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1.  TOMM40 rs2075650 May Represent a New Candidate Gene for Vulnerability to Major Depressive Disorder 
Neuropsychopharmacology  2014;39(7):1743-1753.
Evidence suggests that depression is a risk factor for dementia; however, the relationship between the two conditions is not fully understood. A novel gene (TOMM40) has been consistently associated with Alzheimer's disease (AD), but has received no attention in depression. We conducted a three-level cross-sectional study to investigate the association of the TOMM40 rs2075650 SNP with depression. We recruited a community sample of 1220 participants (571 controls, 649 lifetime depression) to complete a psychiatric background questionnaire, the Brief Symptom Inventory, and Big Five Inventory at Level-1, 243 (102 controls, 97 remitted, 44 currently depressed) to complete a face-to-face clinical interview and neuropsychological testing at Level-2 and 58 (33 controls, 25 remitted) to complete an emotional face-processing task during fMRI at Level-3. Our results indicated that the TOMM40 rs2075650 G allele was a significant risk factor for lifetime depression (p=0.00006) and, in depressed subjects, was a significant predictor of low extraversion (p=0.009). Currently depressed risk allele carriers showed subtle executive dysfunction (p=0.004) and decreased positive memory bias (p=0.021) together with reduced activity in the posterior (p(FWE)=0.045) and anterior (p(FWE)=0.041) cingulate during sad face emotion processing. Our results suggest that TOMM40 rs2075650 may be a risk factor for the development of depression characterized by reduced extraversion, impaired executive function, and decreased positive emotional recall, and reduced top-down cortical control during sad emotion processing.
PMCID: PMC4023148  PMID: 24549102
depression; genetics; imaging; TOMM40; rs2075650; dementia; Cognition; Depression; Unipolar/Bipolar; Imaging; Clinical or Preclinical; Psychiatry & Behavioral Sciences; TOMM40
2.  I Know How You Feel: The Warm-Altruistic Personality Profile and the Empathic Brain 
PLoS ONE  2015;10(3):e0120639.
The ability to empathize with other people is a critical component of human social relationships. Empathic processing varies across the human population, however it is currently unclear how personality traits are associated with empathic processing. This study was designed to test the hypothesis that specific personality traits are associated with behavioral and biological indicators of improved empathy. Extraversion and Agreeableness are personality traits designed to measure individual differences in social-cognitive functioning, however each trait-dimension includes elements that represent interpersonal social functioning and elements that do not represent interpersonal social functioning. We tested the prediction that interpersonal elements of Extraversion (Warmth) and Agreeableness (Altruism) are associated with empathy and non-interpersonal elements of Extraversion and Agreeableness are not associated with empathy. We quantified empathic processing behaviorally (empathic accuracy task using video vignettes) and within the brain (fMRI and an emotional perspective taking task) in 50 healthy subjects. Converging evidence shows that highly warm and altruistic people are well skilled in recognizing the emotional states of other people and exhibit greater activity in brain regions important for empathy (temporoparietal junction and medial prefrontal cortex) during emotional perspective taking. A mediation analysis further supported the association between warm-altruistic personality and empathic processing; indicating that one reason why highly warm-altruistic individuals may be skilled empathizers is that they engage the temporoparietal junction and medial prefrontal cortex more. Together, these findings advance the way the behavioral and neural basis of empathy is understood and demonstrates the efficacy of personality scales to measure individual differences in interpersonal social function.
PMCID: PMC4359130  PMID: 25769028
3.  Variability in the Effect of 5-HTTLPR on Depression in a Large European Population: The Role of Age, Symptom Profile, Type and Intensity of Life Stressors 
PLoS ONE  2015;10(3):e0116316.
Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.
In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.
The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals.
Our study is cross-sectional and applies self-report questionnaires.
Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.
PMCID: PMC4351953  PMID: 25747798
4.  Molecular Evolution of Broadly Neutralizing Llama Antibodies to the CD4-Binding Site of HIV-1 
PLoS Pathogens  2014;10(12):e1004552.
To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb) has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH) identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 µg/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols.
Author Summary
Developing a vaccine against HIV-1 is a priority, but it remains unclear whether immunizations in humans can elicit potent broadly neutralizing antibodies able to prevent HIV-1 transmission. Llamas possess heavy chain only antibodies and conventional heavy and light chain antibodies. We previously reported the heavy chain only antibody J3, which potently neutralizes more than 95% of HIV strains, and was induced by immunization. Here we immunized two further llamas and elicited three novel broadly neutralizing heavy chain only antibodies, which were identified by high-throughput screening. These neutralizing llama antibodies target different areas of the CD4-binding site of the virus, therefore breadth and potency are increased when they are used in combination. To gain greater understanding of how the llama immunizations worked, deep sequencing of the HIV binding region of the antibodies was performed. This revealed that the antibodies were matured fully only in response to the protein immunogens. Furthermore, the VHH elicited in different animals, while sharing functional hallmarks, were encoded by distinct sequences and thus could not have been identified by a deep sequencing analysis alone. Our results show that immunization can potentially induce protective antibodies in llamas and provide a method to more extensively evaluate immunization studies.
PMCID: PMC4270772  PMID: 25522326
5.  Cardiovascular disease medication health literacy among Indigenous peoples: design and protocol of an intervention trial in Indigenous primary care services 
BMC Public Health  2014;14:714.
Cardiovascular diseases (CVD) are leading causes of mortality and morbidity among Indigenous people in New Zealand, Australia and Canada and are a major driver of the inequities in life expectancy between Indigenous and non-Indigenous people in these countries. Evidence-based pharmaceutical management of CVD can significantly reduce mortality and morbidity for persons diagnosed with CVD or for those at intermediate or high risk of CVD. Health literacy has been identified as a major barrier in the communication and implementation of appropriate pharmaceutical management plans for CVD. Addressing health literacy is particularly relevant in Indigenous populations where there are unique health and adult literacy challenges.
This study will examine the effect of a customized, structured CVD medication programme, delivered by health professionals, on the health literacy of Indigenous people with, or at risk, of CVD. Primary outcomes are patient’s knowledge about CVD medications; secondary outcomes examine changes in health literacy skills and practices. The study will employ a multi-site pre-post design with multiple measurement points to assess intervention efficacy. Participants will be recruited from four Indigenous primary care services in Australia, Canada and New Zealand. Three educational sessions will be delivered over four weeks. A tablet application will support the education sessions and produce a customized pill card for each participant. Participants will be provided with written information about CVD medications. Medication knowledge scores, and specific health literacy skills and practices will be assessed before and after the three sessions. Statistical analyses will identify significant changes in outcomes over each session, and from the pre-session one to post-session three time points.
This study will make an important contribution to understanding the effect of a structured primary care-based intervention on CVD health literacy in Indigenous populations. The study also illustrates the incorporation of Indigenous health research principles and processes in clinical trials and provides insights that may be useful in other contexts.
Trial registration
Australian and New Zealand Clinical Trials Register (ACTRN12612001309875; date of registration 18/12/2012).
PMCID: PMC4227024  PMID: 25016481
Indigenous health; Health literacy; Cardiovascular diseases; Medication knowledge; Non-randomized study design; Clinical trial
6.  Priority setting in Indigenous health: assessing priority setting process and criteria that should guide the health system to improve Indigenous Australian health 
The health of Indigenous Australians is worse than that of other Australians. Most of the determinants of health are preventable and the poor health outcomes are inequitable. The Australian Government recently pledged to close that health gap. One possible way is to improve the priority setting process to ensure transparency and the use of evidence such as epidemiology, equity and economic evaluation.
The purpose of this research was to elicit the perceptions of Indigenous and non-Indigenous decision-makers on several issues related to priority setting in Indigenous-specific health care services. Specifically, we aimed to:
1. identify the criteria used to set priorities in Indigenous-specific health care services;
2. determine the level of uptake of economic evaluation evidence by decision-makers and how to improve its uptake; and
3. identify how the priority setting process can be improved from the perspective of decision-makers.
We used a paper survey instrument, adapted from Mitton and colleagues’ work, and a face-to-face interview approach to elicit decision-makers’ perceptions in Indigenous-specific health care in Victoria, Australia. We used mixed methods to analyse data from the survey. Responses were summarised using descriptive statistics and content analysis. Results were reported as numbers and percentages.
The size of the health burden; sustainability and acceptability of interventions; historical trends/patterns; and efficiency are key criteria for making choices in Indigenous health in Victoria. There is a need for an explicit priority setting approach, which is systematic, and is able to use available data/evidence, such as economic evaluation evidence. The involvement of Indigenous Australians in the process would potentially make the process acceptable.
An economic approach to priority setting is a potentially acceptable and useful tool for Aboriginal Community Controlled Health Services (ACCHS). It has the ability to use evidence and ensure due process at the same time. The use of evidence can ensure that health outcomes for Indigenous peoples can be maximised – hence, increase the potential for ‘closing the gap’ between Indigenous and other Australians.
PMCID: PMC4065599  PMID: 24906391
7.  Enhanced subgenual cingulate response to altruistic decisions in remitted major depressive disorder 
NeuroImage : Clinical  2014;4:701-710.
Major depressive disorder (MDD) is associated with functional abnormalities in fronto-meso-limbic networks contributing to decision-making, affective and reward processing impairments. Such functional disturbances may underlie a tendency for enhanced altruism driven by empathy-based guilt observed in some patients. However, despite the relevance of altruistic decisions to understanding vulnerability, as well as everyday psychosocial functioning, in MDD, their functional neuroanatomy is unknown.
Using a charitable donations experiment with fMRI, we compared 14 medication-free participants with fully remitted MDD and 15 demographically-matched control participants without MDD.
Compared with the control group, the remitted MDD group exhibited enhanced BOLD response in a septal/subgenual cingulate cortex (sgACC) region for charitable donation relative to receiving simple rewards and higher striatum activation for both charitable donation and simple reward relative to a low level baseline. The groups did not differ in demographics, frequency of donations or response times, demonstrating only a difference in neural architecture.
We showed that altruistic decisions probe residual sgACC hypersensitivity in MDD even after symptoms are fully remitted. The sgACC has previously been shown to be associated with guilt which promotes altruistic decisions. In contrast, the striatum showed common activation to both simple and altruistic rewards and could be involved in the so-called “warm glow” of donation. Enhanced neural response in the depression group, in areas previously linked to altruistic decisions, supports the hypothesis of a possible association between hyper-altruism and depression vulnerability, as shown by recent epidemiological studies.
•Patients show enhanced activation in the sgACC while making altruistic decisions.•Patients show elevated STR response to equitable decisions.•These abnormal neural responses may be associated with depression vulnerability.
PMCID: PMC4053655  PMID: 24936421
Charitable donation; Major depression; Reward processing; Subgenual anterior cingulate; Striatum
8.  Elevated Sputum Interleukin-5 and Submucosal Eosinophilia in Obese Individuals with Severe Asthma 
Rationale: The relationship between airway inflammation and obesity in severe asthma is poorly understood.
Objectives: We sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma.
Methods: Clinical parameters and eight mediators in sputum were assessed in 131 subjects with severe asthma from a single center categorized into lean, overweight, and obese groups defined by their body mass index. In an independent group of people with severe asthma (n = 45) and healthy control subjects (n = 19) eosinophilic inflammation was enumerated in bronchial submucosa, blood, and sputum and related to their body mass index.
Measurements and Main Results: Sputum IL-5 geometric mean (95% confidence interval) (pg/ml) was elevated in the obese (1.8 [1.2–2.6]) compared with overweight (1.1 [0.8–1.3]; P = 0.025) and lean (0.9 [0.6–1.2]; P = 0.018) subjects with asthma and was correlated with body mass index (r = 0.29; P < 0.001). There was no relationship among body mass index, the sputum cell count, or other sputum mediators. In the bronchoscopy group the submucosal eosinophil number in the subjects with asthma was correlated with body mass index (Spearman rank correlation, rs = 0.38; P = 0.013) and the median (interquartile range) number of submucosal eosinophils was increased in obese (19.4 [11.8–31.2]) (cells per square millimeter) versus lean subjects (8.2 [5.4–14.6]) (P = 0.006). There was no significant association between sputum or peripheral blood eosinophil counts and body mass index.
Conclusions: Sputum IL-5 and submucosal eosinophils, but not sputum eosinophils, are elevated in obese people with severe asthma. Whether specific antieosinophilic therapy is beneficial, or improved diet and lifestyle in obese asthma has antiinflammatory effects beyond weight reduction, requires further study.
PMCID: PMC3826183  PMID: 23590263
asthma; obesity; cytokines; phenotypes; eosinophil
9.  Serum arterial lactate concentration predicts mortality and organ dysfunction following liver resection 
The aim of this study was to determine if the post-operative serum arterial lactate concentration is associated with mortality, length of hospital stay or complications following hepatic resection.
Serum lactate concentration was recorded at the end of liver resection in a consecutive series of 488 patients over a seven-year period. Liver function, coagulation and electrolyte tests were performed post-operatively. Renal dysfunction was defined as a creatinine rise of >1.5x the pre-operative value.
The median lactate was 2.8 mmol/L (0.6 to 16 mmol/L) and was elevated (≥2 mmol/L) in 72% of patients. The lactate concentration was associated with peak post-operative bilirubin, prothrombin time, renal dysfunction, length of hospital stay and 90-day mortality (P < 0.001). The 90-day mortality in patients with a post-operative lactate ≥6 mmol/L was 28% compared to 0.7% in those with lactate ≤2 mmol/L. Pre-operative diabetes, number of segments resected, the surgeon’s assessment of liver parenchyma, blood loss and transfusion were independently associated with lactate concentration.
Initial post-operative lactate concentration is a useful predictor of outcome following hepatic resection. Patients with normal post-operative lactate are unlikely to suffer significant hepatic or renal dysfunction and may not require intensive monitoring or critical care.
PMCID: PMC3964326  PMID: 24472571
Liver; Hepatectomy; Post-operative care
10.  Study protocol for the randomised controlled trial: Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) 
BMC Psychiatry  2013;13:205.
Some patients with depression do not respond to first and second line conventional antidepressants and are therefore characterised as suffering from treatment refractory depression (TRD). On-going psychosocial stress and dysfunction of the hypothalamic-pituitary-adrenal axis are both associated with an attenuated clinical response to antidepressants. Preclinical data shows that co-administration of corticosteroids leads to a reduction in the ability of selective serotonin reuptake inhibitors to increase forebrain 5-hydroxytryptamine, while co-administration of antiglucocorticoids has the opposite effect. A Cochrane review suggests that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD and includes a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of anti-Depressants in Depression (The ADD Study) is a multicentre randomised placebo controlled trial of metyrapone augmentation of serotonergic antidepressants in a large population of patients with TRD in the UK National Health Service.
Patients with moderate to severe treatment refractory Major Depression aged 18 to 65 will be randomised to metyrapone 500 mg twice daily or placebo for three weeks, in addition to on-going conventional serotonergic antidepressants. The primary outcome will be improvement in Montgomery-Åsberg Depression Rating Scale score five weeks after randomisation (i.e. two weeks after trial medication discontinuation). Secondary outcomes will include the degree of persistence of treatment effect for up to 6 months, improvements in quality of life and also safety and tolerability of metyrapone. The ADD Study will also include a range of sub-studies investigating the potential mechanism of action of metyrapone.
Strengths of the ADD study include broad inclusion criteria meaning that the sample will be representative of patients with TRD treated within the UK National Health Service, longer follow up, which to our knowledge is longer than any previous study of antiglucocorticoid treatments in depression, and the range of mechanistic investigations being carried out. The data set acquired will be a rich resource for a range of research questions relating to both refractory depression and the use of antiglucocorticoid treatments.
Trial registration
Current Controlled Trials: ISRCTN45338259; EudraCT Number: 2009-015165-31.
PMCID: PMC3750720  PMID: 23914988
Antidepressive agents; Cortisol; Depressive disorder; Metyrapone; Antiglucocorticoid treatment; Treatment refractory depression
11.  Avoidance of total abdominal wall loss despite torso soft tissue clostridial myonecrosis: a case report 
Clostridial necrotizing soft tissue infections are often fatal. Myonecrosis of the torso is a particularly lethal combination given the classic need for radical debridement of the abdominal and thoracic walls, and therefore total exposure of the intraperitoneal and intrathoracic viscera. This case is unusual do to our ability to preserve anatomical separation between the viscera and the atmosphere.
Case presentation
We present a 42-year-old Caucasian man with obesity and diabetes who developed clostridial myonecrosis of his right torso following a mesenteric lymph node biopsy. This required an aggressive debridement (sparing subcutaneous flaps and internal oblique aponeurosis) followed by reconstruction of his right hemi-torso with a biologic prosthesis to prevent subsequent hernia formation.
Although basic principles associated with radical debridement were maintained, a full thickness torso wall resection was avoided. This provided reconstruction advantages that included endogenous subcutaneous flap coverage, separation of the peritoneal cavity by the internal oblique aponeurosis, and prevention of a subsequent hernia below the arcuate line. This technique would be of interest to any surgeon or clinician who treats patients with life-threatening torso soft tissue infections.
PMCID: PMC3599755  PMID: 23298523
Biologic prosthesis; Hernia; Necrotizing soft tissue infection
12.  Navigating the complex path between the oxytocin receptor gene (OXTR) and cooperation: an endophenotype approach 
Although cooperation represents a core facet of human social behavior there exists considerable variability across people in terms of the tendency to cooperate. One factor that may contribute to individual differences in cooperation is a key gene within the oxytocin (OT) system, the OT reception gene (OXTR). In this article, we aim to bridge the gap between the OXTR gene and cooperation by using an endophenotype approach. We present evidence that the association between the OXTR gene and cooperation may in part be due to how the OXTR gene affects brain systems involved in emotion recognition, empathy/theory of mind, social communication and social reward seeking. There is evidence that the OXTR gene is associated with the functional anatomy of the amygdala, visual cortex (VC), anterior cingulate and superior temporal gyrus (STG). However, it is currently unknown how the OXTR gene may be linked to the functional anatomy of other relevant brain regions that include the fusiform gyrus (FG), superior temporal sulcus (STS), ventromedial prefrontal cortex (VMPFC), temporoparietal junction (TPJ) and nucleus accumbens (NAcc). We conclude by highlighting potential future research directions that may elucidate the path between OXTR and complex behaviors such as cooperation.
PMCID: PMC3842510  PMID: 24348360
OXTR; genetics; oxytocin; social-cognition; cooperation
13.  Reversed Frontotemporal Connectivity During Emotional Face Processing in Remitted Depression 
Biological Psychiatry  2012;72(7):604-611.
Vulnerability to relapse persists after remission of an acute episode of major depressive disorder. This has been attributed to abnormal biases in the processing of emotional stimuli in limbic circuits. However, neuroimaging studies have not so far revealed consistent evidence of abnormal responses to emotional stimuli in limbic structures, such as the amygdala, in remitted depression. This suggests the problem might lie in the integrated functioning of emotion processing circuits.
We recruited 22 unmedicated patients in remission from major depressive disorder (rMDD) and 21 age-matched healthy control subjects. Functional magnetic resonance imaging was performed during a face emotion processing task. Dynamic causal modeling was used with Bayesian model selection to determine the most likely brain networks and valence-specific modulation of connectivity in healthy control subjects and rMDD.
In healthy volunteers, sad faces modulated bi-directional connections between amygdala and orbitofrontal cortex and between fusiform gyrus and orbitofrontal cortex. Happy faces modulated unidirectional connections from fusiform gyrus to orbitofrontal cortex. In rMDD, the opposite pattern was observed, with evidence of happy faces modulating bidirectional frontotemporal connections and sad faces modulating unidirectional fusiform–orbitofrontal connections.
Participants with rMDD have abnormal modulation of frontotemporal effective connectivity in response to happy and sad face emotions, despite normal activations within each region. Specifically, processing of mood incongruent happy information was associated with a more richly modulated frontotemporal brain network, whereas mood congruent sad information was associated with less network modulation. This supports a hypothesis of dysfunction within cortico–limbic connections in individuals vulnerable to depression.
PMCID: PMC3657140  PMID: 22682158
Amygdala; connectivity; depression; emotion; fusiform gyrus; orbitofrontal cortex
14.  Differences in primary health care delivery to Australia’s Indigenous population: a template for use in economic evaluations 
Health economics is increasingly used to inform resource allocation decision-making, however, there is comparatively little evidence relevant to minority groups. In part, this is due to lack of cost and effectiveness data specific to these groups upon which economic evaluations can be based. Consequently, resource allocation decisions often rely on mainstream evidence which may not be representative, resulting in inequitable funding decisions. This paper describes a method to overcome this deficiency for Australia’s Indigenous population. A template has been developed which can adapt mainstream health intervention data to the Indigenous setting.
The ‘Indigenous Health Service Delivery Template’ has been constructed using mixed methods, which include literature review, stakeholder discussions and key informant interviews. The template quantifies the differences in intervention delivery between best practice primary health care for the Indigenous population via Aboriginal Community Controlled Health Services (ACCHSs), and mainstream general practitioner (GP) practices. Differences in costs and outcomes have been identified, measured and valued. This template can then be used to adapt mainstream health intervention data to allow its economic evaluation as if delivered from an ACCHS.
The template indicates that more resources are required in the delivery of health interventions via ACCHSs, due to their comprehensive nature. As a result, the costs of such interventions are greater, however this is accompanied by greater benefits due to improved health service access. In the example case of the polypill intervention, 58% more costs were involved in delivery via ACCHSs, with 50% more benefits. Cost-effectiveness ratios were also altered accordingly.
The Indigenous Health Service Delivery Template reveals significant differences in the way health interventions are delivered from ACCHSs compared to mainstream GP practices. It is important that these differences are included in the conduct of economic evaluations to ensure results are relevant to Indigenous Australians. Similar techniques would be generalisable to other disadvantaged minority populations. This will allow resource allocation decision-makers access to economic evidence that more accurately represents the needs and context of disadvantaged groups, which is particularly important if addressing health inequities is a stated goal.
PMCID: PMC3468365  PMID: 22954136
Health economics; Resource allocation; Indigenous Australians; Primary health care services; Health service delivery; Health equity
15.  Hyperthermia Stimulates HIV-1 Replication 
PLoS Pathogens  2012;8(7):e1002792.
HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42–45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38–40°C) on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C) increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity.
Author Summary
Fever is a complex reaction triggered in response to pathogen infection. It induces diverse effects on the human body and especially on the immune system. The functions of immune cells are positively affected by fever, helping them to fight infection. Fever consists in a physiological elevation of temperature and in inflammation. While the role of inflammatory molecules on HIV-1 replication has been widely studied, little is known about the direct effect of temperature on viral replication. Here, we report that hyperthermia (39.5°C) boosts HIV-1 replication in CD4+ T cells. In single-cycle infection experiments, hyperthermia increased HIV-1 infection up to 7-fold. This effect was mediated in part by an increased activation of the HIV-1 promoter by the viral protein Tat. Our results also indicate that hyperthermia may help HIV-1 to reactivate from latency. We also show that the Heat Shock Protein Hsp90, which levels are increased at 39.5°C, mediates in a large part the positive effect of hyperthermia on HIV-1 infection. Our work suggests that in HIV-1-infected patients, fever episodes may facilitate viral replication.
PMCID: PMC3395604  PMID: 22807676
16.  Prescribing antidepressants for depression: time to be dimensional and inclusive 
The article by Middleton and Moncrieff questions the role of antidepressants in treating depression on both philosophical and practical grounds; namely that depression isn't a brain disease to be treated by a drug and that antidepressants are ineffective except as placebos. We argue that their stance is unhelpful and factually incorrect and that a more dimensional and integrative approach is needed in order to be able to best tailor treatment to individual needs. This involves a personalised assessment of the likely benefits and risks of both psychological and drug approaches when recommending treatment for someone with depression.
PMCID: PMC3020051  PMID: 21401994
antidepressants; depression; placebo; psychological treatment; randomised controlled trials
17.  Affective Cognition and its Disruption in Mood Disorders 
Neuropsychopharmacology  2010;36(1):153-182.
In this review, we consider affective cognition, responses to emotional stimuli occurring in the context of cognitive evaluation. In particular, we discuss emotion categorization, biasing of memory and attention, as well as social/moral emotion. We discuss limited neuropsychological evidence suggesting that affective cognition depends critically on the amygdala, ventromedial frontal cortex, and the connections between them. We then consider neuroimaging studies of affective cognition in healthy volunteers, which have led to the development of more sophisticated neural models of these processes. Disturbances of affective cognition are a core and specific feature of mood disorders, and we discuss the evidence supporting this claim, both from behavioral and neuroimaging perspectives. Serotonin is considered to be a key neurotransmitter involved in depression, and there is a considerable body of research exploring whether serotonin may mediate disturbances of affective cognition. The final section presents an overview of this literature and considers implications for understanding the pathophysiology of mood disorder as well as developing and evaluating new treatment strategies.
PMCID: PMC3055516  PMID: 20571485
emotion; cognition; depression; amygdala; anterior cingulate; serotonin; emotion; cognition; depression; amygdala; anterior cingulate; serotonin
18.  A Micro RNA Processing Defect in Rapidly Progressing Idiopathic Pulmonary Fibrosis 
PLoS ONE  2011;6(6):e21253.
Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF.
Methodology and Principal Findings
miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts.
These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.
PMCID: PMC3119674  PMID: 21712985
19.  Risk-Taking Behavior in a Gambling Task Associated with Variations in the Tryptophan Hydroxylase 2 Gene: Relevance to Psychiatric Disorders 
Neuropsychopharmacology  2009;35(5):1109-1119.
Decision making, choosing the best option from the possible outcomes, is impaired in many psychiatric conditions including affective disorders. We tested the hypothesis that variations in serotonergic genes (TPH2, TPH1, SLC6A4, HTR1A), which influence serotonin availability, affect choice behavior in a probabilistic gambling task. A population cohort (N=1035) completed a paper-and-pencil gambling task, filled out personality and symptom questionnaires and gave consent for the use of their DNA in a genetic association study. A subgroup of subjects (N=69) also completed a computer version of the task. The gambling task was designed to estimate an individual's tendency to take a risk when choosing between a smaller but more certain ‘win' and a larger, less probable one. We genotyped seven haplotype tagging SNPs in the TPH2 gene, and previously reported functional polymorphisms from the other genes (rs1800532, 5HTTLPR, and rs6295). Carriers of the more prevalent TPH2 haplotype, which was previously associated with less active enzyme variant, showed reduced risk taking on both tasks compared with subjects not carrying the common haplotype. The effect of TPH2 haplotypes on risk-taking was independent of current depression and anxiety symptoms, neuroticism and impulsiveness scores. We did not find an association between functional polymorphisms in the TPH1, SLC6A4, HTR1A genes and risk-taking behavior. In conclusion, our study demonstrates the role of the TPH2 gene and the serotonin system in risk taking and suggests that TPH2 gene may contribute to the expression of psychiatric phenotypes through altered decision making.
PMCID: PMC3055398  PMID: 20043001
risk taking; TPH2; haplotype analysis; depression; psychiatric disorders; Serotonin; Neurogenetics; Behavioral Science; Mood/Anxiety/Stress Disorders; risk-taking; TPH2; haplotype analysis
20.  Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein* 
The Journal of Biological Chemistry  2010;285(50):39314-39328.
Chemical genetics is an emerging approach to investigate the biology of host-pathogen interactions. We screened several inhibitors of ATP-dependent DNA motors and detected the gyrase B inhibitor coumermycin A1 (C-A1) as a potent antiretroviral. C-A1 inhibited HIV-1 integration and gene expression from acutely infected cell, but the two activities mapped to distinct targets. Target discovery identified Hsp90 as the C-A1 target affecting viral gene expression. Chromatin immunoprecipitation revealed that Hsp90 associates with the viral promoter and may directly regulate gene expression. Molecular docking suggested that C-A1 binds to two novel pockets at the C terminal domain of Hsp90. C-A1 inhibited Hsp90 dimer formation, suggesting that it impairs viral gene expression by preventing Hsp90 dimerization at the C terminus. The inhibition of HIV-1 integration imposed by C-A1 was independent of Hsp90 and mapped to the capsid protein, and a point mutation at residue 105 made the virus resistant to this block. HIV-1 susceptibility to the integration block mediated by C-A1 was influenced by cyclophilin A. Our chemical genetic approach revealed an unexpected function of capsid in HIV-1 integration and provided evidence for a role of Hsp90 in regulating gene expression in mammalian cells. Both activities were amenable to inhibition by small molecules and represent novel antiretroviral drug targets.
PMCID: PMC2998086  PMID: 20937817
DNA Gyrase; Drug Action; Heat Shock Protein; HIV; Protein Targeting; Coumermycin A1; Hsp90; Integration; Capsid; Chemical Genetics
21.  Expression of the T Helper 17-Associated Cytokines IL-17A and IL-17F in Asthma and COPD 
Chest  2010;138(5):1140-1147.
Asthma and COPD are characterized by airway dysfunction and inflammation. Neutrophilic airway inflammation is a common feature of COPD and is recognized in asthma, particularly in severe disease. The T helper (Th) 17 cytokines IL-17A and IL-17F have been implicated in the development of neutrophilic airway inflammation, but their expression in asthma and COPD is uncertain.
We assessed IL-17A and IL-17F expression in the bronchial submucosa from 30 subjects with asthma, 10 ex-smokers with mild to moderate COPD, and 27 nonsmoking and 14 smoking control subjects. Sputum IL-17 concentration was measured in 165 subjects with asthma and 27 with COPD.
The median (interquartile range) IL-17A cells/mm2 submucosa was increased in mild to moderate asthma (2.1 [2.4]) compared with healthy control subjects (0.4 [2.8]) but not in severe asthma (P = .04). In COPD, IL-17A+ cells/mm2 submucosa were increased (0.5 [3.7]) compared with nonsmoking control subjects (0 [0]) but not compared with smoking control subjects (P = .046). IL-17F+ cells/mm2 submucosa were increased in severe asthma (2.7 [3.6]) and mild to moderate asthma (1.6 [1.0]) compared with healthy controls subjects (0.7 [1.4]) (P = .001) but was not increased in subjects with COPD. IL-17A and IL-17F were not associated with increased neutrophilic inflammation, but IL-17F was correlated with the submucosal eosinophil count (rs = 0.5, P = .005). The sputum IL-17 concentration in COPD was increased compared with asthma (2 [0-7] pg/mL vs 0 [0-2] pg/mL, P < .0001) and was correlated with post-bronchodilator FEV1% predicted (r = −0.5, P = .008) and FEV1/FVC (r = −0.4, P = .04).
Our findings support a potential role for the Th17 cytokines IL-17A and IL-17F in asthma and COPD, but do not demonstrate a relationship with neutrophilic inflammation.
PMCID: PMC2972626  PMID: 20538817
22.  Study protocol: national research partnership to improve primary health care performance and outcomes for Indigenous peoples 
Strengthening primary health care is critical to reducing health inequity between Indigenous and non-Indigenous Australians. The Audit and Best practice for Chronic Disease Extension (ABCDE) project has facilitated the implementation of modern Continuous Quality Improvement (CQI) approaches in Indigenous community health care centres across Australia. The project demonstrated improvements in health centre systems, delivery of primary care services and in patient intermediate outcomes. It has also highlighted substantial variation in quality of care. Through a partnership between academic researchers, service providers and policy makers, we are now implementing a study which aims to 1) explore the factors associated with variation in clinical performance; 2) examine specific strategies that have been effective in improving primary care clinical performance; and 3) work with health service staff, management and policy makers to enhance the effective implementation of successful strategies.
The study will be conducted in Indigenous community health centres from at least six States/Territories (Northern Territory, Western Australia, New South Wales, South Australia, Queensland and Victoria) over a five year period. A research hub will be established in each region to support collection and reporting of quantitative and qualitative clinical and health centre system performance data, to investigate factors affecting variation in quality of care and to facilitate effective translation of research evidence into policy and practice. The project is supported by a web-based information system, providing automated analysis and reporting of clinical care performance to health centre staff and management.
By linking researchers directly to users of research (service providers, managers and policy makers), the partnership is well placed to generate new knowledge on effective strategies for improving the quality of primary health care and fostering effective and efficient exchange and use of data and information among service providers and policy makers to achieve evidence-based resource allocation, service planning, system development, and improvements of service delivery and Indigenous health outcomes.
PMCID: PMC2882384  PMID: 20482810
23.  General surgery 2.0: the emergence of acute care surgery in Canada 
Canadian Journal of Surgery  2010;53(2):79-83.
Over the past 5 years, there has been a groundswell of support in Canada for the development of organized, focused and multidisciplinary approaches to caring for acutely ill general surgical patients. Newly forged acute care surgery (ACS) services are beginning to provide prompt, evidence-based and goal-directed care to acutely ill general surgical patients who often present with a diverse range of complex pathologies and little or no pre- or postoperative planning. Through a team-based structure with attention to processes of care and information sharing, ACS services are well positioned to improve outcomes, while finding and developing efficiencies and reducing costs of surgical and emergency health care delivery. The ACS model also offers enhanced opportunities for surgical education for students, residents and practicing surgeons, and it will provide avenues to strengthen clinical and academic bonds between the community and academic surgical centres. In the near future, cooperation of ACS services from community and academic hospitals across the country will lead to the formation of systems of acute surgical care whose development will be informed by rigorous data collection and research and evidence-based quality-improvement initiatives. In an era of increasing subspecialization, ACS is a strong unifying force in general surgery and a platform for collective advocacy for an important patient population.
PMCID: PMC2845950  PMID: 20334738
24.  Setting and meeting priorities in Indigenous health research in Australia and its application in the Cooperative Research Centre for Aboriginal Health 
Priority setting is about making decisions. Key issues faced during priority setting processes include identifying who makes these decisions, who sets the criteria, and who benefits. The paper reviews the literature and history around priority setting in research, particularly in Aboriginal health research. We explore these issues through a case study of the Cooperative Research Centre for Aboriginal Health (CRCAH)'s experience in setting and meeting priorities.
Historically, researchers have made decisions about what research gets done. Pressures of growing competition for research funds and an increased public interest in research have led to demands that appropriate consultation with stakeholders is conducted and that research is of benefit to the wider society. Within Australian Aboriginal communities, these demands extend to Aboriginal control of research to ensure that Aboriginal priorities are met.
In response to these demands, research priorities are usually agreed in consultation with stakeholders at an institutional level and researchers are asked to develop relevant proposals at a project level. The CRCAH's experience in funding rounds was that scientific merit was given more weight than stakeholders' priorities and did not necessarily result in research that met these priorities. After reviewing these processes in 2004, the CRCAH identified a new facilitated development approach. In this revised approach, the setting of institutional priorities is integrated with the development of projects in a way that ensures the research reflects stakeholder priorities.
This process puts emphasis on identifying projects that reflect priorities prior to developing the quality of the research, rather than assessing the relevance to priorities and quality concurrently. Part of the CRCAH approach is the employment of Program Managers who ensure that stakeholder priorities are met in the development of research projects. This has enabled researchers and stakeholders to come together to collaboratively develop priority-driven research. Involvement by both groups in project development has been found to be essential in making decisions that will lead to robust and useful research.
PMCID: PMC2788537  PMID: 19925681
25.  A cost-based equity weight for use in the economic evaluation of primary health care interventions: case study of the Australian Indigenous population 
Efficiency and equity are both important policy objectives in resource allocation. The discipline of health economics has traditionally focused on maximising efficiency, however addressing inequities in health also requires consideration. Methods to incorporate equity within economic evaluation techniques range from qualitative judgements to quantitative outcomes-based equity weights. Yet, due to definitional uncertainties and other inherent limitations, no method has been universally adopted to date. This paper proposes an alternative cost-based equity weight for use in the economic evaluation of interventions delivered from primary health care services.
Equity is defined in terms of 'access' to health services, with the vertical equity objective to achieve 'equitable access for unequal need'. Using the Australian Indigenous population as an illustrative case study, the magnitude of the equity weight is constructed using the ratio of the costs of providing specific interventions via Indigenous primary health care services compared with the costs of the same interventions delivered via mainstream services. Applying this weight to the costs of subsequent interventions deflates the costs of provision via Indigenous health services, and thus makes comparisons with mainstream more equitable when applied during economic evaluation.
Based on achieving 'equitable access', existing measures of health inequity are suitable for establishing 'need', however the magnitude of health inequity is not necessarily proportional to the magnitude of resources required to redress it. Rather, equitable access may be better measured using appropriate methods of health service delivery for the target group. 'Equity of access' also suggests a focus on the processes of providing equitable health care rather than on outcomes, and therefore supports application of equity weights to the cost side rather than the outcomes side of the economic equation.
Cost-based weights have the potential to provide a pragmatic method of equity weight construction which is both understandable to policy makers and sensitive to the needs of target groups. It could improve the evidence base for resource allocation decisions, and be generalised to other disadvantaged groups who share similar concepts of equity. Development of this decision-making tool represents a potentially important avenue for further health economics research.
PMCID: PMC2768712  PMID: 19807930

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