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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

Fibroblast growth factor 20 is protective towards dopaminergic neurons in vivo in a paracrine manner.

Neuroprotective strategies are an unmet medical need for Parkinson's disease. Fibroblast growth factor 20 (FGF20) enhances survival of cultured dopaminergic neurons but little is known about its in vivo potential. We set out to examine whether manipulation of the FGF20 system affected nigrostriatal tract integrity in rats, to identify which fibroblast growth factor receptors (FGFRs) might reside on dopaminergic neurons and to discover the source of endogenous FGF20 in the substantia nigra (SN).

Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients.

Background: Cerebellar ataxias are the result of diverse disease processes that can be genetic or acquired. Establishing a diagnosis requires a methodical approach with expert clinical evaluation and investigations. We describe the causes of ataxia in 1500 patients with cerebellar ataxia.

Is Cognitive Test-Taking Anxiety Associated With Academic Performance Among Nursing Students?

The cognitive component of test anxiety was correlated with academic performance among nursing students. Modest but statistically significant lower examination grade T scores were observed for students with high compared with low levels of cognitive test anxiety (CTA). High levels of CTA were associated with reduced academic performance.

Laundering habits of student nurses and correlation with the presence of Staphylococcus aureus on nursing scrub tops pre- and postlaundering.

Little is known about student nurse laundering practices. Student nurses swabbed their scrub tops after clinical and after laundering, and they completed a laundry survey; 13.5% of students wore the same scrub more than once, and few followed recommended guidelines by using hot water (20%) or bleach (5.

Brain morphometry and the neurobiology of levodopa-induced dyskinesias: current knowledge and future potential for translational pre-clinical neuroimaging studies.

Dopamine replacement therapy in the form of levodopa results in a significant proportion of patients with Parkinson's disease developing debilitating dyskinesia. This significantly complicates further treatment and negatively impacts patient quality of life. A greater understanding of the neurobiological mechanisms underlying levodopa-induced dyskinesia (LID) is therefore crucial to develop new treatments to prevent or mitigate LID.

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.

The use of haematopoietic stem cell transplantation in Fanconi anaemia patients: a survey of decision making among families in the US and Canada.

Background: Fanconi anaemia (FA) is a rare genetic disorder associated with bone marrow failure (BMF), congenital anomalies and cancer susceptibility. Stem cell transplantation (SCT) offers a potential cure for BMF or leukaemia, but incurs substantial risks. Little is known about factors influencing SCT decision making.

Improving satisfaction with care and reducing length of stay in an obstetric triage unit using a nurse-midwife-managed model of care.

Introduction: A quality improvement project was initiated at a tertiary-care center in a suburban area of the northeastern United States to determine whether length of stay and patient satisfaction in an obstetric triage unit could be improved by using a certified nurse-midwife (CNM) to manage and organize care in the triage unit.

Methods: Patient satisfaction was measured using a previously validated instrument that consisted of 6 items using a 6-point Likert-type scale. The items measured patient satisfaction with: wait time for provider, information given, amount of time spent with provider, length of visit, overall care received, and overall triage experience.

Potential sources of bisphenol A in the neonatal intensive care unit.

Objectives: To determine whether nutritional intake and medical devices are bisphenol A (BPA) exposure sources among premature infants in the NICU.

Methods: Mothers and their premature infants cared for in the NICU for the past 3 days were recruited for this exposure assessment study. Forty-three mothers contributed 1 nutrition sample (breast milk or formula) to characterize the infant's intake.