Background: Currently there are no disease modifying treatment for Synucleinopathies including Parkinson’s disease Dementia (PDD). Carrying a mutation in the GBA gene (beta-glucocerebrosidase/ GCAse) is a leading risk factor for synucleinopathies. Raising activity GCAse lowers α-synuclein levels in cells and animal models. Ambroxol is a pharmacological chaperone for GCAse and can raise GCAse levels. Our goal is to test Ambroxol as a disease-modifying treatment in PDD. Methods: We randomized fifty-five individuals with PDD to Ambroxol 1050mg/day, 525mg/day, or placebo for 52 weeks. Primary outcome measures included safety, Alzheimer’s disease Assessment Scale-cognitive (ADAS-Cog) subscale and the Clinician’s Global Impression of Change (CGIC). Secondary outcomes included pharmacokinetics, cognitive and motor outcomes and and plasma and CSF biomarkers. Results: Ambroxol was well tolerated. There were 7 serious adverse events (SAEs) none deemed related to Ambroxol. GCase activity was increased in white blood cells by ~1.5 fold. There were no differences between groups on primary outcome measures. Patients receiving high dose Ambroxol appeared better on the Neuropsychiatric Inventory. GBA carriers appeared to improve on some cognitive tests. pTau 181 was reduced in CSF. Conclusions: Ambroxol was safe and well-tolerated in PDD. Ambroxol may improve biomarkers and cognitive outcomes in GBA1 mutation carrie.rs Ambroxol improved some biomarkerss. ClinicalTrials.gov NCT02914366

Background: Saccade and pupil responses are potential neurodegenerative disease biomarkers due to overlap between oculomotor circuitry and disease-affected areas. Instruction-based tasks have previously been examined as biomarker sources, but are arduous for patients with limited cognitive abilities; additionally, few studies have evaluated multiple neurodegenerative pathologies concurrently. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with Alzheimer’s disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, progressive supranuclear palsy, or Parkinson’s disease (PD). Patients (n=274, age 40-86) and healthy controls (n=101, age 55-86) viewed 10 minutes of frequently changing video clips without instruction while their eyes were tracked. We evaluated differences in saccade and pupil parameters (e.g. saccade frequency and amplitude, pupil size, responses to clip changes) between groups. Results: Preliminary data indicates low-level behavioural alterations in multiple disease cohorts: increased centre bias, lower overall saccade rate and reduced saccade amplitude. After clip changes, patient groups generally demonstrated lower saccade rate but higher microsaccade rate following clip change to varying degrees. Additionally, pupil responses were blunted (AD, MCI, ALS) or exaggerated (PD). Conclusions: This task may generate behavioural biomarkers even in cognitively impaired populations. Future work should explore the possible effects of factors such as medication and disease stage.

Background: Studies of deep brain stimulation (DBS) require accurate electrode localization and image registration. We used anatomical fiducials to investigate localization and registration errors in patients who underwent subthalamic nucleus (STN) DBS for Parkinson’s disease (PD). Methods: We conducted a retrospective analysis of patients who underwent bilateral STN DBS for PD. Pre and post operative MRI scans were non-linearly normalized to a standard template (MNI152NLin2009bAsym). Four raters localized DBS electrodes (Lead-DBS), the anterior commissure (AC) and posterior commissure (PC). Errors between rater localizations were calculated (fiducial localization error; FLE). We transformed AC and PC coordinates from template to patient space to calculate the fiducial registration error (FRE)Results: Ninety-nine patients were analyzed, with a median FLE of 0.76mm, 0.74mm, 0.71mm and 0.66mm for the right electrode, left electrode, AC and PC respectively (no significant difference, Wilcoxon sign rank). The median FRE was 1.59mm for AC and 1.21mm for PC, significantly higher than FLE at those coordinates (Wilcoxon sign rank, p<0.001). Conclusions: Raters can accurately localize DBS electrodes, AC and PC from clinical images with sub-millimetric accuracy. Higher FREs at AC and PC suggested registration errors may contribute more than localization errors to electrode uncertainty in a common space.

Background: Eye movements reveal neurodegenerative disease processes due to overlap between oculomotor circuitry and disease-affected areas. Characterizing oculomotor behaviour in context of cognitive function may enhance disease diagnosis and monitoring. We therefore aimed to quantify cognitive impairment in neurodegenerative disease using saccade behaviour and neuropsychology. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with neurodegenerative disease: one of Alzheimer’s disease, mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, or cerebrovascular disease. Patients (n=450, age 40-87) and healthy controls (n=149, age 42-87) completed a randomly interleaved pro- and anti-saccade task (IPAST) while their eyes were tracked. We explored the relationships of saccade parameters (e.g. task errors, reaction times) to one another and to cognitive domain-specific neuropsychological test scores (e.g. executive function, memory). Results: Task performance worsened with cognitive impairment across multiple diseases. Subsets of saccade parameters were interrelated and also differentially related to neuropsychology-based cognitive domain scores (e.g. antisaccade errors and reaction time associated with executive function). Conclusions: IPAST detects global cognitive impairment across neurodegenerative diseases. Subsets of parameters associate with one another, suggesting disparate underlying circuitry, and with different cognitive domains. This may have implications for use of IPAST as a cognitive screening tool in neurodegenerative disease.

Objective: Multiple system atrophy (MSA) is an incurable neurodegenerative illness in which progressive symptoms, including stridor and acute laryngeal obstruction, occur. Advanced care planning and palliative care discussions in people living with MSA are not well defined. The aim of the present study is to evaluate advanced care planning and current practices in palliative care in MSA to identify opportunities for improving quality of care. Methods: The study is a retrospective chart review assessing the focus and timing of palliative care discussions in people living with MSA. Some 22 charts were reviewed. Results: A total of 22 patients were included. The most common symptoms were parkinsonism, orthostatic hypotension, GI/GU dysfunction, ataxia and gait impairment. Six patients had stridor. Of the palliative care discussions that took place, the most common topics were diagnosis, symptoms or symptom management, and prognosis. In the majority of patients who died and who had a do-not-attempt-resuscitation order, discussions surrounding resuscitation and goals of care took place only hours before death. Conclusions: There is no standard approach to advanced care planning and palliative care discussions in people living with MSA. We propose a framework to guide advanced care planning and palliative care discussions in MSA.

Folate (RBC, serum, CSF) and B12 (serum and CSF) and 5-HIAA and HVA (CSF) concentrations were measured in patients with senile dementia. Those with RBC folate < 130 ng/ml. were given folate/B12 in a double-blind crossover trial. (1) Amine metabolites and folate were unrelated. (2) CSF folate levels rose significantly but slowly on ward diet only independently of the period of intensive replacement. (3) There was no clinical improvement over the 24 weeks of observation but in view of the biochemical findings the period of study may have been too short.

The evaporation and combustion of a single-component fuel droplet which is moving slowly in a hot oxidant atmosphere have been analysed using perturbation methods. Results for the flow field, temperature and species distributions in each phase, inter-facial heat and mass transfer, and the enhancement of the mass burning rate due to the presence of convection have all been developed correct to second order in the translational Reynolds number. This represents an advance over a previous study which analysed the problem to first order in the perturbation parameter. The primary motivation for the development of detailed analytical/numerical solutions correct to second order arises from the need for such a higher-order theory in order to investigate fuel droplet ignition and extinction characteristics in the presence of convective flow. Explanations for such a need, based on order of magnitude arguments, are included in this article. With a moving droplet, the shear at the interface causes circulatory motion inside the droplet. Owing to the large evaporation velocities at the droplet surface that usually accompany drop vaporization and burning, the entire flow field is not in the Stokes regime even for low translational Reynolds numbers. In view of this, the formulation for the continuous phase is developed by imposing slow translatory motion of the droplet as a perturbation to uniform radial flow associated with vigorous evaporation at the surface. Combustion is modelled by the inclusion of a fast chemical reaction in a thin reaction zone represented by the Burke–Schumann flame front. The complete solution for the problem correct to second order is obtained by simultaneously solving a coupled formulation for the dispersed and continuous phases. A noteworthy feature of the higher-order formulation is that both the flow field and transport equations require analysis by coupled singular perturbation procedures. The higher-order theory shows that, for identical conditions, compared with the first-order theory both the flame and the front stagnation point are closer to the surface of the drop, the evaporation is more vigorous, the droplet lifetime is shorter, and the internal vortical motion is asymmetric about the drop equatorial plane. These features are significant for ignition/extinction analyses since the prediction of the location of the point of ignition/extinction will depend upon such details. This article is the first of a two-part study; in the second part, analytical expressions and results obtained here will be incorporated into a detailed investigation of fuel droplet ignition and extinction. In view of the general nature of the formulation considered here, results presented have wider applicability in the general areas of interfacial fluid mechanics and heat/material transport. They are particularly useful in microgravity studies, in atmospheric sciences, in aerosol sciences, and in the prediction of material depletion from spherical particles.

The question as to whether predators preferentially kill sick or disabled individuals has been addressed by many ecologists working with different predator–prey systems. Rau & Caron (1979) showed that heavily infected moose were more susceptible to hunting. Kruuk (1972) observed that hyenas appeared to select sick animals in the Serengeti. Vorisek et al. (1998) demonstrated that voles infected with a species of Frenkelia were taken more frequently by buzzards. As a broad generalization, wherever prey capture is difficult and involves large energy expenditure a greater proportion of sick animals seems to be captured (Fitzgibbon & Fanshawe 1989, Holmes & Bethel 1972, Temple 1987). In a host–parasite association where the prey species is an intermediate host and the predator is the definitive host, the capture of the prey is often an essential part of the life cycle. Therefore any mechanism which makes the prey susceptible to predation would enhance the parasite's fitness. In such relationships the susceptibility induced by the parasite can be very specific to the predator host (Levri 1998). Freedman (1990) suggested that a mutualistic association between the predator and parasite might exist. A mutualistic relationship can be said to exist between a predator and a parasite if the cost of harbouring the parasite is less than the benefit of greater success in catching the prey. There is perhaps no demonstrated example of such a mutualism in natural populations since it is difficult to weigh the parasite cost against the predation benefit.

The frequency of accessory sinus ostia (ASO) has been estimated at between four and 50 per cent in the findings of studies designed for other purposes or from uncontrolled observations. The literature revealed no study specifically designed to determine the prevalence of ASO. We have carried out a prospective cohort study to measure the prevalence of ASO.

The prevalence of ASO was determined in rhinology clinic patients and general ENT clinic controls. Overall ASO occurred in four per cent. Seven per cent of rhinology patients and two per cent of controls had ASO. Of the rhinology patients with rhinitis or sinusitis, eight per cent exhibited ASO. The overall prevalence in this study is lower than most quoted figures in the literature. There was increased prevalence of ASO in patients with rhinitis or sinusitis compared to controls. (p<0.05)

This study should be regarded as a pilot study and further investigations of the relationship between ASO and nasal disease is merited.

We report a case of tracheal stenosis in which a migrated Polyflex (Rusch AG, Germany) stent entered the right main bronchus but could not be identified on the chest radiograph. The stent was identified at bronchoscopy and removed under general anaesthesia.

Polyflex stents are radiopaque but may not always show up on radiograph. We recommend reliance on clinical symptoms rather than imaging to diagnose migration. If stent migration is suspected then imaging should include thoracic inlet films that incorporate a lateral view.

A temporal linear stability analysis has been carried out to predict the instability of a viscous liquid jet surrounded by a swirling air stream with three-dimensional disturbances. The effects of flow conditions and fluid properties on the instability of the liquid jet are investigated via a parametric study by varying axial Weber number axial velocity ratio of the gas to liquid phase, swirl Weber numbers, density ratio and the Ohnesorge number. It is observed that the relative axial velocity between the liquid and gas phases promotes the interfacial instability. As the axial Weber number increases, the growth rates of unstable waves, the most unstable wavenumber and the unstable range of wavenumbers increase. Meanwhile, the increasing importance of helical modes compared to the axisymmetric mode switches the breakup regime from the Rayleigh regime to the first wind-induced regime and on to the second wind-induced regime. The predicted range of wavenumbers in which the first helical mode has higher growth rates than the axisymmetric mode agrees very well with experimental data. Results show that the destabilizing effects of the density ratio and the axial Weber number are nearly the same. Liquid viscosity inhibits the disintegration process of the liquid jet by reducing the growth rate of disturbances and by shifting the most unstable wavenumber to a lower value. Moreover, it damps higher helical modes more significantly than the axisymmetric mode. Air swirl has a stabilizing effect on the liquid jet. As air swirl strength increases, the growth rates of helical modes are reduced more significantly than that of the axisymmetric mode. The air swirl profile is found to have a significant effect on the instability of the liquid jet. The global, as well as local, effects of the swirl profile are examined in detail.

We propose a physical mechanism to explain the origin of the intense burst of massive-star formation seen in physically colliding/ merging, field, spiral galaxies. We consider the detailed evolution of a realistic, two-component interstellar medium (consisting of H2 and Hi) within each galaxy. Also note that, in a typical spiral galaxy - like our Galaxy, the Giant Molecular Clouds (GMCs) are in a near-virial equilibrium and form the current sites of massive-star formation, but the star formation rate is low. We show that this star formation rate is greatly increased following a collision between galaxies. During a collision between two field spiral galaxies, the Hi clouds from the two galaxies undergo collisions at a relative velocity of ∼ 300 km · s−1. However, the GMCs, with their lower volume filling factor, do not collide. The collisions among the Hi clouds lead to the formation of hot, high-pressure remnant gas. The overpressure due to this hot gas causes a radiative shock compression of the outer layers of pre-existing GMCs in the overlapping wedge region. This triggers a burst of massive-star formation in the initially barely stable GMCs. For details, see Jog and Solomon (1990).