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Background: Alternatives to antibiotic as growth promoters in agriculture, such as supplemental prebiotics, are required to maintain healthy and high performing animals without directly contributing to antimicrobial resistance bioburden. While the gut microbiota of broiler hens has been well established and successfully correlated to performance, to our knowledge, a study has yet to be completed on the effect of prebiotic supplementation on correlating the mature laying hen productivity and microbiota. This study focused on establishing the impact of a yeast derived prebiotic, mannan rich fraction (MRF), on the cecal microbiota of late laying hens. This study benefitted from large sample sizes so intra- and intergroup variation effects could be statistically accounted for., Results: Taxonomic richness was significantly greater at all taxonomic ranks and taxonomic evenness was significantly lower for all taxonomic ranks in MRF-supplemented birds (P < 0.005). Use of principal coordinate analyses and principal component analyses found significant variation between treatment groups. When assessed for compositional uniformity (an indicator of flock health), microbiota in MRF-supplemented birds was more uniform than control birds at the species level. From a food safety and animal welfare perspective, Campylobacter jejuni was significantly lower in abundance in MRF-supplemented birds. In this study, species associated with high weight gain (an anticorrelator of performance in laying hens) were significantly lower in abundance in laying hens while health-correlated butyrate and propionate producing species were significantly greater in abundance in MRF-supplemented birds., Conclusions: The use of prebiotics may be a key factor in controlling the microbiota balance limiting agri-food chain pathogen persistence and in promoting uniformity. In previous studies, increased α- and β-diversity indices were determinants of pathogen mitigation and performance. MRF-supplemented birds in this study established greater α- and β-diversity indices in post-peak laying hens, greater compositional uniformity across samples, a lower pathogenic bioburden and a greater abundance of correlators of performance., (© 2024. The Author(s).)

Land spreading of animal manure is an essential process in agriculture. Despite the importance of grassland in global food security the potential of the grass phyllosphere as a reservoir of antimicrobial resistance (AMR) is unknown. Additionally, the comparative risk associated with different manure sources is unclear. Due to the One Health nature of AMR there is an urgent need to fully understand the risk associated with AMR at the agriculture - environmental nexus. We performed a grassland field study to assess and compare the relative and temporal impact of bovine, swine and poultry manure application on the grass phyllosphere and soil microbiome and resistome over a period of four months, using 16S rRNA amplicon sequencing and high-throughput quantitative PCR (HT-qPCR). The soil and grass phyllosphere contained a diverse range of antimicrobial resistance genes (ARGs) and mobile genetic elements (MGEs). Manure treatment was found to introduce ARGs belonging to clinically important antimicrobial classes, such as aminoglycoside and sulphonamide into grass and soil. Temporal analysis of ARGs and MGEs associated with manure treatment indicated ARGs patterns were similar across the different manure types in the manure treated soil and grass phyllosphere. Manure treatment resulted in the enrichment in members of the indigenous microbiota and the introduction of manure associated bacteria, with this impact extending past the recommended six-week exclusion period. However, these bacteria were in low relative abundance and manure treatment was not found to significantly impact the overall composition of the microbiome or resistome. This provides evidence that the current guidelines facilitate reduction of biological risk to livestock. Additionally, in soil and grass samples MGEs correlated with ARGs from clinically important antimicrobial classes, indicating the key role MGEs play in horizontal gene transfer in agricultural grassland. These results demonstrate the role of the grass phyllosphere as an under-studied sink of AMR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The broiler gastrointestinal microbiome is a potent flock performance modulator yet may also serve as a reservoir for pathogen entry into the food chain. The goal of this project was to characterise the effect of mannan rich fraction (MRF) supplementation on microbiome diversity and composition of the intestinum tenue and cecum of commercial broilers. This study also aimed to address some of the intrinsic biases that exist in microbiome studies which arise due to the extensive disparity in 16S rRNA gene copy numbers between bacterial species and due to large intersample variation., Results: We observed a divergent yet rich microbiome structure between different anatomical sites and observed the explicit effect MRF supplementation had on community structure, diversity, and pathogen modulation. Birds supplemented with MRF displayed significantly higher species richness in the cecum and significantly different bacterial community composition in each gastrointestinal (GI) tract section. Supplemented birds had lower levels of the zoonotic pathogens Escherichia coli and Clostridioides difficile across all three intestinum tenue sites highlighting the potential of MRF supplementation in maintaining food chain integrity. Higher levels of probiotic genera (eg. Lactobacillus and Blautia) were also noted in the MRF supplemented birds. Following MRF supplementation, the cecum displayed higher relative abundances of both short chain fatty acid (SFCA) synthesising bacteria and SCFA concentrations., Conclusions: Mannan rich fraction addition has been observed to reduce the bioburden of pathogens in broilers and to promote greater intestinal tract microbial biodiversity. This study is the first, to our knowledge, to investigate the effect of mannan-rich fraction supplementation on the microbiome associated with different GI tract anatomical geographies. In addition to this novelty, this study also exploited machine learning and biostatistical techniques to correct the intrinsic biases associated with microbiome community studies to enable a more robust understanding of community structure., (© 2022. The Author(s).)

Introduction. Enterococcus faecium has emerged as an important nosocomial pathogen, which is increasingly difficult to treat due to the genetic acquisition of vancomycin resistance. Ireland has a recalcitrant vancomycin-resistant bloodstream infection rate compared to other developed countries. Hypothesis/Gap statement. Vancomycin resistance rates persist amongst E. faecium isolates from Irish hospitals. The evolutionary genomics governing these trends have not been fully elucidated. Methodology. A set of 28 vancomycin-resistant isolates was sequenced to construct a dataset alongside 61 other publicly available Irish genomes. This dataset was extensively analysed using in silico methodologies (comparative genomics, pangenomics, phylogenetics, genotypics and comparative functional analyses) to uncover distinct evolutionary, coevolutionary and clinically relevant population trends. Results. These results suggest that a stable (in terms of genome size, GC% and number of genes), yet genetically diverse population (in terms of gene content) of E. faecium persists in Ireland with acquired resistance arising via plasmid acquisition ( vanA ) or, to a lesser extent, chromosomal recombination ( vanB ). Population analysis revealed five clusters with one cluster partitioned into four clades which transcend isolation dates. Pangenomic and recombination analyses revealed an open (whole genome and chromosomal specific) pangenome illustrating a rampant evolutionary pattern. Comparative resistomics and virulomics uncovered distinct chromosomal and mobilomal propensity for multidrug resistance, widespread chromosomal point-mutation-mediated resistance and chromosomally harboured arsenals of virulence factors. Interestingly, a potential difference in biofilm formation strategies was highlighted by coevolutionary analysis, suggesting differential biofilm genotypes between vanA and vanB isolates. Conclusions. These results highlight the evolutionary history of Irish E. faecium isolates and may provide insight into underlying infection dynamics in a clinical setting. Due to the apparent ease of vancomycin resistance acquisition over time, susceptible E. faecium should be concurrently reduced in Irish hospitals to mitigate potential resistant infections.

Our study provides novel insights into the global nature of antimicrobial resistance (AMR) plasmids across the food chain. We provide compelling evidence of the globetrotting nature of AMR plasmids and the need for surveillance to sequence plasmids with a template of analyses for others to expand these data. The AMR plasmids analysed were detected in 63 countries and in samples from humans, animals and the environment. They contained a combination of known and novel AMR genes, metal resistance genes, virulence factors, phage and replicon types.

Voluntary rapid eye movements (saccades) redirect the fovea toward objects of visual interest. The saccadic system can be considered as a dual-mode system: in one mode the eye is fixating, in the other it is making a saccade. In this review, we consider two examples of dysfunctional saccades, interrupted saccades in late-onset Tay-Sachs disease and gaze-position dependent opsoclonus after concussion, which fail to properly shift between fixation and saccade modes. Insights and benefits gained from bi-directional collaborative exchange between clinical and basic scientists are emphasized. In the case of interrupted saccades, existing mathematical models were sufficiently detailed to provide support for the cause of interrupted saccades. In the case of gaze-position dependent opsoclonus, existing models could not explain the behavior, but further development provided a reasonable hypothesis for the mechanism underlying the behavior. Collaboration between clinical and basic science is a rich source of progress for developing biologically plausible models and understanding neurological disease. Approaching a clinical problem with a specific hypothesis (model) in mind often prompts new experimental tests and provides insights into basic mechanisms., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A computational system consisting of an urban mobility simulator, validated fluid dynamics and an integral exposure model, is proposed to obtain cyclist and pedestrian exposure to PM x and NO x . Pedestrian activities in the urban anthroposphere include walking and running. The computational experiments take place in a computer-generated urban canyon, subject to emissions from diesel and gasoline Euro 5 and Euro 6 vehicular technologies, in continuous and stop-and-go traffic scenarios, and three wind directions at two speeds. The exposure time in the computational domain of slow and fast pedestrians were obtained. Slow pedestrians had exposure times around 17% more than fast pedestrians due to their higher sidewalk residence time. Runners and cyclists decreased their exposures by 57% and 73% respectively compared with walkers. Two traffic scenarios are implemented: one due the presence of a hump and another without a hump. The presence of the hump, increased exposure and fuel consumption by 60% per heavy duty vehicle, about 44-48% per light duty vehicle and about 54-71% per passenger car. Vehicular technology had a large influence on exposure: Heavy duty-Euro 6 vehicle decreased 86% the exposure to PM 2.5 and 66% to NO X with respect to Euro 5. The proposed computational system provides information on how wind velocity influenced the inhomogeneous pollutant distribution in the street-canyon, causing exposure to be dependent on pedestrian route location. Microscale sidewalk areas in the order of meters containing higher concentrations were thus located. The cleanest routes in the urban canyon were identified. When the wind intensity doubled from 2 to 4 m s -1 , exposure concentration decreased around 45%. The proposed system provides a computational platform to study urban atmospheric fluids, scenarios such as pedestrian routes, vehicular technologies, traffic velocities, meteorological conditions and urban morphology affecting pollution exposure., (Copyright © 2019. Published by Elsevier B.V.)

Traditionally, clinicians have used their experience and intuition to diagnose and treat disease states, including neurological disorders. However, the rapid increase in basic knowledge, coupled with a realization that human judgments are often flawed, has made it helpful to approach many clinical disorders by casting them in the form of models (quantitative hypotheses) that can be tested experimentally; in this way the power of the scientific method can be applied. This is especially the case in systems neuroscience, in which the experimental testing of mathematical models has proven an effective approach to understanding a range of clinical problems. Here, we focus on disorders of the neural control of eye movements, which offer many advantages to clinician scientists, providing examples of how thorny clinical mysteries became much clearer once they were formulated as models, and tested experimentally. Such an approach inevitably raises new questions and experimental tests and may suggest novel therapies., (© 2019 Elsevier B.V. All rights reserved.)

The first models that were proposed to account for the neural control of eye movements applied a classic control systems approach, including feedback, and measured system responses to sinusoidal and transient stimuli. Although such models provided many insights, their limitations were quickly recognized, such as their inability to account for anticipatory responses. Another question was whether models with lumped transfer functions could usefully represent a population of neurons, in which individual units were shown to encode a spectrum of different signals, including resting discharge rates and noise. Recent trends have been towards neural network models and Bayesian operators, which account for observed properties such as the variability of responses and predictive behavior, but often puzzle clinicians by their complexity and non-intuitive operations. We propose that, since all models are incomplete, it makes sense to select the simplest model that can address the topic of interest. We examine two aspects of abnormal ocular motor control, affecting the common integrator for eye movements, and the vestibular velocity storage mechanism. In both cases, we show how classic control systems provided substantial insights into clinical disorders-such as gaze-evoked nystagmus and periodic alternating nystagmus-as well as suggesting new questions, experiments, and potential treatments., (© 2019 Elsevier B.V. All rights reserved.)

Objective: Prompted by the unexpected finding of gadolinium leakage into ocular structures (GLOS) in acute stroke patients, we studied the frequency and nature of this finding in 167 patients., Methods: Patients were selected who had an MRI with gadolinium at baseline and another MRI with fluid-attenuated inversion recovery (FLAIR) imaging at 2 and/or 24 hours later. GLOS was detected as lack of vitreous and/or aqueous fluid suppression on postcontrast FLAIR images., Results: GLOS, evident on postcontrast FLAIR MRI, occurred in 127/167 (76%) patients: 86/109 (79%) patients treated with tissue plasminogen activator and 41/58 (71%) who were untreated. At 2 hours after administration of the contrast, GLOS was more common in the aqueous chamber alone, occurring in 67% of patients, compared to the vitreous chamber alone, seen in 6% of patients; it occurred in both chambers in 27% of patients. At 24 hours, GLOS was present in 121/162 (75%) patients, always involving the vitreous chamber, but also affecting the aqueous chamber in 6% of cases. Vitreous GLOS at 24 hours was associated with increasing age ( p = 0.002) and a higher burden of cerebral white matter hyperintensities ( p = 0.017). Patients with rapid diffuse GLOS, defined as GLOS involving both chambers at 2 hours, had larger infarcts ( p = 0.022) and a higher degree of blood-brain barrier permeability ( p = 0.025)., Conclusions: We found GLOS to be common in patients with acute stroke; delayed GLOS was a marker for chronic vascular disease. The mechanism for acute GLOS remains uncertain but may be a remote effect of acute cerebral injury on the blood-ocular barrier., (© 2018 American Academy of Neurology.)

Recently, an expert system was developed to provide feedback to examiners with the aim of improving reliability of marker-based gait analysis. The purpose of the current study was to evaluate the effectiveness of this novel feedback tool in improving the reliability of gait analysis for individuals with lower limb osteoarthritis. Three-dimensional gait analysis was conducted for n=27 individuals, at two different time points, and during each session the feedback tool was used to refine marker placement. Results for both discrete variables and support vector machine classifications demonstrated improved reliability of the data with the feedback tool., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The potential of inexpensive Metal Oxide Semiconductor (MOS) gas sensors to be used for urban air quality monitoring has been the topic of increasing interest in the last decade. This paper discusses some of the lessons of three years of experience working with such sensors on a novel instrument platform (Small Open General purpose Sensor (SOGS)) in the measurement of atmospheric nitrogen dioxide and ozone concentrations. Analytic methods for increasing long-term accuracy of measurements are discussed, which permit nitrogen dioxide measurements with 95% confidence intervals of 20.0 μ g m - 3 and ozone precision of 26.8 μ g m - 3 , for measurements over a period one month away from calibration, averaged over 18 months of such calibrations. Beyond four months from calibration, sensor drift becomes significant, and accuracy is significantly reduced. Successful calibration schemes are discussed with the use of controlled artificial atmospheres complementing deployment on a reference weather station exposed to the elements. Manufacturing variation in the attributes of individual sensors are examined, an experiment possible due to the instrument being equipped with pairs of sensors of the same kind. Good repeatability (better than 0.7 correlation) between individual sensor elements is shown. The results from sensors that used fans to push air past an internal sensor element are compared with mounting the sensors on the outside of the enclosure, the latter design increasing effective integration time to more than a day. Finally, possible paths forward are suggested for improving the reliability of this promising sensor technology for measuring pollution in an urban environment., Competing Interests: The Zephyr air quality sensor is currently being developed by Earthsense systems Ltd., a company in which Roland Leigh has direct commercial involvement.

Air pollution continues to be a problem in the urban environment. A range of different pollutant mitigation strategies that promote dispersion and deposition exist, but there is little evidence with respect to their comparative performance from both an environmental and economic perspective. This paper focuses on examining different NO 2 mitigation strategies such as trees, buildings facades coated with photocatalytic paint and solid barriers in Oxford Street in London. The case study findings will support ranking the environmental and economic impacts of these different strategies to improve personal exposure conditions on the footpath and on the road in a real urban street canyon. CFD simulations of airflow and NO 2 dispersion in Oxford Street in London were undertaken using the OpenFOAM software platform with the k-ε model, taking into account local prevailing wind conditions. Trees are shown to be the most cost-effective strategy, with a small reduction in NO 2 concentrations of up to 0.7% on the road. However, solid barriers with and without the application of photocatalytic paint and an innovative material (20 times more expensive than trees) can improve air quality on the footpaths more substantially, up to 7.4%, yet this has a significant detrimental impact on NO 2 concentrations (≤23.8%) on the road. Photocatalytic paint on building surfaces presented a minimal environmental reductions (1.2%) and economic (>100 times more expensive than trees) mitigation strategy. The findings recognised the differences between footpath and road concentrations occurred and that a focused examination of three pollution hotspots can provide more cost effective pollution mitigation. This study considers how a number of pollutant mitigation measures can be applied in a single street canyon and demonstrates the strengths and weaknesses of these strategies from economic and environmental perspectives. Further research is required to extrapolate the findings presented here to different street geometries., (Copyright © 2017. Published by Elsevier Ltd.)

A fundamental challenge to the brain is how to prevent intrusive movements when quiet is needed. Unwanted limb movements such as tremor impair fine motor control and unwanted eye drifts such as nystagmus impair vision. A stable platform is also necessary to launch accurate movements. Accordingly, nature has designed control systems with agonist (excitation) and antagonist (inhibition) muscle pairs functioning in push-pull, around a steady level of balanced tonic activity, the set-point Sensory information can be organized similarly, as in the vestibulo-ocular reflex, which generates eye movements that compensate for head movements. The semicircular canals, working in coplanar pairs, one in each labyrinth, are reciprocally excited and inhibited as they transduce head rotations. The relative change in activity is relayed to the vestibular nuclei, which operate around a set-point of stable balanced activity. When a pathological imbalance occurs, producing unwanted nystagmus without head movement, an adaptive mechanism restores the proper set-point and eliminates the nystagmus. Here we used 90 min of continuous 7 T magnetic field labyrinthine stimulation (MVS) in normal humans to produce sustained nystagmus simulating vestibular imbalance. We identified multiple time-scale processes towards a new zero set-point showing that MVS is an excellent paradigm to investigate the neurobiology of set-point adaptation.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'., (© 2017 The Author(s).)

Senescent cancer-associated fibroblasts (CAF) develop a senescence-associated secretory phenotype (SASP) that is believed to contribute to cancer progression. The mechanisms underlying SASP development are, however, poorly understood. Here we examined the functional role of microRNA in the development of the SASP in normal fibroblasts and CAF. We identified a microRNA, miR-335, up-regulated in the senescent normal fibroblasts and CAF and able to modulate the secretion of SASP factors and induce cancer cell motility in co-cultures, at least in part by suppressing the expression of phosphatase and tensin homologue (PTEN). Additionally, elevated levels of cyclo-oxygenase 2 (PTGS2; COX-2) and prostaglandin E2 (PGE2) secretion were observed in senescent fibroblasts, and inhibition of COX-2 by celecoxib reduced the expression of miR-335, restored PTEN expression and decreased the pro-tumourigenic effects of the SASP. Collectively these data demonstrate the existence of a novel miRNA/PTEN-regulated pathway modulating the inflammasome in senescent fibroblasts., Competing Interests: The authors declare no conflicts of interest.

Background: Mild-to-moderate hip osteoarthritis is often managed clinically in a non-surgical manner. Effective non-surgical management of this population requires characterizing the specific impairments within this group. To date, a complete description of all lower extremity kinematics in mild-to-moderate hip osteoarthritis patients has not been presented. The aim of the present study is to describe the lower extremity gait kinematics in mild-to-moderate hip osteoarthritis patients and explore the relationship between kinematics and pain., Methods: 22 subjects with mild-to-moderate radiographic hip osteoarthritis (Kellgren-Lawrence grade 2-3) and 22 healthy age and BMI matched control subjects participated. Kinematic treadmill walking data were collected across all lower extremity joints. A two-way repeated measures analysis of variance estimated mean differences in gait kinematics between groups. Correlations between gait kinematics and pain were assessed using a Spearman correlation coefficient., Findings: Hip osteoarthritis subjects hiked their unsupported hemi-pelvis 1.40° (P<0.001) more than controls and tilted their pelvis 4.65° more anteriorly (P=0.01). Osteoarthritis subjects walked with 4.30° more peak hip abduction (P<0.001), 8.57° less peak hip extension (P<0.001), and 10.54° more peak hip external rotation (P<0.001). Kinematics were related to pain in the ankle frontal plane only (r=-0.43, P<0.05)., Interpretation: Individuals with mild-to-moderate hip osteoarthritis demonstrate altered gait biomechanics not related to pain. These altered biomechanics may represent effective therapeutic targets by clinicians working with this population. Understanding the underlying patho-anatomic changes that lead to these biomechanical changes requires further investigation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Perineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements - saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy., Methods: Together with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses., Results: Excitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation., Interpretation: Our findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease.

Human eyes move continuously, even during visual fixation. These "fixational eye movements" (FEMs) include microsaccades, intersaccadic drift and oculomotor tremor. Research in human FEMs has grown considerably in the last decade, facilitated by the manufacture of noninvasive, high-resolution/speed video-oculography eye trackers. Due to the small magnitude of FEMs, obtaining reliable data can be challenging, however, and depends critically on the sensitivity and precision of the eye tracking system. Yet, no study has conducted an in-depth comparison of human FEM recordings obtained with the search coil (considered the gold standard for measuring microsaccades and drift) and with contemporary, state-of-the art video trackers. Here we measured human microsaccades and drift simultaneously with the search coil and a popular state-of-the-art video tracker. We found that 95% of microsaccades detected with the search coil were also detected with the video tracker, and 95% of microsaccades detected with video tracking were also detected with the search coil, indicating substantial agreement between the two systems. Peak/mean velocities and main sequence slopes of microsaccades detected with video tracking were significantly higher than those of the same microsaccades detected with the search coil, however. Ocular drift was significantly correlated between the two systems, but drift speeds were higher with video tracking than with the search coil. Overall, our combined results suggest that contemporary video tracking now approaches the search coil for measuring FEMs.

The ocular motor system provides several advantages for studying the brain, including well-defined populations of neurons that contribute to specific eye movements. Generation of rapid eye movements (saccades) depends on excitatory burst neurons (EBN) and omnipause neurons (OPN) within the brainstem, both types of cells are highly active. Experimental lesions of EBN and OPN cause slowing or complete loss of saccades. We report a patient who developed a permanent, selective saccadic palsy following cardiac surgery. When she died several years later, surprisingly, autopsy showed preservation of EBN and OPN. We therefore considered other mechanisms that could explain her saccadic palsy. Recent work has shown that both EBN and OPN are ensheathed by perineuronal nets (PN), which are specialized extracellular matrix structures that may help stabilize synaptic contacts, promote local ion homeostasis, or play a protective role in certain highly active neurons. Here, we review the possibility that damage to PN, rather than to the neurons they support, could lead to neuronal dysfunction-such as saccadic palsy. We also suggest how future studies could test this hypothesis, which may provide insights into the vulnerability of other active neurons in the nervous system that depend on PN., (© 2015 New York Academy of Sciences.)

Objectives: To determine whether tester experience influences the reliability of three-dimensional gait collections., Design: Reliability study., Participants: Ten healthy subjects visited a university gait laboratory on two separate days and underwent a walking gait analysis. During each visit, kinematic data were collected by a biomechanist with 8 years of 3D gait analysis experience (EXP) and a physical therapist with no previous 3D gait analysis experience (NOV)., Main Outcome Measures: Joint kinematic angles were calculated using either a functional or predictive joint identification method. Within-tester and between-tester measures of reliability were determined by calculating the root mean square error (RMS) and coefficient of multiple correlations (CMC)., Results: Within-tester RMS and CMC values were not significantly different (P > 0.05) between the EXP and NOV testers using either a functional or predictive joint approach. Within-tester CMC values exceeded 0.90 for both testers across all kinematic variables. Between-tester CMC reliability values were greater than 0.85 for all variables measured., Conclusions: Following basic training, a physiotherapy clinician with no previous 3D gait experience is as reliable as an experienced gait biomechanist with respect to marker placement accuracy. In addition, reliability comparisons between an experienced and novice tester appear independent of the joint identification method chosen., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: During head translations, vestibular eye movements are ∼ 60% of those required to hold the line of sight on target but, during translation of the orbits due to head rotation about an eccentric axis, the eyes are held %eye on target., Objective: To resolve this paradoxical behavior of vestibulo-ocular reflexes., Methods: Subjects sat on a moving platform viewing a near target and were: (1) rotated en bloc in yaw about a vertical axis centered on the head at 1 Hz; (2) rotated with their head displaced ∼ 10 cm anterior (eccentric rotation) at 1 Hz; (3) translated along the inter-aural axis at 1.9 Hz; (4) rotated with the head centered at 1 Hz while they were translated along the inter-aural axis at 1.9 Hz. We calculated compensation ratio (CR): Eye velocity/eye velocity geometrically required to hold the eye on target., Results: During yaw, mean CR was 0.88 and during eccentric rotation CR was 0.93. During translation at 1.9 Hz, CR was 0.65. During combined rotation at 1.0 Hz and translation at 1.9 Hz, CR was 0.81 for head rotations and 0.74 for head translations., Conclusions: Translations of the orbits due to head rotation are better compensated for than translations of the orbits due to head translation. These different behaviors may be determined by context, the important difference being whether the subject is moving through the environment.

Fixation instability due to saccadic intrusions is a feature of autosomal recessive spinocerebellar ataxias, and includes square wave intrusions (SWI) and macrosaccadic oscillations (MSO). A recent report suggested that the non-competitive antagonist of NMDA receptors, memantine, could decrease MSO and improve fixation in patients with spinocerebellar ataxia with saccadic intrusions (SCASI). We similarly tested two sisters, respectively of 58 and 60 years, with an unrecognized form of recessive, adult-onset cerebellar ataxia, peripheral neuropathy and slow saccades, who showed prominent SWI and also complained with difficulty in reading. We tested horizontal visually guided saccades (10°-18°) and three minutes of steady fixation in each patient and in thirty healthy controls. Both patients showed a significant reduction of peak and mean velocity compared with control subjects. Large SWI interrupting steady fixation were prominent during steady fixation and especially following visually guided saccades. Eye movements were recorded before and during the treatment with memantine, 20 mg/daily for 6 months. The treatment with memantine reduced both the magnitude and frequency of SWI (the former significantly), but did not modified neurological conditions or saccade parameters. Thus, our report suggests that memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO, thereby restoring the capacity of reading and visual attention in these and in other recessive forms of ataxia, including Friedreich's, in which saccadic intrusions are prominent.

During attempted visual fixation, saccades of a range of sizes occur. These "fixational saccades" include microsaccades, which are not apparent in regular clinical tests, and "saccadic intrusions", predominantly horizontal saccades that interrupt accurate fixation. Square-wave jerks (SWJs), the most common type of saccadic intrusion, consist of an initial saccade away from the target followed, after a short delay, by a "return saccade" that brings the eye back onto target. SWJs are present in most human subjects, but are prominent by their increased frequency and size in certain parkinsonian disorders and in recessive, hereditary spinocerebellar ataxias. Here we asked whether fixational saccades showed distinctive features in various parkinsonian disorders and in recessive ataxia. Although some saccadic properties differed between patient groups, in all conditions larger saccades were more likely to form SWJs, and the intervals between the first and second saccade of SWJs were similar. These findings support the proposal of a common oculomotor mechanism that generates all fixational saccades, including microsaccades and SWJs. The same mechanism also explains how the return saccade in SWJs is triggered by the position error that occurs when the first saccadic component is large, both in the healthy brain and in neurological disease.

When normal subjects fix their eyes upon a stationary target, their gaze is not perfectly still, due to small movements that prevent visual fading. Visual loss is known to cause greater instability of gaze, but reported comparisons with normal subjects using reliable measurement techniques are few. We measured binocular gaze using the magnetic search coil technique during attempted fixation (monocular or binocular viewing) of 4 individuals with childhood-onset of monocular visual loss, 2 individuals with late-onset monocular visual loss due to age-related macular degeneration, 2 individuals with bilateral visual loss, and 20 healthy control subjects. We also measured saccades to visual or somatosensory cues. We tested the hypothesis that gaze instability following visual impairment is caused by loss of inputs that normally optimize the performance of the neural network (integrator), which ensures both monocular and conjugate gaze stability. During binocular viewing, patients with early-onset monocular loss of vision showed greater instability of vertical gaze in the eye with visual loss and, to a lesser extent, in the normal eye, compared with control subjects. These vertical eye drifts were much more disjunctive than upward saccades. In individuals with late monocular visual loss, gaze stability was more similar to control subjects. Bilateral visual loss caused eye drifts that were larger than following monocular visual loss or in control subjects. Accurate saccades could be made to somatosensory cues by an individual with acquired blindness, but voluntary saccades were absent in an individual with congenital blindness. We conclude that the neural gaze-stabilizing network, which contains neurons with both binocular and monocular discharge preferences, is under adaptive visual control. Whereas monocular visual loss causes disjunctive gaze instability, binocular blindness causes both disjunctive and conjugate gaze instability (drifts and nystagmus). Inputs that bypass this neural network, such as projections to motoneurons for upward saccades, remain conjugate.

An appropriate density of acetylcholine receptors (AChRs) and Na(+) channels (NaChs) in the normal neuromuscular junction (NMJ) determines the magnitude of safety factor (SF) that guarantees fidelity of neuromuscular transmission. In myasthenia gravis (MG), an overall simplification of the postsynaptic folding secondary to NMJ destruction results in AChRs and NaChs depletion. Loss of AChRs and NaChs accounts, respectively, for 59% and 40% reduction of the SF at the endplate, which manifests as neuromuscular transmission failure. The extraocular muscles (EOM) have physiologically less developed postsynaptic folding, hence a lower baseline SF, which predisposes them to dysfunction in MG and development of fatigue during "high performance" eye movements, such as saccades. However, saccades in MG show stereotyped, conjugate initial components, similar to normal, which might reflect preserved neuromuscular transmission fidelity at the NMJ of the fast, pale global fibers, which have better developed postsynaptic folding than other extraocular fibers., (© 2012 New York Academy of Sciences.)

Using electrical stimulation to the deep, most caudal part of the right frontal eye field (FEF), we demonstrate a novel pattern of vertical (upward) eye movement that was previously only thought possible by stimulating both frontal eye fields simultaneously. If stimulation was started when the subject looked laterally, the initial eye movement was back to the midline, followed by upward deviation. Our finding challenges current view of topological organisation in the human FEF and may have general implications for concepts of topological organisation of the motor cortex, since sustained stimulation also induced upward head movements as a component of the vertical gaze shift. [Published with video sequences].

Opinion Statement: Patients with congenital and acquired forms of nystagmus are commonly encountered in clinical practice. Many report visual symptoms, such as oscillopsia and blurred vision, which can be alleviated if the nystagmus can be suppressed. Pharmacologic, optical, and surgical treatments are available, with the choice of treatment depending on the characteristics of the nystagmus and the severity of the associated visual symptoms. Downbeat nystagmus can be treated with 4-aminopyridine, 3,4-diaminopyridine, or clonazepam. Upbeat nystagmus can be reduced with memantine, 4-aminopyridine, or baclofen. Torsional nystagmus may respond to gabapentin. Acquired pendular nystagmus in patients with multiple sclerosis is often partially suppressed by gabapentin or memantine. Acquired pendular nystagmus in patients with oculopalatal tremor can respond to gabapentin, memantine, or trihexyphenidyl. Although acquired periodic alternating nystagmus is often completely suppressed by baclofen, memantine can be effective in refractory cases. Seesaw nystagmus can be reduced with alcohol, clonazepam, or memantine. Infantile nystagmus may not cause significant visual symptoms if "foveation periods" are well developed, but the nystagmus can be treated in symptomatic patients with gabapentin, memantine, acetazolamide, topical brinzolamide, contact lenses, or base-out prisms to induce convergence. Several surgical therapies have also been reported to improve infantile nystagmus syndrome (INS), but selection of the appropriate therapy requires preoperative evaluation of visual acuity and nystagmus intensity in different gaze positions. Other treatment options for nystagmus include botulinum toxin injections into the extraocular muscles or retrobulbar space. Electro-optical devices are currently being developed, in order to noninvasively negate the visual consequences of nystagmus.

Objective: Heightened awareness of Creutzfeldt-Jakob disease (CJD) among physicians and the lay public has led to its frequent consideration in the differential diagnosis of patients with rapidly progressive dementia (RPD). Our goal was to determine which treatable disorders are most commonly mistaken for CJD., Methods: We performed a retrospective clinical and neuropathological review of prion-negative brain autopsy cases referred to the US National Prion Disease Pathology Surveillance Center at Case Western Reserve University from January 2006 through December 2009., Results: Of 1,106 brain autopsies, 352 (32%) were negative for prion disease, 304 of which had adequate tissue for histopathological analysis. Alzheimer disease (n = 154) and vascular dementia (n = 36) were the 2 most frequent diagnoses. Seventy-one patients had potentially treatable diseases. Clinical findings included dementia (42 cases), pyramidal (n = 20), cerebellar (n = 14), or extrapyramidal (n = 12) signs, myoclonus (n = 12), visual disturbance (n = 9), and akinetic mutism (n = 5); a typical electroencephalogram occurred only once. Neuropathological diagnoses included immune-mediated disorders (n = 26), neoplasia (n = 25, most often lymphoma), infections (n = 14), and metabolic disorders (n = 6)., Interpretation: In patients with RPD, treatable disorders should be considered and excluded before diagnosing CJD. Misdiagnosed patients often did not fulfill World Health Organization criteria. RPD with positive 14-3-3 cerebrospinal fluid protein should not be regarded as sufficient for the diagnosis of CJD. Adherence to revised criteria for CJD, which include distinctive magnetic resonance imaging features of prion disease, is likely to improve diagnostic accuracy., (Copyright © 2011 American Neurological Association.)

Disturbance of vertical saccades is a cardinal feature of progressive supranuclear palsy (PSP). We investigated whether the amplitude and peak velocity (PV) of saccades are affected by the orbital position from which movements start in PSP patients and age-matched control subjects. Subjects made vertical saccades in response to ±5° vertical target jumps with their heads in one of three positions: head "center," head pitched forward ∼15°, and head pitched back ∼15°. All patients showed some effect of starting eye position, whether beginning in the upward or downward field of gaze, on saccade amplitude, PV, and net range of movement. Generally, reduction of amplitude and PV were commensurate and bidirectional in the affected hemifield of gaze. Such findings are unlikely to be because of orbital factors and could be explained by varying degrees of involvement of rostral midbrain nuclei in the pathological process., (© 2011 New York Academy of Sciences.)

Prior studies indicate that the human translational vestibulo-ocular reflex (tVOR) generates eye rotations approximately half the magnitude required to keep the line of sight pointed at a stationary object--a compensation ratio (CR) of ∼0.5. We asked whether changes of visual or vestibular stimuli could increase the CR of tVOR. First, subjects viewed their environment through an optical device that required eye movements to increase by ∼50% to maintain fixation of a stationary visual target. During vertical translation, eye movements did increase, but tVOR CR remained at ∼0.5. Second, subjects viewed through LCD goggles providing 4 Hz strobe vision that minimized retinal image motion; this reduced tVOR CR. Finally, subjects were rotated in roll while they translated vertically; no increase in tVOR occurred. Taken with prior studies, we conclude that tVOR is optimally set to generate eye rotations that are about 50% of those required to stabilize the line of sight., (© 2011 New York Academy of Sciences.)