The current state of biomarker research for Friedreich's ataxia: a report from the 2018 FARA biomarker meeting

The 2018 FARA Biomarker Meeting highlighted the current state of development of biomarkers for Friedreich's ataxia. A mass spectroscopy assay to sensitively measure mature frataxin (reduction of which is the root cause of disease) is being developed. Biomarkers to monitor neurological disease progression include imaging, electrophysiological measures and measures of nerve function, which may be measured either in serum and/or through imaging-based technologies. Potential pharmacodynamic biomarkers include metabolic and protein biomarkers and markers of nerve damage. Cardiac imaging and serum biomarkers may reflect cardiac disease progression. Considerable progress has been made in the development of biomarkers for various contexts of use, but further work is needed in terms of larger longitudinal multisite studies, and identification of novel biomarkers for additional use cases

Video Game Telemetry as a Critical Tool in the Study of Complex Skill Learning

Cognitive science has long shown interest in expertise, in part because prediction and control of expert development would have immense practical value. Most studies in this area investigate expertise by comparing experts with novices. The reliance on contrastive samples in studies of human expertise only yields deep insight into development where differences are important throughout skill acquisition. This reliance may be pernicious where the predictive importance of variables is not constant across levels of expertise. Before the development of sophisticated machine learning tools for data mining larger samples, and indeed, before such samples were available, it was difficult to test the implicit assumption of static variable importance in expertise development. To investigate if this reliance may have imposed critical restrictions on the understanding of complex skill development, we adopted an alternative method, the online acquisition of telemetry data from a common daily activity for many: video gaming. Using measures of cognitive-motor, attentional, and perceptual processing extracted from game data from 3360 Real-Time Strategy players at 7 different levels of expertise, we identified 12 variables relevant to expertise. We show that the static variable importance assumption is false - the predictive importance of these variables shifted as the levels of expertise increased - and, at least in our dataset, that a contrastive approach would have been misleading. The finding that variable importance is not static across levels of expertise suggests that large, diverse datasets of sustained cognitive-motor performance are crucial for an understanding of expertise in real-world contexts. We also identify plausible cognitive markers of expertise

GHRS and ORFEUS-II Observations of the Highly Ionized Interstellar Medium Toward ESO141-055

We present Goddard High Resolution Spectrograph and ORFEUS-II measurements of Si IV, CIV, N V, and O VI absorption in the interstellar medium of the Galactic disk and halo toward the nucleus of the Seyfert galaxy ESO141-055. The high ionization absorption is strong, with line strengths consistent with the spectral signature expected for hot (log T = 5-6) collisionally ionized gas in either a ``Galactic fountain'' or an inhomogeneous medium containing a mixture of conductive interfaces and turbulent mixing layers. The total O VI column density of log N ~ 15 suggests that the scale height of O VI is large (>3 kpc) in this direction. Comparison of the high ion column densities with measurements for other sight lines indicates that the highly ionized gas distribution is patchy. The amount of O VI perpendicular to the Galactic plane varies by at least a factor of ~4 among the complete halo sight lines thus far studied. In addition to the high ion absorption, lines of low ionization species are also present in the spectra. With the possible exception of Ar I, which may have a lower than expected abundance resulting from partial photoionization of gas along the sight line, the absorption strengths are typical of those expected for the warm, neutral interstellar medium. The sight line intercepts a cold molecular cloud with log N(H2) ~ 19. The cloud has an identifiable counterpart in IRAS 100-micron emission maps of this region of the sky. We detect a Ly-alpha absorber associated with ESO141-055 at z = 0.03492. This study presents an enticing glimpse into the interstellar and intergalactic absorption patterns that will be observed at high spectral resolution by the Far Ultraviolet Spectroscopic Explorer.Comment: 24 pages + 8 figures, uses aaspp4.sty. Accepted for publication in Ap

Dynamics of tongue microbial communities with single-nucleotide resolution using oligotyping

.© The Author(s), 2014. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Frontiers in Microbiology 5 (2014): 568, doi:10.3389/fmicb.2014.00568.The human mouth is an excellent system to study the dynamics of microbial communities and their interactions with their host. We employed oligotyping to analyze, with single-nucleotide resolution, oral microbial 16S ribosomal RNA (rRNA) gene sequence data from a time course sampled from the tongue of two individuals, and we interpret our results in the context of oligotypes that we previously identified in the oral data from the Human Microbiome Project. Our previous work established that many of these oligotypes had dramatically different distributions between individuals and across oral habitats, suggesting that they represented functionally different organisms. Here we demonstrate the presence of a consistent tongue microbiome but with rapidly fluctuating proportions of the characteristic taxa. In some cases closely related oligotypes representing strains or variants within a single species displayed fluctuating relative abundances over time, while in other cases an initially dominant oligotype was replaced by another oligotype of the same species. We use this high temporal and taxonomic level of resolution to detect correlated changes in oligotype abundance that could indicate which taxa likely interact synergistically or occupy similar habitats, and which likely interact antagonistically or prefer distinct habitats. For example, we found a strong correlation in abundance over time between two oligotypes from different families of Gamma Proteobacteria, suggesting a close functional or ecological relationship between them. In summary, the tongue is colonized by a microbial community of moderate complexity whose proportional abundance fluctuates widely on time scales of days. The drivers and functional consequences of these community dynamics are not known, but we expect they will prove tractable to future, targeted studies employing taxonomically resolved analysis of high-throughput sequencing data sampled at appropriate temporal intervals and spatial scales.Supported by National Institutes of Health (NIH) National Institute of Dental and Craniofacial Research Grant DE022586 (to Gary G. Borisy). Daniel R. Utter was supported by the Woods Hole Partnership Education Program; A. Murat Eren was supported by a G. Unger Vetlesen Foundation grant to the Marine Biological Laboratory; David B. Mark Welch was supported by NSF DBI-126259

Age-related mitochondrial DNA depletion and the impact on pancreatic beta cell function

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes

A study of National Health Service management of chronic osteoarthritis and low back pain

AIM: To describe treatment and referral patterns and National Health Service resource use in patients with chronic pain associated with low back pain or osteoarthritis, from a Primary Care perspective. BACKGROUND: Osteoarthritis and low back pain are the two commonest debilitating causes of chronic pain, with high health and social costs, and particularly important in primary care. Understanding current practice and resource use in their management will inform health service and educational requirements and the design and optimisation of future care. METHOD: Multi-centre, retrospective, descriptive study of adults (⩾18 years) with chronic pain arising from low back pain or osteoarthritis, identified through primary care records. Five general practices in Scotland, England (two), Northern Ireland and Wales. All patients with a diagnosis of low back pain or osteoarthritis made on or before 01/09/2006 who had received three or more prescriptions for pain medication were identified and a sub-sample randomly selected then consented to an in-depth review of their medical records (n=264). Data on management of chronic pain were collected retrospectively from patients’ records for three years from diagnosis (‘newly diagnosed’ patients) or for the most recent three years (‘established’ patients). FINDINGS: Patients received a wide variety of pain medications with no overall common prescribing pattern. GP visits represented the majority of the resource use and ‘newly diagnosed’ patients were significantly more likely to visit their GP for pain management than ‘established’ patients. Although ‘newly diagnosed’ patients had more referrals outside the GP practice, the number of visits to secondary care for pain management was similar for both groups. CONCLUSION: This retrospective study confirmed the complexity of managing these causes of chronic pain and the associated high resource use. It provides an in-depth picture of prescribing and referral patterns and of resource use

Coverage of the left subclavian artery during thoracic endovascular aortic repair

BackgroundThoracic aortic stent grafts require proximal and distal landing zones of adequate length to effectively exclude thoracic aortic lesions. The origins of the left subclavian artery and other aortic arch branch vessels often impose limitations on the proximal landing zone, thereby disallowing endovascular repair of more proximal thoracic lesions.MethodsBetween October 2000 and November 2005, 112 patients received stent grafts to treat lesions involving the thoracic aorta. The proximal aspect of the stent graft partially or totally occluded the origin of at least one great vessel in 28 patients (25%). The proximal attachment site was in zone 0 in one patient (3.6%), zone 1 in three patients (10.7%), and zone 2 in 24 patients (85.7%). Patients with proximal implantation in zones 0 or 1 underwent debranching procedures of the supra-aortic vessels before stent graft repair. In one patient who underwent zone 1 deployment, the left subclavian artery was revascularized before stent graft deployment. Among patients who underwent zone 2 deployment with partial or complete occlusion of the left subclavian artery, none underwent prior revascularization. Patients were assessed postoperatively and at follow-up for development of neurologic symptoms as well as symptoms of left upper extremity claudication or ischemia.ResultsMean follow-up was 7.3 months. Among the 24 patients with zone 2 implantation, 10 (42%) had partial left subclavian artery coverage at the time of their primary procedure. A total of 19 patients experienced complete cessation of antegrade flow through the origin of the left subclavian artery without revascularization at the time of the initial endograft repair as a result of a secondary procedure or as a consequence of left subclavian artery thrombosis. Left upper extremity symptoms developed in three (15.8%) patients that did not warrant intervention, and rest pain developed in one (5.3%), which was treated with the deployment of a left subclavian artery stent. Two primary (type IA and type III) endoleaks (7.1%) and one secondary endoleak (type IA) (3.6%) were observed in patients who underwent zone 2 deployment. Three cerebrovascular accidents were observed. Thoracic aortic lesions were successfully excluded in all patients who underwent supra-aortic debranching procedures.ConclusionIntentional coverage of the origin of the left subclavian artery to obtain an adequate proximal landing zone during endovascular repair of thoracic aortic lesions is well tolerated and may be managed expectantly, with some exceptions

Treatment of superficial and perforator venous incompetence without deep venous insufficiency: is routine perforator ligation necessary?

Abstract Purpose We investigated whether routine ligation of incompetent perforator veins is necessary in treatment of symptomatic chronic venous insufficiency (CVI) due to combined superficial and perforator vein incompetence, without deep venous insufficiency. Methods This was a retrospective review of prospectively collected data. Twenty-four limbs with both superficial and perforator venous incompetence but no deep venous insufficiency were identified at venous duplex scanning. Air plethysmography (APG) was performed preoperatively, to obtain venous volume (VV), venous filling index (VFI), ejection fraction (EF), and residual volume fraction (RVF) of the affected limb. Saphenous vein stripping from the groin to knee and powered transilluminated phlebectomy for varicosity ablation were performed in all patients. Postoperatively, all patients underwent duplex scanning and APG to determine the status of the perforator veins and hemodynamic improvement from surgery. Results Average patient age was 55.8 years; 62% of patients were women. CVI was class 3 in 4 limbs, class 4 in 12 limbs, and class 5 and class 6 in 4 limbs each. Postoperative duplex scans demonstrated that 71% of previously incompetent perforator vessels were now competent or absent. Significant improvement in all APG values was documented after superficial surgery. VFI improved from 6.0 ± 2.9 preoperatively to 2.2 ± 1.3 after surgery (P < .001); EF improved from 56.3 ± 18 to 62 ± 21 (P = .02); and RVF improved from 40.1 ± 19 to 28.3 ± 18 (P = .009). Mean preoperative symptom score (5.3 ± 1.9) was significantly improved at mean follow-up of 18.3 months (1.4 ± 1.2; P < .001). Conclusion Patients with superficial and perforator vein incompetence and a normal deep venous system experienced significant improvement in APG-measured hemodynamic parameters and clinical symptom score after superficial ablative surgery alone. This suggests that ligation of the perforator veins can be reserved for patients with persistent incompetent perforator vessels, with abnormal hemodynamic parameters or continued symptoms after superficial ablative surgery

Classic Motor Chunking Theory Fails To Account for Behavioural Diversity and Speed in a Complex Naturalistic Task

In tasks that demand rapid performance, actions must be executed as efficiently as possible. Theories of expert motor performance such as the motor chunking framework suggest that efficiency is supported by automatization, where many serial actions are automatized into smaller chunks, or groups of commonly co-occuring actions. We use the fast-paced, professional eSport StarCraft 2 as a test case of the explanatory power of the motor chunking framework and assess the importance of chunks in explaining expert performance. To do so, we test three predictions motivated by a simple motor chunking framework. (1) StarCraft 2 players should exhibit an increasing number of chunks with expertise. (2) The proportion of actions falling within a chunk should increase with skill. (3) Chunks should be faster than non-chunks containing the same atomic behaviours. Although our findings support the existence of chunks, they also highlight two problems for existing accounts of rapid motor execution and expert performance. First, while better players do use more chunks, the proportion of actions within a chunks is stable across expertise and expert sequences are generally more varied (the diversity problem). Secondly, chunks, which are supposed to enjoy the most extreme automatization, appear to save little or no time overall (the time savings problem). Instead, the most parsimonious description of our latency analysis is that players become faster overall regardless of chunking

Avian thermoregulation in the heat : efficient evaporative cooling in two southern African nightjars

Please read abstract in the article.The DST-NRF Center of Excellence at the Percy FitzPatrick Institute and University of Pretoria.http://link.springer.com/journal/3602018-04-30hj2018Zoology and Entomolog