135 research outputs found

    Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients

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    Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD

    Long-term blood pressure variability and risk of cognitive decline and dementia among older adults

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    Background: Blood pressure variability (BPV) in midlife increases risk of late-life dementia, but the impact of BPV on the cognition of adults who have already reached older ages free of major cognitive deficits is unknown. We examined the risk of incident dementia and cognitive decline associated with long-term, visit-to-visit BPV in a post hoc analysis of the ASPREE (Aspirin in Reducing Events in the Elderly) trial. Methods and Results: ASPREE participants (N=19 114) were free of dementia and significant cognitive impairment at enrollment. Measurement of BP and administration of a standardized cognitive battery evaluating global cognition, delayed episodic memory, verbal fluency, and processing speed and attention occurred at baseline and follow-up visits. Time-to-event analysis using Cox proportional hazards regression models were used to calculate hazard ratios (HR) and corresponding 95% CI for incident dementia and cognitive decline, according to tertile of SD of systolic BPV. Individuals in the highest BPV tertile compared with the lowest had an increased risk of incident dementia and cognitive decline, independent of average BP and use of antihypertensive drugs. There was evidence that sex modified the association with incident dementia (interaction P=0.02), with increased risk in men (HR, 1.68; 95% CI, 1.19-2.39) but not women (HR, 1.01; 95% CI, 0.72-1.42). For cognitive decline, similar increased risks were observed for men and women (interaction P=0.15; men: HR, 1.36; 95% CI, 1.16-1.59; women: HR, 1.14; 95% CI, 0.98-1.32). Conclusions: High BPV in older adults without major cognitive impairment, particularly men, is associated with increased risks of dementia and cognitive decline

    An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations

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    Protein-protein interactions govern almost all cellular functions. These complex networks of stable and transient associations can be mapped by affinity purification mass spectrometry (AP-MS) and complementary proximity-based labeling methods such as BioID. To exploit the advantages of both strategies, we here design and optimize an integrated approach combining AP-MS and BioID in a single construct, which we term MAC-tag. We systematically apply the MAC-tag approach to 18 subcellular and 3 sub-organelle localization markers, generating a molecular context database, which can be used to define a protein's molecular location. In addition, we show that combining the AP-MS and BioID results makes it possible to obtain interaction distances within a protein complex. Taken together, our integrated strategy enables the comprehensive mapping of the physical and functional interactions of proteins, defining their molecular context and improving our understanding of the cellular interactome.Peer reviewe

    Incidence, severity, aetiology and type of neck injury in men's amateur rugby union: a prospective cohort study

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    <p>Abstract</p> <p>Background</p> <p>There is a paucity of epidemiological data on neck injury in amateur rugby union populations. The objective of this study was to determine the incidence, severity, aetiology and type of neck injury in Australian men's amateur rugby union.</p> <p>Methods</p> <p>Data was collected from a cohort of 262 participants from two Australian amateur men's rugby union clubs via a prospective cohort study design. A modified version of the Rugby Union Injury Report Form for Games and Training was used by the clubs physiotherapist or chiropractor in data collection.</p> <p>Results</p> <p>The participants sustained 90 (eight recurrent) neck injuries. Exposure time was calculated at 31143.8 hours of play (12863.8 hours of match time and 18280 hours of training). Incidence of neck injury was 2.9 injuries/1000 player-hours (95%CI: 2.3, 3.6). As a consequence 69.3% neck injuries were minor, 17% mild, 6.8% moderate and 6.8% severe. Neck compression was the most frequent aetiology and was weakly associated with severity. Cervical facet injury was the most frequent neck injury type.</p> <p>Conclusions</p> <p>This is the first prospective cohort study in an amateur men's rugby union population since the inception of professionalism that presents injury rate, severity, aetiology and injury type data for neck injury. Current epidemiological data should be sought when evaluating the risks associated with rugby union football.</p

    How Much Rugby is Too Much? A Seven-Season Prospective Cohort Study of Match Exposure and Injury Risk in Professional Rugby Union Players.

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    INTRODUCTION: Numerous studies have documented the incidence and nature of injuries in professional rugby union, but few have identified specific risk factors for injury in this population using appropriate statistical methods. In particular, little is known about the role of previous short-term or longer-term match exposures in current injury risk in this setting. OBJECTIVES: Our objective was to investigate the influence that match exposure has upon injury risk in rugby union. METHOD: We conducted a seven-season (2006/7-2012/13) prospective cohort study of time-loss injuries in 1253 English premiership professional players. Players' 12-month match exposure (number of matches a player was involved in for ≥20 min in the preceding 12 months) and 1-month match exposure (number of full-game equivalent [FGE] matches in preceding 30 days) were assessed as risk factors for injury using a nested frailty model and magnitude-based inferences. RESULTS: The 12-month match exposure was associated with injury risk in a non-linear fashion; players who had been involved in fewer than ≈15 or more than ≈35 matches over the preceding 12-month period were more susceptible to injury. Monthly match exposure was linearly associated with injury risk (hazard ratio [HR]: 1.14 per 2 standard deviation [3.2 FGE] increase, 90% confidence interval [CI] 1.08-1.20; likely harmful), although this effect was substantially attenuated for players in the upper quartile for 12-month match exposures (>28 matches). CONCLUSION: A player's accumulated (12-month) and recent (1-month) match exposure substantially influences their current injury risk. Careful attention should be paid to planning the workloads and monitoring the responses of players involved in: (1) a high (>≈35) number of matches in the previous year, (2) a low (<≈15) number of matches in the previous year, and (3) a low-moderate number of matches in previous year but who have played intensively in the recent past. These findings make a major contribution to evidence-based policy decisions regarding match workload limits in professional rugby union

    Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

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    Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

    The association of levels of physical activity with metabolic syndrome in rural Australian adults

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    Background:&nbsp; Physical activity (PA) reduces risk factors related to metabolic syndrome. Rurality influences the way people incorporate physical activity into daily life. The aim of this study is to determine the association of PA level with metabolic syndrome in a rural Australian population. The influence of adiposity on these associations is also investigated.Methods: Three cross-sectional population health surveys were conducted in south-east Australia during 2004&ndash;2006 using a random population sample (n = 1563, participation rate 49%) aged 25&ndash;74 years. PA was assessed via a self-administered questionnaire, and components of the metabolic syndrome via anthropometric measurements taken by specially trained nurses and laboratory tests.Results: Approximately one-fifth of participants were inactive in leisure-time and over one-third had metabolic syndrome (men 39%, women 33%; p = 0.022). There was an inverse association between level of PA and metabolic syndrome (p &lt; 0.001). Men who were inactive in leisure-time were more than twice as likely and women more than three times as likely to have metabolic syndrome compared with those having high PA. Body mass index (BMI) is a mediating factor in the association between level of PA and metabolic syndrome.Conclusion: Some PA is better than none if adults, particularly women, are to reduce their risk of metabolic syndrome and associated vascular diseases. Specialised interventions that take rurality into consideration are recommended for adults who are inactive.<br /

    High-level classification of the Fungi and a tool for evolutionary ecological analyses

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    High-throughput sequencing studies generate vast amounts of taxonomic data. Evolutionary ecological hypotheses of the recovered taxa and Species Hypotheses are difficult to test due to problems with alignments and the lack of a phylogenetic backbone. We propose an updated phylum-and class-level fungal classification accounting for monophyly and divergence time so that the main taxonomic ranks are more informative. Based on phylogenies and divergence time estimates, we adopt phylum rank to Aphelidiomycota, Basidiobolomycota, Calcarisporiellomycota, Glomeromycota, Entomophthoromycota, Entorrhizomycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota and Olpidiomycota. We accept nine subkingdoms to accommodate these 18 phyla. We consider the kingdom Nucleariae (phyla Nuclearida and Fonticulida) as a sister group to the Fungi. We also introduce a perl script and a newick-formatted classification backbone for assigning Species Hypotheses into a hierarchical taxonomic framework, using this or any other classification system. We provide an example of testing evolutionary ecological hypotheses based on a global soil fungal data set.Peer reviewe
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