorder. This study also evaluated these differences between postmenopausal women with major depressive disorder who are taking and not taking hormone therapy.
Analyses conducted with data from the Sequenced Treatment Alternatives to Relieve Depression study focused on female outpatients with non-psychotic major depressive disorder seeking treatment in 41 primary or psychiatric care settings across the United States. Baseline demographic and clinical characteristics were compared among women not taking hormone therapy who were premenopausal (N=950), perimenopausal (N=380), or postmenopausal (N=562). These comparisons were also made between postmenopausal women (n=768) taking (N=171) or not taking (N=562) hormone therapy.
After adjusting for sociodemographic and clinical baseline differences, premenopausal women were more likely to present with irritability than either peri- or postmenopausal women, and were more likely to have decreased appetite and less likely to have early morning insomnia than perimenopausal women. Postmenopausal women were more likely to have suicidal ideation and poorer physical functioning than either of the other groups, and were more likely to have sympathetic arousal and gastrointestinal symptoms than premenopausal women. After adjusting for baseline differences, postmenopausal women taking hormone therapy had better physical functioning, fewer melancholic features, less sympathetic arousal, and more lack of involvement in activities than women not taking hormone therapy.
Menopausal status and postmenopausal use of hormone therapy may influence the clinical presentation of major depressive episodes in women.
PMCID: PMC2949279  PMID: 20616669
menopause; hormone therapy; depression; major depressive disorder
16.  Cognitive modulation of endocrine responses to CRH stimulation in healthy subjects 
Psychoneuroendocrinology  2009;35(3):451-459.
The hypothalamic-pituitary adrenal (HPA) axis is critical for biobehavioral adaptation to challenge and appears dysregulated in a range of psychiatric disorders. Its precise role in psychopathology remains unclear and discrepant and difficult to explain findings abound in the clinical literature. Basic research suggests this system is sensitive to psychosocial cues, but psychosocial milieu factors are rarely controlled or examined in psychiatric studies using biological probes of the HPA axis. To test the hypothesis that psychological factors might complicate HPA study results even in direct, pharmacological challenge paradigms, endocrine responses to corticotropin-releasing hormone (CRH) were examined under two different cognitive preparation conditions.
Healthy subjects (n=32) received standard instructions or a cognitive intervention (CI) prior to injection with CRH and placebo, given on separate days in random order. The CI combined access to control over drug exposure with novelty reduction and coping enhancement. Blood samples were obtained via intravenous catheter before and after CRH.
Cognitive intervention reduced corticotropin (ACTH) levels, but only when CRH was given first (intervention by order interaction). It did not reduce cortisol response. The CI and visit (1st or 2nd) both impacted cortisol levels on placebo day.
Modifiable psychological factors may amplify or inhibit HPA axis activity in pharmacological activation paradigms, including CRH stimulation tests. The factors manipulated by the CI (novelty/familiarity, control and coping) may have particular salience to the HPA axis. Differential sensitivity to such factors could impact results in studies applying biological HPA probes to psychiatric populations.
PMCID: PMC2824051  PMID: 19758763
stress; cortisol; ACTH, corticotropin-releasing hormone; control; coping
17.  Gender Specific Disruptions in Emotion Processing in Younger Adults with Depression 
Depression and anxiety  2009;26(2):182-189.
One of the principal theories regarding the biological basis of Major Depressive Disorder (MDD) implicates a dysregulation of emotion processing circuitry. Gender differences in how emotions are processed and relative experience with emotion processing might help to explain some of the disparities in the prevalence of MDD between women and men. The current study sought to explore how gender and depression status relate to emotion processing.
This study employed a 2 (MDD status) × 2 (gender) factorial design to explore differences in classifications of posed facial emotional expressions (N = 151).
For errors, there was an interaction between gender and depression status. Women with MDD made more errors than did non-depressed women and men with MDD, particularly for fearful and sad stimuli (ps < .02), which they were likely to misinterpret as angry (ps < .04). There was also an interaction of diagnosis and gender for response cost for negative stimuli, with significantly greater interference from negative faces present in women with MDD compared with non-depressed women (p = .01). Men with MDD, conversely, performed similarly to control men (p = .61).
These results provide novel and intriguing evidence that depression in younger adults (< 35 years) differentially disrupts emotion processing in women as compared to men. This interaction could be driven by neurobiological and social learning mechanisms, or interactions between them, and may underlie differences in the prevalence of depression in women and men.
PMCID: PMC3013355  PMID: 18800371
psychiatric disorders; affect perception; sex differences
19.  SSRI response in depression may be influenced by SNPs in HTR1B and HTR1A 
Psychiatric genetics  2009;19(6):281-291.
Desensitization of serotonin 1A (HTR1A) and 1B (HTR1B) autoreceptors has been proposed to be involved in the delayed onset of response to SSRIs. Variations in gene expression in these genes may thus affect SSRI response. Here we test this hypothesis in two samples from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), and show evidence for involvement of several genetic variants alone and in interaction. Initially, three functional SNPs in the HTR1B gene and in the HTR1A gene were analyzed in 153 depressed patients treated with citalopram. QIDS-C scores were evaluated over time with respect to genetic variation. Subjects homozygous for the - 1019 G allele (rs6295) in HTR1A showed higher baseline QIDS scores (p = 0.033), and by 12 weeks had a significantly lower response rate (p = 0.005). HTR1B haplotypes were estimated according to previously reported in-vitro expression levels. Individuals who were homozygous for the high-expression haplotype showed significantly slower response to citalopram (p = 0.034).
We then analyzed more SNPs in the extended overall STAR*D sample. Although we could not directly test the same functional SNPs, we found that homozygotes for the G allele at rs1364043 in HTR1A (p = 0.045) and the C allele of rs6298 in HTR1B showed better response to citalopram over time (p = 0.022). Test for interaction between rs6298 in HTR1B and rs1364043 in HTR1A was significant (overall p = 0.032)
Our data suggest that an enhanced capacity of HTR1B or HTR1A transcriptional activity may impair desensitization of the autoreceptors during SSRI treatment.
PMCID: PMC2783179  PMID: 19829169
SSRI; depression; haplotype; HTR1B; HTR1A; association
20.  Association of Daily Stressors and Salivary Cortisol in Spinal Cord Injury 
Rehabilitation psychology  2009;54(3):288-298.
Examine the diurnal variation of salivary cortisol in adults with spinal cord injury (SCI) and the effect of stressors on cortisol and mood.
Ecological momentary assessment (EMA) to capture cortisol, stress and mood from 25 persons with SCI and 26 without SCI. Data were analyzed using linear mixed models.
There were no systematic differences between groups on missing data. Diurnal variation of cortisol of participants with SCI reflected an expected pattern. No significant group differences for cortisol diurnal pattern, stress or mood; when group interactions were significant, results indicated lower cortisol reactivity to stress in participants with SCI. Stress had a significant impact on positive, negative and agitated moods.
Stress in daily life and its association with cortisol and mood were largely similar between persons with and without SCI. A key methodological contribution is the demonstration of using EMA to collect biological and behavioral data in the field from participants with SCI. The use of EMA in rehabilitation psychology research has great potential to advance our understanding of the dynamics of daily life with disability.
PMCID: PMC2924200  PMID: 19702427
spinal cord injuries; stress, psychological; hydrocortisone; ecological momentary assessment
21.  Frontal and Limbic Activation During Inhibitory Control Predicts Treatment Response in Major Depressive Disorder 
Biological psychiatry  2007;62(11):1272-1280.
Inhibitory control or regulatory difficulties have been explored in major depressive disorder (MDD) but typically in the context of affectively salient information. Inhibitory control is addressed specifically by using a task devoid of affectively-laden stimuli, to disentangle the effects of altered affect and altered inhibitory processes in MDD.
Twenty MDD and 22 control volunteer participants matched by age and gender completed a contextual inhibitory control task, the Parametric Go/No-go (PGNG) task during functional magnetic resonance imaging. The PGNG includes three levels of difficulty, a typical continuous performance task and two progressively more difficult versions including Go/No-go hit and rejection trials. After this test, 15 of 20 MDD patients completed a full 10-week treatment with s-citalopram.
There was a significant interaction among response time (control subjects better), hits (control subjects better), and rejections (patients better). The MDD participants had greater activation compared with the control group in frontal and anterior temporal areas during correct rejections (inhibition). Activation during successful inhibitory events in bilateral inferior frontal and left amygdala, insula, and nucleus accumbens and during unsuccessful inhibition (commission errors) in rostral anterior cingulate predicted post-treatment improvement in depression symptoms.
The imaging findings suggest that in MDD subjects, greater neural activation in frontal, limbic, and temporal regions during correct rejection of lures is necessary to achieve behavioral performance equivalent to control subjects. Greater activation in similar regions was further predictive of better treatment response in MDD.
PMCID: PMC2860742  PMID: 17585888
Depression; executive functioning; fMRI; imaging; inhibitory control; mood disorders; SSRIs; treatment response
22.  Why are we fat? Discussions on the socioeconomic dimensions and responses to obesity 
This paper draws together contributions to a scientific table discussion on obesity at the European Science Open Forum 2008 which took place in Barcelona, Spain. Socioeconomic dimensions of global obesity, including those factors promoting it, those surrounding the social perceptions of obesity and those related to integral public health solutions, are discussed. It argues that although scientific accounts of obesity point to large-scale changes in dietary and physical environments, media representations of obesity, which context public policy, pre-eminently follow individualistic models of explanation. While the debate at the forum brought together a diversity of views, all the contributors agreed that this was a global issue requiring an equally global response. Furthermore, an integrated ecological model of obesity proposes that to be effective, policy will need to address not only human health but also planetary health, and that therefore, public health and environmental policies coincide.
PMCID: PMC2873249  PMID: 20416037
23.  Sex Differences in Response to Citalopram: A STAR*D Report 
Journal of psychiatric research  2008;43(5):503-511.
Controversy exists as to whether women with depression respond better to selective serotonin reuptake inhibitors (SSRIs) than men. The purpose of this report was to determine whether men and women differ in their responses to treatment with the SSRI citalopram using a large sample of real world patients from primary and psychiatric specialty care settings.
As part of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, 2876 participants were treated with citalopram for up to 12-14 weeks. Baseline demographic and clinical characteristics and outcomes were gathered and compared between men and women.
At baseline, women were younger, had more severe depressive symptoms and were more likely to have: early onset; previous suicide attempt(s); a family history of depression, alcohol abuse or drug abuse; atypical symptom features; and one or more of several concurrent psychiatric disorders. Despite greater baseline severity and more Axis I comorbidities, women were more likely to reach remission and response with citalopram than men.
Women have a better response to the SSRI citalopram than men, which may be due to sex-specific biological differences particularly in serotonergic systems.
PMCID: PMC2681489  PMID: 18752809
antidepressants; gender differences; estradiol; women's health; depression
24.  Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes 
Human Molecular Genetics  2009;19(3):535-544.
Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
PMCID: PMC2798726  PMID: 19933169
25.  Effects of perceived control and cognitive coping on endocrine stress responses to pharmacological activation 
Biological psychiatry  2008;64(8):701-707.
The hypothalamic-pituitary adrenal (HPA) axis may mediate negative health effects of stress. It is sensitive to cognitive/emotional factors like novelty, perceived control and coping. Psychological intervention that reduces novelty, and enhances cognitive coping and sense of control can reduce cortisol responses to pentagastrin, a pharmacological HPA activator. This study attempted to identify the core factors that modulate HPA axis activity in this model.
Varying instructions were administered prior to drug exposure in a two-visit (placebo first) pentagastrin infusion paradigm. Healthy subjects (n=40) were randomly assigned to 1 of 4 instruction groups: (1) Standard instruction (SI); (2) Full cognitive intervention (CI); (3) The CI control component alone; or (4) The CI novelty reduction/coping components alone. Blood samples were obtained via intravenous catheter before and after pentagastrin.
Subjects receiving an intervention had smaller cortisol responses than subjects receiving standard instructions. “Coping” alone had as strong an impact as the more complex intervention that combined “coping” and “control.” “Control alone” also reduced cortisol but its HPA impact appeared less robust.
Brief psychological manipulation can significantly reduce HPA activation in challenge paradigms. Cognitive preparation that focused on side effects, reduced potential surprise and enhanced cognitive coping modulated HPA axis activity as effectively as a previously tested intervention that combined coping and control manipulations. A sense of control alone also reduced cortisol release. The results support development of “control” or “coping” techniques to combat negative health effects of stress that are mediated by HPA axis activation.
PMCID: PMC2579765  PMID: 18571624
stress; cortisol; pentagastrin; control; coping; anxiety

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