Blood oxygen transport and depletion in diving emperor penguins.

Oxygen store management underlies dive performance and is dependent on the slow heart rate and peripheral vasoconstriction of the dive response to control tissue blood flow and oxygen uptake. Prior research has revealed two major patterns of muscle myoglobin saturation profiles during dives of emperor penguins. In Type A profiles, myoglobin desaturated rapidly, consistent with minimal muscle blood flow and low tissue oxygen uptake. Type B profiles, with fluctuating and slower declines in myoglobin saturation, were consistent with variable tissue blood flow patterns and tissue oxygen uptake during dives. We examined arterial and venous blood oxygen profiles to evaluate blood oxygen extraction and found two primary patterns of venous hemoglobin desaturation that complemented corresponding myoglobin saturation profiles. Type A venous profiles had a hemoglobin saturation that (a) increased/plateaued for most of a dive's duration, (b) only declined during the latter stages of ascent, and (c) often became arterialized [arterio-venous (a-v) shunting]. In Type B venous profiles, variable but progressive hemoglobin desaturation profiles were interrupted by inflections in the profile that were consistent with fluctuating tissue blood flow and oxygen uptake. End-of-dive saturation of arterial and Type A venous hemoglobin saturation profiles were not significantly different, but did differ from those of Type B venous profiles. These findings provide further support that the dive response of emperor penguins is a spectrum of cardiac and vascular components (including a-v shunting) that are dependent on the nature and demands of a given dive and even of a given segment of a dive.

Yoga Breathing (Maheshwarananda's Modified Bhujangini Pranayama): A Randomized Study in Hypobaric Hypoxemia at 3,650 m Elevation.

Hypobaric hypoxemia represents a risk factor for body integrity and challenges its homeostasis. We examined whether practicing Maheshwarananda's modified bhujangini pranayama yoga breathing technique would influence hypobaric hypoxemia at an altitude of 3,650 m. An international randomized two-period, two-sequence crossover intervention study was conducted in September 2019 in the Himalayas. We compared 5-minute testing periods of pranayama breathing with normal resting breathing in 20 subjects divided randomly into two groups of 10 individuals; all had a daily practice of Maheshwarananda's modified bhujangini pranayama and were nonsmokers, lacto vegetarians, and alcohol abstainers. We measured the arterial saturation by pulse oximetry (SpO2; our primary outcome variable), end-tidal carbon dioxide partial pressure (EtCO2), respiratory rate, and heart rate at two altitudes: (1) 378 m (T0); and (2) 3,650 m (T1 = 2nd day, T2 = 4th day at the camp) immediately after finishing each testing period. We also monitored the presence of acute mountain sickness using the Lake Louise Scoring System. Mean SpO2 at 3,650 m increased right after the yoga breathing exercise from 88.60% to 90.35% at T1, and from 88.35% to 90.60% at T2 (T1 p = 0.007, T2 p = 0.004). No significant changes were observed in heart rate or EtCO2. The mean rate of normal control resting breathing was 13/min; the mean rate was 7/min during the yoga breathing. Right after Maheshwarananda's modified bhujangini pranayama hypobaric hypoxemia decreased as measured by SpO2, whereas EtCO2 and heart rate stayed comparable with the control resting breathing.

Evaluation of Tumor Development Using Hemoglobin Saturation Profile on Rodent Dorsal Window Chamber.

Tumor development can be indirectly evaluated using features of the tumor microenvironment (TME), such as hemoglobin saturation (HbSat), blood vessel dilation, and formation of new vessels. High values of HbSat and other features of the TME could indicate high metabolic activity and could precede the formation of angiogenic tumors; therefore, changes in HbSat profile can be used as a biomarker for tumor progression. One methodology to evaluate HbSat profile over time, and correlate it with tumor development in vivo in a preclinical model, is through a dorsal skin-fold window chamber. In this chapter, we provide a detailed description of this methodology to evaluate hemoglobin saturation profile and to predict tumor development. We will cover the surgical preparation of the mouse, the installation/maintenance of the dorsal window chamber, and the imaging processing and evaluation to the HbSat profile to predict new development of new tumor areas over time. We included, in this chapter, step by step examples of the imaging processing method to obtain pixel level HbSat values from raw pixels data, the computational method to determine the HbSat profile, and the steps for the classification of the areas into tumor and no-tumor.

Yogic breathing in hypobaric environment: breathing exercising and its effect on hypobaric hypoxemia and heart rate at 3,650-m elevation.

High altitude sojourn is a risk factor for hypobaric hypoxemia and subsequent altitude sickness. The aim of this study was to analyze the effect of new type of yogic breathing-Maheshwarananda's new Modified Bhujangini Pranayama performed by active yoga practitioners-on the arterial haemoglobin saturation of oxygen (measured by the pulse oximetry - SpO2) and the heart rate compared to normal spontaneous resting breathing. A pilot prospective study was conducted in the Himalayas at an altitude of 3,650 m. We monitored SpO2 and pulse rate in 34 experienced yoga practitioners. Within the 3 measurement days at the altitude of 3,650 m, the mean value of SpO2 increased from 89.11± 4.78 to 93.26±4.44 (P<0.001) after the yogic breathing exercise. No significant changes were observed in pulse rate (P<0.230) measured before and after yogic breathing. The new Yogic breathing-Maheshwarananda's Modified Bhujangini Pranayama-is increasing the arterial haemoglobin saturation compared to normal resting spontaneous breathing. The heart rate was not affected by this type of yogic breathing.

Reflectance spectra analysis for mucous assessment.

This review report represents an overview of research and development on medical hyperspectral imaging technology and its applications. Spectral imaging technology is attracting attention as a new imaging modality for medical applications, especially in disease diagnosis and image-guided surgery. Considering the recent advances in imaging, this technology provides an opportunity for two-dimensional mapping of oxygen saturation (SatO2) of blood with high accuracy, spatial spectral imaging, and its analysis and provides detection and diagnostic information about the tissue physiology and morphology. Multispectral imaging also provides information about tissue oxygenation, perfusion, and potential function during surgery. Analytical algorithm has been examined, and indication of accurate map of relative hemoglobin concentration and SatO2 can be indicated with preferable resolution and frame rate. This technology is expected to provide promising biomedical information in practical use. Several studies suggested that blood flow and SatO2 are associated with gastrointestinal disorders, particularly malignant tumor conditions. The use and analysis of spectroscopic images are expected to potentially play a role in the detection and diagnosis of these diseases.

Implication of Blood Rheology and Pulmonary Hemodynamics on Exercise-Induced Hypoxemia at Sea Level and Altitude in Athletes.

This study aimed to investigate the changes in blood viscosity, pulmonary hemodynamics, nitric oxide (NO) production, and maximal oxygen uptake (V˙O2max) during a maximal incremental test conducted in normoxia and during exposure to moderate altitude (2,400 m) in athletes exhibiting exercise-induced hypoxemia at sea level (EIH). Nine endurance athletes with EIH and eight without EIH (NEIH) performed a maximal incremental test under three conditions: sea level, 1 day after arrival in hypoxia, and 5 days after arrival in hypoxia (H5) at 2,400 m. Gas exchange and oxygen peripheral saturation (SpO2) were continuously monitored. Cardiac output, pulmonary arterial pressure, and total pulmonary vascular resistance were assessed by echocardiography. Venous blood was sampled before and 3 min after exercise cessation to analyze blood viscosity and NO end-products. At sea level, athletes with EIH exhibited an increase in blood viscosity and NO levels during exercise while NEIH athletes showed no change. Pulmonary hemodynamics and aerobic performance were not different between the two groups. No between-group differences in blood viscosity, pulmonary hemodynamics, and V˙O2max were found at 1 day after arrival in hypoxia. At H5, lower total pulmonary vascular resistance and greater NO concentration were reported in response to exercise in EIH compared with NEIH athletes. EIH athletes had greater cardiac output and lower SpO2 at maximal exercise in H5, but no between-group differences occurred regarding blood viscosity and V˙O2max. The pulmonary vascular response observed at H5 in EIH athletes may be involved in the greater cardiac output of EIH group and counterbalanced the drop in SpO2 in order to achieve similar V˙O2max than NEIH athletes.

Muscle and cerebral oxygenation during exercise in athletes with exercise-induced hypoxemia: A comparison between sea level and acute moderate hypoxia.

The objective of the present study was to evaluate the influence of exercise-induced hypoxemia (EIH) on muscle and cerebral oxygenation responses during maximal exercise in normoxia and in acute moderate hypoxia (fraction of inspired oxygen: 15.3%, 2400 m). EIH was defined as a drop in hemoglobin saturation of at least 4% for at least three consecutive minutes during maximal exercise at sea level. Twenty-five athletes performed incremental treadmill tests to assess maximal oxygen consumption (VO2max) in normoxia and in hypoxia. Oxygenation of the vastus lateralis muscle and the left prefrontal cortex of the brain was monitored using near-infrared spectroscopy. During the normoxic test, 15 athletes exhibited EIH; they displayed a larger change in muscle levels of oxyhemoglobin (ΔO2Hb) (p = 0.04) and a greater change in cerebral levels of deoxyhemoglobin (ΔHHb) (p = 0.02) than athletes without EIH (NEIH group). During the hypoxic test, muscle ΔO2Hb was lower in the EIH group than in the NEIH group (p = 0.03). At VO2max, hypoxia was associated with a smaller cerebral ΔO2Hb in both groups, and a greater cerebral ΔHHb compared to normoxia in the NEIH group only (p = 0.02). No intergroup differences in changes in muscle oxygenation were observed. The severity of O2 arterial desaturation was negatively correlated with changes in total muscle hemoglobin in normoxia (r = -0.48, p = 0.01), and positively correlated with the cerebral ΔHHb in normoxia (r = 0.45, p = 0.02). The occurrence of EIH at sea level was associated with specific muscle and cerebral oxygenation responses to exercise under both normoxia and moderate hypoxia.

Mitochondrial function and brain Metabolic Score (BMS) in ischemic Stroke: Evaluation of "neuroprotectants" safety and efficacy.

The initial and significant event developed in ischemic stroke is the sudden decrease in blood flow and oxygen supply to brain tissue, leading to dysfunction of the mitochondria. Many attempts were and are being made to develop new drugs and treatments that will save the ischemic brain, but the efficacy is not optimal and in many patients, irreversible damage to the brain will persist. We review a unique approach to evaluate mitochondrial function and microcirculatory hemodynamic in real time in vivo. Three out of four monitored physiological parameters are integrated into a new Brain Metabolic Score (BMS) calculated in real time and is correlated to Brain Oxygen Balance. The technology was adapted to various experimental as well as clinical situations for monitoring the brain in real time. The developed protocols could be used in testing the efficacy and safety of new drugs in experimental animals. Few models of brain monitoring during partial or complete ischemia were developed and used in naive animals or under brain activation protocols. It was found that mitochondrial function/dysfunction is the major and dominant parameter affecting the calculated Brain Metabolic Score. Using our monitoring system and protocols will provide direct information regarding the ability of the tested brain to provide enough oxygen consumed by the mitochondria in the "resting" or in the "activated" brain in vivo and in real-time. Preliminary studies, indicated that testing the efficacy and safety of new neuroprotectant drugs provided significant results to the R&D studies of ischemic stroke related to mitochondrial function.

Retrospective comparison of equine hemoglobin oxygen saturation measured by a human-specific co-oximeter, or derived from an algorithm using temperature-corrected and -uncorrected oxygen tension.

OBJECTIVE: Hemoglobin oxygen saturation (SO2) is measured by co-oximetry (SO2cox) or calculated from partial pressure of oxygen (PO2) using algorithms (SO2alg). To compare venous and systemic arterial blood sample data retrospectively and to examine whether temperature correction of PO2 is important. STUDY DESIGN: Retrospective study. ANIMALS: A group of 21 healthy, adult, sedated or anesthetized horses. METHODS: Mixed-venous and systemic arterial blood samples (1 mL) were anaerobically collected using commercial preheparinized syringes from the right ventricle and facial artery, respectively. Blood was analyzed using a commercial gas analyzer and human-specific co-oximeter within 10 minutes of collection or stored on ice and analyzed within 30 minutes. PO2 was measured at 37 °C and corrected using body temperature (Tcore) from a pulmonary artery catheter thermistor. SO2cox and hemoglobin subtypes were measured by co-oximetry (37 °C). An algorithm developed for Thoroughbred horse blood was used to calculate SO2alg using PO2 at 37 °C and SO2algcorr with PO2 corrected to Tcore. SO2alg and SO2algcorr were each paired with SO2cox using Bland-Altman (repeated measures) ratio of SO2alg/SO2cox (204 samples). RESULTS: SO2alg overestimated SO2cox when PO2 was <80 mmHg (10.7 kPa); ratio and limits of agreement: 1.2 (0.9-1.6) but became accurate when PO2 was ≥80 mmHg: 1.0 (1.0-1.0). With all data, SO2algcorr did not differ from SO2alg:1.1 (0.8-1.4). Methemoglobin (FMetHb) and carboxyhemoglobin (FCOHb) were significantly higher in venous [FMetHb: median (range): 1.8 (0-2.9)%; FCOHb: 0.1 (0-2)%] than in arterial blood [FMetHb: 0.5 (0-2.2)%; FCOHb: 0 (0-0.3)%]. CONCLUSIONS: The algorithm appeared robust when PO2 was ≥80 mmHg (10.7 kPa) but overestimated when PO2 was lower. Temperature correction was not important within 34.9-37.3 °C. CLINICAL RELEVANCE: SO2alg overestimation in venous blood can result in calculation of higher intrapulmonary shunt fraction than SO2cox values.

Pharmacological safety of Plinia cauliflora (Mart.) Kausel in rabbits.

Fruit peels of Plinia cauliflora (Mart.) Kausel are widely used in Brazilian traditional medicine, but no studies have proved the safety of its pharmacological effects on the respiratory, cardiovascular, and central nervous systems. The present study assessed the safety pharmacology of P. cauliflora in New Zealand rabbits. First, an ethanol extract (EEPC) was selected for the pharmacological experiments and chemical characterization. Then, different groups of rabbits were orally treated with EEPC (200 and 2000 mg/kg) or vehicle. Acute behavioral and physiological alterations in the modified Irwin test, respiratory rate, arterial blood gas, and various cardiovascular parameters (i.e., heart rate, blood pressure, and electrocardiography) were evaluated. The main secondary metabolites that were identified in EEPC were ellagic acid, gallic acid, O-deoxyhexosyl quercetin, and the anthocyanin O-hexosyl cyanidin. No significant behavioral or physiological changes were observed in any of the groups. None of the doses of EEPC affected respiratory rate or arterial blood gas, with no changes on blood pressure or electrocardiographic parameters. The present study showed that EEPC did not cause any significant changes in respiratory, cardiovascular, or central nervous system function. These data provide scientific evidence of the effects of this species and important safety data for its clinical use.

The Relation Between Capillary Transit Times and Hemoglobin Saturation Heterogeneity. Part 2: Capillary Networks.

Brain metabolism is highly dependent on continuous oxygen supply. Cortical microvascular networks exhibit heterogeneous blood flow, leading to non-uniform tissue oxygenation and capillary hemoglobin saturation. We recently proposed capillary outflow saturation heterogeneity (COSH) to represent effects of heterogeneity on oxygen supply to tissue regions most vulnerable to hypoxia, and showed that diffusive oxygen exchange among red blood cells within capillaries and among capillaries (diffusive interaction) significantly reduces COSH in simplified geometrical configurations. Here, numerical simulations of oxygen transport in capillary network geometries derived from mouse somatosensory cortex are presented. Diffusive interaction was found to reduce COSH by 41 to 62% compared to simulations where diffusive interaction was excluded. Hemoglobin saturation drop across the microvascular network is strongly correlated with red blood cell transit time, but the coefficient of variation of saturation drop is approximately one third lower. Unexpectedly, the radius of the tissue cylinder supplied by a capillary correlates weakly with the anatomical tissue cylinder radius, but strongly with hemoglobin saturation. Thus, diffusive interaction contributes greatly to the microcirculation's ability to achieve tissue oxygenation, despite heterogeneous capillary transit time and hematocrit distribution. These findings provide insight into the effects of cerebral small vessel disease on tissue oxygenation and brain function.

The Relation Between Capillary Transit Times and Hemoglobin Saturation Heterogeneity. Part 1: Theoretical Models.

Capillary dysfunction impairs oxygen supply to parenchymal cells and often occurs in Alzheimer's disease, diabetes and aging. Disturbed capillary flow patterns have been shown to limit the efficacy of oxygen extraction and can be quantified using capillary transit time heterogeneity (CTH). However, the transit time of red blood cells (RBCs) through the microvasculature is not a direct measure of their capacity for oxygen delivery. Here we examine the relation between CTH and capillary outflow saturation heterogeneity (COSH), which is the heterogeneity of blood oxygen content at the venous end of capillaries. Models for the evolution of hemoglobin saturation heterogeneity (HSH) in capillary networks were developed and validated using a computational model with moving RBCs. Two representative situations were selected: a Krogh cylinder geometry with heterogeneous hemoglobin saturation (HS) at the inflow, and a parallel array of four capillaries. The heterogeneity of HS after converging capillary bifurcations was found to exponentially decrease with a time scale of 0.15-0.21 s due to diffusive interaction between RBCs. Similarly, the HS difference between parallel capillaries also drops exponentially with a time scale of 0.12-0.19 s. These decay times are substantially smaller than measured RBC transit times and only weakly depend on the distance between microvessels. This work shows that diffusive interaction strongly reduces COSH on a small spatial scale. Therefore, we conclude that CTH influences COSH yet does not determine it. The second part of this study will focus on simulations in microvascular networks from the rodent cerebral cortex. Actual estimates of COSH and CTH will then be given.

Association of Oral Intake and Transient Mixed Venous Oxygen Desaturation in Patients Undergoing Fast-Track Postoperative Care After Open-Heart Surgery.

OBJECTIVE: The impact of early resumption of oral intake after cardiac surgery on hemodynamics has not been characterized. The authors examined the effects of early oral intake on the oxygen supply-demand relationship in patients undergoing on-pump cardiac surgery in an early recovery after surgery program. DESIGN: Prospective data were collected in postcardiac surgical patients in a multidisciplinary intensive care unit (ICU) during an 18-month period. SETTING: Single institution study. PARTICIPANTS: Forty-three patients who underwent either mitral or aortic valve repair and were successfully liberated from ventilatory support within 10 hours after surgery. INTERVENTIONS: Patients were either allowed to resume oral intake on the morning of the first postoperative day or not at the discretion of the surgical team after extubation. MEASUREMENTS AND MAIN RESULTS: The oxygen supply-demand relationship was assessed continuously with cardiac index and mixed venous oxygen saturation (SvO2). Among the subjects, 22 patients were allowed to eat, and transient SvO2 decrease was noted in 13 patients. All transient SvO2 decreases occurred in the patients with early oral intake. The hemodynamic status and oxygen supply-demand relationship did not differ between the patients with and without transient SvO2 decrease. All the subjects were discharged successfully from the ICU on the first postoperative day, and the length of hospital stay was similar irrespective of SvO2 decrease after early oral intake. CONCLUSIONS: Early oral intake shortly after extubation was associated with transient but significant SvO2 decrease in patients who underwent fast-track recovery after open-heart surgery. Because this phenomenon did not negatively affect the postoperative outcome, early oral intake may not be harmful.

Low Cerebral Oxygenation Is Associated with Cognitive Impairment in Chronic Hemodialysis Patients.

BACKGROUND/AIMS: High rates of cognitive impairment (CI) are an alarming problem in patients undergoing chronic hemodialysis (HD). Its pathophysiology remains unclear and there are indications that brain ischemia might be one of the key causes. Cerebral tissue oxygenation, as measured by near-infrared spectroscopy, is known to be decreased in HD patients. However, it is unknown whether CI is associated or not associated with lower cerebral oxygenation in these patients. The primary aim of our study was to probe this possible association. Our secondary aim was to assess other factors possibly related to cerebral ischemia and CI. METHODS: Thirty-nine patients treated by chronic HD were included in this cross-sectional study. All measurements were performed before the initiation of an HD session. The Montreal Cognitive Assessment (MoCA) was administered according to published recommendations. Regional saturation of oxygen (rSO2) of the left frontal lobe was measured using the INVOS 5100C device. Basic medical history and laboratory data were recorded, and handgrip strength was analyzed. We used the unpaired t test to compare the rSO2 and other variables between cognitively normal patients (MoCA score ≥26) and those who displayed CI (MoCA score <26). Multiple linear regression analysis was used to adjust for principal confounders. RESULTS: Cognitively impaired patients had lower brain rSO2 values compared to cognitively normal patients (48 ± 9 vs. 57 ± 10%, p = 0.01). Among other variables, higher red cell distribution width (15.8 ± 1.9 vs. 13.8 ± 1.6%, p = 0.01) and lower hand grip strength (49.2 ± 23.3 vs. 99.3 ± 31.4 lbs, p < 0.001) also displayed a significant association with CI. The relation between rSO2 and MoCA score was significant after adjustment for age and gender (p = 0.007). CONCLUSION: Decreased brain oxygenation is associated with weaker cognitive performance in patients undergoing chronic HD. Further understanding the causes of cerebral ischemia in HD patients could lead to the prevention of cognitive decline in this population.

Anterior vena caval oxygen profiles in a deep-diving California sea lion: arteriovenous shunts, a central venous oxygen store and oxygenation during lung collapse.

Deep-diving California sea lions (Zalophus californianus) can maintain arterial hemoglobin saturation (SO2 ) above 90% despite lung collapse (lack of gas exchange) and extremely low posterior vena caval SO2  in the middle of the dive. We investigated anterior vena caval PO2 and SO2  during dives of an adult female sea lion to investigate two hypotheses: (1) posterior vena caval SO2  is not representative of the entire venous oxygen store and (2) a well-oxygenated (arterialized) central venous oxygen reservoir might account for maintenance of arterial SO2  during lung collapse. During deep dives, initial anterior vena caval SO2  was elevated at 83.6±8.4% (n=102), presumably owing to arteriovenous shunting. It remained high until the bottom phase of the dive and then decreased during ascent, whereas previously determined posterior vena caval SO2  declined during descent and then often increased during ascent. These divergent patterns confirmed that posterior vena caval SO2  was not representative of the entire venous oxygen store. Prior to and early during descent of deep dives, the high SO2  values of both the anterior and posterior venae cavae may enhance arterialization of a central venous oxygen store. However, anterior vena caval SO2  values at depths beyond lung collapse reached levels as low as 40%, making it unlikely that even a completely arterialized central venous oxygen store could account for maintenance of high arterial SO2 These findings suggest that maintenance of high arterial SO2  during deep dives is due to persistence of some gas exchange at depths beyond presumed lung collapse.

Nonlinear extension of a hemodynamic linear model for coherent hemodynamics spectroscopy.

In this work, we are proposing an extension of a recent hemodynamic model (Fantini, 2014a), which was developed within the framework of a novel approach to the study of tissue hemodynamics, named coherent hemodynamics spectroscopy (CHS). The previous hemodynamic model, from a signal processing viewpoint, treats the tissue microvasculature as a linear time-invariant system, and considers changes of blood volume, capillary blood flow velocity and the rate of oxygen diffusion as inputs, and the changes of oxy-, deoxy-, and total hemoglobin concentrations (measured in near infrared spectroscopy) as outputs. The model has been used also as a forward solver in an inversion procedure to retrieve quantitative parameters that assess physiological and biological processes such as microcirculation, cerebral autoregulation, tissue metabolic rate of oxygen, and oxygen extraction fraction. Within the assumption of "small" capillary blood flow velocity oscillations the model showed that the capillary and venous compartments "respond" to this input as low pass filters, characterized by two distinct impulse response functions. In this work, we do not make the assumption of "small" perturbations of capillary blood flow velocity by solving without approximations the partial differential equation that governs the spatio-temporal behavior of hemoglobin saturation in capillary and venous blood. Preliminary comparison between the linear time-invariant model and the extended model (here identified as nonlinear model) are shown for the relevant parameters measured in CHS as a function of the oscillation frequency (CHS spectra). We have found that for capillary blood flow velocity oscillations with amplitudes up to 10% of the baseline value (which reflect typical scenarios in CHS), the discrepancies between CHS spectra obtained with the linear and nonlinear models are negligible. For larger oscillations (~50%) the linear and nonlinear models yield CHS spectra with differences within typical experimental errors, but further investigation is needed to assess the effect of these differences. Flow oscillations larger than 10-20% are not typically induced in CHS; therefore, the results presented in this work indicate that a linear hemodynamic model, combined with a method to elicit controlled hemodynamic oscillations (as done for CHS), is appropriate for the quantitative assessment of cerebral microcirculation.

Antisense oligonucleotides on neurobehavior, respiratory, and cardiovascular function, and hERG channel current studies.

INTRODUCTION: Safety Pharmacology studies were conducted in mouse, rat, and non-human primate to determine in vivo effects of antisense oligonucleotides (ASOs) on the central nervous system, respiratory system, and cardiovascular system. Effects on the hERG potassium channel current was evaluated in vitro. METHODS: ASOs contained terminal 2'-O-methoxyethyl nucleotides, central deoxy nucleotides, and a phosphorothioate backbone. Neurobehavior was evaluated by Functional Observatory Battery in rodents. Respiratory function was directly measured in rodents by plethysmograph; respiratory rate and blood gases were measured in monkey. Basic cardiovascular endpoints were measured in rat; cardiovascular evaluation in monkey involved implanted telemetry units. In single and repeat dose studies ASOs were administered by subcutaneous injection at up to 300 mg/kg, 250 mg/kg, and 40 mg/kg in mouse, rat, or monkey, respectively. Assays were performed in HEK293 or CHO-K1 cells, stably transfected with hERG cDNA, at ASO concentrations of up to 300 µM. RESULTS: No apparent effects were noted for respiratory or CNS function. Continuous monitoring of the cardiovascular system in monkey demonstrated no ASO-related changes in blood pressures, heart rate, or ECG and associated parameters (i.e., QRS duration). Specific assessment of the hERG potassium channel indicated no potential for actions on ventricular repolarization or modest effects only at excessive concentrations. DISCUSSION: The absence of direct actions on neurobehavior and respiratory function associated with the administration of ASOs in safety pharmacology core battery studies is consistent with published toxicology studies. The combination of in vitro hERG studies and in vivo studies in rat and monkey are consistent with no direct actions by ASOs on cardiac cell function or electrical conduction at relevant concentrations and dose levels. Taken as a whole, dedicated studies focused on the safety pharmacology of specific organ systems do not appear to add significant data for interpretation of potential adverse effects. The need for dedicated studies for future ASOs in the same class is questionable, as a more encompassing data set can be collected in repeat dose and longer-term toxicology studies.

Forecasting new development of tumor areas using spatial and temporal distribution profiles of hemoglobin saturation in a mouse model.

Features of the tumor microenvironment (TME), such as hemoglobin saturation (HbSat), can provide valuable information on early development and progression of tumors. HbSat correlates with high metabolism and precedes the formation of angiogenic tumors; therefore, changes in HbSat profile can be used as a biomarker for early cancer detection. In this project, we develop a methodology to evaluate HbSat for forecasting early tumor development in a mouse model. We built a delta ([Formula: see text]) cumulative feature that includes spatial and temporal distribution of HbSat for classifying tumor/normal areas. Using a two-class (normal and tumor) logistic regression, the [Formula: see text] feature successfully forecasts tumor areas in two window chamber mice ([Formula: see text] and 0.85). To assess the performance of the logistic regression-based classifier utilizing the [Formula: see text] feature of each region, we conduct a 10-fold cross-validation analysis (AUC of the [Formula: see text]). These results show that the TME features based on HbSat can be used to evaluate tumor progression and forecast new occurrences of tumor areas.

Insights from venous oxygen profiles: oxygen utilization and management in diving California sea lions.

The management and depletion of O2 stores underlie the aerobic dive capacities of marine mammals. The California sea lion (Zalophus californianus) presumably optimizes O2 store management during all dives, but approaches its physiological limits during deep dives to greater than 300 m depth. Blood O2 comprises the largest component of total body O2 stores in adult sea lions. Therefore, we investigated venous blood O2 depletion during dives of California sea lions during maternal foraging trips to sea by: (1) recording venous partial pressure of O2 (P(O2)) profiles during dives, (2) characterizing the O2-hemoglobin (Hb) dissociation curve of sea lion Hb and (3) converting the P(O2) profiles into percent Hb saturation (S(O2)) profiles using the dissociation curve. The O2-Hb dissociation curve was typical of other pinnipeds (P50=28±2 mmHg at pH 7.4). In 43% of dives, initial venous S(O2) values were greater than 78% (estimated resting venous S(O2)), indicative of arterialization of venous blood. Blood O2 was far from depleted during routine shallow dives, with minimum venous S(O2) values routinely greater than 50%. However, in deep dives greater than 4 min in duration, venous S(O2) reached minimum values below 5% prior to the end of the dive, but then increased during the last 30-60 s of ascent. These deep dive profiles were consistent with transient venous blood O2 depletion followed by partial restoration of venous O2 through pulmonary gas exchange and peripheral blood flow during ascent. These differences in venous O2 profiles between shallow and deep dives of sea lions reflect distinct strategies of O2 store management and suggest that underlying cardiovascular responses will also differ.

Sickle cell anemia: iron availability and nocturnal oximetry.

STUDY OBJECTIVE: To test the hypothesis that low iron availability, measured as transferrin saturation, is associated with low nocturnal hemoglobin oxygen saturation (SpO(2)) in children with homozygous sickle cell anemia (SCA; hemoglobin SS). METHODS: This was a cross-sectional study of Tanzanian children with SCA who were not receiving regular blood transfusions. Thirty-two children (16 boys) with SCA (mean age 8.0, range 3.6-15.3 years) underwent motion-resistant nocturnal oximetry (Masimo Radical) and had steady state serum transferrin saturation and hematological indices assessed. RESULTS: Higher transferrin saturation, adjusted for age and α-thalassemia deletion, was associated with lower nocturnal mean SpO(2) (p = 0.013, r(2) = 0.41), number of SpO(2) dips/h > 3% from baseline (p = 0.008, r(2) = 0.19) and with min/h with SpO(2) < 90% (p = 0.026 r(2) = 0.16). Transferrin saturation < 16% (indicative of iron deficiency) was associated with a 2.2% higher nocturnal mean SpO(2). CONCLUSIONS: Contrary to our hypothesis, higher iron availability, assessed by transferrin saturation, is associated with nocturnal chronic and intermittent hemoglobin oxygen desaturation in SCA. Whether these associations are causal and are driven by hypoxia-inducible factor and hepcidin-mediated upregulation of demand for iron warrants further investigation.