ORCID Profile
0000-0001-8145-6787
Current Organisation
Griffith University - Gold Coast Campus
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Nanoscale characterisation | Colloid and surface chemistry | Microfluidics and nanofluidics | Physical chemistry |
Publisher: American Physiological Society
Date: 05-2019
Abstract: This study aimed to quantify how acute hypoxia impacts firing characteristics of biceps brachii motor units (MUs) during sustained isometric elbow flexions. MU data were extracted from surface electromyography (EMG) during 25% maximal voluntary contractions (MVC) in 10 healthy subjects (age 22 ± 1 yr). Blood oxygen saturation (SpO 2 ) was then stabilized at 80% by reducing 1% of the fraction of inspired oxygen every 3 min for 35 min. MU data were once again collected 1 h and 2 h following the 35-min desaturation phase. Although MVC remained unaffected during 2 h of 80% SpO 2 , subject-specific changes in MU firing rate were observed. Four of 10 subjects exhibited a decrease in firing rate 1 h postdesaturation (12 ± 11%) and 2 h postdesaturation (16 ± 12%), whereas 6 of 10 subjects exhibited an increase in firing rate 1 h (9 ± 6%) and 2 h (9 ± 4%) postdesaturation. These bidirectional changes in firing rate were strongly correlated to the desaturation phase and the subjects’ SpO 2 sensitivity to oxygen availability, where subjects who had decreased firing rates reached the target SpO 2 20 min into the desaturation phase ( R 2 = 0.90–0.98) and those who had increased firing rates reached the target SpO 2 35 min into the desaturation phase ( R 2 = 0.87–0.98). It is unlikely that a single mechanism accounted for these subject-specific changes in firing rate. Instead, differences in intrinsic properties of the neurons, afferent input to the motoneurons, neuromodulators, and sympathetic nerve activity may exist between groups. NEW & NOTEWORTHY The mechanisms of compromised motor control when exposed to hypoxia are largely unknown. The current study examined how severe acute hypoxia affects motor unit firing rate during sustained isometric contractions of the bicep brachii. The response to hypoxia was different across subjects, where motor unit firing rate increased for some in iduals and decreased for others. This bidirectional change in firing rate was associated with how fast subjects desaturated during hypoxic exposure.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-09-2023
Publisher: Elsevier BV
Date: 03-2010
Publisher: Public Library of Science (PLoS)
Date: 30-11-2016
Publisher: MDPI AG
Date: 18-10-2018
Abstract: With accumulating evidence that exercise capacity decreases all-cause mortality independent of adiposity, benefits may be gained by developing cardiorespiratory fitness measures that are specifically and sensitively designed for use with pediatric populations when cardiorespiratory fitness may be a contributing factor for obesity. This study aimed to examine the criterion validity of the Modified Shuttle Test-Paeds (MSTP) as a measure of cardiorespiratory fitness in children, against the gold-standard reference VO2peak, compared to the commonly used field-test 20-m Multi-Stage-Shuttle-Run-Test (20-m MSRT). A cross-sectional pilot study, with 25 school-aged children (age: 6–16 year male/female: 19/5 BMI: 21 ± 9 kg/m2) was employed. Physical measures included: Bruininks-Oseretsky-Test-of-Motor-Proficiency-2nd Edition (BOT2), VO2peak, 20-m MSRT, MSTP, body composition/anthropometry. The mean cardiorespiratory fitness of participants was: VO2peak: 43.8 ± 11.2 (mL/kg/min) 20-m MSRT: 5.48 ± 2.96 (level) MSTP: 22.10 ± 3.05 (no.). A strong predictive relationship was found between the 20-m MSRT and VO2peak (r2 = 0.486, p 0.001) whereas a very strong predictive relationship existed between the newly designed MSTP and VO2peak (r2 = 0.749, p 0.001). Whilst further research with larger study cohorts is needed, this pilot study found the MSTP to have a very high predictive validity for estimating VO2peak in children, suggesting it may be a valid child-specific indicator of cardiorespiratory fitness requiring only a simple equation that is clinically relevant.
Publisher: Wiley
Date: 16-06-2017
DOI: 10.1111/AOR.12919
Abstract: Rotary blood pumps (RBPs) are used for mechanical circulatory support in heart failure patients but exhibit a reduced response to preload changes, which can lead to ventricular suction events. A passive control system, in the form of a compliant inflow cannula (IC), has been developed to mitigate suction, although this device may cause significant hemolysis. This study compared the incidence of mechanically induced hemolysis of two compliant IC designs (strutted and nonstrutted) with a rigid IC (control) in a blood circulation loop over 90 min. The nonstrutted compliant IC introduced high frequency and high litude oscillations in RBP inlet pressure and RBP IC resistance. These oscillations were correlated with a significant increase in plasma-free hemoglobin (pfHb) and hemolysis: pfHb increased to 2.005 ± 0.665 g/L, while normalized index of hemolysis (NIH) and modified index of hemolysis (MIH) increased to 0.04945 ± 0.01276 g/100 L and 4.0505 ± 0.6589 after 90 min (P < 0.05). In contrast, the strutted compliant IC performed similar to the clinically utilized rigid IC and did not increase pfHb (0.300 ± 0.090 and 0.320 ± 0.171 g/L, respectively) and rate of hemolysis (NIH 0.00435 ± 0.00155 and 0.00543 ± 0.00371 g/100 L MIH 0.3896 ± 0.1749 and 0.4261 ± 0.2792, respectively) within the RBP circuit. These data indicated that strutted, compliant ICs meet the hemocompatibility of clinically used rigid ICs while also offering a potential solution to prevent ventricular suction events.
Publisher: SAGE Publications
Date: 07-05-2022
DOI: 10.1177/03913988221095581
Abstract: Animal blood products are routinely used as surrogates for human tissue in haemocompatibility testing of rotary blood pumps. Bovine blood is particularly attractive due to the animal’s large blood volume however, bovine red blood cells (RBC) differ substantially from those of human, both in biophysical properties and molecular composition. We aimed to determine whether differences also exist in the sensitivity of bovine RBC to a standardised shear stress protocol. Fresh blood from healthy human and bovine donors was exposed to discrete combinations of shear stress using a Couette shearing system, prior to assessment of cellular deformability and mechanical sensitivity. Each s le was exposed to 25 sublethal shear stress combinations (ranging 60–100 Pa × 5–300 s). While bovine RBC exhibited decreased maximal elongation in the absence of conditioning shear, overall deformability at lower shears was ~1.8-fold greater than human. When exposed to any conditioning shear stresses Pa (or 60–70 Pa beyond 5 s), human RBC were significantly rigidified, with greater magnitudes and prolonged exposure compounding this effect. Significantly larger shears were required to rigidify bovine RBC the most extreme shear condition (100 Pa × 300 s) resulted in approximately three-times more rigidification of human RBC than bovine (137% and 47% respectively). Bovine RBC have superior resilience to mechanical stress when compared with human. Using bovine blood in ex vivo evaluation of rotary blood pumps may thus misrepresent and overestimate device-blood success, and may also have flow-on effects for eventual users. Fresh human blood during early-phase ex vivo testing is thus recommended, given shear-inducing blood pumps are designed for humans – not cattle.
Publisher: Wiley
Date: 25-08-2020
DOI: 10.1111/MICC.12652
Publisher: Wiley
Date: 06-09-2017
DOI: 10.1111/AOR.12997
Abstract: Patients receiving mechanical circulatory support often present with heightened inflammation and free radical production associated with pre-existing conditions in addition to that which is due to blood interactions with nonbiological surfaces. The aim of this experimental laboratory study was to assess the deformability of red blood cells (RBC) previously exposed to oxygen free radicals and determine the susceptibility of these cells to mechanical forces. In the present study, RBC from 15 healthy donors were washed and incubated for 60 min at 37°C with 50 µM phenazine methosulfate (PMS an agent that generates superoxide within RBC). Incubated RBC and negative controls were assessed for their deformability and susceptibility to mechanical damage (using ektacytometry) prior to the application of shear stress, and also following exposure to 25 different shear conditions of varied magnitudes (shear stress 1, 4, 16, 32, 64 Pa) and durations (1, 4, 16, 32, 64 s). The salient findings demonstrate that incubation with PMS impaired important indices of RBC deformability indicating altered cell mechanics by ∼19% in all conditions (pre- and postexposure to shear stress). The typical trends in shear-mediated changes in RBC susceptibility to mechanical damage, following conditioning shear stresses, were maintained for PMS incubated and control conditions. We demonstrated that free radicals hinder the ability of RBC to deform however, RBC retained their typical mechanical response to shear stress, albeit at a decreased level compared with control following exposure to PMS. Our findings also indicate that low shear exposure may decrease cell sensitivity to mechanical damage upon subsequent shear stress exposures. As patients receiving mechanical circulatory support have elevated exposure to free radicals (which limits RBC deformability), concomitant exposure to high shear environments needs to be minimized.
Publisher: SAGE Publications
Date: 03-2019
Publisher: Wiley
Date: 13-09-2020
DOI: 10.1113/EP088887
Abstract: What is the central question of this study? How does acute hypoxia alter central and peripheral fatigue during brief and sustained maximal voluntary muscle contractions? What is the main finding and its importance? Perception of fatigue during muscle contractions was increased progressively for 2 h after hypoxic exposure. However, an increase in motor cortex excitability and a decrease in voluntary activation of skeletal muscle were observed across the entire protocol when performing brief (3 s) maximal contractions. These adaptations were abolished if the brief contraction was held for a duration of 20 s, which was presumably attributable to a successful redistribution of blood to overcome the reduced oxygen content. Few studies have examined the time course of changes in the motor system after acute exposure to hypoxia. Thus, the purpose of this study was to examine how acute hypoxia affects corticospinal excitability, voluntary activation (VA) and the perception of fatigue during brief (3 s) and sustained (20 s) maximal voluntary contractions (MVCs). Fourteen healthy in iduals (23 ± 2.2 years of age four female) were exposed to hypoxia and sham conditions. During hypoxia, peripheral blood oxygen saturation was titrated over a 15 min period and remained at 80% during testing. Corticospinal excitability and VA were assessed before titration (Pre), 0, 1 and 2 h after. At each time point, the brief and sustained elbow flexion MVCs were performed. Motor evoked potentials (MEPs) were obtained using transcranial magnetic stimulation. Superimposed and resting twitches were obtained from motor point stimulation of biceps brachii to calculate the level of VA, and ratings of perceived fatigue were obtained with a modified CR‐10 Borg scale. A condition‐by‐time interaction was detected for the CR‐10 Borg scale, whereby perception of fatigue increased progressively throughout the hypoxia protocol. However, main effects of MEP area and VA indicated that corticospinal excitability increased, and VA of the biceps brachii decreased, throughout the hypoxia protocol. Given that these changes in MEP area and VA were seen only when performing the brief MVCs (and not during the sustained MVCs), performing longer contractions might overcome reduced oxygen content by redirecting blood flow to active areas of the motor system.
Publisher: SAGE Publications
Date: 03-08-2018
Abstract: Accumulating evidence demonstrates that subhaemolytic mechanical stresses, typical of circulatory support, induce physical and biochemical changes to red blood cells. It remains unclear, however, whether cell age affects susceptibility to these mechanical forces. This study thus examined the sensitivity of density-fractionated red blood cells to sublethal mechanical stresses. Red blood cells were isolated and washed twice, with the least and most dense fractions being obtained following centrifugation (1500 g × 5 min). Red blood cell deformability was determined across an osmotic gradient and a range of shear stresses (0.3–50 Pa). Cell deformability was also quantified before and after 300 s exposure to shear stresses known to decrease (64 Pa) or increase (10 Pa) red blood cell deformability. The time course of accumulated sublethal damage that occurred during exposure to 64 Pa was also examined. Dense red blood cells exhibited decreased capacity to deform when compared with less dense cells. Cellular response to mechanical stimuli was similar in trend for all red blood cells, independent of density however, the magnitude of impairment in cell deformability was exacerbated in dense cells. Moreover, the rate of impairment in cellular deformability, induced by 64 Pa, was more rapid for dense cells. Relative improvement in red blood cell deformability, due to low-shear conditioning (10 Pa), was consistent for both cell populations. Red blood cell populations respond differently to mechanical stimuli: older (more dense) cells are highly susceptible to sublethal mechanical trauma, while cell age (density) does not appear to alter the magnitude of improved cell deformability following low-shear conditioning.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.MVR.2018.05.008
Abstract: Circulation of blood depends, in part, on the ability of red blood cells (RBCs) to aggregate, disaggregate, and deform. The primary intrinsic disaggregating force of RBCs is derived from their electronegativity, which is largely determined by sialylated glycoproteins on the plasma membrane. Given supraphysiological shear exposure - even at levels below those which induce hemolysis - alters cell morphology, we hypothesized that exposure to supraphysiological and subhemolytic shear would cleave membrane-bound sialic acid, altering the electrochemical and physical properties of RBCs, and thus increase RBC aggregation. Isolated RBCs from healthy donors (n = 20) were suspended in polyvinylpyrrolidinone. Using a Poiseuille shearing system, RBC suspensions were exposed to 125 Pa for 1.5 s for three duty-cycles. Following the first and third shear duty-cycle, s les were assessed for: RBC aggregation the ability of RBCs to aggregate independent of plasma ("aggregability") disaggregation shear rate membrane-bound sialic acid content, and cell electrophoretic mobility. Initial shear exposure significantly increased RBC aggregation, aggregability, and the shear required for rouleaux dispersion. Sialic acid concentration significantly decreased on isolated RBC membranes ghosts, and increased in the supernatant following shear. Initial shear exposure decreased the electrophoretic mobility of RBCs, decreasing the electronegative charge from -15.78 ± 0.31 to -7.55 ± 0.21 mV. Three exposures to the shear duty-cycle did not further compound altered RBC measures. A single exposure to supraphysiological and subhemolytic shear significantly decreased the electrochemical charge of the RBC membrane, concurrently increasing cell aggregation/aggregability. The cascading implications of hyperaggregation appears to potentially explain the ischemia-associated complications commonly reported following mechanical circulatory support.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2010
DOI: 10.1007/S00421-009-1351-8
Abstract: The purpose of this study was to determine if improved supramaximal exercise performance in trained cyclists following caffeine ingestion was associated with enhanced O(2) uptake (VO2 kinetics), increased anaerobic energy provision (accumulated O(2)-AO(2)-deficit), or a reduction in the accumulation of metabolites (for ex le, K(+)) associated with muscular fatigue. Six highly trained male cyclists (VO2peak 68 +/- 8 mL kg(-1) min(-1)) performed supramaximal (120% VO2peak) exercise bouts to exhaustion on an electronically braked cycle ergometer, following double-blind and randomized ingestion of caffeine lacebo (5 mg kg(-1)). Time to exhaustion (TE), VO2 kinetics, AO(2) deficit, blood lactate (La(-)), plasma potassium (K(+)), caffeine and paraxanthine concentrations were measured. Caffeine ingestion elicited significant increases in TE (14.8%, p < 0.01) and AO(2) deficit (6.5%, p < 0.05). In contrast, no changes were observed in AO(2) deficit at isotime, VO2 kinetics, blood [La(-)] at exhaustion or peak [K(+)] following caffeine ingestion. However, [K(+)] was significantly reduced (13.4%, p < 0.01) during warm-up cycling immediately prior to the onset of the supramaximal bout for the caffeine trials, compared with placebo. It appears that caffeine ingestion is beneficial to supramaximal cycling performance in highly trained men. The reduced plasma [K(+)] during submaximal warm-up cycling may prolong the time taken to reach critical [K(+)] at exhaustion, thus delaying fatigue. Considering caffeine ingestion did not change VO2 kinetics or isotime AO(2) deficit, increases in absolute AO(2) deficit may be a consequence of prolonged TE, rather than causal.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Frontiers Media SA
Date: 06-07-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2017
Publisher: American Physiological Society
Date: 11-2016
Abstract: The aim of this study was to investigate how maximal intermittent contractions for a hand muscle influence cortical and reflex activity, as well as the ability to voluntarily activate the homologous muscle in the opposite limb. Twelve healthy subjects (age 24 ± 3 yr, all right-hand dominant) performed maximal contractions of the dominant limb first dorsal interosseous (FDI), and activity of the contralateral FDI was examined in a series of experiments. Index finger abduction force, FDI electromyography (EMG), motor evoked potentials, and heteronomous reflexes were obtained from the contralateral limb during brief, nonfatiguing contractions. The same measures, as well as the ability to voluntarily activate the contralateral FDI, were then assessed in an extended intermittent contraction protocol that elicited fatigue. Brief contractions under nonfatigued conditions increased index finger abduction force, FDI EMG, and motor evoked potential litude of the contralateral limb. However, when intermittent maximal contractions were continued until fatigue, there was an inability to produce maximal force with the contralateral limb (∼30%), which was coupled to a decrease in the level of voluntary activation (∼20%). These declines were present without changes in reflex activity and regardless of whether cortical or motor point stimulation was used to assess voluntary activation. It is concluded that performing maximal intermittent contractions with a single limb causes an inability of the central nervous system to maximally drive the homologous muscle of the contralateral limb. This is, in part, mediated by mechanisms that involve the motor cortex ipsilateral to the contracting limb.
Publisher: Elsevier BV
Date: 2023
Publisher: Wiley
Date: 29-12-2020
DOI: 10.1111/AOR.13877
Abstract: Despite technological advances in ventricular assist devices (VADs) to treat end‐stage heart failure, hemocompatibility remains a constant concern, with supraphysiological shear stresses an unavoidable reality with clinical use. Given that impeller rotational speed is related to the instantaneous shear within the pump housing, it is plausible that the modulation of pump speed may regulate peak mechanical shear stresses and thus ameliorate blood damage. The present study investigated the hemocompatibility of the HeartWare HVAD in three configurations typical of clinical applications: standard systemic support left VAD (LVAD), pediatric support LVAD, and pulmonary support right VAD (RVAD) conditions. Two ex vivo mock circulation blood loops were constructed using explanted HVADs, in which pump speed and external loop resistance were manipulated to reflect the flow rates and differential pressures reported in configurations for standard adult LVAD (at 3150 rev⸱min −1 ), pediatric LVAD (at 2400 rev⸱min −1 ), and adult RVAD (at 1900 rev⸱min −1 ). Using bovine blood, the mock circulation blood loops were tested at 37°C over a period of 6 hours (consistent with ASTM F1841‐97) and compared with static control. Hemocompatibility assessments were conducted for each test condition, examining hematology, hemolysis (absolute and normalized index), osmotic fragility, and blood viscosity. Regardless of configuration, continuous exposure of blood to the VAD over the 6‐hour period significantly altered hematological and rheological blood parameters, and induced increased hemolysis when compared with a static control s le. Comparison of the three operational VAD configurations identified that the adult LVAD condition—associated with the highest pump speed, flow rate, and differential pressure across the pump—resulted in increased normalized hemolysis index (NIH 0.07) when compared with the lower pump speed “off‐label” counterparts (NIH of 0.04 in pediatric LVAD and 0.01 in adult RVAD configurations). After normalizing blood residence times between configurations, pump speed was identified as the primary determinant of accumulated blood damage plausibly, blood damage could be limited by restricting pump speed to the minimum required to support matched cardiac output, but not beyond.
Publisher: Mary Ann Liebert Inc
Date: 06-2021
Publisher: Public Library of Science (PLoS)
Date: 07-01-2016
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.MVR.2021.104261
Abstract: Red blood cell (RBC) populations are inherently heterogeneous, given mature RBC lack the transcriptional machinery to re-synthesize proteins affected during in vivo aging. Clearance of older, less functional cells thus aids in maintaining consistent hemorheological properties. Scenarios occur, however, where portions of mechanically impaired RBC are re-introduced into blood (e.g., damaged from circulatory support, blood transfusion) and may alter whole blood fluid behavior. Given such perturbations are associated with poor clinical outcomes, determining the tolerable level of abnormal RBC in blood is valuable. Thus, the current study aimed to define the critical threshold of blood fluid properties to re-infused physically-impaired RBC. Cell mechanics of RBC were impaired through membrane cross-linking (glutaraldehyde) or intracellular oxidation (phenazine methosulfate). Mechanically impaired RBC were progressively re-introduced into the native cell population. Negative alterations of cellular deformability and high shear blood viscosity were observed following additions of only 1-5% rigidified RBC. Low-shear blood viscosity was conversely decreased following addition of glutaraldehyde-treated cells high-resolution microscopy of these mixed cell populations revealed decreased capacity to form reversible aggregates and decreased aggregate size. Mixed RBC populations, when exposed to supraphysiological shear, presented with compounded mechanical impairment. Collectively, key determinants of blood flow behavior are sensitive to mechanical perturbations in RBC, even when only 1-5% of the cell population is affected. Given this fraction is well-below the volume of rigidified RBC introduced during circulatory support or transfusion practice, it is plausible that some adverse events following surgery and/or transfusion may be related to impaired blood fluidity.
Publisher: American Physiological Society
Date: 09-2023
DOI: 10.1152/AJPREGU.00017.2023
Abstract: In vitro investigations demonstrate that human erythrocytes synthesize nitric oxide via a functional isoform of endothelial nitric oxide synthase (NOS) (RBC-NOS). We tested the hypothesis that phosphorylation of RBC-NOS at serine residue 1177 (RBC-NOS 1177 ) would be lified in blood draining-active skeletal muscle. Furthermore, given hypoxemia modulates local blood flow and thus shear stress, and nitric oxide availability, we performed duplicate experiments under normoxia and hypoxia. Nine healthy volunteers performed rhythmic handgrip exercise at 60% of in idualized maximal workload for 3.5 min while breathing room air (normoxia) and after being titrated to an arterial oxygen saturation ≈80% (hypoxemia). We measured brachial artery blood flow by high-resolution duplex ultrasound, while continuously monitoring vascular conductance and mean arterial pressure using finger photoplethysmography. Blood was s led during the final 30 s of each stage from an indwelling cannula. Blood viscosity was measured to facilitate calculation of accurate shear stresses. Erythrocytes were assessed for levels of phosphorylated RBC-NOS 1177 and cellular deformability from blood collected at rest and during exercise. Forearm exercise increased blood flow, vascular conductance, and vascular shear stress, which coincided with a 2.7 ± 0.6-fold increase in RBC-NOS 1177 phosphorylation ( P 0.0001) and increased cellular deformability ( P 0.0001) under normoxia. When compared with normoxia, hypoxemia elevated vascular conductance and shear stress ( P 0.05) at rest, while cellular deformability ( P 0.01) and RBC-NOS 1177 phosphorylation ( P 0.01) increased. Hypoxemic exercise elicited further increases in vascular conductance, shear stress, and cell deformability ( P 0.0001), although a subject-specific response in RBC-NOS 1177 phosphorylation was observed. Our data yield novel insights into the manner that hemodynamic force and oxygen tension modulate RBC-NOS in vivo.
Publisher: Springer Science and Business Media LLC
Date: 07-12-2021
Publisher: Elsevier BV
Date: 07-2023
Publisher: Wiley
Date: 18-09-2020
DOI: 10.1111/TRF.16086
Publisher: American Physiological Society
Date: 08-2020
DOI: 10.1152/AJPCELL.00210.2020
Abstract: The classic view of the red blood cell (RBC) presents a biologically inert cell that upon maturation has limited capacity to alter its physical properties. This view developed largely because of the absence of translational machinery and inability to synthesize or repair proteins in circulating RBC. Recent developments have challenged this perspective, in light of observations supporting the importance of posttranslational modifications and greater understanding of ion movement in these cells, that each regulate a myriad of cellular properties. There is thus now sufficient evidence to induce a step change in understanding of RBC: rather than passively responding to the surrounding environment, these cells have the capacity to actively regulate their physical properties and thus alter flow behavior of blood. Specific evidence supports that the physical and rheological properties of RBC are subject to active modulation, primarily by the second-messenger molecules nitric oxide (NO) and calcium-ions (Ca 2+ ). Furthermore, an isoform of nitric oxide synthase is expressed in RBC (RBC-NOS), which has been recently demonstrated to have an active role in regulating the physical properties of RBC. Mechanical stimulation of the cell membrane activates RBC-NOS, leading to NO generation, which has several intracellular effects, including the S-nitrosylation of integral membrane components. Intracellular concentration of Ca 2+ is increased upon mechanical stimulation via the recently identified mechanosensitive cation channel piezo1. Increased intracellular Ca 2+ modifies the physical properties of RBC by regulating cell volume and potentially altering several important intracellular proteins. A synthesis of recent advances in understanding of molecular processes within RBC thus challenges the classic view of these cells and rather indicates a highly active cell with self-regulated mechanical properties.
Publisher: MDPI AG
Date: 11-01-2021
Abstract: Red blood cell (RBC) deformability is an essential component of microcirculatory function that appears to be enhanced by physiological shear stress, while being negatively affected by supraphysiological shears and/or free radical exposure. Given that blood contains RBCs with non-uniform physical properties, whether all cells equivalently tolerate mechanical and oxidative stresses remains poorly understood. We thus partitioned blood into old and young RBCs which were exposed to phenazine methosulfate (PMS) that generates intracellular superoxide and/or specific mechanical stress. Measured RBC deformability was lower in old compared to young RBCs. PMS increased total free radicals in both sub-populations, and RBC deformability decreased accordingly. Shear exposure did not affect reactive species in the sub-populations but reduced RBC nitric oxide synthase (NOS) activation and intriguingly increased RBC deformability in old RBCs. The co-application of PMS and shear exposure also improved cellular deformability in older cells previously exposed to reactive oxygen species (ROS), but not in younger cells. Outputs of NO generation appeared dependent on cell age in general, stressors applied to younger RBCs tended to induce S-nitrosylation of RBC cytoskeletal proteins, while older RBCs tended to reflect markers of nitrosative stress. We thus present novel findings pertaining to the interplay of mechanical stress and redox metabolism in circulating RBC sub-populations.
Publisher: Wiley
Date: 12-2021
DOI: 10.1113/JP281897
Abstract: The purpose of this study was to determine how severe acute hypoxia alters neural mechanisms during, and following, a sustained fatiguing contraction. Fifteen participants (25 ± 3.2 years, six female) were exposed to a sham condition and a hypoxia condition where they performed a 10 min elbow flexor contraction at 20% of maximal torque. For hypoxia, peripheral blood oxygen saturation ( ) was titrated to 80% over a 15 min period and maintained for 2 h. Maximal voluntary contraction torque, EMG root mean square, voluntary activation, rating of perceived muscle fatigue, and corticospinal excitability (motor‐evoked potential) and inhibition (silent period duration) were then assessed before, during and for 6 min after the fatiguing contraction. No hypoxia‐related effects were identified for neuromuscular variables during the fatigue task. However, for recovery, voluntary activation assessed by motor point stimulation of biceps brachii was lower for hypoxia than sham at 4 min (sham: 89% ± 7% hypoxia: 80% ± 12% P = 0.023) and 6 min (sham: 90% ± 7% hypoxia: 78% ± 11% P = 0.040). Similarly, voluntary activation ( P = 0.01) and motor‐evoked potential area ( P = 0.002) in response to transcranial magnetic stimulation of the motor cortex were 10% and 11% lower during recovery for hypoxia compared to sham, respectively. Although an of 80% did not affect neural activity during the fatiguing task, motor cortical output and corticospinal excitability were reduced during recovery in the hypoxic environment. This was probably due to hypoxia‐related mechanisms involving supraspinal motor circuits. image Acute hypoxia has been shown to impair voluntary activation of muscle and alter the excitability of the corticospinal motor pathway during exercise. However, little is known about how hypoxia alters the recovery of the motor system after performing fatiguing exercise. Here we assessed hypoxia‐related responses of motor pathways both during active contractions and during recovery from active contractions, with transcranial magnetic stimulation and motor point stimulation of the biceps brachii. Fatiguing exercise caused reductions in voluntary activation, which was exacerbated during recovery from a 10 min sustained elbow flexion in a hypoxic environment. These results suggest that reductions in blood oxygen concentration impair the ability of motor pathways in the CNS to recover from fatiguing exercise, which is probably due to hypoxia‐induced mechanisms that reduce output from the motor cortex.
Publisher: American Physiological Society
Date: 07-2022
DOI: 10.1152/AJPHEART.00185.2022
Abstract: The mechanosensitive ion channel Piezo1 is expressed in enucleated red blood cells and provides a mechanisms of shear-induced red cell nitric oxide production via nitric oxide synthase phosphorylation. Thiol oxidation of red cells decreases Piezo1-dependent calcium movement and thus impairs nitric oxide generation in response to mechanical force. The emerging descriptions of exclusively posttranslational signaling networks in circulating red cells as acute regulators of cell function support that these cells play an important role in cardiovascular physiology that extends beyond passive oxygen transport.
Publisher: Wiley
Date: 16-10-2018
DOI: 10.1111/TRF.14901
Publisher: MDPI AG
Date: 08-01-2021
DOI: 10.3390/LIFE11010036
Abstract: Red blood cells (RBC) express a nitric oxide synthase isoform (RBC-NOS) that appears dependent on shear stress for Serine1177 phosphorylation. Whether this protein is equally activated by varied shears in the physiological range is less described. Here, we explored RBC-NOS Serine1177 phosphorylation in response to shear stress levels reflective of in vivo conditions. Whole blood s les were exposed to specific magnitudes of shear stress (0.5, 1.5, 4.5, 13.5 Pa) for discrete exposure times (1, 10, 30 min). Thereafter, RBC-NOS Serine1177 phosphorylation was measured utilising immunofluorescence labelling. Shear stress exposure at 0.5, 1.5, and 13.5 Pa significantly increased RBC-NOS Serine1177 phosphorylation following 1 min (p 0.0001) exposure to 4.5 Pa had no effect after 1 min. RBC-NOS Serine1177 phosphorylation was significantly increased following 10 min at each magnitude of shear stress (0.5, 1.5, 13.5 Pa, p 0.0001 4.5 Pa, p = 0.0042). Shear stress exposure for 30 min significantly increased RBC-NOS Serine1177 phosphorylation at 0.5 Pa and 13.5 Pa (p 0.0001). We found that RBC-NOS phosphorylation via shear stress is non-linear and differs for a given magnitude and duration of exposure. This study provides a new understanding of the discrete relation between RBC-NOS and shear stress.
Publisher: Wiley
Date: 03-05-2018
DOI: 10.1111/AOR.13142
Abstract: Although rotary blood pumps (RBPs) sustain life, blood exposure to continuous supra-physiological shear stress induces adverse effects (e.g., thromboembolism) thus, pulsatile flow in RBPs represents a potential solution. The present study introduced pulsatile flow to the HeartWare HVAD using a custom-built controller and compared hemocompatibility biomarkers (i.e., platelet aggregation, concentrations for ADAMTS13, von Willebrand factor (vWf), and free-hemoglobin in plasma (pfHb), red blood cell (RBC) deformability, and RBC-nitric oxide synthase (NOS) activity) between continuous and pulsatile flow in a blood circulation loop over 5 h. The HeartWare HVAD was operated using a custom-built controller, at continuous speed (3282 rev/min) or in a pulsatile mode (mean speed = 3273 rev/min, litude = 430 rev/min, frequency = 1 Hz) to generate a blood flow rate of 5.0 L/min, HVAD differential pressure of 90 mm Hg for continuous flow and 92 mm Hg for pulsatile flow, and systolic and diastolic pressures of 121/80 mm Hg. For both flow regimes, the current study found (i) ADP- and collagen-induced platelet aggregation, and ADAMTS13 concentration significantly decreased after 5 h (P < 0.01 P < 0.05), (ii) ristocetin-induced platelet aggregation significantly increased after 45 min (P < 0.05), (iii) vWf concentration did not significantly differ at any time point, (iv) pfHb significantly increased after 5 h (P < 0.01), (v) RBC deformability improved during the continuous flow regime (P < 0.05) but not during pulsatile flow, and (vi) RBC-NOS activity significantly increased during continuous flow (15 min), and pulsatile flow (5 h P < 0.05). The current study demonstrated: (i) speed modulation does not improve hemocompatibility of the HeartWare HVAD based on no observable differences being detected for routine biomarkers, and (ii) the time-course for increased RBC-NOS activity observed during continuous flow may have improved RBC deformability.
Publisher: Wiley
Date: 15-08-2020
DOI: 10.1111/AOR.13783
Publisher: Wiley
Date: 23-05-2017
DOI: 10.1111/AOR.12890
Abstract: The supra-physiological shear stress that blood is exposed to while traversing mechanical circulatory assist devices affects the physical properties of red blood cells (RBCs), impairs RBC deformability, and may induce hemolysis. Previous studies exploring RBC damage following exposure to supra-physiological shear stress have employed durations exceeding clinical instrumentation, thus we explored changes in RBC deformability following exposure to shear stress below the reported "hemolytic threshold" using shear exposure durations per minute (i.e., duty-cycles) reflective of that employed by circulatory assist devices. Blood collected from 20 male donors, aged 18-38 years, was suspended in a viscous medium and exposed to an intermittent shear stress protocol of 1 s at 100 Pa, every 60 s for 60 duty-cycles. During the remaining 59 s/min, the cells were left at stasis until the subsequent duty-cycle commenced. At discrete time points (15/30/45/60 duty-cycles), an ektacytometer measured RBC deformability immediately after shear exposure at 100 Pa. Plasma-free hemoglobin, a measurement of hemolysis, was quantified via spectrophotometry. Supra-physiological shear stress impaired RBC properties, as indicated by: (1) decreased maximal elongation of RBCs at infinite shear stress following 15 duty-cycles (P <0.05) (2) increased real-time RBC deformability during application of the supra-physiological shear stress protocol (100 Pa) following exposure to 1 duty-cycle (F (1.891, 32.15) = 12.21, P = 0.0001) and (3) increased plasma-free hemoglobin following 60 duty-cycles (P < 0.01). The present study indicates that exposure of RBCs to short-term, repeated supra-physiological shear stress, impairs RBC deformability, with the extent of impairment exacerbated with each duty-cycle, and ultimately precipitates hemolysis.
Publisher: Frontiers Media SA
Date: 05-02-2019
Publisher: MDPI AG
Date: 14-02-2022
DOI: 10.3390/BIOS12020120
Abstract: Plasma extraction from blood is essential for diagnosis of many diseases. The critical process of plasma extraction requires removal of blood cells from whole blood. Fluid viscoelasticity promotes cell migration towards the central axis of flow due to differences in normal stress and physical properties of cells. We investigated the effects of altering fluid viscoelasticity on blood plasma extraction in a serpentine microchannel. Poly (ethylene oxide) (PEO) was dissolved into blood to increase its viscoelasticity. The influences of PEO concentration, blood dilution, and flow rate on the performance of cell focusing were examined. We found that focusing performance can be significantly enhanced by adding PEO into blood. The optimal PEO concentration ranged from 100 to 200 ppm with respect to effective blood cell focusing. An optimal flow rate from 1 to 15 µL/min was determined, at least for our experimental setup. Given less than 1% haemolysis was detected at the outlets in all experimental combinations, the proposed microfluidic methodology appears suitable for applications sensitive to haemocompatibility.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2020
DOI: 10.1007/S10237-019-01252-Z
Abstract: Mechanical circulatory support device (MCS) design has improved over the years and yet blood damage (e.g., hemolysis) remains a problem. Accumulating evidence indicates a subhemolytic threshold for red blood cells (RBC)-a threshold at which RBC deformability is impaired prior to hemolysis. The current study aimed to assess the deformability of RBC exposed to supra-physiological shear stresses that are typical of MCS devices and assess whether a method used to estimate an in idualized subhemolytic threshold, accurately demarcates whether future application of shear stress was damaging. Suspensions of RBC were "conditioned" with discrete magnitudes of shear stress (5-100 Pa) for specific durations (1-16 s). Cellular deformability was subsequently measured via ektacytometry and a mechanical sensitivity (MS) index was calculated to identify the subhemolytic threshold. Thereafter, fresh RBC suspensions were exposed to a magnitude of shear stress 10 Pa above, 10 Pa below, or matched to a donor's previously estimated subhemolytic threshold for a given duration (1, 4, 16 s) to ascertain the sensitivity of the subhemolytic threshold. The MS index of RBC was significantly impaired following exposure to 10 Pa above the subhemolytic threshold (p < 0.0001), and significantly enhanced following exposure to 10 Pa below the subhemolytic threshold (p < 0.01). For all shear conditions, there was no significant increase in free hemoglobin. Functional assessments of RBC may be useful when conducting biocompatibility testing of MCS devices, to detect trauma to blood prior to overt cell rupture being induced.
Publisher: Wiley
Date: 22-07-2022
DOI: 10.1111/EJN.15773
Abstract: The purpose of this study was to assess how severe acute hypoxia alters the neural mechanisms of muscle activation across a wide range of torque output in a fatigued muscle. Torque and electromyography responses to transcranial and motor nerve stimulation were collected from 10 participants (27 years ± 5 years, 1 female ) following repeated performance of a sustained maximal voluntary contraction that reduced torque to 60% of the pre‐fatigue peak torque. Contractions were performed after 2 h of hypoxic exposure and during a sham intervention. For hypoxia, peripheral blood oxygen saturation was titrated to 80% over a 15‐min period and remained at 80% for 2 h. Maximal voluntary torque, electromyography root mean square, voluntary activation and corticospinal excitability (motor evoked potential area) and inhibition (silent period duration) were then assessed at 100%, 90%, 80%, 70%, 50% and 25% of the target force corresponding to the fatigued maximal voluntary contraction. No hypoxia‐related effects were identified for voluntary activation elicited during motor nerve stimulation. However, during measurements elicited at the level of the motor cortex, voluntary activation was reduced at each torque output considered ( P = .002, η p 2 = .829). Hypoxia did not impact the correlative linear relationship between cortical voluntary activation and contraction intensity or the correlative curvilinear relationship between motor nerve voluntary activation and contraction intensity. No other hypoxia‐related effects were identified for other neuromuscular variables. Acute severe hypoxia significantly impairs the ability of the motor cortex to voluntarily activate fatigued muscle across a wide range of torque output.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-07-2020
Publisher: Elsevier BV
Date: 04-2023
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.JBIOMECH.2021.110898
Abstract: Despite decades of technological advancements in blood-contacting medical devices, complications related to shear flow-induced blood trauma are still frequently observed in clinic. Blood trauma includes haemolysis, platelet activation, and degradation of High Molecular Weight von Willebrand Factor (HMW vWF) multimers, all of which are dependent on the exposure time and magnitude of shear stress. Specifically, accumulating evidence supports that when blood is exposed to shear stresses above a certain threshold, blood trauma ensues however, it remains unclear how various constituents of blood are affected by discrete shears experimentally. The aim of this study was to expose blood to discrete shear stresses and evaluate blood trauma indices that reflect red cell, platelet, and vWF structure. Citrated human whole blood (n = 6) was collected and its haematocrit was adjusted to 30 ± 2% by adding either phosphate buffered saline (PBS) or polyvinylpyrrolidone (PVP). Viscosity of whole blood was adjusted to 3.0, 12.5, 22.5 and 37.5 mPa·s to yield stresses of 3, 6, 9, 12, 50, 90 and 150 Pa in a custom-developed shearing system. Blood s les were exposed to shear for 0, 300, 600 and 900 s. Haemolysis was measured using spectrophotometry, platelet activation using flow cytometry, and HMW vWF multimer degradation was quantified with gel electrophoresis and immunoblotting. For tolerance to 300, 600 and 900 s of exposure time, the critical threshold of haemolysis was reached after blood was exposed to 90 Pa for 600 s (P < 0.05), platelet activation and HMW vWF multimer degradation were 50 Pa for 600 s and 12 Pa for 300 s respectively (P < 0.05). Our experimental results provide simultaneous comparison of blood trauma indices and thus also the relation between shear duration and magnitude required to induce damage to red cells, platelets, and vWF. Our results also demonstrate that near-physiological shear stress (<12 Pa) is needed in order to completely avoid any form of blood trauma. Therefore, there is an urgent need to design low shear-flow medical devices in order to avoid blood trauma in this blood-contacting medical device field.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2017
Publisher: Wiley
Date: 17-09-2020
DOI: 10.1111/TRF.16080
Publisher: Elsevier BV
Date: 2022
Publisher: Mary Ann Liebert Inc
Date: 09-2014
Abstract: Endurance exercise can cause immunosuppression and increase the risk of upper respiratory illness. The present study examined changes in the secretion of T helper (Th) cell cytokines after endurance exercise. Ten highly trained road cyclists [mean±SEM: age 24.2±1.7 years height 1.82±0.02 m body mass 73.8±2.0 kg peak oxygen uptake 65.9±2.3 mL/(kg•min)] performed 2 h of cycling exercise at 90% of the second ventilatory threshold. Peripheral blood mononuclear cells were isolated and stimulated with phytohemagglutinin. Plasma cortisol concentrations and the concentration of Th1/Th2/Th17 cell cytokines were examined. Data were analyzed using both traditional statistics and magnitude-based inferences. Results revealed a significant decrease in plasma cortisol at 4-24 h postexercise compared with pre-exercise values. Qualitative analysis revealed postexercise changes in concentrations of plasma cortisol, IL-2, TNF, IL-4, IL-6, IL-10, and IL-17A compared with pre-exercise values. A Th1/Th2 shift was evident immediately postexercise. Furthermore, for multiple cytokines, including IL-2 and TNF (Th1), IL-6 and IL-10 (Th2), and IL-17 (Th17), no meaningful change in concentration occurred until more than 4 h postexercise, highlighting the duration of exercise-induced changes in immune function. These results demonstrate the importance of considering "clinically" significant versus statistically significant changes in immune cell function after exercise.
Publisher: American Physiological Society
Date: 20-10-0011
DOI: 10.1152/AJPHEART.00441.2020
Abstract: It was classically thought that the function of mammalian red blood cells (RBCs) was limited to serving as a vehicle for oxygen, given the cells’ abundance of cytosolic hemoglobin. Over the past decades, however, accumulating evidence indicates that RBCs have the capacity to sense low-oxygen tensions in hypoxic tissues, and, subsequently, release signaling molecules that influence the distribution of blood flow. The precise mechanisms that facilitate RBC modulation of blood flow are still being elucidated, although recent evidence indicates involvement of 1) adenosine triphosphate, capable of binding to purinergic receptors located on the vascular wall before initiating nitric oxide (NO a powerful vasodilator) production in endothelial cells, and/or 2) nonvascular NO, which is now known to have several modes of production within RBCs, including an enzymatic process via a unique isoform of NO synthase (i.e., RBC-NOS), which has potential effects on the vascular smooth muscle. The physical properties of RBCs, including their tendency to form three-dimensional structures in low shear flow (i.e., aggregation) and their capacity to elongate in high shear flow (i.e., deformability), are only recently being viewed as mechanotransductive processes, with profound effects on vascular reactivity and tissue perfusion. Recent developments in intracellular signaling in RBCs, and the subsequent effects on the mechanical properties of blood, and blood flow, thus present a vivid expansion on the classic perspective of these abundant cells.
Publisher: Springer Science and Business Media LLC
Date: 12-08-0008
DOI: 10.1007/S00421-013-2742-4
Abstract: Although markers of myocyte injury, electrolyte disturbances and an autonomic imbalance have been reported following exercise, the effect of prolonged strenuous activity on cardiac electrical conduction is not well understood. This study examined atrial and ventricular conduction dynamics during recovery from exercise. Electrocardiographic intervals were obtained from eight highly-trained males before, during recovery (15, 30, 45 and 60 min post-exercise) and 24 h after a prolonged bout of strenuous exercise. Time-domain, frequency-domain and non-linear analyses of the RR, PR and QT intervals were analysed to investigate the effect of exercise on autonomic modulation and cardiac electrical conduction. Serum electrolyte and high-sensitivity cardiac troponin T (hs-cTnT) concentrations were measured before exercise, and after 60 min and 24 h of recovery. The root mean square of the successive differences of RR, PR and QT intervals was significantly reduced during recovery (p < 0.05). Normalised low- and high-frequency power of RR intervals significantly increased and decreased, respectively, during recovery. Approximate entropy of PR and QT intervals, and the QT-variability index significantly increased during recovery. All measures except mean QT interval (pre 422 ± 10 ms vs 24 h post 442 ± 11 ms, p = 0.013) returned to pre-exercise values after 24 h. Serum hs-cTnT was significantly elevated 60 min after exercise (pre 5.2 ± 0.7 ng L(-1) vs 60 min post 27.4 ± 6.2 ng L(-1), p = 0.01) and correlated with exercising heart rate (R(2) = 0.89, p 0.05). The results suggest suppressed parasympathetic and/or sustained sympathetic modulation of heart rate during recovery, concomitant with perturbations in atrial and ventricular conduction dynamics. Exercise-induced hs-cTnT release was heart rate dependent.
Publisher: Wiley
Date: 24-12-2019
DOI: 10.1113/EP088226
Start Date: 2023
End Date: 2025
Funder: Australian Research Council
View Funded ActivityStart Date: 2023
End Date: 12-2025
Amount: $407,907.00
Funder: Australian Research Council
View Funded Activity