Impact of Oxidative DNA Damage and the Role of DNA Glycosylases in Neurological Dysfunction

The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders.

Dive Performance and Aquatic Thermoregulation of the World’s Smallest Mammalian Diver, the American Water Shrew (Sorex palustris)

Allometry predicts that the 12–17 g American water shrew (Sorex palustris)—the world’s smallest mammalian diver—will have the highest diving metabolic rate (DMR) coupled with the lowest total body oxygen storage capacity, skeletal muscle buffering capacity, and glycolytic potential of any endothermic diver. Despite these constraints, the maximum dive time (23.7 sec) and calculated aerobic dive limit (cADL; 10.8–14.4 sec) of wild-caught water shrews match or exceed values predicted by allometry based on studies of larger-bodied divers. The mean voluntary dive time of water shrews in 3, 10, 20, and 30°C water was 5.1±0.1 sec (N=25, n=1584), with a mean maximum dive time of 10.3±0.4 sec. Only 2.3–3.9% of dives in 30 and 10°C water, respectively, exceeded the cADL. Mean dive duration, duration of the longest dive, and total time in water all decreased significantly as temperature declined, suggesting that shrews employed behavioural thermoregulation to defend against immersion hypothermia. As expected from their low thermal inertia, diving shrews had a significantly higher DMR in 10°C (8.77 mL O2 g-1 hr-1) compared to 30°C water (6.57 mL O2 g-1 hr-1). Diving behavior of radio-telemetered shrews exclusively foraging in a simulated riparian environment (3°C water) for 12- to 28-hours suggest that mean (but not maximum) dive times of water shrews in the wild may be longer than predicted from our voluntary dive trials, as the average dive duration (6.9±0.2 sec, n=257) was ∼1.75× longer than during 20-min trials with no access to food at the same water temperature. Notably, free-diving shrews in the 24-hr trials consistently elevated core body temperature by ∼1.0–1.5°C immediately prior to initiating aquatic foraging bouts, and ended these bouts when body temperature was still at or above normal resting levels (∼37.8°C). We suggest this observed pre-dive hyperthermia aids to heighten the impressive somatosensory physiology, and hence foraging efficiency, of this diminutive predator while submerged.

Cervical air sac oxygen profiles in diving emperor penguins: parabronchial ventilation and the respiratory oxygen store

Some marine birds and mammals can perform dives of extraordinary duration and depth. Such dive performance is dependent on many factors, including total body oxygen (O2) stores. For diving penguins, the respiratory system (air sacs and lungs) constitutes 30-50% of the total body O2 store. To better understand the role and mechanism of parabronchial ventilation and O2 utilization in penguins both on the surface and during the dive, we examined air sac partial pressures of O2 (PO2) in emperor penguins (Aptenodytes forsteri) equipped with backpack PO2 recorders. Cervical air sac PO2s at rest were lower than in other birds, while the cervical air sac to posterior thoracic air sac PO2 difference was larger. Pre-dive cervical air sac PO2s were often greater than those at rest, but had a wide range and were not significantly different from those at rest. The maximum respiratory O2 store and total body O2 stores calculated with representative anterior and posterior air sac PO2 data did not differ from prior estimates. The mean calculated anterior air sac O2 depletion rate for dives up to 11 min was approximately one-tenth that of the posterior air sacs. Low cervical air sac PO2s at rest may be secondary to a low ratio of parabronchial ventilation to parabronchial blood O2 extraction. During dives, overlap of simultaneously recorded cervical and posterior thoracic air sac PO2 profiles supported the concept of maintenance of parabronchial ventilation during a dive by air movement through the lungs.

Diving deep into trouble: the role of foraging strategy and morphology in adapting to a changing environment

Physiology places constraints on an animal’s ability to forage and those unable to adapt to changing conditions may face increased challenges to reproduce and survive. As the global marine environment continues to change, small, air-breathing, endothermic marine predators such as otariids (fur seals and sea lions) and particularly females, who are constrained by central place foraging during breeding, may experience increased difficulties in successfully obtaining adequate food resources. We explored whether physiological limits of female otariids may be innately related to body morphology (fur seals vs sea lions) and/or dictate foraging strategies (epipelagic vs mesopelagic or benthic). We conducted a systematic review of the increased body of literature since the original reviews of Costa et al. (When does physiology limit the foraging behaviour of freely diving mammals? Int Congr Ser 2004;1275:359–366) and Arnould and Costa (Sea lions in drag, fur seals incognito: insights from the otariid deviants. In Sea Lions of the World Fairbanks. Alaska Sea Grant College Program, Alaska, USA, pp. 309–324, 2006) on behavioural (dive duration and depth) and physiological (total body oxygen stores and diving metabolic rates) parameters. We estimated calculated aerobic dive limit (cADL—estimated duration of aerobic dives) for species and used simulations to predict the proportion of dives that exceeded the cADL. We tested whether body morphology or foraging strategy was the primary predictor of these behavioural and physiological characteristics. We found that the foraging strategy compared to morphology was a better predictor of most parameters, including whether a species was more likely to exceed their cADL during a dive and the ratio of dive time to cADL. This suggests that benthic and mesopelagic divers are more likely to be foraging at their physiological capacity. For species operating near their physiological capacity (regularly exceeding their cADL), the ability to switch strategies is limited as the cost of foraging deeper and longer is disproportionally high, unless it is accompanied by physiological adaptations. It is proposed that some otariids may not have the ability to switch foraging strategies and so be unable adapt to a changing oceanic ecosystem.

Preparation for Advanced Airway Management: Pre-oxygenation and Positioning

Preoxygenation allows a margin of safety prior to establishing control of a patient’s airway. Effective preoxygenation is influenced by careful technique, respiratory physiology, blood oxygen content, and total body oxygen consumption. Total body oxygen consumption is increased in the pregnant, pediatric, and obese populations, making maintenance of oxygenation more difficult during apnea. In addition to a standard facemask, advanced equipment such as high-flow nasal cannula, THRIVE, and various mask variants may be used. Positioning of a patient for advanced airway management affects preoxygenation, respiratory mechanics, and the conditions for establishing a definitive airway. The “triple airway support” maneuver consists of head extension, neck flexion, and protrusion of the mandibular teeth over the upper teeth; and provides effective mechanics for positive-pressure mask ventilation. Patients with potentially unstable cervical spines present additional challenges and, especially in emergency situations, require careful negotiation of priorities. Common maneuvers such as head tilt, jaw thrust, cricoid pressure, and manual in-line stabilization can cause motion in the unstable cervical spine with uncertain effects. This review contains 7 figures, 5 tables, and 43 references. Keywords: preoxygenation, functional residual capacity, blood oxygen content, alveolar fraction of oxygen, total body oxygen consumption, high-flow nasal cannula, apneic oxygenation, sniffing position, triple airway support maneuver, manual in-line stabilization

β1-Blockade increases maximal apnea duration in elite breath-hold divers

We hypothesized that the cardioselective β1-adrenoreceptor antagonist esmolol would improve maximal apnea duration in elite breath-hold divers. In elite national-level divers ( n = 9), maximal apneas were performed in a randomized and counterbalanced order while receiving either iv esmolol (150 μg·kg−1·min−1) or volume-matched saline (placebo). During apnea, heart rate (ECG), beat-by-beat blood pressure, stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were measured (finger photoplethysmography). Myocardial oxygen consumption (MV̇o2) was estimated from rate pressure product. Cerebral blood flow through the internal carotid (ICA) and vertebral arteries (VA) was assessed using Duplex ultrasound. Apnea duration improved in the esmolol trial when compared with placebo (356 ± 57 vs. 323 ± 61 s, P < 0.01) despite similar end-apnea peripheral oxyhemoglobin saturation (71.8 ± 10.3 vs. 74.9 ± 9.5%, P = 0.10). The HR response to apnea was reduced by esmolol at 10–30% of apnea duration, whereas MAP was unaffected. Esmolol reduced SV (main effect, P < 0.05) and CO (main effect; P < 0.05) and increased TPR (main effect, P < 0.05) throughout apnea. Esmolol also reduced MV̇o2 throughout apnea (main effect, P < 0.05). Cerebral blood flow through the ICA and VA was unchanged by esmolol at baseline and the last 30 s of apnea; however, global cerebral blood flow was reduced in the esmolol trial at end-apnea ( P < 0.05). Our findings demonstrate that, in elite breath-hold divers, apnea breakpoint is improved by β1-blockade, likely owing to an improved total body oxygen sparring through increased centralization of blood volume (↑TPR) and reduced MV̇o2. NEW & NOTEWORTHY The governing bodies for international apnea competition, the Association Internationale pour le Développment de l’Apnée and La Confédération Mondaile des Activités Subaquatiques, have banned the use of β-blockers based on anecdotal reports that they improve apnea duration. Using a randomized placebo-controlled trial, we are the first to empirically confirm that β-blockade improves apnea duration. This improvement in apnea duration coincided with a reduced myocardial oxygen consumption.

The effects of aerobic fitness and β1-adrenergic receptor blockade on cardiac work during dynamic exercise

The purpose of this investigation was to determine whether cardiovascular adaptations characteristic of long-term endurance exercise compensate more effectively during cardioselective β1-adrenergic receptor blockade-induced reductions in sympathoadrenergic-stimulated contractility. Endurance-trained (ET) athletes ( n = 8) and average-trained (AT; n = 8) subjects performed submaximal cycling exercise at moderate [45% maximum oxygen uptake (V̇o2max)] and heavy (70% V̇o2max) workloads, with and without metoprolol. Cardiac output (Q̇c), heart rate (HR), and systolic blood pressure were recorded at rest and during exercise. Cardiac work was calculated from the triple product of HR, stroke volume, and systolic blood pressure, and myocardial efficiency is represented as cardiac work for a given total body oxygen consumption. Metoprolol reduced Q̇c at 45% V̇o2max ( P = 0.004) and 70% V̇o2max ( P = 0.022) in ET subjects, but did not alter Q̇c in the AT subjects. In ET subjects at 45% V̇o2max, metoprolol-induced reductions in Q̇c were a result of decreases in HR ( P < 0.05) and the absence of a compensatory increase in stroke volume ( P > 0.05). The cardiac work and calculated cardiac efficiency were reduced with metoprolol in ET subjects at both exercise intensities and in the AT subjects during the high-intensity workload ( P < 0.01). The cardiac work and the calculated cardiac efficiency were not affected by metoprolol in the AT subjects during the 45% V̇o2max exercise. Therefore, in AT subjects, β-blockade reduced the amount of pressure generation necessary to produce the same amount of work during moderate-intensity exercise. In patients with heart disease receiving metoprolol, a decrease in the generation of cardiac pressure necessary to perform a given amount of work during mild-to-moderate exercise would prove to be beneficial.