Effects of exercise and media consumption on sleep and cognitive performance in children as well as alterations induced by exercise, sleep and sleep deprivation in brain energy metabolism in rats

Zusammenfassung:<p> In der letzten Dekade gab es in der Schlafforschung enorme Fortschritte. Jahrzehntelang wurde angenommen, dass der Schlaf ein einfaches und ruhiges Verhaltensstadium ist. Jedoch kann heute als gesichert angesehen werden, dass der Schlaf ein komplexes und hoch organisiertes Stadium mit einer wesentlichen Bedeutung für die physische und psychische Leistungsfähigkeit darstellt. Laut aktuellen Studien treten Schlafstörungen mit einer Prävalenz von 25% auf und resultieren in multiplen Symptomen wie Stress, einer gestörten Vigilanz, sowie einer reduzierten kognitiven Leistungsfähigkeit und Motivation. In zahlreichen Diskussionen bezüglich der Schlafhygiene, wird körperliche Aktivität als non-pharmakologische Intervention zur Verbesserung des Schlafes empfohlen. Jedoch existieren in der internationalen einschlägigen Fachliteratur inkonsistente Befunde bezüglich der Effekte von körperlicher Aktivität auf die einzelnen Schlafarchitektur- und Schlafkontinuitätsparameter. Divergenzen in der Untersuchungs-methodik, dem Probandengut, sowie der Qualität und Quantität der körperlichen Belastung lassen nur unzureichende Vergleiche der einzelnen Befunde zu und resultieren in einem Forschungsdefizit bezüglich der Auswirkungen von körperlicher Aktivität auf Schlafarchitektur- und Schlafkontinuitätsparameter. Demnach fokussierte sich die erste experimentelle Studie der vorliegenden kumulativen Dissertation auf die Auswirkungen moderater und intensiver körperlicher Aktivität auf Schlafarchitektur- und Schlafkontinuitätsparameter bei Kindern. Die standardisierten Belastungen in Form einer allgemeinen dynamischen Ausdauerbelastung auf dem Fahrradergometer differierten nur in der Belastungsintensität. Die intensiven Belastungen resultierten in signifikant erhöhten Tiefschlafanteilen und weniger Schlag in Stadium 2. Eine erhöhte Schlafeffizienz und reduzierte Einschlaflatenzen konnten ebenfalls nur nach den intensiven Belastungen diagnostiziert werden. Diese Studie zeigte zum ersten Mal in der internationalen Fachliteratur, dass die Intensität der Belastung ausschlaggebend für die Veränderungen der Schlafarchitektur- und Schlafkontinuitätsparameter ist und stützt die Nutzung von körperlicher Aktivität als non-pharmakologische Intervention zur Behandlung von Schlafstörungen und Schlafproblemen. Da die Intensität der physischen Belastung ausschlaggebend für die Veränderungen im Schlaf-EEG (Elektroenzephalogramm) war, konnte angenommen werden, dass metabolische Veränderungen im Gehirn in Verbindung mit der Belastungsintensität eine wesentliche Rolle in der Regulation des Schlafes spielen. Demnach fokussierte sich die zweite experimentelle Studie auf den Einfluss von körperlicher Aktivität (moderater und intensiver Belastungsintensität), 3- und 5-stündigem Schlaf und Schlafentzug auf die Nukleotid- und Nukleosidkonzentrationen im Gesamthirn der adulten Ratte. Die Untersuchungsergebnisse zeigten, dass nur intensive Belastungen in einer signifikant erhöhten Konzentration des schlaffördernden Nukleosides Adenosin resultierten, während 3- und 5-stündige Schlafperioden zu reduzierten Adenosin- und Inosinkonzentrationen führten, mit einem gleichzeitigen Anstieg von ADP (Adenosindiphosphat) und ATP (Adenosintriphosphat). Die Studie zeigte zum ersten Mal, dass die Intensität der physischen Belastung ausschlaggebend für die Nukleosidveränderungen im Säugetiergehirn ist und stützt die zentralen Rolle des Gehirnenergiestoffwechsels in der Schlafregulation, sowie die Hypothese bezüglich der Funktion des Schlafes in der Auffüllung zerebraler Energiespeicher. <p> Die ersten beiden experimentellen Studien stützen den Einfluss von körperlicher Aktivität auf Schlafarchitektur- und Schlaf-kontinuitätsparameter, sowie schlafregulatorische Stoffwechsel-prozesse. Zunehmende Befunde deuten jedoch darauf hin, dass die gegenwärtige Generation von Erwachsenen und Kindern von körperlicher Inaktivität und einer erhöhten Prävalenz für Schlafstörungen geprägt ist. Vor allem Fernseh- und Computerspielkonsum sind ein enormer Einflussfaktor im Leben der meisten Kinder. Zahlreiche epidemiologische Befunde deuten darauf hin, dass exzessiver Medienkonsum zu Aufmerksamkeitsstörungen, Hyperaktivität, Schlafstörungen und Lernproblemen führen kann. Aufgrund unzureichender experimenteller Befunde untersuchte die dritte Studie den Einfluss von akutem Computerspiel- und TV-Konsum auf das Schlafverhalten und die kognitive Gedächtnisleistung von Kindern. Die Untersuchungsergebnisse zeigten, dass akuter Computerspielkonsum in signifikant reduzierten Tiefschlafanteilen und Reduktionen der verbalen Gedächtnisleistung resultiert. Fernsehkonsum führte zu einer reduzierten Schlafeffizienz, jedoch keinen Effekt auf die Schlafarchitekturparameter. Die Studie zeigte zum ersten Mal den negativen Einfluss von akutem Computerspiel- und Fernsehkonsum auf das Schlafverhalten und die verbale Gedächtnisleistung von Kindern und stimmt mit der Hypothese überein, dass exzessiver Medienkonsum in negativen Auswirkungen auf den Schlaf, die Gesundheit und die Entwicklung von Kindern resultiert. Weiterhin wird die Rolle des Tiefschlafes in der deklarativen Gedächtniskonsolidierung diskutiert.<p> Summary of the current thesis:<p> „Effects of exercise and media consumption on sleep and cognitive performance in children as well as alterations induced by exercise, sleep and sleep deprivation in brain energy metabolism in rats“<p> In the last decade there has been enormous progress regarding the phenomenon of sleep. For centuries, sleep has been classified as a quite simple behavioural state, but today we appreciate that it is a complex and highly organized state with enormous importance for physical and mental health and performance. Sleep is important for mental and physical health and performance. In most discussions regarding sleep hygiene, exercise is considered as a non-pharmacological intervention to improve sleep. However, the current literature provides inconsistent and contrasting results regarding the effects of exercise on subsequent sleep. The variety of different methodology, age, gender, fitness level and body mass as well as time before sleep when exercise was completed makes it difficult to compare the results of these studies. Therefore it was first attempted to examine the effects of dynamic physical exercise on sleep patterns and vigilance state in humans using two standardized exercise sessions, which differed only in intensity. The results show for the first time that intensity of exercise is responsible for the effects on sleep architecture and sleep continuity parameters. Especially the amount of homeostatic regulated non-rapid eye-movement (NREM) slow-wave sleep (SWS) was significantly increased after exhaustive exercise, with an accompanied decrease in stage 2 sleep. In addition, significant increases in sleep efficiency as well as a decreased SOL were observed after high-intensity exercise. We conclude that intense exercise has a positive influence on sleep architecture and sleep continuity parameters in children, which support the capability of dynamic exercise as a non-pharmacological intervention in treatment against sleep disturbances which are highly prevalent in the general population. Because exercise intensity is responsible for subsequent changes in sleep, we hypothesized that metabolic changes in the human brain associated with exercise intensity may play a key role in regulation of sleep. Thus, we have attempted to clarify the influence of moderate and high-intensity exercise, sleep and sleep deprivation on nucleotide and nucleoside concentrations in the mammalian brain. Considering that the brain is one of the most active tissues in nucleoside and nucleotide syntheses and during ischemia metabolites are very unstable, we used freeze-clamp technique to freeze brain tissue immediately and prevent enzymatic activity. The results show that only high-intensity exercise leads to significant increases of the sleep-promoting substance adenosine, while sleep results in a progressive decline of these nucleosides with an accompanying increase of ADP and ATP in a temporal manner. We conclude that accumulation of the sleep-promoting substance adenosine after high-intensity exercise may be an important factor in homeostatic sleep regulation and that sleep could have an essential function in replenishment of high-energy phosphates. The study demonstrates for the first time that intensity of exercise is responsible for nucleoside changes in the mammalian brain, which are in accordance with the current hypothesis in the sleep research area that the brain energy metabolism is essential in sleep regulation, and it provides fundamental basics regarding the use of exercise in treatment against disturbances in sleep and alertness. <p> In the third study of the current thesis we examine the effects of singular excessive computer game and television exposure on sleep patterns and memory performance in school-aged children. The main results confirm the notion that computer game playing leads to significantly reduced amounts of slow-wave sleep as well as significant declines in verbal memory performance. Television exposure reduced sleep efficiency significantly but did not affect sleep patterns. Therefore, we conclude that excessive television and computer game consumption disrupt sleep and verbal memory performance in children, which supports the hypothesis of the negative influence of excessive media consumption on children’s sleep, health and development. Thus, the current thesis provides an insight regarding the relationship of exercise and sleep, accompanied by fundamental causes in brain energy metabolism, as well as the negative influence of media consumption on sleep and memory performance in children

Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial

Background: Introduction of calcineurin inhibitors had led to improved survival rates in liver transplant recipients. However, long-term use of calcineurin inhibitors is associated with a higher risk of chronic renal failure, neurotoxicity, de novo malignancies, recurrence of hepatitis C viral (HCV) infection and hepatocellular carcinoma. Several studies have shown that everolimus has the potential to provide protection against viral replication, malignancy, and progression of fibrosis, as well as preventing nephrotoxicity by facilitating calcineurin inhibitor reduction without compromising efficacy. The Hephaistos study evaluates the beneficial effects of early initiation of everolimus in de novo liver transplant recipients. Methods/Design: Hephaistos is an ongoing 12-month, multi-center, open-label, controlled study aiming to enroll 330 de novo liver transplant recipients from 15 centers across Germany. Patients are randomized in a 1:1 ratio (7–21 days post-transplantation) to receive everolimus (trough levels 3–8 ng/mL) with reduced tacrolimus (trough levels <5 ng/mL), or standard tacrolimus (trough levels 6–10 ng/mL) after entering a run-in period (3–5 days post-transplantation). In the run-in period, patients are treated with induction therapy, mycophenolate mofetil, tacrolimus, and corticosteroids according to local practice. Randomization is stratified by HCV status and model of end-stage liver disease scores at transplantation. The primary objective of the study is to exhibit superior renal function (estimated glomerular filtration rate assessed by the Modification of Diet in Renal Disease (MDRD)-4 formula) with everolimus plus reduced tacrolimus compared to standard tacrolimus at Month 12. Other objectives are: to assess the incidence of treated biopsy-proven acute rejection, graft loss, or death; the incidences of components of the composite efficacy endpoint; renal function via estimated glomerular filtration rate using various formulae (MDRD-4, Nankivell, Cockcroft-Gault, chronic kidney disease epidemiology collaboration and Hoek formulae); the incidence of proteinuria; the incidence of adverse events and serious adverse events; the incidence and severity of cytomegalovirus and HCV infections and HCV-related fibrosis. Discussion: This study aims to demonstrate superior renal function, comparable efficacy, and safety in de novo liver transplant recipients receiving everolimus with reduced tacrolimus compared with standard tacrolimus. This study also evaluates the antiviral benefit by early initiation of everolimus. Trial registration: NCT0155121

Myocardial metbolism in heart failure:Purinergic signalling and other metabolic concepts

Despite significant therapeutic advances in heart failure (HF) therapy, the morbidity and mortality associated with this disease remains unacceptably high. The concept of metabolic dysfunction as an important underlying mechanism in HF is well established. Cardiac function is inextricably linked to metabolism, with dysregulation of cardiac metabolism pathways implicated in a range of cardiac complications, including HF. Modulation of cardiac metabolism has therefore become an attractive clinical target. Cardiac metabolism is based on the integration of adenosine triphosphate (ATP) production and utilization pathways. ATP itself impacts the heart not only by providing energy, but also represents a central element in the purinergic signaling pathway, which has received considerable attention in recent years. Furthermore, novel drugs that have received interest in HF include angiotensin receptor blocker-neprilysin inhibitor (ARNi) and sodium glucose cotransporter 2 (SGLT-2) inhibitors, whose favorable cardiovascular profile has been at least partly attributed to their effects on metabolism. This review, describes the major metabolic pathways and concepts of the healthy heart (including fatty acid oxidation, glycolysis, Krebs cycle, Randle cycle, and purinergic signaling) and their dysregulation in the progression to HF (including ketone and amino acid metabolism). The cardiac implications of HF comorbidities, including metabolic syndrome, diabetes mellitus and cachexia are also discussed. Finally, the impact of current HF and diabetes therapies on cardiac metabolism pathways and the relevance of this knowledge for current clinical practice is discussed. Targeting cardiac metabolism may have utility for the future treatment of patients with HF, complementing current approaches

Coherent phonons in CdSe quantum dots triggered by ultrafast electron transfer

The origin of coherent oscillations in CdSe quantum dots and in the CdSe/methylviologen electron transfer system is studied. In CdSe/methylviologen coherent phonons are triggered by the electron transfer from the quantum dot to methylviologen

Patient preference and tolerability of a DPP-4 inhibitor a GLP-1 analog in patients with type 2 diabetes mellitus inadequately controlled with metformin: a 24-week, randomized, multicenter, crossover study

Objective: The present study aimed to assess the patient preference and tolerability of oral dipeptidyl peptidase-4 inhibitor (vildagliptin) versus injectable glucagon-like peptide-1 analog (liraglutide) in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy. Methods: This 24-week, randomized, multicenter, crossover study, patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy with hemoglobin A1c (HbA 1c ) ⩾6.5% and ⩽9.0% were randomized in a crossover manner to receive either vildagliptin/metformin single-pill combination (SPC) 50/1000 mg twice daily ( n = 32) or 1.2 mg liraglutide as an add-on to metformin (0.6 mg [weeks 0–1] followed by 1.2 mg [weeks 2–12] once daily/1000 mg twice daily) ( n = 30) for the first 12 weeks. Results: Patient preference at week 24 was similar, with 51.7% ( n = 31) patients preferring vildagliptin/metformin SPC compared with 48.3% ( n = 29) preferring liraglutide as an add-on to metformin therapy ( p = 0.449). Post hoc analyses showed that more elderly patients (⩾65 years) preferred vildagliptin (65%; n = 13) over liraglutide (35%; n = 7) therapy. Liraglutide was associated with better improvement in fasting plasma glucose (–21.5 mg/dl versus –3.4 mg/dl) and HbA 1c (–0.5% versus –0.3%) levels. Fewer adverse events were reported with vildagliptin/metformin SPC ( n = 16) compared with liraglutide as add-on to metformin treatment ( n = 46). Conclusions: In this pilot study, although both vildagliptin and liraglutide therapies were preferred similarly by the patients and showed effective control of glycemia over 12 weeks, vildagliptin was associated with fewer adverse events and was preferred more by elderly patients

Higher Risk of Hypoglycemia with Glimepiride Versus Vildagliptin in Patients with Type 2 Diabetes is not Driven by High Doses of Glimepiride: Divergent Patient Susceptibilities?

In a previously published study, vildagliptin showed a reduced risk of hypoglycemia versus glimepiride as add-on therapy to metformin at similar efficacy. Glimepiride was titrated from a starting dose of 2 mg/day to a maximum dose of 6 mg/day. It is usually assumed that the increased hypoglycemia with glimepiride was driven by the 6 mg/day dose; it was therefore of interest to assess whether the risk of hypoglycemia is also different between vildagliptin and a low (2 mg/day) dose of glimepiride

Initiators Based on Benzaldoximes: Bimolecular and Covalently Bound Systems

Typical bimolecular photoinitiators (PIs) for radical polymerization of acrylates show only poor photoreactivity because of the undesired effect of back electron transfer. To overcome this limitation, PIs consisting of a benzaldoxime ester and various sensitizers based on aromatic ketones were introduced. The core of the photoinduced reactivity was established by laser flash photolysis, photo-CIDNP, and EPR experiments at short time scales. According to these results, the primarily formed iminyl radicals are not particularly active. The polymerization is predominantly initiated by C-centered radicals. Photo-DSC experiments show reactivities comparable to that of classical monomolecular type I PIs like Darocur 1173