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1.  Rounding Behavior in the Reporting of Headache Frequency Complicates Headache Chronification Research 
Headache  2013;53(6):908-919.
Objectives
To characterize the extent of measurement error arising from rounding in headache frequency reporting (days per month) in a population sample of headache sufferers.
Background
When reporting numerical health information, individuals tend to round their estimates. The tendency to round to the nearest 5 days when reporting headache frequency can distort distributions and engender unreliability in frequency estimates in both clinical and research contexts.
Methods
This secondary analysis of the 2005 American Migraine Prevalence and Prevention study (AMPP) survey characterized the population distribution of 30-day headache frequency among community headache sufferers and determined the extent of numerical rounding (“heaping”) in self-reported data. Headache frequency distributions (days per month) were examined using a simplified version of Wang and Heitjan’s (2008) approach to heaping to estimate the probability that headache sufferers round to a multiple of 5 when providing frequency reports. Multiple imputation was used to estimate a theoretical “true” headache frequency.
Results
Of the 24,000 surveys, headache frequency data were available for 15,976 respondents diagnosed with migraine (68.6%), probable migraine (8.3%), or episodic tension-type headache (10.0%); the remainder had other headache types. The mean number of headaches days/month was 3.7 (SD = 5.6). Examination of the distribution of headache frequency reports revealed a disproportionate number of responses centered on multiples of 5 days. The odds that headache frequency was rounded to 5 increased by 24% with each one-day increase in headache frequency (OR: 1.24, 95% CI: 1.23 to 1.25), indicating that heaping occurs most commonly at higher headache frequencies. Women were more likely to round than men, and rounding decreased with increasing age and increased with symptoms of depression.
Conclusions
Because of the coarsening induced by rounding, caution should be used when distinguishing between episodic and chronic headache sufferers using self-reported estimates of headache frequency. Unreliability in frequency estimates is of particular concern among individuals with high-frequency (chronic) headache. Employing shorter recall intervals when assessing headache frequency, preferably using daily diaries, may improve accuracy and allow more precise estimation of chronic migraine onset and remission.
doi:10.1111/head.12126
PMCID: PMC4546843  PMID: 23721238
Headache frequency; rounding; statistics; headache chronification
2.  Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [11C]-(+)-PHNO PET Study in Humans 
Neuropsychopharmacology  2015;41(2):529-537.
There is considerable interest in blocking the dopamine D3 receptor (DRD3) versus the D2 receptor (DRD2) to treat drug addiction. However, there are currently no selective DRD3 antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD3, binds to DRD3 in brain of living non-human primate, and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3-preferring probe, [11C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [11C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [11C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60, and 120 mg of buspirone in a single-blind within-subjects design. [11C]-(+)-PHNO binding in DRD2- and DRD3-rich areas was decreased by the highest (60–120 mg), but not the lowest (30 mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD2 and DRD3 even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD3 in humans.
doi:10.1038/npp.2015.177
PMCID: PMC5130128  PMID: 26089182
3.  Sexual Behaviors and HIV Status: A Population-Based Study Among Older Adults in Rural South Africa 
Supplemental Digital Content is Available in the Text.
Objective:
To identify the unmet needs for HIV prevention among older adults in rural South Africa.
Methods:
We analyzed data from a population-based sample of 5059 men and women aged 40 years and older from the study Health and Aging in Africa: Longitudinal Studies of INDEPTH Communities (HAALSI), which was carried out in the Agincourt health and sociodemographic surveillance system in the Mpumalanga province of South Africa. We estimated the prevalence of HIV (laboratory-confirmed and self-reported) and key sexual behaviors by age and sex. We compared sexual behavior profiles across HIV status categories with and without age–sex standardization.
Results:
HIV prevalence was very high among HAALSI participants (23%, 95% confidence interval [CI]: 21 to 24), with no sex differences. Recent sexual activity was common (56%, 95% CI: 55 to 58) across all HIV status categories. Condom use was low among HIV-negative adults (15%, 95% CI: 14 to 17), higher among HIV-positive adults who were unaware of their HIV status (27%, 95% CI: 22 to 33), and dramatically higher among HIV-positive adults who were aware of their status (75%, 95% CI: 70 to 80). Casual sex and multiple partnerships were reported at moderate levels, with slightly higher estimates among HIV-positive compared to HIV-negative adults. Differences by HIV status remained after age–sex standardization.
Conclusions:
Older HIV-positive adults in an HIV hyperendemic community of rural South Africa report sexual behaviors consistent with high HIV transmission risk. Older HIV-negative adults report sexual behaviors consistent with high HIV acquisition risk. Prevention initiatives tailored to the particular prevention needs of older adults are urgently needed to reduce HIV risk in this and similar communities in sub-Saharan Africa.
doi:10.1097/QAI.0000000000001173
PMCID: PMC5147032  PMID: 27926667
aging population; older adults; sexual behavior; South Africa; HIV acquisition risk; HIV transmission risk
4.  Lack of age-dependent decrease in dopamine D3 receptor availability: a [11C]-(+)-PHNO and [11C]-raclopride positron emission tomography study 
Positron emission tomography with antagonist radiotracers has showed that striatal dopamine D2/3 receptor (D2/3R) availability decreases with age. However, no study has specifically assessed whether D2/3R availability decreases with age in healthy persons as measured with agonist radiotracers. Moreover, it is unknown whether D3R availability changes with age in healthy humans. Thus, we explored the relationship between age and D2/3R availability in healthy humans using the D3 receptor (D3R)-preferential agonist radiotracer [11C]-(+)-PHNO (n=72, mean±s.d. age=40±15, range=18 to 73) and the antagonist [11C]-Raclopride (n=70, mean±s.d. age =40±14, range=18 to 73) (both, n=33). The contribution of D3R to the [11C]-(+)-PHNO signal varies across regions of interest; the substantia nigra and hypothalamus represent D3R-specific regions, the ventral pallidum, globus pallidus, and ventral striatum represent D2/3R-mixed regions, and the caudate and putamen represent D2 receptor (D2R)-specific regions. With [11C]-(+)-PHNO, a negative correlation was observed between age and nondisplaceable binding potential (BPND) in the caudate (r(70)=−0.32, P=0.005). No correlations were observed in the other regions. With [11C]-Raclopride, negative correlations were observed between age and BPND in the caudate (r(68)=−0.50, P<0.001), putamen (r(68)=−0.41, P<0.001), and ventral striatum (r(68)=−0.43, P<0.001). In conclusion, in contrast with the age-dependent decrease in D2R availability, these findings suggest that D3R availability does not change with age.
doi:10.1038/jcbfm.2015.129
PMCID: PMC4635236  PMID: 26058690
aging; dopamine; D2 receptor; D3 receptor; positron emission tomography; [11C]-(+)-PHNO; [11C]-Raclopride
5.  Blocking of fatty acid amide hydrolase activity with PF-04457845 in human brain: a positron emission tomography study with the novel radioligand [11C]CURB 
Positron emission tomography with [11C]CURB was recently developed to quantify fatty acid amide hydrolase (FAAH), the enzyme responsible for hydrolyzing the endocannabinoid anandamide. This study investigated the test–retest reliability of [11C]CURB as well as its in vivo specificity and the validity of the kinetic model by using the highly specific FAAH inhibitor, PF-04457845. Five healthy volunteers completed test–retest [11C]CURB scans 1 to 2 months apart and six subjects completed baseline and blocking scans on the same day after PF-04457845 (p.o.) administration (1, 4, or 20 mg; n=2 each). The composite parameter λk3 (an index of FAAH activity, λ=K1/k2) was estimated using an irreversible two-tissue compartment model with plasma input function. There were no clinically observable responses to oral PF-04457845 or [11C]CURB injection. Oral administration of PF-04457845 reduced [11C]CURB binding to a homogeneous level at all three doses, with λk3 values decreased by ⩾91%. Excellent reproducibility and good reliability (test–retest variability=9% intraclass correlation coefficient=0.79) were observed across all regions of interest investigated. Our findings suggest that λk3/[11C]CURB is a reliable, highly sensitive, and selective tool to measure FAAH activity in human brain in vivo. Moreover, PF-04457845 is a highly potent FAAH inhibitor (>95% inhibition at 1 mg) in living human brain.
doi:10.1038/jcbfm.2015.133
PMCID: PMC4635238  PMID: 26082009
[11C]CURB; fatty acid amide hydrolase; PF-04457845; positron emission tomography; test–retest
6.  Pay-for-performance remuneration for pharmacist prescribers’ management of hypertension 
Canadian Pharmacists Journal : CPJ  2016;149(6):345-351.
Background:
To be sustainable, pharmacists providing direct patient care must receive appropriate payment for these services. This prespecified substudy of the RxACTION trial (a randomized trial of pharmacist prescribing vs usual care in patients with above-target blood pressure [BP]) aimed to determine if BP reduction achieved differed between patients whose pharmacist was paid by pay-for-performance (P4P) vs fee-for-service (FFS).
Methods:
Within RxACTION, patients with elevated BP assigned to the pharmacist prescribing group were further randomized to P4P or FFS payment for the pharmacist. In FFS, pharmacists received $150 for the initial visit and $75 for follow-up visits. P4P included FFS payments plus incentives of $125 and $250 for each patient who reached 50% and 100% of the BP target, respectively. The primary outcome was difference in change in systolic BP between P4P and FFS groups.
Results:
A total of 89 patients were randomized to P4P and 92 to the FFS group. Patients’ average (SD) age was 63.0 (13.2) years, 49% were male and 76% were on antihypertensive drug therapy at baseline, taking a median of 2 (interquartile range = 1) medications. Mean systolic BP reductions in the P4P and FFS groups were 19.7 (SD = 18.4) vs 17.0 (SD = 16.4) mmHg, respectively (p = 0.47 for the comparison of deltas and p = 0.29 after multivariate adjustment).
Conclusions:
This trial of pharmacist prescribing found substantial reductions in systolic BP among poorly controlled hypertensive individuals but with no appreciable difference when pharmacists were paid by P4P vs FFS.
doi:10.1177/1715163516671745
PMCID: PMC5089333  PMID: 27829858
8.  Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors 
Nature Communications  2016;7:13042.
Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.
Several β-secretase (BACE) inhibitors exhibit unexplained ocular toxicity in preclinical studies. Here the authors generate a clickable photoaffinity probe to interrogate off-targets in cells and animals, and identify inhibition of cathepsin D as a driver of ocular toxicity.
doi:10.1038/ncomms13042
PMCID: PMC5062570  PMID: 27727204
9.  Psychometric Validation of the English and French Versions of the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) 
PLoS ONE  2016;11(10):e0161645.
The purpose of this study is to assess the psychometric properties of a French version of the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), a self-report measure of posttraumatic stress disorder (PTSD) symptoms, and to further validate the existing English version of the measure. Undergraduate students (n = 838 English, n = 262 French) completed the PCL-5 as well as other self-report symptom measures of PTSD and depression online. Both the English and French versions PCL-5 total scores demonstrated excellent internal consistency (English: α = .95; French: α = .94), and strong convergent and divergent validity. Strong internal consistency was also observed for each of the four subscales for each version (α’s > .79). Test-retest reliability for the French version of the measure was also very good (r = .89). Confirmatory factor analysis indicated that the four-factor DSM-5 model was not a good fit of the data. The seven-factor hybrid model best fit the data in each sample, but was only marginally superior to the six-factor anhedonia model. The French version of the PCL-5 demonstrated the same psychometric qualities as both the English version of the same measure and previous versions of the PCL. Thus clinicians serving French-speaking clients now have access to this highly used screening instrument. With regards to the structural validity of the PCL-5 and of the new PTSD diagnostic structure of the DSM-5, additional research is warranted. Replication of our results in clinical samples is much needed.
doi:10.1371/journal.pone.0161645
PMCID: PMC5056703  PMID: 27723815
10.  Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [11C] Harmine Positron Emission Tomography Study 
Neuropsychopharmacology  2015;40(11):2596-2603.
Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [11C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A VT were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F2,33=6.8, P=0.003; OFC and VS MAO-A VT each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28=2.7, P=0.029). In ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r=−0.50 to −0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity.
doi:10.1038/npp.2015.106
PMCID: PMC4569949  PMID: 26081301
11.  Strategies and impacts of patient and family engagement in collaborative mental healthcare: protocol for a systematic and realist review 
BMJ Open  2016;6(9):e012949.
Introduction
Collaborative mental healthcare (CMHC) has garnered worldwide interest as an effective, team-based approach to managing common mental disorders in primary care. However, questions remain about how CMHC works and why it works in some circumstances but not others. In this study, we will review the evidence on one understudied but potentially critical component of CMHC, namely the engagement of patients and families in care. Our aims are to describe the strategies used to engage people with depression or anxiety disorders and their families in CMHC and understand how these strategies work, for whom and in what circumstances.
Methods and analysis
We are conducting a review with systematic and realist review components. Review part 1 seeks to identify and describe the patient and family engagement strategies featured in CMHC interventions based on systematic searches and descriptive analysis of these interventions. We will use a 2012 Cochrane review of CMHC as a starting point and perform new searches in multiple databases and trial registers to retrieve more recent CMHC intervention studies. In review part 2, we will build and refine programme theories for each of these engagement strategies. Initial theory building will proceed iteratively through content expert consultations, electronic searches for theoretical literature and review team brainstorming sessions. Cluster searches will then retrieve additional data on contexts, mechanisms and outcomes associated with engagement strategies, and pairs of review authors will analyse and synthesise the evidence and adjust initial programme theories.
Ethics and dissemination
Our review follows a participatory approach with multiple knowledge users and persons with lived experience of mental illness. These partners will help us develop and tailor project outputs, including publications, policy briefs, training materials and guidance on how to make CMHC more patient-centred and family-centred.
PROSPERO registration number
CRD42015025522.
doi:10.1136/bmjopen-2016-012949
PMCID: PMC5051434  PMID: 27678546
Collaborative mental health care; Patient and family engagement; Realist review; Depression and Anxiety; Protocol
12.  DISCUSSION: PRACTICE-BASED EVALUATION AS A RESPONSE TO ADRESS INTERVENTION COMPLEXITY 
The aim of this special issue of the Canadian Journal of Program Evaluation was to present an overview of current practices in the field of evaluation of complex interventions. Seasoned evaluators described their approaches to these types of evaluation in the healthcare context. Building upon their contributions, this synthesis offers a cross-sectional reading of their experiences, highlighting the common and divergent features of their approaches as well as their most pressing concerns and interests.
PMCID: PMC5036968  PMID: 27682477 CAMSID: cams2583
13.  Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia 
mBio  2016;7(5):e01397-16.
ABSTRACT
Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro, siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia.
IMPORTANCE
Klebsiella pneumoniae causes a wide range of bacterial diseases, including pneumonia, urinary tract infections, and sepsis. To cause infection, K. pneumoniae steals iron from its host by secreting siderophores, small iron-chelating molecules. Classically, siderophores are thought to worsen infections by promoting bacterial growth. In this study, we determined that siderophore-secreting K. pneumoniae causes lung inflammation and bacterial dissemination to the bloodstream independently of bacterial growth. Furthermore, we determined that siderophore-secreting K. pneumoniae activates a host protein, hypoxia inducible factor (HIF)-1α, and requires it for siderophore-dependent bacterial dissemination. Although HIF-1α can protect against some infections, it appears to worsen infection with K. pneumoniae. Together, these results indicate that bacterial siderophores directly alter the host response to pneumonia in addition to providing iron for bacterial growth. Therapies that disrupt production of siderophores could provide a two-pronged attack against K. pneumoniae infection by preventing bacterial growth and preventing bacterial dissemination to the blood.
doi:10.1128/mBio.01397-16
PMCID: PMC5021805  PMID: 27624128
14.  Intra-axonal protein synthesis – a new target for neural repair? 
Neural Regeneration Research  2016;11(9):1365-1367.
Although initially argued to be a feature of immature neurons with incomplete polarization, there is clear evidence that neurons in the peripheral nervous system retain the capacity for intra-axonal protein synthesis well into adulthood. This localized protein synthesis has been shown to contribute to injury signaling and axon regeneration in peripheral nerves. Recent works point to potential for protein synthesis in axons of the vertebrate central nervous system. mRNAs and protein synthesis machinery have now been documented in lamprey, mouse, and rat spinal cord axons. Intra-axonal protein synthesis appears to be activated in adult vertebrate spinal cord axons when they are regeneration-competent. Rat spinal cord axons regenerating into a peripheral nerve graft contain mRNAs and markers of activated translational machinery. Indeed, levels of some growth-associated mRNAs in these spinal cord axons are comparable to the regenerating sciatic nerve. Markers of active translation tend to decrease when these axons stop growing, but can be reactivated by a second axotomy. These emerging observations raise the possibility that mRNA transport into and translation within axons could be targeted to facilitate regeneration in both the peripheral and central nervous systems.
doi:10.4103/1673-5374.191193
PMCID: PMC5090821  PMID: 27857722
mRNA transport; translational control; RNA binding protein; axon regeneration; spinal cord injury; peripheral nerve injury
15.  Altered lysosomal positioning affects lysosomal functions in a cellular model of Huntington's disease 
The European journal of neuroscience  2015;42(3):1941-1951.
Huntington's disease (HD) is a hereditary and devastating neurodegenerative disorder caused by a mutation in the huntingtin protein. Understanding the functions of normal and mutant huntingtin protein is the key to reveal the pathogenesis of HD and develop therapeutic targets. Huntingtin plays an important role in vesicular and organelle trafficking. Lysosomes are dynamic organelles that integrate several degradative pathways and regulate the activity of mammalian target of rapamycin complex 1 (mTORC1). In the present study, we show that the perinuclear accumulation of lysosomes is increased in a cellular model of HD derived from HD knock-in mice and primary fibroblasts from a HD patient. This perinuclear lysosomal accumulation can be reversed when normal huntingtin is overexpressed in HD cells. To further investigate the functional significance of the increased perinuclear lysosomal accumulation in HD cells, we demonstrate subsequently that basal mTORC1 activity is increased in HD cells. In addition, autophagic influx is also increased in HD cells in response to serum deprivation, which leads to a premature fusion of lysosomes with autophagosomes. Taken together, our data suggest that the increased perinuclear accumulation of lysosomes may play an important role in HD pathogenesis by altering lysosomal-dependent functions.
Graphical Abstract
doi:10.1111/ejn.12957
PMCID: PMC4523460  PMID: 25997742
vesicular trafficking; Lamp1; autophagy; autophagic influx; mTORC1
16.  The fatty acid amide hydrolase C385A variant affects brain binding of the positron emission tomography tracer [11C]CURB 
The common functional single-nucleotide polymorphism (rs324420, C385A) of the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) has been associated with anxiety disorder relevant phenotype and risk for addictions. Here, we tested whether the FAAH polymorphism affects in vivo binding of the FAAH positron emission tomography (PET) probe [11C]CURB ([11C-carbonyl]-6-hydroxy-[1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)). Participants (n=24) completed one [11C]CURB/PET scan and were genotyped for rs324420. Relative to C/C (58%), A-allele carriers (42%) had 23% lower [11C]CURB binding (λk3) in brain. We report evidence that the genetic variant rs324420 in FAAH is associated with measurable differences in brain FAAH binding as per PET [11C]CURB measurement.
doi:10.1038/jcbfm.2015.119
PMCID: PMC4527995  PMID: 26036940
[11C]CURB; fatty acid amide hydrolase; FAAH polymorphism (rs324420, C385A); positron emission tomography
18.  Making quantitative morphological variation from basic developmental processes: where are we? The case of the Drosophila wing 
One of the aims of evolutionary developmental biology is to discover the developmental origins of morphological variation. The discipline has mainly focused on qualitative morphological differences (e.g., presence or absence of a structure) between species. Studies addressing subtle, quantitative variation are less common. The Drosophila wing is a model for the study of development and evolution, making it suitable to investigate the developmental mechanisms underlying the subtle quantitative morphological variation observed in nature. Previous reviews have focused on the processes involved in wing differentiation, patterning and growth. Here, we investigate what is known about how the wing achieves its final shape, and what variation in development is capable of generating the variation in wing shape observed in nature. Three major developmental stages need to be considered: larval development, pupariation, and pupal development. The major cellular processes involved in the determination of tissue size and shape are cell proliferation, cell death, oriented cell division and oriented cell intercalation. We review how variation in temporal and spatial distribution of growth and transcription factors affects these cellular mechanisms, which in turn affects wing shape. We then discuss which aspects of the wing morphological variation are predictable on the basis of these mechanisms.
doi:10.1002/dvdy.24255
PMCID: PMC4512935  PMID: 25619644
Evo-Devo; Developmental systematics; Quantitative development; Evolutionary morphology; Drosophila wing morphogenesis
19.  Elevated Monoamine Oxidase-A Distribution Volume in Borderline Personality Disorder Is Associated With Severity Across Mood Symptoms, Suicidality, and Cognition 
Biological psychiatry  2014;79(2):117-126.
BACKGROUND
Monoamine oxidase-A (MAO-A) is a treatment target in neurodegenerative illness and mood disorders that increases oxidative stress and predisposition toward apoptosis. Increased MAO-A levels in prefrontal cortex (PFC) and anterior cingulate cortex (ACC) occur in rodent models of depressive behavior and human studies of depressed moods. Extreme dysphoria is common in borderline personality disorder (BPD), especially when severe, and the molecular underpinnings of severe BPD are largely unknown. We hypothesized that MAO-A levels in PFC and ACC would be highest in severe BPD and would correlate with symptom magnitude.
METHODS
[11C] Harmine positron emission tomography measured MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in severe BPD subjects (n = 14), moderate BPD subjects (n = 14), subjects with a major depressive episode (MDE) only (n = 14), and healthy control subjects (n = 14). All subjects were female.
RESULTS
Severe BPD was associated with greater PFC and ACC MAO-A VT compared with moderate BPD, MDE, and healthy control subjects (multivariate analysis of variance group effect: F6,102 = 5.6, p < .001). In BPD, PFC and ACC MAO-A VT were positively correlated with mood symptoms (PFC: r = .52, p = .005; ACC: r = .53, p = .004) and suicidality (PFC: r = .40, p = .037; ACC: r = .38, p = .046), while hippocampus MAO-A VT was negatively correlated with verbal memory (r = −.44, p = .023).
CONCLUSIONS
These results suggest that elevated MAO-A VT is associated with multiple indicators of BPD severity, including BPD symptomatology, mood symptoms, suicidality, and neurocognitive impairment.
doi:10.1016/j.biopsych.2014.11.024
PMCID: PMC4942262  PMID: 25698585 CAMSID: cams5580
Borderline personality disorder; Harmine; Imaging; Monoamine oxidase-A; Positron emission tomography; Suicidal behavior
20.  Greater Monoamine Oxidase A Binding in Perimenopausal Age as Measured With Carbon 11–Labeled Harmine Positron Emission Tomography 
JAMA psychiatry  2014;71(8):873-879.
IMPORTANCE
Perimenopause is a period of high risk for mood disorders, and it has been proposed that perimenopause is also a window of risk for processes linked to later dementia. However, in human perimenopause, the neurobiological changes implicated in the genesis of mood disorders or dementia have not been identified. Monoamine oxidase A (MAO-A) is an important brain enzyme that creates oxidative stress, influences apoptosis, and metabolizes monoamines. After declines in estrogen level, MAO-A density may be elevated for a month or longer, and repeated declines in estrogen level occur with greater magnitude during perimenopause.
OBJECTIVE
To investigate whether MAO-A total distribution volume (VT), an index of MAO-A density, is elevated in women of perimenopausal age (41–51 years).
DESIGN, SETTING, AND PARTICIPANTS
In a cross-sectional study at a tertiary care psychiatric hospital, 58 women underwent carbon 11–labeled harmine positron emission tomography. These included 19 young women of reproductive age (mean [SD], 28.26 [5.05] years), 27 women of perimenopausal age (mean [SD] age, 45.21 [3.41] years; including 14 women with change in menstrual cycle length with a mean [SD] age of 45.50 [4.00] years and 13 women with no change in menstrual cycle length with a mean [SD] age of 44.92 [2.81] years), and 12 women in menopause (mean [SD] age, 56.25 [3.19] years).
MAIN OUTCOMES AND MEASURES
Values of MAO-A VT in the prefrontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, thalamus, hippocampus, and midbrain.
RESULTS
On average, MAO-A VT in perimenopausal age was elevated by 34% compared with reproductive age and by 16% compared with menopause (multivariate analysis of variance, group effect, F16,94 = 3.03; P < .001). Within the perimenopausal age group, meeting Stages of Reproductive Aging Workshop criteria for perimenopause, which is mainly based on menstrual cycle length, was not associated with MAO-A VT (F8,18 = 0.548; P = .81) but tendency to cry was positively correlated with MAO-A VT in the prefrontal cortex (r = 0.54; P = .008).
CONCLUSIONS AND RELEVANCE
To our knowledge, this is the first report of a change in a central biomarker during perimenopausal age that is also present during major depressive episodes and high-risk states for major depressive episodes. The functions of MAO-A influence oxidative stress and apoptosis, 2 processes implicated as excessive in both mood disorders and dementia. Hence, greater MAO-A VT during perimenopause may represent a new target for assessing novel interventions to prevent mood disorders and reduce longer-term risk of neurodegenerative disease.
doi:10.1001/jamapsychiatry.2014.250
PMCID: PMC4942269  PMID: 24898155 CAMSID: cams5582
21.  Greater Monoamine Oxidase A Binding in Alcohol Dependence 
Biological psychiatry  2013;75(10):756-764.
Background
Alcohol dependence (AD) is a multiorgan disease in which excessive oxidative stress and apoptosis are implicated. Monoamine oxidase A (MAO-A) is an important enzyme on the outer mitochondrial membrane that participates in the cellular response to oxidative stress and mitochondrial toxicity. It is unknown whether MAO-A levels are abnormal in AD. We hypothesized that MAO-A VT, an index of MAO-A level, is elevated in the prefrontal cortex (PFC) during AD, because markers of greater oxidative stress and apoptosis are reported in the brain in AD and a microarray analysis reported greater MAO-A messenger RNA in the PFC of rodents exposed to alcohol vapor.
Methods
Sixteen participants with alcohol dependence and 16 healthy control subjects underwent [11C]-harmine positron emission tomography. All were nonsmoking, medication- and drug-free, and had no other past or present psychiatric or medical illnesses.
Results
MAO-A VT was significantly greater in the PFC (37%, independent samples t test, t30 = 3.93, p < .001), and all brain regions analyzed (mean 32%, multivariate analysis of variance, F7,24 = 3.67, p = .008). Greater duration of heavy drinking correlated positively with greater MAO-A VT in the PFC (r = .67, p = .005) and all brain regions analyzed (r = .73 to .57, p = .001–.02).
Conclusions
This finding represents a new pathological marker present in AD that is therapeutically targetable through direct inhibition or by novel treatments toward oxidative/pro-apoptotic processes implicated by MAO-A overexpression.
doi:10.1016/j.biopsych.2013.10.010
PMCID: PMC4942263  PMID: 24269057 CAMSID: cams5583
Addictions; alcohol dependence; monoamine oxidase A; neurotoxicity; oxidative stress; positron emission tomography
22.  Light therapy and serotonin transporter binding in the anterior cingulate and prefrontal cortex 
Acta psychiatrica Scandinavica  2015;132(5):379-388.
Objective
To investigate the effects of light therapy on serotonin transporter binding (5-HTT BPND), an index of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) of healthy individuals during the fall and winter. Twenty-five per cent of healthy individuals experience seasonal mood changes that affect functioning. 5-HTT BPND has been found to be higher across multiple brain regions in the fall and winter relative to spring and summer, and elevated 5-HTT BPND may lead to extracellular serotonin loss and low mood. We hypothesized that, during the fall and winter, light therapy would reduce 5-HTT BPND in the ACC and PFC, which sample brain regions involved in mood regulation.
Method
In a single-blind, placebo-controlled, counterbalanced, crossover design, [11C]DASB positron emission tomography was used measure 5-HTT BPND following light therapy and placebo conditions during fall and winter.
Results
In winter, light therapy significantly decreased 5-HTT BPND by 12% in the ACC relative to placebo (F1,9 = 18.04, P = 0.002). In the fall, no significant change in 5-HTT BPND was found in any region across conditions.
Conclusion
These results identify, for the first time, a central biomarker associated with the intervention of light therapy in humans which may be applied to further develop this treatment for prevention of seasonal depression.
doi:10.1111/acps.12424
PMCID: PMC4942271  PMID: 25891484 CAMSID: cams5581
light therapy; serotonin transporter; serotonin; anterior cingulate cortex; seasonal affective disorder
23.  Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [11C] Harmine Positron Emission Tomography Study 
Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [11C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A VT were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F2,33 = 6.8, P = 0.003; OFC and VS MAO-A VT each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28 = 2.7, P = 0.029). In ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r = −0.50 to −0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity.
doi:10.1038/npp.2015.106
PMCID: PMC4569949  PMID: 26081301 CAMSID: cams5584
24.  Mechanistic insights into chemical and photochemical transformations of bismuth vanadate photoanodes 
Nature Communications  2016;7:12012.
Artificial photosynthesis relies on the availability of semiconductors that are chemically stable and can efficiently capture solar energy. Although metal oxide semiconductors have been investigated for their promise to resist oxidative attack, materials in this class can suffer from chemical and photochemical instability. Here we present a methodology for evaluating corrosion mechanisms and apply it to bismuth vanadate, a state-of-the-art photoanode. Analysis of changing morphology and composition under solar water splitting conditions reveals chemical instabilities that are not predicted from thermodynamic considerations of stable solid oxide phases, as represented by the Pourbaix diagram for the system. Computational modelling indicates that photoexcited charge carriers accumulated at the surface destabilize the lattice, and that self-passivation by formation of a chemically stable surface phase is kinetically hindered. Although chemical stability of metal oxides cannot be assumed, insight into corrosion mechanisms aids development of protection strategies and discovery of semiconductors with improved stability.
Metal oxide semiconductors are promising materials for solar energy capture but can suffer from stability problems. Here, the authors present a methodology for evaluating corrosion mechanisms and apply it to BiVO4, revealing chemical instabilities that are not predicted from thermodynamic considerations alone.
doi:10.1038/ncomms12012
PMCID: PMC4935965  PMID: 27377305
25.  Are Migraine and Tension-Type Headache Diagnostic Types or Points on a Severity Continuum?: An Exploration of the Latent Taxometric Structure of Headache 
Pain  2015;156(7):1200-1207.
The objective of this study was to assess whether migraine and tension-type headache (TTH) are best viewed as discrete entities or points on a severity continuum using taxometric analysis. Historically, classification systems have conceptualized the primary headache disorders of migraine and TTH as fundamentally different disorders that are differentiated by their characteristic symptom profiles and, as such, imply differing pathophysiologies and required treatments. Despite this categorical nosology, findings continue to emerge suggesting that migraine and TTH instead reflect dimensions of severity within the same headache construct. However, few studies have assessed this issue using taxometric statistical analyses or investigated how this taxonomic structure varies as a function of age and headache frequency. We conducted a latent-mode factor analysis of headache symptomatology obtained from 3449 individuals with headache from 2 previous, large-scale cross-sectional studies of primary headache sufferers (Martin et al., 2005, and Smitherman and Kolivas, 2013). Stratified taxometric analyses suggest that the validity of a categorical vs dimensional classification varies as a function of sample characteristics. Specifically, graphical results revealed that high headache frequency (≥ 15 d/mo) and younger age (≤ 24 years old) were associated with unimodal distributions suggestive of a dimensional construct of primary headache, whereas lower headache frequency and older age were associated with bimodal distributions characteristic of discrete diagnostic entities. Conceptualizing primary headache as a severity continuum was supported for young adults and those with frequent headaches. The distinctions of a categorical classification system were supported for adults (> 24 years old) and those with infrequent headache.
doi:10.1097/j.pain.0000000000000157
PMCID: PMC4524296  PMID: 25775357
Migraine; Tension type headache; Taxometric analysis

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