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Deep learning has great potential for accurate detection and classification of diseases with medical imaging data, but the performance is often limited by the number of training datasets and memory requirements. In addition, many deep learning models are considered a "black-box," thereby often limiting their adoption in clinical applications. To address this, we present a successive subspace learning model, termed VoxelHop, for accurate classification of Amyotrophic Lateral Sclerosis (ALS) using T2-weighted structural MRI data. Compared with popular convolutional neural network (CNN) architectures, VoxelHop has modular and transparent structures with fewer parameters without any backpropagation, so it is well-suited to small dataset size and 3D imaging data. Our VoxelHop has four key components, including (1) sequential expansion of near-to-far neighborhood for multi-channel 3D data; (2) subspace approximation for unsupervised dimension reduction; (3) label-assisted regression for supervised dimension reduction; and (4) concatenation of features and classification between controls and patients. Our experimental results demonstrate that our framework using a total of 20 controls and 26 patients achieves an accuracy of 93.48 % and an AUC score of 0.9394 in differentiating patients from controls, even with a relatively small number of datasets, showing its robustness and effectiveness. Our thorough evaluations also show its validity and superiority to the state-of-the-art 3D CNN classification approaches. Our framework can easily be generalized to other classification tasks using different imaging modalities.

Objective: To summarize applications of muscle magnetic resonance imaging (MRI) in cross-sectional assessment and longitudinal monitoring of motor neuron diseases and evaluate associations with clinical assessment techniques.Methods: PubMed and Scopus were searched for research published up to May 2021 relating to muscle MRI in motor neuron diseases, according to predefined inclusion and exclusion criteria. Studies were systematically appraised for bias and data were extracted for discussion.Results: Twenty-eight papers met inclusion criteria. The studies assessed muscle T1- and T2-weighted signal, diffusion, muscle volume, and fat infiltration, employing quantitative, qualitative, and semi-quantitative approaches. Various regions of interest were considered; changes in thigh and calf muscles were most frequently reported. Preliminary evidence of concordance between clinical and radiological findings and utility as an objective longitudinal biomarker is emerging.Conclusion: Muscle MRI appears a promising objective, versatile, and practical biomarker to assess motor neuron diseases.

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) share a common molecular basis: both are associated with CAG-repeat expansion of ATXN2 and TDP-43-positive neuronal cytoplasmic inclusions. To date, the two disorders are viewed as clinically distinct with ALS resulting from 30-33 CAG-repeats and SCA2 from >34 CAG-repeats. We describe a 67-year old with a 32 CAG-repeat expansion of ATXN2 who presented with simultaneous symptoms of ALS and SCA2. Our case demonstrates that the clinical dichotomy between SCA2 and ATXN2-ALS is false. We suggest instead that CAG-repeat expansion length determines the timing of SCA2 clinical symptoms relative to onset of ALS; consistent with this age of onset of SCA2 but not ATXN2-ALS, is dependent upon expansion length. Review of the literature and our local cohort provides evidence for occurrence of ALS in late stage SCA2, which may be under-recognised by clinicians who think of the two diseases as distinct.

The routine clinical integration of individualized objective markers of disease activity in those diagnosed with the neurodegenerative disorder amyotrophic lateral sclerosis is a key requirement for therapeutic development. A large, multicentre, clinic-based, longitudinal cohort was used to systematically appraise the leading candidate biofluid biomarkers in the stratification and potential therapeutic assessment of those with amyotrophic lateral sclerosis. Incident patients diagnosed with amyotrophic lateral sclerosis (n = 258), other neurological diseases (n = 80) and healthy control participants (n = 101), were recruited and followed at intervals of 3–6 months for up to 30 months. Cerebrospinal fluid neurofilament light chain and chitotriosidase 1 and blood neurofilament light chain, creatine kinase, ferritin, complement C3 and C4 and C-reactive protein were measured. Blood neurofilament light chain, creatine kinase, serum ferritin, C3 and cerebrospinal fluid neurofilament light chain and chitotriosidase 1 were all significantly elevated in amyotrophic lateral sclerosis patients. First-visit plasma neurofilament light chain level was additionally strongly associated with survival (hazard ratio for one standard deviation increase in log10 plasma neurofilament light chain 2.99, 95% confidence interval 1.65–5.41, P = 0.016) and rate of disability progression, independent of other prognostic factors. A small increase in level was noted within the first 12 months after reported symptom onset (slope 0.031 log10 units per month, 95% confidence interval 0.012–0.049, P = 0.006). Modelling the inclusion of plasma neurofilament light chain as a therapeutic trial outcome measure demonstrated that a significant reduction in sample size and earlier detection of disease-slowing is possible, compared with using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale. This study provides strong evidence that blood neurofilament light chain levels outperform conventional measures of disease activity at the group level. The application of blood neurofilament light chain has the potential to radically reduce the duration and cost of therapeutic trials. It might also offer a first step towards the goal of more personalized objective disease activity monitoring for those living with amyotrophic lateral sclerosis.

INTRODUCTION: The motor unit size index (MUSIX) may provide insight into reinnervation patterns in diseases such as amyotrophic lateral sclerosis (ALS). However, it is not known if MUSIX detects clinically relevant changes in reinnervation, or if all muscles manifest changes in MUSIX in response reinnervation following motor unit loss. METHODS: 57 patients with ALS were assessed at 3-monthly intervals for 12 months in 4 centres. Muscles examined were abductor pollicis brevis, abductor digiti minimi, biceps brachii and tibialis anterior. Results were split into two groups: muscles with increases in MUSIX and those without. Longitudinal changes in MUSIX, motor unit number index (MUNIX), compound muscle action potential (CMAP) amplitude and medical research council (MRC) strength score were investigated. RESULTS: 133 muscles were examined. 59% of muscles exhibited an increase in MUSIX during the study. Muscles with MUSIX increases lost more motor units (MUNIX decline at 12 months -58%, p

Coronavirus disease 2019 (COVID‐19), a multi‐organ disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), continues to challenge health and care systems around the globe. The pandemic has disrupted acute neurology services and routine patient care and has impacted the clinical course in patients with chronic neurological disease. COVID‐19 appears to have exposed inequalities of societies and healthcare systems and had a disproportionate impact on already vulnerable communities. The next challenge will be to set up initiatives to stop disparities in all aspects related to COVID‐19. From the medical perspective, there is a need to consider inequalities in prevention, treatment and long‐term consequences. Some of the issues of direct relevance to neurologists are summarised. With this appraisal, the European Academy of Neurology NeuroCOVID‐19 Task Force intends to raise awareness of the potential impact of COVID‐19 on inequalities in healthcare and calls for action to prevent disparity at individual, national and supranational levels.

Immunization by means of vaccination is a global health success story, saving millions of lives every year. In this regard, the epidemiology of measles, rabies, polio, rubella, varicella, influenza and mumps infections, all of which can harm the nervous system, could be contained by global vaccination campaigns. In addition, toxoid vaccines against bacterial toxins such as tetanus and diphtheria are indispensable and effective interventions for toxin-mediated neurologic diseases.

Background Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression. Materials and methods A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months. Results MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7–29%, p p p Conclusion MUNIX and relative T2-weighted MR represent objective surrogate markers of progressive denervation in MND. Radiological changes were maximal in leg muscles, irrespective of clinical onset-site.

Background Glutathione (GSH) is an important brain antioxidant and a number of studies have reported its measurement by edited and nonedited localized 1 H spectroscopy techniques within a range of applications in healthy volunteers and disease states. Good test-retest reproducibility is key when assessing the efficacy of treatments aimed at modulating GSH levels within the central nervous system or when noninvasively assessing changes in GSH content over time. Purpose To evaluate the intraday (in vitro and in vivo) and 1-month apart (in vivo) test-retest reproducibility of GSH measurements from GSH-edited MEGA-PRESS acquisitions at 3 T in a phantom and in the brain of a cohort of middle-aged and older healthy volunteers. Study type Prospective. Subjects/phantoms A phantom containing physiological concentrations of GSH and metabolites with overlapping spectral signatures and 10 healthy volunteers (4 F, 6 M, 55 ± 14 years old). Field strength/sequence GSH-edited spectra were acquired at 3 T using the MEGA-PRESS sequence. Assessment The phantom was scanned twice and the healthy subjects were scanned three times (on two separate days, 1 month apart). GSH was quantified from each acquisition, with the in vivo voxels placed at the primary motor cortex (PMC) and the occipital cortex (OCC). Statistical tests Mean coefficients of variation (CV) were used to assess short-term (in vitro and in vivo) and longer-term (in vivo) test-retest reproducibility. Results In vitro, the CV was 2.3%. In vivo, the mean intraday CV was 3.3% in the PMC and 2.4% in the OCC, while the CVs at 1 month apart were 4.6% in the PMC and 7.8% in the OCC. Data conclusion GSH-edited MEGA-PRESS spectroscopy allows measurement of GSH with excellent precision. Evidence level 1 TECHNICAL EFFICACY: Stage 2.

BackgroundSporadic Parkinson’s disease (sPD) is an aetiologically heterogeneous disorder. Identification of distinct pathogenic mechanisms causing sPD will be crucial to develop future “Precision Medicine” approaches. 31P-MRS is a non-invasive tool that can quantify key bionenergetic metabolites in individual patients.ObjectiveTo determine whether 31P-MRS can identify mitochondrial dysfunction in the midbrain/sub- stantia nigra of individual PD patients and correlates with trial-relevant clinical aspects of PD.Methods31P-MRS spectra were obtained from 35 sPD patients and 25 healthy, age-matched controls. Spectra were analysed using the jMRUI software package and AMARES spectral fitting algorithm. Clinical assessment included widely utilised clinical rating scales, genetic analysis and the calculation of predicted risk of rapid disease progression.ResultsThere was a significantly broader variance in 31P-MRS midbrain ATP with 1/3 of all PD patients having ATP levels > 2 standard deviations outside the mean control values (p=0.0030). Higher midbrain phosphocreatine was associated with greater risk of rapid disease progression (p= 0.0384).Conclusions31P-MRS may help to identify a subgroup of sPD with significant mitochondrial dysfunction or at higher risk of more rapid progression and facilitate stratification for future precision medicine neu- roprotective trials. Longitudinal studies are required to characterise if changes 31P-MRS measures mirror clinical progression.

Background and purpose\ud \ud The recent SARS‐CoV‐2 pandemic has posed multiple challenges to the practice of clinical neurology including recognition of emerging neurological complications and management of coexistent neurological diseases. In a fast‐evolving pandemic, evidence‐based studies are lacking in many areas. This paper presents European Academy of Neurology (EAN) expert consensus statements to guide neurologists caring for patients with COVID‐19.\ud \ud \ud Methods\ud \ud A refined Delphi methodology was applied. In round 1, statements were provided by EAN scientific panels (SPs). In round 2, these statements were circulated to SP members not involved in writing them, asking for agreement/disagreement. Items with agreement >70% were retained for round 3, in which SP co‐chairs rated importance on a five‐point Likert scale. Results were graded by importance and reported as consensus statements.\ud \ud \ud Results\ud \ud In round one, 70 statements were provided by 23 SPs. In round two, 259/1061 SP member responses were received. Fifty‐nine statements obtained >70% agreement and were retained. In round three, responses were received from 55 co‐chairs of 29 SPs. Whilst general recommendations related to prevention of COVID‐19 transmission had high levels of agreement and importance, opinion was more varied concerning statements related to therapy.\ud \ud \ud Conclusion\ud \ud This is the first structured consensus statement on good clinical practice in patients with neurological disease during the COVID‐19 pandemic that provides immediate guidance for neurologists. In this fast‐evolving pandemic, a rapid response using refined Delphi methodology is possible, but guidance may be subject to change as further evidence emerges.

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) share a common molecular basis: both are associated with CAG-repeat expansion of

PURPOSE Whilst core curricula in neurology are nationally standardised, in real-world clinical practice, different approaches may be taken by individual consultants. The aims of this study were to investigate differences by assessing: (a) variance in diagnostic and investigative practice, using a case-based analysis of inter-rater agreement; (b) potential importance of any differences in terms of patient care; (c) relationships between clinical experience, diagnostic certainty, diagnostic peer-agreement and investigative approach. The objective was to develop novel individualised metrics to facilitate reflection and appraisal. METHODS Three neurologists with 6-23 years' experience at consultant level provided diagnosis, certainty (10-point Likert scale), and investigative approach for 200 consecutive general neurology outpatients seen by a newly qualified consultant in 2015. Diagnostic agreement was evaluated by percentage agreement. The potential importance of any diagnostic differences on patient outcome was assigned a score (6-point Likert scale) by the evaluating neurologist. Associations between diagnostic agreement, certainty and investigative approach were assessed using Spearman correlation, logistic and ordinal regression, and reported as individualised metrics for each rater. RESULTS Diagnostic peer-agreement was 3/3, 2/3 and 1/3 in 55.5%, 31.0% and 13.5% of cases, respectively. In 15.5%, differences in patient management were judged potentially important. Investigation rates were 42%-73%. Mean diagnostic certainty ranged from 6.63/10 (SD 1.98) to 7.72/10 (SD 2.20) between least and most experienced consultants. Greater diagnostic certainty was associated with greater diagnostic peer-agreement (individual-rater regression coefficients 0.33-0.44, P

IntroductionThere are no disease-modifying treatments for Parkinson’s disease (PD). We undertook the first drug screen in PD patient tissue and idntified ursodeoxycholic acid (UDCA) as a promising mitochondrial rescue agent. The aims of this trial are to determine safety and tolerability of UDCA in PD at 30 mg/kg, confirm the target engagement of UDCA, apply a novel motion sensor-based approach to quantify disease progression objectively, and estimate the mean effect size and its variance on the change in motor severity.Methods and analysisThis is a phase II, two-centre, double-blind, randomised, placebo-controlled trial of UDCA at a dose of 30 mg/kg in 30 participants with early PD. Treatment duration is 48 weeks, followed by an 8-week washout phase. Randomisation is 2:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48 and 56. The primary outcome is safety and tolerability. Secondary outcomes will compare the change between baseline and week 48 using the following three approaches: the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part 3 in the practically defined ‘OFF’ medication state; confirmation of target engagement, applying 31Phosphorus MR Spectroscopy to assess the levels of ATP and relevant metabolites in the brain; and objective quantification of motor impairment, using a validated, motion sensor-based approach. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups. For each secondary outcome, the change from baseline will be summarised within treatment groups using summary statistics and appropriate statistical tests assessing for significant differences. All outcomes will use an intention-to-treat analysis population.Ethics and disseminationThis trial has been approved by the East of England – Cambridgeshire and Hertfordshire Research Ethics committee. Results will be disseminated in peer-reviewed journals, presentations at scientific meetings and to patients in a lay-summary format.Trial registration numberNCT03840005.

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in people living with amyotrophic lateral sclerosis using phosphorus-31 magnetic resonance spectroscopy, the modality of choice to assess energy metabolism in vivo. We recruited twenty patients and 10 healthy age and gender-matched controls in this cross-sectional clinico-radiological study. Phosphorus-31 magnetic resonance spectroscopy was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: adenosine triphosphate, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of adenosine triphosphate hydrolysis, phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in brainstem where Gibbs free energy of adenosine triphosphate hydrolysis and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting Gibbs free energy of adenosine triphosphate hydrolysis, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in amyotrophic lateral sclerosis in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. Phosphorus-31 magnetic resonance spectroscopy represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in amyotrophic lateral sclerosis and a potential tool for future clinical trials targeting bioenergetic dysfunction.

ObjectiveTo assess clinical, electrophysiological and whole-body muscle MRI measurements of progression in patients with motor neuron disease (MND), as tools for future clinical trials, and to probe pathophysiological mechanisms in vivo.MethodsA prospective, longitudinal, observational, clinicoelectrophysiological and radiological cohort study was performed. Twenty-nine patients with MND and 22 age-matched and gender-matched healthy controls were assessed with clinical measures, electrophysiological motor unit number index (MUNIX) and T2-weighted whole-body muscle MRI, at first clinical presentation and 4 months later. Between-group differences and associations were assessed using age-adjusted and gender-adjusted multivariable regression models. Within-subject longitudinal changes were assessed using paired t-tests. Patterns of disease spread were modelled using mixed-effects multivariable regression, assessing associations between muscle relative T2 signal and anatomical adjacency to site of clinical onset.ResultsPatients with MND had 30% higher relative T2 muscle signal than controls at baseline (all regions mean, 95% CI 15% to 45%, pConclusionsWhole-body muscle MRI offers a new approach to objective assessment of denervation over short timescales in MND and enables investigation of patterns of disease spread in vivo. Muscles inaccessible to conventional clinical and electrophysiological assessment may be investigated using this methodology.

Background and purpose: Although the main clinical features of COVID-19 infection are pulmonary, several associated neurological signs, symptoms and diseases are emerging. The incidence and characteristics of neurological complications are unclear. For this reason, the European Academy of Neurology (EAN) core COVID-19 Task Force initiated a survey on neurological symptoms observed in patients with COVID-19 infection. Methods: A 17-question online survey was made available on the EAN website and distributed to EAN members and other worldwide physicians starting on 9 April 2020. Results: By 27 April 2020, proper data were collected from 2343 responders (out of 4199), of whom 82.0% were neurologists, mostly from Europe. Most responders (74.7%) consulted patients with COVID-19 mainly in emergency rooms and in COVID-19 units. The majority (67.0%) had evaluated fewer than 10 patients with neurological manifestations of COVID-19 (neuro COVID-19). The most frequently reported neurological findings were headache (61.9%), myalgia (50.4%), anosmia (49.2%), ageusia (39.8%), impaired consciousness (29.3%) and psychomotor agitation (26.7%). Encephalopathy and acute cerebrovascular disorders were reported at 21.0%. Neurological manifestations were generally interpreted as being possibly related to COVID-19; they were most commonly recognized in patients with multiple general symptoms and occurred at any time during infection. Conclusion: Neurologists are currently and actively involved in the management of neurological issues related to the COVID-19 pandemic. This survey justifies setting up a prospective registry to better capture the prevalence of patients with neuro COVID-19, neurological disease characteristics and the contribution of neurological manifestations to outcome. info:eu-repo/semantics/publishedVersion

Perfluorocarbons' path into soils Covering carbon chains with fluorines has produced a variety of useful nonstick coatings. However, growing concern about the toxicity and extraordinary environmental persistence of the underlying compounds is spurring a search for alternatives. The precise structure of these next-generation alternatives often remains a trade secret. Washington et al. sampled soils in New Jersey and then used mass spectrometry to assign plausible structures—incorporating chlorine and ether segments into the CF 2 chain—to compounds that appear to have emanated from their manufacture (see the Policy Forum by Gold and Wagner). The data can inform in-depth studies of these compounds' environmental transport and persistence. Science , this issue p. 1103 ; see also p. 1066

Objectives: To identify the cognitive and functional deficits in a well-characterized group of patients with vasculitis of the nervous system. Methods: Sixty-seven patients diagnosed with Central Nervous System (CNS) or Peripheral nervous System (PNS) vasculitis over a 14-year period were retrospectively identified. Data on clinical presentation, laboratory, radiographic and tissue biopsy investigations, and treatment were collated. Cognitive, functional and quality of life evaluation assessments were performed in 31 patients who agreed to participate and included Addenbrooke's Cognitive Examination-revised (ACE-R), Nottingham Extended Activities of Daily Living (NEADL) and EQ-5D-3L quality of life questionnaires. Results: CNS vasculitis patients exhibited cognitive impairment, with a mean ACE-R score of 74/100 (standard deviation (SD) 16). NEADL and EQ-5D-3L scores were in the impaired range at 41/66 (SD 21) and 57/81 (SD 22), respectively. Patients with just PNS vasculitis exhibited fewer cognitive deficits with ACE-R and NEADL scores of 87 (SD 8) and 46 (SD 16) respectively. EQ-5D-3L score was in the impaired range of 65 (SD 22). Conclusions: Vasculitis of the nervous system and, in particular, CNS vasculitis causes cognitive impairment and deficits in functional ability. Such patients should be targeted for cognitive rehabilitation.

Motor neuron disease can be viewed as an umbrella term describing a heterogeneous group of conditions, all of which are relentlessly progressive and ultimately fatal. The average life expectancy is 2 years, but with a broad range of months to decades. Biomarker research deepens disease understanding through exploration of pathophysiological mechanisms which, in turn, highlights targets for novel therapies. It also allows differentiation of the disease population into sub-groups, which serves two general purposes: (a) provides clinicians with information to better guide their patients in terms of disease progression, and (b) guides clinical trial design so that an intervention may be shown to be effective if population variation is controlled for. Biomarkers also have the potential to provide monitoring during clinical trials to ensure target engagement. This review highlights biomarkers that have emerged from the fields of systemic measurements including biochemistry (blood, cerebrospinal fluid, and urine analysis); imaging and electrophysiology, and gives examples of how a combinatorial approach may yield the best results. We emphasize the importance of systematic sample collection and analysis, and the need to correlate biomarker findings with detailed phenotype and genotype data.

Introduction The contribution of cranial and thoracic region electromyography (EMG) to diagnostic criteria for amyotrophic lateral sclerosis (ALS) has not been evaluated. Methods Clinical and EMG data from each craniospinal region were retrospectively assessed in 470 patients; 214 had ALS. Changes to diagnostic classification in Awaji-Shima and revised El Escorial criteria after withdrawal of cranial/thoracic EMG data were ascertained. Results Sensitivity for lower motor neuron involvement in ALS was highest in the cervical/lumbar regions; specificity was highest in cranial/thoracic regions. Cranial EMG contributed to definite/probable Awaji-Shima categorization in 1.4% of patients. Thoracic EMG made no contribution. For revised El Escorial criteria, cranial and thoracic data reclassified 1% and 5% of patients, respectively. Conclusion Cranial EMG data make small contributions to both criteria, whereas thoracic data contribute only to the revised El Escorial criteria. However, cranial and thoracic region abnormalities are specific in ALS. Consideration should be given to allowing greater diagnostic contribution from thoracic EMG. Muscle Nerve 54: 378-385, 2016.

MSS and TI: Dhaka is the capital of Bangladesh (figure 1) and the fifth largest city by population in the world. It is home to more than 14 million people and to the National Institute of Neurosciences & Hospital (NINS), a government-run neurological centre of excellence, recognised with the health minister’s best performance award for the past 3 consecutive years, since inauguration in 2012. Patients with neurological disorders from all over the country access the hospital resulting in ever-increasing caseloads. There were more than 268 000 outpatient visits and 36 000 emergency visits last year to a hospital with 450 beds, staffed by 13 professors, 19 associate professors, 34 assistant professors, 11 registrars and medical officers. Figure 1 Map of Asia (A) showing location of Bangladesh (B) Table reports national statistics for Bangladesh. Images adapted from free Wikimedia Commons (free access). Specialised outpatient clinics are run by senior neurologists. Patient registration costs 10 taka (approximately 9 pence). Experienced neurologists may see more than a hundred patients in each clinic per day, meaning that consultations are extremely focused, each lasting only a few minutes, and require a high level of clinical acumen. Waiting times can be long. Outpatient services run from 8:30 until 14:30 6 days a week and emergency services are open 24/7. NINS has both paying and non-paying beds. Paying bed costs are 275 taka per day including food (£2.50). Most medication is free …

Invasive species pose a threat to global biodiversity. Recently there has been a growth in research into the chemical aspect of invasions, with some plants reported to introduce compounds to the soil which impair the growth of competing native plants. One such species is Rhododendron ponticum, which has become a damaging invasive shrub in Britain. Here we investigate whether water-soluble compounds introduced from R. ponticum leaves in Ceredigion, Wales, suppressed seed germination, and whether this varied temporally. Leachates from leaf material collected monthly (March to July) were analysed for their chemical composition by liquid chromatography-mass spectrometry and Lactuca sotiva bioassays. In total, 19 compounds were identified, displaying both qualitative and quantitative seasonal variation. Total concentrations peaked in June, however L sativa germination inhibition was only found in leachates from April and May (15% and 17% respectively). The study provides evidence that phytotoxic chemical introduction from R. ponticum leaves is seasonal and most bioactive at a time of year when the seeds of other species germinate. We propose this is one of several mechanisms including shading, lowering of soil pH and the deposition of thick litter, that this species exploits when in competition with other species. We argue that for studies on the phytotoxicity of invasive plants, there is a need to consider temporal variation in the rate and quality of bioactive chemicals produced and released, local precipitation rates, persistence of chemicals in the soil plus synergistic interactions between individual chemicals.

Analytical data for ultra-high-performance liquid chromatography (UHPLC), nontargeted, high-resolution, mass-spectrometry (HR/MS) molecular features from a wide array of samples are used to calculate (13)C(1)(12)C((n-1))/(12)C(n) isotopologue ratios. These ratios increase with molecular carbon number roughly following a trend defined by atmospheric carbon. When the effective source reservoir (13)C/(12)C ratio is calculated from the isotopologue ratio (assuming a fractionation factor of unity), features in biotic samples uniformly are tightly grouped, proximate to atmospheric (13)C/(12)C ratio. In contrast, features in soil natural organic matter (NOM), dust NOM and anthropogenic compounds range from proximate to relatively divergent from atmospheric (13)C/(12)C. For the NOM, (13)C/(12)C ratios are consistent with an expected preferential volatilization of (12)C, rendering features in soil NOM (13)C-enriched and some features in dust NOM (13)C-depleted. Anthropogenic compounds tend to diverge most dramatically from atmospheric (13)C/(12)C, generally toward (13)C-depletion, but pesticides we tested tended toward (13)C-enriched. This pattern is robust and evident in: i) anthropogenic vs natural features in dust; ii) perfluorinated compounds in standards and as soil contaminants; and iii) sunscreen compounds in commercial products and wastewater. Considering the observed wide (13)C/(12)C range for anthropogenic compounds, we suggest Rayleigh distillation during synthetic processes commonly favors one isotope over the other, rendering a source reservoir that is progressively depleted as synthesis proceeds and, consequently, generates a wide variation in (13)C/(12)C for man-made products. However, kinetic-isotopic effects and/or synthesis from petroleum/natural gas might contribute to the anthropogenic isotopic signature as well. Regardless of cause, (13)C/(12)C can be used to cull HR/MS molecular features that are more likely to be of anthropogenic or non-biotic origin.

Background Clinical phenotypic heterogeneity represents a major barrier to trials in motor neuron disease (MND) and objective surrogate outcome measures are required, especially for slowly progressive patients. We assessed responsiveness of clinical, electrophysiological and radiological muscle-based assessments to detect MND-related progression. Materials and methods A prospective, longitudinal cohort study of 29 MND patients and 22 healthy controls was performed. Clinical measures, electrophysiological motor unit number index/size (MUNIX/MUSIX) and relative T2- and diffusion-weighted whole-body muscle magnetic resonance (MR) were assessed three times over 12 months. Multi-variable regression models assessed between-group differences, clinico-electrophysiological associations, and longitudinal changes. Standardized response means (SRMs) assessed sensitivity to change over 12 months. Results MND patients exhibited 18% higher whole-body mean muscle relative T2-signal than controls (95% CI 7–29%, p

Fluorotelomer-based polymers (FTPs) are the main product of the fluorotelomer industry. For nearly 10 years, whether FTPs degrade to form perfluorooctanoate (PFOA) and perfluorocarboxylate (PFCA) homologues has been vigorously contested. Here we show that circum-neutral abiotic hydrolysis of a commercial FTP proceeds with half-life estimates of 55-89 years and that base-mediated hydrolysis overtakes neutral hydrolysis at about pH = 10, with a half-life of ~0.7 years at pH ∼ 12. Considered in light of the large production volume of FTPs and the poor efficacy of conventional treatments for recovery of PFCAs from waste streams, these results suggest that FTPs manufactured to date potentially could increase PFCAs 4- to 8-fold over current oceanic loads, largely depending on the integrity of disposal units to contain PFCAs upon hydrolytic generation from FTPs.

A pair of homologous series of polyfluorinated degradation products have been identified, both having structures similar to perfluorocarboxylic acids but (i) having a H substitution for F on the α carbon for 2H polyfluorocarboxylic acids (2HPFCAs) and (ii) bearing a double bond between the α-β carbons for the unsaturated PFCAs (2uPFCAs). Obtaining an authentic sample containing 2uPFOA and 2HPFOA, we optimized a mass-spectrometric multiple-reaction-monitoring (MS/MS) technique and then identified uPFCA and HPFCA homologous series in sludge-applied agricultural soils and fodder grasses for cattle grazing. Analysis of samples from a degradation experiment of commercial fluorotelomer-based polymers (FTPs), the dominant product of the fluorotelomer industry, confirmed that commercial FTPs are a potential source of uPFCAs and HPFCAs to the environment. We further confirmed the identity of the uPFCAs by imposing high-energy ionization to decarboxylate the uPFCAs then focused on the fluorinated chains in the first MS quadrupole. We also employed this high-energy ionization to decarboxylate and analyze PFCAs by MS/MS (for the first time, to our knowledge). In exploratory efforts, we report the possible detection of unsaturated perfluorooctanesulfonate in environmental samples, having a conceptual double-bond structure analogous to uPFOA. Using microcosms spiked with fluorotelomer compounds, we found 2uPFOA and 2HPFOA to be generated from unsaturated 8:2 fluorotelomer acid (8:2 FTUCA) and propose β- and α-oxidation mechanisms for generation of these compounds from 8:2 FTUCA. In light of these experimental results, we also reexamined the proposed biodegradation pathways of 8:2 fluorotelomer alcohol.

There is strong evidence of a key role for mitochondrial dysfunction in both sporadic and all forms of familial Parkinson's disease (PD). However, none of the clinical trials carried out with putative mitochondrial rescue agents has been successful. Firm establishment of a wet biomarker or a reliable readout from imaging studies detecting mitochondrial dysfunction and reflecting disease progression is also awaited. We will provide an overview of our current knowledge about mitochondrial dysfunction in PD and related drug screens. We will also summarize previously undertaken mitochondrial wet biomarker studies and relevant imaging studies with particular focus on 31P-MRI Spectroscopy. We will conclude with an overview of clinical trials which tested putative mitochondrial rescue agents in PD patients. Parkinson's disease is a common, relentlessly progressive neurodegenerative disorder. The pathological hallmark is loss of dopaminergic neurons in the substantia nigra. The resulting motor presentation includes rest tremor, bradykinesia and rigidity but the importance of non-motor symptoms such as cognitive impairment and depression is increasingly recognized, too. Currently available dopaminergic treatment often only addresses the motor impairment partially. This review will summarize our current knowledge about mitochondrial dysfunction as a key target for disease-modifying treatment for PD. We will also provide an update on mitochondrial readouts in PD patients, namely imaging and putative mitochondrial biomarkers, which may become highly relevant in the context of future drug trials. This article is protected by copyright. All rights reserved.

Introduction Nocebo is very prevalent among neurological disorders, resulting in low adherence and treatment outcome. We sought to examine the adverse events (AE) following placebo administration in placebo-controlled randomized clinical trials (RCTs) for chronic inflammatory demyelinating polyneuropathy (CIDP). Methods After a systematic literature search for RCTs for CIDP pharmacotherapy treatments, we assessed the number of AE in the placebo groups and the number discontinuations because of placebo intolerance. Results Our literature search strategy revealed 82 papers. Data were extracted from three RCTs fulfilling our inclusion criteria. Approximately two in five placebo-treated patients (42.0%) reported at least one AE and approximately one in fifty placebo-treated patients discontinued placebo treatment because of AEs (2.1%). All patients participating in the CIDP trials reported similar AEs independently of the study arm they belonged. Conclusion Compared to other neurological diseases the nocebo effect in CIDP is significantly smaller.

We discuss two adult siblings who presented with symptoms of myalgia and rhabdomyolysis following exercise with myoglobinuria; genetic testing confirmed carnitine palmitoyltransferase II deficiency and resulted in institution of appropriate crisis management and dietary advice. We explore the phenotypic variability of this commonest fatty oxidation defect that remains under-diagnosed in the adult population and provide clues for early recognition and diagnosis., Highlights • CPT II deficiency should be considered as an important differential diagnosis in individuals presenting with recurrent or even single attacks of muscle weakness. • If the clinical history includes ‘unexplained’ rhabdomyolysis, clinicians should have a low threshold to perform plasma acylcarnitine analysis as a first line investigation, especially in the context of elevated CK. • Confirmatory diagnosis is by identification of disease-causing variants in CPT2 through targeted testing. • It is important that these individuals have specialist dietary advice and annual monitoring.

BackgroundThe anatomical location of the earliest damage in amyotrophic lateral sclerosis (ALS) is still debated. Two main competing hypotheses have been proposed: the dying-forward hypothesis states the damage occurs in the precentral gyrus (PCG) and spreads caudally, which is in contrast with the dying-back hypothesis. This study aims to address this question of directionality of neurodegeneration in vivo using a multimodal neuroimaging approach to derive measures of damage of the motor pathway and analyse them in a common domain.MethodsMRI was performed on 78 ALS patients and 13 controls. PCG thickness was derived from using FreeSurfer, corticospinal tract (CST) fractional anisotropy (FA) from diffusion tensor imaging using FSL, and axial C3 cord area estimates using Philips online software. Comparisons between patients and controls were reported using unpaired t-tests. Parameter estimates were converted to z-scores, referenced to control data, plotted from PCG through CST to cord and directionality of damage assessed by fitting a mixed-effects linear regression model.ResultsZ-scores were not significantly different between PCG and FA (0.24,[95%CI -0.13,0.61], p=0.208) but were significantly lower in FA compared to cross-sectional cord area (-0.85,[95%CI -1.25,-0.46] pDiscussionThis novel multimodal imaging approach supports a dying-forward neurodegenerative process in ALS.

Labetalol is frequently prescribed for the treatment of hypertension during pregnancy; however, the influence of pregnancy on labetalol pharmacokinetics is uncertain, with inconsistent findings reported by previous studies. This study examined the population pharmacokinetics of oral labetalol during and after pregnancy in women receiving labetalol for hypertension. Data were collected from 57 women receiving the drug for hypertension from the 12th week of pregnancy through 12 weeks postpartum using a prospective, longitudinal design. A sparse sampling strategy guided collection of plasma samples. Samples were assayed for labetalol by high-performance liquid chromatography. Estimation of population pharmacokinetic parameters and covariate effects was performed by nonlinear mixed effects modeling using NONMEM. The final population model was validated by bootstrap analysis and visual predictive check. Simulations were performed with the final model to evaluate the appropriate body weight to guide labetalol dosing. Lean body weight (LBW) and gestational age, i.e. weeks of pregnancy, were identified as significantly influencing oral clearance (CL/F) of labetalol, with CL/F ranging from 1.4-fold greater than postpartum values at 12 weeks’ gestational age to 1.6-fold greater at 40 weeks. Doses adjusted for LBW provide more consistent drug exposure than doses adjusted for total body weight. The apparent volumes of distribution for the central compartment and at steady-state were 1.9-fold higher during pregnancy. Gestational age and LBW impact the pharmacokinetics of labetalol during pregnancy and have clinical implications for adjusting labetalol doses in these women.

PURPOSE OF REVIEW: Acute optic neuritis is a common clinical problem, requiring a structured assessment to guide management and prevent visual loss. The optic nerve is the most accessible part of the central nervous system, so optic neuritis also represents an important paradigm to help decipher mechanisms of damage and recovery in the central nervous system. Important developments include the advent of optical coherence tomography as a biomarker of central nervous system axonal loss, the discovery of new pathological antibodies, notably against aquaporin-4 and, more recently, myelin oligodendrocyte protein, and emerging evidence for sodium channel blockade as a novel therapeutic approach to address energy failure in neuroinflammatory disease. RECENT FINDINGS: We will present a practical approach to assessment of optic neuritis, highlighting the role of optical coherence tomography, when to test for new antibodies and the results of recent trials of sodium channel blockers. SUMMARY: Optic neuritis remains a clinical diagnosis; increasingly optical coherence tomography is a key ancillary investigation. Patients with 'typical' optic neuritis, commonly a first presentation of multiple sclerosis, must be distinguished from 'atypical' optic neuritis, who require testing for new pathological antibodies and require more aggressive-targeted treatment. Sodium channel blockade is an emerging and novel potential therapeutic pathway in neuroinflammatory disease.

The distribution of 32 per/polyfluoroalkyl substances (PFASs) in surface soils was determined at 62 locations representing all continents (North America n = 33, Europe n = 10, Asia n = 6, Africa n = 5, Australia n = 4, South America n = 3 and Antarctica n = 1) using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) systems. Quantifiable levels of perfluoroalkyl carboxylates (PFCAs: PFHxA-PFTeDA) were observed in all samples with total concentrations ranging from 29 to 14,300 pg/g (dry weight), while perfluoroalkane sulfonates (PFSAs: PFHxS, PFOS and PFDS) were detected in all samples but one, ranging from

Concentrations of perfluorinated chemicals (PFCs) were measured in surface waters and sediments from the Coosa River watershed in northwest Georgia, USA, to examine their distribution downstream of a suspected source. Samples from eight sites were analyzed using liquid chromatography-tandem mass spectrometry. Sediments were also used in 28-d exposures with the aquatic oligochaete, Lumbriculus variegatus, to assess PFC bioaccumulation. Concentrations of PFCs in surface waters and sediments increased significantly below a land-application site (LAS) of municipal/industrial wastewater and were further elevated by unknown sources downstream. Perfluorinated carboxylic acids (PFCAs) with eight or fewer carbons were the most prominent in surface waters. Those with 10 or more carbons predominated sediment and tissue samples. Perfluorooctane sulfonate (PFOS) was the major homolog in contaminated sediments and tissues. This pattern among sediment PFC concentrations was consistent among sites and reflected homolog concentrations emanating from the LAS. Concentrations of PFCs in oligochaete tissues revealed patterns similar to those observed in the respective sediments. The tendency to bioaccumulate increased with PFCA chain length and the presence of the sulfonate moiety. Biota-sediment accumulation factors indicated that short-chain PFCAs with fewer than seven carbons may be environmentally benign alternatives in aquatic ecosystems; however, sulfonates with four to seven carbons may be as likely to bioaccumulate as PFOS. Environ. Toxicol. Chem. 2011;30:2194–2201. © 2011 SETAC

Background Non-arteritic anterior ischaemic optic neuropathy (NA-AION) can cause disabling visual loss and traditionally, visual prognosis has been considered poor, although recent studies have demonstrated improvements in visual acuity in about 30% of patients over time. The aim of the study was to determine whether there was significant cortical reorganisation with functional MRI (fMRI) after acute NA-AION by comparing affected individuals with healthy controls. Methods 9 patients with NA-AION were studied acutely and then after 1, 2, 3 and 6 months. 23 healthy volunteers underwent scanning at least twice. At each time point, patients were assessed clinically and with fMRI. For the fMRI experiments, subjects underwent monocular visual stimulation (wearing goggles with flashing LED displays). Results When stimulating the affected eye, occipital activation was reduced in patients compared with controls. Also, within the NA-AION group, activation in the right Brodmann areas (BA) 44 and 45 was seen during the early phase of the condition. The same areas were activated within the NA-AION group several months later for fellow eye stimulation. When the NA-AION and healthy control groups were formally compared however, these areas (BA 44/45) were not significantly different. NA-AION subjects did show greater activation in visual related areas compared with controls when stimulating the fellow eye. Visual acuity was correlated with more occipital cortex activation when stimulating the affected eye. Conclusions There is cortical re-organisation of the fMRI response in extra-visual areas, seen when both affected and fellow eyes are stimulated after NA-AION.

Sludges generated at a wastewater treatment plant (WWTP) in Decatur, Alabama have been applied to agricultural fields for more than a decade. Waste-stream sources to this WWTP during this period included industries that work with fluorotelomer compounds, and sludges from this facility have been found to be elevated in perfluoroalkylates (PFAs). With this knowledge, the U.S. Environmental Protection Agency collected soil samples from sludge-applied fields as well as nearby "background" fields for PFA analysis. Samples from the sludge-applied fields had PFAs at much higher concentrations than in the background fields; generally the highest concentrations were perfluorodecanoic acid (≤ 990 ng/g), perfluorododecanoic acid (≤ 530 ng/g), perfluorooctanoic acid (≤ 320 ng/g), and perfluorooctane sulfonate (≤ 410 ng/g). Contrasts in PFA concentration between surface and deeper soil samples tended to be more pronounced in long-chain congeners than shorter chains, perhaps reflecting relatively lower environmental mobilities for longer chains. Several PFAs were correlated with secondary fluorotelomer alcohols (sec-FTOHs) suggesting that PFAs are being formed by degradation of sec-FTOHs. Calculated PFA disappearance half-lives for C6 through C11 alkylates ranged from about 1 to 3 years and increase with increasing chain-length, again perhaps reflecting lower mobility of the longer-chained compounds.

Soil samples were collected for fluorotelomer alcohol (FTOH) analyses from six fields to which sludge had been applied and one "background" field that had not received sludge. Ten analytes in soil extracts were quantified using GC/MS. Sludge-applied fields had surface soil FTOH concentrations exceeding levels found in the background field. For 8:2nFTOH, which can degrade to perfluorooctanoic acid, impacted surface-soils ranged from 5 to 73 ng/g dry weight, clearly exceeding the background field in which 8:2nFTOH was not detected. The highest [FTOH] generally was 10:2nFTOH, which had concentrations of

The objective was to test three motor system-specific hypotheses in multiple sclerosis patients: (i) corticospinal tract and primary motor cortex imaging measures differ between multiple sclerosis patients and controls; (ii) in patients, these measures correlate with disability; (iii) in patients, corticospinal tract measures correlate with measures of the ipsilateral primary motor cortex. Eleven multiple sclerosis patients with a history of hemiparesis attributable to a lesion within the contralateral corticospinal tract, and 12 controls were studied. We used two advanced imaging techniques: (i) diffusion-based probabilistic tractography, to obtain connectivity and fractional anisotropy of the corticospinal tract; and (ii) FreeSurfer, to measure volume, thickness, surface area, and curvature of precentral and paracentral cortices. Differences in these measures between patients and controls, and relationships between each other and to clinical scores, were investigated. Patients showed lower corticospinal tract fractional anisotropy and smaller volume and surface area of the precentral gyrus than controls. In patients, corticospinal tract connectivity and paracentral cortical volume, surface area, and curvature were lower with increasing disability; lower connectivity of the affected corticospinal tract was associated with greater surface area of the ipsilateral paracentral cortex. Corticospinal tract connectivity and new measures of the primary motor cortex, such as surface area and curvature, reflect the underlying white and grey matter damage that contributes to disability. The correlation between lower connectivity of the affected corticospinal tract and greater surface area of the ipsilateral paracentral cortex suggests the possibility of cortical adaptation. Combining tractography and cortical measures is a useful approach in testing hypotheses which are specific to clinically relevant functional systems in multiple sclerosis, and can be applied to other neurological diseases.

Objectives: To determine whether lateral occipital complex (LOC) activation with functional magnetic resonance imaging (fMRI) predicts visual outcome after clinically isolated optic neuritis (ON). To investigate the reasons behind good recovery following ON, despite residual optic nerve demyelination and neuroaxonal damage.Methods: Patients with acute ON and healthy volunteers were studied longitudinally over 12 months. Structural MRI, visual evoked potentials (VEPs), and optical coherence tomography (OCT) were used to quantify acute inflammation, demyelination, conduction block, and later to estimate remyelination and neuroaxonal loss over the entire visual pathway. The role of neuroplasticity was investigated using fMRI. Multivariable linear regression analysis was used to study associations between vision, structure, and function.Results: Greater baseline fMRI responses in the LOCs were associated with better visual outcome at 12 months. This was evident on stimulation of either eye (p = 0.007 affected; p = 0.020 fellow eye), and was independent of measures of demyelination and neuroaxonal loss. A negative fMRI response in the LOCs at baseline was associated with a relatively worse visual outcome. No acute electrophysiological or structural measures, in the anterior or posterior visual pathways, were associated with visual outcome.Interpretation: Early neuroplasticity in higher visual areas appears to be an important determinant of recovery from ON, independent of tissue damage in the anterior or posterior visual pathway, including neuroaxonal loss (as measured by MRI, VEP, and OCT) and demyelination (as measured by VEP). ANN NEUROL 2010;67:99-113

A fast, rigorous method was developed to maximize the extraction efficacy for ten perfluorocarboxylic acids and perfluorooctanesulfonate from waste-water-treatment sludge and to quantitate using liquid chromatography, tandem-mass spectrometry (LC/MS/MS). First, organic solvents were tested for extraction efficiency, including acetonitrile (ACN), methanol (MeOH), isopropanol (IPA), tetrahydrofuran (THF), and 50/50 ACN/MeOH (v/v). Among the extractants tested, 50/50 ACN/MeOH yielded the best results for our combined criteria of extraction efficacy and solvent-handling convenience. Second, chemical pretreatment prior to solvent extraction was tested with sodium hydroxide (NaOH), potassium hydroxide (KOH), hydrochloric acid (HCl), and potassium persulfate (K(2)S(2)O(8)). Pretreatment with NaOH and HCl effectively recovered additional PFCs from the sludge, but KOH and K(2)S(2)O(8) digestion were less effective than no pretreatment. Third, cleanup methods were investigated with solid-phase extraction using HLB (hydrophilic-lipophilic balanced) and WAX (weak-anion exchange) stationary phases, and with ion-pairing. The HLB stationary phase yielded a slight edge over the other two cleanup strategies in terms of recoverable PFCs and chromatographic separation. Finally, the appropriateness of isotopically labeled PFCs for quantitating unlabeled PFCs using isotopic dilution in complex sludge extracts was evaluated by comparison to results obtained with the standard-addition method. A National Institute of Standards and Technology (NIST) domestic sludge (CRM 2781) was analyzed using our finalized method and compared with previously reported results.

Purpose: To describe and demonstrate a new technique that allows diffusion tensor imaging of small structures such as the spinal cord (SC) and optic nerve (ON) with contiguous slices and reduced image distortions using a narrow field of view (FOV). Materials and Methods: Images were acquired with a modified single-shot echo-planar imaging (EPI) sequence that contains a refocusing radio frequency (RF) pulse in the presence of the phase-encoding (rather than slice-select) gradient. As a result, only a narrow volume may be both excited and refocused. removing the problem of signal aliasing for narrow FOVs. Two variants of this technique were developed: cardiac gating is included in the study of the SC to reduce pulsation artifacts, whereas inversion-recovery (IR) cerebrospinal fluid (CSF) suppression is utilized in the study of the ON to eliminate partial volume effects. The technique was evaluated with phantoms, and mean diffusivity (MD) and fractional anisotropy (FA) measurements were made in the SC and ON of two healthy volunteers. Results: The technique provides contiguous-slice, reduced-FOV images that do not suffer from aliasing and have reduced magnetic susceptibility artifacts. MD and FA values determined here lie within the ranges quoted in the literature. Conclusion: Contiguous-slice zonally orthogonal multislice (CO-ZOOM-EPI is a new technique for diffusion-weighted imaging of small structures such as the ON and SC with high resolution and reduced distortions due to susceptibility variations. This technique is able to acquire contiguous slices that may allow further nerve-tracking analyses.

Methods were developed for the extraction from soil, identification, confirmation and quantitation by LC/MS/MS of trace levels of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA). Whereas PFOA, PFNA and PFDA all can be quantitated using the method of standard additions, PFOA also can be quantitated less laboriously using 13C4-PFOA as a matrix internal standard. The impact of extract matrices on signal varied between soils and temporally during analytical runs rendering 13C4-PFOA unsuitable as a matrix internal standard for quantitating perfluorinated carboxylic acids (PFCAs) other than PFOA, which co-elutes with 13C4-PFOA. In fact, for soil extracts, quantitation of PFCAs based on external calibrations proved about as accurate as use of matrix internal standards for target analytes that do not co-elute with the matrix internal standard. Also, 13C4-PFOA should be used carefully as a matrix internal standard for trace levels of PFOA because some 13C4-PFOA standards contain trace impurities of unlabelled PFOA. When the presence of PFCAs in soil extracts is being determined by LC/MS/MS, detection limits are best defined by statistical methods that quantify the significance of contrast between analytical signal and background noise using multiple analyses. Further, when developing a calibration of low concentrations using weighted regression, the central tendency of the calibration line is best fitted using graphical depictions of error. As the MDL for the transition-product quantitation ion is approached in LC/MS/MS, relatively weak signals of transition-product confirmation ions can be used as a rejection criterion by looking for anomalously high values of the ratio of the confirmation to the quantitation ion.

A 77-year-old woman gave a 10-day history of pain and weakness in her arms and legs, worsening over 12 h. Her muscle aching in the neck, shoulders, back and limbs progressed over the next 48 h; her limbs weakened, and she became unable to walk. She reported intermittent abdominal pain, and had recently lost 12 kg of weight. She had no joint pain or swelling, headache, fever, breathlessness, visual disturbance, bladder or bowel dysfunction. She had travelled to Turkey 3 months before, but was well while away with no insect bites. She had a history of biopsy-proven nodular prurigo and a vestibular schwannoma under observation since 2013. Before admission, she had been very active and took no medications. She was a carer for her husband, and drove her grandchildren to school. There was no relevant family history. On examination, she was in severe pain. The proximal limb muscles were tender to palpation. Tone was normal. There was symmetrical proximal weakness in all four limbs with a give-way component. Reflexes were present, and plantars were flexor. Coordination and sensation were normal. She had a soft systolic murmur, but respiratory and abdominal examinations were normal. She had several skin lesions on her arm, previously diagnosed as nodular prurigo. The joints were normal. Investigations included an erythrocyte sedimentation rate of 35 mm/1st h (

In multiple sclerosis, microstructural damage of normal-appearing brain tissue is an important feature of its pathology. Understanding these mechanisms is vital to help develop neuroprotective strategies. The visual pathway is a key model to study mechanisms of damage and recovery in demyelination. Anterograde trans-synaptic degeneration across the lateral geniculate nuclei has been suggested as a mechanism of tissue damage to explain optic radiation abnormalities seen in association with demyelinating disease and optic neuritis, although evidence for this has relied solely on cross-sectional studies. We therefore aimed to assess: (i) longitudinal changes in the diffusion properties of optic radiations after optic neuritis suggesting trans-synaptic degeneration; (ii) the predictive value of early optic nerve magnetic resonance imaging measures for late optic radiations changes; and (iii) the impact on visual outcome of both optic nerve and brain post-optic neuritis changes. Twenty-eight consecutive patients with acute optic neuritis and eight healthy controls were assessed visually (logMAR, colour vision, and Sloan 1.25%, 5%, 25%) and by magnetic resonance imaging, at baseline, 3, 6, and 12 months. Magnetic resonance imaging sequences performed (and metrics obtained) were: (i) optic nerve fluid-attenuated inversion-recovery (optic nerve cross-sectional area); (ii) optic nerve proton density fast spin-echo (optic nerve proton density-lesion length); (iii) optic nerve post-gadolinium T1-weighted (Gd-enhanced lesion length); and (iv) brain diffusion-weighted imaging (to derive optic radiation fractional anisotropy, radial diffusivity, and axial diffusivity). Mixed-effects and multivariate regression models were performed, adjusting for age, gender, and optic radiation lesion load. These identified changes over time and associations between early optic nerve measures and 1-year global optic radiation/clinical measures. The fractional anisotropy in patients' optic radiations decreased (P = 0.018) and radial diffusivity increased (P = 0.002) over 1 year following optic neuritis, whereas optic radiation measures were unchanged in controls. Also, smaller cross-sectional areas of affected optic nerves at 3 months post-optic neuritis predicted lower fractional anisotropy and higher radial diffusivity at 1 year (P = 0.007) in the optic radiations, whereas none of the inflammatory measures of the optic nerve predicted changes in optic radiations. Finally, greater Gd-enhanced lesion length at baseline and greater optic nerve proton density-lesion length at 1 year were associated with worse visual function at 1 year (P = 0.034 for both). Neither the cross-sectional area of the affected optic nerve after optic neuritis nor the damage in optic radiations was associated with 1-year visual outcome. Our longitudinal study shows that, after optic neuritis, there is progressive damage to the optic radiations, greater in patients with early residual optic nerve atrophy, even after adjusting for optic radiation lesions. These findings provide evidence for trans-synaptic degeneration.