Oxygen - Mitochondrial fuel as a missing link in depressive pathophysiology

Major depressive disorder (MDD) causes enormous individual suffering and socioeconomic costs. Biochemical mechanisms leading to MDD are poorly understood and therapy success is not satisfactory. At present, there is evidence of low-grade inflammation, oxidative stress, and most interestingly, a disturbed energy metabolism in MDD and other mental health diseases. Mitochondria play a central part in energy production and stress signaling. Mitochondrial electron transport chain uses molecular oxygen (O2) as final electron acceptor during adenosine triphosphate production attributing a crucial role to an intact O2 supply. Adaptation to altered O2 availability by the highly conserved hypoxic response is essential for maintaining allostasis. Previous research confirmed the role of O2 metabolism in the pathophysiology of MDD. In this perspective article, we compile the evidence linking O2 transport, O2 homeostasis, and mitochondrial energy metabolism to MDD. Furthermore, we hypothesize that inflammation and oxidative stress-related alterations in O2 transport might lead to a hypoxic response, which explains changes in O2 homeostasis and energy metabolism in MDD. Our forthcoming studies will investigate the interplay between energy metabolism and O2 homeostasis in MDD that aim to improve the overall understanding of the pathophysiology of MDD and to guide medical and psychological diagnostics towards a holistic strategy.

Abstract 10679: Tissue-to-Arterial Carbon Dioxide Partial Pressure Gradient as a Useful Measure for Monitoring Tissue Perfusion in a Pig Model of Hemorrhagic Shock and Resuscitation

Introduction: Transcutaneous CO 2 (tcPCO 2 ) and arterial CO 2 (artPCO 2 ) become decoupled during shock. Aim: To test the hypotheses the gradient between tcPCO 2 and artPCO 2 (tc-artPCO 2 ) can be an early, sensitive measure to detect inadequate tissue perfusion in a pig model of hemorrhage shock. Methods: Six female pigs were used. A transcutaneous monitor was attached to the ear for measuring transcutaneous O 2 (tcPO 2 ) and tcPCO 2 . Pulmonary artery catheter and the pulse index continuous cardiac output (PiCCO) were instrumented for monitoring a variety of hemodynamic parameters. To induce massive hemorrhagic shock, blood was withdrawn stepwisely. Then, animals were resuscitated in stages with transfusions of the stored blood. The parameters were measured at the timings of 10, 20, and 30 ml/kg of blood withdrawals and the completions of 10, 20, and 30 ml/kg of blood transfusion . Levels of systemic oxygen delivery (DO 2 ) were also calculated at all measurement points. Results: Hemorrhage and blood transfusion impacted hemodynamic and laboratory data, such as cardiac output (CO), stroke volume, MAP, heart rate, pulmonary artery wedge pressure, global end-diastolic volume, hemoglobin, and arterial lactate. The tc-artPCO 2 markedly increased as CO decreased ( Figure A ). The critical level of DO 2 (DO 2crit ) was defined as 11.72 ml/kg/min according to tcPO 2 (a threshold as 30 mmHg). There was significant correlation between tc-artPCO 2 and DO 2 (r = -0.83, P<.0001). ROC analyses revealed that the AUCs to predict DO 2crit for tc-artPCO 2 , shock index (SI), and lactate were 0.94 (95% CI, 0.87-1.00), 0.78 (0.63-0.93), and 0.65 (0.47-0.82), respectively. The AUC for tc-artPCO 2 was greater with respect to the prediction of DO 2crit than for SI (P<.05) ( Figure B ). Conclusions: The tc-artPCO 2 strongly correlated with CO and DO 2 during hemorrhage shock and resuscitation. The less-invasive tc-artPCO 2 monitoring can sensitively detect systemic inadequate O2 supply in hemorrhagic shock.

Hypoxia Performance Curve: Assess a Whole-Organism Metabolic Shift from a Maximum Aerobic Capacity towards a Glycolytic Capacity in Fish

The utility of measuring whole-animal performance to frame the metabolic response to environmental hypoxia is well established. Progressively reducing ambient oxygen (O2) will initially limit maximum metabolic rate as a result of a hypoxemic state and ultimately lead to a time-limited, tolerance state supported by substrate-level phosphorylation when the O2 supply can no longer meet basic needs (standard metabolic rate, SMR). The metabolic consequences of declining ambient O2 were conceptually framed for fishes initially by Fry’s hypoxic performance curve, which characterizes the hypoxemic state and its consequences to absolute aerobic scope (AAS), and Hochachka’s concept of scope for hypoxic survival, which characterizes time-limited life when SMR cannot be supported by O2 supply. Yet, despite these two conceptual frameworks, the toolbox to assess whole-animal metabolic performance remains rather limited. Here, we briefly review the ongoing debate concerning the need to standardize the most commonly used assessments of respiratory performance in hypoxic fishes, namely critical O2 (the ambient O2 level below which maintenance metabolism cannot be sustained) and the incipient lethal O2 (the ambient O2 level at which a fish loses the ability to maintain upright equilibrium), and then we advance the idea that the most useful addition to the toolbox will be the limiting-O2 concentration (LOC) performance curve. Using Fry & Hart’s (1948) hypoxia performance curve concept, an LOC curve was subsequently developed as an eco-physiological framework by Neil et al. and derived for a group of fish during a progressive hypoxia trial by Claireaux and Lagardère (1999). In the present review, we show how only minor modifications to available respirometry tools and techniques are needed to generate an LOC curve for individual fish. This individual approach to the LOC curve determination then increases its statistical robustness and importantly opens up the possibility of examining individual variability. Moreover, if peak aerobic performance at a given ambient O2 level of each individual is expressed as a percentage of its AAS, the water dissolved O2 that supports 50% of the individual’s AAS (DOAAS-50) can be interpolated much like the P50 for an O2 hemoglobin dissociation curve (when hemoglobin is 50% saturated with O2). Thus, critical O2, incipient lethal O2, DOAAS-50 and P50 and can be directly compared within and across species. While an LOC curve for individual fish represents a start to an ongoing need to seamlessly integrate aerobic to anaerobic capacity assessments in a single, multiplexed respirometry trial, we close with a comparative exploration of some of the known whole-organism anaerobic and aerobic capacity traits to examine for correlations among them and guide the next steps.

Normoxic limitation of maximal oxygen consumption rate, aerobic scope and cardiac performance in exhaustively exercised rainbow trout (Oncorhynchus mykiss)

In fish, maximum O2 consumption rate (MO2max) and aerobic scope can be expanded following exhaustive exercise in hyperoxia; however, the mechanisms explaining this are yet to be identified. Here, in exhaustively exercised rainbow trout (Oncorhynchus mykiss), we assessed the influence of hyperoxia on MO2max, aerobic scope, cardiac function and blood parameters to address this knowledge gap. Relative to normoxia, MO2max was 33% higher under hyperoxia, and this drove a similar increase in aerobic scope. Cardiac output, due to increased stroke volume, was significantly elevated under hyperoxia at MO2max indicating hyperoxia released a constraint on cardiac contractility apparent with normoxia. Thus, hyperoxia improved maximal cardiac performance, thereby enhancing tissue O2 delivery and allowing a higher MO2max. Venous blood O2 partial pressure (PvO2) was elevated in hyperoxia at MO2max, suggesting a contribution of improved luminal O2 supply in enhanced cardiac contractility. Additionally, despite reduced haemoglobin and higher PvO2, hyperoxia treated fish retained a higher arterio-venous O2 content difference at MO2max. This may have been possible due to hyperoxia offsetting declines in arterial oxygenation known to occur following exhaustive exercise in normoxia. If this occurs, increased contractility at MO2max with hyperoxia may also relate to an improved O2 supply to the compact myocardium via the coronary artery. Our findings show MO2max and aerobic scope may be limited in normoxia following exhaustive exercise due to constrained maximal cardiac performance and highlight the need to further examine whether or not exhaustive exercise protocols are suitable for eliciting MO2max and estimating aerobic scope in rainbow trout.

Is hypoxia vulnerability in fishes a by-product of maximum metabolic rate?

ABSTRACT The metabolic index concept combines metabolic data and known thermal sensitivities to estimate the factorial aerobic scope of animals in different habitats, which is valuable for understanding the metabolic demands that constrain species' geographical distributions. An important assumption of this concept is that the O2 supply capacity (which is equivalent to the rate of oxygen consumption divided by the environmental partial pressure of oxygen: ) is constant at O2 tensions above the critical O2 threshold (i.e. the where O2 uptake can no longer meet metabolic demand). This has led to the notion that hypoxia vulnerability is not a selected trait, but a by-product of selection on maximum metabolic rate. In this Commentary, we explore whether this fundamental assumption is supported among fishes. We provide evidence that O2 supply capacity is not constant in all fishes, with some species exhibiting an elevated O2 supply capacity in hypoxic environments. We further discuss the divergent selective pressures on hypoxia- and exercise-based cardiorespiratory adaptations in fishes, while also considering the implications of a hypoxia-optimized O2 supply capacity for the metabolic index concept.

Intravenous infusion of glucose improved farrowing performance of hyperprolific crossbred sows

The sow at parturition is challenged with respect to energy status due to increases in energetic expenses associated with 1) nest building 2) uterine contractions and 3) colostrum production. A previous study indicated that sows were depleted of glucogenic energy around farrowing. The aim was to investigate whether intravenous infusion of glucose from observed nest building behavior to 24 h postpartum affected the farrowing kinetics and colostrum production in sows. Ten multiparous sows (DanBred landrace × DanBred Yorkshire) were fitted with a jugular vein catheter on each side (one for infusion, one for blood sampling). Sows were infused with either 0.9% saline (CON; n=5) or 10% glucose (GLU; n=5) solution at a constant rate of 125 ml/h. From day 108 of gestation, sows were fed once daily with 3.33 kg of a standard lactation diet. During farrowing sows were monitored to register the onset of farrowing, time of birth, birth status (live or dead), sex, stillbirth rate (SR) and weight of newborn piglets. Farrowing assistance (FA) was provided when birth interval exceeded 60 min. In late gestation, 1 mL of blood was collected every third h for blood gas analysis and every sixth h for harvesting plasma. During farrowing, 1 mL (for blood gas) and 9 mL blood was collected at 0, 3, 6, 9, 12, 15, 18, 21 and 24 hours in milk (HIM). Colostrum and milk samples were collected at 0, 6, 12, 18, 24 and 36 HIM and also at 3, 10, 17 and 24 days in milk. Compared with CON sows, GLU infusion decreased the SR (16.1 vs 7.4%; P= = 0.03), FA (21 vs 9.0%; P = 0.01) and surprisingly also blood glucose at onset of farrowing (5.53 vs 5.09 mmol/L; P = 0.03), respectively. A tendency to higher plasma lactate at the onset of farrowing (P = 0.05) but decreased piglet mortality from 0-24 h (P = 0.06) were also found for GLU sows. No effects of treatment on farrowing duration or mean birth intervals were found. Lactate in whole blood (P = 0.003) and plasma (P = 0.002) was increased for GLU sows as compared with CON sows during the colostrum period. No effect of GLU infusion was seen on colostrum and milk composition and yield. The increase in lactate was most likely due to a shift towards a greater proportion of glucose oxidation and insufficient O2 supply to fuel uterine contractions. In conclusion, infusion of glucose reduced the frequency of SR and FA, and improved energy status of the sow seems to be a crucial trait to enhance total piglet survival.

Identification of Breathing Patterns through EEG Signal Analysis Using Machine Learning

This study was to investigate the changes in brain function due to lack of oxygen (O2) caused by mouth breathing, and to suggest a method to alleviate the side effects of mouth breathing on brain function through an additional O2 supply. For this purpose, we classified the breathing patterns according to EEG signals using a machine learning technique and proposed a method to reduce the side effects of mouth breathing on brain function. Twenty subjects participated in this study, and each subject performed three different breathings: nose and mouth breathing and mouth breathing with O2 supply during a working memory task. The results showed that nose breathing guarantees normal O2 supply to the brain, but mouth breathing interrupts the O2 supply to the brain. Therefore, this comparative study of EEG signals using machine learning showed that one of the most important elements distinguishing the effects of mouth and nose breathing on brain function was the difference in O2 supply. These findings have important implications for the workplace environment, suggesting that special care is required for employees who work long hours in confined spaces such as public transport, and that a sufficient O2 supply is needed in the workplace for working efficiency.

Denitrification in soil as a function of oxygen availability at the microscale

The prediction of nitrous oxide (N2O) and of dinitrogen (N2) emissions formed by biotic denitrification in soil is notoriously difficult due to challenges in capturing co-occurring processes at microscopic scales. N2O production and reduction depend on the spatial extent of anoxic conditions in soil, which in turn are a function of oxygen (O2) supply through diffusion and O2 demand by respiration in the presence of an alternative electron acceptor (e.g. nitrate). This study aimed to explore controlling factors of complete denitrification in terms of N2O and (N2O + N2) fluxes in repacked soils by taking micro-environmental conditions directly into account. This was achieved by measuring microscale oxygen saturation and estimating the anaerobic soil volume fraction (ansvf) based on internal air distribution measured with X-ray computed tomography (X-ray CT). O2 supply and demand were explored systemically in a full factorial design with soil organic matter (SOM; 1.2 % and 4.5 %), aggregate size (2–4 and 4–8 mm), and water saturation (70 %, 83 %, and 95 % water-holding capacity, WHC) as factors. CO2 and N2O emissions were monitored with gas chromatography. The 15N gas flux method was used to estimate the N2O reduction to N2. N gas emissions could only be predicted well when explanatory variables for O2 demand and O2 supply were considered jointly. Combining CO2 emission and ansvf as proxies for O2 demand and supply resulted in 83 % explained variability in (N2O + N2) emissions and together with the denitrification product ratio [N2O / (N2O + N2)] (pr) 81 % in N2O emissions. O2 concentration measured by microsensors was a poor predictor due to the variability in O2 over small distances combined with the small measurement volume of the microsensors. The substitution of predictors by independent, readily available proxies for O2 demand (SOM) and O2 supply (diffusivity) reduced the predictive power considerably (60 % and 66 % for N2O and (N2O+N2) fluxes, respectively). The new approach of using X-ray CT imaging analysis to directly quantify soil structure in terms of ansvf in combination with N2O and (N2O + N2) flux measurements opens up new perspectives to estimate complete denitrification in soil. This will also contribute to improving N2O flux models and can help to develop mitigation strategies for N2O fluxes and improve N use efficiency.

Characteristics of patients with carbon monoxide poisoning due to smoke inhalation and pre-hospital factors related to intensive care unit admission of these patients: a nationwide observational study

This study aimed to investigate the pre-hospital clinical status of patients with carbon monoxide (CO) poisoning by smoke inhalation and the pre-hospital factors associated with these patients’ admission to the intensive care unit (ICU). In this observational study from January 2016 to December 2018, the National Fire Agency’s first aid activity log on patients with smoke inhalation was matched with National Emergency Department Information System’s patient data with CO poisoning and further analyzed retrospectively. Multiple logistic regression analysis was conducted to identify the relevant pre-hospital associative factors for the decision to admit a patient with CO poisoning to the ICU. Of the 4422 patients with CO poisoning included in the study, 358 (8.09%) were admitted to the ICU. In such patients transported by pre-hospital emergency medical services, age (odds ratio [OR], 1.020; 95% confidence interval [CI], 1.010–1.029), verbal (OR, 3.564; 95% CI, 2.390–5.315), pain (OR, 4.011; 95%CI, 2.661–6.045), unconsciousness (OR, 5.728; 95% CI, 2.708–12.113), SBP (OR, 0.979; 95% CI, 0.969–0.989), HR (OR, 1.011; 95% CI, 1.004–1.018), SpO2 (OR, 0.965; 95% CI, 0.946–0.985), O2 supply (OR, 1.725; 95% CI, 1.143–2.603), use of nasal prongs (OR, 0.504; 95% CI, 0.281–0.905), and intentional inhalation (OR, 2.282; 95% CI, 1.659–3.139) were independently associated with ICU admission. Our study demonstrated that age, mental change, SBP, HR, SPO2, O2 supply, use of nasal prongs, and intentional inhalation in patients with CO poisoning were associated with their ICU admission.