Identifying elements for a comprehensive paediatric cardiac rehabilitation programme.

INTRODUCTION: The aim of this study was to identify relevant content among four important domains for the development and structure of a paediatric cardiac rehabilitation curriculum for young patients with congenital heart disease using a consensus approach. METHODS: A three-round e-Delphi study among congenital heart disease and paediatric exercise physiology experts was conducted. Round 1, experts provided opinions in a closed- and open-ended electronic questionnaire to identify specific elements necessary for inclusion in a paediatric cardiac rehabilitation programme. Round 2, experts were asked to re-rate the same items after feedback and summary data were provided from round 1. Round 3, the same experts were asked to re-rate items that did not reach consensus from round 2. RESULTS: Forty-seven experts were contacted via e-mail to participate on the Delphi panel, 37 consented, 35 completed round 1, 29 completed round 2, and 28 completed the final round. After round 2, consensus was reached in 55 of 60 (92%) questionnaire items across four domains: exercise training, education, outcome metrics, and self-confidence. CONCLUSION: This study established consensus towards programme structure, exercise training principles, educational content, patient outcome measures, and self-confidence promotion. By identifying the key components within each domain, there is potential to benchmark recommended standards and practice guidelines for the development of a paediatric cardiac rehabilitation curriculum to be used and tested by exercise physiologists, paediatric and adult congenital cardiologists, and other healthcare team members for optimising the health and wellness of paediatric patients with congenital heart disease.

Pain in Parkinson's disease: new concepts in pathogenesis and treatment.

PURPOSE OF REVIEW: In this review, we discuss the most recent evidence on mechanisms underlying pathological nociceptive processing in Parkinson's disease patients, as well as novel treatment strategies. RECENT FINDINGS: In Parkinson's disease, specific neurodegenerative changes may cause alterations in nociceptive processing at multiple levels. Optimization of dopaminergic therapies should always be the first step in the management of Parkinson's disease pain. Reportedly, rotigotine transdermal patch, a monoamine oxidase type B inhibitor safinamide (as an add-on therapy to levodopa), subcutaneous apomorphine and intrajejunal levodopa infusion therapy may have a beneficial effect on pain sensations in Parkinson's disease patients. Among the nondopaminergic pharmacological therapies, prolonged-release oxycodone/naloxone and duloxetine may be effective in the treatment of chronic pain in Parkinson's disease. Botulinum toxin (BTX) injections should be considered for the treatment of dystonic Parkinson's disease pain. Deep brain stimulation (DBS) may lead to pain relief with a long-lasting effect in Parkinson's disease patients. Physiotherapy and physical activity in general are essential for Parkinson's disease patients suffering from pain. SUMMARY: Pain in Parkinson's disease is not simply a consequence of motor complainants. The management of Parkinson's disease-related pain implicates maintenance of stable levels of dopaminergic drugs. Nondopaminergic pharmacological therapies (prolonged-release oxycodone/naloxone, duloxetine, BTX) and nonpharmacological interventions (DBS, physiotherapie) may also be beneficial in treatment of Parkinson's disease pain.

Chondroitinase ABC reduces dopaminergic nigral cell death and striatal terminal loss in a 6-hydroxydopamine partial lesion mouse model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterised by dopaminergic cell loss within the substantia nigra pars compacta (SNc) that leads to reduced striatal dopamine content and resulting motor deficits. Identifying new strategies to protect these cells from degeneration and retain striatal dopaminergic innervation is therefore of great importance. Chondroitin sulphate proteoglycans (CSPGs) are recognised contributors to the inhibitory extracellular milieu known to hinder tissue recovery following CNS damage. Digestion of these molecules by the bacterial lyase chondroitinase ABC (ChABC) has been shown to promote functional recovery in animal models of neurological injury. Although ChABC has been shown to promote sprouting of dopaminergic axons following transection of the nigrostriatal pathway, its ability to protect against nigrostriatal degeneration in a toxin-based module with better construct validity for PD has yet to be explored. Here we examined the neuroprotective efficacy of ChABC treatment in the full and partial 6-hydroxydopamine (6-OHDA) lesion mouse models of PD. RESULTS: In mice bearing a full 6-OHDA lesion, ChABC treatment failed to protect against the loss of either nigral cells or striatal terminals. In contrast, in mice bearing a partial 6-OHDA lesion, ChABC treatment significantly protected cells of the rostral SNc, which remained at more than double the numbers seen in vehicle-treated animals. In the partial lesion model, ChABC treatment also significantly preserved dopaminergic fibres of the rostral dorsal striatum which increased from 15.3 ± 3.5% of the intact hemisphere in saline-treated animals to 36.3 ± 6.5% in the ChABC-treated group. These protective effects of ChABC treatment were not accompanied by improvements in either the cylinder or amphetamine-induced rotations tests of motor function. CONCLUSIONS: ChABC treatment provided significant protection against a partial 6-OHDA lesion of the nigrostriatal tract although the degree of protection was not sufficient to improve motor outcomes. These results support further investigations into the benefits of ChABC treatment for providing neuroprotection in PD.

Transforming the Workforce for Primary Palliative Care Through a System-Wide Educational Initiative.

Palliative care (PC) is a national and global priority, yet there is insufficient knowledge regarding PC among generalist clinicians. An interdisciplinary educational initiative was implemented to enhance a hospital workforce's PC knowledge and skills. More than 1000 clinicians attended at least 1 of 27 educational offerings. Measurable gains were evident in key outcome measures including PC referrals and advanced directive documentation. Changes reflected a transformation of workforce culture and resulted in 2 national awards for improving PC.

Therapeutic potential of targeting glutamate receptors in Parkinson's disease.

Glutamate plays a complex role in many aspects of Parkinson's disease including the loss of dopaminergic neurons, the classical motor symptoms as well as associated non-motor symptoms and the treatment-related side effect, L-DOPA-induced dyskinesia. This widespread involvement opens up possibilities for glutamate-based therapies to provide a more rounded approach to treatment than is afforded by current dopamine replacement therapies. Beneficial effects of blocking postsynaptic glutamate transmission have already been noted in a range of preclinical studies using antagonists of NMDA receptors or negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5), while positive allosteric modulators of mGlu4 in particular, although at an earlier stage of investigation, also look promising. This review addresses each of the key features of Parkinson's disease in turn, summarising the contribution glutamate makes to that feature and presenting an up-to-date account of the potential for drugs acting at ionotropic or metabotropic glutamate receptors to provide relief. Whilst only a handful of these have progressed to clinical trials to date, notably NMDA and NR2B antagonists against motor symptoms and L-DOPA-induced dyskinesia, with mGlu5 negative allosteric modulators also against L-DOPA-induced dyskinesia, the mainly positive outcomes of these trials, coupled with supportive preclinical data for other strategies in animal models of Parkinson's disease and L-DOPA-induced dyskinesia, raise cautious optimism that a glutamate-based therapeutic approach will have significant impact on the treatment of Parkinson's disease.

Insight gained from using animal models to study pain in Parkinson's disease.

Pain is one of the key non-motor symptoms experienced by a large proportion of people living with Parkinson's disease (PD), yet the mechanisms behind this pain remain elusive and as such its treatment remains suboptimal. It is hoped that through the study of animal models of PD, we can start to unravel some of the contributory mechanisms, and perhaps identify models that prove useful as test beds for assessing the efficacy of potential new analgesics. However, just how far along this journey are we right now? Is it even possible to model pain in PD in animal models of the disease? And have we gathered any insight into pain mechanisms from the use of animal models of PD so far? In this chapter we intend to address these questions and in particular highlight the findings generated by others, and our own group, following studies in a range of rodent models of PD.

Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia.

Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release. Objective: We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.

Periaqueductal grey and spinal cord pathology contribute to pain in Parkinson's disease.

Pain is a key non-motor feature of Parkinson's disease (PD) that significantly impacts on life quality. The mechanisms underlying chronic pain in PD are poorly understood, hence the lack of effective treatments. Using the 6-hydroxydopamine (6-OHDA) lesioned rat model of PD, we identified reductions in dopaminergic neurons in the periaqueductal grey (PAG) and Met-enkephalin in the dorsal horn of the spinal cord that were validated in human PD tissue samples. Pharmacological activation of D1-like receptors in the PAG, identified as the DRD5+ phenotype located on glutamatergic neurons, alleviated the mechanical hypersensitivity seen in the Parkinsonian model. Downstream activity in serotonergic neurons in the Raphé magnus (RMg) was also reduced in 6-OHDA lesioned rats, as detected by diminished c-FOS positivity. Furthermore, we identified increased pre-aggregate α-synuclein, coupled with elevated activated microglia in the dorsal horn of the spinal cord in those people that experienced PD-related pain in life. Our findings have outlined pathological pathways involved in the manifestation of pain in PD that may present targets for improved analgesia in people with PD.

Riluzole neuroprotection in a Parkinson's disease model involves suppression of reactive astrocytosis but not GLT-1 regulation.

BACKGROUND: Riluzole is a neuroprotective drug used in the treatment of motor neurone disease. Recent evidence suggests that riluzole can up-regulate the expression and activity of the astrocyte glutamate transporter, GLT-1. Given that regulation of glutamate transport is predicted to be neuroprotective in Parkinson's disease, we tested the effect of riluzole in parkinsonian rats which had received a unilateral 6-hydroxydopamine injection into the median forebrain bundle. RESULTS: Rats were treated with intraperitoneal riluzole (4 mg/kg or 8 mg/kg), 1 hour before the lesion then once daily for seven days. Riluzole produced a modest but significant attenuation of dopamine neurone degeneration, assessed by suppression of amphetamine-induced rotations, preservation of tyrosine hydroxylase positive neuronal cell bodies in the substantia nigra pars compacta and attenuation of striatal tyrosine hydroxylase protein loss. Seven days after 6-hydroxydopamine lesion, reactive astrocytosis was observed in the striatum, as determined by increases in expression of glial fibrillary acidic protein, however the glutamate transporter, GLT-1, which is also expressed in astrocytes was not regulated by the lesion. CONCLUSIONS: The results confirm that riluzole is a neuroprotective agent in a rodent model of parkinson's disease. Riluzole administration did not regulate GLT-1 levels but significantly reduced GFAP levels, in the lesioned striatum. Riluzole suppression of reactive astrocytosis is an intriguing finding which might contribute to the neuroprotective effects of this drug.

Proinflammatory profile in the skin of Parkinson's disease patients with and without pain.

BACKGROUND: Pain is a common non-motor symptom of Parkinson`s disease (PD), however, its pathomechanism remains elusive. OBJECTIVE: We aimed to investigate the local gene expression of selected proinflammatory mediators in patients with PD and correlated our data with patients`pain phenotype. METHODS: We recruited 30 patients with PD and 30 healthy controls. Pain intensity of patients was assessed using the Numeric Rating Scale (NRS) and patients were stratified into PD pain (NRS≥4) and PD No Pain (NRS<4) subgroups. Skin punch biopsies were immunoassayed for protein-gene product 9.5 as a pan-neuronal marker and intraepidermal nerve fiber density (IEFND). Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to assess the gene expression of inflammatory mediators in the skin compared to controls. RESULTS: Patients with PD had lower distal IENFD compared to healthy controls. In skin samples, IL-2 (p<0.001) and TNF-α (p<0.01) were expressed higher in PD patients compared to controls. IL-1ß (p<0.05) was expressed higher in the PD pain group compared to healthy controls. PD patients with pain receiving analgesics had a lower expression of TNF-α (p<0.05) in the skin compared to those not receiving treatment. CONCLUSIONS: Our data suggest the occurrence of a local, peripheral inflammatory response in the skin in PD, but do not support this being a relevant factor contributing to pain in PD.

A Single Domain Shark Antibody Targeting the Transferrin Receptor 1 Delivers a TrkB Agonist Antibody to the Brain and Provides Full Neuroprotection in a Mouse Model of Parkinson's Disease.

Single domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells have been used to shuttle antibodies and other cargos across the blood brain barrier (BBB) to the brain. For these studies the TXB4 brain shuttle was fused to a TrkB neurotrophin receptor agonist antibody. The TXB4-TrkB fusion retained potent agonist activity at its cognate receptor and after systemic administration showed a 12-fold increase in brain levels over the unmodified antibody. Only the TXB4-TrkB antibody fusion was detected within the brain and localized to TrkB positive cells in the cortex and tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra pars compacta (SNc), where it was associated with activated ERK1/2 signaling. When tested in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD), TXB4-TrkB, but not the unmodified antibody, completely prevented the 6-OHDA induced death of TH positive neurons in the SNc. In conclusion, the fusion of the TXB4 brain shuttle allows a TrkB agonist antibody to reach neuroprotective concentrations in the brain parenchyma following systemic administration.

Drug repurposing strategies of relevance for Parkinson's disease.

Parkinson's disease is a highly disabling, progressive neurodegenerative disease that manifests as a mix of motor and non-motor signs. Although we are equipped with some symptomatic treatments, especially for the motor signs of the disease, there are still no established disease-modifying drugs so the disease progresses unchecked. Standard drug discovery programs for disease-modifying therapies have provided key insights into the pathogenesis of Parkinson's disease but, of the many positive candidates identified in pre-clinical studies, none has yet translated into a successful clinically efficacious drug. Given the huge cost of drug discovery programs, it is not surprising that much attention has turned toward repurposing strategies. The trialing of an established therapeutic has the advantage of bypassing the need for preclinical safety testing and formulation optimization, thereby cutting both time and costs involved in getting a treatment to the clinic. Additional reduced failure rates for repurposed drugs are also a potential bonus. Many different strategies for drug repurposing are open to researchers in the Parkinson's disease field. Some of these have already proven effective in identifying suitable drugs for clinical trials, lending support to such approaches. In this review, we present a summary of the different strategies for drug repurposing, from large-scale epidemiological correlation analysis through to single-gene transcriptional approaches. We provide examples of past or ongoing studies adopting each strategy, where these exist. For strategies that have yet to be applied to Parkinson's disease, their utility is illustrated using examples taken from other disorders.

Animal models of Parkinson's disease: a guide to selecting the optimal model for your research.

Parkinson's disease (PD) is a complex, multisystem disorder characterised by α-synuclein (SNCA) pathology, degeneration of nigrostriatal dopaminergic neurons, multifactorial pathogenetic mechanisms and expression of a plethora of motor and non-motor symptoms. Animal models of PD have already been instructive in helping us unravel some of these aspects. However, much remains to be discovered, requiring continued interrogation by the research community. In contrast with the situation for many neurological disorders, PD benefits from of a wide range of available animal models (pharmacological, toxin, genetic and α-synuclein) but this makes selection of the optimal one for a given study difficult. This is especially so when a study demands a model that displays a specific combination of features. While many excellent reviews of animal models already exist, this review takes a different approach with the intention of more readily informing this decision-making process. We have considered each feature of PD in turn - aetiology, pathology, pathogenesis, motor dysfunctions and non-motor symptoms (NMS) - highlighting those animal models that replicate each. By compiling easily accessible tables and a summary figure, we aim to provide the reader with a simple, go-to resource for selecting the optimal animal model of PD to suit their research needs.

Educating ethnic minority students for the nursing workforce: facilitators and barriers to success.

The number of ethnic minorities graduating from nursing programs does not meet the number of ethnic minority nurses that are needed for patient care. In order to identify the facilitators and barriers to success, a survey was sent to current students and to those who graduated within 2 years. There were 314 responses, which was an overall response rate of 39.6%. Among the 4 facilitator factors, only the general academic support factor was perceived as more helpful by African-American students (p = 0.001). Among the 5 barrier factors, African-American students and Other Ethnic Minority students perceived program workload and pace (African-Americans p < 0.005; Other multicultural groups p < 0.02), computer access (African-Americans p < 0.05; Other multicultural groups p < 0.05) and technology competence (African-Americans p < 0.02) to be barriers. Any student, regardless of ethnicity, who worked at a job 13 to 40 hours a week, perceived family and financial concerns as a barrier. Results indicated that curriculum content should include technology basics and testing for competence. Financial support for students must be expanded through loans and scholarships so workload and pace become more manageable.

Potential of animal models for advancing the understanding and treatment of pain in Parkinson's disease.

Pain is a commonly occurring non-motor symptom of Parkinson's disease (PD). Treatment of pain in PD remains less than optimal and a better understanding of the underlying mechanisms would facilitate discovery of improved analgesics. Animal models of PD have already proven helpful for furthering the understanding and treatment of motor symptoms of PD, but could these models offer insight into pain in PD? This review addresses the current position regarding pain in preclinical models of PD, covering the face and predictive validity of existing models and their use so far in advancing understanding of the mechanisms contributing to pain in PD. While pain itself is not usually measured in animals, nociception in the form of thermal, mechanical or chemical nociceptive thresholds offers a useful readout, given reduced nociceptive thresholds are commonly seen in PD patients. Animal models of PD including the reserpine-treated rat and neurodegenerative models such as the MPTP-treated mouse and 6-hydroxydopamine (6-OHDA)-treated rat each exhibit reduced nociceptive thresholds, supporting face validity of these models. Furthermore, some interventions known clinically to relieve pain in PD, such as dopaminergic therapies and deep brain stimulation of the subthalamic nucleus, restore nociceptive thresholds in one or more models, supporting their predictive validity. Mechanistic insight gained already includes involvement of central and spinal dopamine and opioid systems. Moving forward, these preclinical models should advance understanding of the cellular and molecular mechanisms underlying pain in PD and provide test beds for examining the efficacy of novel analgesics to better treat this debilitating non-motor symptom.

Antiparkinsonian Effects of a Metabotropic Glutamate Receptor 4 Agonist in MPTP-Treated Marmosets.

BACKGROUND: Increased firing across glutamatergic synapses may contribute to both the motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson's disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both motor dysfunction and dyskinesia in Parkinson's disease. OBJECTIVE: We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset model of Parkinson's disease. METHODS: Common marmosets were previously treated with MPTP and pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3, or 6 mg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8 mg/kg + benserazide (10 mg/kg) p.o.) or vehicle (10% sucrose p.o.). Locomotor activity was measured in automated test cages and animals were scored for dyskinesia and disability. RESULTS: As expected, L-DOPA reversed motor disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the motor disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia. CONCLUSION: Systemic administration of LSP1-2111 reduces motor disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested.

Neuroanatomical and Microglial Alterations in the Striatum of Levodopa-Treated, Dyskinetic Hemi-Parkinsonian Rats.

Dyskinesia associated with chronic levodopa treatment in Parkinson's disease is associated with maladaptive striatal plasticity. The objective of this study was to examine whether macroscale structural changes, as captured by magnetic resonance imaging (MRI) accompany this plasticity and to identify plausible cellular contributors in a rodent model of levodopa-induced dyskinesia. Adult male Sprague-Dawley rats were rendered hemi-parkinsonian by stereotaxic injection of 6-hydroxydopamine into the left medial forebrain bundle prior to chronic treatment with saline (control) or levodopa to induce abnormal involuntary movements (AIMs), reflective of dyskinesia. Perfusion-fixed brains underwent ex vivo structural MRI before sectioning and staining for cellular markers. Chronic treatment with levodopa induced significant AIMs (p < 0.0001 versus saline). The absolute volume of the ipsilateral, lesioned striatum was increased in levodopa-treated rats resulting in a significant difference in percentage volume change when compared to saline-treated rats (p < 0.01). Moreover, a significant positive correlation was found between this volume change and AIMs scores for individual levodopa-treated rats (r = 0.96; p < 0.01). The density of Iba1+ cells was increased within the lesioned versus intact striatum (p < 0.01) with no difference between treatment groups. Conversely, Iba1+ microglia soma size was significantly increased (p < 0.01) in the lesioned striatum of levodopa-treated but not saline-treated rats. Soma size was not, however, significantly correlated with either AIMs or MRI volume change. Although GFAP+ astrocytes were elevated in the lesioned versus intact striatum (p < 0.001), there was no difference between treatment groups. No statistically significant effects of either lesion or treatment on RECA1, a marker for blood vessels, were observed. Collectively, these data suggest chronic levodopa treatment in 6-hydroxydopamine lesioned rats is associated with increased striatal volume that correlates with the development of AIMs. The accompanying increase in number and size of microglia, however, cannot alone explain this volume expansion. Further multi-modal studies are warranted to establish the brain-wide effects of chronic levodopa treatment.

Addressing a Gap in Healthcare Access for Transition-Age Youth with Autism: A Pilot Educational Intervention for Family Nurse Practitioner Students.

A mixed-methods randomized controlled trial pilot study evaluated an educational curriculum focused on the medical needs of transition-age youth (TAY) with autism (ASD) for family nurse practitioner students. Fourteen out of a cohort of 16 (87.5%) nursing students consented to participate in the study and were randomly assigned to either a waitlist control group (WLC) (n = 8) or an intervention group (INT) (n = 6). Three measures were used to determine pre- and post-intervention levels of self-efficacy, knowledge, and attitudes. Quantitative and qualitative data provide preliminary support that participation in intervention may improve and enhance knowledge and level of self-efficacy in working with TAY with ASD.

Targeted repositioning identifies drugs that increase fibroblast growth factor 20 production and protect against 6-hydroxydopamine-induced nigral cell loss in rats.

Endogenous fibroblast growth factor 20 (FGF20) supports maintenance of dopaminergic neurones within the nigrostriatal pathway. Moreover, direct intracerebral infusion of FGF20 protects against nigrostriatal tract loss in the 6-hydroxydopamine lesion rat model of Parkinson's disease. Increasing endogenous FGF20 production might provide a less-invasive, more translational way of providing such protection. Accordingly, we adopted a targeted repositioning approach to screen for candidate FDA-approved drugs with potential to enhance endogenous FGF20 production in brain. In silico interrogation of the Broad Institute's Connectivity Map database (CMap), revealed 50 candidate drugs predicted to increase FGF20 transcription, 16 of which had profiles favourable for use in Parkinson's disease. Of these, 11 drugs were found to significantly elevate FGF20 protein production in MCF-7 cells, between two- and four-fold. Four drugs were selected for examination in vivo. Following oral dosing in rats for 7 days, salbutamol and triflusal, but not dimethadione or trazodone, significantly elevated FGF20 levels in the nigrostriatal tract. Preliminary examination in the unilateral 6-hydroxydopamine-lesioned rat revealed a modest but significant protection against nigral cell loss with both drugs. Our data demonstrate the power of targeted repositioning as a method to identify existing drugs that may combat disease progression in Parkinson's by boosting FGF20 levels.

Group III metabotropic glutamate receptors act as hetero-receptors modulating evoked GABA release in the globus pallidus in vivo.

In vitro studies suggest that group III metabotropic glutamate (mGlu) receptors function as hetero-receptors to modulate GABA release within the globus pallidus. In the present study we examined this hypothesis in vivo, using microdialysis to assess the ability of locally infused group III mGlu receptor agonists to modulate KCl-evoked GABA release in the globus pallidus of anaesthetised rats. Extra-cellular levels of GABA in dialysate samples were assayed using High Pressure Liquid Chromatography (HPLC) coupled to electrochemical detection. Infusion of KCl (50-100 mM) evoked a dose-dependent increase in GABA levels in the globus pallidus. Addition of the group III mGlu receptor agonists l-AP4 (30 and 300 microM) and l-SOP (3-300 microM) significantly reduced the extra-synaptic levels of GABA that resulted after 100 mM KCl challenge. The effect of L-SOP (30 microM) was almost totally abolished by co-infusion with M-SOP (30 microM). These data confirm that activation of group III mGlu receptors inhibits GABA release in the globus pallidus, thereby supporting their hetero-receptor role in vivo.