The aging brain: sleep, the circadian clock and exercise

Aging is a multifactorial process likely stemming from damage accumulation and/or a decline in maintenance and repair mechanisms in the organisms that eventually determine their lifespan. In our review, we focus on the morphological and functional alterations that the aging brain undergoes affecting sleep and the circadian clock in both human and rodent models. Although both species share mammalian features, differences have been identified on several experimental levels, which we outline in this review. Additionally, we delineate some challenges on the preferred analysis and we suggest that a uniform route is followed so that findings can be smoothly compared. We conclude by discussing potential interventions and highlight the influence of physical exercise as a beneficial lifestyle intervention, and its effect on healthy aging and longevity. We emphasize that even moderate age-matched exercise is able to ameliorate several aging characteristics as far as sleep and circadian rhythms are concerned, independent of the species studied.Circadian clocks in health and diseas

Reduced Plasticity in Coupling Strength in the Aging SCN Clock as Revealed by Kuramoto Modeling

The mammalian circadian clock is located in the suprachiasmatic nucleus (SCN) and consists of a network of coupled neurons, which are entrained to the environmental light-dark cycle. The phase coherence of the neurons is plastic and driven by the duration of daylight. With aging, the capacity to behaviorally adapt to seasonal changes in photoperiod reduces. The mechanisms underlying photoperiodic adaptation are largely unknown, but are important to unravel for the development of novel interventions to improve the quality of life of the elderly. We analyzed the phase coherence of single-cell PERIOD2::LUCIFERASE (PER2::LUC) expression rhythms in the SCN of young and old mice entrained to either long or short photoperiod. The phase coherence was used as input to a 2-community noisy Kuramoto model to estimate the coupling strength between and within neuronal subpopulations. The model revealed a correlation between coupling strength and photoperiod-induced changes in the phase relationship among neurons, suggesting a functional link. We found that the SCN of young mice adapts in coupling strength over a large range, with weak coupling in long photoperiod (LP) and strong coupling in short photoperiod (SP). In aged mice, we also found weak coupling in LP, but a reduced capacity to reach strong coupling in SP. The inability to respond with an increase in coupling strength suggests that manipulation of photoperiod is not a suitable strategy to enhance clock function with aging. We conclude that the inability of aged mice to reach strong coupling contributes to deficits in behavioral adaptation to seasonal changes in photoperiod. Circadian clocks in health and diseas

Oxygenated versus non-oxygenated flush out and storage of donor livers:An experimental study

Background: During donor organ procurement and subsequent static cold storage (SCS), hepatic adenosine triphosphate (ATP) levels are progressively depleted, which contributes to ischemia-reperfusion injury (IRI). We sought to investigate a simple approach to prevent ATP depletion and IRI using a porcine donation after circulatory death (DCD) liver reperfusion model. Methods: After 30 min warm ischemia, porcine livers were flushed via the portal vein with cold (4 degrees C) non-oxygenated University of Wisconsin (UW) preservation solution (n = 6, control group) or with oxygenated UW (n = 6, OxyFlush group). Livers were then subjected to 4 h SCS in non-oxygenated (control) or oxygenated (OxyFlush) UW, followed by 4 h normothermic reperfusion using whole blood. Hepatic ATP levels were compared, and hepatobiliary function and injury were assessed. Results: At the end of SCS, ATP was higher in the OxyFlush group compared to controls (delta ATP of +0.26 vs. -0.68 mu mol/g protein, p = 0.04). All livers produced bile and metabolized lactate, and there were no differences between the groups. Grafts in the OxyFlush group had lower blood glucose levels after reperfusion (p = 0.04). Biliary pH, glucose and bicarbonate were not different between the groups. Injury markers including liver transaminases, lactate dehydrogenase, malondialdehyde, cell-free DNA and flavin mononucleotide in the SCS solution and during reperfusion were also similar. Histological assessment of the parenchyma and bile ducts did not reveal differences between the groups. Conclusion: Oxygenated flush out and storage of DCD porcine livers prevents ATP depletion during ischemia, but this does not seem sufficient to mitigate early signs of IRI

Prolonged dual hypothermic oxygenated machine preservation (DHOPE-PRO) in liver transplantation:study protocol for a stage 2, prospective, dual-arm, safety and feasibility clinical trial

INTRODUCTION: End-ischaemic preservation of a donor liver by dual hypothermic oxygenated machine perfusion (DHOPE) for 2 hours prior to transplantation is sufficient to mitigate ischaemia-reperfusion damage and fully restore cellular energy levels. Clinical studies have shown beneficial outcomes after transplantation of liver grafts preserved by DHOPE compared with static cold storage. In addition to graft reconditioning, DHOPE may also be used to prolong preservation time, which could facilitate logistics for allocation and transplantation globally. METHODS AND ANALYSIS: This is a prospective, pseudo-randomised, dual-arm, IDEAL-D (Idea, Development, Exploration, Assessment, Long term study-Framework for Devices) stage 2 clinical device trial designed to determine safety and feasibility of prolonged DHOPE (DHOPE-PRO). The end-time of the donor hepatectomy will determine whether the graft will be assigned to the intervention (16:00–3:59 hour) or to the control arm (4:00–15:59 hour). In total, 36 livers will be included in the study. Livers in the intervention group (n=18) will undergo DHOPE-PRO (≥4 hours) until implantation the following morning, whereas livers in the control group (n=18) will undergo regular DHOPE (2 hours) prior to implantation. The primary endpoint of this study is a composite of the occurrence of all (serious) adverse events during DHOPE and up to 30 days after liver transplantation. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Ethical Committee of Groningen, METc2020.126 in June 2020, and the study was registered in the Netherlands National Trial Registry (https://www.trialregister.nl/) prior to initiation. TRIAL REGISTRATION NUMBER: NL8740

Which activities threaten independent living of elderly when becoming problematic : inspiration for meaningful service robot functionality

Purpose: In light of the increasing elderly population and the growing demand for home care, the potential of robot support is given increasing attention. In this paper, an inventory of activities was made that threaten independent living of elderly when becoming problematic. Results will guide the further development of an existing service robot, the Care-O-bot®. Method: A systematic literature search of PubMed was performed, focused on the risk factors for institutionalization. Additionally, focus group sessions were conducted in the Netherlands, United Kingdom and France. In these focus group sessions, problematic activities threatening the independence of elderly people were discussed. Three separate target groups were included in the focus group sessions: (1) elderly persons (n = 41), (2) formal caregivers (n = 40) and (3) informal caregivers (n = 32). Results: Activities within the International Classification of Functioning domains mobility, self-care, and interpersonal interaction and relationships were found to be the most problematic. Conclusions: A distinct set of daily activities was identified that may threaten independent living, but no single activity could be selected as the main activity causing a loss of independence as it is often a combination of problematic activities that is person-specific. Supporting the problematic activities need not involve a robotic solution Read More: http://informahealthcare.com/doi/abs/10.3109/17483107.2013.840861Peer reviewe

Sublingual sufentanil for postoperative pain relief: First clinical experiences

Background: The sublingual sufentanil tablet system (SSTS) is a novel hand-held patientcontrolled analgesia device developed for treatment of moderate-to-severe postoperative pain. Here we present the first results of its clinical use. Methods: Adult patients undergoing major surgery in five hospitals in the Netherlands received the SSTS for postoperative pain relief as part of multimodal pain management that further included paracetamol and a nonsteroidal anti-inflammatory drug (NSAID). The following variables were collected: postoperative pain scores using the 11-point numerical rating score (NRS) at rest, number of tablets used, occurrence of nausea, and patient satisfaction scores. Results: We included 280 patients in the study; the majority underwent laparoscopic abdominal (49%) or orthopedic (knee replacement) surgery (34%). The median NRS was 3.5 (interquartile range 2.3–4.0) on the day of surgery, 3.3 (2.3–4.0) on the first postoperative day, and 2.8 (2.0–4.0) on the second postoperative day; pain scores did not differ between surgery types. Mean number of tablets used was 19 (range 0–86). Nausea occurred in 34% of patients, more often in women (45% vs 19%). Overall satisfaction was high in 73% of patients. Satisfaction was correlated with pain relief (p < 0.001) and inversely correlated with occurrence of nausea (p=0.01). Discussion: In this data set obtained under real-life conditions we show that the SSTS effectively managed postoperative pain in abdominal and orthopedic surgeries. Future studies should determine patient populations that benefit most from the SSTS, assess the added values versus intravenous patient-controlled analgesia, and determine the pharmacoeconomics of the system

Therapeutic anticoagulation after liver transplantation is not useful among patients with pre-transplant Yerdel-grade I/II portal vein thrombosis:A two-center retrospective study

BACKGROUND: Portal vein thrombosis (PVT) is no longer a contraindication for liver transplantation (LT). While therapeutic anticoagulation (tAC) is recommended during the waiting period, there is no evidence for its usefulness in the prevention of PVT recurrence after LT. OBJECTIVES: The aim of our study was to evaluate the role of tAC post-LT in the prevention of PVT recurrence. PATIENTS/METHODS: All adult LTs performed in 2 high volume centres between 2003 and 2018, were retrospectively analysed. Only patients with PVT classified as Yerdel grade I or II and with standard portal reconstruction were included. PVT recurrence and tAC-associated morbidity within 1 year were compared between patients receiving tAC or not. RESULTS: During the study period, out of 2612 LTs performed, 235 (9%) patients with PVT were included. 113 patients (48.1%) received post-LT tAC (tAC group) while 122 (51.9%) did not (non-tAC group). The incidence of bleeding events was significantly higher in the tAC group (26 (23%) vs. 5 (4.1%), p<0.01) and the initial hospitalization duration was longer (21 vs. 17.5 days, p<0.01). Within the first year, PVT recurrence was observed for 9 (3.8%) patients without any difference between the tAC and non-tAC groups (6 (5.1%) vs. 3 (2.5%), p=0.39). The only identified risk factor for PVT recurrence was the recipients' age (OR=0.94, p=0.03). Graft (p=0.11) and patient (p=0.44) survival were similar between the 2 groups. CONCLUSION: Therapeutic anticoagulation is not necessary in the prevention of grade I/II PVT recurrence and is associated with higher morbidity and longer hospital stay

Evaluation of a field-deployable Nafion (TM)-based air-drying system for collecting whole air samples and its application to stable isotope measurements of CO2

Atmospheric flask samples are either collected at atmospheric pressure by opening a valve of a pre-evacuated flask or pressurized with the help of a pump to a few bar above ambient pressure. Under humid conditions, there is a risk that water vapor in the sample leads to condensation on the walls of the flask, notably at higher than ambient sampling pressures. Liquid water in sample flasks is known to affect the CO2 mixing ratios and also alters the isotopic composition of oxygen (17O and 18O) in CO2 via isotopic equilibration. Hence, for accurate determination of CO2 mole fractions and its stable isotopic composition, it is vital to dry the air samples to a sufficiently low dew point before they are pressurized in flasks to avoid condensation. Moreover, the drying system itself should not influence the mixing ratio and the isotopic composition of CO2 or that of the other constituents under study. For the Airborne Stable Isotopes of Carbon from the Amazon (ASICA) project focusing on accurate measurements of CO2 and its singly substituted stable isotopologues over the Amazon, an air-drying system capable of removing water vapor from air sampled at a dew point lower than -2 °C, flow rates up to 12 L min-1 and without the need for electrical power was needed. Since to date no commercial air-drying device that meets these requirements has been available, we designed and built our own consumable-free, power-free and portable drying system based on multitube Nafion™ gas sample driers (Perma Pure, Lakewood, USA). The required dry purge air is provided by feeding the exhaust flow of the flask sampling system through a dry molecular sieve (type 3A) cartridge. In this study we describe the systematic evaluation of our Nafion™-based air sample dryer with emphasis on its performance concerning the measurements of atmospheric CO2 mole fractions and the three singly substituted isotopologues of CO2 (16O13C16O, 16O12C17O and 16O12C18O), as well as the trace gas species CH4, CO, N2O and SF6. Experimental results simulating extreme tropical conditions (saturated air at 33 °C) indicated that the response of the air dryer is almost instantaneous and that approximately 85 L of air, containing up to 4 % water vapor, can be processed staying below a -2 °C dew point temperature (at 275 kPa). We estimated that at least eight flasks can be sampled (at an overpressure of 275 kPa) with a water vapor content below -2 °C dew point temperature during a typical flight sampling up to 5 km altitude over the Amazon, whereas the remaining samples would stay well below 5 °C dew point temperature (at 275 kPa). The performance of the air dryer on measurements of CO2, CH4, CO, N2O, and SF6 and the CO2 isotopologues 16O13C16O and 16O12C18O was tested in the laboratory simulating real sampling conditions by compressing humidified air from a calibrated cylinder, after being dried by the air dryer, into sample flasks. We found that the mole fraction and the isotopic composition difference between the different test conditions (including the dryer) and the base condition (dry air, without dryer) remained well within or very close to, in the case of N2O, the World Meteorological Organization recommended compatibility goals for independent measurement programs, proving that the test condition induced no significant bias on the sample measurements