The effect of neuronal conditional knock-out of peroxisome proliferator-activated receptors in the MPTP mouse model of Parkinson's disease

This study was supported by Parkinson’s Disease Foundation (IRGP 09-11 (P.T.)), the Royal Society (2006/R1 (P.T.)), the Wellcome Trust (WT080782MF (P.T.)), the Biotechnology and Biological Sciences Research Council (P.T. and H.L.M.), the National Institutes of Health (DK057978) (R.M.E.), and by grants from the Leona M. and Harry B. Helmsley Charitable Trust (R.M.E.), the Glenn Foundation for Medical Research (R.M.E.), and the Ellison Medical Foundation (R.M.E.). R.M.E. is an investigator at the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. The authors would like to thank Lynne J. Hocking, University of Aberdeen, for her assistance with the statistics. We are grateful to the staff of the Medical Research Facility for their help with the animal care and the microscopy core facility at the University of Aberdeen for the use of microscopy equipment.Peer reviewedPublisher PD

Quantitative PCR-based genome size estimation of the astigmatid mites Sarcoptes scabiei, Psoroptes ovis and Dermatophagoides pteronyssinus

Background: The lack of genomic data available for mites limits our understanding of their biology. Evolving high-throughput sequencing technologies promise to deliver rapid advances in this area, however, estimates of genome size are initially required to ensure sufficient coverage. Methods. Quantitative real-time PCR was used to estimate the genome sizes of the burrowing ectoparasitic mite Sarcoptes scabiei, the non-burrowing ectoparasitic mite Psoroptes ovis, and the free-living house dust mite Dermatophagoides pteronyssinus. Additionally, the chromosome number of S. scabiei was determined by chromosomal spreads of embryonic cells derived from single eggs. Results: S. scabiei cells were shown to contain 17 or 18 small (< 2 M) chromosomes, suggesting an XO sex-determination mechanism. The average estimated genome sizes of S. scabiei and P. ovis were 96 ( 7) Mb and 86 ( 2) Mb respectively, among the smallest arthropod genomes reported to date. The D. pteronyssinus genome was estimated to be larger than its parasitic counterparts, at 151 Mb in female mites and 218 Mb in male mites. Conclusions: This data provides a starting point for understanding the genetic organisation and evolution of these astigmatid mites, informing future sequencing projects. A comparitive genomic approach including these three closely related mites is likely to reveal key insights on mite biology, parasitic adaptations and immune evasion

An exploratory study to assess the activity of the acarine growth inhibitor, fluazuron, against Sarcoptes scabei infestation in pigs

Background: The most common treatments for scabies in human and veterinary settings are topical 5% permethrin or systemic treatment with ivermectin. However, these treatments have very little activity against arthropod eggs, and therefore repeated treatment is frequently required. In-vitro, biochemical and molecular studies have demonstrated that human mites are becoming increasingly resistant to both acaricides. To identify alternate acaricides, we undertook a pilot study of the in vivo activity of the benzoylphenyl urea inhibitor of chitin synthesis, fluazuron, in pigs with sarcoptic mange. Findings. Pigs (n = 5) were infested with S. scabei var suis, and randomised to treatment at the start of peak infestation with fluazuron at a dose of 10 mg/kg/day per os for 7 days (n = 3) or no treatment (n = 2). Clinical scores, skin scrapings for mite counts and blood sampling for pharmacokinetic analysis were undertaken. Fluazuron was well absorbed in treated pigs with measureable blood levels up to 4 weeks post treatment. No adverse effects were observed. Modest acaricidal activity of the compound was observed, with a reduction in severity of skin lesions in treated pigs, as well as a reduction in number of scabies mite's early life stages. Conclusions: The moderate efficacy of fluazuron against scabies mites indicates a lead to the development of alternate treatments for scabies, such as combination therapies that maybe applicable for human use in the future

Incorporating a gender lens into nutrition and health-related policies in Fiji: analysis of policies and stakeholder perspectives

Background: Gender equality, zero hunger and healthy lives and well-being for all, are three of the Sustainable Development Goals (SDGs) that underpin Fiji’s National Development Plan. Work towards each of these goals contributes to the reduction of non-communicable diseases (NCDs). There are gender differences in NCD burden in Fiji. It is, however, unclear whether a gender lens could be more effectively included in nutrition and health-related policies. Methods: This study consisted of three components: (i) a policy content analysis of gender inclusion in nutrition and health-related policies (n = 11); (ii) policy analysis using the WHO Gender Analysis tool to identify opportunities for strengthening future policy; and (iii) informant interviews (n = 18), to understand perceptions of the prospects for gender considerations in future policies. Results: Gender equality was a goal in seven policies (64%); however, most focused on women of reproductive age. One of the policies was ranked as gender responsive. Main themes from key informant interviews were: 1) a needs-based approach for the focus on specific population groups in policies; 2) gender-related roles and responsibilities around nutrition and health; 3) what is considered “equitable” when it comes to gender, nutrition, and health; 4) current considerations of gender in policies and ideas for further gender inclusion; and 5) barriers and enablers to the inclusion of gender considerations in policies. Informants acknowledged gender differences in the burden of nutrition-related NCDs, yet most did not identify a need for stronger inclusion of gender considerations within policies. Conclusions: There is considerable scope for greater inclusion of gender in nutrition and health-related policies in Fiji. This could be done by: 1) framing gender considerations in ways that are actionable and inclusive of a range of gender identities; 2) undertaking advocacy through actor networks to highlight the need for gender-responsive nutrition and health-related policies for key stakeholder groups; 3) ensuring that data collected to monitor policy implementation is disaggregated by sex and genders; and 4) promoting equitable participation in nutrition related issues in communities and governance processes. Action on these four areas are likely critical enablers to more gender equitable NCD reduction in Fiji

Prospective Study in a Porcine Model of Sarcoptes scabiei Indicates the Association of Th2 and Th17 Pathways with the Clinical Severity of Scabies

BackgroundUnderstanding of scabies immunopathology has been hampered by the inability to undertake longitudinal studies in humans. Pigs are a useful animal model for scabies, and show clinical and immunologic changes similar to those in humans. Crusted scabies can be readily established in pigs by treatment with the glucocorticoid dexamethasone (Dex).Methodology/ Principal FindingsProspective study of 24 pigs in four groups: a) Scabies+/Dex+, b) Scabies+/Dex-, c) Scabies-/Dex+ and d) Scabies-/Dex-. Clinical symptoms were monitored. Histological profiling and transcriptional analysis of skin biopsies was undertaken to compare changes in cell infiltrates and representative cytokines. A range of clinical responses to Sarcoptes scabiei were observed in Dex treated and non-immunosuppressed pigs. An association was confirmed between disease severity and transcription of the Th2 cytokines IL-4 and IL-13, and up-regulation of the Th17 cytokines IL-17 and IL-23 in pigs with crusted scabies. Immunohistochemistry revealed marked infiltration of lymphocytes and mast cells, and strong staining for IL-17.Conclusions/ SignificanceWhile an allergic Th2 type response to scabies has been previously described, these results suggest that IL-17 related pathways may also contribute to immunopathology of crusted scabies. This may lead to new strategies to protect vulnerable subjects from contracting recurrent crusted scabies

Medial septal beta-amyloid 1-40 injections alter septo-hippocampal anatomy and function

Degeneration of septal neurons in Alzheimer’s disease (AD) results in abnormal information processing at cortical circuits and consequent brain dysfunction. The septum modulates the activity of hippocampal and cortical circuits and is crucial to the initiation and occurrence of oscillatory activities such as the hippocampal theta rhythm. Previous studies suggest that amyloid β peptide (Aβ) accumulation may trigger degeneration in AD. This study evaluates the effects of single injections of Aβ 1–40 into the medial septum. Immunohistochemistry revealed a decrease in septal cholinergic (57%) and glutamatergic (53%) neurons in Aβ 1–40 treated tissue. Additionally, glutamatergic terminals were significantly less in Aβ treated tissue. In contrast, septal GABAergic neurons were spared. Unitary recordings from septal neurons and hippocampal field potentials revealed an approximately 50% increase in firing rates of slow firing septal neurons during theta rhythm and large irregular amplitude (LIA) hippocampal activities and a significantly reduced hippocampal theta rhythm power (49%) in Aβ 1–40 treated tissue. Aβ also markedly reduced the proportion of slow firing septal neurons correlated to the hippocampal theta rhythm by 96%. These results confirm that Aβ alters the anatomy and physiology of the medial septum contributing to septohippocampal dysfunction. The Aβ induced injury of septal cholinergic and glutamatergic networks may contribute to an altered hippocampal theta rhythm which may underlie the memory loss typically observed in AD patients

A Tractable Experimental Model for Study of Human and Animal Scabies

Scabies, a neglected parasitic disease caused by the microscopic mite Sarcoptes scabiei, is a major driving force behind bacterial skin infections in tropical settings. Aboriginal and Torres Strait Islander peoples are nearly twenty times more likely to die from acute rheumatic fever and rheumatic heart disease than individuals from the wider Australian community. These conditions are caused by bacterial pathogens such as Group A streptococci, which have been linked to underlying scabies infestations. Community based initiatives to reduce scabies and associated disease have expanded, but have been threatened in recent years by emerging drug resistance. Critical biological questions surrounding scabies remain unanswered due to a lack of biomedical research. This has been due in part to a lack of either a suitable animal model or an in vitro culture system for scabies mites. The pig/mite model reported here will be a much needed resource for parasite material and will facilitate in vivo studies on host immune responses to scabies, including relations to associated bacterial pathogenesis, and more detailed studies of molecular evolution and host adaptation. It represents the missing tool to extrapolate emerging molecular data into an in vivo setting and may well allow the development of clinical interventions