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1.  Does physical trauma lead to an increase in the risk of new onset widespread pain? 
Annals of the Rheumatic Diseases  2005;65(3):391-393.
To determine the rate of new onset of widespread pain after a traumatic event (motor vehicle crash).
A prospective cohort study of persons registered with an insurance company who had or had not experienced a motor vehicle crash. All participants were sent a questionnaire to assess pre‐crash (or for the non‐crash group, prior) psychosocial factors and widespread pain. Participants reporting pre‐crash (prior) widespread pain were excluded. At six months, participants were sent a follow up questionnaire to ascertain new prevalent widespread pain.
597 (51%) of participants returned a baseline questionnaire (465 crash and 132 non‐crash). Among the cohort who had experienced a crash, the new onset rate of widespread pain six months later was low (8%), though in comparison with the non‐crash group there was an increased risk (RR = 1.9 (95% CI, 0.8 to 4.8, adjusted for age and sex)); this was attenuated after adjustment for pre‐crash (prior) psychological distress and somatic symptoms (RR = 1.4 (95% CI, 0.5 to 3.2)).
The findings suggest that a motor vehicle crash (as an example of a physically traumatic event) is unlikely to have a major impact on the new onset of widespread pain. Any observed relation may, in part, be explained by psychological distress.
PMCID: PMC1798040  PMID: 16014672
fibromyalgia; pain; trauma
3.  Stra6, a retinoic acid-responsive gene, participates in p53-induced apoptosis after DNA damage 
Cell Death and Differentiation  2013;20(7):910-919.
Stra6 is the retinoic acid (RA)-inducible gene encoding the cellular receptor for holo-retinol binding protein. This transmembrane protein mediates the internalization of retinol, which then upregulates RA-responsive genes in target cells. Here, we show that Stra6 can be upregulated by DNA damage in a p53-dependent manner, and it has an important role in cell death responses. Stra6 expression induced significant amounts of apoptosis in normal and cancer cells, and it was also able to influence p53-mediated cell fate decisions by turning an initial arrest response into cell death. Moreover, inhibition of Stra6 severely compromised p53-induced apoptosis. We also found that Stra6 induced mitochondria depolarization and accumulation of reactive oxygen species, and that it was present not only at the cellular membrane but also in the cytosol. Finally, we show that these novel functions of Stra6 did not require downstream activation of RA signalling. Our results present a previously unknown link between the RA and p53 pathways and provide a rationale to use retinoids to upregulate Stra6, and thus enhance the tumour suppressor functions of p53. This may have implications for the role of vitamin A metabolites in cancer prevention and treatment.
PMCID: PMC3679452  PMID: 23449393
apoptosis; p53; reactive oxygen species; retinoic acid; Stra6
4.  Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma 
Journal of medical genetics  2007;45(3):142-146.
Background and objective
Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position −93, rs1800734) modifies the risk of cancer after methylating chemotherapy.
133 patients who developed cancer following chemotherapy and/or radiotherapy (n=133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 −93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 −93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression.
Carrier frequency of the MLH1 −93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n=12) or breast cancer (53.3%. n=15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n=69; breast cancer patients, 27.2%, n=22). The MLH1 −93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n=420) and healthy controls (36.3%, n=952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent.
These data support the hypothesis that the common polymorphism at position −93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.
PMCID: PMC4022773  PMID: 17959715
5.  Immune Focusing and Enhanced Neutralization Induced by HIV-1 gp140 Chemical Cross-Linking 
Journal of Virology  2013;87(18):10163-10172.
Experimental vaccine antigens based upon the HIV-1 envelope glycoproteins (Env) have failed to induce neutralizing antibodies (NAbs) against the majority of circulating viral strains as a result of antibody evasion mechanisms, including amino acid variability and conformational instability. A potential vaccine design strategy is to stabilize Env, thereby focusing antibody responses on constitutively exposed, conserved surfaces, such as the CD4 binding site (CD4bs). Here, we show that a largely trimeric form of soluble Env can be stably cross-linked with glutaraldehyde (GLA) without global modification of antigenicity. Cross-linking largely conserved binding of all potent broadly neutralizing antibodies (bNAbs) tested, including CD4bs-specific VRC01 and HJ16, but reduced binding of several non- or weakly neutralizing antibodies and soluble CD4 (sCD4). Adjuvanted administration of cross-linked or unmodified gp140 to rabbits generated indistinguishable total gp140-specific serum IgG binding titers. However, sera from animals receiving cross-linked gp140 showed significantly increased CD4bs-specific antibody binding compared to animals receiving unmodified gp140. Moreover, peptide mapping of sera from animals receiving cross-linked gp140 revealed increased binding to gp120 C1 and V1V2 regions. Finally, neutralization titers were significantly elevated in sera from animals receiving cross-linked gp140 rather than unmodified gp140. We conclude that cross-linking favors antigen stability, imparts antigenic modifications that selectively refocus antibody specificity and improves induction of NAbs, and might be a useful strategy for future vaccine design.
PMCID: PMC3754013  PMID: 23843636
6.  Atomoxetine modulates spontaneous and sensory-evoked discharge of locus coeruleus noradrenergic neurons 
Neuropharmacology  2012;64(1):53-64.
Atomoxetine (ATM) is a potent norepinephrine (NE) uptake inhibitor and increases both NE and dopamine synaptic levels in prefrontal cortex, where it is thought to exert its beneficial effects on attention and impulsivity. At the behavioral level, ATM has been shown to cause improvements on measures of executive functions, such as response inhibition, working memory and attentional set shifting across different species. However, the exact mechanism of action for ATM’s effects on cognition is still not clear. One possible target for the cognitive enhancing effects of ATM is the noradrenergic locus coeruleus (LC), the only source of NE to key forebrain areas such as cerebral cortex and hippocampus. Although it is known that ATM increases NE availability overall by blocking reuptake of NE, the effects of this agent on impulse activity of LC neurons have not been reported. Here, the effect of ATM (0.1 – 1 mg/kg, ip) on NE-LC neurons was investigated by recording extracellular activity of LC neurons in isoflurane-anesthetized rats. ATM caused a significant decrease of the tonic activity of LC single-units, although leaving intact the sensory-evoked excitatory component of LC phasic response. Moreover, the magnitude of the inhibitory component of LC response to paw stimulation was increased after 1 mg/kg of ATM and its duration was prolonged at 0.3 mg/kg. Together, these effects of ATM produced an increase in the phasic-to-tonic ratio of LC phasic response to sensory stimulation. ATM also modulated the average sensory-evoked local field potential (LFP) and spike-field coherence in LC depending on the dose tested. The lower dose (0.1 mg/kg) significantly decreased early positive and negative components of the sensory-evoked LFP response. Higher doses (0.3–1 mg/kg) initially increased and then decreased the amplitude of components of the evoked fields, whereas the spike-field coherence was enhanced by 1 mg/kg ATM across frequency bands. Finally, coherence between LC fields and EEG signals was generally increased by 1 mg/kg ATM, whereas 0.1 and 0.3 mg/kg respectively decreased and increased coherence values in specific frequency bands. Taken together these results suggest that ATM effects on LC neuronal activity are dose-dependent, with different doses affecting different aspects of LC firing. This modulation of activity of LC-NE neurons may play a role in the cognitive effects of ATM.
PMCID: PMC3445720  PMID: 22820275
atomoxetine; norepinephrine; locus coeruleus; sensory response; local field potentials; spike-field coherence
7.  Delayed developmental changes in neonatal vocalizations correlates with variations in ventral medial hypothalamus and central amygdala development in the rodent infant: effects of prenatal cocaine 
Behavioural brain research  2012;235(2):166-175.
While variations in neonatal distress vocalizations have long been shown to reflect the integrity of nervous system development following a wide range of prenatal and perinatal insults, a paucity of research has explored the neurobiological basis of these variations. To address this, virgin Sprague-Dawley rats were bred and divided into three groups: (1) untreated, (2) chronic-cocaine treated (30mg/kg/day, gestation days (GDs) 1–20); or (3) chronic-saline treated (2mg/kg/day, GDs 1–20). Pregnant dams were injected with Bromodeoxyuridine (10mg/kg) on GDs 13–15 to label proliferating cells in limbic regions of interest. Ultrasonic vocalizations (USVs) were recorded on PNDs 1, 14, and 21, from one male and female pup per litter. Variations in acoustic properties of USVs following cocaine-exposure were age and sex-dependent including measures of total number, total duration and amplitude of USVs, and percent of USVs with at least one harmonic. Following USV testing brains were stained with standard fluorescent immunohistochemistry protocols and examined for variations in neuronal development and if variations were associated with acoustic characteristics. Limbic region developmental differences following cocaine-exposure were sex- and age-dependent with variations in the ventral medial hypothalamus and central amygdala correlating with variations in vocalizations on PND 14 and 21. Results suggest maturation of the ventral medial hypothalamus and central amygdala may provide the basis for variations in the sound and production of USVs. As vocalizations may serve as a neurobehavioral marker for nervous system integrity, understanding the neurobiological basis of neonatal vocalizations may provide the basis for early intervention strategies in high-risk infant populations.
PMCID: PMC3461834  PMID: 22867871
neonate; vocalization; development; limbic; prenatal; cocaine
8.  Transient activation of specific neurons in mice by selective expression of the capsaicin receptor 
Nature communications  2012;3:746.
The ability to control the electrical activity of a neuronal subtype is a valuable tool in deciphering the role of discreet cell populations in complex neural circuits. Recent techniques that allow remote control of neurons are either labor intensive and invasive or indirectly coupled to neural electrical potential with low temporal resolution. Here we show the rapid, reversible and direct activation of genetically identified neuronal subpopulations by generating two inducible transgenic mouse models. Confined expression of the capsaicin receptor, TRPV1, allows cell-specific activation after peripheral or oral delivery of ligand in freely moving mice. Capsaicin-induced activation of dopaminergic or serotonergic neurons reversibly alters both physiological and behavioural responses within minutes, and lasts ~10 min. These models showcase a robust and remotely controllable genetic tool that modulates a distinct cell population without the need for invasive and labour-intensive approaches.
PMCID: PMC3592340  PMID: 22434189
9.  Empyema and Respiratory Failure Secondary to Nephropleural Fistula Caused by Chronic Urinary Tract Infection: A Case Report 
Case Reports in Pulmonology  2012;2012:595402.
We report a case of nephropleural fistula causing empyema and respiratory failure in a 68-year-old gentleman with a long history of urological problems including recurrent nephrolithiasis and urinary tract infections. He was admitted with sepsis, a productive cough, pyuria, and reduced breath sounds over the left hemithorax. Radiological imaging revealed a fistulous connection between a left-sided perinephric abscess and the pleural space. He was commenced on broad spectrum intravenous antibiotics but developed progressive respiratory failure requiring intensive care admission. Urinary and pleural aspirates cultured facultative anaerobic pathogens with identical resistance patterns. Drainage of thoracic and perinephric collections was carried out, allowing him to be extubated after 24 hours and discharged home after 18 days on an extended course of oral antibiotics. Left nephrectomy is now planned after a period of convalescence. Empyema developing in patients with known urolithiasis should alert the treating physician to the possibility that a pathological communication has formed especially if typical urinary tract pathogens are cultured from respiratory sampling.
PMCID: PMC3504369  PMID: 23198240
10.  Is leaf dry matter content a better predictor of soil fertility than specific leaf area? 
Annals of Botany  2011;108(7):1337-1345.
Background and Aims
Specific leaf area (SLA), a key element of the ‘worldwide leaf economics spectrum’, is the preferred ‘soft’ plant trait for assessing soil fertility. SLA is a function of leaf dry matter content (LDMC) and leaf thickness (LT). The first, LDMC, defines leaf construction costs and can be used instead of SLA. However, LT identifies shade at its lowest extreme and succulence at its highest, and is not related to soil fertility. Why then is SLA more frequently used as a predictor of soil fertility than LDMC?
SLA, LDMC and LT were measured and leaf density (LD) estimated for almost 2000 species, and the capacity of LD to predict LDMC was examined, as was the relative contribution of LDMC and LT to the expression of SLA. Subsequently, the relationships between SLA, LDMC and LT with respect to soil fertility and shade were described.
Key Results
Although LD is strongly related to LDMC, and LDMC and LT each contribute equally to the expression of SLA, the exact relationships differ between ecological groupings. LDMC predicts leaf nitrogen content and soil fertility but, because LT primarily varies with light intensity, SLA increases in response to both increased shade and increased fertility.
Gradients of soil fertility are frequently also gradients of biomass accumulation with reduced irradiance lower in the canopy. Therefore, SLA, which includes both fertility and shade components, may often discriminate better between communities or treatments than LDMC. However, LDMC should always be the preferred trait for assessing gradients of soil fertility uncoupled from shade. Nevertheless, because leaves multitask, individual leaf traits do not necessarily exhibit exact functional equivalence between species. In consequence, rather than using a single stand-alone predictor, multivariate analyses using several leaf traits is recommended.
PMCID: PMC3197453  PMID: 21948627
Ellenberg numbers; functional traits; leaf density; leaf nitrogen; leaf size; leaf thickness; relative growth rate (RGR); shade tolerance; variation in trait expression
11.  Home ovulation tests and stress in women trying to conceive: a randomized controlled trial 
Does the use of a digital home ovulation test have any effect on the level of stress in women seeking to conceive?
No difference was found in levels of stress between women using digital ovulation tests to time intercourse compared with women who were trying to conceive without any additional aids: in addition, their use did not negatively impact time to conception in users but may provide additional benefits, including an increased understanding of the menstrual cycle, reassurance and confidence in focusing conception attempts to the correct time in the cycle.
It has been suggested that timing of intercourse in such a way that it coincides with ovulation by using ovulation tests can lead to emotional distress; however, no study has been conducted to investigate this hypothesis specifically, until now.
The study was performed over two complete menstrual cycles as a prospective, randomized, controlled trial including quantitative and qualitative methods. The intervention (test) group were given digital ovulation tests to time intercourse to the most fertile time of the cycle and the control group were provided with the current National Institute for Health and Clinical Excellence guidelines for increasing the chances of conception (intercourse every 2–3 days) and asked not to use any additional methods to time when ovulation occurs.
A total of 210 women who were seeking to conceive were recruited from the general UK population. A total of 115 women were randomized to the test group and 95 to the control group through block randomization. The positive and negative affect schedule (PANAS) and the Perceived Stress Scale (PSS) were used to measure subjective stress levels, the Short-Form 12 health survey was used as a measure of general health and well-being and urine samples were measured for biochemical markers of stress including urinary cortisol. Qualitative data were collected in the form of a telephone interview upon study completion.
There was no evidence for a difference either in total stress as measured using the PSS or in total positive or negative affect using the PANAS questionnaire between the test and control groups at any time point for the duration of the study. During cycle 1, for example, on Day 6, the difference in total stress score (test–control) was −0.62 [95% confidence interval (CI) −2.47 to 1.24] and on the day of the LH surge, it was 0.53 (95% CI −1.38 to 2.44). In addition, no correlation was observed between time trying to conceive and levels of stress, or between age and levels of stress, and no evidence was found to show that stress affected whether or not a pregnancy was achieved. There is also no evidence that the biochemistry measurements are related to whether a pregnancy was achieved or of a difference in biochemistry between the treatment groups. The use of digital ovulation tests did not negatively affect time to conception and with an adequately sized study, could potentially show improvement. To ensure that the results of this study were not affected by chance, we used a number of different methods for measuring stress, each of which had been independently validated.
Randomization occurred before the start of the study because of the need to provide the ovulation tests in readiness for Day 6 of the first cycle. As a consequence, a number of women fell pregnant during this period (22 and 13 in the test and control groups, respectively). A further 15 women were either lost to follow-up or withdrew consent prior to study start. Pregnancy rate was higher overall in the test group, so to ensure that there were sufficient data from women who failed to become pregnant in the test group, we implemented an additional biased recruitment. This second cohort may have been different from the first, although no significant differences were observed between the two phases of recruitment for any of the information collected upon admission to the study.
Women who seek medical advice while trying to conceive should not be discouraged by health care professionals from using digital ovulation tests in order to time intercourse. The cohort of women recruited to this study initially had no evidence of infertility and were looking to conceive in a non-medical setting. A separate study to assess the impact of home ovulation tests in a subfertile population would be of interest and complementary to the present study.
This study was funded by SPD Swiss Precision Diagnostics, GmbH, manufacturer of Clearblue® pregnancy and ovulation tests. SPD Development Company Ltd is a wholly owned subsidiary of SPD Swiss Precision Diagnostics GmbH; together referred to as SPD.
NCT01084304 (
PMCID: PMC3522415  PMID: 23081872
stress; ovulation tests; cortisol; questionnaire; timed intercourse
13.  Definition of osteoarthritis on MRI: results of a Delphi exercise 
Osteoarthritis and Cartilage  2011;19(8):963-969.
Despite a growing body of Magnetic Resonance Imaging (MRI) literature in osteoarthritis (OA), there is little uniformity in its diagnostic application. We envisage in the first instance the definition requiring further validation and testing in the research setting before considering implementation/feasibility testing in the clinical setting. The objective of our research was to develop an MRI definition of structural OA.
We undertook a multistage process consisting of a number of different steps. The intent was to develop testable definitions of OA (knee, hip and/or hand) on MRI. This was an evidence driven approach with results of a systematic review provided to the group prior to a Delphi exercise. Each participant of the steering group was allowed to submit independently up to five propositions related to key aspects in MRI diagnosis of knee OA. The steering group then participated in a Delphi exercise to reach consensus on which propositions we would recommend for a definition of structural OA on MRI. For each round of voting, ≥60% votes led to include and ≥20% votes led to exclude a proposition. After developing the proposition one of the definitions developed was tested for its validity against radiographic OA in an extant database.
For the systematic review we identified 25 studies which met all of our inclusion criteria and contained relevant diagnostic measure and performance data. At the completion of the Delphi voting exercise 11 propositions were accepted for definition of structural OA on MRI. We assessed the diagnostic performance of the tibiofemoral MRI definition against a radiographic reference standard. The diagnostic performance for individual features was: osteophyte C statistic = 0.61, for cartilage loss C statistic = 0.73, for bone marrow lesions C statistic= 0.72 and for meniscus tear in any region C statistic = 0.78. The overall composite model for these four features was a C statistic = 0.59. We detected good specificity (1) but less optimal sensitivity (0.46) likely due to detection of disease earlier on MRI.
We have developed MRI definition of knee OA that requires further formal testing with regards their diagnostic performance (especially in datasets of persons with early disease), before they are more widely used. Our current analysis suggests that further testing should focus on comparisons other than the radiograph, that may capture later stage disease and thus nullify the potential for detecting early disease that MRI may afford. The propositions are not to detract from, nor to discourage the use of traditional means of diagnosing OA.
PMCID: PMC3261513  PMID: 21620986
Osteoarthritis; Magnetic resonance imaging; Diagnosis
14.  Connectivity and resilience of coral reef metapopulations in marine protected areas: matching empirical efforts to predictive needs 
Coral reefs (Online)  2009;28(2):327-337.
Design and decision-making for marine protected areas (MPAs) on coral reefs require prediction of MPA effects with population models. Modeling of MPAs has shown how the persistence of metapopulations in systems of MPAs depends on the size and spacing of MPAs, and levels of fishing outside the MPAs. However, the pattern of demographic connectivity produced by larval dispersal is a key uncertainty in those modeling studies. The information required to assess population persistence is a dispersal matrix containing the fraction of larvae traveling to each location from each location, not just the current number of larvae exchanged among locations. Recent metapopulation modeling research with hypothetical dispersal matrices has shown how the spatial scale of dispersal, degree of advection versus diffusion, total larval output, and temporal and spatial variability in dispersal influence population persistence. Recent empirical studies using population genetics, parentage analysis, and geochemical and artificial marks in calcified structures have improved the understanding of dispersal. However, many such studies report current self-recruitment (locally produced settlement/settlement from elsewhere), which is not as directly useful as local retention (locally produced settlement/total locally released), which is a component of the dispersal matrix. Modeling of biophysical circulation with larval particle tracking can provide the required elements of dispersal matrices and assess their sensitivity to flows and larval behavior, but it requires more assumptions than direct empirical methods. To make rapid progress in understanding the scales and patterns of connectivity, greater communication between empiricists and population modelers will be needed. Empiricists need to focus more on identifying the characteristics of the dispersal matrix, while population modelers need to track and assimilate evolving empirical results.
PMCID: PMC3402229  PMID: 22833699
Connectivity; Larval dispersal; Marine protected areas; Resilience; Replacement; Genetics
15.  Reactions of the Tridentate and Tetradentate Amine Ligands di-(2-picolyl)(N-ethyl)amine and 2,5-Bis-(2-pyridylmethyl)-2,5 diazohexane with Technetium Nitrosyl Complexes 
Inorganica chimica acta  2011;373(1):301-305.
The reaction of the Tc(II) nitrosyl complex (Bu4N)[Tc(NO)Cl4] with Di-(2-picolyl)(NEt)amine in methanol yields the neutral complex [Tc(NO)Cl(py-N(Et)-py)]. The reaction of the Tc(I) nitrosyl complex [Tc(NO)Cl2(HOMe)(PPh3)2] with this tridentate ligand yields cationic [Tc(NO)Cl(py-N(Et)-py)(PPh3)]Cl. These two complexes have been structurally characterized. The reaction of [Tc(NO)Cl2(HOMe)(PPh3)2] with the tetradentate ligand 1,4-Bis(2-pyridylmethyl)-1,4-diazobutane yields a mixture of products including cationic [Tc(NO)Cl(py-NH-NH-py)]Cl and cationic [Tc(NO)Cl(PPh3)(py-NH-NH~py)]Cl, with a pyridyl terminus left dangling.
PMCID: PMC3152200  PMID: 21836726
Technetium; nitrosyl; tridentate ligand; tetradentate ligand
16.  Historic hybridization and introgression between two iconic Australian anemonefish and contemporary patterns of population connectivity 
Ecology and Evolution  2012;2(7):1592-1604.
Endemic species on islands are considered at risk of extinction for several reasons, including limited dispersal abilities, small population sizes, and low genetic diversity. We used mitochondrial DNA (D-Loop) and 17 microsatellite loci to explore the evolutionary relationship between an endemic anemonefish, Amphiprion mccullochi (restricted to isolated locations in subtropical eastern Australia) and its more widespread sister species, A. akindynos. A mitochondrial DNA (mtDNA) phylogram showed reciprocal monophyly was lacking for the two species, with two supported groups, each containing representatives of both species, but no shared haplotypes and up to 12 species, but not location-specific management units (MUs). Population genetic analyses suggested evolutionary connectivity among samples of each species (mtDNA), while ecological connectivity was only evident among populations of the endemic, A. mccullochi. This suggests higher dispersal between endemic anemonefish populations at both evolutionary and ecological timeframes, despite separation by hundreds of kilometers. The complex mtDNA structure results from historical hybridization and introgression in the evolutionary past of these species, validated by msat analyses (NEWHYBRIDS, STRUCTURE, and DAPC). Both species had high genetic diversities (mtDNA h > 0.90, π = 4.0%; msat genetic diversity, gd > 0.670). While high gd and connectivity reduce extinction risk, identifying and protecting populations implicated in generating reticulate structure among these species should be a conservation priority.
PMCID: PMC3434915  PMID: 22957165
Amphiprion; coral reef fish; endemism; extinction risk; Great Barrier Reef; isolated islands; Lord Howe Island
17.  Attenuating GABAA Receptor Signaling in Dopamine Neurons Selectively Enhances Reward Learning and Alters Risk Preference in Mice 
Phasic dopamine transmission encodes the value of reward-predictive stimuli and influences both learning and decision-making. Altered dopamine signaling is associated with psychiatric conditions characterized by risky choices such as pathological gambling. These observations highlight the importance of understanding how dopamine neuron activity is modulated. While excitatory drive onto dopamine neurons is critical for generating phasic dopamine responses, emerging evidence suggests that inhibitory signaling also modulates these responses. To address the functional importance of inhibitory signaling in dopamine neurons, we generated mice lacking the β3 subunit of the GABAA receptor specifically in dopamine neurons (β3-KO mice) and examined their behavior in tasks that assessed appetitive learning, aversive learning, and risk preference. Dopamine neurons in midbrain slices from β3-KO mice exhibited attenuated GABA-evoked inhibitory post-synaptic currents. Furthermore, electrical stimulation of excitatory afferents to dopamine neurons elicited more dopamine release in the nucleus accumbens of β3-KO mice as measured by fast-scan cyclic voltammetry. β3-KO mice were more active than controls when given morphine, which correlated with potential compensatory upregulation of GABAergic tone onto dopamine neurons. β3-KO mice learned faster in two food-reinforced learning paradigms, but extinguished their learned behavior normally. Enhanced learning was specific for appetitive tasks, as aversive learning was unaffected in β3-KO mice. Finally, we found that β3-KO mice had enhanced risk preference in a probabilistic selection task that required mice to choose between a small certain reward and a larger uncertain reward. Collectively, these findings identify a selective role for GABAA signaling in dopamine neurons in appetitive learning and decision-making.
PMCID: PMC3235504  PMID: 22114279
Reinforcement learning; reward-prediction; fast-scan cyclic voltammetry; electrophysiology; aversive learning; gambling
18.  Increased Mortality in Young Candidemia Patients Associated with Presence of a Candida albicans General-Purpose Genotype ▿ †  
Journal of Clinical Microbiology  2011;49(9):3250-3256.
The yeast Candida albicans causes life-threatening candidemia. A general-purpose genotype (GPG; corresponds to clade 1) causes more infections than other C. albicans genotypes. To investigate if GPG strains also cause higher mortality, we developed a duplex PCR assay which was 98% accurate in identifying GPG strains in an international collection of strains typed with probe Ca3. We applied the assay to 635 European C. albicans candidemia isolates. Of these, 18% conformed to the GPG genotype, 4% were of a borderline genotype, and 78% were of a non-GPG genotype, broadly consistent with genotype distributions in earlier studies. The prevalence of GPG strains was increased in females and in younger patients, exceeding 40% in infants aged ≤1 year. Logistic regression confirmed sex and age as significant determinants of GPG prevalence. Across the entire patient cohort, there was no difference in mortality for patients infected with GPG strains or other strains (36% versus 37%). However, mortality in patients aged ≤48 years was 33% for infection with GPG strains but only 15% for infection with other strains (z test; P < 0.01). Mortality rates associated with GPG and non-GPG strains were comparable in older patients (39% versus 46%). A logistic regression analysis confirmed the age-dependent impact of genotype on mortality. Thus, GPG strains may be more virulent than other strains in younger patients. Because candidemia is usually caused by endogenous strains, our PCR assay could potentially be used as a risk assessment tool for identifying younger patients most at risk of death from candidemia.
PMCID: PMC3165600  PMID: 21775553
19.  The Contribution of NMDAR Signaling in the Cortico-Basal Ganglia Reward Network to Appetitive Pavlovian Learning 
N-methyl-D-aspartate type glutamate receptors (NMDARs) contribute to phasic transmission and synaptic plasticity and are thought to be important for learning. To better understand where NMDAR signalling is necessary for learning, we combined viral-genetic strategies with genetic mouse models to investigate the contribution of NMDARs in the dopamine system to appetitive Pavlovian conditioning. NMDAR signaling in dopamine neurons was not required for Pavlovian conditioning; however, NMDARs in D1 dopamine receptor (D1R)-expressing medium spiny neurons (MSNs) which receive input from dopamine neurons were critical for this type of learning. NMDAR signaling was also required in brain regions that project to dopamine neurons, since removing NMDARs from afferent neurons to the ventral tegmental area (VTA) also prevented learning. This effect was likely due to loss of NMDAR signaling in the neurons of the prefrontal cortex (PFC), as learning could be restored in these animals by rescuing NMDAR expression in the PFC. Moreover, removing NMDARs exclusively from the PFC also prevented learning. Our findings suggest that NMDARs in neurons that project to and receive projections from the VTA are necessary for Pavlovian conditioning and specifically implicate the PFC and D1R-expressing MSNs in associative learning.
PMCID: PMC3156031  PMID: 21813695
Reinforcement Learning; NMDA; Prefrontal Cortex; Medium Spiny Neurons; D1-Receptor
20.  Survivorship services for adult cancer populations: a pan-Canadian guideline 
Current Oncology  2011;18(6):e265-e281.
Our goal was to develop evidence-based recommendations for the organization and structure of cancer survivorship services, and best-care practices to optimize the health and well-being of post–primary treatment survivors. This review sought to determine the optimal organization and care delivery structure for cancer survivorship services, and the specific clinical practices and interventions that would improve or maximize the psychosocial health and overall well-being of adult cancer survivors.
Data Sources
We conducted a systematic search of the Inventory of Cancer Guidelines at the Canadian Partnership Against Cancer, the U.S. National Guideline Clearinghouse, the Canadian Medical Association InfoBase, medline (ovid: 1999 through November 2009), embase (ovid: 1999 through November 2009), Psychinfo (ovid: 1999 through November 2009), the Cochrane Library (ovid; Issue 1, 2009), and cinahl (ebsco: 1999 through December 2009). Reference lists of related papers and recent review articles were scanned for additional citations.
Articles were selected for inclusion as evidence in the systematic review if they reported on organizational system components for survivors of cancer, or on psychosocial or supportive care interventions HOWELL et al. designed for survivors of cancer. Articles were excluded from the systematic review if they focused only on pediatric cancer survivor populations or on populations that transitioned from pediatric cancer to adult services; if they addressed only pharmacologic interventions or diagnostic testing and follow-up of cancer survivors; if they were systematic reviews with inadequately described methods; if they were qualitative or descriptive studies; and if they were opinion papers, letters, or editorials.
Data Extraction and Synthesis
Evidence was selected and reviewed by three members of the Cancer Journey Survivorship Expert Panel (SM, TC, TKO). The resulting summary of the evidence was guided further and reviewed by the members of Cancer Journey Survivorship Expert Panel. Fourteen practice guidelines, eight systematic reviews, and sixty-thee randomized controlled trials form the evidence base for this guidance document. These publications demonstrate that survivors benefit from coordinated post-treatment care, including interventions to address specific psychosocial, supportive care, and rehabilitative concerns.
Ongoing high-quality research is essential to optimize services for cancer survivors. Interventions that promote healthy lifestyle behaviours or that address psychosocial concerns and distress appear to improve physical functioning, psychosocial well-being, and quality of life for survivors.
PMCID: PMC3224035  PMID: 22184494
Psychosocial; supportive care; cancer survivor; survivorship; organization of care; care plan
22.  A behavioral genetics approach to understanding D1 receptor involvement in phasic dopamine signaling 
Dopamine-producing neurons fire with both basal level tonic patterns and phasic bursts. Varying affinities of the five dopamine receptors have led to a hypothesis that higher affinity receptors are primarily activated by basal level tonic dopamine, while lower affinity receptors may be tuned to be sensitive to higher levels caused by phasic bursts. Genetically modified mice provide a method to begin to probe this hypothesis. Here we discuss three mouse models. Dopamine-deficient mice were used to determine which behaviors require dopamine. These behaviors were then analyzed in mice lacking D1 receptors and in mice with reduced phasic dopamine release. Comparison of the latter two mouse models revealed a similar failure to learn about and respond normally to cues that indicate either a positive or negative outcome, giving support to the hypothesis that phasic dopamine release and the D1 receptor act in the same pathway. However, the D1 receptor likely has additional roles beyond those of phasic dopamine detection, because D1 receptor knockout mice have deficits in addition to what has been observed in mice with reduced phasic dopamine release.
PMCID: PMC3035386  PMID: 20888914
23.  Are physiological attributes of jockeys predictors of falls? A pilot study 
BMJ Open  2011;1(1):e000142.
This pilot study describes the physiological attributes of jockeys and track-work riders in Tasmania and investigates whether these attributes are associated with falls.
All jockeys and track-work riders licensed in Tasmania were invited to participate. The study group consisted of eight jockeys (two female, six male) and 20 track-work riders (14 female, six male). Measures of anthropometry, balance, reaction time, isometric strength, vertical jump, glycolytic and aerobic fitness, flexibility and body composition were conducted. Tests were designed to assess specific aspects of rider fitness and performance relevant to horse racing. For a subset of participants (n=14), the authors obtained information on falls and injuries. The authors used Poisson regression to estimate incidence rate ratios.
Jockeys had better balance, a faster mean reaction time, a lower fatigue index and a higher estimated V.O2max than their track-work riding counterparts. Jockeys were also younger and smaller in stature than track-work riders, and when differences in body mass were taken into account, they had a greater muscular strength and muscular (alactic) power. Important factors found to be associated with falls were lower aerobic and anaerobic fitness, greater muscular strength and power, and riding with the full foot in the stirrup irons compared with riding on the ball of the foot.
This pilot study shows that physiological attributes of jockeys and track-work riders can predict their risk of falling and are measurable using methods feasible for large-scale fieldwork.
Article summary
Article focus
Riding racehorses is a physically demanding and hazardous occupation, with most injuries to jockeys caused by falls.
This study aims to investigate the association between physiological attributes and risk of falls for jockeys and track-work riders.
Key messages
Lower anaerobic and aerobic fitness, and higher muscular strength and power were associated with greater risk of falls.
Placement of the foot in the stirrup irons was also found to be associated with falls.
This pilot study has confirmed that it is feasible to measure the physiological attributes of jockeys and track-work riders that are predictive of the risk of falling.
Strengths and limitations of this study
This was the first study to investigate whether physiological attributes are associated with falls to jockeys and track-work rides.
Tests were deliberately restricted to those that could be conducted with robustly constructed and transportable equipment.
We were able to recruit only a small number of participants, but our sample comprised 44% of the jockey population and 24% of the track-work rider population licensed in Tasmania.
Some refinements to the testing methodology are needed.
PMCID: PMC3191430  PMID: 22021775
24.  Stomatal vs. genome size in angiosperms: the somatic tail wagging the genomic dog? 
Annals of Botany  2010;105(4):573-584.
Background and Aims
Genome size is a function, and the product, of cell volume. As such it is contingent on ecological circumstance. The nature of ‘this ecological circumstance’ is, however, hotly debated. Here, we investigate for angiosperms whether stomatal size may be this ‘missing link’: the primary determinant of genome size. Stomata are crucial for photosynthesis and their size affects functional efficiency.
Stomatal and leaf characteristics were measured for 1442 species from Argentina, Iran, Spain and the UK and, using PCA, some emergent ecological and taxonomic patterns identified. Subsequently, an assessment of the relationship between genome-size values obtained from the Plant DNA C-values database and measurements of stomatal size was carried out.
Key Results
Stomatal size is an ecologically important attribute. It varies with life-history (woody species < herbaceous species < vernal geophytes) and contributes to ecologically and physiologically important axes of leaf specialization. Moreover, it is positively correlated with genome size across a wide range of major taxa.
Stomatal size predicts genome size within angiosperms. Correlation is not, however, proof of causality and here our interpretation is hampered by unexpected deficiencies in the scientific literature. Firstly, there are discrepancies between our own observations and established ideas about the ecological significance of stomatal size; very large stomata, theoretically facilitating photosynthesis in deep shade, were, in this study (and in other studies), primarily associated with vernal geophytes of unshaded habitats. Secondly, the lower size limit at which stomata can function efficiently, and the ecological circumstances under which these minute stomata might occur, have not been satisfactorally resolved. Thus, our hypothesis, that the optimization of stomatal size for functional efficiency is a major ecological determinant of genome size, remains unproven.
PMCID: PMC2850795  PMID: 20375204
Stomatal size; genome size; seed size; life history; photosynthesis; allometry; ecology; evolution; SLA; leaf structure; CAM; C4
25.  Predictors of abdominal pain in schoolchildren: a 4‐year population‐based prospective study 
Archives of Disease in Childhood  2007;92(12):1094-1098.
Chronic abdominal pain (CAP) is common among schoolchildren, but risk factors for its onset are still largely unknown.
To determine the frequency of onset of CAP in schoolchildren and investigate risk factors for its development.
1411 schoolchildren aged 11–14 years were recruited from schools in North West England. Information was collected on recent pain symptoms and potential risk factors for developing CAP. Participants were followed up 1 and 4 years later and new episodes of CAP were identified.
22% reported new‐onset abdominal pain at 1‐year follow‐up which persisted at 4‐year follow‐up (CAP). CAP was almost three times higher in girls than boys (34% vs 13%; χ2: 26.0; p<0.001). In girls, reporting headache at baseline was the only predictive factor for CAP onset: those reporting headaches experienced a doubling in the risk of symptom onset (relative risk: 2.1; 95% confidence interval: 0.95 to 4.7). In contrast, in boys, development of CAP was independently predicted by daytime tiredness (3.0; 1.2 to 7.6), lack of school enjoyment (2.0; 0.95 to 4.2), adverse psychosocial exposures (2.3; 1.2 to 4.5) and taller stature (1.9; 0.8 to 4.5).
Our results suggest that over 20% of adolescent schoolchildren experience new‐onset non‐self‐limiting abdominal pain over a 1‐year period. Future abdominal pain is predicted by previous somatic symptom reporting in girls and both somatic symptom reporting and psychosocial factors in boys. These risk factors indicate a possible mechanism for understanding the development of CAP, and might have important implications for both primary and secondary preventive strategies.
PMCID: PMC2066073  PMID: 17804590

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