Measuring dopaminergic function in the 6-OHDA-lesioned rat: a comparison of PET and microdialysis

BACKGROUND: [(18) F]fluorodopa (FDOPA) positron emission tomography (PET) allows assessment of levodopa (LDOPA) metabolism and is widely used to study Parkinson's disease. We examined how [(18) F]FDOPA PET-derived kinetic parameters relate the dopamine (DA) and DA metabolite content of extracellular fluid measured by microdialysis to aid in the interpretation of data from both techniques. METHODS: [(18) F]FDOPA PET imaging and microdialysis measurements were performed in unilaterally 6-hydroxydopamine-lesioned rats (n = 8) and normal control rats (n = 3). Microdialysis testing included baseline measurements and measurements following acute administration of LDOPA. PET imaging was also performed using [(11)C]dihydrotetrabenazine (DTBZ), which is a ligand for the vesicular monoamine transporter marker and allowed assessment of denervation severity. RESULTS: The different methods provided highly correlated data. Lesioned rats had reduced DA metabolite concentrations ipsilateral to the lesion (p < 0.05 compared to controls), with the concentration being correlated with FDOPA's effective distribution volume ratio (EDVR; r = 0.86, p < 0.01) and DTBZ's binding potential (BP(ND); r = 0.89, p < 0.01). The DA metabolite concentration in the contralateral striatum of severely (>80%) lesioned rats was lower (p < 0.05) than that of less severely lesioned rats (<80%) and was correlated with the ipsilateral PET measures (r = 0.89, p < 0.01 for BP(ND)) but not with the contralateral PET measures. EDVR and BP(ND) in the contralateral striatum were not different from controls and were not correlated with the denervation severity. CONCLUSIONS: The demonstrated strong correlations between the PET and microdialysis measures can aid in the interpretation of [(18) F]FDOPA-derived kinetic parameters and help compare results from different studies. The contralateral striatum was affected by the lesioning and so cannot always serve as an unaffected control

A brief intervention to increase uptake and adherence of an online program for depression and anxiety: Protocol for the Enhancing Engagement with Psychosocial Interventions (EEPI) Randomized Controlled Trial

BACKGROUND There is substantial evidence that psychosocial programs delivered online can be effective in treating and preventing mental health problems. However, use of evidence-based programs in the community is currently suboptimal, and there is a lack of evidence around how to increase engagement with existing evidence-based programs. Novel approaches to increasing the acceptability of online programs such as the use of brief engagement-facilitation interventions (EFI) require evaluation. AIMS The aims of this study are to 1) examine the effectiveness of a brief online engagement-facilitation intervention (EFI) presented prior to an online self-help mental health program (myCompass) in improving uptake of and adherence to that program, and 2) assess if greater uptake and/or adherence are associated with improved efficacy (greater reduction in symptoms of depression and anxiety) relative to a control condition). METHODS A three-arm randomized controlled trial will be conducted (target sample: N = 693 participants recruited via social media). An active online cognitive behavioural therapy (iCBT) intervention will be delivered either with (arm 1) or without (arm 2) the EFI. An attention control group (arm 3) will enable testing of the relative efficacy of the iCBT intervention. Primary outcomes are uptake of the intervention (initiation) and adherence (module completion). RESULTS Findings will inform the more efficient dissemination of a range of psychosocial programs into the community, with potential for significant efficiency gains in treating common mental health problems. CONCLUSIONS Greater engagement with online psychosocial programs may lead to significant reductions in the burden of common mental health problems in the community. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001565235.This project is supported by a National Health and Medical Research Fund (NHMRC) grant (#1138713). The lead author can disseminate the results of this trial without the express permission of the funder. PB is supported by NHMRC Fellowship 1083311; ALC is supported by NHMRC Fellowship (#1122544); FK-L is supported by NHMRC Fellowship (#1110371)

Using false discovery rates to benchmark SNP-callers in next-generation sequencing projects

Funding: R.A.F. was funded by the Natural Environment Research Council (NERC). D.A.H. and M.C.F. were supported by the Wellcome Trust. No additional external funding received for this study.Peer reviewedPublisher PD

Activated carbon-plasticised agarose composite films for the adsorption of thiol as a model of wound malodour

Conditions such as diabetes, cardiovascular disease and long-term immobilisation can precipitate the development of chronic dermal ulcers. Such wounds are associated with inflammation and bacterial contamination which in turn can lead to the liberation of offensive odours that cause patient embarrassment and, in some instances, social isolation. Activated carbon-containing dressings have been used to manage the odours from such wounds. However, these can be bulky and can become fouled by wound exudate. Agarose is a natural polysaccharide derived from seaweed that forms brittle free-standing films that can be made pliable by addition of a plasticiser. In this study, activated carbon-containing plasticised agarose films were evaluated for their ability to sequester thiol-containing molecules from solution and the gaseous phase. The water vapour transmission rate was also evaluated to determine the potential breathability of these films should they be considered for application to the skin. It was found that the adsorption of thiols was directly proportional to the activated carbon content of the films. Water vapour was found to pass relatively freely through the films indicating that sweat-induced tissue maceration would be unlikely to occur if applied clinically. In conclusion, activated carbon-containing plasticised agarose films have some potential in the sequestration of malodourous molecules such as those liberated from chronic dermal wounds

Evaluating the role of a galanin enhancer genotype on a range of metabolic, depressive and addictive phenotypes

Funded by •ERC. Grant Number: 284167 •NIH. Grant Number: 1RO1DK0921127-01 •NWO. Grant Numbers: 463-06-001, 451-04-034Peer reviewedPublisher PD

Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen

Data deposition: The sequence reported in this paper has been deposited in the NCBI Sequence Read Archive, https://www.ncbi.nlm.nih.gov/bioproject (BioProject ID PRJNA345600). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1806002115/-/DCSupplemental.Peer reviewedPublisher PD

MARDy : Mycology Antifungal Resistance Database

J.R. was supported by an Antimicrobial Research Collaborative (ARC) early career research fellowship, Imperial College London (RSRO_54990). T.S. and J.M.G.S. were supported by a Natural Environment Research Council grant awarded to MCF (NE/P001165/1).Peer reviewedPublisher PD

Chromosomal copy number variation, selection and uneven rates of recombination reveal cryptic genome diversity linked to pathogenicity

This project was funded by the UK Natural Environmental Research Council (NERC) grant NE/E006701/1, the European Research Council (ERC) grant 260801-BIG_IDEA, the Swiss National Science Foundation grant 31-125099 and the Biodiversa project RACE: Risk Assessment of Chytridiomycosis to European Amphibian Biodiversity (http://www.bd-maps.eu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Microevolutionary traits and comparative population genomics of the emerging pathogenic fungus Cryptococcus gattii

Emerging fungal pathogens cause an expanding burden of disease across the animal kingdom, including a rise in morbidity and mortality in humans. Yet, we currently have only a limited repertoire of available therapeutic interventions. A greater understanding of the mechanisms of fungal virulence and of the emergence of hypervirulence within species is therefore needed for new treatments and mitigation efforts. For example, over the past decade, an unusual lineage of Cryptococcus gattii, which was first detected on Vancouver Island, has spread to the Canadian mainland and the Pacific Northwest infecting otherwise healthy individuals. The molecular changes that led to the development of this hypervirulent cryptococcal lineage remain unclear. To explore this, we traced the history of similar microevolutionary events that can lead to changes in host range and pathogenicity. Here, we detail fine-resolution mapping of genetic differences between two highly related Cryptococcus gattii VGIIc isolates that differ in their virulence traits (phagocytosis, vomocytosis, macrophage death, mitochondrial tubularization and intracellular proliferation). We identified a small number of single site variants within coding regions that potentially contribute to variations in virulence. We then extended our methods across multiple lineages of C. gattii to study how selection is acting on key virulence genes within different lineages. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’

Dopamine Transporter Genetic Variants and Pesticides in Parkinson’s Disease

BackgroundResearch suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson's disease (PD) risk.MaterialsMethodsIn 324 incident PD patients and 334 population controls from our rural California case-control study, we genotyped rs2652510, rs2550956 (for the DAT 5' clades), and the 3' variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele-pesticide interactions.ResultsPD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08-2.57] and 3' VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96-3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88-10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70-12.1). We obtained similar results for occupational pesticide measures.DiscussionUsing two independent pesticide measures, we a) replicated previously reported gene-environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure.ConclusionOur results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk