Does a Hypertrophying Muscle Fibre Reprogramme its Metabolism Similar to a Cancer Cell?

In 1924, Otto Warburg asked “How does the metabolism of a growing tissue differ from that of a non-growing tissue?” Currently, we know that proliferating healthy and cancer cells reprogramme their metabolism. This typically includes increased glucose uptake, glycolytic flux and lactate synthesis. A key function of this reprogramming is to channel glycolytic intermediates and other metabolites into anabolic reactions such as nucleotide-RNA/DNA synthesis, amino acid-protein synthesis and the synthesis of, for example, acetyl and methyl groups for epigenetic modification. In this review, we discuss evidence that a hypertrophying muscle similarly takes up more glucose and reprogrammes its metabolism to channel energy metabolites into anabolic pathways. We specifically discuss the functions of the cancer-associated enzymes phosphoglycerate dehydrogenase and pyruvate kinase muscle 2 in skeletal muscle. In addition, we ask whether increased glucose uptake by a hypertrophying muscle explains why muscularity is often negatively associated with type 2 diabetes mellitus and obesity

Chiral photoelectron angular distributions from ionization of achiral atomic and molecular species

We show that the combination of two achiral components - atomic or molecular target plus a circularly polarized photon - can yield chirally structured photoelectron angular distributions. For photoionization of CO, the angular distribution of carbon K-shell photoelectrons is chiral when the molecular axis is neither perpendicular nor (anti-)parallel to the light propagation axis. In photo-double-ionization of He, the distribution of one electron is chiral, if the other electron is oriented like the molecular axis in the former case and if the electrons are distinguishable by their energy. In both scenarios, the circularly polarized photon defines a plane with a sense of rotation and an additional axis is defined by the CO molecule or one electron. This is sufficient to establish an unambiguous coordinate frame of well-defined handedness. To produce a chirally structured electron angular distribution, such a coordinate frame is necessary, but not sufficient. We show that additional electron-electron interaction or scattering processes are needed to create the chiral angular distribution

L-SeqSleepNet: Whole-cycle Long Sequence Modelling for Automatic Sleep Staging

Human sleep is cyclical with a period of approximately 90 minutes, implying long temporal dependency in the sleep data. Yet, exploring this long-term dependency when developing sleep staging models has remained untouched. In this work, we show that while encoding the logic of a whole sleep cycle is crucial to improve sleep staging performance, the sequential modelling approach in existing state-of-the-art deep learning models are inefficient for that purpose. We thus introduce a method for efficient long sequence modelling and propose a new deep learning model, L-SeqSleepNet, which takes into account whole-cycle sleep information for sleep staging. Evaluating L-SeqSleepNet on four distinct databases of various sizes, we demonstrate state-of-the-art performance obtained by the model over three different EEG setups, including scalp EEG in conventional Polysomnography (PSG), in-ear EEG, and around-the-ear EEG (cEEGrid), even with a single EEG channel input. Our analyses also show that L-SeqSleepNet is able to alleviate the predominance of N2 sleep (the major class in terms of classification) to bring down errors in other sleep stages. Moreover the network becomes much more robust, meaning that for all subjects where the baseline method had exceptionally poor performance, their performance are improved significantly. Finally, the computation time only grows at a sub-linear rate when the sequence length increases.Comment: 9 pages, 4 figures, updated affiliation

Myocardial Blood Flow during General Anesthesia with Xenon in Humans A Positron Emission Tomography Study

ABSTRACT Background: Xenon has only minimal hemodynamic side effects and induces pharmacologic preconditioning. Thus, the use of xenon could be an interesting option in patients at risk for perioperative myocardial ischemia. However, little is known about the effects of xenon anesthesia on myocardial blood flow (MBF) and coronary vascular resistance in humans. Methods: Myocardial blood flow was noninvasively quantified by H 2 15 O positron emission tomography in six healthy volunteers (age: 38 Ϯ 8 yr). MBF was measured at baseline and during general anesthesia induced with propofol and maintained with xenon, 59 Ϯ 0%. Absolute quantificatio

Predictors of Nocturnal Hypoxemic Burden in Patients Undergoing Elective Coronary Artery Bypass Grafting Surgery

Nocturnal hypoxemia has been linked to increased cardiovascular morbidity and mortality. Several common diseases, such as sleep-disordered breathing (SDB), heart failure (HF), obesity, and pulmonary disease, coincide with an elevated nocturnal hypoxemic burden with and without repetitive desaturations. Research question: This study aimed to evaluate the association of relevant common diseases with distinctive metrics of nocturnal hypoxemic burden with and without repetitive desaturations in patients undergoing coronary artery bypass grafting surgery. Study design and methods: In this subanalysis of the prospective observational study, CONSIDER-AF (NCT02877745) portable SDB monitoring was performed on 429 patients with severe coronary artery disease the night before cardiac surgery. Pulse oximetry was used to determine nocturnal hypoxemic burden, as defined by total recording time spent with oxygen saturation levels < 90% (T90). T90 was further characterized as T90 due to intermittent hypoxemia (T90desaturation) and T90 due to nonspecific and noncyclic SpO2-drifts (T90non-specific). Results: Multivariable linear regression analysis identified SDB (apnea–hypopnea-index ≥ 15/h; B [95% CI]: 6.5 [0.4; 12.5], p = 0.036), obesity (8.2 [2.5; 13.9], p = 0.005), and mild-to-moderate chronic obstructive pulmonary disease (COPD, 16.7 [8.5; 25.0], p < 0.001) as significant predictors of an increased nocturnal hypoxemic burden. Diseases such as SDB, obesity and HF were significantly associated with elevated T90desaturation. In contrast, obesity and mild-to-moderate COPD were significant modulators of T90non-specific. Interpretation: SDB and leading causes for SDB, such as obesity and HF, are associated with an increased nocturnal hypoxemic burden with repetitive desaturations. Potential causes for hypoventilation syndromes, such as obesity and mild-to-moderate COPD, are linked to an increased hypoxemic burden without repetitive desaturations. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02877745

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) – protocol of a randomized phase II trial (NOA 10/ARO 2013-1)

Background: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone. Methods: This protocol describes a prospective, open label, randomized, multi-center phase II trial designed to test if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS) in patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based on T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary endpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious of progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression or death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRIor PET-derived target volumes, rate of long term survivors (> 1 year), localization of necrosis after re-irradiation, quality of life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET imaging and toxicity of re-irradiation. Discussion: This is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target volume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a standardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning. Trial registration: The GLIAA trial is registered with ClinicalTrials.gov (NCT01252459, registration date 02.12.2010), German Clinical Trials Registry (DRKS00000634, registration date 10.10.2014), and European Clinical Trials Database (EudraCT-No. 2012-001121-27, registration date 27.02.2012)

Playing Position is Associated with Injury Incidence Rate in Male Academy Soccer Players

Context: It is unclear whether playing position influences injury in male academy soccer players (ASP). Objective: To determine if playing position is associated with injury in ASP. Design: Descriptive Epidemiology Study. Setting: English, Spanish, Uruguayan and Brazilian soccer academies. Participants: 369 ASP from Under 14 (U14) to U23 age groups, classified as ‘post-peak height velocity' using maturity offset, and grouped as goalkeepers (GK), lateral defenders (LD), central defenders (CD), lateral midfielders (LM), central midfielders (CM) and forwards (FWD). Additional analysis compared central (CENT) with lateral/forward (LAT/FWD) positions. Main Outcome Measures: Injuries were recorded prospectively over one season. Injury prevalence proportion (IPP), days missed and injury incidence rate (IIR, injuries per 1000 training/match hours, n=116) were analysed according to playing position. Results: No association with playing position was observed for any injury type/location regarding IPP (P≥0.089) or days missed (P≥0.235). The IIR was higher in CD than LD for general (9.30 vs. 4.18 injuries/1000h, P=0.009), soft-tissue (5.14 vs. 1.95 injuries/1000h, P=0.026) and ligament/tendon injuries (2.69 vs. 0.56 injuries/1000h, P=0.040). Regarding CENT vs. LAT/FWD, there were no associations with IPP (P≥0.051) or days missed (P≥0.083), but general IIR was greater in CENT than LAT/FWD (8.67 vs. 6.12 injuries/1000h, P=0.047). Conclusions: ASP playing position was not associated with IPP or days missed but the higher general, soft-tissue and ligament/tendon IIR in CD suggests this position warrants specific attention regarding injury prevention strategies. These novel findings highlight the importance of including training/match exposure when investigating the influence of playing position on injury in ASP

Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia

Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10−41) and in 1690 AA subjects (rs505102; P = 1.05 × 10−8). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10−12; rs35897051, P = 3.32 × 10−8). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10−12), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case–control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study