To report sex- and age-specific physical fitness levels in European adolescents.
A sample of 3428 adolescents (1845 girls) aged 12.5-17.49 years from 10 European cities in Austria, Belgium, France, ...Germany, Greece (an inland city and an island city), Hungary, Italy, Spain and Sweden was assessed in the Healthy Lifestyle in Europe by Nutrition in Adolescence study between 2006 and 2008. The authors assessed muscular fitness, speed/agility, flexibility and cardiorespiratory fitness using nine different fitness tests: handgrip, bent arm hang, standing long jump, Bosco jumps (squat jump, counter movement jump and Abalakov jump), 4×10-m shuttle run, back-saver sit and reach and 20-m shuttle run tests.
The authors derived sex- and age-specific normative values for physical fitness in the European adolescents using the LMS statistical method and expressed as tabulated percentiles from 10 to 100 and as smoothed centile curves (P₅, P₂₅, P₅₀, P₇₅ and P₉₅). The figures showed greater physical fitness in the boys, except for the flexibility test, and a trend towards increased physical fitness in the boys as their age increased, whereas the fitness levels in the girls were more stable across ages.
The normative values hereby provided will enable evaluation and correct interpretation of European adolescents' fitness status.
DNA hydroxymethylation has recently been shown to play critical roles in regulating gene expression and terminal differentiation events in a variety of developmental contexts. However, little is ...known about its function during eye development. Methylcytosine dioxygenases of the Tet family convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), an epigenetic mark thought to serve as a precursor for DNA demethylation and as a stable mark in neurons. Here, we report a requirement for Tet activity during zebrafish retinal neurogenesis. In tet2-/-;tet3-/- mutants, retinal neurons are specified but most fail to terminally differentiate. While differentiation of the first born retinal neurons, the retinal ganglion cells (RGCs), is less affected in tet2-/-;tet3-/- mutants than other retinal cell types, the majority of RGCs do not undergo terminal morphogenesis and form axons. Moreover, the few photoreceptors that differentiate in tet2-/-;tet3-/- mutants fail to form outer segments, suggesting that Tet function is also required for terminal morphogenesis of differentiated retinal neurons. Mosaic analyses revealed a surprising cell non-autonomous requirement for tet2 and tet3 activity in facilitating retinal neurogenesis. Through a combination of candidate gene analysis, transcriptomics and pharmacological manipulations, we identified the Notch and Wnt pathways as cell-extrinsic pathways regulated by tet2 and tet3 activity during RGC differentiation and morphogenesis. Transcriptome analyses also revealed the ectopic expression of non-retinal genes in tet2-/-;tet3-/- mutant retinae, and this correlated with locus-specific reduction in 5hmC. These data provide the first evidence that Tet-dependent regulation of 5hmC formation is critical for retinal neurogenesis, and highlight an additional layer of complexity in the progression from retinal progenitor cell to differentiated retinal neuron during development of the vertebrate retina.
The retinal pigment epithelium (RPE) plays numerous critical roles in maintaining vision and this is underscored by the prevalence of degenerative blinding diseases like age-related macular ...degeneration (AMD), in which visual impairment is caused by progressive loss of RPE cells. In contrast to mammals, zebrafish possess the ability to intrinsically regenerate a functional RPE layer after severe injury. The molecular underpinnings of this regenerative process remain largely unknown yet hold tremendous potential for developing treatment strategies to stimulate endogenous regeneration in the human eye. In this study, we demonstrate that the mTOR pathway is activated in RPE cells post-genetic ablation. Pharmacological and genetic inhibition of mTOR activity impaired RPE regeneration, while mTOR activation enhanced RPE recovery post-injury, demonstrating that mTOR activity is essential for RPE regeneration in zebrafish. RNA-seq of RPE isolated from mTOR-inhibited larvae identified a number of genes and pathways dependent on mTOR activity at early and late stages of regeneration; amongst these were components of the immune system, which is emerging as a key regulator of regenerative responses across various tissue and model systems. Our results identify crosstalk between macrophages/microglia and the RPE, wherein mTOR activity is required for recruitment of macrophages/microglia to the RPE injury site. Macrophages/microglia then reinforce mTOR activity in regenerating RPE cells. Interestingly, the function of macrophages/microglia in maintaining mTOR activity in the RPE appeared to be inflammation-independent. Taken together, these data identify mTOR activity as a key regulator of RPE regeneration and link the mTOR pathway to immune responses in facilitating RPE regeneration.
A method for the synthesis of benzylsilanes starting from the corresponding ammonium triflates is reported. Silyl boronic esters are employed as silicon pronucleophiles, and the reaction is catalyzed ...by copper(I) salts. Enantioenriched benzylic ammonium salts react stereospecifically through an SN2‐type displacement of the ammonium group to afford α‐chiral silanes with inversion of the configuration. A cyclopropyl‐substituted substrate does not undergo ring opening, thus suggesting an ionic reaction mechanism with no benzyl radical intermediate.
SiR, the NMe has surrendered: Benzylic ammonium salts can be transformed into the corresponding silanes by a copper‐catalyzed SN2‐type displacement. The enantioenrichment of the precursors is completely retained in the α‐chiral silanes. A cyclopropyl group at the benzylic carbon atom remains intact, thereby supporting an ionic reaction mechanism.
Objective: To provide an overview of the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (HELENA-CSS) design, with particular attention to its quality control ...procedures. Other important methodological aspects are described in detail throughout this supplement. Design: Description of the HELENA-CSS sampling and recruitment approaches, standardization and harmonization processes, data collection and analysis strategies and quality control activities. Results: The HELENA-CSS is a multi-centre collaborative study conducted in European adolescents located in urban settings. The data management systems, quality assurance monitoring activities, standardized manuals of operating procedures and training and study management are addressed in this paper. Various quality controls to ensure collection of valid and reliable data will be discussed in this supplement, as well as quantitative estimates of measurement error. Conclusion: The great advantage of the HELENA-CSS is the strict standardization of the fieldwork and the blood analyses, which precludes to a great extent the kind of immeasurable confounding bias that often interferes when comparing results from isolated studies.
Purpose
Low-dose multislice-CT (MSCT) detects many early-stage lung cancers with good prognosis, but whether it decreases lung cancer mortality and at which costs is yet insufficiently explored. ...Scope of the present study is to examine within a common European effort whether MSCT screening is capable to reduce the lung cancer mortality by at least 20 % and at which amount of undesired side effects this could be achieved.
Methods
Overall 4,052 heavy smoking men and women were recruited by a population-based approach and randomized into a screening arm with five annual MSCT screens and an initial quit-smoking counseling, and a control arm with initial quit-smoking counseling and five annual questionnaire inquiries.
Results
In the first screening round, 2,029 participants received a MSCT providing 1,488 negative and 540 suspicious screens with early recalls (early recall rate 26.6 %) leading to 31 biopsies (biopsy rate 1.5 %) and 22 confirmed lung cancers (detection rate 1.1 %). Among the lung cancers, 15 were adenocarcinomas, 3 squamous cell carcinomas, one small-cell lung cancer, and 3 others, whereby 18 were in clinical stage I, one in stage II, and 3 in stage III. One interval cancer occurred.
Conclusions
The indicated performance indicators fit into the range observed in comparable trials. The study continues finalizing the second screening round and for the first participants even the last screening round. The unresolved issue of the precise amount of side effects and the high early recall rate precludes currently the recommendation of MSCT as screening tool for lung cancer.
The German Lung Cancer Screening Intervention Trial (LUSI) is one of the European randomized trials investigating the efficacy of low-dose multislice computed tomography (MSCT) as a screening tool ...for lung cancer. In the evaluation of the first (prevalence) screening round, we observed exceptionally high early recall rates, which made the routine application of MSCT screening questionable. Because screening may behave differently in subsequent (incidence) screening rounds, we analyzed (a) basic characteristics for the annual rounds 2 to 4, which have now also been completed, and (b) the first 3 years with complete follow-up since time of randomization.
Data material was the data record of LUSI after the fourth screening round and the 3-year follow-up had been completed. Basic characteristics of screening, e.g., early recall rate, detection rate, and interval cancers as well of proportion of advanced cancers, were descriptively evaluated and, if informative, group differences were tested for statistical significance.
Early recall rates were significantly lower in the subsequent screening rounds than in the first one if the MSCT information from the previous screening rounds was available. Detection and biopsy rates were approximately 1% or lower, ratio of benign:malignant biopsies: 1:1.6 to 1:3.
Our recent data may not only settle one concern regarding high recall rates in routine MSCT screening but also indicate that screening must be strictly organized to be effective. Performance indicators are similar to those in mammography screening. Nevertheless, possible consequences for the participants (diagnostic workup of suspicious findings, biopsies) are more invasive than in mammography screening.
The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy.
In a phase III, randomized, double-blind trial, ...patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease independent review committee (IRC) confirmed. The intent-to-treat population included all randomized patients ≥pT2 and/or N+, any Fuhrman grade (FG), Eastern Cooperative Oncology Group status 0/1. Patients (stratified by risk group/country) received (1 : 1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted.
A total of 724 patients (363 versus 361, axitinib versus placebo) were randomized from 8 May 2012, to 1 July 2016. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per IRC hazard ratio (HR) = 0.870; 95% confidence interval (CI) : 0.660–1.147; P = 0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (0.641; 0.468–0.879; P = 0.0051), and by IRC (0.735; 0.525–1.028; P = 0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% versus 92%) and serious AEs (19% versus 14%), but more grade 3/4 AEs (61% versus 30%) were reported for axitinib versus placebo.
ATLAS did not meet its primary end point; however, improvement in DFS per investigator was seen in the highest-risk subpopulation. No new safety signals were reported.
NCT01599754
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