Knowledge interface co-design of a diabetes and metabolic syndrome initiative with and for Aboriginal people living on Ngarrindjeri country.

Objectives: This research program involves two phases to identify enablers and barriers to diabetes care for Aboriginal people on Ngarrindjeri country; and co-design a strength-based metabolic syndrome and Type 2 Diabetes (T2D) remission program with the Ngarrindjeri community. Study design: A study protocol on qualitative research. Methods: The study will recruit Aboriginal people living on Ngarrindjeri country above 18 years of age with a diagnosis of metabolic syndrome or T2D. Recruitment for phases one and two will occur through the Aboriginal Health Team at the Riverland Mallee Coorong Local Health Network. The lived experiences of T2D will be explored with 10-15 Aboriginal participants, through an Aboriginal conversational technique called 'yarning' (60-90 min) in phase 1. Elders and senior community representatives (n = 20-30) will participate in four co-design workshops (2-4 h) in phase 2. Qualitative data will be transcribed and thematically analysed (NVivo version 12). The analysis will focus on protective factors for the Cultural Determinants of Health. Ethics approval was obtained from Aboriginal Health Research Ethics Committee in South Australia (04-22-1009), and Flinders University Human Research Ethics Committee (5847). Results: This work will be used to pilot the co-designed diabetes remission trial. Outcomes will be published in peer-reviewed journals, presented at conferences, focusing on following best practice guidelines from the Australian Institute of Aboriginal and Torres Strait Islander Studies and National Health and Medical Research Council. Research translation will occur through digital posters, manuals, and infographics. Conclusions: The findings will be summarised to all Aboriginal organisations involved in this study, along with peak bodies, stakeholders, Aboriginal Services, and interested participants.

Selective expression of Narp in primary nociceptive neurons: role in microglia/macrophage activation following nerve injury.

Neuronal activity regulated pentraxin (Narp) is a secreted protein implicated in regulating synaptic plasticity via its association with the extracellular surface of AMPA receptors. We found robust Narp immunostaining in dorsal root ganglia (DRG) that is largely restricted to small diameter neurons, and in the superficial layers of the dorsal horn of the spinal cord. In double staining studies of DRG, we found that Narp is expressed in both IB4- and CGRP-positive neurons, markers of distinct populations of nociceptive neurons. Although a panel of standard pain behavioral assays were unaffected by Narp deletion, we found that Narp knockout mice displayed an exaggerated microglia/macrophage response in the dorsal horn of the spinal cord to sciatic nerve transection 3days after surgery compared with wild type mice. As other members of the pentraxin family have been implicated in regulating innate immunity, these findings suggest that Narp, and perhaps other neuronal pentraxins, also regulate inflammation in the nervous system.

Age-related changes in Arc transcription and DNA methylation within the hippocampus.

The transcription of genes that support memory processes are likely to be impacted by the normal aging process. Because Arc is necessary for memory consolidation and enduring synaptic plasticity, we examined Arc transcription within the aged hippocampus. Here, we report that Arc transcription is reduced within the aged hippocampus compared to the adult hippocampus during both "off line" periods of rest, and following spatial behavior. This reduction is observed within ensembles of CA1 "place cells", which make less mRNA per cell, and in the dentate gyrus (DG) where fewer granule cells are activated by behavior. In addition, we present data suggesting that aberrant changes in methylation of the Arc gene may be responsible for age-related decreases in Arc transcription within CA1 and the DG. Given that Arc is necessary for normal memory function, these subregion-specific epigenetic and transcriptional changes may result in less efficient memory storage and retrieval during aging.

Functional integration of new neurons into hippocampal networks and poststroke comorbidities following neonatal stroke in mice.

Stroke in the developing brain is an important cause of chronic neurological morbidities including neurobehavioral dysfunction and epilepsy. Here, we describe a mouse model of neonatal stroke resulting from unilateral carotid ligation that results in acute seizures, long-term hyperactivity, spontaneous lateralized circling behavior, impaired cognitive function, and epilepsy. Exploration-dependent induction of the immediate early gene Arc (activity-regulated cytoskeleton associated protein) in hippocampal neurons was examined in the general population of neurons versus neurons that were generated approximately 1 week after the ischemic insult and labeled with bromodeoxyuridine. Although Arc was inducible in a network-specific manner after severe neonatal stroke, it was impaired, not only in the ipsilateral injured but also in the contralateral uninjured hippocampi when examined 6 months after the neonatal stroke. Severity of both the stroke injury and the acquired poststroke epilepsy negatively correlated with Arc induction and new neuron integration into functional circuits in the injured hippocampi.

Evaluation of the parallel rural community curriculum at flinders university of south Australia: lessons learnt for Africa

Objectives. To review data collected during an evaluation of the Flinders University Parallel Rural Community Curriculum (PRCC) in order to reflect on its relevance for medical education in Africa.Setting. The PRCC offers a community-based longitudinal curriculum as an alternative for students in their pre-final year of medical training. Design. Individual and focus group interviews were conducted with students; staff; health service managers; preceptors and community members. Results. Students are exposed to comprehensive; holistic; relationship-based care of patients; with a graded increase in responsibility. Students have varying experience at different sites; yet achieve the same outcomes. There is a strong partnership with the health service.Conclusions. The principle of balancing sound education and exposure to a variety of contexts; including longitudinal community-based attachments; deserves consideration by medical educators in Africa

A new model to understand the career choice and practice location decisions of medical graduates.

INTRODUCTION: Australian medical education is increasingly influenced by rural workforce policy. Therefore, understanding the influences on medical graduates' practice location and specialty choice is crucial for medical educators and medical workforce planners. The South Australian Flinders University Parallel Rural Community Curriculum (PRCC) was funded by the Australian Government to help address the rural doctor workforce shortage. The PRCC was the first community based medical education program in Australia to teach a full academic year of medicine in South Australian rural general practices. The aim of this research was to identify what factors influence the career choices of PRCC graduates. METHODS: A retrospective survey of all contactable graduates of the PRCC was undertaken. Quantitative data were analysed using SPSS 14.0 for Windows. Qualitative data were entered into NVIVO 7 software for coding, and analysed using content analysis. RESULTS: Usable data were collected from 46 of the 86 contactable graduates (53%). More than half of the respondents (54%) reported being on a rural career path. A significant relationship exists between being on a rural career pathway and making the decision prior to or during medical school (p = 0.027), and between graduates in vocational training who are on an urban career path and making a decision on career specialty after graduation from medical school (p = .004). Graduates in a general practice vocational training program are more likely to be on a rural career pathway than graduates in a specialty other than general practice (p = .003). A key influence on graduates' practice location is geographic location prior to entering medical school. Key influences on graduates choosing a rural career pathway are: having a spouse/partner with a rural background; clinical teachers and mentors; the extended rural based undergraduate learning experience; and a specialty preference for general practice. A lack of rural based internships and specialist training places is influencing both urban- and rural-origin graduates to practise in urban locations. Further analysis of graduates' career pathway choices (rural or urban) and geographic background (rural or urban) was conducted. This resulted in the development of a new model, 'The Four Qs Model'. This model consists of four quadrants derived from the variables career pathway choice (rural or urban) and geographic background (rural or urban). Clustering of consistent demographic and qualitative trends unique to each quadrant was demonstrated. The distinctive clustering that emerged from the data resulted in the quadrants being renamed 'The True Believers', 'The Convertibles' 'The Frustrated' and 'The Metro Docs'. CONCLUSIONS: The PRCC is influencing graduates to choose a rural career path. The PRCC program affirms the career preferences of rural origin students while graduates with little rural exposure prior to the PRCC report being positively influenced to pursue a rural career path. The Four Qs Model is a useful model in that it demonstrates consistent themes in the characteristics of PRCC graduates and assists understanding of why they choose a rural medical career. This could be relevant to the selection of medical students into rural medical education programs and in the construction of rural curricula. The model also offers a useful framework for further research in this field.

Depolarization-induced slow current in cerebellar Purkinje cells does not require metabotropic glutamate receptor 1.

Activation of cerebellar Purkinje cells by either brief depolarizing steps or bursts of climbing fiber synaptic activation evokes a slow inward current, which we have previously called depolarization-induced slow current or DISC. DISC is triggered by Ca influx via voltage-sensitive Ca channels and is attenuated by inhibitors of vacuolar ATPase or vesicle fusion. This led us to suggest that DISC required vesicular release of glutamate from the somatodendritic region of Purkinje cells. Furthermore, we found that DISC was attenuated by the mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), indicating that DISC required autocrine activation of metabotropic glutamate receptor 1 (mGluR1). Here, we have revisited the role of mGluR1 and found that it is, in fact, not required for DISC. CPCCOEt, but not three other specific mGluR1 antagonists (JNJ16259685, alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA), Bay 36-7620), attenuated DISC, even though all four of these drugs produced near-complete blockade of current evoked by puffs of the exogenous mGluR1/5 agonist DHPG. Cerebellar slices derived from mGluR1 null mice showed substantial DISC that was still attenuated by CPCCOEt. mGluR5 is functionally similar to mGluR1, but is not expressed at high levels in cerebellar Purkinje cells. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an mGluR5 antagonist, did not attenuate DISC, and DISC was still present in Purkinje cells derived from mGluR1/mGluR5 double null mice. Thus, neither mGluR1 nor mGluR5 is required for DISC in cerebellar Purkinje cells.

Developing the accredited postgraduate assessment program for Fellowship of the Australian College of Rural and Remote Medicine.

INTRODUCTION: Accreditation of the Australian College of Rural and Remote Medicine (ACRRM) as a standards and training provider, by the Australian Medical Council (AMC) in 2007, is the first time in the world that a peak professional organisation for rural and remote medical education has been formally recognised. As a consequence, the Australian Government provided rural and remote medicine with formal recognition under Medicare as a generalist discipline. This accreditation was based on the ability of ACRRM to meet the AMC's guidelines for its training and assessment program. METHODS: The methodology was a six-step process that included: developing an assessment blueprint and a classification scheme; identifying an assessment model; choosing innovative summative and formative assessment methods that met the needs of rural and remote located medical practitioner candidates; 21 rural doctors and academics developing the assessment items as part of a week-long writing workshop; investigating the feasibility of purchasing assessment items; and 48 rural candidates piloting three of the assessment items to ensure they would meet the guidelines for national accreditation. RESULTS: The project resulted in an innovative formative and summative assessment program that occurs throughout 4 years of vocational training, using innovative, reliable, valid and acceptable methods with educational impact. The piloting process occurred for 3 of the 6 assessment tools. Structured Assessment Using Multiple Patient Scenarios (StAMPS) is a new assessment method developed as part of this project. The StAMPS pilot found that it was reliable, with a generalisability coefficient of >0.76 and was a valid, acceptable and feasible assessment tool with desired educational impact. The multiple choice question (MCQ) examination pilot found that the applied clinical nature of the questions and their wide range of scenarios proved a very acceptable examination to the profession. The web based in-training assessment examination pilot revealed that it would serve well as a formative process until ACRRM can further develop their MCQ database. CONCLUSIONS: The ACRRM assessment program breaks new ground for assessing rural and remote doctors in Australia, and provides new evidence regarding how a comprehensive and contemporary assessment system can work within a postgraduate medical setting.

Complex, multimodal behavioral profile of the Homer1 knockout mouse.

Proteins of the Homer1 immediate early gene family have been associated with synaptogenesis and synaptic plasticity suggesting broad behavioral consequences of loss of function. This study examined the behavior of male Homer1 knockout (KO) mice compared with wild-type (WT) and heterozygous mice using a battery of 10 behavioral tests probing sensory, motor, social, emotional and learning/memory functions. KO mice showed mild somatic growth retardation, poor motor coordination, enhanced sensory reactivity and learning deficits. Heterozygous mice showed increased aggression in social interactions with conspecifics. The distribution of mGluR5 and N-methyl-D-aspartate receptors (NMDA) receptors appeared to be unaltered in the hippocampus (HIP) of Homer1 KO mice. The results indicate an extensive range of disrupted behaviors that should contribute to the understanding of the Homer1 gene in brain development and behavior.

Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat.

Neuroinflammation is reliably associated with the pathogenesis of a number of neurodegenerative diseases, and can be detected by the presence of activated microglia. Neuroinflammation can be induced by chronic lipopolysaccharide (LPS) infusion into the 4th ventricle of the rat resulting in region-selective microglia activation and impaired hippocampal-dependent memory. Furthermore, this treatment results in altered behaviorally-induced expression of the immediate early gene Arc, indicating altered network activity. LPS is known to activate microglia directly, leading to increased glutamate release, and in enhanced N-methyl-d-aspartate (NMDA) -dependent signaling. Taken together, the foregoing suggests that decreasing NMDA receptor activation during early stages of chronic neuroinflammation should reduce a) microglia activation, b) overexpression of Arc, and c) spatial memory deficits. Memantine, a low to moderate affinity open channel uncompetitive NMDA receptor antagonist, at low doses was used here to test these hypotheses. Rats were chronically infused into the 4th ventricle for 28 days with LPS alone, vehicle alone (via osmotic minipump) or LPS and memantine (10 mg/kg/day memantine s.c.). The results reported here demonstrate that memantine reduces OX6-immunolabeling for activated microglia, spares resident microglia, returns Arc (activity-regulated cytoskeletal associated protein, protein) -expressing neuronal populations to control levels (as revealed by Arc immunolabeling and fluorescence in situ hybridization), and ameliorates the spatial memory impairments produced by LPS alone. These data indicate that memantine therapy at low doses, recreating plasma levels similar to those of therapeutic doses in human, acts in part through its ability to reduce the effects of neuroinflammation, resulting in normal gene expression patterns and spatial learning. Combined, these findings suggest that low, therapeutically relevant doses of memantine delivered early in the development of neuroinflammation-influenced diseases may confer neural and cognitive protection.

Glomerular expression of neuronal activity-regulated pentraxin precedes the development of anti-Thy-1-induced progressive glomerulosclerosis.

Although it is clear that genetic predispositions play a role in progressive glomerulosclerosis, identification of specific genes is difficult because of natural genetic heterogeneity among individuals. We have reported a differential susceptibility to progressive glomerulosclerosis after induction of experimental glomerulonephritis anti-Thy-1 nephritis in Lewis rat substrains. Glomerular lesions in Lewis/Møllegard rats resolve spontaneously, whereas Lewis/Maastricht (Lew/Maa) rats develop progressive glomerulosclerosis. This predisposition for progressive glomerulosclerosis is governed by unknown genes that are expressed by renal cells. Here, differential gene expression analysis using a rat complementary DNA micro array revealed neuronal activity-regulated pentraxin (Narp) as a candidate gene involved in the remodeling or progression of damaged glomeruli. Glomerular Narp mRNA expression was monitored during disease in both Lewis sub strains. Immunohistochemistry revealed that Narp protein is exclusively expressed in Lew/Maa glomeruli 7 and 14 days after induction of anti-Thy-1 nephritis. Double-immunofluorescent staining showed that proliferating mesangial cells and parietal epithelial cells (PECs) at sites of adhesion to podocytes are partially Narp-positive, whereas podocytes fail to express Narp. Immunohistochemistry in nephritic Wistar, unilaterally nephrectomized Wistar and Sprague-Dawley rats showed that Narp protein is present only in strains that develop progressive glomerulosclerosis but never in strains that show remodeling. We conclude that Narp is a predictor for anti-Thy-1 nephritis-induced glomerulosclerosis and its expression by PECs may be involved in the progression to glomerulosclerosis.

The impact of medical students on rural general practitioner perceptors.

INTRODUCTION: As universities rely more heavily on rural GPs to precept medical students, the formation of symbiotic partnerships benefiting students, universities and GPs, becomes imperative. In order to develop and consolidate these partnerships Universities must understand who their rural GP preceptors are and how precepting impacts on them. METHODS: A review of the literature was undertaken to determine the significant themes of student impacts from articles where conclusions were clearly based on empirical findings. RESULTS: Forty-three articles were included in the final review, but only nine specifically looked at impacts on rural GPs. Impacts were categorised into six domains: personal; time; patient care; professional relationships and professional development; business and infrastructure; and recognition and remuneration. CONCLUSIONS: Literature specifically addressing the impact of precepting on rural GPs is scarce. Further studies are required to evaluate the relationship between the quality of teaching delivered to students, the type and length of student attachments and the likely impacts on rural GPs.

Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy.

OBJECTIVE: To investigate whether neuronal activity-regulated pentraxin (Narp) colocalizes with hypocretin (Hcrt or orexin) in the normal human brain and to determine if Narp staining is lost in the narcoleptic human brain. BACKGROUND: Human narcolepsy is characterized by a loss of the peptide hypocretin in the hypothalamus. This loss could result from the degeneration of neurons containing hypocretin or from a more specific loss of the ability of these neurons to synthesize Hcrt. Narp has been found to colocalize with hypocretin in the rat hypothalamus. METHODS: We investigated the distribution of Narp in three normal and four narcoleptic human postmortem brains using immunohistochemistry with an antibody to Narp. Colocalization studies of Narp and hypocretin were also performed in two normal brains using immunohistochemistry with an antibody to Narp and an antibody to hypocretin. RESULTS: We found that Narp colocalizes with hypocretin in the lateral hypothalamic area (LHA), the dorsomedial hypothalamus (DMH), the dorsal hypothalamic area (DHA), and the posterior hypothalamic area (PHA) of the normal human. The number of Narp-positive neurons was reduced by 89% in these areas of the narcoleptic hypothalamus. In contrast, Narp staining in the paraventricular (Pa) and supraoptic nuclei (SO) of the human hypothalamus did not differ between normal and narcoleptic brains. CONCLUSIONS: This finding supports the hypothesis that narcolepsy results from the specific loss of hypocretin neurons. Loss of hypothalamic Narp may contribute to the symptoms of narcolepsy.

Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia.

Homer proteins are involved in the functional assembly of postsynaptic density proteins at glutamatergic synapses and are implicated in learning, memory and drug addiction. Here, we report that Homer1-knockout (Homer1-KO) mice exhibit behavioral and neurochemical abnormalities that are consistent with the animal models of schizophrenia. Relative to wild-type mice, Homer1-KO mice exhibited deficits in radial arm maze performance, impaired prepulse inhibition, enhanced 'behavioral despair', increased anxiety in a novel objects test, enhanced reactivity to novel environments, decreased instrumental responding for sucrose and enhanced MK-801- and methamphetamine-stimulated motor behavior. No-net-flux in vivo microdialysis revealed a decrease in extracellular glutamate content in the nucleus accumbens and an increase in the prefrontal cortex. Moreover, in Homer1-KO mice, cocaine did not stimulate a rise in frontal cortex extracellular glutamate levels, suggesting hypofrontality. These behavioral and neurochemical data derived from Homer1 mutant mice are consistent with the recent association of schizophrenia with a single-nucleotide polymorphism in the Homer1 gene and suggest that the regulation of extracellular levels of glutamate within limbo-corticostriatal structures by Homer1 gene products may be involved in the pathogenesis of this neuropsychiatric disorder.

Sparse, environmentally selective expression of Arc RNA in the upper blade of the rodent fascia dentata by brief spatial experience.

After a spatial behavioral experience, hippocampal CA1 pyramidal cells express the activity-regulated, immediate early gene Arc in an environment-specific manner, and in similar proportions ( 40%) to cells exhibiting electrophysiologically recorded place fields under similar conditions. Theoretical accounts of the function of the fascia dentata suggest that it plays a role in pattern separation during encoding. The hypothesis that the dentate gyrus (DG) uses a sparse, and thus more orthogonal, coding scheme has been supported by the observation that, while granule cells do exhibit place fields, most are silent in a given environment. To quantify the degree of sparsity of DG coding and its corresponding ability to generate distinct environmental representations, behaviorally induced Arc expression was assessed using in situ hybridization coupled with confocal microscopy. The proportion of Arc(+) cells in the "upper blade" of the fascia dentata (i.e., the portion that abuts CA1) increased in an environment-specific fashion, approximately 4-fold above cage-control activity, after behavioral exploration. Surprisingly, cells in the lower blade of the fascia dentata, which are capable of expressing Arc following electrical stimulation, exhibited virtually no behaviorally-induced Arc expression. This difference was confirmed using "line scan" analyses, which also revealed no patterns or gradients of activity along the upper blade of the DG. The expression of Arc in the upper blade was quantitatively similar after exploring familiar or novel environments. When animals explored two different environments, separated by 20 min, a new group of cells responded to the second environment, whereas two separated experiences in the same environment did not activate a new set of granular cells. Thus, granule cells generate distinct codes for different environments. These findings suggest differential contribution of upper and lower blade neurons to plastic networks and confirm the hypothesis that the DG uses sparse coding that may facilitate orthogonalization of information.

Activity-regulated cytoskeletal-associated protein is localized to recently activated excitatory synapses.

Activity-regulated, cytoskeletal-associated protein (Arc) is an immediate early gene induced in excitatory circuits following behavioral episodes. Arc mRNA is targeted to activated regions of the dendrite after long-term potentiation (LTP) of the dentate gyrus, a process dependent on NMDA receptor activation. We used post-embedding immunogold electron microscopy (EM) to test whether synaptic Arc expression patterns are selectively modified by plasticity. Consistent with previous light microscopic observations, Arc protein was rapidly induced in the dentate gyrus following LTP-producing stimulation of the perforant path and was detectable in granule cell nuclei, somata and dendrites after two hours of high frequency stimulation. Post-embedding EM revealed Arc immunogold labeling in three times as many spines in the middle molecular layer of the stimulated dentate gyrus than in either the ipsilateral outer molecular layer or the contralateral middle and outer molecular layers. This upregulation did not occur with low frequency stimulation of the perforant path. Therefore Arc protein localization may be a powerful tool to isolate recently activated dendritic spines.

Vertical integration of medical education: Riverland experience, South Australia.

INTRODUCTION: Vertical integration of medical education is currently a prominent international topic, resulting from recent strategic initiatives to improve medical education and service delivery in areas of poorly met medical need. In this article, vertical integration of medical education is defined as 'a grouping of curricular content and delivery mechanisms, traversing the traditional boundaries of undergraduate, postgraduate and continuing medical education, with the intent of enhancing the transfer of knowledge and skills between those involved in the learning-teaching process'. METHODS: Educators closely involved with vertically integrated teaching in the Riverland of South Australia present an analytical description of the educational dynamics of this system. RESULTS: From this analysis, five elements are identified which underpin the process of successful vertical integration: (1) raised educational stakes; (2) local ownership; (3) broad university role; (4) longer attachments; and (5) shared workforce vision. CONCLUSIONS: Given the benefits to the Riverland medical education programs described in this paper, it is not surprising that vertical integration of medical education is a popular goal in many rural regions throughout the world. Although different contexts will result in different functional arrangements, it could be argued that the five principles outlined in this article can be applied in any region.