Magnetic Resonance Imaging Characteristics of LGI1-Antibody and CASPR2-Antibody Encephalitis.

Importance: Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy.

Objective: To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD).

Frequency of inter-specialty consensus decisions and adherence to advice following discussion at a weekly neurovascular multidisciplinary meeting.

Background/aims: Data are limited on the frequency of 'consensus decisions' between sub-specialists attending a neurovascular multidisciplinary meeting (MDM) regarding management of patients with extracranial carotid/vertebral stenoses and post-MDM 'adherence' to such advice.

Methods: This prospective audit/quality improvement project collated prospectively-recorded data from a weekly Neurovascular/Stroke Centre MDM documenting the proportion of extracranial carotid/vertebral stenosis patients in whom 'consensus management decisions' were reached by neurologists, vascular surgeons, stroke physicians-geriatricians and neuroradiologists. Adherence to MDM advice was analysed in asymptomatic carotid stenosis (ACS), symptomatic carotid stenosis (SCS), 'indeterminate symptomatic status stenosis' (ISS) and vertebral artery stenosis (VAS) patients, including intervals between index event to MDM + / - intervention.

Seeing the Woods for the Trees? Applying Diagnostic Criteria for Dementia with Lewy Bodies to Patients Presenting with Posterior Cortical Atrophy.

Posterior cortical atrophy (PCA) is a clinico-radiological syndrome characterised by progressive decline in visual processing and other posterior cognitive functions, relatively preserved memory and language in the early stages, and atrophy of posterior brain regions. Often considered a "visual variant" of Alzheimer's disease, a number of other pathological substrates are recognised. Dementia with Lewy Bodies is the second most common neurodegenerative dementia and there is increasing recognition of presentations with little or no parkinsonism, highlighting significant under-recognition of this condition.

Manipulation of the inflammatory reflex as a therapeutic strategy.

The cholinergic anti-inflammatory pathway is the efferent arm of the inflammatory reflex, a neural circuit through which the CNS can modulate peripheral immune responses. Signals communicated via the vagus and splenic nerves use acetylcholine, produced by Choline acetyltransferase (ChAT)+ T cells, to downregulate the inflammatory actions of macrophages expressing α7 nicotinic receptors. Pre-clinical studies using transgenic animals, cholinergic agonists, vagotomy, and vagus nerve stimulation have demonstrated this pathway's role and therapeutic potential in numerous inflammatory diseases.

The Cost of Living with Inherited Ataxia in Ireland.

Inherited ataxias are a heterogenous group of neurodegenerative disorders characterised by progressive impairment of balance and coordination, typically leading to permanent and progressive disability. Diagnosis and management of these disorders incurs a range of direct and indirect financial costs. The aim of this study was to collect individual ataxia-related healthcare resources in a large cohort of individuals with different subtypes of inherited ataxia and calculate the associated cost of illness in the Republic of Ireland.

Spectrum of impulse control behaviours in Parkinson's disease: pathophysiology and management.

Impulse control behaviours (ICBs) are a range of behaviours linked by their reward-based, repetitive natures. They can be precipitated in Parkinson's disease (PD) by dopamine replacement therapy, often with detrimental consequences for patients and caregivers. While now a well-recognised non-motor feature of treated PD, much remains unknown about the influence of risk factors, pathophysiological mechanisms, vulnerability factors for specific types of behaviour and the optimal management strategies.

Impulse control disorders in Parkinson disease and RBD: A longitudinal study of severity.

Objective: To describe the prevalence, natural history, and risk factors for impulse control behaviors (ICBs) among people with Parkinson disease (PD), those with REM sleep behavior disorder (RBD), and controls.

Methods: Participants with early PD (within 3.5 years of diagnosis), those with RBD, and controls were clinically phenotyped and screened for ICBs longitudinally (with the Questionnaire for Impulsivity in Parkinson's Disease).

Predictors of motor complications in early Parkinson's disease: A prospective cohort study.

Objective: The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis.

Methods: An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete-time survival analysis. A subset analysis was used to validate an online dyskinesia-risk calculator developed from the results of the Stalevo Reduction in Dyskinesia Evaluation PD trial.

Allosteric N-WASP activation by an inter-SH3 domain linker in Nck.

Actin filament networks assemble on cellular membranes in response to signals that locally activate neural Wiskott-Aldrich-syndrome protein (N-WASP) and the Arp2/3 complex. An inactive conformation of N-WASP is stabilized by intramolecular contacts between the GTPase binding domain (GBD) and the C helix of the verprolin-homology, connector-helix, acidic motif (VCA) segment. Multiple SH3 domain-containing adapter proteins can bind and possibly activate N-WASP, but it remains unclear how such binding events relieve autoinhibition to unmask the VCA segment and activate the Arp2/3 complex.

Biophysical methods for identifying fragment-based inhibitors of protein-protein interactions.

Fragment-based lead discovery complements high-throughput screening and computer-aided drug design for the discovery of small-molecule inhibitors of protein-protein interactions. Fragments are molecules with molecular masses ca 280 Da or smaller, and are generally screened using structural or biophysical approaches. Several methods of fragment-based screening are feasible for any soluble protein that can be expressed and purified; specific techniques also have size limitations and/or require multiple milligrams of protein.

A Fragment-Based Ligand Screen Against Part of a Large Protein Machine: The ND1 Domains of the AAA+ ATPase p97/VCP.

The ubiquitous AAA+ ATPase p97 functions as a dynamic molecular machine driving several cellular processes. It is essential in regulating protein homeostasis, and it represents a potential drug target for cancer, particularly when there is a greater reliance on the endoplasmic reticulum-associated protein degradation pathway and ubiquitin-proteasome pathway to degrade an overabundance of secreted proteins. Here, we report a case study for using fragment-based ligand design approaches against this large and dynamic hexamer, which has multiple potential binding sites for small molecules.

Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism.

The retinoblastoma binding protein KDM5A removes methyl marks from lysine 4 of histone H3 (H3K4). Misregulation of KDM5A contributes to the pathogenesis of lung and gastric cancers. In addition to its catalytic jumonji C domain, KDM5A contains three PHD reader domains, commonly recognized as chromatin recruitment modules.

Elucidating the mechanism of substrate recognition by the bacterial Hsp90 molecular chaperone.

Hsp90 is a conformationally dynamic molecular chaperone known to promote the folding and activation of a broad array of protein substrates ("clients"). Hsp90 is believed to preferentially interact with partially folded substrates, and it has been hypothesized that the chaperone can significantly alter substrate structure as a mechanism to alter the substrate functional state. However, critically testing the mechanism of substrate recognition and remodeling by Hsp90 has been challenging.

Interventions to promote informed consent for patients undergoing surgical and other invasive healthcare procedures.

Background: Achieving informed consent is a core clinical procedure and is required before any surgical or invasive procedure is undertaken.  However, it is a complex process which requires patients be provided with information which they can understand and retain, opportunity to consider their options, and to be able to express their opinions and ask questions.  There is evidence that at present some patients undergo procedures without informed consent being achieved.

13C NMR metabolomic evaluation of immediate and delayed mild hypothermia in cerebrocortical slices after oxygen-glucose deprivation.

Background: Mild brain hypothermia (32°-34°C) after human neonatal asphyxia improves neurodevelopmental outcomes. Astrocytes but not neurons have pyruvate carboxylase and an acetate uptake transporter. C nuclear magnetic resonance spectroscopy of rodent brain extracts after administering [1-C]glucose and [1,2-C]acetate can distinguish metabolic differences between glia and neurons, and tricarboxylic acid cycle entry via pyruvate dehydrogenase and pyruvate carboxylase.

1H nuclear magnetic resonance brain metabolomics in neonatal mice after hypoxia-ischemia distinguished normothermic recovery from mild hypothermia recoveries.

Background: Mild brain hypothermia (31-34 °C) after neonatal hypoxia-ischemia (HI) improves neurodevelopmental outcomes in human and animal neonates. Using an asphyxia model with neonatal mice treated with mild hypothermia after HI, we investigated whether (1)H nuclear magnetic resonance (NMR) metabolomics of brain extracts could suggest biomarkers and distinguish different treatments and outcome groups.

Methods: At postnatal day 7 (P7), CD1 mice underwent right carotid artery occlusion, 30 min of HI (8% oxygen), and 3.

Variation in family physicians' recording of auscultation abnormalities in patients with acute cough is not explained by case mix. A study from 12 European networks.

Background: Conflicting data on the diagnostic and prognostic value of auscultation abnormalities may be partly explained by inconsistent use of terminology.

Objectives: To describe general practitioners use of chest auscultation abnormality terms for patients presenting with acute cough across Europe, and to explore the influence of geographic location and case mix on use of these terms.

Methods: Clinicians recorded whether 'diminished vesicular breathing', 'wheezes', 'crackles' and 'rhonchi' were present in an observational study of adults with acute cough in 13 networks in 12 European countries.

Collaboration between local health and local government agencies for health improvement.

Background: In many countries, national, regional and local inter- and intra-agency collaborations have been introduced to improve health outcomes. Evidence is needed on the effectiveness of locally developed partnerships which target changes in health outcomes and behaviours.

Objectives: To evaluate the effects of interagency collaboration between local health and local government agencies on health outcomes in any population or age group.

Metabolomics of oxidative stress in recent studies of endogenous and exogenously administered intermediate metabolites.

Aerobic metabolism occurs in a background of oxygen radicals and reactive oxygen species (ROS) that originate from the incomplete reduction of molecular oxygen in electron transfer reactions. The essential role of aerobic metabolism, the generation and consumption of ATP and other high energy phosphates, sustains a balance of approximately 3000 essential human metabolites that serve not only as nutrients, but also as antioxidants, neurotransmitters, osmolytes, and participants in ligand-based and other cellular signaling. In hypoxia, ischemia, and oxidative stress, where pathological circumstances cause oxygen radicals to form at a rate greater than is possible for their consumption, changes in the composition of metabolite ensembles, or metabolomes, can be associated with physiological changes.

Beating Bipolar: exploratory trial of a novel Internet-based psychoeducational treatment for bipolar disorder.

Objectives:   Psychoeducational approaches are promising interventions for the long-term management of bipolar disorder. In consultation with professionals, patients, and their families we have developed a novel web-based psychoeducational intervention for bipolar disorder called Beating Bipolar. We undertook a preliminary exploratory randomized trial to examine efficacy, feasibility and acceptability.

Collaboration between local health and local government agencies for health improvement.

Background: In many countries, national, regional and local inter- and intra-agency collaborations have been introduced in order to improve health outcomes. Evidence is needed on the effectiveness of locally-developed partnerships which target changes in individual health outcomes and behaviours.

Objectives: To evaluate the effects of interagency collaboration between local health and local government agencies on health outcomes.

Radically different amyloid conformations dictate the seeding specificity of a chimeric Sup35 prion.

A remarkable feature of prion biology is that the same prion protein can misfold into more than one infectious conformation, and these conformations in turn lead to distinct heritable prion strains with different phenotypes. The yeast prion [PSI(+)] is a powerful system for studying how changes in strain conformation affect cross-species transmission. We have previously established that a chimera of the Saccharomyces cerevisiae (SC) and Candida albicans (CA) Sup35 prion domains can cross the SC/CA species barrier in a strain-dependent manner.