Resistance training increases basal limb blood flow and vascular conductance in aging humans.

Age-related reductions in basal limb blood flow and vascular conductance are associated with the metabolic syndrome, functional impairments, and osteoporosis. We tested the hypothesis that a strength training program would increase basal femoral blood flow in aging adults. Twenty-six sedentary but healthy middle-aged and older subjects were randomly assigned to either a whole body strength training intervention group (52 +/- 2 yr, 3 men, 10 women) who underwent three supervised resistance training sessions per week for 13 wk or a control group (53 +/- 2 yr, 4 men, 9 women) who participated in a supervised stretching program. At baseline, there were no significant differences in blood pressure, cardiac output, basal femoral blood flow (via Doppler ultrasound), vascular conductance, and vascular resistance between the two groups. The strength training group increased maximal strength in all the major muscle groups tested (P < 0.05). Whole body lean body mass increased (P < 0.05) with strength training, but leg fat-free mass did not. Basal femoral blood flow and vascular conductance increased by 55-60% after strength training (both P < 0.05). No such changes were observed in the control group. In both groups, there were no significant changes in brachial blood pressure, plasma endothelin-1 and angiotensin II concentrations, femoral artery wall thickness, cardiac output, and systemic vascular resistance. Our results indicate that short-term strength training increases basal femoral blood flow and vascular conductance in healthy middle-aged and older adults.     

Otolithic and tonic neck receptors control of limb blood flow in humans

Normand, Hervé, Olivier Etard, and Pierre Denise.Otolithic and tonic neck receptors control of limb blood flow in humans. J. Appl. Physiol. 82(6):1734-1738, 1997.The aim of this study was to evaluate the roleof otolithic receptors and neck mechanoreceptors on the control of thecardiovascular system. We measured calf (CBF) and forearm blood flow(FBF) by strain-gauge plethysmography, mean arterial pressure (MAP),and heart rate (HR) in 12 healthy subjects in two body positions (lyingprone and on the left side) and three head positions (reference,flexion, and extension). When the subjects were lying prone, CBF andFBF were lower in head flexion (5.2 ± 0.6 and 3.2 ± 0.4 ml · min¹ · 100 ml¹, respectively) than inreference position (5.8 ± 0.4 and 3.8 ± 0.3 ml · min¹ · 100 ml¹;P < 0.05), with nosignificant difference in MAP and HR. When the subjects were lying onthe side, changing the head position from reference to flexionsignificantly increased FBF (from 3.7 ± 0.2 to. 4.2 ± 0.4 ml · min¹ · 100 ml¹), MAP (from 97.2 ± 3.3 to 102.4 ± 5.8 mmHg), and HR (from 63.7 ± 1.4 to 65.9 ± 2.5 beats/min; P < 0.05). Because otolithic receptors andneck mechanoreceptors are involved when the subjects are lying prone,and otolithic receptors are not involved when the subjects are lying onthe side, the results suggest that otolithic and neck mechanoreceptorsexert significant influences over the cardiovascular system.

     

A simple water-filled plethysmograph for measurement of limb blood flow in humans

Fundamental principles underpinning the study of cardiovascular physiology can be emphasized by measuring blood flow. Plethysmography is an appropriate, noninvasive technique to use but may not be available to some institutions. Therefore, for measurement of blood flow in human limbs, we developed a simple water-filled plethysmograph that may be built with minimal technical support. The device is formed from a plastic cylinder and houses a latex sleeve sealed at either end by means of circular flanges and rubber O-ring seals. Limb volume changes are transcribed using an air-filled piston recorder. This instrument proves to be sensitive and accurately determines limb volume changes over time. Utilizing an appropriate venous occlusion protocol, predicted vascular responses to postural challenge and physical exercise may be followed. In response to a questionnaire, a majority of students (n = 33) agreed that performing blood flow measurements succeeded in relating theory to practice, improved technical and observational skills, and made the learning experience real. This modified plethysmograph proves to be a valuable teaching tool in human physiology classes.     

The effects of aging and activity on muscle blood flow

Background

Our purpose was to determine if aging had an influence on muscle blood flow independent of habitual physical activity levels.

Methods

Blood flow was measured in the femoral artery by Doppler ultrasound after cuff occlusion of 10 minutes. Active and inactive older subjects (73 ± 7 years) were compared to active and inactive young subjects (26 ± 6 years).

Results

Peak blood flow capacity when normalized to lean muscle mass was related to activity level (p < 0.001), but not to age. Specifically, the young active group had higher peak blood flows than the young inactive (p = 0.031) or older inactive (p = 0.005) groups. Resting blood flow and conductance were not significantly different between groups. Mean arterial pressure was significantly higher in the older compared to young group (p = 0.002). Conductance was related to both activity (p = 0.002) and age (p = 0.003). A prolonged time for blood flow to recover was found in the older compared to the young group (p = 0.038) independent of activity status.

Conclusions

The prolonged recovery time in the older subjects may suggest a reduced vascular reactivity associated with increased cardiovascular disease risk. Peak blood flow capacity is maintained in older subjects by physical activity. In summary, maximal flow capacity and prolonged recovery of blood flow are influenced by different mechanisms in young and older active and inactive subjects.

     

Differential sensitivities of cerebral and brachial blood flow to hypercapnia in humans.

Although it is known that the vasculatures of the brain and the forearm are sensitive to changes in arterial Pco(2), previous investigations have not made direct comparisons of the sensitivities of cerebral blood flow (CBF) (middle cerebral artery blood velocity associated with maximum frequency of Doppler shift; Vp) and brachial blood flow (BBF) to hypercapnia. We compared the sensitivities of Vp and BBF to hypercapnia in humans. On the basis of the critical importance of the brain for the survival of the organism, we hypothesized that Vp would be more sensitive than BBF to hypercapnia. Nine healthy males (30.1 +/- 5.2 yr, mean +/- SD) participated. Euoxic hypercapnia (end-tidal Po(2) = 88 Torr, end-tidal Pco(2) = 9 Torr above resting) was achieved by using the technique of dynamic end-tidal forcing. Vp was measured by transcranial Doppler ultrasound as an index of CBF, whereas BBF was measured in the brachial artery by echo Doppler. Vp and BBF were measured during two 60-min trials of hypercapnia, each trial separated by 60 min. Since no differences in the responses were found between trials, data from both trials were averaged to make comparisons between Vp and BBF. During hypercapnia, Vp and BBF increased by 34 +/- 8 and 14 +/- 8%, respectively. Vp remained elevated throughout the hypercapnic period, but BBF returned to baseline levels by 60 min. The Vp CO(2) sensitivity was greater than BBF (4 +/- 1 vs. 2 +/- 1%/Torr; P < 0.05). Our findings confirm that Vp has a greater sensitivity than BBF in response to hypercapnia and show an adaptive response of BBF that is not evident in Vp.     

Differential effects of 4-hydroperoxycyclophosphamide on limb development in vitro

Cyclophosphamide must be metabolically activated to produce malformations in limbs developing in culture; 4-hydroperoxycyclophosphamide is an analog of the active metabolite of cyclophosphamide, 4-hydroxycyclophosphamide, that breaks down spontaneously in solution to form 4-hydroxycyclophosphamide. To study the mechanism by which metabolites of cyclophosphamide produce limb malformations in vitro we determined the effects of exposure of cultured limb buds to 4-hydroperoxycyclophosphamide. Fore- and hindlimbs were excised from ICR mice on day 12 of gestation and cultured in roller bottles for 6 days. Limbs were exposed to 4-hydroperoxycyclophosphamide for the first 20 hours of the culture period. Addition of 10 micrograms/ml of 4-hydroperoxycyclophosphamide to forelimb or to hindlimb buds in culture produced limb reduction malformations. A dramatic decrease in total limb bone area in fore- and hindlimbs was observed with 10 micrograms/ml of 4-hydroperoxycyclophosphamide. In forelimbs, the long bone area decreased and the paw area remained constant so that the relative contribution of the long bone area to total limb bone area was decreased. In hindlimbs treated with 10 micrograms/ml of 4-hydroperoxycyclophosphamide, no paw skeleton was observed. The DNA, RNA, and protein contents of the limbs were not affected by exposure to 1 microgram/ml of 4-hydroperoxycyclophosphamide, but were decreased by exposure to 10 micrograms/ml of this compound. Exposure to the higher concentration of 4-hydroperoxycyclophosphamide also decreased alkaline phosphatase activity, a marker for osteogenesis, in both fore- and hindlimbs; in contrast, neither concentration of 4-hydroperoxycyclophosphamide had an effect on creatine phosphokinase activity, a marker for myogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of lower body negative pressure on forearm and calf blood flow

Modest degrees of lower body negative pressure (less than 20 mmHg) cause a reflex constriction of forearm resistance vessels attributable to a decrease in activity of cardiopulmonary mechanoreceptors. In the present study, we sought to determine whether the calf vessels respond similarly. Left forearm and right calf blood flows were measured simultaneously by strain-gauge plethysmography in 10 healthy volunteers. Forearm flows decreased significantly from control during negative pressures of 10, 15, or 20 mmHg, whereas calf flows did not decrease significantly until 20 mmHg; at 10, 15, and 20 mmHg, decreases in forearm flow were significantly greater than those of the calf. Similar results were obtained in a second series of experiments in which venous pooling in the right leg during lower body negative pressure was prevented by enclosing it in a boot. At 40 mmHg, or after a Valsalva maneuver, both forearm and calf vessels constricted markedly and to the same degree. It appears that the reflex reduction in blood flow to the skeletal muscles of the limbs resulting from deactivation of the low-pressure intrathoracic mechanoreceptors is directed primarily to the arm.     

Effect of Ilizarov tibial lengthening on limb blood flow

The experiment in 23 adult dogs was based on the study of volumetric blood flow velocity in the superficial femoral artery and femoral vein, pulse changes in blood filling of the m. gastrocnemius in the conditions of tibial lengthening to 17.5-23% from the initial length. Complex changes in the blood flow parameters were revealed after surgical intervention and within 7 distraction days. When the distraction ended, the volumetric blood flow velocity in the femoral artery was reduced by 19% and the blood flow out of the vessel was improved by 17%. When fixation was over, the volumetric blood flow velocity in the vessel increased by 37% and the improved outflow preserved. At each experimental stage, there was an increased volumetric blood flow velocity in the femoral vein as compared to its value in the control group, its correspondence to the superficial femoral artery as well as similar dynamics in blood flow changes in the femoral vessels and m. gastrocnemius. The findings show that the vascular system of bone regeneration provides accelerated arterial blood transportation into the venous system during organotypical bone area formation.     

Differential effects of aging on EEG after baclofen administration

Baclofen is a selective gamma-aminobutyric acid (GABA) type B agonist that may have important medicinal uses, such as in analgesics and drug addiction treatment. In addition, evidence is accumulating that suggests GABAergic-mediated neurotransmission is altered during aging. This study investigated whether baclofen administration (5 mg kg⁻¹) induces differential effects on cortical electrical activity with age. Electroencephalograms (EEGs) were recorded from young (3–4 months) and aged (15–17 months) rats, and both the absolute and relative powers in five frequency bands (delta: 2–4 Hz; theta: 4–8 Hz; alpha: 8–12 Hz; beta: 12–20 Hz; gamma: 20–100 Hz) were analyzed. Before administration of baclofen, we found that the EEG relative power in the beta band was higher in the aged than that in the young rats. After administration of baclofen, there was a slower increase in the relative power in the delta band in the aged than that in the young rats. Moreover, there was no significant difference between the two age groups in absolute power in any frequency band. These findings indicate that baclofen treatment appears to differentially modify cortical EEG activity as a function of age. Our data further elucidate the relationship between GABA_B receptor-mediated neurotransmission and aging.     

Gravity-independent inequality in pulmonary blood flow in humans

Single-photon emission computerized tomography of the lung with 99mTc-labeled human albumin macroaggregates (99mTc-MAA) was used in six healthy subjects to study the three-dimensional distribution of pulmonary blood flow. 99mTc-MAA was injected while the subjects were resting in the supine position and holding their lung volume at normal end expiration. Tomography was performed on each subject from 120 projections of radioactivity in the lungs acquired with a rotating gamma camera. To minimize lung motion artifacts, the subjects were asked to hold their breath at end expiration during the 10-s duration of data acquisition in each projectional angle. Perfusion images of lung slices (11 mm thick) were reconstructed, and the radioactivity within each slice was expressed per unit lung volume of 3.7 X 3.7 X 11 mm. Perfusion images of a midcoronal slice from each subject manifested a concentric pattern of radioactivity that decreased significantly from the center to the periphery, suggesting that blood flow rate per unit lung volume was up to 10 times larger near the central region. This gradient in activity between the center and the periphery of the coronary slices was gravity independent as the subjects were supine. Images of sagittal slices from the middle of the right lung also manifested a similar pattern of concentric gradient in activity, with the vertical distribution (gravity related) almost comparable with the horizontal distribution (gravity independent). These results indicate that pulmonary blood flow in resting supine humans is spatially stratified with a marked central-to-peripheral gradient in all directions. It appears that zone 4 (reduced blood flow) is not a phenomenon limited to the dependent region of the lung as commonly thought but rather is a manifestation of this spatial distribution whereby blood flow is lowest in all peripheral regions of the lung.     

Cerebral blood flow during static exercise in humans

Cerebral blood flow (CBF) was determined in humans at rest and during four consecutive unilateral static contractions of the knee extensors. Each contraction was maintained for 3 min 15 s with the subjects in a semisupine position. The contractions corresponded to 8, 16, 24, and 32% of the maximal voluntary contraction (MVC) and utilized alternate legs. CBF (measured by the 133Xe clearance technique) was expressed by a noncompartmental flow index (ISI). Heart rate and mean arterial pressure increased from resting values of 73 (55-80) beats/min and 88 (74-104) mmHg to 106 (86-138) beats/min and 124 (102-146) mmHg, respectively (P less than 0.0005), during the contraction at 32% MVC. Arterial PCO2 and central venous pressure did not change. Corrected to the average resting PCO2, CBF during control was 55 (35-73) ml.100 g-1.min-1 and remained constant during contractions. Cerebral vascular resistance increased from 1.5 (1.0-2.2) to 2.4 (1.4-3.0) mmHg. 100 g.min.ml-1 (P less than 0.025) at 32% of MVC. There was no difference in CBF between the two hemispheres at rest or during exercise. In contrast to dynamic leg exercise, static leg exercise is not associated with an increase in global CBF when measured by the 133Xe clearance technique.     

Melatonin differentially affects vascular blood flow in humans

Melatonin is synthesized and released into the circulation by the pineal gland in a circadian rhythm. Melatonin has been demonstrated to differentially alter blood flow to assorted vascular beds by the activation of different melatonin receptors in animal models. The purpose of the present study was to determine the effect of melatonin on blood flow to various vascular beds in humans. Renal (Doppler ultrasound), forearm (venous occlusion plethysmography), and cerebral blood flow (transcranial Doppler), arterial blood pressure, and heart rate were measured in 10 healthy subjects (29±1 yr; 5 men and 5 women) in the supine position for 3 min. The protocol began 45 min after the ingestion of either melatonin (3 mg) or placebo (sucrose). Subjects returned at least 2 days later at the same time of day to repeat the trial after ingesting the other substance. Melatonin did not alter heart rate and mean arterial pressure. Renal blood flow velocity (RBFV) and renal vascular conductance (RVC) were lower during the melatonin trial compared with placebo (RBFV, 40.5±2.9 vs. 45.4±1.5 cm/s; and RVC, 0.47±0.02 vs. 0.54±0.01 cm·s(-1)·mmHg(-1), respectively). In contrast, forearm blood flow (FBF) and forearm vascular conductance (FVC) were greater with melatonin compared with placebo (FBF, 2.4±0.2 vs. 1.9±0.1 ml·100 ml(-1)·min(-1); and FVC, 0.029±0.003 vs. 0.023±0.002 arbitrary units, respectively). Melatonin did not alter cerebral blood flow measurements compared with placebo. Additionally, phentolamine (5-mg bolus) after melatonin reversed the decrease in RVC, suggesting that melatonin increases sympathetic outflow to the kidney to mediate renal vasoconstriction. In summary, exogenous melatonin differentially alters vascular blood flow in humans. These data suggest the complex nature of melatonin on the vasculature in humans.     

Effect of brain blood flow on hypoxic ventilatory response in humans

To assess the effect of brain blood flow on hypoxic ventilatory response, we measured arterial and internal jugular venous blood gases and ventilation simultaneously and repeatedly in eight healthy male humans in two settings: 1) progressive and subsequent sustained hypoxia, and 2) stepwise and progressive hypercapnia. Ventilatory response to progressive isocapnic hypoxia [arterial O2 partial pressure 155.9 +/- 4.0 (SE) to 46.7 +/- 1.5 Torr] was expressed as change in minute ventilation per change in arterial O2 saturation and varied from -0.16 to -1.88 [0.67 +/- 0.19 (SE)] l/min per % among subjects. In the meanwhile, jugular venous PCO2 (PjCO2) decreased significantly from 51.0 +/- 1.1 to 47.3 +/- 1.0 Torr (P less than 0.01), probably due to the increase in brain blood flow, and stayed at the same level during 15 min of sustained hypoxia. Based on the assumption that PjCO2 reflects the brain tissue PCO2, we evaluated the depressant effect of fall in PjCO2 on hypoxic ventilatory response, using a slope for ventilation-PjCO2 line which was determined in the second set of experiments. Hypoxic ventilatory response corrected with this factor was -1.31 +/- 0.33 l/min per %, indicating that this factor modulated hypoxic ventilatory response in humans. The ventilatory response to progressive isocapnic hypoxia did not correlate with this factor but significantly correlated with the withdrawal test (modified transient O2 test), which was performed on a separate day. Accordingly we conclude that an increase in brain blood flow during exposure to moderate hypoxia may substantially attenuate the ventilatory response but that it is unlikely to be the major factor of the interindividual variation of progressive isocapnic hypoxic ventilatory response in humans.     

Differential effects of aging on estrogen negative and positive feedback

Recent studies have demonstrated an age-related decline in gonadotropins and a decrease in pituitary responsiveness to GnRH, indicating that aging influences the neuroendocrine components of the female reproductive axis independently of changes in ovarian function. To determine whether aging might also affect the luteinizing hormone (LH) negative and positive feedback responses to gonadal steroids, we administered a controlled, graded sex steroid infusion to 11 younger (45-56 yr) and nine older (70-80 yr) postmenopausal women (PMW) in whom endogenous ovarian steroids and peptides are uniformly low. The doses of estradiol (E(2)) and progesterone (P) were chosen to mimic levels across the normal follicular phase and have been shown previously to induce negative followed by positive feedback on LH. Similar E(2) and P levels were achieved in younger and older PMW (P = 0.4 and 0.3, respectively) and produced a biphasic LH response in all subjects. The early decline in LH to 53% of baseline was not different in older vs. younger PMW. However, the positive feedback effect was attenuated in older compared with younger PMW (peak LH 144.4 ± 19.5 vs. 226.8 ± 22.3 IU/l, respectively, P = 0.01). In conclusion, these studies in PMW demonstrate preservation of short-term steroid negative and positive feedback in response to exogenous E(2) and P with aging. Attenuation of positive feedback in older compared with younger PMW is consistent with previous reports of declining GnRH responsiveness with aging.     

Multiple coherence of cerebral blood flow velocity in humans

The coherence function has been used in transfer function analysis of dynamic cerebral autoregulation to assess the statistical significance of spectral estimates of gain and phase frequency response. Interpretation of the coherence function and choice of confidence limits has not taken into account the intrinsic nonlinearity represented by changes in cerebrovascular resistance due to vasomotor activity. For small spontaneous changes in arterial blood pressure (ABP), the relationship between ABP and cerebral blood flow velocity (CBFV) can be linearized, showing that corresponding changes in cerebrovascular resistance should be included as a second input variable. In this case, the standard univariate coherence function needs to be replaced by the multiple coherence, which takes into account the contribution of both inputs to explain CBFV variability. With the use of two different indicators of cerebrovascular resistance index [CVRI = ABP/CBFV and the resistance-area product (RAP)], multiple coherences were calculated for 42 healthy control subjects, aged 20 to 40 yr (28 +/- 4.6 yr, mean +/- SD), at rest in the supine position. CBFV was measured in both middle cerebral arteries, and ABP was recorded noninvasively by finger photoplethysmography. Results for the ABP + RAP inputs show that the multiple coherence of CBFV for frequencies <0.05 Hz is significantly higher than the corresponding values obtained for univariate coherence (P < 10(-5)). Corresponding results for the ABP + CVRI inputs confirm the principle of multiple coherence but are less useful due to the interdependence between CVRI, ABP, and CBFV. The main conclusion is that values of univariate coherence between ABP and CBFV should not be used to reject spectral estimates of gain and phase, derived from small fluctuations in ABP, because the true explained power of CBFV in healthy subjects is much higher than what has been usually predicted by the univariate coherence functions.     

Sex-specific influence of aging on exercising leg blood flow.

Our previous work suggests that healthy human aging is associated with sex-specific differences in leg vascular responses during large muscle mass exercise (2-legged cycling) (Proctor DN, Parker BA. Microcirculation 13: 315-327, 2006). The present study determined whether age x sex interactions in exercising leg hemodynamics persist during small muscle mass exercise that is not limited by cardiac output. Thirty-one young (20-30 yr; 15 men/16 women) and 31 older (60-79 yr; 13 men/18 women) healthy, normally active adults performed graded single-leg knee extensions to maximal exertion. Femoral artery blood velocity and diameter (Doppler ultrasound), heart rate (ECG), and beat-to-beat arterial blood pressure (mean arterial pressure, radial artery tonometry) were measured during each 3-min work rate (4.8 and 8 W/stage for women and men, respectively). The results (means +/- SE) were as follows. Despite reduced resting leg blood flow and vascular conductance, older men exhibited relatively preserved exercising leg hemodynamic responses. Older women, by contrast, exhibited attenuated hyperemic (young: 52 +/- 3 ml.min(-1).W(-1); vs. older: 40 +/- 4 ml.min(-1).W(-1); P = 0.02) and vasodilatory responses (young: 0.56 +/- 0.06 ml.min(-1).mmHg(-1).W(-1) vs. older: 0.37 +/- 0.04 ml.min(-1).mmHg(-1) W(-1); P < 0.01) to exercise compared with young women. Relative (percentage of maximal) work rate comparisons of all groups combined also revealed attenuated vasodilator responses in older women (P < 0.01 for age x sex x work rate interaction). These sex-specific age differences were not abolished by consideration of hemoglobin, quadriceps muscle, muscle recruitment, and mechanical influences on muscle perfusion. Collectively, these findings suggest that local factors contribute to the sex-specific effects of aging on exercising leg hemodynamics in healthy adults.     

Hyperbaric hyperoxia reduces exercising forearm blood flow in humans

Hypoxia during exercise augments blood flow in active muscles to maintain the delivery of O(2) at normoxic levels. However, the impact of hyperoxia on skeletal muscle blood flow during exercise is not completely understood. Therefore, we tested the hypothesis that the hyperemic response to forearm exercise during hyperbaric hyperoxia would be blunted compared with exercise during normoxia. Seven subjects (6 men/1 woman; 25 ± 1 yr) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Forearm blood flow (FBF; in ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC; in ml·min(-1)·100 mmHg(-1)) was calculated from FBF and blood pressure (in mmHg; brachial arterial catheter). Studies were performed in a hyperbaric chamber with the subjects supine at 1 atmospheres absolute (ATA) (sea level) while breathing normoxic gas [21% O(2), 1 ATA; inspired Po(2) (Pi(O(2))) ≈ 150 mmHg] and at 2.82 ATA while breathing hyperbaric normoxic (7.4% O(2), 2.82 ATA, Pi(O(2)) ≈ 150 mmHg) and hyperoxic (100% O(2), 2.82 ATA, Pi(O(2)) ≈ 2,100 mmHg) gas. Resting FBF and FVC were less during hyperbaric hyperoxia compared with hyperbaric normoxia (P < 0.05). The change in FBF and FVC (Δ from rest) during exercise under normoxia (204 ± 29 ml/min and 229 ± 37 ml·min(-1)·100 mmHg(-1), respectively) and hyperbaric normoxia (203 ± 28 ml/min and 217 ± 35 ml·min(-1)·100 mmHg(-1), respectively) did not differ (P = 0.66-0.99). However, the ΔFBF (166 ± 21 ml/min) and ΔFVC (163 ± 23 ml·min(-1)·100 mmHg(-1)) during hyperbaric hyperoxia were substantially attenuated compared with other conditions (P < 0.01). Our data suggest that exercise hyperemia in skeletal muscle is highly dependent on oxygen availability during hyperoxia.