Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction

Botulinum toxin for the treatment of lower limb cramp pain in patients with Amyotrophic Lateral Sclerosis

Background: Muscle cramps and pain associated with them can be seen in patients with amyotrophic lateral sclerosis (ALS) and are known to reduce the quality of life. Pharmacological treatment may not benefit all patients in treating these cramps. We assess the efficacy of Onabotulinum toxin A (BTX-A) in the treatment of lower limb cramps in patients with ALS. Methods: This retrospective chart review included a total of ten patients with ALS who suffered from pain due to lower limb cramps and were managed with BTX-A. Data including patient demographics, visual analog pain scale at different intervals during follow up, ALS functional rating scale and site of onset of ALS symptoms were documented. The pain score at baseline (before administration), at 3 months follow up and at 6 months follow up were compared using Wilcoxon test to assess BTX-A’s efficacy. Results: A significant improvement in average pain score due to cramps from baseline to the 6-month interval with a change of 3.1±0.7 (p<0.05,95%CI) was seen on the pain scale. No adverse events were noted during administration or post injections. Conclusion: Local BTX-A administration is an efficacious and safe procedure for improving pain associated with cramps in patients with ALS

Estimation of 3D vegetation structure from waveform and discrete return airborne laser scanning data

This study presents and compares new methods to describe the 3D canopy structure with Airborne Laser Scanning (ALS) waveform data as well as ALS point data. The ALS waveform data were analyzed in three different ways; by summing the intensity of the waveforms in height intervals (a); by first normalizing the waveforms with an algorithm based on Beer-Lambert law to compensate for the shielding effect of higher vegetation layers on reflection from lower layers and then summing the intensity (b); and by deriving points from the waveforms (c). As a comparison, conventional, discrete return ALS point data from the laser scanning system were also analyzed (d). The study area was located in hemi-boreal, spruce dominated forest in the southwest of Sweden (Lat. 58° N, Long. 13° E). The vegetation volume profile was defined as the volume of all tree crowns and shrubs in 1 dm height intervals in a field plot and the total vegetation volume as the sum of the vegetation volume profile in the field plot. The total vegetation volume was estimated for 68 field plots with 12 m radius from the proportion between the amount of ALS reflections from the vegetation and the total amount of ALS reflections based on Beer-Lambert law. ALS profiles were derived from the distribution of the ALS data above the ground in 1 dm height intervals. The ALS profiles were rescaled using the estimated total vegetation volume to derive the amount of vegetation at different heights above the ground. The root mean square error (RMSE) for cross validated regression estimates of the total vegetation volume was 31.9% for ALS waveform data (a), 27.6% for normalized waveform data (b), 29.1% for point data derived from the ALS waveforms (c), and 36.5% for ALS point data from the laser scanning system (d). The correspondence between the estimated vegetation volume profiles was also best for the normalized waveform data and the point data derived from the ALS waveforms and worst for ALS point data from the laser scanning system as demonstrated by the Reynolds error index. The results suggest that ALS waveform data describe the volumetric aspects of vertical vegetation structure somewhat more accurately than ALS point data from the laser scanning system and that compensation for the shielding effect of higher vegetation layers is useful. The new methods for estimation of vegetation volume profiles from ALS data could be used in the future to derive 3D models of the vegetation structure in large areas

Effects of Instantons on the YN Interaction

We investigate the symmetric and anti-symmetric spin-orbit forces (SLS and ALS) of the effective $\Lambda$N interaction derived from a quark cluster model with the instanton-induced interaction (\III), which can reproduce the observed YN cross sections as well as the observed NN scattering data. It is found that coupling to the $\Sigma$N channel enhances $\Lambda$N ALS, and therefore that the cancellation between SLS and ALS in the $\Lambda$N channel becomes more complete. This may be one of the major reasons why the single-particle spin-orbit force of $\Lambda$ in nuclei is weak.Comment: 3 pages, 2 figures, FewBody XV

Patients with ALS show highly correlated progression rates in left and right limb muscles.

ObjectiveAmyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.MethodsA large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.ResultsThis report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent.ConclusionsFirst, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials

A comparative study of X-ray tomographic microscopy on shales at different synchrotron facilities: ALS, APS and SLS.

Synchrotron radiation X-ray tomographic microscopy (SRXTM) was used to characterize the three-dimensional microstructure, geometry and distribution of different phases in two shale samples obtained from the North Sea (sample N1) and the Upper Barnett Formation in Texas (sample B1). Shale is a challenging material because of its multiphase composition, small grain size, low but significant amount of porosity, as well as strong shape- and lattice-preferred orientation. The goals of this round-robin project were to (i) characterize microstructures and porosity on the micrometer scale, (ii) compare results measured at three synchrotron facilities, and (iii) identify optimal experimental conditions of high-resolution SRXTM for fine-grained materials. SRXTM data of these shales were acquired under similar conditions at the Advanced Light Source (ALS) of Lawrence Berkeley National Laboratory, USA, the Advanced Photon Source (APS) of Argonne National Laboratory, USA, and the Swiss Light Source (SLS) of the Paul Scherrer Institut, Switzerland. The data reconstruction of all datasets was handled under the same procedures in order to compare the data quality and determine phase proportions and microstructures. With a 10× objective lens the spatial resolution is approximately 2 µm. The sharpness of phase boundaries in the reconstructed data collected from the APS and SLS was comparable and slightly more refined than in the data obtained from the ALS. Important internal features, such as pyrite (high-absorbing), and low-density features, including pores, fractures and organic matter or kerogen (low-absorbing), were adequately segmented on the same basis. The average volume fractions of low-density features for sample N1 and B1 were estimated at 6.3 (6)% and 4.5 (4)%, while those of pyrite were calculated to be 5.6 (6)% and 2.0 (3)%, respectively. The discrepancy of data quality and volume fractions were mainly due to different types of optical instruments and varying technical set-ups at the ALS, APS and SLS

Understanding Disease Heterogeneity and Patient Characteristics in Patients with Amyotrophic Lateral Sclerosis (ALS)

Background: Amytrophic lateral sclerosis (ALS) is a fatal neurologic disease that is projected to double in worldwide incidence in the next 20 years. The heterogenic nature of the disease and relatively limited research data, compared to non-rare diseases, have made it difficult for clinician researchers to alter the course of the disease within the short life expectancy after symptom onset. Method: This was a mixed-method retrospective review and live sampling study using three distinct data sources. Retrospective data was abstracted from the electronic medical record systems for a select group of ALS patients seen at the University of California, Irvine Neuromuscular Center (UCI NMC). Additional retrospective datasets curated by the Pooled Resources Open-Access Clinical Trials (PRO-ACT) database were also analyzed. Observational data was collected using a 9-item survey developed on Google Forms and disseminated through the ALS Association Golden West Chapter. The items measured symptom onset, diagnostic journey, and patient demographics.Results: The analyses confirmed current reports of higher disease incidence in Caucasian populations, usually comprising at least 60% of each dataset. The gender prevalence towards males was only observed in the PRO-ACT dataset. There was also a difference in mean age between PRO-ACT (56 years), UCI (61 years), and Online Questionnaire respondents (66 years). Discussion: Ultimately retrospective data analyses were limited by substantial missing, not at random data. Large data repositories can bridge the gap between non-rare and rare disease research, but only with robust and methodologic data collection across all participating sites

Predicting growing stock volume of Eucalyptus plantations using 3-D point clouds derived from UAV imagery and ALS data

Estimating forest inventory variables is important in monitoring forest resources and mitigating climate change. In this respect, forest managers require flexible, non-destructive methods for estimating volume and biomass. High-resolution and low-cost remote sensing data are increasingly available to measure three-dimensional (3D) canopy structure and to model forest structural attributes. The main objective of this study was to evaluate and compare the individual tree volume estimates derived from high-density point clouds obtained from airborne laser scanning (ALS) and digital aerial photogrammetry (DAP) in Eucalyptus spp. plantations. Object-based image analysis (OBIA) techniques were applied for individual tree crown (ITC) delineation. The ITC algorithm applied correctly detected and delineated 199 trees from ALS-derived data, while 192 trees were correctly identified using DAP-based point clouds acquired fromUnmannedAerialVehicles(UAV), representing accuracy levels of respectively 62% and 60%. Addressing volume modelling, non-linear regression fit based on individual tree height and individual crown area derived from the ITC provided the following results: Model E ciency (Mef) = 0.43 and 0.46, Root Mean Square Error (RMSE) = 0.030 m3 and 0.026 m3, rRMSE = 20.31% and 19.97%, and an approximately unbiased results (0.025 m3 and 0.0004 m3) using DAP and ALS-based estimations, respectively. No significant di erence was found between the observed value (field data) and volume estimation from ALS and DAP (p-value from t-test statistic = 0.99 and 0.98, respectively). The proposed approaches could also be used to estimate basal area or biomass stocks in Eucalyptus spp. plantationsinfo:eu-repo/semantics/publishedVersio

Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS)

Background: Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation in CHMP2B was recently identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis. Methodology/Principal Findings: Sequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p. Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA)) variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B. Conclusions/Significance: We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype