[Protective effect of Uncaria rhynchophylla total alkaloids pretreatment on hippocampal neurons after acute hypoxia].

PubMed

Liu, Wei; Zhang, Zhao-qin; Zhao, Xiao-min; Gao, Yun-sheng

2006-05-01

To investigate the effect of Uncaria rhynchophylla total alkaloids (RTA) pretreatment on the voltage-gated sodium currents of the rat hippocampal neurons after acute hypoxia. Primary cultured hippocampal neurons were divided into RTA pre-treated and non-pretreated groups. Patch clamp whole-cell recording was used to compare the voltage-gated sodium current amplitude and threshold with those before hypoxia. After acute hypoxia, sodium current amplitude was significantly decreased and its threshold was upside. RTA pretreatment could inhibit the reduction of sodium current amplitude. RTA pretreatment alleviates the acute hypoxia-induced change of sodium currents, which may be one of the mechanisms for protective effect of RTA on cells.

Acute and chronic hypoxia: implications for cerebral function and exercise tolerance

PubMed Central

Goodall, Stuart; Twomey, Rosie; Amann, Markus

2015-01-01

Purpose To outline how hypoxia profoundly affects neuronal functionality and thus compromise exercise-performance. Methods Investigations using electroencephalography (EEG) and transcranial magnetic stimulation (TMS) detecting neuronal changes at rest and those studying fatiguing effects on whole-body exercise performance in acute (AH) and chronic hypoxia (CH) were evaluated. Results At rest during very early hypoxia (<1-h), slowing of cerebral neuronal activity is evident despite no change in corticospinal excitability. As time in hypoxia progresses (3-h), increased corticospinal excitability becomes evident; however, changes in neuronal activity are unknown. Prolonged exposure (3–5 d) causes a respiratory alkalosis which modulates Na+ channels, potentially explaining reduced neuronal excitability. Locomotor exercise in AH exacerbates the development of peripheral-fatigue; as the severity of hypoxia increases, mechanisms of peripheral-fatigue become less dominant and CNS hypoxia becomes the predominant factor. The greatest central-fatigue in AH occurs when SaO2 is ≤75%, a level that coincides with increasing impairments in neuronal activity. CH does not improve the level of peripheral-fatigue observed in AH; however, it attenuates the development of central-fatigue paralleling increases in cerebral O2 availability and corticospinal excitability. Conclusions The attenuated development of central-fatigue in CH might explain, the improvements in locomotor exercise-performance commonly observed after acclimatisation to high altitude. PMID:25593787

Acute effects of head-down tilt and hypoxia on modulators of fluid homeostasis

NASA Technical Reports Server (NTRS)

Whitson, P. A.; Cintron, N. M.; Pietrzyk, R. A.; Scotto, P.; Loeppky, J. A.

1994-01-01

In an effort to understand the interaction between acute postural fluid shifts and hypoxia on hormonal regulation of fluid homeostasis, the authors measured the responses to head-down tilt with and without acute exposure to normobaric hypoxia. Plasma atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), plasma aldosterone (ALD), and plasma renin activity (PRA) were measured in six healthy male volunteers who were exposed to a head-down tilt protocol during normoxia and hypoxia. The tilt protocol consisted of a 17 degrees head-up phase (30 minutes), a 28 degrees head-down phase (1 hour), and a 17 degrees head-up recovery period (2 hours, with the last hour normoxic in both experiments). Altitude equivalent to 14,828 ft was simulated by having the subjects breathe an inspired gas mixture with 13.9% oxygen. The results indicate that the postural fluid redistribution associated with a 60-minute head-down tilt induces the release of ANP and cGMP during both hypoxia and normoxia. Hypoxia increased cGMP, cAMP, ALD, and PRA throughout the protocol and significantly potentiated the increase in cGMP during head-down tilt. Hypoxia had no overall effect on the release of ANP, but appeared to attenuate the increase with head-down tilt. This study describes the acute effects of hypoxia on the endocrine response during fluid redistribution and suggests that the magnitude, but not the direction, of these changes with posture is affected by hypoxia.

Skeletal Muscle Pyruvate Dehydrogenase Phosphorylation and Lactate Accumulation During Sprint Exercise in Normoxia and Severe Acute Hypoxia: Effects of Antioxidants.

PubMed

Morales-Alamo, David; Guerra, Borja; Santana, Alfredo; Martin-Rincon, Marcos; Gelabert-Rebato, Miriam; Dorado, Cecilia; Calbet, José A L

2018-01-01

Compared to normoxia, during sprint exercise in severe acute hypoxia the glycolytic rate is increased leading to greater lactate accumulation, acidification, and oxidative stress. To determine the role played by pyruvate dehydrogenase (PDH) activation and reactive nitrogen and oxygen species (RNOS) in muscle lactate accumulation, nine volunteers performed a single 30-s sprint (Wingate test) on four occasions: two after the ingestion of placebo and another two following the intake of antioxidants, while breathing either hypoxic gas (P I O 2 = 75 mmHg) or room air (P I O 2 = 143 mmHg). Vastus lateralis muscle biopsies were obtained before, immediately after, 30 and 120 min post-sprint. Antioxidants reduced the glycolytic rate without altering performance or VO 2 . Immediately after the sprints, Ser 293 - and Ser 300 -PDH-E1α phosphorylations were reduced to similar levels in all conditions (~66 and 91%, respectively). However, 30 min into recovery Ser 293 -PDH-E1α phosphorylation reached pre-exercise values while Ser 300 -PDH-E1α was still reduced by 44%. Thirty minutes after the sprint Ser 293 -PDH-E1α phosphorylation was greater with antioxidants, resulting in 74% higher muscle lactate concentration. Changes in Ser 293 and Ser 300 -PDH-E1α phosphorylation from pre to immediately after the sprints were linearly related after placebo ( r = 0.74, P < 0.001; n = 18), but not after antioxidants ingestion ( r = 0.35, P = 0.15). In summary, lactate accumulation during sprint exercise in severe acute hypoxia is not caused by a reduced activation of the PDH. The ingestion of antioxidants is associated with increased PDH re-phosphorylation and slower elimination of muscle lactate during the recovery period. Ser 293 re-phosphorylates at a faster rate than Ser 300 -PDH-E1α during the recovery period, suggesting slightly different regulatory mechanisms.

Skeletal Muscle Pyruvate Dehydrogenase Phosphorylation and Lactate Accumulation During Sprint Exercise in Normoxia and Severe Acute Hypoxia: Effects of Antioxidants

PubMed Central

Morales-Alamo, David; Guerra, Borja; Santana, Alfredo; Martin-Rincon, Marcos; Gelabert-Rebato, Miriam; Dorado, Cecilia; Calbet, José A. L.

2018-01-01

Compared to normoxia, during sprint exercise in severe acute hypoxia the glycolytic rate is increased leading to greater lactate accumulation, acidification, and oxidative stress. To determine the role played by pyruvate dehydrogenase (PDH) activation and reactive nitrogen and oxygen species (RNOS) in muscle lactate accumulation, nine volunteers performed a single 30-s sprint (Wingate test) on four occasions: two after the ingestion of placebo and another two following the intake of antioxidants, while breathing either hypoxic gas (PIO2 = 75 mmHg) or room air (PIO2 = 143 mmHg). Vastus lateralis muscle biopsies were obtained before, immediately after, 30 and 120 min post-sprint. Antioxidants reduced the glycolytic rate without altering performance or VO2. Immediately after the sprints, Ser293- and Ser300-PDH-E1α phosphorylations were reduced to similar levels in all conditions (~66 and 91%, respectively). However, 30 min into recovery Ser293-PDH-E1α phosphorylation reached pre-exercise values while Ser300-PDH-E1α was still reduced by 44%. Thirty minutes after the sprint Ser293-PDH-E1α phosphorylation was greater with antioxidants, resulting in 74% higher muscle lactate concentration. Changes in Ser293 and Ser300-PDH-E1α phosphorylation from pre to immediately after the sprints were linearly related after placebo (r = 0.74, P < 0.001; n = 18), but not after antioxidants ingestion (r = 0.35, P = 0.15). In summary, lactate accumulation during sprint exercise in severe acute hypoxia is not caused by a reduced activation of the PDH. The ingestion of antioxidants is associated with increased PDH re-phosphorylation and slower elimination of muscle lactate during the recovery period. Ser293 re-phosphorylates at a faster rate than Ser300-PDH-E1α during the recovery period, suggesting slightly different regulatory mechanisms. PMID:29615918

Effect of acute exposure to moderate altitude on muscle power: hypobaric hypoxia vs. normobaric hypoxia.

PubMed

Feriche, Belén; García-Ramos, Amador; Calderón-Soto, Carmen; Drobnic, Franchek; Bonitch-Góngora, Juan G; Galilea, Pedro A; Riera, Joan; Padial, Paulino

2014-01-01

When ascending to a higher altitude, changes in air density and oxygen levels affect the way in which explosive actions are executed. This study was designed to compare the effects of acute exposure to real or simulated moderate hypoxia on the dynamics of the force-velocity relationship observed in bench press exercise. Twenty-eight combat sports athletes were assigned to two groups and assessed on two separate occasions: G1 (n = 17) in conditions of normoxia (N1) and hypobaric hypoxia (HH) and G2 (n = 11) in conditions of normoxia (N2) and normobaric hypoxia (NH). Individual and complete force-velocity relationships in bench press were determined on each assessment day. For each exercise repetition, we obtained the mean and peak velocity and power shown by the athletes. Maximum power (Pmax) was recorded as the highest P(mean) obtained across the complete force-velocity curve. Our findings indicate a significantly higher absolute load linked to P(max) (∼ 3%) and maximal strength (1 RM) (∼ 6%) in G1 attributable to the climb to altitude (P<0.05). We also observed a stimulating effect of natural hypoxia on P(mean) and P(peak) in the middle-high part of the curve (≥ 60 kg; P<0.01) and a 7.8% mean increase in barbell displacement velocity (P<0.001). No changes in any of the variables examined were observed in G2. According to these data, we can state that acute exposure to natural moderate altitude as opposed to simulated normobaric hypoxia leads to gains in 1 RM, movement velocity and power during the execution of a force-velocity curve in bench press.

Effect of Acute Exposure to Moderate Altitude on Muscle Power: Hypobaric Hypoxia vs. Normobaric Hypoxia

PubMed Central

Feriche, Belén; García-Ramos, Amador; Calderón-Soto, Carmen; Drobnic, Franchek; Bonitch- Góngora, Juan G.; Galilea, Pedro A.; Riera, Joan; Padial, Paulino

2014-01-01

When ascending to a higher altitude, changes in air density and oxygen levels affect the way in which explosive actions are executed. This study was designed to compare the effects of acute exposure to real or simulated moderate hypoxia on the dynamics of the force-velocity relationship observed in bench press exercise. Twenty-eight combat sports athletes were assigned to two groups and assessed on two separate occasions: G1 (n = 17) in conditions of normoxia (N1) and hypobaric hypoxia (HH) and G2 (n = 11) in conditions of normoxia (N2) and normobaric hypoxia (NH). Individual and complete force-velocity relationships in bench press were determined on each assessment day. For each exercise repetition, we obtained the mean and peak velocity and power shown by the athletes. Maximum power (Pmax) was recorded as the highest Pmean obtained across the complete force-velocity curve. Our findings indicate a significantly higher absolute load linked to Pmax (∼3%) and maximal strength (1RM) (∼6%) in G1 attributable to the climb to altitude (P<0.05). We also observed a stimulating effect of natural hypoxia on Pmean and Ppeak in the middle-high part of the curve (≥60 kg; P<0.01) and a 7.8% mean increase in barbell displacement velocity (P<0.001). No changes in any of the variables examined were observed in G2. According to these data, we can state that acute exposure to natural moderate altitude as opposed to simulated normobaric hypoxia leads to gains in 1RM, movement velocity and power during the execution of a force-velocity curve in bench press. PMID:25474104

[Using of reamberin for correction of free radicals disturbances in patients with acute severe methadone poisonings].

PubMed

Shilov, V V; Vasil'ev, S A; Batotsyrenov, B V; Loladze, A T; Kuznetsov, O A

2012-03-01

The article deals with the materials, which have been received in the process of the examination and treatment of 44 patients with acute severe methadone poisonings. It has been revealed, that gravity of these patient's condition depends on intensity of hypoxia due to breath deficiency because of the methadone. The development of hypoxia, in its turn, cause violations of antiradical protection system and intensification of processes of peroxide lipid oxidation. It has been registered that the including of reamberin into the complex program of the intensive therapy of acute severe methadone poisonings lead to a more rapid restoration of antiradical protection system and to a decrease of activity of processes of peroxide lipid oxidation. The correction of hypoxia and free-radical violations led to improvement of the acute poisonings clinic, what had been characterized by a decrease of coma-period duration, duration of treatment with artificial lung ventilation, a decrease of secondary lung complications and a decrease of lethality.

Alterations of hypoxia-inducible factor-1 alpha in the hippocampus of mice acutely and repeatedly exposed to hypoxia.

PubMed

Shao, Guo; Gao, Cui-Ying; Lu, Guo-Wei

2005-01-01

This work aims at investigating the effects of hypoxic preconditioning on hypoxia-inducible factor-1 alpha (HIF-1alpha) expression in the hippocampus of mice during acute and repeated hypoxic exposures. The mice were randomly divided into three groups and exposed, respectively, to hypoxia for 4 runs (group H4), 1 run (group H1), and 0 run (group H0). Reverse transcription-polymerase chain reaction (RT-PCR), Western blot, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation were used to examine the HIF-1alpha responses in the mouse hippocampus following exposure to hypoxia. The tolerance of mice to hypoxia increased significantly following acute and repetitive exposure to autoprogressive hypoxia. Total mRNA, total protein, and nuclear protein were extracted from the hippocampus for RT-PCR, Western blot, and EMSA, respectively. The HIF-1alpha mRNA levels were found to be increased in group H1 and decreased in group H4. The HIF-1alpha protein levels and HIF-1 DNA-binding activities were increased in group H1 and markedly increased in group H4. One of the HIF-1 target genes, vascular endothelial growth factor, increased in group H4. HIF-1 activation is thought to be involved in the protection of the brain of hypoxic preconditioned mice. Copyright 2005 S. Karger AG, Basel

Comparative iTRAQ-Based Quantitative Proteomic Analysis of Pelteobagrus vachelli Liver under Acute Hypoxia: Implications in Metabolic Responses.

PubMed

Zhang, Guosong; Zhang, Jiajia; Wen, Xin; Zhao, Cheng; Zhang, Hongye; Li, Xinru; Yin, Shaowu

2017-09-01

More and more frequently these days, aquatic ecosystems are being stressed by nutrient enrichment, pollutants, and global warming, leading to a serious depletion in oxygen concentrations. Although a sudden, significant lack of oxygen will result in mortality, fishes can have an acute behavior (e.g., an increase in breathing rate, reduction in swimming frequency) and physiology responses (e.g., increase in oxygen delivery, and reduction in oxygen consumption) to hypoxia, which allows them to maintain normal physical activity. Therefore, in order to shed further light on the molecular mechanisms of hypoxia adaptation in fishes, the authors conduct comparative quantitative proteomics on Pelteobagrus vachelli livers using iTRAQ. The research identifies 511 acute hypoxia-responsive proteins in P. vachelli. Furthermore, comparison of several of the diverse key pathways studied (e.g., peroxisome pathway, PPAR signaling pathway, lipid metabolism, glycolysis/gluco-neogenesis, and amino acid metabolism) help to articulate the different mechanisms involved in the hypoxia response of P. vachelli. Data from proteome analysis shows that P. vachelli can have an acute reaction to hypoxia, including detoxification of metabolic by-products and oxidative stress in light of continued metabolic activity (e.g., peroxisomes), an activation in the capacity of catabolism to get more energy (e.g., lipolysis and amino acid catabolism), a depression in the capacity of biosynthesis to reduce energy consumption (e.g., biosynthesis of amino acids and lipids), and a shift in the aerobic and anaerobic contributions to total metabolism. The observed hypoxia-related changes in the liver proteome of the fish can help to understand or can be related to the hypoxia-related response that takes place in similar conditions in the liver or other proteomes of mammals. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Acute hypoxia during organogenesis affects cardiac autonomic balance in pregnant rats.

PubMed

Maslova, M V; Graf, A V; Maklakova, A S; Krushinskaya, Ya V; Sokolova, N A; Koshelev, V B

2005-02-01

Changes in ECG parameters were studied in pregnant rats exposed to acute hypobaric hypoxia during the period of organogenesis (gestation days 9 to 10). Rats with low, medium, and high tolerance to hypoxia exhibited pronounced autonomic nervous system imbalance, which become apparent as a loss of correlation between various parameters of ECG signals recorded at rest and during exposure to some stress factors existing under normal conditions.

Severe acute intermittent hypoxia elicits phrenic long-term facilitation by a novel adenosine-dependent mechanism

PubMed Central

Nichols, Nicole L.; Dale, Erica A.

2012-01-01

Acute intermittent hypoxia [AIH; 3, 5-min episodes; 35–45 mmHg arterial Po2 (PaO2)] elicits serotonin-dependent phrenic long-term facilitation (pLTF), a form of phrenic motor facilitation (pMF) initiated by Gq protein-coupled metabotropic 5-HT2 receptors. An alternate pathway to pMF is induced by Gs protein-coupled metabotropic receptors, including adenosine A2A receptors. AIH-induced pLTF is dominated by the serotonin-dependent pathway and is actually restrained via inhibition from the adenosine-dependent pathway. Here, we hypothesized that severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent form of pMF. pLTF induced by severe (25–30 mmHg PaO2) and moderate (45–55 mmHg PaO2) AIH were compared in anesthetized rats, with and without intrathecal (C4) spinal A2A (MSX-3, 130 ng/kg, 12 μl) or 5-HT receptor antagonist (methysergide, 300 μg/kg, 15 μl) injections. During severe, but not moderate AIH, progressive augmentation of the phrenic response during hypoxic episodes was observed. Severe AIH (78% ± 8% 90 min post-AIH, n = 6) elicited greater pLTF vs. moderate AIH (41% ± 12%, n = 8; P < 0.05). MSX-3 (28% ± 6%; n = 6; P < 0.05) attenuated pLTF following severe AIH, but enhanced pLTF following moderate AIH (86% ± 26%; n = 8; P < 0.05). Methysergide abolished pLTF after moderate AIH (12% ± 5%; n = 6; P = 0.035), but had no effect after severe AIH (66 ± 13%; n = 5; P > 0.05). Thus severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent mechanism; the adenosinergic pathway inhibits the serotonergic pathway following moderate AIH. Here we demonstrate a novel adenosine-dependent pathway to pLTF following severe AIH. Shifts in the mechanisms of respiratory plasticity provide the ventilatory control system greater flexibility as challenges that differ in severity are confronted. PMID:22403346

Effects of acute moderate hypoxia on anaerobic capacity in endurance-trained runners.

PubMed

Friedmann, Birgit; Frese, Falko; Menold, Elmar; Bärtsch, Peter

2007-09-01

While there is some controversy whether anaerobic capacity might be improved after altitude training little is known about changes in anaerobic capacity during hypoxic exposure in highly trained athletes. In order to analyze the effects of acute moderate normobaric hypoxia on anaerobic capacity, 18 male competitive triathletes, middle- and long-distance runners VO2max 67.4 +/- 3.8 ml kg min(-1) performed 2 supra-VO2max treadmill runs with the same speed, one in normoxia and one after 4 h exposure to normobaric hypoxia (FiO(2) 0.15), for estimation of their maximal accumulated oxygen deficit (MAOD) and measurement of peak capillary lactate and peak capillary ammonia concentration. MAOD was not significantly different in normoxia and in moderate hypoxia while time to exhaustion and accumulated O(2) uptake were significantly (P < 0.001) reduced in hypoxia compared to normoxia by 28 and 45%, respectively. The reduction in time to exhaustion was significantly correlated to the decrement in accumulated O(2) uptake (R = 0.730, P = 0.001). In hypoxia, there was a tendency for peak capillary lactate concentration to be decreased compared to normoxia (12.9 +/- 2.1 vs. 13.8 +/- 2.2 mmol l(-1), P = 0.082); peak capillary ammonia concentration was significantly decreased in hypoxia (97 +/- 52 vs. 121 +/- 44 micromol l(-1), P = 0.032). In conclusion, anaerobic capacity is not significantly changed during acute exposure to moderate hypoxia in endurance-trained athletes. The performance reduction during all-out exercise of short duration has to be attributed to the decrement in aerobic capacity.

Video monitoring of oxygen saturation during controlled episodes of acute hypoxia.

PubMed

Addison, Paul S; Foo, David M H; Jacquel, Dominique; Borg, Ulf

2016-08-01

A method for extracting video photoplethysmographic information from an RGB video stream is tested on data acquired during a porcine model of acute hypoxia. Cardiac pulsatile information was extracted from the acquired signals and processed to determine a continuously reported oxygen saturation (SvidO2). A high degree of correlation was found to exist between the video and a reference from a pulse oximeter. The calculated mean bias and accuracy across all eight desaturation episodes were -0.03% (range: -0.21% to 0.24%) and accuracy 4.90% (range: 3.80% to 6.19%) respectively. The results support the hypothesis that oxygen saturation trending can be evaluated accurately from a video system during acute hypoxia.

Baroreflex sensitivity in acute hypoxia and carbohydrate loading.

PubMed

Klemenc, Matjaž; Golja, Petra

2011-10-01

Hypoxia decreases baroreflex sensitivity (BRS) and can be a sufficient cause for syncope in healthy individuals. Carbohydrate loading enhances efferent sympathetic activity, which affects cardiac contractility, heart rate and vascular resistance, the main determinants of blood pressure. Thus, in both normoxia and hypoxia, carbohydrate loading may be more than simply metabolically beneficial, as it may affect blood pressure regulation. We hypothesised that carbohydrate loading will, in both normoxia and hypoxia, alter the regulation of blood pressure, as reflected in a change in baroreflex sensitivity. Fourteen subjects participated in two experiments, composed of a 15-min normoxic period, after which the subjects ingested water or an equal amount of water with carbohydrates. A 30-min rest period was then followed by a 10-min second normoxic and a 30-min hypoxic period. Blood pressure and heart rate were monitored continuously during the experiment to determine BRS. Despite an increased sympathetic activation, reflected in increased heart rate (P < 0.001) BRS was lower (P < 0.01) after carbohydrate loading, as compared to the water experiment, in both normoxic [23.7 (12.4) versus 28.8 (13.8) ms/mmHg] and hypoxic [16.8 (11.0) versus 24.3 (12.3) ms/mmHg] phases of the present study. As BRS was decreased in acute hypoxic exposure, the results confirm that hypoxia interferes with blood pressure regulation. However, although oral carbohydrate loading induced sympathoexcitation, it did not improve blood pressure regulation in hypoxia, as evident from the BRS data. Baroreflex effects of other forms of carbohydrate loading, not causing postprandial blood shifts to digestive system, should therefore be investigated.

[Electrophysiological study on rat conduit pulmonary artery smooth muscle cells under normoxia and acute hypoxia].

PubMed

Hu, Ying; Zou, Fei; Cai, Chun-Qing; Wu, Hang-Yu; Yun, Hai-Xia; Chen, Yun-Tian; Jin, Guo-En; Ge, Ri-Li

2006-10-25

The present study was designed to investigate the electrophysiological characteristics of rat conduit pulmonary artery smooth muscle cells (PASMCs) and the response to acute hypoxia. PASMCs of the 1st to 2nd order branches in the conduit pulmonary arteries were obtained by enzymatic isolation. The PASMCs were divided into acute hypoxia preconditioned group and normoxia group. Hypoxia solutions were achieved by bubbling with 5% CO2 plus 95% N2 for at least 30 min before cell perfusion. Potassium currents were compared between these two groups using whole-cell patch clamp technique. The total outward current of PASMCs was measured under normoxia condition when iBTX [specific blocking agent of large conductance Ca-activated K(+) (BK(Ca)) channel] and 4-AP [specific blocking agent of delayed rectifier K(+) (K(DR)) channel] were added consequently into bath solution. PASMCs were classified into three types according to their size, shape and electrophysiological characteristics. Type I cells are the smallest with spindle shape, smooth surface and discrete perinuclear bulge. Type II cells show the biggest size with banana-like appearance. Type III cells have the similar size with type I, and present intermediary shape between type I and type II. iBTX had little effect on the total outward current in type I cells, while 4-AP almost completely blocked it. Most of the total outward current in type II cells was inhibited by iBTX, and the remaining was sensitive to 4-AP. In type III cells, the total outward current was sensitive to both iBTX and 4-AP. Acute hypoxia reduced the current in all three types of cells: (1614.8+/-62.5) pA to (892.4+/-33.6) pA for type I cells (P<0.01); (438.3+/-42.8) pA to (277.5+/-44.7) pA for type II cells (P<0.01); (1 042.0+/-37.2) pA to (613.6+/-23.8) pA for type III (P<0.01), and raised the resting membrane potentials (E(m)) in all these three types of cells: (-41.6+/-1.6) mV to (-18.6+/-1.5) mV (P<0.01), (-42.3+/-3.8) mV to (-30.6+/-3.0) mV (P

Evidence of decrease in peak heart rate in acute hypoxia: effect of exercise-induced arterial hypoxemia.

PubMed

Grataloup, O; Busso, T; Castells, J; Denis, C; Benoit, H

2007-03-01

This study focuses on the influence of the arterial oxygen saturation level at exhaustion on peak heart rate under acute moderate hypoxia, in endurance-trained subjects. Nineteen competing male cyclists performed exhaustive ramp exercise (cycle ergometer) under normoxia and normobaric hypoxia (15 % O (2)). After the normoxic trial, the subjects were divided into those demonstrating exercise-induced arterial hypoxemia during exercise (> 5 % decrease in SaO (2) between rest and the end of exercise, n = 10) and those who did not (n = 9). O (2) uptake, heart rate and arterial O (2) saturation (ear-oximeter) levels were measured. Under hypoxia, peak heart rate decreased for both groups (p < 0.001) and to a greater extent for hypoxemic subjects (p < 0.01). Arterial O (2) saturation under hypoxia was lower for the hypoxemic than for the non-hypoxemic subjects (p < 0.001) and it was correlated to the fall in peak heart rate between normoxia and hypoxia for all subjects (p < 0.01; r = 0.65). Hypoxemic subjects presented greater decrease in maximal O (2) uptake than non-hypoxemic ones (19.6 vs. 15.6 %; p < 0.05). The results confirm the greater decrement in arterial O (2) saturation under hypoxia in hypoxemic subjects and demonstrates a more pronounced reduction in peak heart rate in those subjects compared with non-hypoxemic ones. These data confirm the possible influence of arterial oxygenation on the decrease in peak heart rate in acute hypoxia.

[The modification of nitric oxide production by exogenous substrates of Krebs cycle during acute hypoxia].

PubMed

Kurhaliuk, N M; Kotsiuruba, A V; Sahach, V F

2005-01-01

Hypoxia causes the disruption of mitochondria electron respiratory chain, production of active oxygen forms and the unoxidative protection. In experiments on Wistar rats the influence of sodium succinate (50 mg/kg) and 6-ketoglutarate (200 mg/kg) on NO2-, NO3-, urea and polyamines contents in blood and liver under acute hypoxia (7% O2 in N2, 30 min) was investigated. Nitrite and nitrate content decreased in erythrocytes and liver but not in plasma under acute hypoxia. The exogenous succinate (SK) stimulated production of nitric oxide in erythrocytes and liver while 6-ketoglutarate (KG) only in liver. The switch from more intensive SK oxidation that reveals adrenomimetic influence and causes the synthesis and release of NO from erythrocyte, to less intensive KG correlates with well-known decrease of tissue respiration under the activation of the cholinergic system due to urea cycle activation particularly in liver. The activation of the SK oxidation takes place mainly under the different stress conditions and causes NO production in the blood cells. These conditions of the intensive and fast action under acute hypoxia are accompanied on the one hand by the increase of oxygen input ratio and on the other hand by activation of the free radical oxidation. The protective effect of the natural Krebs cycle intermediates--SK and KG in particular, is related to the regulation of NO synthesis and its metabolism in the main organs. These results proved the existence not only metabolite control of NO system by Krebs cycle intermediates, but the existence of the systemic mechanism for the support of the functional state of mitochondria under hypoxia.

[The influence of acute hypoxia on motility of rats in the open field test under the conditions of an altered photoperiod].

PubMed

Sopova, I Iu

2014-01-01

The influence of acute hypoxia on the motility of rats under the conditions of an altered photoperiod in the open field test was studied. Thus, keeping the animals in constant darkness after the modeling of acute hypoxia leads to the depression of locomotive and exploratory components of the behavior. At the same time the animals that were kept under the conditions of constant light show a change in the correlation between the components of motility after the action of hypoxia.

Microenvironmental oxygen partial pressure in acute myeloid leukemia: Is there really a role for hypoxia?

PubMed

Rieger, Christina T; Fiegl, Michael

2016-07-01

Reduced oxygen partial pressure (pO2) has been recognized as being relevant in hematopoiesis and the pathophysiology of malignant diseases. Although hypoxic (meaning insufficient supply of oxygen) and anoxic areas are present and of pathophysiologic importance (by hypoxia-induced pathways such as HiF1α) in solid tumors, this may not be true for (malignant) hematologic cells. Hematopoiesis occurs in the stem cell niche, which is characterized, among other things, by extremely low pO2. However, in contrast to solid tumors, in this context, the low pO2 is physiological and this feature, among others, is shared by the malignant stem cell niche harboring leukemia-initiating cells. Upon differentiation, hematopoietic cells are constantly exposed to changes in pO2 as they travel throughout the human body and encounter arterial and venous blood and migrate into oxygen-carrier-free tissue with low pO2. Hematologic malignancies such as acute myeloid leukemia (AML) make little difference in this respect and, whereas low oxygen is the usual environment of AML cells, recent evidence suggests no role for real hypoxia. Although there is no evidence that AML pathophysiology is related to hypoxia, leukemic blasts still show several distinct biological features when exposed to reduced pO2: they down- or upregulate membrane receptors such as CXCR4 or FLT3, activate or inhibit intracellular signaling pathways such as PI3K, and specifically secrete cytokines (IL-8). In summary, reduced pO2 should not be mistaken for hypoxia (nor should it be so called), and it does not automatically induce hypoxia-response mechanisms; therefore, a strict distinction should be made between physiologically low pO2 (physoxia) and hypoxia. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Hypoxic pretreatment protects against neuronal damage of the rat hippocampus induced by severe hypoxia.

PubMed

Gorgias, N; Maidatsi, P; Tsolaki, M; Alvanou, A; Kiriazis, G; Kaidoglou, K; Giala, M

1996-04-01

The present study investigates whether under conditions of successive hypoxic exposures pretreatment with mild (15% O(2)) or moderate (10% O(2)) hypoxia, protects hippocampal neurones against damage induced by severe (3% O(2)) hypoxia. The ultrastructural findings were also correlated with regional superoxide dismutase (SOD) activity changes. In unpretreated rats severe hypoxia induced ultrastructural changes consistent with the aspects of delayed neuronal death (DND). However, in preexposed animals hippocampal damage was attenuated in an inversely proportional way with the severity of the hypoxic pretreatment. The ultrastructural hypoxic tolerance findings were also closely related to increased regional SOD activity levels. Thus the activation of the endogenous antioxidant defense by hypoxic preconditioning, protects against hippocampal damage induced by severe hypoxia. The eventual contribution of increased endogenous adenosine and/or reduced excitotoxicity to induce hypoxic tolerance is discussed.

Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers

PubMed Central

Louis, Mariam; Punjabi, Naresh M.

2009-01-01

Accumulating evidence suggests that obstructive sleep apnea is associated with alterations in glucose metabolism. Although the pathophysiology of metabolic dysfunction in obstructive sleep apnea is not well understood, studies of murine models indicate that intermittent hypoxemia has an important contribution. However, corroborating data on the metabolic effects of intermittent hypoxia on glucose metabolism in humans are not available. Thus the primary aim of this study was to characterize the acute effects of intermittent hypoxia on glucose metabolism. Thirteen healthy volunteers were subjected to 5 h of intermittent hypoxia or normoxia during wakefulness in a randomized order on two separate days. The intravenous glucose tolerance test (IVGTT) was used to assess insulin-dependent and insulin-independent measures of glucose disposal. The IVGTT data were analyzed using the minimal model to determine insulin sensitivity (SI) and glucose effectiveness (SG). Drops in oxyhemoglobin saturation were induced during wakefulness at an average rate of 24.3 events/h. Compared with the normoxia condition, intermittent hypoxia was associated with a decrease in SI [4.1 vs. 3.4 (mU/l)−1·min−1; P = 0.0179] and SG (1.9 vs. 1.3 min−1×10−2, P = 0.0065). Despite worsening insulin sensitivity with intermittent hypoxia, pancreatic insulin secretion was comparable between the two conditions. Heart rate variability analysis showed the intermittent hypoxia was associated with a shift in sympathovagal balance toward an increase in sympathetic nervous system activity. The average R-R interval on the electrocardiogram was 919.0 ms during the normoxia condition and 874.4 ms during the intermittent hypoxia condition (P < 0.04). Serum cortisol levels after intermittent hypoxia and normoxia were similar. Hypoxic stress in obstructive sleep apnea may increase the predisposition for metabolic dysfunction by impairing insulin sensitivity, glucose effectiveness, and insulin secretion. PMID

Acute hypoxia stress induced abundant differential expression genes and alternative splicing events in heart of tilapia.

PubMed

Xia, Jun Hong; Li, Hong Lian; Li, Bi Jun; Gu, Xiao Hui; Lin, Hao Ran

2018-01-10

Hypoxia is one of the critical environmental stressors for fish in aquatic environments. Although accumulating evidences indicate that gene expression is regulated by hypoxia stress in fish, how genes undergoing differential gene expression and/or alternative splicing (AS) in response to hypoxia stress in heart are not well understood. Using RNA-seq, we surveyed and detected 289 differential expressed genes (DEG) and 103 genes that undergo differential usage of exons and splice junctions events (DUES) in heart of a hypoxia tolerant fish, Nile tilapia, Oreochromis niloticus following 12h hypoxic treatment. The spatio-temporal expression analysis validated the significant association of differential exon usages in two randomly selected DUES genes (fam162a and ndrg2) in 5 tissues (heart, liver, brain, gill and spleen) sampled at three time points (6h, 12h, and 24h) under acute hypoxia treatment. Functional analysis significantly associated the differential expressed genes with the categories related to energy conservation, protein synthesis and immune response. Different enrichment categories were found between the DEG and DUES dataset. The Isomerase activity, Oxidoreductase activity, Glycolysis and Oxidative stress process were significantly enriched for the DEG gene dataset, but the Structural constituent of ribosome and Structural molecule activity, Ribosomal protein and RNA binding protein were significantly enriched only for the DUES genes. Our comparative transcriptomic analysis reveals abundant stress responsive genes and their differential regulation function in the heart tissues of Nile tilapia under acute hypoxia stress. Our findings will facilitate future investigation on transcriptome complexity and AS regulation during hypoxia stress in fish. Copyright © 2017 Elsevier B.V. All rights reserved.

CO2-O2 interactions in extension of tolerance to acute hypoxia

NASA Technical Reports Server (NTRS)

Lambertsen, C. J.

1995-01-01

Objectives and results of experimental projects a re summarized. The scope of information desired included (1) physiological and performance consequences of exposures to simulated microgravity, in rest and graded physical activity, (2) separate influences of graded degrees of atmospheric hypercapnia and hypoxia, and (3) composite effects of hypoxia and hypercapnia. The research objectives were selected for close relevance to existing quantitative information concerning interactions of hypercapnia and hypoxia on respiratory and brain circulatory control. They include: (1) to determine influences of normoxic immersion on interrelations of pulmonary ventilation, arterial PCO2 and PO2, and brain blood flow, in rest and physical work; (2) to determine influence of normoxic immersion on respiratory reactivity to atmospheric hypercapnia at rest; (3) to determine influence of atmospheric hypoxia on respiratory reactivity to hypercapnia at rest and in work; and (4) to provide physiological baselines of data concerning adaptations in acute exposures to aid in investigation of rates of adaptation or deteriorations in physiological or performance capability during subsequent multi-day exposures. A list of publications related to the present grant period is included along with an appendix describing the Performance Measurement System (human perceptual, cognitive and psychomotor functions).

Influence of Acute Normobaric Hypoxia on Hemostasis in Volunteers with and without Acute Mountain Sickness

PubMed Central

Schaber, Marc; Leichtfried, Veronika; Fries, Dietmar; Wille, Maria; Gatterer, Hannes; Faulhaber, Martin; Würtinger, Philipp; Schobersberger, Wolfgang

2015-01-01

Introduction. The aim of the present study was to investigate whether a 12-hour exposure in a normobaric hypoxic chamber would induce changes in the hemostatic system and a procoagulant state in volunteers suffering from acute mountain sickness (AMS) and healthy controls. Materials and Methods. 37 healthy participants were passively exposed to 12.6% FiO2 (simulated altitude hypoxia of 4,500 m). AMS development was investigated by the Lake Louise Score (LLS). Prothrombin time, activated partial thromboplastin time, fibrinogen, and platelet count were measured and specific methods (i.e., thromboelastometry and a thrombin generation test) were used. Results. AMS prevalence was 62.2% (LLS cut off of 3). For the whole group, paired sample t-tests showed significant increase in the maximal concentration of generated thrombin. ROTEM measurements revealed a significant shortening of coagulation time and an increase of maximal clot firmness (InTEM test). A significant increase in maximum clot firmness could be shown (FibTEM test). Conclusions. All significant changes in coagulation parameters after exposure remained within normal reference ranges. No differences with regard to measured parameters of the hemostatic system between AMS-positive and -negative subjects were observed. Therefore, the hypothesis of the acute activation of coagulation by hypoxia can be rejected. PMID:26451374

Influence of Acute Normobaric Hypoxia on Hemostasis in Volunteers with and without Acute Mountain Sickness.

PubMed

Schaber, Marc; Leichtfried, Veronika; Fries, Dietmar; Wille, Maria; Gatterer, Hannes; Faulhaber, Martin; Würtinger, Philipp; Schobersberger, Wolfgang

2015-01-01

The aim of the present study was to investigate whether a 12-hour exposure in a normobaric hypoxic chamber would induce changes in the hemostatic system and a procoagulant state in volunteers suffering from acute mountain sickness (AMS) and healthy controls. 37 healthy participants were passively exposed to 12.6% FiO2 (simulated altitude hypoxia of 4,500 m). AMS development was investigated by the Lake Louise Score (LLS). Prothrombin time, activated partial thromboplastin time, fibrinogen, and platelet count were measured and specific methods (i.e., thromboelastometry and a thrombin generation test) were used. AMS prevalence was 62.2% (LLS cut off of 3). For the whole group, paired sample t-tests showed significant increase in the maximal concentration of generated thrombin. ROTEM measurements revealed a significant shortening of coagulation time and an increase of maximal clot firmness (InTEM test). A significant increase in maximum clot firmness could be shown (FibTEM test). All significant changes in coagulation parameters after exposure remained within normal reference ranges. No differences with regard to measured parameters of the hemostatic system between AMS-positive and -negative subjects were observed. Therefore, the hypothesis of the acute activation of coagulation by hypoxia can be rejected.

Short-term exposure to hypoxia for work and leisure activities in health and disease: which level of hypoxia is safe?

PubMed

Burtscher, Martin; Mairer, Klemens; Wille, Maria; Gatterer, Hannes; Ruedl, Gerhard; Faulhaber, Martin; Sumann, Günther

2012-06-01

Exposures to natural and simulated altitudes entail reduced oxygen availability and thus hypoxia. Depending on the level of hypoxia, the duration of exposure, the individual susceptibility, and preexisting diseases, health problems of variable severity may arise. Although millions of people are regularly or occasionally performing mountain sport activities, are transported by airplanes, and are more and more frequently exposed to short-term hypoxia in athletic training facilities or at their workplace, e.g., with fire control systems, there is no clear consensus on the level of hypoxia which is generally well tolerated by human beings when acutely exposed for short durations (hours to several days). Available data from peer-reviewed literature report adaptive responses even to altitudes below 2,000 m or corresponding normobaric hypoxia (F(i)O(2) > 16.4%), but they also suggest that most of exposed subjects without severe preexisting diseases can tolerate altitudes up to 3,000 m (F(i)O(2) > 14.5%) well. However, physical activity and unusual environmental conditions may increase the risk to get sick. Large interindividual variations of responses to hypoxia have to be expected, especially in persons with preexisting diseases. Thus, the assessment of those responses by hypoxic challenge testing may be helpful whenever possible.

Air exposure behavior of the semiterrestrial crab Neohelice granulata allows tolerance to severe hypoxia but not prevent oxidative damage due to hypoxia-reoxygenation cycle.

PubMed

de Lima, Tábata Martins; Geihs, Márcio Alberto; Nery, Luiz Eduardo Maia; Maciel, Fábio Everton

2015-11-01

The air exposure behavior of the semi-terrestrial crab Neohelice granulata during severe hypoxia was studied. This study also verified whether this behavior mitigates possible oxidative damage, namely lipoperoxidation, caused by hypoxia and reoxygenation cycles. The lethal time for 50% of the crabs subjected to severe hypoxia (0.5 mgO2 · L(-1)) with free access to air was compared to that of crabs subjected to severe hypoxia without access to air. Crabs were placed in aquaria divided into three zones: water (when the animal was fully submersed), land (when the animal was completely emerged) and intermediate (when the animal was in contact with both environments) zones. Then the crabs were held in this condition for 270 min, and the time spent in each zone was recorded. Lipid peroxidation (LPO) damage to the walking leg muscles was determined for the following four experimental conditions: a--normoxic water with free access to air; b--hypoxic water without access to air; c--hypoxic water followed by normoxic water without air access; and d--hypoxic water with free access to air. When exposed to hypoxic water, N. granulata spent significantly more time on land, 135.3 ± 17.7 min, whereas control animals (exposed to normoxic water) spent more time submerged, 187.4 ± 20.2 min. By this behavior, N. granulata was able to maintain a 100% survival rate when exposed to severe hypoxia. However, N. granulata must still return to water after periods of air exposure (~ 14 min), causing a sequence of hypoxia/reoxygenation events. Despite increasing the survival rate, hypoxia with air access does not decrease the lipid peroxidation damage caused by the hypoxia and reoxygenation cycle experienced by these crabs.

Effects of copper, hypoxia and acute temperature shifts on mitochondrial oxidation in rainbow trout (Oncorhynchus mykiss) acclimated to warm temperature.

PubMed

Sappal, Ravinder; Fast, Mark; Stevens, Don; Kibenge, Fred; Siah, Ahmed; Kamunde, Collins

2015-12-01

Temperature fluctuations, hypoxia and metals pollution frequently occur simultaneously or sequentially in aquatic systems and their interactions may confound interpretation of their biological impacts. With a focus on energy homeostasis, the present study examined how warm acclimation influences the responses and interactions of acute temperature shift, hypoxia and copper (Cu) exposure in fish. Rainbow trout (Oncorhynchus mykiss) were acclimated to cold (11°C; control) and warm (20°C) temperature for 3 weeks followed by exposure to environmentally realistic levels of Cu and hypoxia for 24h. Subsequently, mitochondrial electron transport system (ETS) respiratory activity supported by complexes I-IV (CI-IV), plasma metabolites and condition indices were measured. Warm acclimation reduced fish condition, induced aerobic metabolism and altered the responses of fish to acute temperature shift, hypoxia and Cu. Whereas warm acclimation decelerated the ETS and increased the sensitivity of maximal oxidation rates of the proximal (CI and II) complexes to acute temperature shift, it reduced the thermal sensitivity of state 4 (proton leak). Effects of Cu with and without hypoxia were variable depending on the acclimation status and functional index. Notably, Cu stimulated respiratory activity in the proximal ETS segments, while hypoxia was mostly inhibitory and minimized the stimulatory effect of Cu. The effects of Cu and hypoxia were modified by temperature and showed reciprocal antagonistic interaction on the ETS and plasma metabolites, with modest additive actions limited to CII and IV state 4. Overall, our results indicate that warm acclimation came at a cost of reduced ETS efficiency and increased sensitivity to added stressors. Copyright © 2015 Elsevier B.V. All rights reserved.

Exogenous sphingosine-1-phosphate boosts acclimatization in rats exposed to acute hypobaric hypoxia: assessment of haematological and metabolic effects.

PubMed

Chawla, Sonam; Rahar, Babita; Singh, Mrinalini; Bansal, Anju; Saraswat, Deepika; Saxena, Shweta

2014-01-01

The physiological challenges posed by hypobaric hypoxia warrant exploration of pharmacological entities to improve acclimatization to hypoxia. The present study investigates the preclinical efficacy of sphingosine-1-phosphate (S1P) to improve acclimatization to simulated hypobaric hypoxia. Efficacy of intravenously administered S1P in improving haematological and metabolic acclimatization was evaluated in rats exposed to simulated acute hypobaric hypoxia (7620 m for 6 hours) following S1P pre-treatment for three days. Altitude exposure of the control rats caused systemic hypoxia, hypocapnia (plausible sign of hyperventilation) and respiratory alkalosis due to suboptimal renal compensation indicated by an overt alkaline pH of the mixed venous blood. This was associated with pronounced energy deficit in the hepatic tissue along with systemic oxidative stress and inflammation. S1P pre-treatment improved blood oxygen-carrying-capacity by increasing haemoglobin, haematocrit, and RBC count, probably as an outcome of hypoxia inducible factor-1α mediated erythropoiesis and renal S1P receptor 1 mediated haemoconcentation. The improved partial pressure of oxygen in the blood could further restore aerobic respiration and increase ATP content in the hepatic tissue of S1P treated animals. S1P could also protect the animals from hypoxia mediated oxidative stress and inflammation. The study findings highlight S1P's merits as a preconditioning agent for improving acclimatization to acute hypobaric hypoxia exposure. The results may have long term clinical application for improving physiological acclimatization of subjects venturing into high altitude for occupational or recreational purposes.

Exogenous Sphingosine-1-Phosphate Boosts Acclimatization in Rats Exposed to Acute Hypobaric Hypoxia: Assessment of Haematological and Metabolic Effects

PubMed Central

Chawla, Sonam; Rahar, Babita; Singh, Mrinalini; Bansal, Anju; Saraswat, Deepika; Saxena, Shweta

2014-01-01

Background The physiological challenges posed by hypobaric hypoxia warrant exploration of pharmacological entities to improve acclimatization to hypoxia. The present study investigates the preclinical efficacy of sphingosine-1-phosphate (S1P) to improve acclimatization to simulated hypobaric hypoxia. Experimental Approach Efficacy of intravenously administered S1P in improving haematological and metabolic acclimatization was evaluated in rats exposed to simulated acute hypobaric hypoxia (7620m for 6 hours) following S1P pre-treatment for three days. Major Findings Altitude exposure of the control rats caused systemic hypoxia, hypocapnia (plausible sign of hyperventilation) and respiratory alkalosis due to suboptimal renal compensation indicated by an overt alkaline pH of the mixed venous blood. This was associated with pronounced energy deficit in the hepatic tissue along with systemic oxidative stress and inflammation. S1P pre-treatment improved blood oxygen-carrying-capacity by increasing haemoglobin, haematocrit, and RBC count, probably as an outcome of hypoxia inducible factor-1α mediated erythropoiesis and renal S1P receptor 1 mediated haemoconcentation. The improved partial pressure of oxygen in the blood could further restore aerobic respiration and increase ATP content in the hepatic tissue of S1P treated animals. S1P could also protect the animals from hypoxia mediated oxidative stress and inflammation. Conclusion The study findings highlight S1P’s merits as a preconditioning agent for improving acclimatization to acute hypobaric hypoxia exposure. The results may have long term clinical application for improving physiological acclimatization of subjects venturing into high altitude for occupational or recreational purposes. PMID:24887065

Preclinical Positron Emission Tomographic Imaging of Acute Hyperoxia Therapy of Chronic Hypoxia during Pregnancy.

PubMed

Zheleznyak, Alexander; Garbow, Joel R; Neeman, Michal; Lapi, Suzanne E

2015-01-01

The goal of this work was to study the efficacy of the positron emission tomography (PET) tracers 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and 64Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([64Cu]ATSM) and in monitoring placental and fetal functional response to acute hyperoxia in late-term pregnant mice subjected to experimentally induced chronic hypoxia. E15 mice were maintained at 12% inspired oxygen for 72 hours and then imaged during oxygen inhalation with either [18F]FDG to monitor nutrient transport or 64Cu-ATSM to establish the presence of hypoxia. Computed tomography (CT) with contrast allowed clear visualization of both placentas and fetuses. The average ratio of fetal to placental [18F]FDG uptake was 0.45 ± 0.1 for the hypoxic animals and 0.55 ± 0.1 for the normoxic animals, demonstrating a significant decrease (p = .0002) in placental function in dams exposed to chronic hypoxic conditions. Hypoxic placentas and fetuses retained more 64Cu-ATSM compared to normoxic placentas and fetuses. Herein we report first-in-mouse PET imaging of fetuses employing both tracers [18F]FDG (metabolism) and 64Cu-ATSM (hypoxia). [18F]FDG PET/CT imaging allowed clear visualization of placental-fetal structures and supported quantification of tracer uptake, making this a sensitive tool for monitoring placental function in preclinical rodent models. These measurements illustrate the potentially irreversible damage generated by chronic exposure to hypoxia, which cannot be corrected by acute exposure to hyperoxia.

Cardiac responses to hypoxia and reoxygenation in Drosophila.

PubMed

Zarndt, Rachel; Piloto, Sarah; Powell, Frank L; Haddad, Gabriel G; Bodmer, Rolf; Ocorr, Karen

2015-12-01

An adequate supply of oxygen is important for the survival of all tissues, but it is especially critical for tissues with high-energy demands, such as the heart. Insufficient tissue oxygenation occurs under a variety of conditions, including high altitude, embryonic and fetal development, inflammation, and thrombotic diseases, often affecting multiple organ systems. Responses and adaptations of the heart to hypoxia are of particular relevance in human cardiovascular and pulmonary diseases, in which the effects of hypoxic exposure can range in severity from transient to long-lasting. This study uses the genetic model system Drosophila to investigate cardiac responses to acute (30 min), sustained (18 h), and chronic (3 wk) hypoxia with reoxygenation. Whereas hearts from wild-type flies recovered quickly after acute hypoxia, exposure to sustained or chronic hypoxia significantly compromised heart function upon reoxygenation. Hearts from flies with mutations in sima, the Drosophila homolog of the hypoxia-inducible factor alpha subunit (HIF-α), exhibited exaggerated reductions in cardiac output in response to hypoxia. Heart function in hypoxia-selected flies, selected over many generations for survival in a low-oxygen environment, revealed reduced cardiac output in terms of decreased heart rate and fractional shortening compared with their normoxia controls. Hypoxia-selected flies also had smaller hearts, myofibrillar disorganization, and increased extracellular collagen deposition, consistent with the observed reductions in contractility. This study indicates that longer-duration hypoxic insults exert deleterious effects on heart function that are mediated, in part, by sima and advances Drosophila models for the genetic analysis of cardiac-specific responses to hypoxia and reoxygenation. Copyright © 2015 the American Physiological Society.

Tissue hypoxia during ischemic stroke: adaptive clues from hypoxia-tolerant animal models.

PubMed

Nathaniel, Thomas I; Williams-Hernandez, Ashley; Hunter, Anan L; Liddy, Caroline; Peffley, Dennis M; Umesiri, Francis E; Imeh-Nathaniel, Adebobola

2015-05-01

The treatment and prevention of hypoxic/ischemic brain injury in stroke patients remain a severe and global medical issue. Numerous clinical studies have resulted in a failure to develop chemical neuroprotection for acute, ischemic stroke. Over 150 estimated clinical trials of ischemic stroke treatments have been done, and more than 200 drugs and combinations of drugs for ischemic and hemorrhagic strokes have been developed. Billions of dollars have been invested for new scientific breakthroughs with only limited success. The revascularization of occluded cerebral arteries such as anti-clot treatments of thrombolysis has proven effective, but it can only be used in a 3-4.5h time frame after the onset of a stroke, and not for every patient. This review is about novel insights on how to resist tissue hypoxia from unconventional animal models. Ability to resist tissue hypoxia is an extraordinary ability that is not common in many laboratory animals such as rat and mouse models. For example, we can learn from a naked mole-rat, Chrysemys picta, how to actively regulate brain metabolic activity to defend the brain against fluctuating oxygen tension and acute bouts of oxidative stress following the onset of a stroke. Additionally, a euthermic arctic ground squirrel can teach us how the brain of a stroke patient can remain well oxygenated during tissue hypoxia with no evidence of cellular stress. In this review, we discuss how these animals provide us with a system to gain insight into the possible mechanisms of tissue hypoxia/ischemia. This issue is of clinical significance to stroke patients. We describe specific physiological and molecular adaptations employed by different animals' models of hypoxia tolerance in aquatic and terrestrial environments. We highlight how these adaptations might provide potential clues on strategies to adapt for the clinical management of tissue hypoxia during conditions such as stroke where oxygen demand fails to match the supply. Copyright

Metabolic Plasticity Enables Circadian Adaptation to Acute Hypoxia in Zebrafish Cells.

PubMed

Sandbichler, Adolf M; Jansen, Bianca; Peer, Bettina A; Paulitsch, Monika; Pelster, Bernd; Egg, Margit

2018-01-01

Reduced oxygen availability, hypoxia, is frequently encountered by organisms, tissues and cells, in aquatic environments as well as in high altitude or under pathological conditions such as infarct, stroke or cancer. The hypoxic signaling pathway was found to be mutually intertwined with circadian timekeeping in vertebrates and, as reported recently, also in mammals. However, the impact of hypoxia on intracellular metabolic oscillations is still unknown. For determination of metabolites we used Multilabel Reader based fluorescence and luminescence assays, circadian levels of Hypoxia Inducible Factor 1 alpha and oxidized peroxiredoxins were semi quantified by Western blotting and ratiometric quantification of cytosolic and mitochondrial H2O2 was achieved with stable transfections of a redox sensitive green fluorescent protein sensor into zebrafish fibroblasts. Circadian oscillations of core clock gene mRNA´s were assessed using realtime qPCR with subsequent cosine wave fit analysis. Here we show that under normoxia primary metabolic activity of cells predominately occurs during day time and that after acute hypoxia of two hours, administrated immediately before each sampling point, steady state concentrations of glycolytic key metabolites such as glucose and lactate reveal to be highly rhythmic, following a circadian pattern with highest levels during the night periods and reflecting the circadian variation of the cellular response to hypoxia. Remarkably, rhythms in glycolysis are transferred to cellular energy states under normoxic conditions, so that ADP/ATP ratios oscillate as well, which is the first evidence for cycling ADP/ATP pools in a metazoan cell line to our knowledge. Furthermore, the hypoxia induced alterations in rhythms of glycolysis lead to the alignment of three major cellular redox systems, namely the circadian oscillations of NAD+/NADH and NADP+/NADPH ratios and of increased nocturnal levels of oxidized peroxiredoxins, resulting in a highly

Experimental evidence of obesity as a risk factor for severe acute pancreatitis.

PubMed

Frossard, Jean-Louis; Lescuyer, Pierre; Pastor, Catherine M

2009-11-14

The incidence of acute pancreatitis, an inflammation of the pancreas, is increasing worldwide. Pancreatic injury is mild in 80%-90% of patients who recover without complications. The remaining patients may develop a severe disease with local complications such as acinar cell necrosis, abscess and remote organ injury including lung injury. The early prediction of the severity of the disease is an important goal for physicians in management of patients with acute pancreatitis in order to optimize the therapy and to prevent organ dysfunction and local complications. For that purpose, multiple clinical scale scores have been applied to patients with acute pancreatitis. Recently, a new problem has emerged: the increased severity of the disease in obese patients. However, the mechanisms by which obesity increases the severity of acute pancreatitis are unclear. Several hypotheses have been suggested: (1) obese patients have an increased inflammation within the pancreas; (2) obese patients have an increased accumulation of fat within and around the pancreas where necrosis is often located; (3) increase in both peri- and intra-pancreatic fat and inflammatory cells explain the high incidence of pancreatic inflammation and necrosis in obese patients; (4) hepatic dysfunction associated with obesity might enhance the systemic inflammatory response by altering the detoxification of inflammatory mediators; and (5) ventilation/perfusion mismatch leading to hypoxia associated with a low pancreatic flow might reduce the pancreatic oxygenation and further enhance pancreatic injury. Recent experimental investigations also show an increased mortality and morbidity in obese rodents with acute pancreatitis and the implication of the adipokines leptin and adiponectin. Such models are important to investigate whether the inflammatory response of the disease is enhanced by obesity. It is exciting to speculate that manipulation of the adipokine milieu has the potential to influence the

Effects of hypoxia-induced neonatal seizures on acute hippocampal injury and later-life seizure susceptibility and anxiety-related behavior in mice.

PubMed

Rodriguez-Alvarez, Natalia; Jimenez-Mateos, Eva M; Dunleavy, Mark; Waddington, John L; Boylan, Geraldine B; Henshall, David C

2015-11-01

Seizures are common during the neonatal period, often due to hypoxic-ischemic encephalopathy and may contribute to acute brain injury and the subsequent development of cognitive deficits and childhood epilepsy. Here we explored short- and long-term consequences of neonatal hypoxia-induced seizures in 7 day old C57BL/6J mice. Seizure activity, molecular markers of hypoxia and histological injury were investigated acutely after hypoxia and response to chemoconvulsants and animal behaviour was explored at adulthood. Hypoxia was induced by exposing pups to 5% oxygen for 15 min (global hypoxia). Electrographically defined seizures with behavioral correlates occurred in 95% of these animals and seizures persisted for many minutes after restitution of normoxia. There was minimal morbidity or mortality. Pre- or post-hypoxia injection of phenobarbital (50mg/kg) had limited efficacy at suppressing seizures. The hippocampus from neonatal hypoxia-seizure mice displayed increased expression of vascular endothelial growth factor and the immediate early gene c-fos, minimal histological evidence of cell injury and activation of caspase-3 in scattered neurons. Behavioral analysis of mice five weeks after hypoxia-induced seizures detected novel anxiety-related and other behaviors, while performance in a spatial memory test was similar to controls. Seizure threshold tests with kainic acid at six weeks revealed that mice previously subject to neonatal hypoxia-induced seizures developed earlier, more frequent and longer-duration seizures. This study defines a set of electro-clinical, molecular, pharmacological and behavioral consequences of hypoxia-induced seizures that indicate short- and long-term deleterious outcomes and may be a useful model to investigate the pathophysiology and treatment of neonatal seizures in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

Protective Effects of Myricetin on Acute Hypoxia-Induced Exercise Intolerance and Mitochondrial Impairments in Rats

PubMed Central

Zou, Dan; Liu, Peng; Chen, Ka; Xie, Qi; Liang, Xinyu; Bai, Qian; Zhou, Qicheng; Liu, Kai; Zhang, Ting; Zhu, Jundong; Mi, Mantian

2015-01-01

Purpose Exercise tolerance is impaired in hypoxia. The aim of this study was to evaluate the effects of myricetin, a dietary flavonoid compound widely found in fruits and vegetables, on acute hypoxia-induced exercise intolerance in vivo and in vitro. Methods Male rats were administered myricetin or vehicle for 7 days and subsequently spent 24 hours at a barometric pressure equivalent to 5000 m. Exercise capacity was then assessed through the run-to-fatigue procedure, and mitochondrial morphology in skeletal muscle cells was observed by transmission electron microscopy (TEM). The enzymatic activities of electron transfer complexes were analyzed using an enzyme-linked immuno-sorbent assay (ELISA). mtDNA was quantified by real-time-PCR. Mitochondrial membrane potential was measured by JC-1 staining. Protein expression was detected through western blotting, immunohistochemistry, and immunofluorescence. Results Myricetin supplementation significantly prevented the decline of run-to-fatigue time of rats in hypoxia, and attenuated acute hypoxia-induced mitochondrial impairment in skeletal muscle cells in vivo and in vitro by maintaining mitochondrial structure, mtDNA content, mitochondrial membrane potential, and activities of the respiratory chain complexes. Further studies showed that myricetin maintained mitochondrial biogenesis in skeletal muscle cells under hypoxic conditions by up-regulating the expressions of mitochondrial biogenesis-related regluators, in addition, AMP-activated protein kinase(AMPK) plays a crucial role in this process. Conclusions Myricetin may have important applications for improving physical performance under hypoxic environment, which may be attributed to the protective effect against mitochondrial impairment by maintaining mitochondrial biogenesis. PMID:25919288

Dexamethasone mimics aspects of physiological acclimatization to 8 hours of hypoxia but suppresses plasma erythropoietin

PubMed Central

Liu, Chun; Croft, Quentin P. P.; Kalidhar, Swati; Brooks, Jerome T.; Herigstad, Mari; Smith, Thomas G.; Dorrington, Keith L.

2013-01-01

Dexamethasone ameliorates the severity of acute mountain sickness (AMS) but it is unknown whether it obtunds normal physiological responses to hypoxia. We studied whether dexamethasone enhanced or inhibited the ventilatory, cardiovascular, and pulmonary vascular responses to sustained (8 h) hypoxia. Eight healthy volunteers were studied, each on four separate occasions, permitting four different protocols. These were: dexamethasone (20 mg orally) beginning 2 h before a control period of 8 h of air breathing; dexamethasone with 8 h of isocapnic hypoxia (end-tidal Po2 = 50 Torr); placebo with 8 h of air breathing; and placebo with 8 h of isocapnic hypoxia. Before and after each protocol, the following were determined under both euoxic and hypoxic conditions: ventilation; pulmonary artery pressure (estimated using echocardiography to assess maximum tricuspid pressure difference); heart rate; and cardiac output. Plasma concentrations of erythropoietin (EPO) were also determined. Dexamethasone had no early (2-h) effect on any variable. Both dexamethasone and 8 h of hypoxia increased euoxic values of ventilation, pulmonary artery pressure, and heart rate, together with the ventilatory sensitivity to acute hypoxia. These effects were independent and additive. Eight hours of hypoxia, but not dexamethasone, increased the sensitivity of pulmonary artery pressure to acute hypoxia. Dexamethasone, but not 8 h of hypoxia, increased both cardiac output and systemic arterial pressure. Dexamethasone abolished the rise in EPO induced by 8 h of hypoxia. In summary, dexamethasone enhances ventilatory acclimatization to hypoxia. Thus, dexamethasone in AMS may improve oxygenation and thereby indirectly lower pulmonary artery pressure. PMID:23393065

Developmental Hypoxia Has Negligible Effects on Long-Term Hypoxia Tolerance and Aerobic Metabolism of Atlantic Salmon (Salmo salar).

PubMed

Wood, Andrew T; Clark, Timothy D; Andrewartha, Sarah J; Elliott, Nicholas G; Frappell, Peter B

Exposure to developmental hypoxia can have long-term impacts on the physiological performance of fish because of irreversible plasticity. Wild and captive-reared Atlantic salmon (Salmo salar) can be exposed to hypoxic conditions during development and continue to experience fluctuating oxygen levels as juveniles and adults. Here, we examine whether developmental hypoxia impacts subsequent hypoxia tolerance and aerobic performance of Atlantic salmon. Individuals at 8°C were exposed to 50% (hypoxia) or 100% (normoxia) dissolved oxygen (DO) saturation (as percent of air saturation) from fertilization for ∼100 d (800 degree days) and then raised in normoxic conditions for a further 15 mo. At 18 mo after fertilization, aerobic scope was calculated in normoxia (100% DO) and acute (18 h) hypoxia (50% DO) from the difference between the minimum and maximum oxygen consumption rates ([Formula: see text] and [Formula: see text], respectively) at 10°C. Hypoxia tolerance was determined as the DO at which loss of equilibrium (LOE) occurred in a constantly decreasing DO environment. There was no difference in [Formula: see text], [Formula: see text], or aerobic scope between fish raised in hypoxia or normoxia. There was some evidence that hypoxia tolerance was lower (higher DO at LOE) in hypoxia-raised fish compared with those raised in normoxia, but the magnitude of the effect was small (12.52% DO vs. 11.73% DO at LOE). Acute hypoxia significantly reduced aerobic scope by reducing [Formula: see text], while [Formula: see text] remained unchanged. Interestingly, acute hypoxia uncovered individual-level relationships between DO at LOE and [Formula: see text], [Formula: see text], and aerobic scope. We discuss our findings in the context of developmental trajectories and the role of aerobic performance in hypoxia tolerance.

Accelerated recovery from acute hypoxia in obese mice is due to obesity-associated up-regulation of interleukin-1 receptor antagonist.

PubMed

Sherry, Christina L; Kim, Stephanie S; Freund, Gregory G

2009-06-01

The proinflammatory consequences of obesity are thought to be due, in part, to macrophage infiltration into adipose tissue. There are, however, potential antiinflammatory consequences of obesity that include obesity-associated up-regulation of IL-1 receptor antagonist (IL-1RA). Here we show that obesity-associated up-regulation of IL-1RA speeds recovery from hypoxia. We found that high-fat diet-fed (HFD) mice recovered from acute hypoxia 5 times faster than normal-diet-fed (ND) mice. HFD mice had a 10-fold increase in serum IL-1RA when compared with ND mice. White adipose tissue (WAT) was a significant source of IL-RA, generating 330 +/- 77 pg/mg protein in HFD mice as compared with 15 +/- 5 pg/mg protein in ND mice. Peritoneal macrophages isolated from HFD mice showed little difference in IL-1RA production when compared with ND mice, but WAT macrophages from HFD mice generated 11-fold more IL-1RA than those from ND mice. When ND mice were given an ip transfer of the stromal vascular fraction portion of WAT from HFD mice, serum IL-1RA increased 836% and recovery from acute hypoxia was faster than in mice that did not receive a stromal vascular fraction transfer. To determine whether IL-1RA was important to this accelerated recovery, ND mice were administered exogenous IL-1RA prior to hypoxia, and their recovery matched that of HFD mice. Inversely, when IL-1RA was immunoabsorbed in HFD mice with IL-1RA antiserum, recovery from acute hypoxia was attenuated. Taken together these data demonstrate that HFD-induced obesity speeds recovery from hypoxia due to obesity-associated up-regulation of IL-1RA.

Accelerated Recovery from Acute Hypoxia in Obese Mice Is Due to Obesity-Associated Up-Regulation of Interleukin-1 Receptor Antagonist

PubMed Central

Sherry, Christina L.; Kim, Stephanie S.; Freund, Gregory G.

2009-01-01

The proinflammatory consequences of obesity are thought to be due, in part, to macrophage infiltration into adipose tissue. There are, however, potential antiinflammatory consequences of obesity that include obesity-associated up-regulation of IL-1 receptor antagonist (IL-1RA). Here we show that obesity-associated up-regulation of IL-1RA speeds recovery from hypoxia. We found that high-fat diet-fed (HFD) mice recovered from acute hypoxia 5 times faster than normal-diet-fed (ND) mice. HFD mice had a 10-fold increase in serum IL-1RA when compared with ND mice. White adipose tissue (WAT) was a significant source of IL-RA, generating 330 ± 77 pg/mg protein in HFD mice as compared with 15 ± 5 pg/mg protein in ND mice. Peritoneal macrophages isolated from HFD mice showed little difference in IL-1RA production when compared with ND mice, but WAT macrophages from HFD mice generated 11-fold more IL-1RA than those from ND mice. When ND mice were given an ip transfer of the stromal vascular fraction portion of WAT from HFD mice, serum IL-1RA increased 836% and recovery from acute hypoxia was faster than in mice that did not receive a stromal vascular fraction transfer. To determine whether IL-1RA was important to this accelerated recovery, ND mice were administered exogenous IL-1RA prior to hypoxia, and their recovery matched that of HFD mice. Inversely, when IL-1RA was immunoabsorbed in HFD mice with IL-1RA antiserum, recovery from acute hypoxia was attenuated. Taken together these data demonstrate that HFD-induced obesity speeds recovery from hypoxia due to obesity-associated up-regulation of IL-1RA. PMID:19213834

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

PubMed Central

Legrand, Matthieu; Mik, Egbert G; Johannes, Tanja; Payen, Didier; Ince, Can

2008-01-01

Ischemia is the most common cause of acute renal failure. Ischemic-induced renal tissue hypoxia is thought to be a major component in the development of acute renal failure in promoting the initial tubular damage. Renal oxygenation originates from a balance between oxygen supply and consumption. Recent investigations have provided new insights into alterations in oxygenation pathways in the ischemic kidney. These findings have identified a central role of microvascular dysfunction related to an imbalance between vasoconstrictors and vasodilators, endothelial damage and endothelium–leukocyte interactions, leading to decreased renal oxygen supply. Reduced microcirculatory oxygen supply may be associated with altered cellular oxygen consumption (dysoxia), because of mitochondrial dysfunction and activity of alternative oxygen-consuming pathways. Alterations in oxygen utilization and/or supply might therefore contribute to the occurrence of organ dysfunction. This view places oxygen pathways’ alterations as a potential central player in the pathogenesis of acute kidney injury. Both in regulation of oxygen supply and consumption, nitric oxide seems to play a pivotal role. Furthermore, recent studies suggest that, following acute ischemic renal injury, persistent tissue hypoxia contributes to the development of chronic renal dysfunction. Adaptative mechanisms to renal hypoxia may be ineffective in more severe cases and lead to the development of chronic renal failure following ischemia-reperfusion. This paper is aimed at reviewing the current insights into oxygen transport pathways, from oxygen supply to oxygen consumption in the kidney and from the adaptation mechanisms to renal hypoxia. Their role in the development of ischemia-induced renal damage and ischemic acute renal failure are discussed. PMID:18488066

Effects of hypoxia and hypercapnia on geniohyoid contractility and endurance.

PubMed

Salmone, R J; Van Lunteren, E

1991-08-01

Sleep apnea and other respiratory diseases produce hypoxemia and hypercapnia, factors that adversely affect skeletal muscle performance. To examine the effects of these chemical alterations on force production by an upper airway dilator muscle, the contractile and endurance characteristics of the geniohyoid muscle were examined in situ during severe hypoxia (arterial PO2 less than 40 Torr), mild hypoxia (PO2 45-65 Torr), and hypercapnia (PCO2 55-80 Torr) and compared with hyperoxic-normocapnic conditions in anesthetized cats. Muscles were studied at optimal length, and contractile force was assessed in response to supramaximal electrical stimulation of the hypoglossal nerve (n = 7 cats) or geniohyoid muscle (n = 2 cats). There were no significant changes in the twitch kinetics or force-frequency curve of the geniohyoid muscle during hypoxia or hypercapnia. However, the endurance of the geniohyoid, as reflected in the fatigue index (ratio of force at 2 min to initial force in response to 40-Hz stimulation at a duty cycle 0.33), was significantly reduced by severe hypoxia but not by hypercapnia or mild hypoxia. In addition, the downward shift in the force-frequency curve after the repetitive stimulation protocol was greater during hypoxia than hyperoxia, especially at higher frequencies. In conclusion, the ability of the geniohyoid muscle to maintain force output during high levels of activation is adversely affected by severe hypoxia but not mild hypoxia or hypercapnia. However, none of these chemical perturbations affected muscle contractility acutely.

[Effect of bemethyl on the glutathione system in the rat liver in acute hypoxia].

PubMed

Zarubina, I V; Mironova, O P

2002-01-01

The effect of bemithyl on the state of liver glutathione system was studied in rats under acute hypoxic hypoxia conditions modeled by "elevating" animals in a pressure chamber up to an altitude of 8000-11,000 m for 30 min. Bemithyl (25 mg/kg, i.p.) administered 30 min before the hypoxia onset, prevents a decrease in the content of reduced glutathione and SH groups and impedes a drop in the activity of glutathione reductase and glutathione peroxidase. By means of the inhibition analysis using actinomycin D (a protein synthesis inhibitor), it was established that the protective action of bemithyl is related to the ability of enhancing the synthesis of antioxidant enzymes in the liver glutathione system.

Effects of acute hypoxia on heart rate variability, sample entropy and cardiorespiratory phase synchronization.

PubMed

Zhang, Da; She, Jin; Zhang, Zhengbo; Yu, Mengsun

2014-06-11

Investigating the responses of autonomic nervous system (ANS) in hypoxia may provide some knowledge about the mechanism of neural control and rhythmic adjustment. The integrated cardiac and respiratory system display complicated dynamics that are affected by intrinsic feedback mechanisms controlling their interaction. To probe how the cardiac and respiratory system adjust their rhythms in different simulated altitudes, we studied heart rate variability (HRV) in frequency domain, the complexity of heartbeat series and cardiorespiratory phase synchronization (CRPS) between heartbeat intervals and respiratory cycles. In this study, twelve male subjects were exposed to simulated altitude of sea level, 3000 m and 4000 m in a hypobaric chamber. HRV was assessed by power spectral analysis. The complexity of heartbeat series was quantified by sample entropy (SampEn). CRPS was determined by cardiorespiratory synchrogram. The power spectral HRV indices at all frequency bands depressed according to the increase of altitude. The SampEn of heartbeat series increased significantly with the altitude (P < 0.01). The duration of CRPS epochs at 3000 m was not significantly different from that at sea level. However, it was significantly longer at 4000 m (P < 0.01). Our results suggest the phenomenon of CRPS exists in normal subjects when they expose to acute hypoxia. Further, the autonomic regulation has a significantly stronger influence on CRPS in acute hypoxia. The changes of CRPS and HRV parameters revealed the different regulatory mechanisms of the cardiac and respiratory system at high altitude.

Physiological determinants of human acute hypoxia tolerance.

DOT National Transportation Integrated Search

2013-11-01

AbstractIntroduction. We investigated possible physiological determinants of variability in hypoxia tolerance in subjects given a 5-minute normobaric exposure to 25,000 ft equivalent. Physiological tolerance to hypoxia was defined as the magnitude of...

Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models.

PubMed

Portwood, Scott; Lal, Deepika; Hsu, Yung-Chun; Vargas, Rodrigo; Johnson, Megan K; Wetzler, Meir; Hart, Charles P; Wang, Eunice S

2013-12-01

Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth. We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models. We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O2, 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in dose- and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1α expression, induced cell-cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models. Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy. ©2013 AACR.

Impact of the mitochondria-targeted antioxidant MitoQ on hypoxia-induced pulmonary hypertension.

PubMed

Pak, Oleg; Scheibe, Susan; Esfandiary, Azadeh; Gierhardt, Mareike; Sydykov, Akylbek; Logan, Angela; Fysikopoulos, Athanasios; Veit, Florian; Hecker, Matthias; Kroschel, Florian; Quanz, Karin; Erb, Alexandra; Schäfer, Katharina; Fassbinder, Mirja; Alebrahimdehkordi, Nasim; Ghofrani, Hossein A; Schermuly, Ralph T; Brandes, Ralf P; Seeger, Werner; Murphy, Michael P; Weissmann, Norbert; Sommer, Natascha

2018-02-01

Increased mitochondrial reactive oxygen species (ROS), particularly superoxide have been suggested to mediate hypoxic pulmonary vasoconstriction (HPV), chronic hypoxia-induced pulmonary hypertension (PH) and right ventricular (RV) remodelling.We determined ROS in acute, chronic hypoxia and investigated the effect of the mitochondria-targeted antioxidant MitoQ under these conditions.The effect of MitoQ or its inactive carrier substance, decyltriphenylphosphonium (TPP + ), on acute HPV (1% O 2 for 10 minutes) was investigated in isolated blood-free perfused mouse lungs. Mice exposed for 4 weeks to chronic hypoxia (10% O 2 ) or after banding of the main pulmonary artery (PAB) were treated with MitoQ or TPP + (50 mg/kg/day).Total cellular superoxide and mitochondrial ROS levels were increased in pulmonary artery smooth muscle cells (PASMC), but decreased in pulmonary fibroblasts in acute hypoxia. MitoQ significantly inhibited HPV and acute hypoxia-induced rise in superoxide concentration. ROS was decreased in PASMC, while it increased in the RV after chronic hypoxia. Correspondingly, MitoQ did not affect the development of chronic hypoxia-induced PH, but attenuated RV remodelling after chronic hypoxia as well as after PAB.Increased mitochondrial ROS of PASMC mediate acute HPV, but not chronic hypoxia-induced PH. MitoQ may be beneficial under conditions of exaggerated acute HPV. Copyright ©ERS 2018.

Hypoxia and inflammation indicate significant differences in the severity of obstructive sleep apnea within similar apnea-hypopnea index groups.

PubMed

Yilmaz Avci, Aynur; Avci, Suat; Lakadamyali, Huseyin; Can, Ufuk

2017-09-01

We determined whether hypoxia parameters are associated with C-reactive protein (CRP), mean platelet volume (MPV), white matter hyperintensity (WMH), and the severity of obstructive sleep apnea (OSA), and also evaluated whether hypoxia parameters, CRP, MPV, and WMH differ in patients with similar apnea-hypopnea index (AHI) scores. A total of 297 patients, who were evaluated using polysomnography, were assessed retrospectively. The measured hypoxia parameters included total sleep time with oxygen saturation <90% (ST 90 ), percentage of cumulative time with oxygen saturation <90% (CT 90 ), and lowest oxygen saturation (min SaO 2 ). The patients were divided into subgroups according to their CT 90 values, and patients with different AHI severities were divided into subgroups according to their ST 90 and min SaO 2 levels. Hypoxia parameters are associated with CRP, MPV, WMH, and the severity of OSA (P < 0.05). The hypoxia parameters differed in all subgroup analyses of similar AHI groups (P < 0.001), and CRP differed only in severe OSA (P < 0.008, P < 0.001). In subgroup analyses of similar AHI groups, MPV and WMH were not significantly different (P > 0.05). Above the hypoxia threshold (CT 90  ≥ 10%) of CRP, MPV increased significantly and the presence of WMH increased twofold. These data suggest that increased hypoxia severity may mediate increased inflammation and activation of platelets and contribute to the pathogenesis of WMH in patients with OSA. In addition, patients with severe OSA may show significant variability in inflammation and vascular risk. Further prospective data are needed.

The Effect of Acute and Chronic Exposure to Hypobaric Hypoxia on Loaded Squat Jump Performance

PubMed Central

García-Ramos, Amador; Padial, Paulino; De la Fuente, Blanca; Argüelles-Cienfuegos, Javier; Bonitch-Góngora, Juan

2017-01-01

Abstract The present study aimed (1) to compare loaded squat jump performance after an acute and chronic exposure to a moderate natural altitude between normoxia and hypobaric hypoxia conditions, and (2) to analyze the effect of an altitude training camp on loaded jump squat development. Sixteen male swimmers (17.1 ± 0.8 years) took part in a 17-day training camp at a natural moderate altitude. They were randomly tested in counterbalanced order on days 1 and 3 in normoxia and hypoxia (pretest) and on days 15 and 17 again in normoxia and hypoxia (posttest). The peak velocity reached with loads equivalent to 25%, 50%, 75% and 100% of swimmers’ pretest body weight in the loaded squat jump exercise was the dependent variable analyzed. An overall increase in peak velocity during the test performed in hypoxia of 6.5% in pretest (p < 0.001, ES = 0.98) and 4.5% in posttest (p < 0.001, ES = 0.81) was observed. An overall increment in peak velocity of 4.0% considering the data for normoxia tests (p < 0.001, ES = 0.61) and 2.1% considering the data for hypoxia tests (p = 0.008, ES = 0.36) was achieved after the altitude training camp. These results highlight the beneficial effects of hypobaric hypoxia on jump performance after short and longer term exposure to a natural moderate altitude. The increase in loaded squat jump performance following the 17-day training camp suggests that altitude training could constitute a favorable stimulus in explosive strength. PMID:28469753

Oxidative phosphorylation of liver mitochondria from mice acclimatized to hypobaric hypoxia

NASA Astrophysics Data System (ADS)

Leon-Velarde, F.; Whittembury, J.; Monge, C.

1986-09-01

Mice exposed to intermittent hypobaric hypoxia for 20 hours a day, 6 days a week, develop extracellular adaptive responses similar to those found in humans exposed to oxygen tension equivalent to that found at an altitude of 4500 m. Isolated liver mitochondria from these animals show no significant differences in rates of substrate-stimulated respiration, ADP-stimulated respiration and the respiratory control ratio (RCR), when compared with sea level controls. Undetectable or negligible differences in these parameters are also noted when sea level animals are exposed for one hour to severe hypoxia (7% O2). We therefore conclude that the oxidative phosphorylation capacity of the isolated mouse liver mitochondria remains unaltered in both acute and chronic hypoxia. However the in vivo oxygen consumption by mice at this degree of hypoxia was markedly reduced. Lack of observable changes in oxidative phosphorylation could be accounted for by extracellular adaptations in mitochondria isolated from acclimatized animals. This explanation, however, is not consistent with the lack of changes on oxidative phosphorylation in mitochondria isolated from mice undergoing acute hypoxia at sea level. It is then suggested that isolated mitochondrial preparations are of limited value for investigating biochemical mechanisms underlying the variation of cellular respiration occurring in vivo.

Treating Obstructive Sleep Apnea and Chronic Intermittent Hypoxia Improves the Severity of Nonalcoholic Fatty Liver Disease in Children.

PubMed

Sundaram, Shikha S; Halbower, Ann C; Klawitter, Jelena; Pan, Zhaoxing; Robbins, Kristen; Capocelli, Kelley E; Sokol, Ronald J

2018-07-01

To determine the effects of treating obstructive sleep apnea/nocturnal hypoxia on pediatric nonalcoholic fatty liver disease (NAFLD) severity and oxidative stress. Biopsy proven participants (n = 9) with NAFLD and obstructive sleep apnea/hypoxia were studied before and after treatment with continuous positive airway pressure (CPAP) for sleep disordered breathing, including laboratory testing and markers of oxidative stress, urine F(2)-isoprostanes. Adolescents (age 11.5 ± 1.2 years; body mass index, 29.5 ± 3.8 kg/m 2 ) with significant NAFLD (mean histologic necroinflammation grade, 2.3 ± 0.9; fibrosis stage, 1.4 ± 1.3; NAFLD Activity Score summary, 4.8 ± 1.6) had obstructive sleep apnea/hypoxia by polysomnography. At baseline, they had severe obstructive sleep apnea/hypoxia, elevated aminotransferases, the metabolic syndrome, and significant oxidative stress (high F(2)-isoprostanes). Obstructive sleep apnea/hypoxia was treated with home CPAP for a mean 89 ± 62 days. Although body mass index increased, obstructive sleep apnea/hypoxia severity improved on CPAP and was accompanied by reduced alanine aminotransferase, metabolic syndrome markers, and F(2)-isoprostanes. This study provides strong evidence that treatment of obstructive sleep apnea/nocturnal hypoxia with CPAP in children with NAFLD may reverse parameters of liver injury and reduce oxidative stress. These data also suggest CPAP as a new therapy to prevent progression of NAFLD in those children with obesity found to have obstructive sleep apnea/nocturnal hypoxia. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of sinusoidal modulated currents and acute hypoxia on corticosterone content and activity of certain dehydrogenases in tissues of different rat organs during hypokinesia

NASA Technical Reports Server (NTRS)

Melik-Aslanova, L. L.; Frenkel, I. D.

1980-01-01

The state of hypokinesia in rats was reproduced by keeping them for 30 days in special box cages that restricted their mobility in all directions. Results show the resistance to acute hypoxic hypoxia is increased. This is linked to the considerable rise in the reduced level of corticosterone in different organs and the succinate dehydrogenase activity in the liver and brain. The letter indicated the primary oxidation of succinate, which has great importance in the adaptation of the oxidative metabolism to acute oxygen insufficiency. The use of sinusoidal modulated currents in the period of hypokinesia promotes normalization of the indices for resistance of the rats to acute hypoxia.

Ibuprofen does not reverse ventilatory acclimatization to chronic hypoxia.

PubMed

De La Zerda, D J; Stokes, J A; Do, J; Go, A; Fu, Z; Powell, F L

2017-07-27

Ventilatory acclimatization to hypoxia involves an increase in the acute hypoxic ventilatory response that is blocked by non-steroidal anti-inflammatory drugs administered during sustained hypoxia. We tested the hypothesis that inflammatory signals are necessary to sustain ventilatory acclimatization to hypoxia once it is established. Adult, rats were acclimatized to normoxia or chronic hypoxia (CH, [Formula: see text] =70Torr) for 11-12days and treated with ibuprofen or saline for the last 2days of hypoxia. Ventilation, metabolic rate, and arterial blood gas responses to O 2 and CO 2 were not affected by ibuprofen after acclimatization had been established. Immunohistochemistry and image analysis showed acute (1h) hypoxia activated microglia in a medullary respiratory center (nucleus tractus solitarius, NTS) and this was blocked by ibuprofen administered from the beginning of hypoxic exposure. Microglia returned to the control state after 7days of CH and were not affected by ibuprofen administered for 2 more days of CH. In contrast, NTS astrocytes were activated by CH but not acute hypoxia and activation was not reversed by administering ibuprofen for the last 2days of CH. Hence, ibuprofen cannot reverse ventilatory acclimatization or astrocyte activation after they have been established by sustained hypoxia. The results are consistent with a model for microglia activation or other ibuprofen-sensitive processes being necessary for the induction but not maintenance of ventilatory acclimatization to hypoxia. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of acute progestational hypoxia on the content of biogenic amines in the brain of albino rat pups: Peptide correction.

PubMed

Maslova, M V; Graf, A V; Sokolova, N A; Goncharenko, E N; Shestakova, S V; Kudryashova, N Yu; Andreeva, L A

2003-08-01

We studied the effect of exposure to acute hypobaric hypoxia in the progestational period on the content of biogenic amines in the brainstem and cerebral cortex in rat pups of different age. The possibility of correcting hypoxia-induced changes with regulatory peptides was evaluated. We found that early antenatal hypoxia disturbs maturation of catecholaminergic systems in the brain. It should be emphasized that the differences from the control varied depending on the age of rat pups. Single intranasal administration of Semax heptapeptides and beta-casomorphine-7 to pregnant females prevented changes in the content of biogenic amines in CNS of the offspring during postnatal ontogeny.

Protective role of hypoxia-inducible factor-1α-dependent CD39 and CD73 in fulminant acute liver failure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tak, Eunyoung

Acute liver failure (ALF) is a severe life-threatening disease which usually arises in patients with-irreversible liver illnesses. Although human ectonucleotide triphosphate diphosphohydrolase-1, E-NTPDase1 (CD39) and ecto-5′-nucleotidase, Ecto5′NTase (CD73) are known to protect tissues from ALF, the expression and function of CD39 and CD73 during ALF are currently not fully investigated. We tested whether CD39 and CD73 are upregulated by hypoxia inducible factor (HIF)-1α, and improve ischemic tolerance to ALF. To test our hypothesis, liver biopsies were obtained and we found that CD39 and CD73 mRNA and proteins from human specimens were dramatically elevated in ALF. We investigated that induction ofmore » CD39 and CD73 in ALF-related with wild type mice. In contrast, deletion of cd39 and cd73 mice has severe ALF. In this study, we concluded that CD39 and CD73 are molecular targets for the development of drugs for ALF patients care. - Highlights: • HIF-1a is stabilized during acute liver failure • Upregulation of CD39 and CD73 following acute liver failure • CD39 and CD73 are transcriptionally induced by HIF-1a • Deletion of Cd39 and CD73 aggravates murine acute liver failure • DMOG treatment induces HIF-1a stabilization, CD39 and CD73 during acute liver failure in WT mice.« less

Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptor.

PubMed

Pügge, Carolin; Mediratta, Jai; Marcus, Noah J; Schultz, Harold D; Schiller, Alicia M; Zucker, Irving H

2016-02-01

Recent data suggest that exercise training (ExT) is beneficial in chronic heart failure (CHF) because it improves autonomic and peripheral vascular function. In this study, we hypothesized that ExT in the CHF state ameliorates the renal vasoconstrictor responses to hypoxia and that this beneficial effect is mediated by changes in α1-adrenergic receptor activation. CHF was induced in rabbits. Renal blood flow (RBF) and renal vascular conductance (RVC) responses to 6 min of 5% isocapnic hypoxia were assessed in the conscious state in sedentary (SED) and ExT rabbits with CHF with and without α1-adrenergic blockade. α1-adrenergic receptor expression in the kidney cortex was also evaluated. A significant decline in baseline RBF and RVC and an exaggerated renal vasoconstriction during acute hypoxia occurred in CHF-SED rabbits compared with the prepaced state (P < 0.05). ExT diminished the decline in baseline RBF and RVC and restored changes during hypoxia to those of the prepaced state. α1-adrenergic blockade partially prevented the decline in RBF and RVC in CHF-SED rabbits and eliminated the differences in hypoxia responses between SED and ExT animals. Unilateral renal denervation (DnX) blocked the hypoxia-induced renal vasoconstriction in CHF-SED rabbits. α1-adrenergic protein in the renal cortex of animals with CHF was increased in SED animals and normalized after ExT. These data provide evidence that the acute decline in RBF during hypoxia is caused entirely by the renal nerves but is only partially mediated by α1-adrenergic receptors. Nonetheless, α1-adrenergic receptors play an important role in the beneficial effects of ExT in the kidney. Copyright © 2016 the American Physiological Society.

Cerebrovascular response to acute hypocapnic and eucapnic hypoxia in normal man

PubMed Central

Shapiro, William; Wasserman, Albert J.; Baker, James P.; Patterson, John L.

1970-01-01

Alterations in human cerebral blood flow and related blood constituents were studied during exposure to acute hypoxia. Observations were made during serial inhalation of decreasing O2 concentrations with and without maintenance of normocarbia, during 8 min inhalation of 10% O2, and after hyperventilation at an arterial PO2 of about 40 mm Hg. In the range of hypoxemia studied, from normal down to arterial PO2 of about 40 mm Hg, the magnitude of the cerebral vasodilator response to hypoxia appeared to be largely dependent upon the coexisting arterial CO2 tension. The mean slope of the increase in cerebral blood flow with decreasing arterial O2 tension rose more quickly (P < 0.05) when eucapnia was maintained when compared with the slope derived under similar hypoxic conditions without maintenance of eucapnia. When 12 subjects inhaled 10% oxygen, cerebral blood flow rose to more than 135% of control in four whose mean decrease in arterial CO2 tension was - 2.0 mm Hg. The remaining eight had flows ranging from 97 to 120% of control, and their mean decrease in CO2 tension was - 5.1 mm Hg. When mean arterial PO2 was 37 mm Hg, hyperventilation was carried out in 10 subjects. Arterial PO2 increased insignificantly, arterial PCO2 declined from 34 to 27 mm Hg (P < 0.05), and cerebral blood flow which had been 143% of control decreased to 109%, a figure not significantly different from control. These data demonstrate the powerful counterbalancing constrictor effects of modest reductions in CO2 tension on the vasodilator influence of hypoxia represented by arterial PO2 reductions to about 40 mm Hg. Indeed, mild hyperventilation completely overcame the vasodilator effect provided by an arterial O2 tension as low as 40 mm Hg. The effects of hypoxia on the control of the cerebral circulation must be analyzed in terms of the effects of any associated changes in CO2 tension. PMID:5480859

Cardiovascular development in embryos of the American alligator Alligator mississippiensis: effects of chronic and acute hypoxia.

PubMed

Crossley, Dane A; Altimiras, Jordi

2005-01-01

Chronic hypoxic incubation is a common tool used to address the plasticity of morphological and physiological characteristics during vertebrate development. In this study chronic hypoxic incubation of embryonic American alligators resulted in both morphological (mass) and physiological changes. During normoxic incubation embryonic mass, liver mass and heart mass increased throughout the period of study, while yolk mass fell. Chronic hypoxia (10%O2) resulted in a reduced embryonic mass at 80% and 90% of incubation. This reduction in embryonic mass was accompanied by a relative enlargement of the heart at 80% and 90% of incubation, while relative embryonic liver mass was similar to the normoxic group. Normoxic incubated alligators maintained a constant heart rate during the period of study, while mean arterial pressure rose continuously. Both levels of hypoxic incubation (15% and 10%O2) resulted in a lower mean arterial pressure at 90% of incubation, while heart rate was lower in the 10%O2 group only. Acute (5 min) exposure to 10%O2 in the normoxic group resulted in a biphasic response, with a normotensive bradycardia occurring during the period of exposure and a hypertensive tachycardic response occurring during recovery. The embryos incubated under hypoxia also showed a blunted response to acute hypoxic stress. In conclusion, the main responses elicited by chronic hypoxic incubation, namely, cardiac enlargement, blunted hypoxic response and systemic vasodilation, may provide chronically hypoxic embryos with a new physiological repertoire for responding to hypoxia.

Preinduction of HSP70 promotes hypoxic tolerance and facilitates acclimatization to acute hypobaric hypoxia in mouse brain

PubMed Central

Zhang, Kuan; Zhao, Tong; Huang, Xin; Liu, Zhao-hui; Xiong, Lei; Li, Ming-ming; Wu, Li-ying; Zhao, Yong-qi

2008-01-01

It has been shown that induction of HSP70 by administration of geranylgeranylacetone (GGA) leads to protection against ischemia/reperfusion injury. The present study was performed to determine the effect of GGA on the survival of mice and on brain damage under acute hypobaric hypoxia. The data showed that the mice injected with GGA survived significantly longer than control animals (survival time of 9.55 ± 3.12 min, n = 16 vs. controls at 4.28 ± 4.29 min, n = 15, P < 0.005). Accordingly, the cellular necrosis or degeneration of the hippocampus and the cortex induced by sublethal hypoxia for 6 h could be attenuated by preinjection with GGA, especially in the CA2 and CA3 regions of the hippocampus. In addition, the activity of nitric oxide synthase (NOS) of the hippocampus and the cortex was increased after exposure to sublethal hypoxia for 6 h but could be inhibited by the preinjection of GGA. Furthermore, the expression of HSP70 was significantly increased at 1 h after GGA injection. These results suggest that administration of GGA improved survival rate and prevented acute hypoxic damage to the brain and that the underlying mechanism involved induction of HSP70 and inhibition of NOS activity. PMID:19105051

Ventilatory responses to acute and chronic hypoxia are altered in female but not male Paskin-deficient mice.

PubMed

Soliz, Jorge; Soulage, Christophe; Borter, Emanuela; van Patot, Martha Tissot; Gassmann, Max

2008-08-01

Proteins harboring a Per-Arnt-Sim (PAS) domain are versatile and allow archaea, bacteria, and plants to sense oxygen partial pressure, as well as light intensity and redox potential. A PAS domain associated with a histidine kinase domain is found in FixL, the oxygen sensor molecule of Rhizobium species. PASKIN is the mammalian homolog of FixL, but its function is far from being understood. Using whole body plethysmography, we evaluated the ventilatory response to acute and chronic hypoxia of homozygous deficient male and female PASKIN mice (Paskin-/-). Although only slight ventilatory differences were found in males, female Paskin-/- mice increased ventilatory response to acute hypoxia. Unexpectedly, females had an impaired ability to reach ventilatory acclimatization in response to chronic hypoxia. Central control of ventilation occurs in the brain stem respiratory centers and is modulated by catecholamines via tyrosine hydroxylase (TH) activity. We observed that TH activity was altered in male and female Paskin-/- mice. Peripheral chemoreceptor effects on ventilation were evaluated by exposing animals to hyperoxia (Dejours test) and domperidone, a peripheral ventilatory stimulant drug directly affecting the carotid sinus nerve discharge. Male and female Paskin-/- had normal peripheral chemosensory (carotid bodies) responses. In summary, our observations suggest that PASKIN is involved in the central control of hypoxic ventilation, modulating ventilation in a gender-dependent manner.

Reducing intratumour acute hypoxia through bevacizumab treatment, referring to the response of quiescent tumour cells and metastatic potential

PubMed Central

Masunaga, S; Liu, Y; Tanaka, H; Sakurai, Y; Suzuki, M; Kondo, N; Maruhashi, A; Ono, K

2011-01-01

Objectives The aim was to evaluate the influence of bevacizumab on intratumour oxygenation status and lung metastasis following radiotherapy, with specific reference to the response of quiescent (Q) cell populations within irradiated tumours. Methods B16-BL6 melanoma tumour-bearing C57BL/6 mice were continuously given 5-bromo-2-deoxyuridine (BrdU) to label all proliferating (P) cells. They received γ-ray irradiation following treatment with the acute hypoxia-releasing agent nicotinamide or local mild temperature hyperthermia (MTH) with or without the administration of bevacizumab under aerobic conditions or totally hypoxic conditions, achieved by clamping the proximal end of the tumours. Immediately after the irradiation, cells from some tumours were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In the other tumour-bearing mice, macroscopic lung metastases were enumerated 17 days after irradiation. Results 3 days after bevacizumab administration, acute hypoxia-rich total cell population in the tumour showed a remarkably enhanced radiosensitivity to γ-rays, and the hypoxic fraction (HF) was reduced, even after MTH treatment. However, the hypoxic fraction was not reduced after nicotinamide treatment. With or without γ-ray irradiation, bevacizumab administration showed some potential to reduce the number of lung metastases as well as nicotinamide treatment. Conclusion Bevacizumab has the potential to reduce perfusion-limited acute hypoxia and some potential to cause a decrease in the number of lung metastases as well as nicotinamide. PMID:21586505

Long-term facilitation of ventilation following acute continuous hypoxia in awake humans during sustained hypercapnia

PubMed Central

Griffin, Harry S; Pugh, Keith; Kumar, Prem; Balanos, George M

2012-01-01

In awake humans, long-term facilitation of ventilation (vLTF) following acute intermittent hypoxia (AIH) is only expressed if CO2 is maintained above normocapnic levels. vLTF has not been reported following acute continuous hypoxia (ACH) and it is not known whether this might be unmasked by elevated CO2. Twelve healthy participants completed three trials. In all trials end-tidal pressure of CO2 was elevated 4–5 mmHg above normocapnic levels. During Trial 1 (AIH) participants were exposed to eight 4 min episodes of hypoxia. During Trial 2 (ACH) participants were exposed to continuous hypoxia for 32 min. In Trial 3 (Control) participants were exposed to euoxia throughout. To assess the contribution of the carotid body (CB) in observed ventilatory responses, CB afferent discharge before and after each trial was transiently inhibited with hyperoxia. Minute ventilation () increased following all trials, but was significantly greater in Trials 1 and 2 when compared with Trial 3 (Trial 1: 4.96 ± 0.87, Trial 2: 5.07 ± 0.7, Trial 3: 2.55 ± 0.98 l min−1, P < 0.05). Hyperoxia attenuated to a similar extent in baseline and recovery in all trials (Trial 1: 3.0 ± 0.57 vs. 3.27 ± 0.68, Trial 2: 1.97 ± 0.62 vs. 2.56 ± 0.62, Trial 3: 2.23 ± 0.49 vs. 2.15 ± 0.55 l min−1, P > 0.05). Data are means ± SEM. In awake humans with elevated CO2, ACH evokes a sustained increase in ventilation that is comparable to that evoked by AIH. However, a gradual positive drift in ventilation in response to elevated CO2 accounts for approximately half of this apparent vLTF. Additionally, our data support the view that the CB is not directly involved in maintaining vLTF. PMID:22826133

Sustained Hypoxia Elicits Competing Spinal Mechanisms of Phrenic Motor Facilitation

PubMed Central

Devinney, Michael J.; Nichols, Nicole L.

2016-01-01

Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a form of spinal motor plasticity. Competing mechanisms give rise to phrenic motor facilitation (pMF; a general term including pLTF) depending on the severity of hypoxia within episodes. In contrast, moderate acute sustained hypoxia (mASH) does not elicit pMF. By varying the severity of ASH and targeting competing mechanisms of pMF, we sought to illustrate why moderate AIH (mAIH) elicits pMF but mASH does not. Although mAIH elicits serotonin-dependent pLTF, mASH does not; thus, mAIH-induced pLTF is pattern sensitive. In contrast, severe AIH (sAIH) elicits pLTF through adenosine-dependent mechanisms, likely from greater extracellular adenosine accumulation. Because serotonin- and adenosine-dependent pMF interact via cross talk inhibition, we hypothesized that pMF is obscured because the competing mechanisms of pMF are balanced and offsetting during mASH. Here, we demonstrate the following: (1) blocking spinal A2A receptors with MSX-3 reveals mASH-induced pMF; and (2) sASH elicits A2A-dependent pMF. In anesthetized rats pretreated with intrathecal A2A receptor antagonist injections before mASH (PaO2 = 40–54 mmHg) or sASH (PaO2 = 25–36 mmHg), (1) mASH induced a serotonin-dependent pMF and (2) sASH induced an adenosine-dependent pMF, which was enhanced by spinal serotonin receptor inhibition. Thus, competing adenosine- and serotonin-dependent mechanisms contribute differentially to pMF depending on the pattern/severity of hypoxia. Understanding interactions between these mechanisms has clinical relevance as we develop therapies to treat severe neuromuscular disorders that compromise somatic motor behaviors, including breathing. Moreover, these results demonstrate how competing mechanisms of plasticity can give rise to pattern sensitivity in pLTF. SIGNIFICANCE STATEMENT Intermittent hypoxia elicits pattern-sensitive spinal plasticity and improves motor function after spinal injury or

Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression.

PubMed

Hassan, Atiq; Arnold, Breanna M; Caine, Sally; Toosi, Behzad M; Verge, Valerie M K; Muir, Gillian D

2018-01-01

One of the most promising approaches to improve recovery after spinal cord injury (SCI) is the augmentation of spontaneously occurring plasticity in uninjured neural pathways. Acute intermittent hypoxia (AIH, brief exposures to reduced O2 levels alternating with normal O2 levels) initiates plasticity in respiratory systems and has been shown to improve recovery in respiratory and non-respiratory spinal systems after SCI in experimental animals and humans. Although the mechanism by which AIH elicits its effects after SCI are not well understood, AIH is known to alter protein expression in spinal neurons in uninjured animals. Here, we examine hypoxia- and plasticity-related protein expression using immunofluorescence in spinal neurons in SCI rats that were treated with AIH combined with motor training, a protocol which has been demonstrated to improve recovery of forelimb function in this lesion model. Specifically, we assessed protein expression in spinal neurons from animals with incomplete cervical SCI which were exposed to AIH treatment + motor training either for 1 or 7 days. AIH treatment consisted of 10 episodes of AIH: (5 min 11% O2: 5 min 21% O2) for 7 days beginning at 4 weeks post-SCI. Both 1 or 7 days of AIH treatment + motor training resulted in significantly increased expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) relative to normoxia-treated controls, in neurons both proximal (cervical) and remote (lumbar) to the SCI. All other markers examined were significantly elevated in the 7 day AIH + motor training group only, at both cervical and lumbar levels. These markers included vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and phosphorylated and nonphosphorylated forms of the BDNF receptor tropomyosin-related kinase B (TrkB). In summary, AIH induces plasticity at the cellular level after SCI by altering the expression of major plasticity- and hypoxia-related proteins at spinal regions

Preclinical evidence of mitochondrial nicotinamide adenine dinucleotide as an effective alarm parameter under hypoxia

NASA Astrophysics Data System (ADS)

Shi, Hua; Sun, Nannan; Mayevsky, Avraham; Zhang, Zhihong; Luo, Qingming

2014-01-01

Early detection of tissue hypoxia in the intensive care unit is essential for effective treatment. Reduced nicotinamide adenine dinucleotide (NADH) has been suggested to be the most sensitive indicator of tissue oxygenation at the mitochondrial level. However, no experimental evidence comparing the kinetics of changes in NADH and other physiological parameters has been provided. The aim of this study is to obtain the missing data in a systematic and reliable manner. We constructed four acute hypoxia models, including hypoxic hypoxia, hypemic hypoxia, circulatory hypoxia, and histogenous hypoxia, and measured NADH fluorescence, tissue reflectance, cerebral blood flow, respiration, and electrocardiography simultaneously from the induction of hypoxia until death. We found that NADH was not always the first onset parameter responding to hypoxia. The order of responses was mainly affected by the cause of hypoxia. However, NADH reached its alarm level earlier than the other monitored parameters, ranging from several seconds to >10 min. As such, we suggest that the NADH can be used as a hypoxia indicator, although the exact level that should be used must be further investigated. When the NADH alarm is detected, the body still has a chance to recover if appropriate and timely treatment is provided.

Flight Performance During Exposure to Acute Hypobaric Hypoxia.

PubMed

Steinman, Yuval; van den Oord, Marieke H A H; Frings-Dresen, Monique H W; Sluiter, Judith K

2017-08-01

The purpose of the present study was to examine the influence of hypobaric hypoxia (HH) on a pilot's flight performance during exposure to simulated altitudes of 91, 3048, and 4572 m (300, 10,000, and 15,000 ft) and to monitor the pilot's physiological reactions. In a single-blinded counter-balanced design, 12 male pilots were exposed to HH while flying in a flight simulator that had been placed in a hypobaric chamber. Flight performance of the pilots, pilot's alertness level, Spo2, heart rate (HR), minute ventilation (VE), and breathing frequency (BF) were measured. A significant difference was found in Flight Profile Accuracy (FPA) between the three altitudes. Post hoc analysis showed no significant difference in performance between 91 m and 3048 m. A trend was observed at 4572 m, suggesting a decrease in flight performance at that altitude. Significantly lower alertness levels were observed at the start of the flight at 4572 m compared to 91 m, and at the end of the flight at 4572 m compared to the start at that altitude. Spo2 and BF decreased, and HR increased significantly with altitude. The present study did not provide decisive evidence for a decrease in flight performance during exposure to simulated altitudes of 3048 and 4572 m. However, large interindividual variation in pilots' flight performance combined with a gradual decrease in alertness levels observed in the present study puts into question the ability of pilots to safely fly an aircraft while exposed to these altitudes without supplemental oxygen.Steinman Y, van den Oord MHAH, Frings-Dresen MHW, Sluiter JK. Flight performance during exposure to acute hypobaric hypoxia. Aerosp Med Hum Perform. 2017; 88(8):760-767.

Rat reaction to hypokinesia after prior adaptation to hypoxia

NASA Technical Reports Server (NTRS)

Barashova, Z. I.; Tarakanova, O. I.

1980-01-01

The effect of prior hypoxia adaptation on body tolerance to hypokinesia was investigated. Rats trained to a 50 day period of hypokinesia and hypoxia with a preliminary month of adaptation to hypoxia showed less weight loss, higher indices for red blood content, heightened reactivity of the overall organism and the central nervous system to acute hypoxia, and decreased modification of the skeletal muscles compared to rats subjected to hypokinesia alone.

Intersaccadic drift velocity is sensitive to short-term hypobaric hypoxia.

PubMed

Di Stasi, Leandro L; Cabestrero, Raúl; McCamy, Michael B; Ríos, Francisco; Catena, Andrés; Quirós, Pilar; Lopez, Jose A; Saez, Carolina; Macknik, Stephen L; Martinez-Conde, Susana

2014-04-01

Hypoxia, defined as decreased availability of oxygen in the body's tissues, can lead to dyspnea, rapid pulse, syncope, visual dysfunction, mental disturbances such as delirium or euphoria, and even death. It is considered to be one of the most serious hazards during flight. Thus, early and objective detection of the physiological effects of hypoxia is critical to prevent catastrophes in civil and military aviation. The few studies that have addressed the effects of hypoxia on objective oculomotor metrics have had inconsistent results, however. Thus, the question of whether hypoxia modulates eye movement behavior remains open. Here we examined the effects of short-term hypobaric hypoxia on the velocity of saccadic eye movements and intersaccadic drift of Spanish Air Force pilots and flight engineers, compared with a control group that did not experience hypoxia. Saccadic velocity decreased with time-on-duty in both groups, in correlation with subjective fatigue. Intersaccadic drift velocity increased in the hypoxia group only, suggesting that acute hypoxia diminishes eye stability, independently of fatigue. Our results suggest that intersaccadic drift velocity could serve as a biomarker of acute hypoxia. These findings may also contribute to our understanding of the relationship between hypoxia episodes and central nervous system impairments.

[Effect of acute hypoxia on the intensity of free radical processes in the basal nuclei of the brain, and the rat behaviour in the open field test under conditions of altered photoperiod].

PubMed

Sopova, I Iu; Zamorskiĭ, I I

2011-03-01

The effect of acute hypoxia on the intensity of free radical processes in the basal nuclei (the nucleus caudatus, globus pallidus. nucleus accumbens. amygdaloid complex) of the brain, and the rat behaviour in the open field test has been studied under conditions of altered photoperiod. It has been shown that constant darkness levels the effect of acute hypoxia on the intensity of lipid peroxidation, preserves the activity of superoxide dismutase and catalase at a higher level, lowers the activity of glutathione peroxidase. Under light, the sensitivity of basal nuclei neurons to acute hypoxia is enhanced, the latter being reflected in intensification of lipid peroxidation at the expense of increased formation of dien conjugates. The activity of catalase at that considerably exceeds the level of even intact rats in all the structures. It has been established that an altered photoperiod modulates the effect of acute hypoxia on the parameters of rat's activity in the open field, the character of their change depending on the nature of a photophase change.

Hypoxia in paradise: widespread hypoxia tolerance in coral reef fishes.

PubMed

Nilsson, Göran E; Ostlund-Nilsson, Sara

2004-02-07

Using respirometry, we examined the hypoxia tolerance of 31 teleost fish species (seven families) inhabiting coral reefs at a 2-5 m depth in the lagoon at Lizard Island (Great Barrier Reef, Australia). All fishes studied maintained their rate of oxygen consumption down to relatively severe hypoxia (20-30% air saturation). Indeed, most fishes appeared unaffected by hypoxia until the oxygen level fell below 10% of air saturation. This, hitherto unrecognized, hypoxia tolerance among coral reef fishes could reflect adaptations to nocturnal hypoxia in tide pools. It may also be needed to enable fishes to reside deep within branching coral at night to avoid predation. Widespread hypoxia tolerance in a habitat with such an extreme biodiversity as coral reefs indicate that there is a wealth of hypoxia related adaptations to be discovered in reef fishes.

Assessment of hypoxia and TNF-alpha response by a vector with HRE and NF-kappaB response elements.

PubMed

Chen, Zhilin; Eadie, Ashley L; Hall, Sean R; Ballantyne, Laurel; Ademidun, David; Tse, M Yat; Pang, Stephen C; Melo, Luis G; Ward, Christopher A; Brunt, Keith R

2017-01-01

Hypoxia and inflammatory cytokine activation (H&I) are common processes in many acute and chronic diseases. Thus, a single vector that responds to both hypoxia and inflammatory cytokines, such as TNF-alpha, is useful for assesing the severity of such diseases. Adaptation to hypoxia is regulated primarily by hypoxia inducible transcription factor (HIF alpha) nuclear proteins that engage genes containing a hypoxia response element (HRE). Inflammation activates a multitude of cytokines, including TNF-alpha, that invariably modulate activation of the nuclear factor kappa B (NF-kB) transcription factor. We constructed a vector that encompassed both a hypoxia response element (HRE), and a NF-kappaB responsive element. We show that this vector was functionally responsive to both hypoxia and TNF-alpha, in vitro and in vivo . Thus, this vector might be suitable for the detection and assessment of hypoxia or TNF-alpha.

Behavioural effects of near-term acute fetal hypoxia in a small precocial animal, the spiny mouse (Acomys cahirinus).

PubMed

Ireland, Zoe; Dickinson, Hayley; Fleiss, Bobbi; Hutton, Lisa C; Walker, David W

2010-01-01

We have previously developed a model of near-term intra-uterine hypoxia producing significant neonatal mortality (37%) in a small laboratory animal - the spiny mouse - which has precocial offspring at birth. The aim of the present study was to determine if this insult resulted in the appearance of behavioural abnormalities in those offspring which survived the hypoxic delivery. Behavioural tests assessed gait (using footprint patterns), motor coordination and balance on an accelerating rotarod, and spontaneous locomotion and exploration in an open field. We found that the near-term acute hypoxic episode produced a mild neurological deficit in the early postnatal period. In comparison to vaginally delivered controls, hypoxia pups were able to remain on the accelerating rotarod for significantly shorter durations on postnatal days 1-2, and in the open field they travelled significantly shorter distances, jumped less, and spent a greater percentage of time stationary on postnatal days 5 and 15. No changes were observed in gait. Unlike some rodent models of cerebral hypoxia-ischaemia, macroscopic examination of the brain on postnatal day 5 showed no gross cystic lesions, oedema or infarct. Future studies should be directed at identifying hypoxia-induced alterations in the function of specific brain regions, and assessing if maternal administration of neuroprotective agents can prevent against hypoxia-induced neurological deficits and brain damage that occur at birth. Copyright 2009 S. Karger AG, Basel.

Severe hypertriglyceridemia-related acute pancreatitis.

PubMed

Stefanutti, Claudia; Labbadia, Giancarlo; Morozzi, Claudia

2013-04-01

Acute pancreatitis is a potentially life-threatening complication of severe hypertriglyceridemia. In some cases, inborn errors of metabolism such as lipoprotein lipase deficiency, apoprotein C-II deficiency, and familial hypertriglyceridemia have been reported as causes of severe hypertriglyceridemia. More often, severe hypertriglyceridemia describes various clinical conditions characterized by high plasma levels of triglycerides (>1000 mg/dL), chylomicron remnants, or intermediate density lipoprotein like particles, and/or chylomicrons. International guidelines on the management of acute pancreatitis are currently available. Standard therapeutic measures are based on the use of lipid-lowering agents (fenofibrate, gemfibrozil, niacin, Ω-3 fatty acids), low molecular weight heparin, and insulin in diabetic patients. However, when standard medical therapies have failed, non-pharmacological approaches based upon the removal of triglycerides with therapeutic plasma exchange can also provide benefit to patients with severe hypertriglyceridemia and acute pancreatitis. Plasma exchange could be very helpful in reducing triglycerides levels during the acute phase of hyperlipidemic pancreatitis, and in the prevention of recurrence. The current evidence on management of acute pancreatitis and severe hypertriglyceridemia, focusing on symptoms, treatment and potential complications is reviewed herein. © 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.

Impaired acclimatization to chronic hypoxia in adult male and female rats following neonatal hypoxia.

PubMed

Lumbroso, Delphine; Joseph, Vincent

2009-08-01

We tested the hypothesis that neonatal exposure to hypoxia alters acclimatization to chronic hypoxia later in life. Rat pups were exposed to normobaric hypoxia (12% O(2); nHx group) in a sealed chamber, or to normoxia (21% O(2); nNx group) from the day before birth to postnatal day 10. The animals were then raised in normal conditions until reaching 12 wk of age. At this age, we assessed ventilatory and hematological acclimatization to chronic hypoxia by exposing male and female nHx and nNx rats for 2 wk to 10% O(2). Minute ventilation, metabolic rate, hypoxic ventilatory response, hematocrit, and hemoglobin levels were measured both before and after acclimatization. We also quantified right ventricular hypertrophy as an index of pulmonary hypertension both before and after acclimatization. There was a significant effect of neonatal hypoxia that decreases ventilatory response (relative to metabolic rate, VE/VCO(2)) to acute hypoxia before acclimatization in males but not in females. nHx rats had an impaired acclimatization to chronic hypoxia characterized by altered respiratory pattern and elevated hematocrit and hemoglobin levels after acclimatization, in both males and females. Right ventricular hypertrophy was present before and after acclimatization in nHx rats, indicating that neonatal hypoxia results in pulmonary hypertension in adults. We conclude that neonatal hypoxia impairs acclimatization to chronic hypoxia in adults and may be a factor contributing to the establishment of chronic mountain sickness in humans living at high altitude.

Intermittent hypoxia training in prediabetes patients: Beneficial effects on glucose homeostasis, hypoxia tolerance and gene expression.

PubMed

Serebrovska, Tetiana V; Portnychenko, Alla G; Drevytska, Tetiana I; Portnichenko, Vladimir I; Xi, Lei; Egorov, Egor; Gavalko, Anna V; Naskalova, Svitlana; Chizhova, Valentina; Shatylo, Valeriy B

2017-09-01

The present study aimed at examining beneficial effects of intermittent hypoxia training (IHT) under prediabetic conditions. We investigate the effects of three-week IHT on blood glucose level, tolerance to acute hypoxia, and leukocyte mRNA expression of hypoxia inducible factor 1α (HIF-1α) and its target genes, i.e. insulin receptor, facilitated glucose transporter-solute carrier family-2, and potassium voltage-gated channel subfamily J. Seven healthy and 11 prediabetic men and women (44-70 years of age) were examined before, next day and one month after three-week IHT (3 sessions per week, each session consisting 4 cycles of 5-min 12% O 2 and 5-min room air breathing). We found that IHT afforded beneficial effects on glucose homeostasis in patients with prediabetes reducing fasting glucose and during standard oral glucose tolerance test. The most pronounced positive effects were observed at one month after IHT termination. IHT also significantly increased the tolerance to acute hypoxia (i.e. SaO 2 level at 20th min of breathing with 12% O 2 ) and improved functional parameters of respiratory and cardiovascular systems. IHT stimulated HIF-1α mRNA expression in blood leukocytes in healthy and prediabetic subjects, but in prediabetes patients the maximum increase was lagged. The greatest changes in mRNA expression of HIF-1α target genes occurred a month after IHT and coincided with the largest decrease in blood glucose levels. The higher expression of HIF-1α was positively associated with higher tolerance to hypoxia and better glucose homeostasis. In conclusion, our results suggest that IHT may be useful for preventing the development of type 2 diabetes. Impact statement The present study investigated the beneficial effects of intermittent hypoxia training (IHT) in humans under prediabetic conditions. We found that three-week moderate IHT induced higher HIF-1α mRNA expressions as well as its target genes, which were positively correlated with higher tolerance

One- and three-time mild hypobaric hypoxia modifies expression of mitochondrial thioredoxin-2 in hippocampus of rat.

PubMed

Stroev, Sergey Alexandrovich; Tjulkova, Ekaterina Iosifovna; Samoilov, Michail Olegovich; Pelto-Huikko, Markku Tapio

2011-01-01

Our previous study demonstrated that preconditioning by 3-times repetitive mild hypoxia significantly augmented expression of mitochondrial thioredoxin-2 (Trx-2) at 3 h after subsequent acute severe hypoxia in rat hippocampus. However, it was unclear whether this augmentation was due to build up of Trx-2 by mild hypoxia before severe hypoxia or by modification of reaction to severe hypoxia itself. To answer on this question we study the expression level during and after preconditioning without subsequent severe hypoxia. Trx-2 expression was studied by immunocytochemistry 3 h and 24 h after first session and 3 h and 24 h after last session of 3-times (spaced at 24 h) mild hypobaric hypoxia (360 Torr, 2h). At 3 h after 1-time hypoxia (first session of 3-time hypoxia) the total number of Trx-2-immunoreactive cells (Nt) was significantly decreased in contrast with control in CA2, CA3 and DG. The number of cells with intensive expression of Trx-2 (Ni) was reduced in CA1 and CA3. At 24 h after the same 1-time hypoxia Nt was lower than in control and at 3 h time-point in all hippocampal areas studied (CA1, CA2, CA3 and DG); Ni was decreased only compared to control in CA1 and CA3. At 3 h after last session of 3-times hypoxia Nt and Ni were significantly down regulated in comparison with control only in CA1. At 24 h after it Nt was significantly decreased compared to control in CA1, CA2 and CA3 (in DG the decrease was not statistically significant) but in all areas was higher than at 24 h after 1-time hypoxia. Dynamics of Nt changes from 3-hours after single to 24-hours after triple moderate hypoxia had the wave phase character. These findings indicate that Trx-2 expression in most areas of hippocampus was decreased to 24 h after 3-time mild hypoxia. Thus the augmentation of Trx-2 expression in hippocampal neurons of preconditioned animals in response to subsequent severe hypoxia is caused obviously not by Trx-2 accumulation during preconditioning sessions but by

Hypoxia in paradise: widespread hypoxia tolerance in coral reef fishes.

PubMed Central

Nilsson, Göran E; Ostlund-Nilsson, Sara

2004-01-01

Using respirometry, we examined the hypoxia tolerance of 31 teleost fish species (seven families) inhabiting coral reefs at a 2-5 m depth in the lagoon at Lizard Island (Great Barrier Reef, Australia). All fishes studied maintained their rate of oxygen consumption down to relatively severe hypoxia (20-30% air saturation). Indeed, most fishes appeared unaffected by hypoxia until the oxygen level fell below 10% of air saturation. This, hitherto unrecognized, hypoxia tolerance among coral reef fishes could reflect adaptations to nocturnal hypoxia in tide pools. It may also be needed to enable fishes to reside deep within branching coral at night to avoid predation. Widespread hypoxia tolerance in a habitat with such an extreme biodiversity as coral reefs indicate that there is a wealth of hypoxia related adaptations to be discovered in reef fishes. PMID:15101411

Hypobaric Hypoxia Regulates Brain Iron Homeostasis in Rats.

PubMed

Li, Yaru; Yu, Peng; Chang, Shi-Yang; Wu, Qiong; Yu, Panpan; Xie, Congcong; Wu, Wenyue; Zhao, Baolu; Gao, Guofen; Chang, Yan-Zhong

2017-06-01

Disruption of iron homeostasis in brain has been found to be closely involved in several neurodegenerative diseases. Recent studies have reported that appropriate intermittent hypobaric hypoxia played a protective role in brain injury caused by acute hypoxia. However, the mechanisms of this protective effect have not been fully understood. In this study, Sprague-Dawley (SD) rat models were developed by hypobaric hypoxia treatment in an altitude chamber, and the iron level and iron related protein levels were determined in rat brain after 4 weeks of treatment. We found that the iron levels significantly decreased in the cortex and hippocampus of rat brain as compared to that of the control rats without hypobaric hypoxia treatment. The expression levels of iron storage protein L-ferritin and iron transport proteins, including transferrin receptor-1 (TfR1), divalent metal transporter 1 (DMT1), and ferroportin1 (FPN1), were also altered. Further studies found that the iron regulatory protein 2 (IRP2) played a dominant regulatory role in the changes of iron hemostasis, whereas iron regulatory protein 1 (IRP1) mainly acted as cis-aconitase. These results, for the first time, showed the alteration of iron metabolism during hypobaric hypoxia in rat models, which link the potential neuroprotective role of hypobaric hypoxia treatment to the decreased iron level in brain. This may provide insight into the treatment of iron-overloaded neurodegenerative diseases. J. Cell. Biochem. 118: 1596-1605, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Limited effects of exogenous glucose during severe hypoxia and a lack of hypoxia-stimulated glucose uptake in isolated rainbow trout cardiac muscle

PubMed Central

Becker, Tracy A.; DellaValle, Brian; Gesser, Hans; Rodnick, Kenneth J.

2013-01-01

SUMMARY We examined whether exogenous glucose affects contractile performance of electrically paced ventricle strips from rainbow trout under conditions known to alter cardiomyocyte performance, ion regulation and energy demands. Physiological levels of d-glucose did not influence twitch force development for aerobic preparations (1) paced at 0.5 or 1.1 Hz, (2) at 15 or 23°C, (3) receiving adrenergic stimulation or (4) during reoxygenation with or without adrenaline after severe hypoxia. Contractile responses to ryanodine, an inhibitor of Ca2+ release from the sarcoplasmic reticulum, were also not affected by exogenous glucose. However, glucose did attenuate the fall in twitch force during severe hypoxia. Glucose uptake was assayed in non-contracting ventricle strips using 2-[3H] deoxy-d-glucose (2-DG) under aerobic and hypoxic conditions, at different incubation temperatures and with different inhibitors. Based upon a lack of saturation of 2-DG uptake and incomplete inhibition of uptake by cytochalasin B and d-glucose, 2-DG uptake was mediated by a combination of facilitated transport and simple diffusion. Hypoxia stimulated lactate efflux sixfold to sevenfold with glucose present, but did not increase 2-DG uptake or reduce lactate efflux in the presence of cytochalasin B. Increasing temperature (14 to 24°C) also did not increase 2-DG uptake, but decreasing temperature (14 to 4°C) reduced 2-DG uptake by 45%. In conclusion, exogenous glucose improves mechanical performance under hypoxia but not under any of the aerobic conditions applied. The extracellular concentration of glucose and cold temperature appear to determine and limit cardiomyocyte glucose uptake, respectively, and together may help define a metabolic strategy that relies predominantly on intracellular energy stores. PMID:23685969

Potential role of the glycolytic oscillator in acute hypoxia in tumors

NASA Astrophysics Data System (ADS)

Che Fru, Leonard; Adamson, Erin B.; Campos, David D.; Fain, Sean B.; Jacques, Steven L.; van der Kogel, Albert J.; Nickel, Kwang P.; Song, Chihwa; Kimple, Randall J.; Kissick, Michael W.

2015-12-01

Tumor acute hypoxia has a dynamic component that is also, at least partially, coherent. Using blood oxygen level dependent magnetic resonance imaging, we observed coherent oscillations in hemoglobin saturation dynamics in cell line xenograft models of head and neck squamous cell carcinoma. We posit a well-established biochemical nonlinear oscillatory mechanism called the glycolytic oscillator as a potential cause of the coherent oscillations in tumors. These data suggest that metabolic changes within individual tumor cells may affect the local tumor microenvironment including oxygen availability and therefore radiosensitivity. These individual cells can synchronize the oscillations in patches of similar intermediate glucose levels. These alterations have potentially important implications for radiation therapy and are a potential target for optimizing the cancer response to radiation.

Progressive hypoxia decouples activity and aerobic performance of skate embryos

PubMed Central

Di Santo, Valentina; Tran, Anna H.; Svendsen, Jon C.

2016-01-01

Although fish population size is strongly affected by survival during embryonic stages, our understanding of physiological responses to environmental stressors is based primarily on studies of post-hatch fishes. Embryonic responses to acute exposure to changes in abiotic conditions, including increase in hypoxia, could be particularly important in species exhibiting long developmental time, as embryos are unable to select a different environment behaviourally. Given that oxygen is key to metabolic processes in fishes and aquatic hypoxia is becoming more severe and frequent worldwide, organisms are expected to reduce their aerobic performance. Here, we examined the metabolic and behavioural responses of embryos of a benthic elasmobranch fish, the little skate (Leucoraja erinacea), to acute progressive hypoxia, by measuring oxygen consumption and movement (tail-beat) rates inside the egg case. Oxygen consumption rates were not significantly affected by ambient oxygen levels until reaching 45% air saturation (critical oxygen saturation, Scrit). Below Scrit, oxygen consumption rates declined rapidly, revealing an oxygen conformity response. Surprisingly, we observed a decoupling of aerobic performance and activity, as tail-beat rates increased, rather than matching the declining metabolic rates, at air saturation levels of 55% and below. These results suggest a significantly divergent response at the physiological and behavioural levels. While skate embryos depressed their metabolic rates in response to progressive hypoxia, they increased water circulation inside the egg case, presumably to restore normoxic conditions, until activity ceased abruptly around 9.8% air saturation. PMID:27293746

Progressive hypoxia decouples activity and aerobic performance of skate embryos.

PubMed

Di Santo, Valentina; Tran, Anna H; Svendsen, Jon C

2016-01-01

Although fish population size is strongly affected by survival during embryonic stages, our understanding of physiological responses to environmental stressors is based primarily on studies of post-hatch fishes. Embryonic responses to acute exposure to changes in abiotic conditions, including increase in hypoxia, could be particularly important in species exhibiting long developmental time, as embryos are unable to select a different environment behaviourally. Given that oxygen is key to metabolic processes in fishes and aquatic hypoxia is becoming more severe and frequent worldwide, organisms are expected to reduce their aerobic performance. Here, we examined the metabolic and behavioural responses of embryos of a benthic elasmobranch fish, the little skate (Leucoraja erinacea), to acute progressive hypoxia, by measuring oxygen consumption and movement (tail-beat) rates inside the egg case. Oxygen consumption rates were not significantly affected by ambient oxygen levels until reaching 45% air saturation (critical oxygen saturation, S crit). Below S crit, oxygen consumption rates declined rapidly, revealing an oxygen conformity response. Surprisingly, we observed a decoupling of aerobic performance and activity, as tail-beat rates increased, rather than matching the declining metabolic rates, at air saturation levels of 55% and below. These results suggest a significantly divergent response at the physiological and behavioural levels. While skate embryos depressed their metabolic rates in response to progressive hypoxia, they increased water circulation inside the egg case, presumably to restore normoxic conditions, until activity ceased abruptly around 9.8% air saturation.

Guinea Pig as a Model to Study the Carotid Body Mediated Chronic Intermittent Hypoxia Effects.

PubMed

Docio, Inmaculada; Olea, Elena; Prieto-LLoret, Jesus; Gallego-Martin, Teresa; Obeso, Ana; Gomez-Niño, Angela; Rocher, Asuncion

2018-01-01

Clinical and experimental evidence indicates a positive correlation between chronic intermittent hypoxia (CIH), increased carotid body (CB) chemosensitivity, enhanced sympatho-respiratory coupling and arterial hypertension and cardiovascular disease. Several groups have reported that both the afferent and efferent arms of the CB chemo-reflex are enhanced in CIH animal models through the oscillatory CB activation by recurrent hypoxia/reoxygenation episodes. Accordingly, CB ablation or denervation results in the reduction of these effects. To date, no studies have determined the effects of CIH treatment in chemo-reflex sensitization in guinea pig, a rodent with a hypofunctional CB and lacking ventilatory responses to hypoxia. We hypothesized that the lack of CB hypoxia response in guinea pig would suppress chemo-reflex sensitization and thereby would attenuate or eliminate respiratory, sympathetic and cardiovascular effects of CIH treatment. The main purpose of this study was to assess if guinea pig CB undergoes overactivation by CIH and to correlate CIH effects on CB chemoreceptors with cardiovascular and respiratory responses to hypoxia. We measured CB secretory activity, ventilatory parameters, systemic arterial pressure and sympathetic activity, basal and in response to acute hypoxia in two groups of animals: control and 30 days CIH exposed male guinea pigs. Our results indicated that CIH guinea pig CB lacks activity elicited by acute hypoxia measured as catecholamine (CA) secretory response or intracellular calcium transients. Plethysmography data showed that only severe hypoxia (7% O 2 ) and hypercapnia (5% CO 2 ) induced a significant increased ventilatory response in CIH animals, together with higher oxygen consumption. Therefore, CIH exposure blunted hyperventilation to hypoxia and hypercapnia normalized to oxygen consumption. Increase in plasma CA and superior cervical ganglion CA content was found, implying a CIH induced sympathetic hyperactivity. CIH

In Vivo Imaging of Retinal Hypoxia in a Model of Oxygen-Induced Retinopathy.

PubMed

Uddin, Md Imam; Evans, Stephanie M; Craft, Jason R; Capozzi, Megan E; McCollum, Gary W; Yang, Rong; Marnett, Lawrence J; Uddin, Md Jashim; Jayagopal, Ashwath; Penn, John S

2016-08-05

Ischemia-induced hypoxia elicits retinal neovascularization and is a major component of several blinding retinopathies such as retinopathy of prematurity (ROP), diabetic retinopathy (DR) and retinal vein occlusion (RVO). Currently, noninvasive imaging techniques capable of detecting and monitoring retinal hypoxia in living systems do not exist. Such techniques would greatly clarify the role of hypoxia in experimental and human retinal neovascular pathogenesis. In this study, we developed and characterized HYPOX-4, a fluorescence-imaging probe capable of detecting retinal-hypoxia in living animals. HYPOX-4 dependent in vivo and ex vivo imaging of hypoxia was tested in a mouse model of oxygen-induced retinopathy (OIR). Predicted patterns of retinal hypoxia were imaged by HYPOX-4 dependent fluorescence activity in this animal model. In retinal cells and mouse retinal tissue, pimonidazole-adduct immunostaining confirmed the hypoxia selectivity of HYPOX-4. HYPOX-4 had no effect on retinal cell proliferation as indicated by BrdU assay and exhibited no acute toxicity in retinal tissue as indicated by TUNEL assay and electroretinography (ERG) analysis. Therefore, HYPOX-4 could potentially serve as the basis for in vivo fluorescence-based hypoxia-imaging techniques, providing a tool for investigators to understand the pathogenesis of ischemic retinopathies and for physicians to address unmet clinical needs.

In Vivo Imaging of Retinal Hypoxia in a Model of Oxygen-Induced Retinopathy

PubMed Central

Uddin, Md. Imam; Evans, Stephanie M.; Craft, Jason R.; Capozzi, Megan E.; McCollum, Gary W.; Yang, Rong; Marnett, Lawrence J.; Uddin, Md. Jashim; Jayagopal, Ashwath; Penn, John S.

2016-01-01

Ischemia-induced hypoxia elicits retinal neovascularization and is a major component of several blinding retinopathies such as retinopathy of prematurity (ROP), diabetic retinopathy (DR) and retinal vein occlusion (RVO). Currently, noninvasive imaging techniques capable of detecting and monitoring retinal hypoxia in living systems do not exist. Such techniques would greatly clarify the role of hypoxia in experimental and human retinal neovascular pathogenesis. In this study, we developed and characterized HYPOX-4, a fluorescence-imaging probe capable of detecting retinal-hypoxia in living animals. HYPOX-4 dependent in vivo and ex vivo imaging of hypoxia was tested in a mouse model of oxygen-induced retinopathy (OIR). Predicted patterns of retinal hypoxia were imaged by HYPOX-4 dependent fluorescence activity in this animal model. In retinal cells and mouse retinal tissue, pimonidazole-adduct immunostaining confirmed the hypoxia selectivity of HYPOX-4. HYPOX-4 had no effect on retinal cell proliferation as indicated by BrdU assay and exhibited no acute toxicity in retinal tissue as indicated by TUNEL assay and electroretinography (ERG) analysis. Therefore, HYPOX-4 could potentially serve as the basis for in vivo fluorescence-based hypoxia-imaging techniques, providing a tool for investigators to understand the pathogenesis of ischemic retinopathies and for physicians to address unmet clinical needs. PMID:27491345

Locomotory, ventilatory and metabolic responses of the subterranean Stenasellus virei (Crustacea, Isopoda) to severe hypoxia and subsequent recovery.

PubMed

Hervant, F; Mathieu, J; Messana, G

1997-02-01

The locomotory and ventilatory activities and the intermediary and energy metabolism modifications of the hypogean aquatic isopod crustacean Stenasellus virei were investigated in severe hypoxia (PO2 < 0.03 kPa) and subsequent recovery. The aims of this study were i) to determine why the subterranean species displayed a greater tolerance of hypoxia than numerous other epigean crustaceans, ii) to confirm previous results obtained with four hypogean and epigean crustaceans, iii) to compare the responses to severe hypoxia in hypogean amphipods and isopods, and iv) to better understand the ecological problems of the hypogean organisms survival in subterranean habitats. S. virei responded to experimental long-term, severe hypoxia with classical anaerobic metabolism mainly characterized by a decrease in adenosine triphosphate (ATP) and phosphagen, utilization of glycogen and glutamate, and accumulation of lactate and alanine. Lactate was also largely excreted by this organism, which is unusual for crustaceans in general. Compared to most other epigean crustaceans, the isopod S. virei showed high amounts of stored glycogen and arginine phosphate. These differences in glycogen and phosphagen stores, and the ability to reduce energetic expenditures linked to locomotion and ventilation, extended the survival of S. virei under experimental anaerobiosis. During recovery, the isopod S. virei showed a higher capacity for glyconeogenesis from lactate and a faster and total replenishment of ATP and arginine phosphate levels than epigean crustaceans. Data concerning responses to hypoxia and subsequent recovery in S. virei are similar to those previously obtained with two other hypogean amphipods, except that this isopod did not synthesize succinate in anaerobiosis.

Effect of acute hypoxia on cognition: A systematic review and meta-regression analysis.

PubMed

McMorris, Terry; Hale, Beverley J; Barwood, Martin; Costello, Joseph; Corbett, Jo

2017-03-01

A systematic meta-regression analysis of the effects of acute hypoxia on the performance of central executive and non-executive tasks, and the effects of the moderating variables, arterial partial pressure of oxygen (PaO 2 ) and hypobaric versus normobaric hypoxia, was undertaken. Studies were included if they were performed on healthy humans; within-subject design was used; data were reported giving the PaO 2 or that allowed the PaO 2 to be estimated (e.g. arterial oxygen saturation and/or altitude); and the duration of being in a hypoxic state prior to cognitive testing was ≤6days. Twenty-two experiments met the criteria for inclusion and demonstrated a moderate, negative mean effect size (g=-0.49, 95% CI -0.64 to -0.34, p<0.001). There were no significant differences between central executive and non-executive, perception/attention and short-term memory, tasks. Low (35-60mmHg) PaO 2 was the key predictor of cognitive performance (R 2 =0.45, p<0.001) and this was independent of whether the exposure was in hypobaric hypoxic or normobaric hypoxic conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

ERK1/2 and Akt phosphorylation were essential for MGF E peptide regulating cell morphology and mobility but not proangiogenic capacity of BMSCs under severe hypoxia.

PubMed

Sha, Yongqiang; Yang, Li; Lv, Yonggang

2018-04-01

Severe hypoxia inhibits the adhesion and mobility of bone marrow-derived mesenchymal stem cells (BMSCs) and limits their application in bone tissue engineering. In this study, CoCl 2 was used to simulate severe hypoxia and the effects of mechano-growth factor (MGF) E peptide on the morphology, adhesion, migration, and proangiogenic capacity of BMSCs under hypoxia were measured. It was demonstrated that severe hypoxia (500-μM CoCl 2 ) significantly caused cell contraction and reduced cell area, roundness, adhesion, and migration of BMSCs. RhoA and ROCK1 expression levels were upregulated by severe hypoxia, but p-RhoA and mobility-relevant protein (integrin β1, p-FAK and fibronectin) expression levels in BMSCs were inhibited. Fortunately, MGF E peptide could restore all abovementioned indexes except RhoA expression. MEK-ERK1/2 pathway was involved in MGF E peptide regulating cell morphological changes, mobility, and relevant proteins (except p-FAK). PI3K-Akt pathway was involved in MGF E peptide regulating cell area, mobility, and relevant proteins. Besides, severe hypoxia upregulated vascular endothelial growth factor α expression but was harmful for proangiogenic capacity of BMSCs. Our study suggested that MGF E peptide might be helpful for the clinical application of tissue engineering strategy in bone defect repair. Sever hypoxia impairs bone defect repair with bone marrow-derived mesenchymal stem cells (BMSCs). This study proved that mechano-growth factor E (MGF E) peptide could improve the severe hypoxia-induced cell contraction and decline of cell adhesion and migration of BMSCs. Besides, MGF E peptide weakened the effects of severe hypoxia on the cytoskeleton arrangement- and mobility-relevant protein expression levels in BMSCs. The underlying molecular mechanism was also verified. Finally, it was confirmed that MGF E peptide showed an adverse effect on the expression level of vascular endothelial growth factor α in BMSCs under severe hypoxia but could

Effects of acute hypoxia on the determination of anaerobic threshold using the heart rate-work rate relationships during incremental exercise tests.

PubMed

Ozcelik, O; Kelestimur, H

2004-01-01

Anaerobic threshold which describes the onset of systematic increase in blood lactate concentration is a widely used concept in clinical and sports medicine. A deflection point between heart rate-work rate has been introduced to determine the anaerobic threshold non-invasively. However, some researchers have consistently reported a heart rate deflection at higher work rates, while others have not. The present study was designed to investigate whether the heart rate deflection point accurately predicts the anaerobic threshold under the condition of acute hypoxia. Eight untrained males performed two incremental exercise tests using an electromagnetically braked cycle ergometer: one breathing room air and one breathing 12 % O2. The anaerobic threshold was estimated using the V-slope method and determined from the increase in blood lactate and the decrease in standard bicarbonate concentration. This threshold was also estimated by in the heart rate-work rate relationship. Not all subjects exhibited a heart rate deflection. Only two subjects in the control and four subjects in the hypoxia groups showed a heart rate deflection. Additionally, the heart rate deflection point overestimated the anaerobic threshold. In conclusion, the heart rate deflection point was not an accurate predictor of anaerobic threshold and acute hypoxia did not systematically affect the heart rate-work rate relationships.

Cerebrovascular and ventilatory responses to acute normobaric hypoxia in girls and women.

PubMed

Morris, Laura E; Flück, Daniela; Ainslie, Philip N; McManus, Ali M

2017-08-01

Physiological responses to hypoxia in children are incompletely understood. We aimed to characterize cerebrovascular and ventilatory responses to normobaric hypoxia in girls and women. Ten healthy girls (9.9 ± 1.7 years; mean ± SD; Tanner stage 1 and 2) and their mothers (43.9 ± 3.5 years) participated. Internal carotid (ICA) and vertebral artery (VA) velocity, diameter and flow (Duplex ultrasound) was recorded pre- and post-1 h of hypoxic exposure (FIO 2  = 0.126;~4000 m) in a normobaric chamber. Ventilation (V˙E) and respiratory drive ( V T / T I ) expressed as delta change from baseline (∆%), and end-tidal carbon-dioxide (P ET CO 2 ) were collected at baseline (BL) and 5, 30 and 60 min of hypoxia (5/30/60 HYP). Heart rate (HR) and oxygen saturation (SpO 2 ) were also collected at these time-points. SpO 2 declined similarly in girls (BL-97%; 60HYP-80%, P  <   0.05) and women (BL-97%; 60HYP-83%, P  <   0.05). Global cerebral blood flow (gCBF) increased in both girls (BL-687; 60HYP-912 mL·min -1 , P  <   0.05) and women (BL-472; 60HYP-651 mL·min -1 , P  <   0.01), though the ratio of ICA:VA (%) contribution to gCBF differed significantly (girls, 75:25%; women, 61:39%). The relative increase in V˙E peaked at 30HYP in both girls (27%, P  <   0.05) and women (19%, P  <   0.05), as did ∆% V T / T I (girls, 41%; women, 27%, P 's < 0.05). Tidal volume ( V T ) increased in both girls and women at 5HYP, remaining elevated above baseline in girls at 30 and 60 HYP, but declined back toward baseline in women. Girls elicit similar increases in gCBF and ventilatory parameters in response to acute hypoxia as women, though the pattern and contributions mediating these responses appear developmentally divergent. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Physiological effects of intermittent hypoxia.

PubMed

Powell, F L; Garcia, N

2000-01-01

Intermittent hypoxia (IH), or periodic exposure to hypoxia interrupted by return to normoxia or less hypoxic conditions, occurs in many circumstances. In high altitude mountaineering, IH is used to optimize acclimatization although laboratory studies have not generally revealed physiologically significant benefits. IH enhances athletic performance at sea level if blood oxygen capacity increases and the usual level of training is not decreased significantly. IH for high altitude workers who commute from low altitude homes is of considerable practical interest and the ideal commuting schedule for physical and mental performance is being studied. The effect of oxygen enrichment at altitude (i.e., intermittent normoxia on a background of chronic hypoxia) on human performance is under study also. Physiological mechanisms of IH, and specifically the differences between effects of IH and acute or chronic continuous hypoxia remains to be determined. Biomedical researchers are defining the molecular and cellular mechanisms for effects of hypoxia on the body in health and disease. A comparative approach may provide additional insight about the biological significance of these effects.

Long-term potentiation protects rat hippocampal slices from the effects of acute hypoxia.

PubMed

Youssef, F F; Addae, J I; McRae, A; Stone, T W

2001-07-13

of propentofylline, a known neuroprotective compound. We conclude that LTP causes an appreciable protection of hippocampal slices to various models of acute hypoxia. This phenomenon does not appear to involve desensitisation of AMPA receptors or mediation by NO, but may account for the recognised inverse relationship between educational attainment and the development of dementia.

Seven Passive 1-h Hypoxia Exposures Do Not Prevent AMS in Susceptible Individuals.

PubMed

Faulhaber, Martin; Pocecco, Elena; Gatterer, Hannes; Niedermeier, Martin; Huth, Maike; Dünnwald, Tobias; Menz, Verena; Bernardi, Luciano; Burtscher, Martin

2016-12-01

The present study evaluated the effects of a preacclimatization program comprising seven passive 1-h exposures to 4500-m normobaric hypoxia on the prevalence and severity of acute mountain sickness (AMS) during a subsequent exposure to real high altitude in persons susceptible to AMS. The project was designed as a randomized controlled trial including 32 healthy female and male participants with known susceptibility to AMS symptoms. After baseline measurements, participants were randomly assigned to the hypoxia or the control group to receive the preacclimatization program (seven passive 1-h exposures within 7 d to normobaric hypoxia or sham hypoxia). After completing preacclimatization, participants were transported (bus, cog railway) to real high altitude (3650 m, Mönchsjoch Hut, Switzerland) and stayed there for 45 h (two nights). Symptoms of AMS and physiological responses were determined repeatedly. AMS incidence and severity did not significantly differ between groups during the high-altitude exposure. In total, 59% of the hypoxia and 67% of the control group suffered from AMS at one or more time points during the high-altitude exposure. Hypoxic and hypercapnic ventilatory responses were not affected by the preacclimatization program. Resting ventilation at high altitude tended to be higher (P = 0.06) in the hypoxia group compared with the control group. No significant between-group differences were detected for heart rate variability, arterial oxygen saturation, and hematological and ventilatory parameters during the high-altitude exposure. Preacclimatization using seven passive 1-h exposures to normobaric hypoxia corresponding to 4500 m did not prevent AMS development during a subsequent high-altitude exposure in AMS-susceptible persons.

[MORPHOLOGICAL DIFFERENCES BETWEEN THE EFFECTS OF VARIOUS MODES OF PRECONDITIONING AIMED AT CORRECTING THE DAMAGE TO THE HIPPOCAMPAL NEURONS BY SEVERE HYPOBARIC HYPOXIA].

PubMed

Samoilov, M O; Churilova, A V; Glushchenko, T S

2015-01-01

In 5 groups of rats (6 animals in each), the changes of neurons in hippocampal fields CA1 and CA4 were studied 7 days after severe hypobaric hypoxia (180 mm Hg, for 3 h) preceded by various numbers (1, 3 and 6) of sessions of preconditioning (PC) by mild hypobaric hypoxia (360 mm Hg, for 2 h, 24 h prior to severe hypoxia). It was found that a single session of PC did not prevent the damage to the structure of neurons and their death after exposure to severe hypoxia. Meanwhile, 6, and especially 3 sessions of PC induced protective mechanisms of neuronal damage prevention. In rats after 6 sessions of PC, unlike those exposed to 3 sessions, mild chromatolysis of hippocampal neurons was demonstrated. This could result from prolonged hypermetabolic activity of neurons and indicate their functional overloading.

The response of human skeletal muscle tissue to hypoxia.

PubMed

Lundby, Carsten; Calbet, Jose A L; Robach, Paul

2009-11-01

Hypoxia refers to environmental or clinical settings that potentially threaten tissue oxygen homeostasis. One unique aspect of skeletal muscle is that, in addition to hypoxia, oxygen balance in this tissue may be further compromised when exercise is superimposed on hypoxia. This review focuses on the cellular and molecular responses of human skeletal muscle to acute and chronic hypoxia, with emphasis on physical exercise and training. Based on published work, it is suggested that hypoxia does not appear to promote angiogenesis or to greatly alter oxidative enzymes in skeletal muscle at rest. Although the HIF-1 pathway in skeletal muscle is still poorly documented, emerging evidence suggests that muscle HIF-1 signaling is only activated to a minor degree by hypoxia. On the other hand, combining hypoxia with exercise appears to improve some aspects of muscle O(2) transport and/or metabolism.

Brain stem NO modulates ventilatory acclimatization to hypoxia in mice.

PubMed

El Hasnaoui-Saadani, R; Alayza, R Cardenas; Launay, T; Pichon, A; Quidu, P; Beaudry, M; Léon-Velarde, F; Richalet, J P; Duvallet, A; Favret, F

2007-11-01

The objective of our study was to assess the role of neuronal nitric oxide synthase (nNOS) in the ventilatory acclimatization to hypoxia. We measured the ventilation in acclimatized Bl6/CBA mice breathing 21% and 8% oxygen, used a nNOS inhibitor, and assessed the expression of N-methyl-d-aspartate (NMDA) glutamate receptor and nNOS (mRNA and protein). Two groups of Bl6/CBA mice (n = 60) were exposed during 2 wk either to hypoxia [barometric pressure (PB) = 420 mmHg] or normoxia (PB = 760 mmHg). At the end of exposure the medulla was removed to measure the concentration of nitric oxide (NO) metabolites, the expression of NMDA-NR1 receptor, and nNOS by real-time RT-PCR and Western blot. We also measured the ventilatory response [fraction of inspired O(2) (Fi(O(2))) = 0.21 and 0.08] before and after S-methyl-l-thiocitrulline treatment (SMTC, nNOS inhibitor, 10 mg/kg ip). Chronic hypoxia caused an increase in ventilation that was reduced after SMTC treatment mainly through a decrease in tidal volume (Vt) in normoxia and in acute hypoxia. However, the difference observed in the magnitude of acute hypoxic ventilatory response [minute ventilation (Ve) 8% - Ve 21%] in acclimatized mice was not different. Acclimatization to hypoxia induced a rise in NMDA receptor as well as in nNOS and NO production. In conclusion, our study provides evidence that activation of nNOS is involved in the ventilatory acclimatization to hypoxia in mice but not in the hypoxic ventilatory response (HVR) while the increased expression of NMDA receptor expression in the medulla of chronically hypoxic mice plays a role in acute HVR. These results are therefore consistent with central nervous system plasticity, partially involved in ventilatory acclimatization to hypoxia through nNOS.

Effect of Acute Hypoxia on Post-Exercise Parasympathetic Reactivation in Healthy Men

PubMed Central

Al Haddad, Hani; Mendez-Villanueva, Alberto; Bourdon, Pitre C.; Buchheit, Martin

2012-01-01

In this study we assessed the effect of acute hypoxia on post-exercise parasympathetic reactivation inferred from heart rate (HR) recovery (HRR) and HR variability (HRV) indices. Ten healthy males participated in this study. Following 10 min of seated rest, participants performed 5 min of submaximal running at the speed associated with the first ventilatory threshold (Sub) followed by a 20-s all-out supramaximal sprint (Supra). Both Sub and Supra runs were immediately followed by 15 min of seated passive recovery. The resting and exercise sequence were performed in both normoxia (N) and normobaric hypoxia (H; FiO2 = 15.4%). HRR indices (e.g., heart beats recovered in the first minute after exercise cessation, HRR60s) and vagal-related HRV indices [i.e., natural logarithm of the square root of the mean of the sum of the squared differences between adjacent normal R–R intervals (Ln rMSSD)] were calculated for both conditions. Difference in the changes between N and H for all HR-derived indices were also calculated for both Sub and Supra. HRR60s was greater in N compared with H following Sub only (60 ± 14 vs. 52 ± 19 beats min−1, P = 0.016). Ln rMSSD was greater in N compared with H (post Sub: 3.60 ± 0.45 vs. 3.28 ± 0.44 ms in N and H, respectively, and post Supra: 2.66 ± 0.54 vs. 2.65 ± 0.63 ms, main condition effect P = 0.02). When comparing the difference in the changes, hypoxia decreased HRR60s (−14.3% ± 17.2 vs. 5.2% ± 19.3; following Sub and Supra, respectively; P = 0.03) and Ln rMSSD (−8.6% ± 7.0 vs. 2.0% ± 13.3, following Sub and Supra, respectively; P = 0.08, Cohen’s effect size = 0.62) more following Sub than Supra. While hypoxia may delay parasympathetic reactivation following submaximal exercise, its effect is not apparent following supramaximal exercise. This may suggest that the effect of blood O2 partial pressure on parasympathetic reactivation is limited

Acute Normobaric Hypoxia Increases Post-exercise Lipid Oxidation in Healthy Males.

PubMed

Kelly, Liam P; Basset, Fabien A

2017-01-01

The primary objective of the current study was to determine the effect of moderate normobaric hypoxia exposure during constant load cycling on post-exercise energy metabolism recorded in normoxia. Indirect calorimetry was used to examine whole body substrate oxidation before, during, 40-60 min post, and 22 h after performing 60 min of cycling exercise at two different fractions of inspired oxygen (F I O 2 ): (i) F I O 2 = 0.2091 (normoxia) and (ii) F I O 2 = 0.15 (hypoxia). Seven active healthy male participants (26 ± 4 years of age) completed both experimental trials in randomized order with a 7-day washout period to avoid carryover effects between conditions. Resting energy expenditure was initially elevated following cycling exercise in normoxia and hypoxia (Δ 0.14 ± 0.05, kcal min -1 , p = 0.037; Δ 0.19 ± 0.03 kcal min -1 , p < 0.001, respectively), but returned to baseline levels the next morning in both conditions. Although, the same absolute workload was used in both environmental conditions (157 ± 10 W), a shift in resting substrate oxidation occurred after exercise performed in hypoxia while post-exercise measurements were similar to baseline after cycling exercise in normoxia. The additional metabolic stress of hypoxia exposure was sufficient to increase the rate of lipid oxidation (Δ 42 ± 11 mg min -1 , p = 0.019) and tended to suppress carbohydrate oxidation (Δ -55 ± 26 mg min -1 , p = 0.076) 40-60 min post-exercise. This shift in substrate oxidation persisted the next morning, where lipid oxidation remained elevated (Δ 9 ± 3 mg min -1 , p = 0.0357) and carbohydrate oxidation was suppressed (Δ -22 ± 6 mg min -1 , p = 0.019). In conclusion, prior exercise performed under moderate normobaric hypoxia alters post-exercise energy metabolism. This is an important consideration when evaluating the metabolic consequences of hypoxia exposure during prolonged exercise, and future studies should evaluate its role in the beneficial effects of

Coenzyme Q10 protects neural stem cells against hypoxia by enhancing survival signals.

PubMed

Park, Jinse; Park, Hyun-Hee; Choi, Hojin; Kim, Young Seo; Yu, Hyun-Jeung; Lee, Kyu-Yong; Lee, Young Joo; Kim, Seung Hyun; Koh, Seong-Ho

2012-10-10

Recanalization and secondary prevention are the main therapeutic strategies for acute ischemic stroke. Neuroprotective therapies have also been investigated despite unsuccessful clinical results. Coenzyme Q10 (CoQ10), which is an essential cofactor for electron transport in mitochondria, is known to have an antioxidant effect. We investigated the protective effects of CoQ10 against hypoxia in neural stem cells (NSCs). We measured cell viability and levels of intracellular signaling proteins after treatment with several concentrations of CoQ10 under hypoxia-reperfusion. CoQ10 protected NSCs against hypoxia-reperfusion in a concentration-dependent manner by reducing growth inhibition and inhibiting free radical formation. It increased the expression of a number of survival-related proteins such as phosphorylated Akt (pAkt), phosphorylated glycogen synthase kinase 3-β (pGSK3-β), and B-cell lymphoma 2 (Bcl-2) in NSCs injured by hypoxia-reperfusion and reduced the expression of death-related proteins such as cleaved caspase-3. We conclude that CoQ10 has effects against hypoxia-reperfusion induced damage to NSCs by enhancing survival signals and decreasing death signals. Copyright © 2012 Elsevier B.V. All rights reserved.

[CLINICAL AND LABORATORY FEATURES OF ACUTE PANCREATITIS BILIARY ETIOLOGY COURSE IN PATIENTS WITH DIABETES MELLITUS].

PubMed

Godlevskiy, A I; Savolyuk, S I; Tomashevskiy, Ya V

2015-07-01

The dynamics of cytopathic hypoxia markers in patients with acute pancreatitis (AP) biliary etiology (BE), depending on the presence of concomitant diabetes mellitus (DM), which is an independent factor of premorbid severity increase and increase in the degree of operational and anesthetic risk. Markers of cytopathic hypoxia use as methods for early diagnosis of acute liver failure (ALF) and monitoring the effectiveness of its correction promising. In terms of cytopathic hypoxia may be at the stage of laboratory diagnostics to distinguish between destructive and non-destructive forms APBE, and for markers of endothelial dysfunction--destructive forms on the area and depth of destruction of the pancreas.

Acute kidney injury and cardiovascular outcomes in acute severe hypertension.

PubMed

Szczech, Lynda A; Granger, Christopher B; Dasta, Joseph F; Amin, Alpesh; Peacock, W Frank; McCullough, Peter A; Devlin, John W; Weir, Matthew R; Katz, Jason N; Anderson, Frederick A; Wyman, Allison; Varon, Joseph

2010-05-25

Little is known about the association of kidney dysfunction and outcome in acute severe hypertension. This study aimed to measure the association between baseline chronic kidney disease (estimated glomerular filtration rate), acute kidney injury (AKI, decrease in estimated glomerular filtration rate > or =25% from baseline) and outcome in patients hospitalized with acute severe hypertension. The Studying the Treatment of Acute Hypertension (STAT) registry enrolled patients with acute severe hypertension, defined as > or =1 blood pressure measurement >180 mm Hg systolic and/or >110 mm Hg diastolic and treated with intravenous antihypertensive therapy. Data were compared across groups categorized by admission estimated glomerular filtration rate and AKI during admission. On admission, 79% of the cohort (n=1566) had at least mild chronic kidney disease (estimated glomerular filtration rate <60 mL/min in 46%, <30 mL/min in 22%). Chronic kidney disease patients were more likely to develop heart failure (P<0.0001), non-ST-elevation myocardial infarction (P=0.003), and AKI (P<0.007). AKI patients were at greater risk of heart failure and cardiac arrest (P< or =0.0001 for both). Subjects with AKI experienced higher mortality at 90 days (P=0.003). Any acute loss of estimated glomerular filtration rate during hospitalization was independently associated with an increased risk of death (odds ratio, 1.05; P=0.03 per 10-mL/min decline). Other independent predictors of mortality included increasing age (P<0.0001), male gender (P=0.016), white versus black race (P=0.003), and worse baseline kidney function (P=0.003). Chronic kidney disease is a common comorbidity among patients admitted with acute severe hypertension, and AKI is a frequent form of acute target organ dysfunction, particularly in those with baseline chronic kidney disease. Any degree of AKI is associated with a greater risk of morbidity and mortality.

Hypoxia, hypoxia-inducible factors and fibrogenesis in chronic liver diseases.

PubMed

Cannito, Stefania; Paternostro, Claudia; Busletta, Chiara; Bocca, Claudia; Colombatto, Sebastiano; Miglietta, Antonella; Novo, Erica; Parola, Maurizio

2014-01-01

Fibrogenic progression of chronic liver diseases (CLDs) towards the end-point of cirrhosis is currently regarded, whatever the aetiology, as a dynamic and highly integrated cellular response to chronic liver injury. Liver fibrogenesis (i.e., the process) is sustained by hepatic populations of highly proliferative, pro-fibrogenic and contractile myofibroblast-like cells (MFs) that mainly originate from hepatic stellate cells (HSC) or, to a less extent, from portal fibroblasts or bone marrow-derived cells. As is well known, liver fibrosis (i.e., the result) is accompanied by perpetuation of liver injury, chronic hepatitis and persisting activation of tissue repair mechanisms, leading eventually to excess deposition of extracellular matrix (ECM) components. In this scenario, hypoxic areas represent a very common and major feature of fibrotic and cirrhotic liver during the progression of CLDs. Cells exposed to hypoxia respond by means of heterodimeric hypoxia-inducible factors (HIFs) that translocate into the nucleus and binds to a specific core sequence defined hypoxia-responsive element (HRE), present in the promoter on several genes which are considered as hypoxia-regulated target genes. HIFs transcription factors can activate a complex genetic program designed to sustain several changes necessary to efficiently counteract the decrease in oxygen tension. Accordingly, hypoxia, through up-regulation of angiogenesis, is currently believed to significantly contribute to fibrogenic progression of CLDs, mostly by affecting the pro-fibrogenic and pro-angiogenic behaviour of hepatic MFs. In addition, experimental and clinical evidence generated in the last decade also indicates that angiogenesis and fibrogenesis in CLDs may also be sustained by HIF-dependent but hypoxia-independent mediators.

The role of hypoxia and HIF1α in the regulation of STAR-mediated steroidogenesis in granulosa cells.

PubMed

Kowalewski, Mariusz Pawel; Gram, Aykut; Boos, Alois

2015-02-05

The adaptive responses to hypoxia are mediated by hypoxia-inducible factor 1 alpha (HIF1α). Its role, however, in regulating steroidogenesis remains poorly understood. We examined the role of hypoxia and HIF1α in regulating steroid acute regulatory protein (STAR) expression and steroidogenesis in immortalized (KK1) mouse granulosa cells under progressively lowering O2 concentrations (20%, 15%, 10%, 5%, 1%). Basal and dbcAMP-stimulated progesterone synthesis was decreased under severe hypoxia (1% and 5% O2). The partial hypoxia revealed opposing effects, with a significant increase in steroidogenic response at 10% O2 in dbcAMP-treated cells: Star-promoter activity, mRNA and protein expression were increased. The hypoxia-stimulated STAR expression was PKA-dependent. Binding of HIF1α to the Star-promoter was potentiated under partial hypoxia. Inhibition of the transcriptional activity or expression of HIF1α suppressed STAR-expression. HIF1α appears to be a positive regulator of basal and stimulated STAR-expression, which under partial hypoxia is capable of increasing the steroidogenic capacity of granulosa cells. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Differential HIF and NOS responses to acute anemia: defining organ-specific hemoglobin thresholds for tissue hypoxia.

PubMed

Tsui, Albert K Y; Marsden, Philip A; Mazer, C David; Sled, John G; Lee, Keith M; Henkelman, R Mark; Cahill, Lindsay S; Zhou, Yu-Qing; Chan, Neville; Liu, Elaine; Hare, Gregory M T

2014-07-01

Tissue hypoxia likely contributes to anemia-induced organ injury and mortality. Severe anemia activates hypoxia-inducible factor (HIF) signaling by hypoxic- and neuronal nitric oxide (NO) synthase- (nNOS) dependent mechanisms. However, organ-specific hemoglobin (Hb) thresholds for increased HIF expression have not been defined. To assess organ-specific Hb thresholds for tissue hypoxia, HIF-α (oxygen-dependent degradation domain, ODD) luciferase mice were hemodiluted to mild, moderate, or severe anemia corresponding to Hb levels of 90, 70, and 50 g/l, respectively. HIF luciferase reporter activity, HIF protein, and HIF-dependent RNA levels were assessed. In the brain, HIF-1α was paradoxically decreased at mild anemia, returned to baseline at moderate anemia, and then increased at severe anemia. Brain HIF-2α remained unchanged at all Hb levels. Both kidney HIF-1α and HIF-2α increased earlier (Hb ∼70-90 g/l) in response to anemia. Liver also exhibited an early HIF-α response. Carotid blood flow was increased early (Hb ∼70, g/l), but renal blood flow remained relatively constant, only increased at Hb of 50 g/l. Anemia increased nNOS (brain and kidney) and endothelia NOS (eNOS) (kidney) levels. Whereas anemia-induced increases in brain HIFα were nNOS-dependent, our current data demonstrate that increased renal HIFα was nNOS independent. HIF-dependent RNA levels increased linearly (∼10-fold) in the brain. However, renal HIF-RNA responses (MCT4, EPO) increased exponentially (∼100-fold). Plasma EPO levels increased near Hb threshold of 90 g/l, suggesting that the EPO response is sensitive. Collectively, these observations suggest that each organ expresses a different threshold for cellular HIF/NOS hypoxia responses. This knowledge may help define the mechanism(s) by which the brain and kidney maintain oxygen homeostasis during anemia. Copyright © 2014 the American Physiological Society.

Oxidative stress response to acute hypobaric hypoxia and its association with indirect measurement of increased intracranial pressure: a field study

PubMed Central

Strapazzon, Giacomo; Malacrida, Sandro; Vezzoli, Alessandra; Dal Cappello, Tomas; Falla, Marika; Lochner, Piergiorgio; Moretti, Sarah; Procter, Emily; Brugger, Hermann; Mrakic-Sposta, Simona

2016-01-01

High altitude is the most intriguing natural laboratory to study human physiological response to hypoxic conditions. In this study, we investigated changes in reactive oxygen species (ROS) and oxidative stress biomarkers during exposure to hypobaric hypoxia in 16 lowlanders. Moreover, we looked at the potential relationship between ROS related cellular damage and optic nerve sheath diameter (ONSD) as an indirect measurement of intracranial pressure. Baseline measurement of clinical signs and symptoms, biological samples and ultrasonography were assessed at 262 m and after passive ascent to 3830 m (9, 24 and 72 h). After 24 h the imbalance between ROS production (+141%) and scavenging (−41%) reflected an increase in oxidative stress related damage of 50–85%. ONSD concurrently increased, but regression analysis did not infer a causal relationship between oxidative stress biomarkers and changes in ONSD. These results provide new insight regarding ROS homeostasis and potential pathophysiological mechanisms of acute exposure to hypobaric hypoxia, plus other disease states associated with oxidative-stress damage as a result of tissue hypoxia. PMID:27579527

Circadian and Sex Differences After Acute High-Altitude Exposure: Are Early Acclimation Responses Improved by Blue Light?

PubMed

Silva-Urra, Juan A; Núñez-Espinosa, Cristian A; Niño-Mendez, Oscar A; Gaitán-Peñas, Héctor; Altavilla, Cesare; Toro-Salinas, Andrés; Torrella, Joan R; Pagès, Teresa; Javierre, Casimiro F; Behn, Claus; Viscor, Ginés

2015-12-01

The possible effects of blue light during acute hypoxia and the circadian rhythm on several physiological and cognitive parameters were studied. Fifty-seven volunteers were randomly assigned to 2 groups: nocturnal (2200-0230 hours) or diurnal (0900-1330 hours) and exposed to acute hypoxia (4000 m simulated altitude) in a hypobaric chamber. The participants were illuminated by blue LEDs or common artificial light on 2 different days. During each session, arterial oxygen saturation (Spo2), blood pressure, heart rate variability, and cognitive parameters were measured at sea level, after reaching the simulated altitude of 4000 m, and after 3 hours at this altitude. The circadian rhythm caused significant differences in blood pressure and heart rate variability. A 4% to 9% decrease in waking nocturnal Spo2 under acute hypoxia was observed. Acute hypoxia also induced a significant reduction (4%-8%) in systolic pressure, slightly more marked (up to 13%) under blue lighting. Women had significantly increased systolic (4%) and diastolic (12%) pressures under acute hypoxia at night compared with daytime pressure; this was not observed in men. Some tendencies toward better cognitive performance (d2 attention test) were seen under blue illumination, although when considered together with physiological parameters and reaction time, there was no conclusive favorable effect of blue light on cognitive fatigue suppression after 3 hours of acute hypobaric hypoxia. It remains to be seen whether longer exposure to blue light under hypobaric hypoxic conditions would induce favorable effects against fatigue. Copyright © 2015 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

Influence of acute moderate hypoxia on time to exhaustion at vVO2max in unacclimatized runners.

PubMed

Billat, V L; Lepretre, P M; Heubert, R P; Koralsztein, J P; Gazeau, F P

2003-01-01

Eight unacclimatized long-distance runners performed, on a level treadmill, an incremental test to determine the maximal oxygen uptake (VO2max) and the minimal velocity eliciting VO2max (vVO2max) in normoxia (N) and acute moderate hypoxia (H) corresponding to an altitude of 2,400 m (PIO 2 of 109 mmHg). Afterwards, on separate days, they performed two all-out constant velocity runs at vO2 max in a random order (one in N and the other in H). The decrease in VO2max between N and H showed a great degree of variability amongst subjects as VO2max decreased by 8.9 +/- 4 ml x min(-1) x kg)(-1) in H vs. N conditions (-15.3 +/- 6.3 % with a range from -7.9 % to -23.8 %). This decrease in VO2max was proportional to the value of VO2max (VO2max vs. delta VO2max N-H, r = 0.75, p = 0.03). The time run at vVO2max was not affected by hypoxia (483 +/- 122 vs. 506 +/- 148 s, in N and H, respectively, p = 0.37). However, the greater the decrease in vVO2max during hypoxia, the greater the runners increased their time to exhaustion at vVO2max (vVO2max N-H vs. tlim @vVO2max N-H, r = -0.75, p = 0.03). In conclusion, this study showed that there was a positive association between the extent of decrease in vVO2max, and the increase in run time at vVO2max in hypoxia.

Postictal behavioural impairments are due to a severe prolonged hypoperfusion/hypoxia event that is COX-2 dependent

PubMed Central

Farrell, Jordan S; Gaxiola-Valdez, Ismael; Wolff, Marshal D; David, Laurence S; Dika, Haruna I; Geeraert, Bryce L; Rachel Wang, X; Singh, Shaily; Spanswick, Simon C; Dunn, Jeff F; Antle, Michael C; Federico, Paolo; Teskey, G Campbell

2016-01-01

Seizures are often followed by sensory, cognitive or motor impairments during the postictal phase that show striking similarity to transient hypoxic/ischemic attacks. Here we show that seizures result in a severe hypoxic attack confined to the postictal period. We measured brain oxygenation in localized areas from freely-moving rodents and discovered a severe hypoxic event (pO2 < 10 mmHg) after the termination of seizures. This event lasted over an hour, is mediated by hypoperfusion, generalizes to people with epilepsy, and is attenuated by inhibiting cyclooxygenase-2 or L-type calcium channels. Using inhibitors of these targets we separated the seizure from the resulting severe hypoxia and show that structure specific postictal memory and behavioral impairments are the consequence of this severe hypoperfusion/hypoxic event. Thus, epilepsy is much more than a disease hallmarked by seizures, since the occurrence of postictal hypoperfusion/hypoxia results in a separate set of neurological consequences that are currently not being treated and are preventable. DOI: http://dx.doi.org/10.7554/eLife.19352.001 PMID:27874832

Determinants of ventilation and pulmonary artery pressure during early acclimatization to hypoxia in humans

PubMed Central

Fatemian, Marzieh; Herigstad, Mari; Croft, Quentin P. P.; Formenti, Federico; Cardenas, Rosa; Wheeler, Carly; Smith, Thomas G.; Friedmannova, Maria; Dorrington, Keith L.

2015-01-01

Key points Lung ventilation and pulmonary artery pressure rise progressively in response to 8 h of hypoxia, changes described as ‘acclimatization to hypoxia’. Acclimatization responses differ markedly between humans for unknown reasons.We explored whether the magnitudes of the ventilatory and vascular responses were related, and whether the degree of acclimatization could be predicted by acute measurements of ventilatory and vascular sensitivities.In 80 healthy human volunteers measurements of acclimatization were made before, during, and after a sustained exposure to 8 h of isocapnic hypoxia.No correlation was found between measures of ventilatory and pulmonary vascular acclimatization.The ventilatory chemoreflex sensitivities to acute hypoxia and hypercapnia all increased in proportion to their pre‐acclimatization values following 8 h of hypoxia. The peripheral (rapid) chemoreflex sensitivity to CO2, measured before sustained hypoxia against a background of hyperoxia, was a modest predictor of ventilatory acclimatization to hypoxia. This finding has relevance to predicting human acclimatization to the hypoxia of altitude. Abstract Pulmonary ventilation and pulmonary arterial pressure both rise progressively during the first few hours of human acclimatization to hypoxia. These responses are highly variable between individuals, but the origin of this variability is unknown. Here, we sought to determine whether the variabilities between different measures of response to sustained hypoxia were related, which would suggest a common source of variability. Eighty volunteers individually underwent an 8‐h isocapnic exposure to hypoxia (end‐tidal P O2=55 Torr) in a purpose‐built chamber. Measurements of ventilation and pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography were made during the exposure. Before and after the exposure, measurements were made of the ventilatory sensitivities to acute isocapnic hypoxia (GpO2) and

Severe hypoxia affects exercise performance independently of afferent feedback and peripheral fatigue.

PubMed

Millet, Guillaume Y; Muthalib, Makii; Jubeau, Marc; Laursen, Paul B; Nosaka, Kazunori

2012-04-01

To test the hypothesis that hypoxia centrally affects performance independently of afferent feedback and peripheral fatigue, we conducted two experiments under complete vascular occlusion of the exercising muscle under different systemic O(2) environmental conditions. In experiment 1, 12 subjects performed repeated submaximal isometric contractions of the elbow flexor to exhaustion (RCTE) with inspired O(2) fraction fixed at 9% (severe hypoxia, SevHyp), 14% (moderate hypoxia, ModHyp), 21% (normoxia, Norm), or 30% (hyperoxia, Hyper). The number of contractions (performance), muscle (biceps brachii), and prefrontal near-infrared spectroscopy (NIRS) parameters and high-frequency paired-pulse (PS100) evoked responses to electrical muscle stimulation were monitored. In experiment 2, 10 subjects performed another RCTE in SevHyp and Norm conditions in which the number of contractions, biceps brachii electromyography responses to electrical nerve stimulation (M wave), and transcranial magnetic stimulation responses (motor-evoked potentials, MEP, and cortical silent period, CSP) were recorded. Performance during RCTE was significantly reduced by 10-15% in SevHyp (arterial O(2) saturation, SpO(2) = ∼75%) compared with ModHyp (SpO(2) = ∼90%) or Norm/Hyper (SpO(2) > 97%). Performance reduction in SevHyp occurred despite similar 1) metabolic (muscle NIRS parameters) and functional (changes in PS100 and M wave) muscle states and 2) MEP and CSP responses, suggesting comparable corticospinal excitability and spinal and cortical inhibition between SevHyp and Norm. It is concluded that, in SevHyp, performance and central drive can be altered independently of afferent feedback and peripheral fatigue. It is concluded that submaximal performance in SevHyp is partly reduced by a mechanism related directly to brain oxygenation.

Association Between the Severity of Nocturnal Hypoxia in Obstructive Sleep Apnea and Non-Alcoholic Fatty Liver Damage

PubMed Central

Cakmak, Erol; Duksal, Faysal; Altinkaya, Engin; Acibucu, Fettah; Dogan, Omer Tamer; Yonem, Ozlem; Yilmaz, Abdulkerim

2015-01-01

Background: Obstructive sleep apnea (OSA) is a major disease that can cause significant mortality and morbidity. Chronic intermittent hypoxia is a potential causal factor in the progression from fatty liver to nonalcoholic steatohepatitis. Objectives: This study evaluated the association between the degree of liver steatosis and severity of nocturnal hypoxia. Patients and Methods: In this study, between December 2011 and December 2013, patients with ultrasound-diagnosed NAFLD evaluated by standart polysomnography were subsequentally recorded. Patients with alcohol use, viral hepatitis and other chronic liver diseases were excluded. We analyzed polysomnographic parameters, steatosis level and severity of obstructive sleep apnea (OSA) in consideration of body mass index (BMI), biochemical tests and ultrasonographic liver data of 137 subjects. Patients with sleep apnea and AHI scores of < 5, 5 - 14, 15 - 29 and ≥30 are categorized as control, mild, moderate and severe, respectively. Results: One hundred and thirty-seven patients (76 women, 61 men) with a mean age of 55.75 ± 10.13 years who underwent polysomnography were included in the study. Of 118 patients diagnosed with OSA, 19 (16.1%) had mild OSA, 39 (33.1%) moderate OSA and 60 (50.8%) severe OSA. Nineteen cases formed the control group. Apnea/hypopnea index and oxygen desaturation index (ODI) values were significantly higher in moderate and severe non-alcoholic fatty liver disease (NAFLD) compared to the non-NAFLD group. Mean nocturnal SpO2 values were significantly lower in mild NAFLD and severe NAFLD compared to the non-NAFLD group. Lowest O2 saturation (LaSO2) was found low in mild, moderate and severe NAFLD compared to the non-NAFLD group in a statistically significant manner. Conclusions: We assessed polysomnographic parameters of AHI, ODI, LaSO2 and mean nocturnal SpO2 levels, which are especially important in the association between NAFLD and OSAS. We think that it is necessary to be attentive

Severely deranged vital signs as triggers for acute treatment modifications on an intensive care unit in a low-income country.

PubMed

Schell, Carl Otto; Castegren, Markus; Lugazia, Edwin; Blixt, Jonas; Mulungu, Moses; Konrad, David; Baker, Tim

2015-07-25

Critical care saves lives of the young with reversible disease. Little is known about critical care services in low-income countries. In a setting with a shortage of doctors the actions of the nurse bedside are likely to have a major impact on the outcome of critically ill patients with rapidly changing physiology. Identification of severely deranged vital signs and subsequent treatment modifications are the basis of modern routines in critical care, for example goal directed therapy and rapid response teams. This study assesses how often severely deranged vital signs trigger an acute treatment modification on an Intensive Care Unit (ICU) in Tanzania. A medical records based, observational study. Vital signs (conscious level, respiratory rate, oxygen saturation, heart rate and systolic blood pressure) were collected as repeated point prevalences three times per day in a 1-month period for all adult patients on the ICU. Severely deranged vital signs were identified and treatment modifications within 1 h were noted. Of 615 vital signs studied, 126 (18%) were severely deranged. An acute treatment modification was in total indicated in 53 situations and was carried out three times (6%) (2/32 for hypotension, 0/8 for tachypnoea, 1/6 for tachycardia, 0/4 for unconsciousness and 0/3 for hypoxia). This study suggests that severely deranged vital signs are common and infrequently lead to acute treatment modifications on an ICU in a low-income country. There may be potential to improve outcome if nurses are guided to administer acute treatment modifications by using a vital sign directed approach. A prospective study of a vital sign directed therapy protocol is underway.

[Content of 2,3-diphosphoglycerate in rat erythrocytes with hypoxia and administration of vitamin D preparations].

PubMed

Epshteĭn, M M; Kakhnover, N B; Pristushok, A M

1979-01-01

With acute hemic hypoxia a rise in the content of 2,3-diphosphoglycerate in the rat erythrocytes is rather pronounced. Under conditions of acute hypoxia (hyprobaric) hypoxia, with a less gravity of hypoxic affection the content is considerabley higher than in normalcy. Daily administration of the vitamin D preparations significant doses to animals causes a gradual rise in the level of 2,3-diphosphoglycerate in erythrocytes. The rise is more intense under the effect of vitamin D2 alchol solution than with administration of videin, a protein complex of vitamin D3.

Antibiotic prophylaxia in patients with severe acute pancreatitis.

PubMed

Zhou, Yan-Ming; Xue, Zuo-Liang; Li, Yu-Min; Zhu, You-Quan; Cao, Nong

2005-02-01

The prophylactic use of antibiotics in patients with severe acute pancreatitis remains contentious. This study was undertaken to review the current studies on antibiotic prophylaxis in patients with severe acute pancreatitis. All papers found by a Medline search were relevant to human trials of antibiotic prophylaxis in patients with severe acute pancreatitis. In the 1970s, three small randomized studies of prophylactic ampicillin in the treatment of acute pancreatitis showed no effect on mortality or morbidity, but the inclusion of patients at low risk for infection and the use of an ineffective antibiotic were insufficient to detect any differences. From 1993 to 2001, eight prospective clinical trials of antibiotic prophylaxis were conducted in patients with severe acute pancreatitis (SAP). Seven of the 8 trials showed significant effect of the prophylaxis in prevention of pancreatic infections, and one showed significant improvement of clinical course documented by the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. Only two trials did demonstrate the significance of the prophylaxis in lowering the mortality rate. Despite variations in drug agents, study size and patient selection, duration of treatment, and methodology (None of the studies was double-blinded), a meta-analysis showed the positive effect of antibiotics in reducing the mortality. We suggested that antibiotic prophylaxis with proven efficacy in necrotic pancreatic tissues should be given to all patients with acute necrotizing pancreatitis. In recent years, however, the first double-blind, placebo-controlled multicenter study from Germany detected no benefit of antibiotic prophylaxis with respect to the risk of developing infected pancreatic necrosis. Prophylactic antibiotics for severe acute pancreatitis is still a matter of discussion and further studies are required to provide adequate data to answer many questions and to define the role of antibiotic prophylaxis in patients

Acclimatization to long-term hypoxia: gene expression in ovine carotid arteries

PubMed Central

Goyal, Ravi

2014-01-01

Exposure to acute high-altitude hypoxia is associated with an increase in cerebral blood flow (CBF) as a consequence of low arterial O2 tension. However, in response to high altitude acclimatization, CBF returns to levels similar to those at sea level, and tissue blood flow is maintained by an increase in angiogenesis. Of consequence, dysregulation of the acclimatization responses and CBF can result in acute mountain sickness, acute cerebral and/or pulmonary edema. To elucidate the signal transduction pathways involved in successful acclimatization to high altitude, in ovine carotid arteries, we tested the hypothesis that high altitude-associated long-term hypoxia results in changes in gene expression of critical signaling pathways. We acclimatized nonpregnant adult sheep to 3,801 m altitude for ∼110 days and conducted oligonucleotide microarray experiments on carotid arteries. Of a total of 116 regulated genes, 58 genes were significantly upregulated and 58 genes were significantly downregulated (each >2-fold, P < 0.05). Major upregulated genes included suprabasin and myelin basic protein, whereas downregulated genes included BAG2. Several of these genes are known to activate the ERK canonical signal transduction pathway and the process of angiogenesis. We conclude that among other changes, the altered signal transduction molecules involved in high-altitude acclimatization are associated ERK activation and angiogenesis. PMID:25052263

Acclimatization to long-term hypoxia: gene expression in ovine carotid arteries.

PubMed

Goyal, Ravi; Longo, Lawrence D

2014-10-01

Exposure to acute high-altitude hypoxia is associated with an increase in cerebral blood flow (CBF) as a consequence of low arterial O2 tension. However, in response to high altitude acclimatization, CBF returns to levels similar to those at sea level, and tissue blood flow is maintained by an increase in angiogenesis. Of consequence, dysregulation of the acclimatization responses and CBF can result in acute mountain sickness, acute cerebral and/or pulmonary edema. To elucidate the signal transduction pathways involved in successful acclimatization to high altitude, in ovine carotid arteries, we tested the hypothesis that high altitude-associated long-term hypoxia results in changes in gene expression of critical signaling pathways. We acclimatized nonpregnant adult sheep to 3,801 m altitude for ∼110 days and conducted oligonucleotide microarray experiments on carotid arteries. Of a total of 116 regulated genes, 58 genes were significantly upregulated and 58 genes were significantly downregulated (each >2-fold, P < 0.05). Major upregulated genes included suprabasin and myelin basic protein, whereas downregulated genes included BAG2. Several of these genes are known to activate the ERK canonical signal transduction pathway and the process of angiogenesis. We conclude that among other changes, the altered signal transduction molecules involved in high-altitude acclimatization are associated ERK activation and angiogenesis. Copyright © 2014 the American Physiological Society.

THE PANC 3 SCORE PREDICTING SEVERITY OF ACUTE PANCREATITIS.

PubMed

Beduschi, Murilo Gamba; Mello, André Luiz Parizi; VON-Mühlen, Bruno; Franzon, Orli

2016-03-01

About 20% of cases of acute pancreatitis progress to a severe form, leading to high mortality rates. Several studies suggested methods to identify patients that will progress more severely. However, most studies present problems when used on daily practice. To assess the efficacy of the PANC 3 score to predict acute pancreatitis severity and its relation to clinical outcome. Acute pancreatitis patients were assessed as to sex, age, body mass index (BMI), etiology of pancreatitis, intensive care need, length of stay, length of stay in intensive care unit and mortality. The PANC 3 score was determined within the first 24 hours after diagnosis and compared to acute pancreatitis grade of the Revised Atlanta classification. Out of 64 patients diagnosed with acute pancreatitis, 58 met the inclusion criteria. The PANC 3 score was positive in five cases (8.6%), pancreatitis progressed to a severe form in 10 cases (17.2%) and five patients (8.6%) died. Patients with a positive score and severe pancreatitis required intensive care more often, and stayed for a longer period in intensive care units. The PANC 3 score showed sensitivity of 50%, specificity of 100%, accuracy of 91.4%, positive predictive value of 100% and negative predictive value of 90.6% in prediction of severe acute pancreatitis. The PANC 3 score is useful to assess acute pancreatitis because it is easy and quick to use, has high specificity, high accuracy and high predictive value in prediction of severe acute pancreatitis.

Hypoxia-Related Hormonal Appetite Modulation in Humans during Rest and Exercise: Mini Review

PubMed Central

Debevec, Tadej

2017-01-01

Obesity is associated with numerous chronic ailments and represents one of the major health and economic issues in the modernized societies. Accordingly, there is an obvious need for novel treatment approaches. Recently, based on the reports of reduced appetite and subsequent weight loss following high-altitude sojourns, exposure to hypoxia has been proposed as a viable weight-reduction strategy. While altitude-related appetite modulation is complex and not entirely clear, hypoxia-induced alterations in hormonal appetite modulation might be among the key underlying mechanisms. The present paper summarizes the up-to-date research on hypoxia/altitude-induced changes in the gut and adipose tissue derived peptides related to appetite regulation. Orexigenic hormone ghrelin and anorexigenic peptides leptin, glucagon-like peptide-1, peptide YY, and cholecystokinin have to-date been investigated as potential modulators of hypoxia-driven appetite alterations. Current evidence suggests that hypoxia can, especially acutely, lead to decreased appetite, most probably via reduction of acylated ghrelin concentration. Hypoxia-related short and long-term changes in other hormonal markers are more unclear although hypoxia seems to importantly modulate leptin levels, especially following prolonged hypoxic exposures. Limited evidence also suggests that different activity levels during exposures to hypoxia do not additively affect hormonal appetite markers. Although very few studies have been performed in obese/overweight individuals, the available data indicate that hypoxia/altitude exposures do not seem to differentially affect appetite regulation via hormonal pathways in this cohort. Given the lack of experimental data, future well-controlled acute and prolonged studies are warranted to expand our understanding of hypoxia-induced hormonal appetite modulation and its kinetics in health and disease. PMID:28611686

Effect of Acute Dietary Nitrate Consumption on Oxygen Consumption During Submaximal Exercise in Hypobaric Hypoxia.

PubMed

Carriker, Colin R; Mermier, Christine M; Van Dusseldorp, Trisha A; Johnson, Kelly E; Beltz, Nicholas M; Vaughan, Roger A; McCormick, James J; Cole, Nathan H; Witt, Christopher C; Gibson, Ann L

2016-08-01

Reduced partial pressure of oxygen impairs exercise performance at altitude. Acute nitrate supplementation, at sea level, may reduce oxygen cost during submaximal exercise in hypobaric hypoxia. Therefore, we investigated the metabolic response during exercise at altitude following acute nitrate consumption. Ten well-trained (61.0 ± 7.4 ml/kg/min) males (age 28 ± 7 yr) completed 3 experimental trials (T1, T2, T3). T1 included baseline demographics, a maximal aerobic capacity test (VO2max) and five submaximal intensity cycling determination bouts at an elevation of 1600 m. A 4-day dietary washout, minimizing consumption of nitrate-rich foods, preceded T2 and T3. In a randomized, double-blind, placebo-controlled, crossover fashion, subjects consumed either a nitrate-depleted beetroot juice (PL) or ~12.8 mmol nitrate rich (NR) beverage 2.5 hr before T2 and T3. Exercise at 3500 m (T2 and T3) via hypobaric hypoxia consisted of a 5-min warm-up (25% of normobaric VO2max) and four 5-min cycling bouts (40, 50, 60, 70% of normobaric VO2max) each separated by a 4-min rest period. Cycling RPM and watts for each submaximal bout during T2 and T3 were determined during T1. Preexercise plasma nitrite was elevated following NR consumption compared with PL (1.4 ± 1.2 and 0.7 ± 0.3 uM respectively; p < .05). There was no difference in oxygen consumption (-0.5 ± 1.8, 0.1 ± 1.7, 0.7 ± 2.1, and 1.0 ± 3.0 ml/kg/min) at any intensity (40, 50, 60, 70% of VO2max, respectively) between NR and PL. Further, respiratory exchange ratio, oxygen saturation, heart rate and rating of perceived exertion were not different at any submaximal intensity between NR and PL either. Blood lactate, however, was reduced following NR consumption compared with PL at 40 and 60% of VO2max (p < .0.05). Our findings suggest that acute nitrate supplementation before exercise at 3500 m does not reduce oxygen cost but may reduce blood lactate accumulation at lower intensity workloads.

Acute Electrocardiographic ST Segment Elevation May Predict Hypotension in a Swine Model of Severe Cyanide Toxicity

DTIC Science & Technology

2012-04-21

model with severe acidosis (pH 6.8), hyperkalemia (up to 10 meq/L), hypoglycemia, and hypoxia and reported that ECG electrical changes were not directly...hypoxia, hyperkalemia , and acidosis on intracellular and extracellular poten tials and metabolism in the isolated porcine heart. Circ Res 46 (5):634

THE PANC 3 SCORE PREDICTING SEVERITY OF ACUTE PANCREATITIS

PubMed Central

BEDUSCHI, Murilo Gamba; MELLO, André Luiz Parizi; VON-MÜHLEN, Bruno; FRANZON, Orli

2016-01-01

Background : About 20% of cases of acute pancreatitis progress to a severe form, leading to high mortality rates. Several studies suggested methods to identify patients that will progress more severely. However, most studies present problems when used on daily practice. Objective : To assess the efficacy of the PANC 3 score to predict acute pancreatitis severity and its relation to clinical outcome. Methods : Acute pancreatitis patients were assessed as to sex, age, body mass index (BMI), etiology of pancreatitis, intensive care need, length of stay, length of stay in intensive care unit and mortality. The PANC 3 score was determined within the first 24 hours after diagnosis and compared to acute pancreatitis grade of the Revised Atlanta classification. Results : Out of 64 patients diagnosed with acute pancreatitis, 58 met the inclusion criteria. The PANC 3 score was positive in five cases (8.6%), pancreatitis progressed to a severe form in 10 cases (17.2%) and five patients (8.6%) died. Patients with a positive score and severe pancreatitis required intensive care more often, and stayed for a longer period in intensive care units. The PANC 3 score showed sensitivity of 50%, specificity of 100%, accuracy of 91.4%, positive predictive value of 100% and negative predictive value of 90.6% in prediction of severe acute pancreatitis. Conclusion : The PANC 3 score is useful to assess acute pancreatitis because it is easy and quick to use, has high specificity, high accuracy and high predictive value in prediction of severe acute pancreatitis. PMID:27120730

A Year in Hypoxia: Epibenthic Community Responses to Severe Oxygen Deficit at a Subsea Observatory in a Coastal Inlet

PubMed Central

Matabos, Marjolaine; Tunnicliffe, Verena; Juniper, S. Kim; Dean, Courtney

2012-01-01

Changes in ocean ventilation driven by climate change result in loss of oxygen in the open ocean that, in turn, affects coastal areas in upwelling zones such as the northeast Pacific. Saanich Inlet, on the west coast of Canada, is a natural seasonally hypoxic fjord where certain continental shelf species occur in extreme hypoxia. One study site on the VENUS cabled subsea network is located in the hypoxic zone at 104 m depth. Photographs of the same 5 m2 area were taken with a remotely-controlled still camera every 2/3 days between October 6th 2009 and October 18th 2010 and examined for community composition, species behaviour and microbial mat features. Instruments located on a near-by platform provided high-resolution measurements of environmental variables. We applied multivariate ordination methods and a principal coordinate analysis of neighbour matrices to determine temporal structures in our dataset. Responses to seasonal hypoxia (0.1–1.27 ml/l) and its high variability on short time-scale (hours) varied among species, and their life stages. During extreme hypoxia, microbial mats developed then disappeared as a hippolytid shrimp, Spirontocaris sica, appeared in high densities (200 m−2) despite oxygen below 0.2 ml/l. The slender sole Lyopsetta exilis was abundant in severe hypoxia and diminished as oxygen increased in the summer. This planktivore may be responding to changes in the depth of the diurnal migration of zooplankton. While the squat lobster Munida quadrispina was common at all times, juveniles disappeared in fluctuating conditions. Despite low oxygen conditions, animal densities were high indicating that the risk from hypoxia is balanced by factors such as food availability and escape from less tolerant predators. As hypoxia increases on the continental shelf, we expect benthic communities to become dominated by low diversity, hypoxia-tolerant species of low commercial significance. PMID:23029145

Applying a Hypoxia-Incorporating TCP Model to Experimental Data on Rat Sarcoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ruggieri, Ruggero, E-mail: ruggieri.ruggero@gmail.com; Stavreva, Nadejda; Naccarato, Stefania

2012-08-01

Purpose: To verify whether a tumor control probability (TCP) model which mechanistically incorporates acute and chronic hypoxia is able to describe animal in vivo dose-response data, exhibiting tumor reoxygenation. Methods and Materials: The investigated TCP model accounts for tumor repopulation, reoxygenation of chronic hypoxia, and fluctuating oxygenation of acute hypoxia. Using the maximum likelihood method, the model is fitted to Fischer-Moulder data on Wag/Rij rats, inoculated with rat rhabdomyosarcoma BA1112, and irradiated in vivo using different fractionation schemes. This data set is chosen because two of the experimental dose-response curves exhibit an inverse dose behavior, which is interpreted as duemore » to reoxygenation. The tested TCP model is complex, and therefore, in vivo cell survival data on the same BA1112 cell line from Reinhold were added to Fischer-Moulder data and fitted simultaneously with a corresponding cell survival function. Results: The obtained fit to the combined Fischer-Moulder-Reinhold data was statistically acceptable. The best-fit values of the model parameters for which information exists were in the range of published values. The cell survival curves of well-oxygenated and hypoxic cells, computed using the best-fit values of the radiosensitivities and the initial number of clonogens, were in good agreement with the corresponding in vitro and in situ experiments of Reinhold. The best-fit values of most of the hypoxia-related parameters were used to recompute the TCP for non-small cell lung cancer patients as a function of the number of fractions, TCP(n). Conclusions: The investigated TCP model adequately describes animal in vivo data exhibiting tumor reoxygenation. The TCP(n) curve computed for non-small cell lung cancer patients with the best-fit values of most of the hypoxia-related parameters confirms previously obtained abrupt reduction in TCP for n < 10, thus warning against the adoption of severely hypofractionated

[Determinant-based classification of acute pancreatitis severity. International multidisciplinary classification of acute pancreatitis severity: the 2013 German edition].

PubMed

Layer, P; Dellinger, E P; Forsmark, C E; Lévy, P; Maraví-Poma, E; Shimosegawa, T; Siriwardena, A K; Uomo, G; Whitcomb, D C; Windsor, J A; Petrov, M S

2013-06-01

The aim of this study was to develop a new international classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of published evidence, and worldwide consultation. The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of pancreatologists but suboptimal because these definitions are based on empiric descriptions of occurrences that are merely associated with severity. A personal invitation to contribute to the development of a new international classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensive medicine specialists, and radiologists who are currently active in clinical research on acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global Web-based survey was conducted and a dedicated international symposium was organised to bring contributors from different disciplines together and discuss the concept and definitions. The new international classification is based on the actual local and systemic determinants of severity, rather than descriptions of events that are correlated with severity. The local determinant relates to whether there is (peri)pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another such that the presence of both infected (peri)pancreatic necrosis and persistent organ failure have a greater effect on severity than either determinant alone. The derivation of a classification based on the above principles results in 4 categories of severity - mild, moderate, severe, and critical. This classification is the result of a consultative process amongst pancreatologists from 49 countries spanning North America, South America

Concepts in hypoxia reborn

PubMed Central

2010-01-01

The human fetus develops in a profoundly hypoxic environment. Thus, the foundations of our physiology are built in the most hypoxic conditions that we are ever likely to experience: the womb. This magnitude of exposure to hypoxia in utero is rarely experienced in adult life, with few exceptions, including severe pathophysiology in critical illness and environmental hypobaric hypoxia at high altitude. Indeed, the lowest recorded levels of arterial oxygen in adult humans are similar to those of a fetus and were recorded just below the highest attainable elevation on the Earth's surface: the summit of Mount Everest. We propose that the hypoxic intrauterine environment exerts a profound effect on human tolerance to hypoxia. Cellular mechanisms that facilitate fetal well-being may be amenable to manipulation in adults to promote survival advantage in severe hypoxemic stress. Many of these mechanisms act to modify the process of oxygen consumption rather than oxygen delivery in order to maintain adequate tissue oxygenation. The successful activation of such processes may provide a new chapter in the clinical management of hypoxemia. Thus, strategies employed to endure the relative hypoxia in utero may provide insights for the management of severe hypoxemia in adult life and ventures to high altitude may yield clues to the means by which to investigate those strategies. PMID:20727228

Severe acute respiratory syndrome (SARS)

MedlinePlus

SARS; Respiratory failure - SARS ... Complications may include: Respiratory failure Liver failure Heart failure ... 366. McIntosh K, Perlman S. Coronaviruses, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). ...

Nonalcoholic fatty liver and the severity of acute pancreatitis.

PubMed

Mikolasevic, I; Orlic, L; Poropat, G; Jakopcic, I; Stimac, D; Klanac, A; Carovic, F; Milic, S

2017-03-01

To explore the effect of nonalcoholic fatty liver as a hepatic manifestation of metabolic syndrome on the severity of acute pancreatitis. We hypothesized that patients with nonalcoholic fatty liver would have a more severe form of acute pancreatitis. We retrospectively analyzed 822 patients hospitalized with acute pancreatitis. We diagnosed acute pancreatitis and determined its severity according the revised Atlanta classification criteria from 2012. We assessed nonalcoholic fatty liver with computed tomography. There were 198 (24.1%) patients out of 822 analyzed who had nonalcoholic fatty liver. Patients with nonalcoholic fatty liver had statistically higher incidence of moderately severe (35.4% vs. 14.6%; p=0.02) and severe acute pancreatitis (20.7% vs. 9.6%; p<0.001) compared to patients without nonalcoholic fatty liver. At the admission patients with nonalcoholic fatty liver had higher values of C-reactive protein as well as at day three, higher APACHE II score at admission and significantly higher incidence of organ failure and local complications as well as higher values of computed tomography severity index compared to patients without nonalcoholic fatty liver. We found independent association between the occurrence of moderately severe and severe acute pancreatitis and nonalcoholic fatty liver (OR 2.13, 95%CI 1.236-3.689). Compared to patients without nonalcoholic fatty liver, patients with nonalcoholic fatty liver had a higher death rate, however not statistically significant (5.6% vs. 4.3%; p=NS). Presence of nonalcoholic fatty liver at admission can indicate a higher risk for developing more severe forms of acute pancreatitis and could be used as an additional prognostic tool. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Hypoxia, gas narcosis, and metabolic response to argon and nitrous oxide

NASA Technical Reports Server (NTRS)

1972-01-01

Studies of the mechanism of inert gas influence on metabolism are reported. The studies reported include: metabolic response of hamsters to argon and nitrous oxide, membrane fatty acids and susceptability to narcotic gas influence, narcosis-induced histotoxic hypoxia, biochemical study of inert gas narcosis, hypoxia-induced protection against cardiovascular deterioration in the weightless state, and acute metabolic and physiologic response of goats to narcosis.

Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress.

PubMed

Farías, Jorge G; Herrera, Emilio A; Carrasco-Pozo, Catalina; Sotomayor-Zárate, Ramón; Cruz, Gonzalo; Morales, Paola; Castillo, Rodrigo L

2016-02-01

Hypoxia is the failure of oxygenation at the tissue level, where the reduced oxygen delivered is not enough to satisfy tissue demands. Metabolic depression is the physiological adaptation associated with reduced oxygen consumption, which evidently does not cause any harm to organs that are exposed to acute and short hypoxic insults. Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability of endogenous antioxidant systems to scavenge ROS, where ROS overwhelms the antioxidant capacity. Oxidative stress plays a crucial role in the pathogenesis of diseases related to hypoxia during intrauterine development and postnatal life. Thus, excessive ROS are implicated in the irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Here, we describe several pathophysiological conditions and in vivo and ex vivo models developed for the study of hypoxic and oxidative stress injury. We reviewed existing literature on the responses to hypoxia and oxidative stress of the cardiovascular, renal, reproductive, and central nervous systems, and discussed paradigms of chronic and intermittent hypobaric hypoxia. This systematic review is a critical analysis of the advantages in the application of some experimental strategies and their contributions leading to novel pharmacological therapies. Copyright © 2015 Elsevier Inc. All rights reserved.

Acute Mountain Sickness Symptoms Depend on Normobaric versus Hypobaric Hypoxia

PubMed Central

Strangman, Gary E.; Harris, N. Stuart; Muza, Stephen R.

2016-01-01

Acute mountain sickness (AMS), characterized by headache, nausea, fatigue, and dizziness when unacclimatized individuals rapidly ascend to high altitude, is exacerbated by exercise and can be disabling. Although AMS is observed in both normobaric (NH) and hypobaric hypoxia (HH), recent evidence suggests that NH and HH produce different physiological responses. We evaluated whether AMS symptoms were different in NH and HH during the initial stages of exposure and if the assessment tool mattered. Seventy-two 8 h exposures to normobaric normoxia (NN), NH, or HH were experienced by 36 subjects. The Environmental Symptoms Questionnaire (ESQ) and Lake Louise Self-report (LLS) were administered, resulting in a total of 360 assessments, with each subject answering the questionnaire 5 times during each of their 2 exposure days. Classification tree analysis indicated that symptoms contributing most to AMS were different in NH (namely, feeling sick and shortness of breath) compared to HH (characterized most by feeling faint, appetite loss, light headedness, and dim vision). However, the differences were not detected using the LLS. These results suggest that during the initial hours of exposure (1) AMS in HH may be a qualitatively different experience than in NH and (2) NH and HH may not be interchangeable environments. PMID:27847819

Cardiopulmonary responses to acute hypoxia, head-down tilt and fluid loading in anesthetized dogs

NASA Technical Reports Server (NTRS)

Loeppky, J. A.; Scotto, P.; Riedel, C.; Avasthi, P.; Koshukosky, V.; Chick, T. W.

1991-01-01

Cardiopulmonary responses to acute hypoxia (HY), fluid loading by saline infusion (FL), and head-down tilt (HD) of mechanically ventilated anesthetized dogs were investigated by measuring thermodynamics and pulmonary gas exchange. It was found that HD decreased the total respiratory compliance both during HY and normoxia (NO) and that the reduction in compliance by FL was twice as large as by HD. Superimposing HD on HY doubled the increase in vascular resistance due to HY alone. In the systemic circulation, HD lowered the resistance to below NO levels. There was a significant positive correlation between the changes in blood volume and in pulmonary artery pressure for experimental transitions, suggesting that a shift in blood volume from systemic to pulmonary circulations and changes in the total blood volume may contribute substantially to these apparent changes in resistance.

Ageing and cardiorespiratory response to hypoxia.

PubMed

Lhuissier, François J; Canouï-Poitrine, Florence; Richalet, Jean-Paul

2012-11-01

The risk of severe altitude-induced diseases is related to ventilatory and cardiac responses to hypoxia and is dependent on sex, age and exercise training status. However, it remains unclear how ageing modifies these physiological adaptations to hypoxia. We assessed the physiological responses to hypoxia with ageing through a cross-sectional 20 year study including 4675 subjects (2789 men, 1886 women; 14-85 years old) and a longitudinal study including 30 subjects explored at a mean 10.4 year interval. The influence of sex, training status and menopause was evaluated. The hypoxia-induced desaturation and the ventilatory and cardiac responses to hypoxia at rest and exercise were measured. In men, ventilatory response to hypoxia increased (P < 0.002), while desaturation was less pronounced (P < 0.001) with ageing. Cardiac response to hypoxia was blunted with ageing in both sexes (P < 0.001). Similar results were found in the longitudinal study, with a decrease in cardiac and an increase in ventilatory response to hypoxia with ageing. These adaptive responses were less pronounced or absent in post-menopausal women (P < 0.01). At exercise, desaturation was greater in trained subjects but cardiac and ventilatory responses to hypoxia were preserved by training, especially in elderly people. In conclusion, respiratory response to hypoxia and blood oxygenation improve with ageing in men while cardiac response is blunted with ageing in both sexes. Training aggravates desaturation at exercise in hypoxia, improves the ventilatory response and limits the ageing-induced blunting of cardiac response to hypoxia. Training limits the negative effects of menopause in cardiorespiratory adaptations to hypoxia.

Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms.

PubMed

Shin, Hwa Kyoung; Salomone, Salvatore; Potts, E Michelle; Lee, Sae-Won; Millican, Eric; Noma, Kensuke; Huang, Paul L; Boas, David A; Liao, James K; Moskowitz, Michael A; Ayata, Cenk

2007-05-01

Rho-kinase is a serine threonine kinase that increases vasomotor tone via its effects on both endothelium and smooth muscle. Rho-kinase inhibition reduces cerebral infarct size in wild type, but not endothelial nitric oxide synthase deficient (eNOS-/-) mice. The mechanism may be related to Rho-kinase activation under hypoxic/ischemic conditions and impaired vasodilation because of downregulation of eNOS activity. To further implicate Rho-kinase in impaired vascular relaxation during hypoxia/ischemia, we exposed isolated vessels from rat and mouse to 60 mins of hypoxia, and showed that hypoxia reversibly abolished acetylcholine-induced eNOS-dependent relaxation, and that Rho-kinase inhibitor hydroxyfasudil partially preserved this relaxation during hypoxia. We, therefore, hypothesized that if hypoxia-induced Rho-kinase activation acutely impairs vasodilation in ischemic cortex, in vivo, then Rho-kinase inhibitors would acutely augment cerebral blood flow (CBF) as a mechanism by which they reduce infarct size. To test this, we studied the acute cerebral hemodynamic effects of Rho-kinase inhibitors in ischemic core and penumbra during distal middle cerebral artery occlusion (dMCAO) in wild-type and eNOS-/- mice using laser speckle flowmetry. When administered 60 mins before or immediately after dMCAO, Rho-kinase inhibitors hydroxyfasudil and Y-27632 reduced the area of severely ischemic cortex. However, hydroxyfasudil did not reduce the area of CBF deficit in eNOS-/- mice, suggesting that its effect on CBF within the ischemic cortex is primarily endothelium-dependent, and not mediated by its direct vasodilator effect on vascular smooth muscle. Our results suggest that Rho-kinase negatively regulates eNOS activity in acutely ischemic brain, thereby worsening the CBF deficit. Therefore, rapid nontranscriptional upregulation of eNOS activity by small molecule inhibitors of Rho-kinase may be a viable therapeutic approach in acute stroke.

HypoxiaDB: a database of hypoxia-regulated proteins

PubMed Central

Khurana, Pankaj; Sugadev, Ragumani; Jain, Jaspreet; Singh, Shashi Bala

2013-01-01

There has been intense interest in the cellular response to hypoxia, and a large number of differentially expressed proteins have been identified through various high-throughput experiments. These valuable data are scattered, and there have been no systematic attempts to document the various proteins regulated by hypoxia. Compilation, curation and annotation of these data are important in deciphering their role in hypoxia and hypoxia-related disorders. Therefore, we have compiled HypoxiaDB, a database of hypoxia-regulated proteins. It is a comprehensive, manually-curated, non-redundant catalog of proteins whose expressions are shown experimentally to be altered at different levels and durations of hypoxia. The database currently contains 72 000 manually curated entries taken on 3500 proteins extracted from 73 peer-reviewed publications selected from PubMed. HypoxiaDB is distinctive from other generalized databases: (i) it compiles tissue-specific protein expression changes under different levels and duration of hypoxia. Also, it provides manually curated literature references to support the inclusion of the protein in the database and establish its association with hypoxia. (ii) For each protein, HypoxiaDB integrates data on gene ontology, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway, protein–protein interactions, protein family (Pfam), OMIM (Online Mendelian Inheritance in Man), PDB (Protein Data Bank) structures and homology to other sequenced genomes. (iii) It also provides pre-compiled information on hypoxia-proteins, which otherwise requires tedious computational analysis. This includes information like chromosomal location, identifiers like Entrez, HGNC, Unigene, Uniprot, Ensembl, Vega, GI numbers and Genbank accession numbers associated with the protein. These are further cross-linked to respective public databases augmenting HypoxiaDB to the external repositories. (iv) In addition, HypoxiaDB provides an online sequence-similarity search tool for

Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neuronal nitric oxide synthase-dependent mechanism

EPA Science Inventory

The adaptive mechanisms that protect brain metabolism during and after hypoxia, for instance, during hypoxic preconditioning, are coordinated in part by nitric oxide (NO). We tested the hypothesis that acute transient hypoxia stimulates NO synthase (NOS)-activated mechanisms of m...

Noninvasive ventilation for patients with acute lung injury or acute respiratory distress syndrome.

PubMed

Nava, Stefano; Schreiber, Ania; Domenighetti, Guido

2011-10-01

Few studies have been performed on noninvasive ventilation (NIV) to treat hypoxic acute respiratory failure in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The outcomes of these patients, for whom endotracheal intubation is not mandatory, depend on the degree of hypoxia, the presence of comorbidities and complications, and their illness severity. The use of NIV as an alternative to invasive ventilation in severely hypoxemic patients with ARDS (ie, P(aO(2))/F(IO(2)) < 200) is not generally advisable and should be limited to hemodynamically stable patients who can be closely monitored in an intensive care unit by highly skilled staff. Early NIV application may be extremely helpful in immunocompromised patients with pulmonary infiltrates, in whom intubation dramatically increases the risk of infection, pneumonia, and death. The use of NIV in patients with severe acute respiratory syndrome and other airborne diseases has generated debate, despite encouraging clinical results, mainly because of safety issues. Overall, the high rate of NIV failure suggests a cautious approach to NIV use in patients with ALI/ARDS, including early initiation, intensive monitoring, and prompt intubation if signs of NIV failure emerge.

Ventilatory responses to hypercapnia and hypoxia after 6 h passive hyperventilation in humans

PubMed Central

Ren, Xiaohui; Robbins, Peter A

1999-01-01

Acute exposure to hypoxia stimulates ventilation and induces hypocapnia. Long-term exposure to hypoxia generates changes in respiratory control known as ventilatory acclimatization to hypoxia. The object of this study was to investigate the degree to which the hyperventilation and hypocapnia can induce the changes known as ventilatory acclimatization to hypoxia, in the absence of the primary hypoxic stimulus itself.Three 6 h protocols were each performed on twelve healthy volunteers: (1) passive hypocapnic hyperventilation, with end-tidal CO2 pressure (PET,CO2) held 10 Torr below the eupnoeic value; (2) passive eucapnic hyperventilation, with PET,CO2 maintained eucapnic; (3) control.Ventilatory responses to acute hypercapnia and hypoxia were assessed before and half an hour after each protocol.The presence of prior hypocapnia, but not prior hyperventilation, caused a reduction in air-breathing PET,CO2 (P < 0·05, ANOVA), and a leftwards shift of the ventilatory response to hypercapnia (P < 0·05). The presence of prior hyperventilation, but not prior hypocapnia, caused an increase in the ventilatory sensitivity to CO2 (P < 0·05). No significant effects of any protocol were detected on the ventilatory sensitivity to hypoxia.We conclude that following 6 h of passive hyperventilation: (i) the left shift of the VE-PET,CO2 relationship is due to alkalosis and not to hyperventilation; (ii) the increase in slope of the VE-PET,CO2 relationship is due to the hyperventilation and not the alkalosis; and (iii) ventilatory sensitivity to hypoxia is unaltered. PMID:9882758

[Severe acute pancreatitis associated with gallbladder gangrene].

PubMed

Arroyo-Sánchez, Abel S; Aguirre-Mejía, Rosa Y; Echenique-Martínez, Sergio E

2014-01-01

We present a diabetic patient who developed severe acute pancreatitis associated to gallbladder gangrene, in this case we assessed the applicability of classification criteria and management of the pathways for acute pancreatitis and also we suggest some topics that could be investigated in the future.

[Identifying the severe acute pancreatitis].

PubMed

Acevedo Tizón, Anais; Targarona Modena, Javier; Málaga Rodríguez, Germán; Barreda Cevasco, Luis

2011-01-01

To compare patients with acute necrotizing pancreatitis without any additional complications during their hospital stay (Group A) versus patients with Acute Necrotizing Pancreatitis with additional complications during their hospital stay (Group B). Data obtained from a pre-existing base from hospitalized patients with diagnosis of acute necrotizing pancreatitis in the specialized unit of "Unidad de Pancreatitis Aguda Grave del Hospital Nacional Edgardo Rebagliati Martins" between 2000 and 2010. Data included patients with diagnosis of acute necrotizing pancreatitis, of ages 18 and over. Data from 215 patients with acute necrotizing pancreatitis was included. Patients from Group A represented 32% (68) and from Group B 68% (147). Group A had a average of 39 hospitalized days and Group B had an average of 56 days (p=0.01). From Group A 22% had more than 50% of necrosis while 43% of Group B had this extension of necrosis (p <0.05, OR 3.4, IC (1.12-10)). Of the 14 deaths of the population, all part of Group B, 12 of them had more than 50% of necrosis. Not every patient classified as severe acute pancreatitis, based on the presence of necrosis, behave likewise. It is an extended necrosis, described as more than 50% of pancreatic necrosis, and not the presence itself which will determine additional complications during the course of disease and a greater mortality.

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

PubMed Central

Larson, John; Drew, Kelly L.; Folkow, Lars P.; Milton, Sarah L.; Park, Thomas J.

2014-01-01

Many vertebrates are challenged by either chronic or acute episodes of low oxygen availability in their natural environments. Brain function is especially vulnerable to the effects of hypoxia and can be irreversibly impaired by even brief periods of low oxygen supply. This review describes recent research on physiological mechanisms that have evolved in certain vertebrate species to cope with brain hypoxia. Four model systems are considered: freshwater turtles that can survive for months trapped in frozen-over lakes, arctic ground squirrels that respire at extremely low rates during winter hibernation, seals and whales that undertake breath-hold dives lasting minutes to hours, and naked mole-rats that live in crowded burrows completely underground for their entire lives. These species exhibit remarkable specializations of brain physiology that adapt them for acute or chronic episodes of hypoxia. These specializations may be reactive in nature, involving modifications to the catastrophic sequelae of oxygen deprivation that occur in non-tolerant species, or preparatory in nature, preventing the activation of those sequelae altogether. Better understanding of the mechanisms used by these hypoxia-tolerant vertebrates will increase appreciation of how nervous systems are adapted for life in specific ecological niches as well as inform advances in therapy for neurological conditions such as stroke and epilepsy. PMID:24671961

[Adaptation to hypoxia and hyperoxia improves physical endurance: the role of reactive oxygen species and redox-signaling].

PubMed

Sazontova, T G; Glazachev, O S; Bolotova, A V; Dudnik, E N; Striapko, N V; Bedareva, I V; Anchishkina, N A; Arkhipenko, Iu V

2012-06-01

We have conducted theoretical foundation, experimental analysis and a pilot study of a new method of adaptation to hypoxia and hyperoxia in the prevention of hypoxic and stress-induced disorders and improving the body's tolerance to physical stress. It has been shown in the experimental part that a combination of physical exercise with adaptation to hypoxia-hyperoxia significantly increased tolerance to acute physical load (APL) and its active phase. Analysis of lipid peroxidation processes, antioxidant enzymes and HSPs showed that short-term training for physical exercise by itself compensates the stressor, but not the hypoxic component of the APL, the combination of training with adaptation to hypoxia-hyperoxia completely normalizes the stressor and hypoxic components of APL. The pilot study has been performed to evaluate the effectiveness of hypoxic-hyperoxic training course in qualified young athletes with over-training syndrome. After completing the course of hypoxia-hyperoxia adaptation, 14 sessions, accompanied by light mode sports training, the athletes set the normalization of autonomic balance, increased resistance to acute hypoxia in hypoxic test, increased physical performance--increased PWC170, maximal oxygen consumption (VO2max) parameters, their relative values to body mass, diminished shift of rate pressure product in the load. Thus, we confirmed experimental findings that hypoxic-hyperoxic training optimizes hypoxic (increased athletes resistance to proper hypoxia) and stress (myocardium economy in acute physical stress testing) components in systemic adaptation and restoration of athletes' with over-training syndrome.

Acute severe asthma presenting in late pregnancy.

PubMed

Holland, S M; Thomson, K D

2006-01-01

Asthma is the commonest pre-existing medical condition to complicate pregnancy. Acute severe asthma in pregnancy is rare, but poses difficult problems. In particular, the decision about when and where to deliver the fetus is complex, since maternal response to asthma treatment is unpredictable. We report the successful management of a parturient presenting with acute severe asthma at 37 weeks' gestation. The controversies involved and the importance of adopting a multi-disciplinary team approach to optimise maternal and neonatal outcomes are discussed.

The role of nitric oxide in the cardiopulmonary response to hypoxia in highland and lowland newborn llamas.

PubMed

Reyes, Roberto V; Díaz, Marcela; Ebensperger, Germán; Herrera, Emilio A; Quezada, Sebastián A; Hernandez, Ismael; Sanhueza, Emilia M; Parer, Julian T; Giussani, Dino A; Llanos, Aníbal J

2018-01-25

Perinatal hypoxia causes pulmonary hypertension in neonates, including humans. However, in species adapted to hypoxia, such as the llama, there is protection against pulmonary hypertension. Nitric oxide (NO) is a vasodilatator with an established role in the cardiopulmonary system of many species, but its function in the hypoxic pulmonary vasoconstrictor response in the newborn llama is unknown. Therefore, we studied the role of NO in the cardiopulmonary responses to acute hypoxia in high- and lowland newborn llamas. We show that high- compared to lowland newborn llamas have a reduced pulmonary vasoconstrictor response to acute hypoxia. Protection against excessive pulmonary vasoconstriction in the highland llama is mediated via enhancement of NO pathways, including increased MYPT1 and reduced ROCK expression as well as Ca 2+ desensitization. Blunting of pulmonary hypertensive responses to hypoxia through enhanced NO pathways may be an adaptive mechanism to withstand life at high altitude in the newborn llama. Llamas are born in the Alto Andino with protection against pulmonary hypertension. The physiology underlying protection against pulmonary vasoconstrictor responses to acute hypoxia in highland species is unknown. We determined the role of nitric oxide (NO) in the cardiopulmonary responses to acute hypoxia in high- and lowland newborn llamas. The cardiopulmonary function of newborn llamas born at low (580 m) or high altitude (3600 m) was studied under acute hypoxia, with and without NO blockade. In pulmonary arteries, we measured the reactivity to potassium and sodium nitroprusside (SNP), and in lung we determined the content of cGMP and the expression of the NO-related proteins: BKCa, PDE5, PSer92-PDE5, PKG-1, ROCK1 and 2, MYPT1, PSer695-MYPT1, PThr696-MYPT1, MLC20 and PSer19-MLC20. Pulmonary vascular remodelling was evaluated by morphometry and based on α-actin expression. High- compared to lowland newborn llamas showed lower in vivo pulmonary arterial

Adaptive Myogenesis under Hypoxia

PubMed Central

Yun, Zhong; Lin, Qun; Giaccia, Amato J.

2005-01-01

Previous studies have indicated that myoblasts can differentiate and repair muscle injury after an ischemic insult. However, it is unclear how hypoxia or glucose deprivation in the ischemic microenvironment affects myoblast differentiation. We have found that myogenesis can adapt to hypoxic conditions. This adaptive mechanism is accompanied by initial inhibition of the myoD, E2A, and myogenin genes followed by resumption of their expression in an oxygen-dependent manner. The regulation of myoD transcription by hypoxia is correlated with transient deacetylation of histones associated with the myoD promoter. It is noteworthy that, unlike the differentiation of other cell types such as preadipocytes or chondroblasts, the effect of hypoxia on myogenesis is independent of HIF-1, a ubiquitous regulator of transcription under hypoxia. While myogenesis can also adapt to glucose deprivation, the combination of severe hypoxia and glucose deprivation found in an ischemic environment results in pronounced loss of myoblasts. Our studies indicate that the ischemic muscle can be repaired via the adaptive differentiation of myogenic precursors, which depends on the levels of oxygen and glucose in the ischemic microenvironment. PMID:15798192

Factors influencing the severity of acute viral hepatitis A

PubMed Central

Kim, Joo Il; Jung, Young Kul; Kwon, Oh Sang; Kim, Yeon Suk; Ku, Yang Suh; Choi, Duck Joo; Kim, Ju Hyun

2010-01-01

Background/Aims Most patients with acute viral hepatitis A have a favorable course, but a few of them suffer from severe forms of hepatitis such as fulminant hepatitis. This study was carried out to identify the factors influencing the severity of acute viral hepatitis A. Methods We retrospectively reviewed the medical records of 713 patients with acute hepatitis A, who were divided into two groups: severe hepatitis A (N=87) and non-severe hepatitis A (N=626). Severe hepatitis was defined as fulminant hepatitis or prolongation of prothrombin time (INR≥1.5). Clinical variables were compared between the two groups. Results The incidence of fulminant hepatitis was 1.4% (10/713) in patients with acute hepatitis A. Thirty-three (4.6%) cases exhibited HBsAg positivity. In multivariate analyses, significant alcohol intake and the presence of HBsAg were significant predictive factors of fulminant hepatitis A, and significant alcohol intake and age were significant predictive factors of severe hepatitis A. HBeAg and HBV-DNA status did not affect the clinical course of hepatitis A in chronic hepatitis B carriers. Conclusions While most patients with acute hepatitis A have an uncomplicated clinical course, our data suggest that a more-severe clinical course is correlated with being older, significant alcohol intake, and chronic hepatitis-B-virus infection. PMID:20924212

Metabolic and cardiorespiratory responses of summer flounder Paralichthys dentatus to hypoxia at two temperatures.

PubMed

Capossela, K M; Brill, R W; Fabrizio, M C; Bushnell, P G

2012-08-01

To quantify the tolerance of summer flounder Paralichthys dentatus to episodic hypoxia, resting metabolic rate, oxygen extraction, gill ventilation and heart rate were measured during acute progressive hypoxia at the fish's acclimation temperature (22° C) and after an acute temperature increase (to 30° C). Mean ±s.e. critical oxygen levels (i.e. the oxygen levels below which fish could not maintain aerobic metabolism) increased significantly from 27 ± 2% saturation (2·0 ± 0·1 mg O(2) l(-1)) at 22° C to 39 ± 2% saturation (2·4 ± 0·1 mg O(2) l(-1)) at 30° C. Gill ventilation and oxygen extraction changed immediately with the onset of hypoxia at both temperatures. The fractional increase in gill ventilation (from normoxia to the lowest oxygen level tested) was much larger at 22° C (6·4-fold) than at 30° C (2·7-fold). In contrast, the fractional decrease in oxygen extraction (from normoxia to the lowest oxygen levels tested) was similar at 22° C (1·7-fold) and 30° C (1·5-fold), and clearly smaller than the fractional changes in gill ventilation. In contrast to the almost immediate effects of hypoxia on respiration, bradycardia was not observed until 20 and 30% oxygen saturation at 22 and 30° C, respectively. Bradycardia was, therefore, not observed until below critical oxygen levels. The critical oxygen levels at both temperatures were near or immediately below the accepted 2·3 mg O(2) l(-1) hypoxia threshold for survival, but the increase in the critical oxygen level at 30° C suggests a lower tolerance to hypoxia after an acute increase in temperature. © 2012 The Authors. Journal of Fish Biology © 2012 The Fisheries Society of the British Isles.

Normobaric Hypoxia and Submaximal Exercise Effects on Running Memory and Mood State in Women.

PubMed

Seo, Yongsuk; Gerhart, Hayden D; Stavres, Jon; Fennell, Curtis; Draper, Shane; Glickman, Ellen L

2017-07-01

An acute bout of exercise can improve cognitive function in normoxic and hypoxic conditions. However, limited research supports the improvement of cognitive function and mood state in women. The purpose of this study was to examine the effects of hypoxia and exercise on working memory and mood state in women. There were 15 healthy women (age = 22 ± 2 yr) who completed the Automated Neuropsychological Assessment Metrics-4th Edition (ANAM), including the Running Memory Continuous Performance Task (RMCPT) and Total Mood Disturbance (TMD) in normoxia (21% O2), at rest in normoxia and hypoxia (12.5% O2), and during cycling exercise at 60% and 40% Vo2max in hypoxia. RMCPT was not significantly impaired at 30 (100.3 ± 17.2) and 60 (96.6 ± 17.3) min rest in hypoxia compared to baseline in normoxia (97.0 ± 17.0). However, RMCPT was significantly improved during exercise (106.7 ± 20.8) at 60% Vo2max compared to 60 min rest in hypoxia. Following 30 (-89.4 ± 48.3) and 60 min of exposure to hypoxia (-79.8 ± 55.9) at rest, TMD was impaired compared with baseline (-107.1 ± 46.2). TMD was significantly improved during exercise (-108.5 ± 42.7) at 40% Vo2max compared with 30 min rest in hypoxia. Also, RMCPT was significantly improved during exercise (104.0 ± 19.1) at 60% Vo2max compared to 60 min rest in hypoxia (96.6 ± 17.3). Hypoxia and an acute bout of exercise partially influence RMCPT and TMD. Furthermore, a moderate-intensity bout of exercise (60%) may be a more potent stimulant for improving cognitive function than low-intensity (40%) exercise. The present data should be considered by aeromedical personnel performing cognitive tasks in hypoxia.Seo Y, Gerhart HD, Stavres J, Fennell C, Draper S, Glickman EL. Normobaric hypoxia and submaximal exercise effects on running memory and mood state in women. Aerosp Med Hum Perform. 2017; 88(7):627-632.

Fetal endocrine and metabolic adaptations to hypoxia: the role of the hypothalamic-pituitary-adrenal axis

PubMed Central

Newby, Elizabeth A.; Myers, Dean A.

2015-01-01

In utero, hypoxia is a significant yet common stress that perturbs homeostasis and can occur due to preeclampsia, preterm labor, maternal smoking, heart or lung disease, obesity, and high altitude. The fetus has the extraordinary capacity to respond to stress during development. This is mediated in part by the hypothalamic-pituitary-adrenal (HPA) axis and more recently explored changes in perirenal adipose tissue (PAT) in response to hypoxia. Obvious ethical considerations limit studies of the human fetus, and fetal studies in the rodent model are limited due to size considerations and major differences in developmental landmarks. The sheep is a common model that has been used extensively to study the effects of both acute and chronic hypoxia on fetal development. In response to high-altitude-induced, moderate long-term hypoxia (LTH), both the HPA axis and PAT adapt to preserve normal fetal growth and development while allowing for responses to acute stress. Although these adaptations appear beneficial during fetal development, they may become deleterious postnatally and into adulthood. The goal of this review is to examine the role of the HPA axis in the convergence of endocrine and metabolic adaptive responses to hypoxia in the fetus. PMID:26173460

Hypoxia signaling – license to metastasize

PubMed Central

Vanharanta, Sakari; Massagué, Joan

2013-01-01

Hypoxia-inducible transcription factors (HIFs) have long been linked to malignant tumor phenotypes in various cancer types, and several downstream mediators of HIF action have been identified in metastatic carcinomas. A new study links hypoxia-induced collagen remodeling to sarcoma progression, providing evidence for unifying mechanisms of carcinoma and sarcoma metastasis. PMID:24124230

The effect of acute hypoxia on short-circuit current and epithelial resistivity in biopsies from human colon.

PubMed

Carra, Graciela E; Ibáñez, Jorge E; Saraví, Fernando D

2013-09-01

In isolated colonic mucosa, decreases in short-circuit current (ISC) and transepithelial resistivity (RTE) occur when hypoxia is either induced at both sides or only at the serosal side of the epithelium. We assessed in human colon biopsies the sensitivity to serosal-only hypoxia and mucosal-only hypoxia and whether Na, K-ATPase blockade with ouabain interacts with hypoxia. Biopsy material from patients undergoing colonoscopy was mounted in an Ussing chamber for small samples (1-mm2 window). In a series of experiments we assessed viability and the electrical response to the mucolytic, dithiothreitol (1 mmol/l). In a second series, we explored the effect of hypoxia without and with ouabain. In a third series, we evaluated the response to a cycle of hypoxia and reoxygenation induced at the serosal or mucosal side while keeping the oxygenation of the opposite side. 1st series: Dithiothreitol significantly decreased the unstirred layer and ISC but increased RTE. 2nd series: Both hypoxia and ouabain decreased ISC, but ouabain increased RTE and this effect on RTE prevailed even during hypoxia. 3rd series: Mucosal hypoxia caused lesser decreases of ISC and RTE than serosal hypoxia; in the former, but not in the latter, recovery was complete upon reoxygenation. In mucolytic concentration, dithiothreitol modifies ISC and RTE. Oxygen supply from the serosal side is more important to sustain ISC and RTE in biopsy samples. The different effect of hypoxia and Na, K-ATPase blockade on RTE suggests that their depressing effect on ISC involves different mechanisms.

WE-FG-BRA-08: Potential Role of the Glycolytic Oscillator in Acute Hypoxia in Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Che Fru, L; Adamson, E; Campos, D

2016-06-15

Purpose: Oscillatory dynamics in acute hypoxia have been observed, but poorly understood. They have mostly been attributed to vascular perturbations, but no link has yet been made to metabolic causes. We set out to determine the fundamental frequencies and test for coherence in tumor oxygen dynamics and spatial properties. Methods: Severe combined immunodeficient (SCID) mice were inoculated onto bilateral flanks with human derived head and neck carcinoma (UW-SCC22) cell line xenografts. Oxygen dynamics were monitored in the tumor every minute for an hour using three modalities: blood oxygen level dependent - magnetic resonance imaging (BOLD-MRI), hemoglobin oxygen saturation photoacoustic, andmore » locally manufactured optical probes for spectral fitting. A statistical test was used to separate fluctuating from non-fluctuating voxels and pixels in BOLD-MRI and photoacoustic data respectively. The power spectrum density (PSD) and the autocorrelation functions were calculated for the time series of each voxel, pixel and region, of the BOLD-MRI, photoacoustic or fiber optic data respectively. Results: Using all three techniques, intermittent oxygen dynamics with both coherent and incoherent signatures was observed in the tumors. Upon averaging the PSDs of fluctuating voxels and pixels, it was found that these oscillations occurred with periods of minutes to tens of minutes from all three approaches. Observations from the BOLD-MRI and photoacoustic data showed that clusters of voxels oscillated in a synchronized manner. Conclusion: We were able to use three different modalities to show that fluctuation in tumor oxygen is both coherent and incoherent, with periods of minutes to tens of minutes. These periods are very similar to those from the well-established metabolic, non-linear biomechanical phenomenon called the glycolytic oscillator. This may provide an additional explanation to the cause of cyclic hypoxia. Such dynamics could have profound implications in

Effects of Hypoxia and Hypercapnic Hypoxia on Oxygen Transport and Acid-Base Status in the Atlantic Blue Crab, Callinectes sapidus, During Exercise.

PubMed

Lehtonen, Mark P; Burnett, Louis E

2016-11-01

The responses of estuarine invertebrates to hypoxic conditions are well established. However, many studies have investigated hypoxia as an isolated condition despite its frequent co-occurrence with hypercapnia (elevated CO 2 ). Although many studies suggest deleterious effects, hypercapnia has been observed to improve blue crab walking performance in hypoxia. To investigate the physiological effects of combined hypercapnic hypoxia, we measured Po 2 , pH, [l-lactate], Pco 2 , and total O 2 in pre- and postbranchial hemolymph sampled from blue crabs during walking exercise. Crabs walked at 8 m min -1 on an aquatic treadmill in normoxic (100% air saturation), moderately hypoxic (50%), and severely hypoxic (20%) seawater with and without the addition of hypercapnia (about 2% CO 2 ). Respiration was almost completely aerobic in normoxic conditions, with little buildup of lactate. During exercise under severe hypoxia, lactate increased from 1.4 to 11.0 mM, indicating a heavy reliance on anaerobic respiration. The O 2 saturation of arterial hemocyanin was 47% in severe hypoxia after 120 min, significantly lower than in normoxia (80%). However, the addition of hypercapnia significantly increased the percentage saturation of arterial hemocyanin in severe hypoxia to 92% after 120 min of exercise, equivalent to normoxic levels. Hypercapnia in severe hypoxia also caused a marked increase in hemolymph Pco 2 (around 1.1 kPa), but caused only a minor decrease in pH of 0.1 units. We suggest that the improved O 2 saturation at the gills results from a specific effect of molecular CO 2 on hemocyanin oxygen binding affinity, which works independently of and counter to the effects of decreased pH. © 2016 Wiley Periodicals, Inc.

Pancreaticoatmospheric fistula following severe acute necrotising pancreatitis

PubMed Central

Simoneau, Eve; Chughtai, Talat; Razek, Tarek; Deckelbaum, Dan L

2014-01-01

Severe acute necrotising pancreatitis is associated with numerous local and systemic complications. Abdominal compartment syndrome requiring urgent decompressive laparotomy is a potential complication of this disease process and is associated with increased morbidity and mortality. We describe the case of a pancreaticoatmospheric fistula following decompressive laparotomy in a patient with severe acute necrotising pancreatitis. While this fistula was managed successfully using the current standard of care for pancreatic fistulas, the wound care for in this patient with drainage of the fistula through an open abdomen, is a significant challenge. PMID:25519860

Severe acute pancreatitis and pregnancy.

PubMed

Robertson, K W; Stewart, I S; Imrie, C W

2006-01-01

For most patients with pregnancy-associated pancreatitis there is little maternal survival threat and only occasionally are there foetal deaths. We describe 4 young women with pregnancy-associated severe acute pancreatitis who each had gallstones. Their ages were 17, 18, 20 and 24 years. Each was a tertiary referral to our unit in Glasgow and each pursued a life-threatening course with hospital stays ranging from 37 to 90 days. One patient required pancreatic necrosectomy for infected necrosis, another had percutaneous management of a pancreatic abscess and 2 had cystogastrostomy as treatment for pancreatic pseudocyst. All underwent early endoscopic sphincterotomy and later cholecystectomy. It is important to be aware that pregnancy-associated acute pancreatitis may be severe, posing a survival threat even in the youngest patients. Gallstones, as we reported almost 20 years ago, are the most common aetiological factor in such patients. Copyright (c) 2006 S. Karger AG, Basel and IAP.

Copper alters hypoxia sensitivity and the behavioural emersion response in the amphibious fish Kryptolebias marmoratus.

PubMed

Blewett, Tamzin A; Simon, Robyn A; Turko, Andy J; Wright, Patricia A

2017-08-01

Elevated levels of metals have been reported in mangrove ecosystems worldwide. Mangrove fishes also routinely experience severe environmental stressors, such as hypoxia. In the amphibious fish Kryptolebias marmoratus (mangrove rivulus), a key behavioural response to avoid aquatic stress is to leave water (emersion). We hypothesized that copper (Cu) exposure would increase the sensitivity of this behavioural hypoxia avoidance response due to histopathological effects of Cu on gill structure and function. K. marmoratus were exposed to either control (no added Cu) or Cu (300μg/L) for 96h. Following this period, fish were exposed to an acute hypoxic challenge (decline in dissolved oxygen to ∼0% over 15min), and the emersion response was recorded. Gills were examined for histological changes. Fish exposed to Cu emersed at a higher dissolved oxygen level (7.5±0.6%), relative to the control treatment group (5.8±0.4%). Histological analysis showed that the gill surface area increased and the interlamellar cell mass (ILCM) was reduced following Cu exposure, contrary to our prediction. Overall, these data indicate that Cu induces hypoxia-like changes to gill morphology and increases the sensitivity of the hypoxia emersion response. Copyright © 2017 Elsevier B.V. All rights reserved.

Hypoxia and Its Acid-Base Consequences: From Mountains to Malignancy.

PubMed

Swenson, Erik R

Hypoxia, depending upon its magnitude and circumstances, evokes a spectrum of mild to severe acid-base changes ranging from alkalosis to acidosis, which can alter many responses to hypoxia at both non-genomic and genomic levels, in part via altered hypoxia-inducible factor (HIF) metabolism. Healthy people at high altitude and persons hyperventilating to non-hypoxic stimuli can become alkalotic and alkalemic with arterial pH acutely rising as high as 7.7. Hypoxia-mediated respiratory alkalosis reduces sympathetic tone, blunts hypoxic pulmonary vasoconstriction and hypoxic cerebral vasodilation, and increases hemoglobin oxygen affinity. These effects and others can be salutary or counterproductive to tissue oxygen delivery and utilization, based upon magnitude of each effect and summation. With severe hypoxia either in the setting of profound arterial hemoglobin desaturation and reduced O2 content or poor perfusion (ischemia) at the global or local level, metabolic and hypercapnic acidosis develop along with considerable lactate formation and pH falling to below 6.8. Although conventionally considered to be injurious and deleterious to cell function and survival, both acidoses may be cytoprotective by various anti-inflammatory, antioxidant, and anti-apoptotic mechanisms which limit total hypoxic or ischemic-reperfusion injury. Attempts to correct acidosis by giving bicarbonate or other alkaline agents under these circumstances ahead of or concurrent with reoxygenation efforts may be ill advised. Better understanding of this so-called "pH paradox" or permissive acidosis may offer therapeutic possibilities. Rapidly growing cancers often outstrip their vascular supply compromising both oxygen and nutrient delivery and metabolic waste disposal, thus limiting their growth and metastatic potential. However, their excessive glycolysis and lactate formation may not necessarily represent oxygen insufficiency, but rather the Warburg effect-an attempt to provide a large amount

[Causes and management of severe acute liver damage during pregnancy].

PubMed

Sepulveda-Martinez, Alvaro; Romero, Carlos; Juarez, Guido; Hasbun, Jorge; Parra-Cordero, Mauro

2015-05-01

Abnormalities in liver function tests appear in 3% of pregnancies. Severe acute liver damage can be an exclusive condition of pregnancy (dependent or independent of pre-eclampsia) or a concomitant disease. HELLP syndrome and acute fatty liver of pregnancy are the most severe liver diseases associated with pregnancy. Both appear during the third trimester and have a similar clinical presentation. Acute fatty liver may be associated with hypoglycemia and HELLP syndrome is closely linked with pre-eclampsia. Among concomitant conditions, fulminant acute hepatitis caused by medications or virus is the most severe disease. Its clinical presentation may be hyper-acute with neurological involvement and severe coagulation disorders. It has a high mortality and patients should be transplanted. Fulminant hepatic failure caused by acetaminophen overdose can be managed with n-acetyl cysteine. Because of the high fetal mortality rate, the gestational age at diagnosis is crucial.

Severe acute copper sulphate poisoning: a case report.

PubMed

Sinkovic, Andreja; Strdin, Alenka; Svensek, Franci

2008-03-01

As copper sulphate pentahydrate (CSP) is a common compound used in agriculture and industry, chronic occupational exposures to CSP are well known, but acute poisoning is rare in the Western world. This case report describes acute poisoning of a 33-year-old woman who attempted suicide by ingesting an unknown amount of CSP. On admission to the hospital, she had symptoms and signs of severe hemorrhagic gastroenteritis, dehydration, renal dysfunction and methaemoglobinaemia with normal serum copper level. Therapy included early gastric lavage, fluid replacement, vasoactive drugs, furosemide, antiemetic drugs, ranitidine, and antidotes methylene blue and 2,3-dimercaptopropane-1-sulphonate (DMPS). However, the patient developed severe intravascular haemolysis, acute severe hepatic and renal failure, as well as adrenal insufficiency. After prolonged, but successful hospital treatment, including haemodialysis and IV hydrocortisone, the patient was discharged with signs of mild renal and liver impairment. Our conclusion is that in severe cases of copper poisoning early supportive measures are essential. In addition, antidotes such as methylene blue for methaemoglobinaemia and chelating agent such as DMPS improve morbidity and survival of severely poisoned victims.

Actions of hypoxia on catecholamine synthetic enzyme mRNA expression before and after development of adrenal innervation in the sheep fetus

PubMed Central

Adams, M B; McMillen, I C

2000-01-01

We have investigated adrenal mRNA expression of the catecholamine synthetic enzymes tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) following acute hypoxia in fetal sheep before (< 105 days gestation, n = 20) and after (> 125 days gestation, n = 20) the development of adrenal innervation and following pretreatment with the nicotinic receptor anatgonist hexamethonium (n = 12). Total RNA was extracted from fetal adrenal glands collected at specific time points at 3-20 h after the onset of either hypoxia (∼50% reduction in fetal arterial oxygen saturation (SO2) for 30 min), or normoxia. Before 105 days, there was a decrease in adrenal TH mRNA expression at 20 h after hypoxia and adrenal TH mRNA expression was directly related to the changes in arterial PO2 measured during normoxia and hypoxia. After 125 days, adrenal TH mRNA levels were suppressed for up to 12 h following hypoxia. In both age groups, adrenal PNMT mRNA expression increased at 3-5 h after hypoxia and was inversely related to the changes in fetal arterial PO2 during normoxia or hypoxia. After 125 days, the administration of hexamethonium (25 mg kg−1, I. V.) reduced TH mRNA but not PNMT mRNA expression after normoxia. After hexamethonium pretreatment, there was no significant change in either adrenal TH or PNMT mRNA expression following hypoxia. We conclude that acute hypoxia differentially regulates adrenal TH and PNMT mRNA expression in the fetal sheep both before and after the development of adrenal innervation. After the development of adrenal innervation, however, the effect of acute hypoxia upon adrenal TH and PNMT mRNA expression is dependent upon neurogenic input acting via nicotinic receptors. PMID:11118487

Intermittent hypoxia and neurorehabilitation

PubMed Central

Gonzalez-Rothi, Elisa J.; Lee, Kun-Ze; Dale, Erica A.; Reier, Paul J.; Mitchell, Gordon S.

2015-01-01

In recent years, it has become clear that brief, repeated presentations of hypoxia [i.e., acute intermittent hypoxia (AIH)] can boost the efficacy of more traditional therapeutic strategies in certain cases of neurologic dysfunction. This hypothesis derives from a series of studies in animal models and human subjects performed over the past 35 yr. In 1980, Millhorn et al. (Millhorn DE, Eldridge FL, Waldrop TG. Respir Physiol 41: 87-103, 1980) showed that electrical stimulation of carotid chemoafferent neurons produced a persistent, serotonin-dependent increase in phrenic motor output that outlasts the stimulus for more than 90 min (i.e., a “respiratory memory”). AIH elicits similar phrenic “long-term facilitation” (LTF) by a mechanism that requires cervical spinal serotonin receptor activation and de novo protein synthesis. From 2003 to present, a series of studies demonstrated that AIH can induce neuroplasticity in the injured spinal cord, causing functional recovery of breathing capacity after cervical spinal injury. Subsequently, it was demonstrated that repeated AIH (rAIH) can induce recovery of limb function, and the functional benefits of rAIH are greatest when paired with task-specific training. Since uncontrolled and/or prolonged intermittent hypoxia can elicit pathophysiology, a challenge of intermittent hypoxia research is to ensure that therapeutic protocols are well below the threshold for pathogenesis. This is possible since many low dose rAIH protocols have induced functional benefits without evidence of pathology. We propose that carefully controlled rAIH is a safe and noninvasive modality that can be paired with other neurorehabilitative strategies including traditional activity-based physical therapy or cell-based therapies such as intraspinal transplantation of neural progenitors. PMID:25997947

Acute cardiac support with intravenous milrinone promotes recovery from early brain injury in a murine model of severe subarachnoid haemorrhage.

PubMed

Mutoh, Tomoko; Mutoh, Tatsushi; Nakamura, Kazuhiro; Yamamoto, Yukiko; Tsuru, Yoshiharu; Tsubone, Hirokazu; Ishikawa, Tatsuya; Taki, Yasuyuki

2017-04-01

Early brain injury/ischaemia (EBI) is a serious complication early after subarachnoid haemorrhage (SAH) that contributes to development of delayed cerebral ischaemia (DCI). This study aimed to determine the role of inotropic cardiac support using milrinone (MIL) on restoring acute cerebral hypoperfusion attributable to EBI and improving outcomes after experimental SAH. Forty-three male C57BL/6 mice were assigned to either sham surgery (SAH-sham), SAH induced by endovascular perforation plus postconditioning with 2% isoflurane (Control), or SAH plus isoflurane combined with MIL with and without hypoxia-inducible factor inhibitor (HIF-I) pretreatment. Cardiac output (CO) during intravenous MIL infusion (0.25-0.75 μg/kg/min) between 1.5 and 2.5 hours after SAH induction was monitored with Doppler echocardiography. Magnetic resonance imaging (MRI)-continuous arterial spin labelling was used for quantitative cerebral blood flow (CBF) measurements. Neurobehavioral function was assessed daily by neurological score and open field test. DCI was analyzed 3 days later by determining infarction on MRI. Mild reduction of cardiac output (CO) and global cerebral blood flow (CBF) depression were notable early after SAH. MIL increased CO in a dose-dependent manner (P<.001), which was accompanied by improved hypoperfusion, incidence of DCI and functional recovery than Control (P<.05). The neuroprotective effects afforded by MIL or Control were attenuated by hypoxia-inducible factor (HIF) inhibition (P<.05). These results suggest that MIL improves acute hypoperfusion by its inotropic effect, leading to neurobehavioral improvement in mice after severe SAH, in which HIF may be acting as a critical mediator. © 2017 John Wiley & Sons Australia, Ltd.

Size restricted silymarin suspension evokes integrated adaptive response against acute hypoxia exposure in rat lung.

PubMed

Paul, Subhojit; Arya, Aditya; Gangwar, Anamika; Bhargava, Kalpana; Ahmad, Yasmin

2016-07-01

Despite its extraordinary antioxidant capacity, the clinical usage of silymarin has remained restricted to amelioration of hepatic pathology. Perhaps its low bioavailability and uneven bio-distribution, owing to its poor aqueous solubility, are two main causes that have dampened the clinical applicability and scope of this preparation. We took these two challenges and suggested an unexplored application of silymarin. Apart from liver, two of the most susceptible vital organs at the highest risk of oxidative stress are brain and lung, especially during reduced oxygen saturation (hypoxia) at anatomical level. Hypoxia causes excess generation of radicals primarily in the lungs as it is the first organ at the interphase of atmosphere and organism making it the most prone and vulnerable to oxidative stress and the first responder against hypobaric hypoxia. As our first objective, we improved the silymarin formulation by restricting its size to the lower threshold and then successfully tested the prophylactic and therapeutic action in rat lung challenged with simulated hypobaric hypoxia. After dose optimization, we observed that 50mg/kg BW silymarin as size restricted and homogenous aqueous suspension successfully minimized the reactive oxygen species and augmented the antioxidant defense by significant upregulation of catalase and superoxide dismutase and reduced glutathione. Moreover, the well-established hypoxia markers and proteins related to hypoxia adaptability, hif1a and VEGF were differentially regulated conferring significant reduction in the inflammation caused by hypobaric hypoxia. We therefore report,the unexplored potential benefits of silymarin for preventing high altitude associated pathophysiology further paving its road to clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

Thermoregulatory responses to exercise at a fixed rate of heat production are not altered by acute hypoxia

PubMed Central

Coombs, Geoff B.; Ravanelli, Nicholas; Imbeault, Pascal

2017-01-01

This study sought to assess the within-subject influence of acute hypoxia on exercise-induced changes in core temperature and sweating. Eight participants [1.75 (0.06) m, 70.2 (6.8) kg, 25 (4) yr, 54 (8) ml·kg−1·min−1] completed 45 min of cycling, once in normoxia (NORM; FIO2 = 0.21) and twice in hypoxia (HYP1/HYP2; FIO2= 0.13) at 34.4(0.2)°C, 46(3)% RH. These trials were designed to elicit 1) two distinctly different %V̇o2peak [NORM: 45 (8)% and HYP1: 62 (7)%] at the same heat production (Hprod) [NORM: 6.7 (0.6) W/kg and HYP1: 7.0 (0.5) W/kg]; and 2) the same %V̇o2peak [NORM: 45 (8)% and HYP2: 48 (5)%] with different Hprod [NORM: 6.7 (0.6) W/kg and HYP2: 5.5 (0.6) W/kg]. At a fixed %V̇o2peak, changes in rectal temperature (ΔTre) and changes in esophageal temperature (ΔTes) were greater at end-exercise in NORM [ΔTre: 0.76 (0.19)°C; ΔTes: 0.64 (0.22)°C] compared with HYP2 [ΔTre: 0.56 (0.22)°C, P < 0.01; ΔTes: 0.42 (0.21)°C, P < 0.01]. As a result of a greater Hprod (P < 0.01) in normoxia, and therefore evaporative heat balance requirements, to maintain a similar %V̇o2peak compared with hypoxia, mean local sweat rates (LSR) from the forearm, upper back, and forehead were greater (all P < 0.01) in NORM [1.10 (0.20) mg·cm−2·min−1] compared with HYP2 [0.71 (0.19) mg·cm−2·min−1]. However, at a fixed Hprod, ΔTre [0.75 (0.24)°C; P = 0.77] and ΔTes [0.63 (0.29)°C; P = 0.69] were not different in HYP1, compared with NORM. Likewise, mean LSR [1.11 (0.20) mg·cm−2·min−1] was not different (P = 0.84) in HYP1 compared with NORM. These data demonstrate, using a within-subjects design, that hypoxia does not independently influence thermoregulatory responses. Additionally, further evidence is provided to support that metabolic heat production, irrespective of %V̇o2peak, determines changes in core temperature and sweating during exercise. NEW & NOTEWORTHY Using a within-subject design, hypoxia does not independently alter core temperature

Haemoglobin function in vertebrates: evolutionary changes in cellular regulation in hypoxia.

PubMed

Nikinmaa, M

2001-11-15

The evolution of erythrocytic hypoxia responses is reviewed by comparing the cellular control of haemoglobin-oxygen affinity in agnathans, teleost fish and terrestrial vertebrates. The most ancient response to hypoxic conditions appears to be an increase in cell volume, which increases the haemoglobin-oxygen affinity in lampreys. In teleost fish, an increase of cell volume in hypoxic conditions is also evident. The volume increase is coupled to an increase in erythrocyte pH. These changes are caused by an adrenergic activation of sodium/proton exchange across the erythrocyte membrane. The mechanism is important in acute hypoxia and is followed by a decrease in cellular adenosine triphosphate (ATP) and guanosine triphosphate (GTP) concentrations in continued hypoxia. In hypoxic bird embryos, the ATP levels are also reduced. The mechanisms by which hypoxia decreases cellular ATP and GTP concentrations remains unknown, although at least in bird embryos cAMP-dependent mechanisms have been implicated. In mammals, hypoxia responses appear to occur mainly via modulation of cellular organic phosphate concentrations. In moderate hypoxia, 2,3-diphosphoglycerate levels are increased as a result of alkalosis caused by increased ventilation.

Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

PubMed Central

Gralinski, Lisa E.; Bankhead, Armand; Jeng, Sophia; Menachery, Vineet D.; Proll, Sean; Belisle, Sarah E.; Matzke, Melissa; Webb-Robertson, Bobbie-Jo M.; Luna, Maria L.; Shukla, Anil K.; Ferris, Martin T.; Bolles, Meagan; Chang, Jean; Aicher, Lauri; Waters, Katrina M.; Smith, Richard D.; Metz, Thomas O.; Law, G. Lynn; Katze, Michael G.; McWeeney, Shannon; Baric, Ralph S.

2013-01-01

ABSTRACT Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a time course of matched virologic, pathological, and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high-priority list of 4 genes in one pathway out of over 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV. PMID:23919993

Impaired ventilatory acclimatization to hypoxia in mice lacking the immediate early gene fos B.

PubMed

Malik, Mohammad T; Peng, Ying-Jie; Kline, David D; Adhikary, Gautam; Prabhakar, Nanduri R

2005-01-15

Earlier studies on cell culture models suggested that immediate early genes (IEGs) play an important role in cellular adaptations to hypoxia. Whether IEGs are also necessary for hypoxic adaptations in intact animals is not known. In the present study we examined the potential importance of fos B, an IEG in ventilatory acclimatization to hypoxia. Experiments were performed on wild type and mutant mice lacking the fos B gene. Ventilation was monitored by whole body plethysmography in awake animals. Baseline ventilation under normoxia, and ventilatory response to acute hypoxia and hypercapnia were comparable between wild type and mutant mice. Hypobaric hypoxia (0.4 atm; 3 days) resulted in a significant elevation of baseline ventilation in wild type but not in mutant mice. Wild type mice exposed to hypobaric hypoxia manifested an enhanced hypoxic ventilatory response compared to pre-hypobaric hypoxia. In contrast, hypobaric hypoxia had no effect on the hypoxic ventilatory response in mutant mice. Hypercapnic ventilatory responses, however, were unaffected by hypobaric hypoxia in both groups of mice. These results suggest that the fos B, an immediate early gene, plays an important role in ventilatory acclimatization to hypoxia in mice.

Medical emergencies: pulmonary embolism and acute severe asthma.

PubMed

Somasundaram, K; Ball, J

2013-01-01

In this, the second of two articles covering specific medical emergencies, we discuss the definitions, epidemiology, pathophysiology, acute and chronic management of pulmonary embolus and acute severe asthma. Anaesthesia © 2012 The Association of Anaesthetists of Great Britain and Ireland.

Lateral parabrachial nucleus mediates shortening of expiration during hypoxia.

PubMed

Song, Gang; Poon, Chi-Sang

2009-01-01

Acute hypoxia elicits complex time-dependent responses including rapid augmentation of inspiratory drive, shortening of inspiratory and expiratory durations (T(I), T(E)), and short-term potentiation and depression. The central pathways mediating these varied effects are largely unknown. Here, we show that the lateral parabrachial nucleus (LPBN) of the dorsolateral pons specifically mediates T(E)-shortening during hypoxia and not other hypoxic response components. Twelve urethane-anesthetized and vagotomized adult Sprague-Dawley rats were exposed to 1-min poikilocapnic hypoxia before and after unilateral kainic acid or bilateral electrolytic lesioning of the LPBN. Bilateral lesions resulted in a significant increase in baseline T(E) under hyperoxia. After unilateral or bilateral lesions, the decrease in T(E) during hypoxia was markedly attenuated without appreciable changes in all other hypoxic response components. These findings add to the mounting evidence that the central processing of peripheral chemoafferent inputs is segregated into parallel integrator and differentiator (low-pass and high-pass filter) pathways that separately modulate inspiratory drive, T(I), T(E) and resultant short-term potentiation and depression.

Acute hypoxia influences collagen and matrix metalloproteinase expression by human keratoconus cells in vitro.

PubMed

McKay, Tina B; Hjortdal, Jesper; Priyadarsini, Shrestha; Karamichos, Dimitrios

2017-01-01

Keratoconus (KC) is a progressive corneal ectasia linked to thinning of the central cornea. Hard contact lenses, rigid gas permeable lenses, and scleral lenses are the primary treatment modalities for early to mid- stages of KC to correct refractive error and astigmatism that develops as a result of an irregular corneal structure. These treatments are associated with significant drawbacks, including reduced availability of the tear film and oxygen to the corneal epithelium and stroma. However, it remains unknown whether hypoxia affects corneal integrity in the KC pathobiology. A number of studies have associated elevated oxidative stress with KC both in vitro and ex vivo. We hypothesized that KC-derived corneal fibroblasts are more susceptible to hypoxia-induced oxidative stress compared to healthy controls leading to exacerbation of corneal thinning in KC. This study investigated the effects of hypoxia on ECM secretion, assembly, and matrix metalloproteinase (MMP) expression in human corneal fibroblasts from healthy controls (HCFs) and KC patients (HKCs) in vitro. HCFs and HKCs were cultured in 3D constructs for 3 weeks and maintained or transferred to normoxic (21% O2) or hypoxic (2% O2) conditions, respectively, for 1 additional week. At the 4 week time-point, constructs were isolated and probed for Collagen I, III, and V, keratocan and MMP-1, -2, -3, -9, and -13, as well as hypoxia markers, hypoxia inducible factor-1α and lactoferrin. Conditioned media was also collected and probed for Collagen I, III, and V by Western blot. Thickness of the ECM assembled by HCFs and HKCs was measured using immunofluorescence microscopy. Results showed that hypoxia significantly reduced Collagen I secretion in HKCs, as well as upregulated the expression of MMP-1 and -2 with no significant effects on MMP-3, -9, or -13. ECM thickness was reduced in both cell types following 1 week in a low oxygen environment. Our study shows that hypoxia influences collagen and MMP expression by

Effects of temperature and cadmium exposure on the mitochondria of oysters (Crassostrea virginica) exposed to hypoxia and subsequent reoxygenation.

PubMed

Ivanina, Anna V; Kurochkin, Ilya O; Leamy, Larry; Sokolova, Inna M

2012-09-15

Intertidal bivalves are commonly exposed to multiple stressors including periodic hypoxia, temperature fluctuations and pollution, which can strongly affect energy metabolism. We used top-down control and elasticity analyses to determine the interactive effects of intermittent hypoxia, cadmium (Cd) exposure and acute temperature stress on mitochondria of the eastern oyster Crassostrea virginica. Oysters were acclimated at 20°C for 30 days in the absence or presence of 50 μg l(-1) Cd and then subjected to a long-term hypoxia (6 days at <0.5% O(2) in seawater) followed by normoxic recovery. Mitochondrial function was assessed at the acclimation temperature (20°C), or at elevated temperature (30°C) mimicking acute temperature stress in the intertidal zone. In the absence of Cd or temperature stress, mitochondria of oysters showed high resilience to transient hypoxia. In control oysters at 20°C, hypoxia/reoxygenation induced elevated flux capacity of all three studied mitochondrial subsystems (substrate oxidation, phosphorylation and proton leak) and resulted in a mild depolarization of resting mitochondria. Elevated proton conductance and enhanced capacity of phosphorylation and substrate oxidation subsystems may confer resistance to hypoxia/reoxygenation stress in oyster mitochondria by alleviating production of reactive oxygen species and maintaining high aerobic capacity and ATP synthesis rates during recovery. Exposure to environmental stressors such as Cd and elevated temperatures abolished the putative adaptive responses of the substrate oxidation and phosphorylation subsystems, and strongly enhanced proton leak in mitochondria of oysters subjected to hypoxia/reoxygenation stress. Our findings suggest that Cd exposure and acute temperature stress may lead to the loss of mitochondrial resistance to hypoxia and reoxygenation and thus potentially affect the ability of oysters to survive periodic oxygen deprivation in coastal and estuarine habitats.

Transcriptomics Modeling of the Late-Gestation Fetal Pituitary Response to Transient Hypoxia

PubMed Central

Wood, Charles E.; Chang, Eileen I.; Richards, Elaine M.; Rabaglino, Maria Belen; Keller-Wood, Maureen

2016-01-01

Background The late-gestation fetal sheep responds to hypoxia with physiological, neuroendocrine, and cellular responses that aid in fetal survival. The response of the fetus to hypoxia represents a coordinated effort to maximize oxygen transfer from the mother and minimize wasteful oxygen consumption by the fetus. While there have been many studies aimed at investigating the coordinated physiological and endocrine responses to hypoxia, and while immunohistochemical or in situ hybridization studies have revealed pathways supporting the endocrine function of the pituitary, there is little known about the coordinated cellular response of the pituitary to the hypoxia. Results Thirty min hypoxia (from 17.0±1.7 to 8.0±0.8 mm Hg, followed by 30 min normoxia) upregulated 595 and downregulated 790 genes in fetal pituitary (123–132 days’ gestation; term = 147 days). Network inference of up- and down- regulated genes revealed a high degree of functional relatedness amongst the gene sets. Gene ontology analysis revealed upregulation of cellular metabolic processes (e.g., RNA synthesis, response to estrogens) and downregulation of protein phosphorylation, protein metabolism, and mitosis. Genes found to be at the center of the network of upregulated genes included genes important for purine binding and signaling. At the center of the downregulated network were genes involved in mRNA processing, DNA repair, sumoylation, and vesicular trafficking. Transcription factor analysis revealed that both up- and down-regulated gene sets are enriched for control by several transcription factors (e.g., SP1, MAZ, LEF1, NRF1, ELK1, NFAT, E12, PAX4) but not for HIF-1, which is known to be an important controller of genomic responses to hypoxia. Conclusions The multiple analytical approaches used in this study suggests that the acute response to 30 min of transient hypoxia in the late-gestation fetus results in reduced cellular metabolism and a pattern of gene expression that is

Landscape-level variation in disease susceptibility related to shallow-water hypoxia.

PubMed

Breitburg, Denise L; Hondorp, Darryl; Audemard, Corinne; Carnegie, Ryan B; Burrell, Rebecca B; Trice, Mark; Clark, Virginia

2015-01-01

Diel-cycling hypoxia is widespread in shallow portions of estuaries and lagoons, especially in systems with high nutrient loads resulting from human activities. Far less is known about the effects of this form of hypoxia than deeper-water seasonal or persistent low dissolved oxygen. We examined field patterns of diel-cycling hypoxia and used field and laboratory experiments to test its effects on acquisition and progression of Perkinsus marinus infections in the eastern oyster, Crassostrea virginica, as well as on oyster growth and filtration. P. marinus infections cause the disease known as Dermo, have been responsible for declines in oyster populations, and have limited success of oyster restoration efforts. The severity of diel-cycling hypoxia varied among shallow monitored sites in Chesapeake Bay, and average daily minimum dissolved oxygen was positively correlated with average daily minimum pH. In both field and laboratory experiments, diel-cycling hypoxia increased acquisition and progression of infections, with stronger results found for younger (1-year-old) than older (2-3-year-old) oysters, and more pronounced effects on both infections and growth found in the field than in the laboratory. Filtration by oysters was reduced during brief periods of exposure to severe hypoxia. This should have reduced exposure to waterborne P. marinus, and contributed to the negative relationship found between hypoxia frequency and oyster growth. Negative effects of hypoxia on the host immune response is, therefore, the likely mechanism leading to elevated infections in oysters exposed to hypoxia relative to control treatments. Because there is considerable spatial variation in the frequency and severity of hypoxia, diel-cycling hypoxia may contribute to landscape-level spatial variation in disease dynamics within and among estuarine systems.

The effect of sustained hypoxia on the cardio-respiratory response of bowfin Amia calva: implications for changes in the oxygen transport system.

PubMed

Porteus, C S; Wright, P A; Milsom, W K

2014-03-01

This study examined mechanisms underlying cardio-respiratory acclimation to moderate sustained hypoxia (6.0 kPa for 7 days at 22° C) in the bowfin Amia calva, a facultative air-breathing fish. This level of hypoxia is slightly below the critical oxygen tension (pcrit ) of A. calva denied access to air (mean ± s.e. = 9.3 ± 1.0 kPa). Before exposure to sustained hypoxia, A. calva with access to air increased air-breathing frequency on exposure to acute progressive hypoxia while A. calva without access to air increased gill-breathing frequency. Exposure to sustained hypoxia increased the gill ventilation response to acute progressive hypoxia in A. calva without access to air, regardless of whether they had access to air or not during the sustained hypoxia. Additionally, there was a decrease in Hb-O2 binding affinity in these fish. This suggests that, in A. calva, acclimation to hypoxia elicits changes that increase oxygen delivery to the gas exchange surface for oxygen uptake and reduce haemoglobin affinity to enhance oxygen delivery to the tissues. © 2013 The Fisheries Society of the British Isles.

Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia

PubMed Central

Petousi, Nayia; Croft, Quentin P. P.; Cavalleri, Gianpiero L.; Cheng, Hung-Yuan; Formenti, Federico; Ishida, Koji; Lunn, Daniel; McCormack, Mark; Shianna, Kevin V.; Talbot, Nick P.; Ratcliffe, Peter J.

2013-01-01

Tibetan natives have lived on the Tibetan plateau (altitude ∼4,000 m) for at least 25,000 years, and as such they are adapted to life and reproduction in a hypoxic environment. Recent studies have identified two genetic loci, EGLN1 and EPAS1, that have undergone natural selection in Tibetans, and further demonstrated an association of EGLN1/EPAS1 genotype with hemoglobin concentration. Both genes encode major components of the hypoxia-inducible factor (HIF) transcriptional pathway, which coordinates an organism's response to hypoxia. Patients living at sea level with genetic disease of the HIF pathway have characteristic phenotypes at both the integrative-physiology and cellular level. We sought to test the hypothesis that natural selection to hypoxia within Tibetans results in related phenotypic differences. We compared Tibetans living at sea level with Han Chinese, who are Tibetans' most closely related major ethnic group. We found that Tibetans had a lower hemoglobin concentration, a higher pulmonary ventilation relative to metabolism, and blunted pulmonary vascular responses to both acute (minutes) and sustained (8 h) hypoxia. At the cellular level, the relative expression and hypoxic induction of HIF-regulated genes were significantly lower in peripheral blood lymphocytes from Tibetans compared with Han Chinese. Within the Tibetans, we found a significant correlation between both EPAS1 and EGLN1 genotype and the induction of erythropoietin by hypoxia. In conclusion, this study provides further evidence that Tibetans respond less vigorously to hypoxic challenge. This is evident at sea level and, at least in part, appears to arise from a hyporesponsive HIF transcriptional system. PMID:24030663

[Epidemiology of severe acute renal failure in Metropolitan Santiago].

PubMed

Vukusich, Antonio; Alvear, Felipe; Villanueva, Pablo; González, Claudio; Francisco, Olivari; Alvarado, Nelly; Zehnder, Carlos

2004-11-01

There is a paucity of information about the epidemiology of acute renal failure in Chile. To perform a prospective multicentric survey of severe acute renal failure in Chile. All patients admitted to ten hospitals in Metropolitan Santiago, during a period of six months with severe acute renal failure, were studied. The criteria for severity was the requirement of renal replacement therapy. All patients information was gathered in special forms and the type of renal replacement therapy and evolution was registeres. One hundred fourteen patients were studied (65 males, age range 18 to 87 years). The calculated incidence of acute renal failure was 1.03 cases per 1000 hospital discharges. The onset was nosocomial in 79 subjects (69%) and community acquired in the rest. Renal failure was oliguric in 64 cases (56%) and in 60% of patients it had two or more causative factors. Sepsis, isolated or combined with other causes, was present in 51 of patients. Other causes included ischemia in 47%, surgery in 26%, exogenous toxicity in 25%, endocenous toxicity in 11%, acute glomerular damage in 6% and obstructive uropathy in 6%. Cardiac surgery was responsible for 47% of post operative cases of acute renal failure. Intermittent conventional hemodialysis, continuous renal replacement techniques and daily prolonged hemodialysis were used in 66%, 29% and 2% of patients, respectively. Overall mortality was 45% and it was higher in oliguric patients. Gender, age, cause or the type of therapy did not influence survival. Nine percent of surviving patients had some degree of kidney dysfunction at discharge. There is still a great space for prevention of severe acute renal failure in Chile, considering the main etiologies found in this study.

Protein synthesis is defended in the mitochondrial fraction of gill but not heart in cunner (Tautogolabrus adspersus) exposed to acute hypoxia and hypothermia.

PubMed

Lewis, Johanne M; Driedzic, William R

2010-02-01

The cunner, Tautogolabrus adspersus, is a north-temperate teleost which relies upon metabolic depression to survive the extreme low water temperatures of its habitat during the winter. Previous study has demonstrated a decrease in protein synthesis accompanies the metabolic depression observed at the whole animal level during seasonal low temperature exposure. As such, the objective of the current study was to determine: (i) if the response of decreased protein synthesis is conserved across environmental stressors and (ii) if the response of metabolic depression is conserved across levels of cellular organization. This was accomplished through the measurement of in vivo protein synthesis rates in the whole tissue, cytosolic and mitochondrial protein pools (reflective of nuclear encoded proteins imported into mitochondria) of heart and gill in cunner exposed to either acute low temperature (8-4 degrees C) or acute hypoxia (10% O(2) saturation). In both heart and gill, rates of protein synthesis in the whole tissue and cytosolic protein pools were substantially depressed by 80% in response to acute hypothermia. In hypoxic heart, protein synthesis was significantly decreased by 50-60% in the whole tissue, cytosolic and mitochondrial pools; however, in gill there was no significant difference in rates of protein synthesis in any cellular fraction between normoxic and hypoxic groups. Most strikingly the rate of new protein accumulation in the mitochondrial fraction of gill did not change in response to either a decrease in temperature or hypoxia. The defense of protein synthesis in the gill is most likely associated with the importance of maintaining ionic regulation and the oxidative capacity in this front line organ for gas and ion exchange.

Intermittent Hypoxia Increases the Severity of Bleomycin-Induced Lung Injury in Mice.

PubMed

Gille, Thomas; Didier, Morgane; Rotenberg, Cécile; Delbrel, Eva; Marchant, Dominique; Sutton, Angela; Dard, Nicolas; Haine, Liasmine; Voituron, Nicolas; Bernaudin, Jean-François; Valeyre, Dominique; Nunes, Hilario; Besnard, Valérie; Boncoeur, Emilie; Planès, Carole

2018-01-01

Severe obstructive sleep apnea (OSA) with chronic intermittent hypoxia (IH) is common in idiopathic pulmonary fibrosis (IPF). Here, we evaluated the impact of IH on bleomycin- (BLM-) induced pulmonary fibrosis in mice. C57BL/6J mice received intratracheal BLM or saline and were exposed to IH (40 cycles/hour; FiO 2 nadir: 6%; 8 hours/day) or intermittent air (IA). In the four experimental groups, we evaluated (i) survival; (ii) alveolar inflammation, pulmonary edema, lung oxidative stress, and antioxidant enzymes; (iii) lung cell apoptosis; and (iv) pulmonary fibrosis. Survival at day 21 was lower in the BLM-IH group ( p < 0.05). Pulmonary fibrosis was more severe at day 21 in BLM-IH mice, as assessed by lung collagen content ( p = 0.02) and histology. At day 4, BLM-IH mice developed a more severe neutrophilic alveolitis, ( p < 0.001). Lung oxidative stress was observed, and superoxide dismutase and glutathione peroxidase expression was decreased in BLM-IH mice ( p < 0.05 versus BLM-IA group). At day 8, pulmonary edema was observed and lung cell apoptosis was increased in the BLM-IH group. These results show that exposure to chronic IH increases mortality, lung inflammation, and lung fibrosis in BLM-treated mice. This study raises the question of the worsening impact of severe OSA in IPF patients.

Drug induced acute pancreatitis: incidence and severity.

PubMed Central

Lankisch, P G; Dröge, M; Gottesleben, F

1995-01-01

To determine the incidence and severity of drug induced acute pancreatitis, data from 45 German centres of gastroenterology were evaluated. Among 1613 patients treated for acute pancreatitis in 1993, drug induced acute pancreatitis was diagnosed in 22 patients (incidence 1.4%). Drugs held responsible were azathioprine, mesalazine/sulfasalazine, 2',3'-dideoxyinosine (ddI), oestrogens, frusemide, hydrochlorothiazide, and rifampicin. Pancreatic necrosis not exceeding 33% of the organ was found on ultrasonography or computed tomography, or both, in three patients (14%). Pancreatic pseudocysts did not occur. A decrease of arterial PO2 reflecting respiratory insufficiency, and an increase of serum creatinine, reflecting renal insufficiency as complications of acute pancreatitis were seen in two (9%) and four (18%) patients, respectively. Artificial ventilation was not needed, and dialysis was necessary in only one (5%) case. Two patients (9%) died of AIDS and tuberculosis, respectively; pancreatitis did not seem to have contributed materially to their death. In conclusion, drugs rarely cause acute pancreatitis, and drug induced acute pancreatitis usually runs a benign course. PMID:7489946

High Resolution ECG for Evaluation of QT Interval Variability during Exposure to Acute Hypoxia

NASA Technical Reports Server (NTRS)

Zupet, P.; Finderle, Z.; Schlegel, Todd T.; Starc, V.

2010-01-01

Ventricular repolarization instability as quantified by the index of QT interval variability (QTVI) is one of the best predictors for risk of malignant ventricular arrhythmias and sudden cardiac death. Because it is difficult to appropriately monitor early signs of organ dysfunction at high altitude, we investigated whether high resolution advanced ECG (HR-ECG) analysis might be helpful as a non-invasive and easy-to-use tool for evaluating the risk of cardiac arrhythmias during exposure to acute hypoxia. 19 non-acclimatized healthy trained alpinists (age 37, 8 plus or minus 4,7 years) participated in the study. Five-minute high-resolution 12-lead electrocardiograms (ECGs) were recorded (Cardiosoft) in each subject at rest in the supine position breathing room air and then after breathing 12.5% oxygen for 30 min. For beat-to-beat RR and QT variability, the program of Starc was utilized to derive standard time domain measures such as root mean square of the successive interval difference (rMSSD) of RRV and QTV, the corrected QT interval (QTc) and the QTVI in lead II. Changes were evaluated with paired-samples t-test with p-values less than 0.05 considered statistically significant. As expected, the RR interval and its variability both decreased with increasing altitude, with p = 0.000 and p = 0.005, respectively. Significant increases were found in both the rMSSDQT and the QTVI in lead II, with p = 0.002 and p = 0.003, respectively. There was no change in QTc interval length (p = non significant). QT variability parameters may be useful for evaluating changes in ventricular repolarization caused by hypoxia. These changes might be driven by increases in sympathetic nervous system activity at ventricular level.

Effects of acute hypoxia/acidosis on intracellular pH in differentiating neural progenitor cells.

PubMed

Nordström, Tommy; Jansson, Linda C; Louhivuori, Lauri M; Akerman, Karl E O

2012-06-21

The response of differentiating mouse neural progenitor cells, migrating out from neurospheres, to conditions simulating ischemia (hypoxia and extracellular or intracellular acidosis) was studied. We show here, by using BCECF and single cell imaging to monitor intracellular pH (pH(i)), that two main populations can be distinguished by exposing migrating neural progenitor cells to low extracellular pH or by performing an acidifying ammonium prepulse. The cells dominating at the periphery of the neurosphere culture, which were positive for neuron specific markers MAP-2, calbindin and NeuN had lower initial resting pH(i) and could also easily be further acidified by lowering the extracellular pH. Moreover, in this population, a more profound acidification was seen when the cells were acidified using the ammonium prepulse technique. However, when the cell population was exposed to depolarizing potassium concentrations no alterations in pH(i) took place in this population. In contrast, depolarization caused an increase in pH(i) (by 0.5 pH units) in the cell population closer to the neurosphere body, which region was positive for the radial cell marker (GLAST). This cell population, having higher resting pH(i) (pH 6.9-7.1) also responded to acute hypoxia. During hypoxic treatment the resting pH(i) decreased by 0.1 pH units and recovered rapidly after reoxygenation. Our results show that migrating neural progenitor cells are highly sensitive to extracellular acidosis and that irreversible damage becomes evident at pH 6.2. Moreover, our results show that a response to acidosis clearly distinguishes two individual cell populations probably representing neuronal and radial cells. Copyright © 2012 Elsevier B.V. All rights reserved.

Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

PubMed

Alimoradi, Houman; Matikonda, Siddharth S; Gamble, Allan B; Giles, Gregory I; Greish, Khaled

2016-01-01

Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents. With the advances in nanotechnology, novel delivery systems activated by the consequent outcomes of hypoxia have been developed. However, developing hypoxia responsive drug delivery systems (which only depend on low oxygen levels) is currently naïve. This review discusses four main hypoxia responsive delivery systems: polymeric based drug delivery systems, oxygen delivery systems combined with radiotherapy and chemotherapy, anaerobic bacteria which are used for delivery of genes to express anticancer proteins such as tumor necrosis alpha (TNF-α) and hypoxia-inducible transcription factors 1 alpha (HIF1α) responsive gene delivery systems.

HIF and HOIL-1L-mediated PKCζ degradation stabilizes plasma membrane Na,K-ATPase to protect against hypoxia-induced lung injury.

PubMed

Magnani, Natalia D; Dada, Laura A; Queisser, Markus A; Brazee, Patricia L; Welch, Lynn C; Anekalla, Kishore R; Zhou, Guofei; Vagin, Olga; Misharin, Alexander V; Budinger, G R Scott; Iwai, Kazuhiro; Ciechanover, Aaron J; Sznajder, Jacob I

2017-11-21

Organisms have evolved adaptive mechanisms in response to stress for cellular survival. During acute hypoxic stress, cells down-regulate energy-consuming enzymes such as Na,K-ATPase. Within minutes of alveolar epithelial cell (AEC) exposure to hypoxia, protein kinase C zeta (PKCζ) phosphorylates the α 1 -Na,K-ATPase subunit and triggers it for endocytosis, independently of the hypoxia-inducible factor (HIF). However, the Na,K-ATPase activity is essential for cell homeostasis. HIF induces the heme-oxidized IRP2 ubiquitin ligase 1L (HOIL-1L), which leads to PKCζ degradation. Here we report a mechanism of prosurvival adaptation of AECs to prolonged hypoxia where PKCζ degradation allows plasma membrane Na,K-ATPase stabilization at ∼50% of normoxic levels, preventing its excessive down-regulation and cell death. Mice lacking HOIL-1L in lung epithelial cells ( Cre SPC /HOIL-1L fl/fl ) were sensitized to hypoxia because they express higher levels of PKCζ and, consequently, lower plasma membrane Na,K-ATPase levels, which increased cell death and worsened lung injury. In AECs, expression of an α 1 -Na,K-ATPase construct bearing an S18A (α 1 -S18A) mutation, which precludes PKCζ phosphorylation, stabilized the Na,K-ATPase at the plasma membrane and prevented hypoxia-induced cell death even in the absence of HOIL-1L. Adenoviral overexpression of the α 1 -S18A mutant Na,K-ATPase in vivo rescued the enhanced sensitivity of Cre SPC/ HOIL-1L fl/fl mice to hypoxic lung injury. These data suggest that stabilization of Na,K-ATPase during severe hypoxia is a HIF-dependent process involving PKCζ degradation. Accordingly, we provide evidence of an important adaptive mechanism to severe hypoxia, whereby halting the exaggerated down-regulation of plasma membrane Na,K-ATPase prevents cell death and lung injury.

Thermoregulatory responses to exercise at a fixed rate of heat production are not altered by acute hypoxia.

PubMed

Coombs, Geoff B; Cramer, Matthew N; Ravanelli, Nicholas; Imbeault, Pascal; Jay, Ollie

2017-05-01

This study sought to assess the within-subject influence of acute hypoxia on exercise-induced changes in core temperature and sweating. Eight participants [1.75 (0.06) m, 70.2 (6.8) kg, 25 (4) yr, 54 (8) ml·kg -1 ·min -1 ] completed 45 min of cycling, once in normoxia (NORM; [Formula: see text] = 0.21) and twice in hypoxia (HYP1/HYP2; [Formula: see text]= 0.13) at 34.4(0.2)°C, 46(3)% RH. These trials were designed to elicit 1 ) two distinctly different %V̇o 2peak [NORM: 45 (8)% and HYP1: 62 (7)%] at the same heat production (H prod ) [NORM: 6.7 (0.6) W/kg and HYP1: 7.0 (0.5) W/kg]; and 2 ) the same %V̇o 2peak [NORM: 45 (8)% and HYP2: 48 (5)%] with different H prod [NORM: 6.7 (0.6) W/kg and HYP2: 5.5 (0.6) W/kg]. At a fixed %V̇o 2peak , changes in rectal temperature (ΔT re ) and changes in esophageal temperature (ΔT es ) were greater at end-exercise in NORM [ΔT re : 0.76 (0.19)°C; ΔT es : 0.64 (0.22)°C] compared with HYP2 [ΔT re : 0.56 (0.22)°C, P < 0.01; ΔT es : 0.42 (0.21)°C, P < 0.01]. As a result of a greater H prod ( P < 0.01) in normoxia, and therefore evaporative heat balance requirements, to maintain a similar %V̇o 2peak compared with hypoxia, mean local sweat rates (LSR) from the forearm, upper back, and forehead were greater (all P < 0.01) in NORM [1.10 (0.20) mg·cm -2 ·min -1 ] compared with HYP2 [0.71 (0.19) mg·cm -2 ·min -1 ]. However, at a fixed H prod , ΔT re [0.75 (0.24)°C; P = 0.77] and ΔT es [0.63 (0.29)°C; P = 0.69] were not different in HYP1, compared with NORM. Likewise, mean LSR [1.11 (0.20) mg·cm -2 ·min -1 ] was not different ( P = 0.84) in HYP1 compared with NORM. These data demonstrate, using a within-subjects design, that hypoxia does not independently influence thermoregulatory responses. Additionally, further evidence is provided to support that metabolic heat production, irrespective of %V̇o 2peak , determines changes in core temperature and sweating during exercise. NEW & NOTEWORTHY Using a within

The role of necrosis, acute hypoxia and chronic hypoxia in 18F-FMISO PET image contrast: a computational modelling study

NASA Astrophysics Data System (ADS)

Warren, Daniel R.; Partridge, Mike

2016-12-01

Positron emission tomography (PET) using 18F-fluoromisonidazole (FMISO) is a promising technique for imaging tumour hypoxia, and a potential target for radiotherapy dose-painting. However, the relationship between FMISO uptake and oxygen partial pressure ({{P}{{\\text{O}2}}} ) is yet to be quantified fully. Tissue oxygenation varies over distances much smaller than clinical PET resolution (<100 μm versus  ˜4 mm), and cyclic variations in tumour perfusion have been observed on timescales shorter than typical FMISO PET studies (˜20 min versus a few hours). Furthermore, tracer uptake may be decreased in voxels containing some degree of necrosis. This work develops a computational model of FMISO uptake in millimetre-scale tumour regions. Coupled partial differential equations govern the evolution of oxygen and FMISO distributions, and a dynamic vascular source map represents temporal variations in perfusion. Local FMISO binding capacity is modulated by the necrotic fraction. Outputs include spatiotemporal maps of {{P}{{\\text{O}2}}} and tracer accumulation, enabling calculation of tissue-to-blood ratios (TBRs) and time-activity curves (TACs) as a function of mean tissue oxygenation. The model is characterised using experimental data, finding half-maximal FMISO binding at local {{P}{{\\text{O}2}}} of 1.4 mmHg (95% CI: 0.3-2.6 mmHg) and half-maximal necrosis at 1.2 mmHg (0.1-4.9 mmHg). Simulations predict a non-linear non-monotonic relationship between FMISO activity (4 hr post-injection) and mean tissue {{P}{{\\text{O}2}}} : tracer uptake rises sharply from negligible levels in avascular tissue, peaking at  ˜5 mmHg and declining towards blood activity in well-oxygenated conditions. Greater temporal variation in perfusion increases peak TBRs (range 2.20-5.27) as a result of smaller predicted necrotic fraction, rather than fundamental differences in FMISO accumulation under acute hypoxia. Identical late FMISO uptake can occur in regions with differing

The role of necrosis, acute hypoxia and chronic hypoxia in 18F-FMISO PET image contrast: a computational modelling study.

PubMed

Warren, Daniel R; Partridge, Mike

2016-12-21

Positron emission tomography (PET) using 18 F-fluoromisonidazole (FMISO) is a promising technique for imaging tumour hypoxia, and a potential target for radiotherapy dose-painting. However, the relationship between FMISO uptake and oxygen partial pressure ([Formula: see text]) is yet to be quantified fully. Tissue oxygenation varies over distances much smaller than clinical PET resolution (<100 μm versus  ∼4 mm), and cyclic variations in tumour perfusion have been observed on timescales shorter than typical FMISO PET studies (∼20 min versus a few hours). Furthermore, tracer uptake may be decreased in voxels containing some degree of necrosis. This work develops a computational model of FMISO uptake in millimetre-scale tumour regions. Coupled partial differential equations govern the evolution of oxygen and FMISO distributions, and a dynamic vascular source map represents temporal variations in perfusion. Local FMISO binding capacity is modulated by the necrotic fraction. Outputs include spatiotemporal maps of [Formula: see text] and tracer accumulation, enabling calculation of tissue-to-blood ratios (TBRs) and time-activity curves (TACs) as a function of mean tissue oxygenation. The model is characterised using experimental data, finding half-maximal FMISO binding at local [Formula: see text] of 1.4 mmHg (95% CI: 0.3-2.6 mmHg) and half-maximal necrosis at 1.2 mmHg (0.1-4.9 mmHg). Simulations predict a non-linear non-monotonic relationship between FMISO activity (4 hr post-injection) and mean tissue [Formula: see text] : tracer uptake rises sharply from negligible levels in avascular tissue, peaking at  ∼5 mmHg and declining towards blood activity in well-oxygenated conditions. Greater temporal variation in perfusion increases peak TBRs (range 2.20-5.27) as a result of smaller predicted necrotic fraction, rather than fundamental differences in FMISO accumulation under acute hypoxia. Identical late FMISO uptake can occur in regions with differing

Intermittent hypoxia increases arterial blood pressure in humans through a Renin-Angiotensin system-dependent mechanism.

PubMed

Foster, Glen E; Hanly, Patrick J; Ahmed, Sofia B; Beaudin, Andrew E; Pialoux, Vincent; Poulin, Marc J

2010-09-01

Intermittent hypoxia (IH) is believed to contribute to the pathogenesis of hypertension in obstructive sleep apnea through mechanisms that include activation of the renin-angiotensin system. The objective of this study was to assess the role of the type I angiotensin II receptor in mediating an increase in arterial pressure associated with a single 6-hour IH exposure. Using a double-blind, placebo-controlled, randomized, crossover study design, we exposed 9 healthy male subjects to sham IH, IH with placebo medication, and IH with the type I angiotensin II receptor antagonist losartan. We measured blood pressure, cerebral blood flow, and ventilation at baseline and after exposure to 6 hours of IH. An acute isocapnic hypoxia experimental protocol was conducted immediately before and after exposure to IH. IH with placebo increased resting mean arterial pressure by 7.9+/-1.6 mm Hg, but mean arterial pressure did not increase with sham IH (1.9+/-1.5 mm Hg) or with losartan IH (-0.2+/-2.4 mm Hg; P<0.05). Exposure to IH prevented the diurnal decrease in the cerebral blood flow response to hypoxia, independently of the renin-angiotensin system. Finally, in contrast to other models of IH, the acute hypoxic ventilatory response did not change throughout the protocol. IH increases arterial blood pressure through activation of the type I angiotensin II receptor, without a demonstrable impact on the cerebrovascular or ventilatory response to acute hypoxia.

Endothelial microvesicles in hypoxic hypoxia diseases.

PubMed

Deng, Fan; Wang, Shuang; Xu, Riping; Yu, Wenqian; Wang, Xianyu; Zhang, Liangqing

2018-05-29

Hypoxic hypoxia, including abnormally low partial pressure of inhaled oxygen, external respiratory dysfunction-induced respiratory hypoxia and venous blood flow into the arterial blood, is characterized by decreased arterial oxygen partial pressure, resulting in tissue oxygen deficiency. The specific characteristics include reduced arterial oxygen partial pressure and oxygen content. Hypoxic hypoxia diseases (HHDs) have attracted increased attention due to their high morbidity and mortality and mounting evidence showing that hypoxia-induced oxidative stress, coagulation, inflammation and angiogenesis play extremely important roles in the physiological and pathological processes of HHDs-related vascular endothelial injury. Interestingly, endothelial microvesicles (EMVs), which can be induced by hypoxia, hypoxia-induced oxidative stress, coagulation and inflammation in HHDs, have emerged as key mediators of intercellular communication and cellular functions. EMVs shed from activated or apoptotic endothelial cells (ECs) reflect the degree of ECs damage, and elevated EMVs levels are present in several HHDs, including obstructive sleep apnoea syndrome and chronic obstructive pulmonary disease. Furthermore, EMVs have procoagulant, proinflammatory and angiogenic functions that affect the pathological processes of HHDs. This review summarizes the emerging roles of EMVs in the diagnosis, staging, treatment and clinical prognosis of HHDs. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Neonatal Hypoxia, Hippocampal Atrophy, and Memory Impairment: Evidence of a Causal Sequence

PubMed Central

Cooper, Janine M.; Gadian, David G.; Jentschke, Sebastian; Goldman, Allan; Munoz, Monica; Pitts, Georgia; Banks, Tina; Chong, W. Kling; Hoskote, Aparna; Deanfield, John; Baldeweg, Torsten; de Haan, Michelle; Mishkin, Mortimer; Vargha-Khadem, Faraneh

2015-01-01

Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life. PMID:24343890

Acute hypoxia and related symptoms on mild exertion at simulated altitudes below 3048 m.

PubMed

Smith, Adrian M

2007-10-01

Helicopter aircrew have reported features of hypoxia below 3048 m (10,000 ft). The aim of this study was to examine the effect of physical activity below 3048 m on the development of hypoxia. Six subjects exercised at 30 W and 60 W for 4 min at sea level, 610 m, 2134 m, and 2743 m (2000 ft, 7000 ft, and 9000 ft). There was an abrupt decrease in Spo2 once physical activity was commenced. This was small at sea level (1%) and 610 m (2.2%), however, the Spo2 fell by 4.3% at 2134 m and 5.5% at 2743 m (to Spo2 88.1% and 85.7%, respectively). Spo2 returned to near-resting values within 3 min of stopping exercise. Symptoms of hypoxia were reported significantly more frequently during activity than rest at each of the altitudes. Helicopter aircrew should be aware that physical activity as low as 2134 m can produce hypoxemia and symptoms of hypoxia similar to that which would normally be expected in a person resting at approximately 3658-4572 m (12,000-15,000 ft).

Biodanza Reduces Acute Pain Severity in Women with Fibromyalgia.

PubMed

Segura-Jiménez, Víctor; Gatto-Cardia, Claudia M; Martins-Pereira, Clélia M; Delgado-Fernández, Manuel; Aparicio, Virginia A; Carbonell-Baeza, Ana

2017-10-01

Biodanza is a useful therapy for the fibromyalgia management; however, there is no evidence of its effectiveness on acute pain. The objectives of the present study were: to determine the changes of a 3-month Biodanza program on acute pain severity (before vs. after session) and cumulative pain severity in women with fibromyalgia; and to check the associations of acute pain severity reduction with presession pain severity, body fat percentage, and satisfaction with the session. This was a 3-month low-moderate intensity (rate of perceived exertion around 12, based on a 6-20 point scale) Biodanza intervention study (1 session/week). Twenty-seven women with fibromyalgia (54.2 ± 6.2 years) participated. Pain severity was assessed before and after each single session with a visual analog scale. There were immediate changes in all sessions (p = .001-.028), except in the first, second, and fourth sessions. An overall 16% decrease of acute pain severity before and after each session was noted (mean presession pain vs. postsession pain, 5.8 ± 2.1 vs. 4.9 ± 2.4; respectively). There was an independent association of pain severity reduction (presession-postsession) with presession pain severity (unstandardized coefficient B = .21 ± .05; standardized coefficient β = .25; p < .001), body fat percentage (B = -.05 ± .02; β = -.18; p = .003), and satisfaction with the session (B = .40 ± .15; β = .16; p = .007). There was a significant cumulative effect decrease in postsession pain severity (p < .001; 95% confidence interval [CI] = -.14, -.05) and presession-postsession pain severity (p = .007; 95% CI = .02, .12) along the 3-month intervention. No significant cumulative effect in presession pain severity was identified (p > .05). In conclusion, Biodanza is an alternative therapy that reduced acute pain severity in women with fibromyalgia. The intervention also yielded cumulative pain severity reduction, which were higher in those

Redox signaling in acute oxygen sensing.

PubMed

Gao, Lin; González-Rodríguez, Patricia; Ortega-Sáenz, Patricia; López-Barneo, José

2017-08-01

Acute oxygen (O 2 ) sensing is essential for individuals to survive under hypoxic conditions. The carotid body (CB) is the main peripheral chemoreceptor, which contains excitable and O 2 -sensitive glomus cells with O 2 -regulated ion channels. Upon exposure to acute hypoxia, inhibition of K + channels is the signal that triggers cell depolarization, transmitter release and activation of sensory fibers that stimulate the brainstem respiratory center to produce hyperventilation. The molecular mechanisms underlying O 2 sensing by glomus cells have, however, remained elusive. Here we discuss recent data demonstrating that ablation of mitochondrial Ndufs2 gene selectively abolishes sensitivity of glomus cells to hypoxia, maintaining responsiveness to hypercapnia or hypoglycemia. These data suggest that reactive oxygen species and NADH generated in mitochondrial complex I during hypoxia are signaling molecules that modulate membrane K + channels. We propose that the structural substrates for acute O 2 sensing in CB glomus cells are "O 2 -sensing microdomains" formed by mitochondria and neighboring K + channels in the plasma membrane. Copyright © 2017. Published by Elsevier B.V.

Determinants of ventilation and pulmonary artery pressure during early acclimatization to hypoxia in humans.

PubMed

Fatemian, Marzieh; Herigstad, Mari; Croft, Quentin P P; Formenti, Federico; Cardenas, Rosa; Wheeler, Carly; Smith, Thomas G; Friedmannova, Maria; Dorrington, Keith L; Robbins, Peter A

2016-03-01

Pulmonary ventilation and pulmonary arterial pressure both rise progressively during the first few hours of human acclimatization to hypoxia. These responses are highly variable between individuals, but the origin of this variability is unknown. Here, we sought to determine whether the variabilities between different measures of response to sustained hypoxia were related, which would suggest a common source of variability. Eighty volunteers individually underwent an 8-h isocapnic exposure to hypoxia (end-tidal P(O2)=55 Torr) in a purpose-built chamber. Measurements of ventilation and pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography were made during the exposure. Before and after the exposure, measurements were made of the ventilatory sensitivities to acute isocapnic hypoxia (G(pO2)) and hyperoxic hypercapnia, the latter divided into peripheral (G(pCO2)) and central (G(cCO2)) components. Substantial acclimatization was observed in both ventilation and PASP, the latter being 40% greater in women than men. No correlation was found between the magnitudes of pulmonary ventilatory and pulmonary vascular responses. For G(pO2), G(pCO2) and G(cC O2), but not the sensitivity of PASP to acute hypoxia, the magnitude of the increase during acclimatization was proportional to the pre-acclimatization value. Additionally, the change in G(pO2) during acclimatization to hypoxia correlated well with most other measures of ventilatory acclimatization. Of the initial measurements prior to sustained hypoxia, only G(pCO2) predicted the subsequent rise in ventilation and change in G(pO2) during acclimatization. We conclude that the magnitudes of the ventilatory and pulmonary vascular responses to sustained hypoxia are predominantly determined by different factors and that the initial G(pCO2) is a modest predictor of ventilatory acclimatization. © 2015 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological

Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus

PubMed Central

Satriotomo, Irawan; Dale, Erica A.; Dahlberg, Jenny M.; Mitchell, Gordon S.

2015-01-01

Acute intermittent hypoxia (AIH) initiates plasticity in respiratory motor control, including phrenic long term facilitation (pLTF). Since pLTF is enhanced by preconditioning with repetitive exposure to AIH (rAIH), we hypothesized that a rAIH protocol consisting of 3 AIH exposures per week for 10 weeks (3×wAIH; AIH: 10, 5-min episodes of 10.5% O2; 5-min normoxic intervals) would enhance expression of molecules that play key roles in pLTF within the phrenic motor nucleus. Immunohistochemical analyses revealed that 3×wAIH for 10 weeks increased serotonin terminal density in the C4 phrenic motor nucleus and serotonin 2A (5-HT2A) receptor expression in presumptive phrenic motor neurons. Immunoreactive brain derived neurotrophic factor (BDNF) and its high affinity receptor (TrkB) also increased following 3×wAIH. 3×wAIH also increased expression of another hypoxia-sensitive growth factor known to elicit phrenic motor facilitation, vascular endothelial growth factor (VEGF), and its receptor (VEGFR-2). Kinases “downstream” from TrkB and VEGFR-2 were up-regulated in or near presumptive phrenic motor neurons, including phosphorylated extracellular-signal regulated kinase (p-ERK) and protein kinase B (p-AKT). Thus, 3×wAIH up-regulates neurochemicals known to be associated with phrenic motor plasticity. Since 3×wAIH upregulates pro-plasticity molecules without evidence for CNS pathology, it may be a useful therapeutic tool in treating disorders that cause respiratory insufficiency, such as spinal injury or motor neuron disease. PMID:22704858

[Pinealon and Cortexin influence on behavior and neurochemical processes in 18-month aged rats within hypoxia and hypothermia].

PubMed

Mendzheritsky, A M; Karantysh, G V; Ryzhak, G A; Prokofiev, V N

The research of Cortexin and Pinealon within two models of stress, acute hypobaric hypoxia and mild hypothermia, within 18-month aged rats has been held. The peculiarities of peptide preparations' influence on behavior and neurochemical indeces have been identified. Cortexin shows a more pronounced effect on free radical processes and caspase 3 activity in brain than Pinealon. Both preparations forward an accumulation of adrenergic mediator within rats' brains in the model of acute hypobaric hypoxia, as well as serotonin within cerebrum cortex in the model of mild hypothermia, which may underlie their geroprotective effects.

Supra- and Sub-Baseline Phosphocreatine Recovery in Developing Brain after Transient Hypoxia-Ischaemia: Relation to Baseline Energetics, Insult Severity and Outcome

ERIC Educational Resources Information Center

Iwata, Osuke; Iwata, Sachiko; Bainbridge, Alan; De Vita, Enrico; Matsuishi, Toyojiro; Cady, Ernest B.; Robertson, Nicola J.

2008-01-01

Following hypoxia-ischaemia (HI), an early biomarker of insult severity is desirable to target neuroprotective therapies to patients most likely to benefit; currently there are no biomarkers within the "latent phase" period before the establishment of secondary energy failure. Brief transient phosphocreatine (PCr) recovery overshoot (measured…

Time dependent impact of perinatal hypoxia on growth hormone, insulin-like growth factor 1 and insulin-like growth factor binding protein-3.

PubMed

Kartal, Ömer; Aydınöz, Seçil; Kartal, Ayşe Tuğba; Kelestemur, Taha; Caglayan, Ahmet Burak; Beker, Mustafa Caglar; Karademir, Ferhan; Süleymanoğlu, Selami; Kul, Mustafa; Yulug, Burak; Kilic, Ertugrul

2016-08-01

Hypoxic-ischemia (HI) is a widely used animal model to mimic the preterm or perinatal sublethal hypoxia, including hypoxic-ischemic encephalopathy. It causes diffuse neurodegeneration in the brain and results in mental retardation, hyperactivity, cerebral palsy, epilepsy and neuroendocrine disturbances. Herein, we examined acute and subacute correlations between neuronal degeneration and serum growth factor changes, including growth hormone (GH), insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) after hypoxic-ischemia (HI) in neonatal rats. In the acute phase of hypoxia, brain volume was increased significantly as compared with control animals, which was associated with reduced GH and IGF-1 secretions. Reduced neuronal survival and increased DNA fragmentation were also noticed in these animals. However, in the subacute phase of hypoxia, neuronal survival and brain volume were significantly decreased, accompanied by increased apoptotic cell death in the hippocampus and cortex. Serum GH, IGF-1, and IGFBP-3 levels were significantly reduced in the subacute phase of HI. Significant retardation in the brain and body development were noted in the subacute phase of hypoxia. Here, we provide evidence that serum levels of growth-hormone and factors were decreased in the acute and subacute phase of hypoxia, which was associated with increased DNA fragmentation and decreased neuronal survival.

Temperature and blood rheology in fingertips as signs of adaptation to acute hypoxia

NASA Astrophysics Data System (ADS)

Urakov, A.; Urakova, N.; Kasatkin, A.; Dementyev, V.

2017-01-01

It is found that the absolute values of temperature and color infrared image of the fingers and palms in healthy volunteers and in patients with hemorrhagic shock are in the same range, so they don’t represent precisely their condition. It turned out that what really matters is the dynamics of temperature and color infrared image of the palms after cuff occlusion test. In healthy volunteers and in patients with high resistance to shock, there is a rise in temperature and change in color from blue to red in the infrared image of the fingers and palms for 1 - 1.5 minutes after elimination of ischemia, but in patients with low resistance to shock there is a decrease in temperature and expansion of blue color in the palm surface in the infrared image. On the other hand, to assess the resistance to hypoxia in a fetus inside a mother’s womb it is proposed to determine the duration of the period of the fetus stationary state during apnea period in pregnant women by using ultrasonography or during period of uterus tonic contractions during childbirth. We found that if fetus has high resistance to hypoxia, the duration of stationary state during the apnea or uterus contraction is greater than 20 seconds, and after exhaustion of reserves for adaptation to hypoxia it approaches zero. It is shown that growing hypoxia causes decrease in the local temperature of the central area of the skull and vice versa.

Young Children's Acute Stress After a Burn Injury: Disentangling the Role of Injury Severity and Parental Acute Stress.

PubMed

Haag, Ann-Christin; Landolt, Markus A

2017-09-01

Although injury severity and parental stress are strong predictors of posttraumatic adjustment in young children after burns, little is known about the interplay of these variables. This study aimed at clarifying mediation processes between injury severity and mother's, father's, and young child's acute stress. Structural equation modeling was used to examine the relationships between injury severity and parental and child acute stress. Parents of 138 burn-injured children (ages 1-4 years) completed standardized questionnaires on average 19 days postinjury. Sixteen children (11.7%) met Diagnostic and Statistical Manual of Mental Disorders, 5th edition, preschool criteria for posttraumatic stress disorder (excluding time criterion). The model revealed a significant mediation of maternal acute stress, with the effect of injury severity on a child's acute stress mediated by maternal acute stress. Paternal acute stress failed to serve as a mediating variable. Our findings confirm mothers' crucial role in the posttraumatic adjustment of young children. Clinically, mothers' acute stress should be monitored. © The Author 2017. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Heroin Contaminated with Fentanyl Dramatically Enhances Brain Hypoxia and Induces Brain Hypothermia.

PubMed

Solis, Ernesto; Cameron-Burr, Keaton T; Kiyatkin, Eugene A

2017-01-01

While opioid abuse is an established medical and public health issue, the increased availability of highly potent synthetic opioids, such as fentanyl, has given rise to acute health complications, including a comatose state and death during drug overdose. Since respiratory depression that leads to acute hypoxia is the most dangerous complication of opioid drug use, we examined the effects of intravenous heroin and heroin contaminated with 10% fentanyl on oxygen levels in the nucleus accumbens (NAc) monitored using high-speed amperometry in freely moving rats. Additionally, we examined the effects of heroin, fentanyl, and their mixture on locomotion and temperatures in the NAc, temporal muscle, and skin. Both fentanyl and heroin at human-relevant doses (400 and 40 μg/kg, respectively) induced rapid, strong and transient decreases in NAc oxygen, indicative of brain hypoxia. When the heroin-fentanyl mixture was injected, the NAc hypoxic response was greatly potentiated in its duration, suggesting sustained hypoxia. In contrast to modest, monophasic brain temperature increases caused by heroin alone, the heroin-fentanyl mixture induced a biphasic temperature response, with a prominent postinjection decrease resulting from peripheral vasodilation. This hypothermic effect, albeit much smaller and more transient, was typical of fentanyl injected alone. Our findings indicate that accidental use of fentanyl instead of heroin, or even a relatively minor contamination of "street heroin" with fentanyl, poses great danger for acute health complications, including a comatose state and death.

Improvement of myocardial perfusion in coronary patients after intermittent hypobaric hypoxia.

PubMed

del Pilar Valle, Maria; García-Godos, Félix; Woolcott, Orison O; Marticorena, José M; Rodríguez, Víctor; Gutiérrez, Isabel; Fernández-Dávila, Luis; Contreras, Abel; Valdivia, Luis; Robles, Juan; Marticorena, Emilio A

2006-01-01

Persons living at high altitude (exposed to hypoxia) have a greater number of coronary and peripheral branches in the heart than persons living at sea level. In this study we investigated the effect of intermittent hypobaric hypoxia on myocardial perfusion in patients with coronary heart disease. We studied 6 male patients (aged>or=53 years) with severe stable coronary heart disease. All patients were born at sea level and lived in that environment. They underwent 14 sessions of exposure to intermittent hypobaric hypoxia (equivalent to a simulated altitude of 4200 m). Myocardial perfusion was assessed at baseline and after treatment with hypoxia by use of exercise perfusion imaging with technetium 99m sestamibi. After the sessions of hypoxia, myocardial perfusion was significantly improved. The summed stress score for hypoperfusion, in arbitrary units, decreased from 9.5+ to 4.5+ after treatment (P=.036). There was no evidence of impairment of myocardial perfusion in any patient after treatment. Intermittent hypobaric hypoxia improved myocardial perfusion in patients with severe coronary heart disease. Though preliminary, our results suggest that exposure to intermittent hypobaric hypoxia could be an alternative for the management of patients with chronic coronary heart disease.

Hypoxic preconditioning facilitates acclimatization to hypobaric hypoxia in rat heart.

PubMed

Singh, Mrinalini; Shukla, Dhananjay; Thomas, Pauline; Saxena, Saurabh; Bansal, Anju

2010-12-01

Acute systemic hypoxia induces delayed cardioprotection against ischaemia-reperfusion injury in the heart. As cobalt chloride (CoCl₂) is known to elicit hypoxia-like responses, it was hypothesized that this chemical would mimic the preconditioning effect and facilitate acclimatization to hypobaric hypoxia in rat heart. Male Sprague-Dawley rats treated with distilled water or cobalt chloride (12.5 mg Co/kg for 7 days) were exposed to simulated altitude at 7622 m for different time periods (1, 2, 3 and 5 days). Hypoxic preconditioning with cobalt appreciably attenuated hypobaric hypoxia-induced oxidative damage as observed by a decrease in free radical (reactive oxygen species) generation, oxidation of lipids and proteins. Interestingly, the observed effect was due to increased expression of the antioxidant proteins hemeoxygenase and metallothionein, as no significant change was observed in antioxidant enzyme activity. Hypoxic preconditioning with cobalt increased hypoxia-inducible factor 1α (HIF-1α) expression as well as HIF-1 DNA binding activity, which further resulted in increased expression of HIF-1 regulated genes such as erythropoietin, vascular endothelial growth factor and glucose transporter. A significant decrease was observed in lactate dehydrogenase activity and lactate levels in the heart of preconditioned animals compared with non-preconditioned animals exposed to hypoxia. The results showed that hypoxic preconditioning with cobalt induces acclimatization by up-regulation of hemeoxygenase 1 and metallothionein 1 via HIF-1 stabilization. © 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society of Great Britain.

Historical perspectives of cellular oxygen sensing and responses to hypoxia.

PubMed

Lahiri, S

2000-04-01

The responses to acute and chronic hypoxia begin with oxygen sensing, and this historical perspective is written in line with this concept. The earliest pertinent work started with studies on fermentation in yeast in the 17th century, before the discovery of oxygen. It required 200 yr to localize the oxygen sensing within the cells and another 100 yr to discover the cellular oxidation reactions. Today, the consensus is that the mitochondrial respiratory chain is in part the site of oxygen sensing. In addition, membrane-bound NAD(P)H oxidase possibly takes part in oxygen sensing. Oxygen-sensing mechanisms occur in a tissue-specific fashion. For example, the carotid body responds to hypoxia promptly by eliciting a ventilatory response, whereas erythropoietin production in response to hypoxia requires more time, involving new expression of genes. The mechanism has therefore moved from the cells to genes.

Air-breathing behavior and physiological responses to hypoxia and air exposure in the air-breathing loricariid fish, Pterygoplichthys anisitsi.

PubMed

da Cruz, André Luis; da Silva, Hugo Ribeiro; Lundstedt, Lícia Maria; Schwantes, Arno Rudi; Moraes, Gilberto; Klein, Wilfried; Fernandes, Marisa Narciso

2013-04-01

Hypoxic water and episodic air exposure are potentially life-threatening conditions that fish in tropical regions can face during the dry season. This study investigated the air-breathing behavior, oxygen consumption, and respiratory responses of the air-breathing (AB) armored catfish Pterygoplichthys anisitsi. The hematological parameters and oxygen-binding characteristics of whole blood and stripped hemoglobin and the intermediate metabolism of selected tissue in normoxia, different hypoxic conditions, and after air exposure were also examined. In normoxia, this species exhibited high activity at night and AB behavior (2-5 AB h(-1)). The exposure to acute severe hypoxia elicited the AB behavior (4 AB h(-1)) during the day. Under progressive hypoxia without access to the water surface, the fish were oxyregulators with a critical O2 tension, calculated as the inspired water O2 pressure, as 47 ± 2 mmHg. At water O2 tensions lower than 40 mmHg, the fish exhibited continuous apnea behavior. The blood exhibited high capacity for transporting O2, having a cathodic hemoglobin component with a high Hb-O2 affinity. Under severe hypoxia, the fish used anaerobic metabolism to maintain metabolic rate. Air exposure revealed physiological and biochemical traits similar to those observed under normoxic conditions.

Hypoxia awareness training for aircrew: a comparison of two techniques.

PubMed

Singh, Bhupinder; Cable, Gordon G; Hampson, Greg V; Pascoe, Glenn D; Corbett, Mark; Smith, Adrian

2010-09-01

Major hazards associated with hypoxia awareness training are the risks of decompression sickness, barotrauma, and loss of consciousness. An alternate method has been developed which combines exposure to a simulated altitude of 10,000 ft (3048 m) with breathing of a gas mixture containing 10% oxygen and 90% nitrogen. The paradigm, called Combined Altitude and Depleted Oxygen (CADO), places the subjects at a physiological altitude of 25,000 ft (7620 m) and provides demonstration of symptoms of hypoxia and the effects of pressure change. CADO is theoretically safer than traditional training at a simulated altitude of 25,000 ft (7620 m) due to a much lower risk of decompression sickness (DCS) and has greater fidelity of training for fast jet aircrew (mask-on hypoxia). This study was conducted to validate CADO by comparing it with hypobaric hypoxia. There were 43 subjects who were exposed to two regimens of hypoxia training: hypobaric hypoxia (HH) at a simulated altitude of 25,000 ft (7620 m) and CADO. Subjective, physiological, and performance data of the subjects were collected, analyzed, and compared. There were no significant differences in the frequency and severity of the 24 commonly reported symptoms, or in the physiological response, between the two types of hypoxia exposure. CADO is similar to HH in terms of the type and severity of symptoms experienced by subjects, and appears to be an effective, useful, and safe tool for hypoxia training.

[PREVENTION AND CORRECTION OF PULMONARY COMPLICATIONS FOR SEVERE ACUTE PANCREATITIS].

PubMed

Fedorkiv, M B

2015-06-01

Increased of proinflammatory cytokines levels, including interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) on severe acute pancreatitis causes vasodilatation, increased permeability of the wall, accumulation of fluid in lung tissue and pleural sinuses. Transudate from acute parapancreatyc clusters of hot liquid and abdomen falls into the chest cavity through microscopic defects in the diaphragm due to the formation of pathological pleural-peritoneal connections or the relevant pressure gradient between the abdominal and pleural cavities. Remediation and removal of acute parapancreatyc clusters combined with the use of a multicomponent drug infusion therapy Cytoflavin provide a reduction in the frequency of pulmonary complications of acute pancreatitis from 48.3 to 31.0%. Use of the drug Cytoflavin reduces the severity of endogenous intoxication and mortality from acute lung injury from 12.9 to 6.1%.

IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia.

PubMed

Kuett, Alexander; Rieger, Christina; Perathoner, Deborah; Herold, Tobias; Wagner, Michaela; Sironi, Silvia; Sotlar, Karl; Horny, Hans-Peter; Deniffel, Christian; Drolle, Heidrun; Fiegl, Michael

2015-12-17

The bone marrow microenvironment is physiologically hypoxic with areas being as low as 1% O2, e.g. the stem cell niche. Acute myeloid leukaemia (AML) blasts misuse these bone marrow niches for protection by the local microenvironment, but also might create their own microenvironment. Here we identify IL-8 as a hypoxia-regulated cytokine in both AML cell lines and primary AML samples that is induced within 48 hours of severe hypoxia (1% O2). IL-8 lacked effects on AML cells but induced migration in mesenchymal stromal cells (MSC), an integral part of the bone marrow. Accordingly, MSC were significantly increased in AML bone marrow as compared to healthy bone marrow. Interestingly, mononuclear cells obtained from healthy bone marrow displayed both significantly lower endogenous and hypoxia-induced production of IL-8. IL-8 mRNA expression in AML blasts from 533 patients differed between genetic subgroups with significantly lower expression of IL-8 in acute promyelocytic leukaemia (APL), while in non APL-AML patients with FLT ITD had the highest IL-8 expression. In this subgroup, high IL-8 expression was also prognostically unfavourable. In conclusion, hypoxia as encountered in the bone marrow specifically increases IL-8 expression of AML, which in turn impacts niche formation. High IL-8 expression might be correlated with poor prognosis in certain AML subsets.

[Effect of Electroacupuncture Stimulation of Acupoints at the Distal Limbs on Heart Function of Volunteers with Acute Hypoxia].

PubMed

Dong, Ya-qin; Xiu, Chun-ying; Sa, Zhe-yan; Xu, Jin-sen

2015-10-01

To observe the effect of electroacupuncture (EA) stimulation of different acupoints at the distal ends of the limbs on cardiac function in volunteers with acute hypoxia, so as to determine if its actions are realized by way of segmental innervations or meridians. Twenty healthy volunteers were divided into control, Quze (PC 3), Shousanli (LI 10), Guangming (GB 37) and Zusanli (ST 36) groups (both PC 3 and LI 10 are innervated by spinal C3-C6, and both ST 36 and GB 37 innervated by L5-S1). Acute hyoxia (simulating the conditions of about 5,000 m height above the sea level) was induced by asking the volunteers to inhale low-oxygen gas mixture (10.8% O2 + 89.2% N2) for 30 min, when, the participants' cardiac output (CO), heart rate (HR), left cardiac work (LOW), left ventricular ejection time (LVET)were measured using a ICG Monitor and EA stimulation (10 Hz/20 Hz, 1-2 V) was also conducted for 20 min following inhaling low-oxygen for 10 min. Before low-oxygen inhale, the levels of CO, HR, LCW and LVET ratios (test value/basic value) of the control, PC 3, LI 10, ST 36 and GB 37 groups were comparable (P > 0.05). After inhaling low-oxygen gas mixture for 10 min, the levels of CO, HR, and LCW ratios were significantly increased, and the LVET ratios were notably decreased in the five groups (P < 0.05). Compared with the 10 min-low-oxygen inhale of the same one group, CO and HR ratios at both EA 10 min and 20 min in the PC 3 and ST 36 groups, LCW ratios at EA 10 min in both PC 3 and ST 36 groups were notably down-regulated (P < 0.05), while the LVET ratios of both PC 3 and ST 36 groups was significantly prolonged (P < 0.05). No significant changes of CO, HR, LCW and LVET ratios were found in the LI 10 and GB 37 groups after EA for 10 min and 20 min (P > 0.05). EA stimulation of Quze (PC 3) and Zusanli (ST 36), but not Shousanli (LI 10) and Guangming (GB 37) can lower CO, HR and LCW levels and increase LVET in volunteer subjects undergoing acute hypoxia, suggesting that the

Cardiovascular function in term fetal sheep conceived, gestated and studied in the hypobaric hypoxia of the Andean altiplano.

PubMed

Herrera, Emilio A; Rojas, Rodrigo T; Krause, Bernardo J; Ebensperger, Germán; Reyes, Roberto V; Giussani, Dino A; Parer, Julian T; Llanos, Aníbal J

2016-03-01

High-altitude hypoxia causes intrauterine growth restriction and cardiovascular programming. However, adult humans and animals that have evolved at altitude show certain protection against the effects of chronic hypoxia. Whether the highland fetus shows similar protection against high altitude gestation is unclear. We tested the hypothesis that high-altitude fetal sheep have evolved cardiovascular compensatory mechanisms to withstand chronic hypoxia that are different from lowland sheep. We studied seven high-altitude (HA; 3600 m) and eight low-altitude (LA; 520 m) pregnant sheep at ∼90% gestation. Pregnant ewes and fetuses were instrumented for cardiovascular investigation. A three-period experimental protocol was performed in vivo: 30 min of basal, 1 h of acute superimposed hypoxia (∼10% O2) and 30 min of recovery. Further, we determined ex vivo fetal cerebral and femoral arterial function. HA pregnancy led to chronic fetal hypoxia, growth restriction and altered cardiovascular function. During acute superimposed hypoxia, LA fetuses redistributed blood flow favouring the brain, heart and adrenals, whereas HA fetuses showed a blunted cardiovascular response. Importantly, HA fetuses have a marked reduction in umbilical blood flow versus LA. Isolated cerebral arteries from HA fetuses showed a higher contractile capacity but a diminished response to catecholamines. In contrast, femoral arteries from HA fetuses showed decreased contractile capacity and increased adrenergic contractility. The blunting of the cardiovascular responses to hypoxia in fetuses raised in the Alto Andino may indicate a change in control strategy triggered by chronic hypoxia, switching towards compensatory mechanisms that are more cost-effective in terms of oxygen uptake. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Brain blood flow and blood pressure during hypoxia in the epaulette shark Hemiscyllium ocellatum, a hypoxia-tolerant elasmobranch.

PubMed

Söderström, V; Renshaw, G M; Nilsson, G E

1999-04-01

The key to surviving hypoxia is to protect the brain from energy depletion. The epaulette shark (Hemiscyllium ocellatum) is an elasmobranch able to resist energy depletion and to survive hypoxia. Using epi-illumination microscopy in vivo to observe cerebral blood flow velocity on the brain surface, we show that cerebral blood flow in the epaulette shark is unaffected by 2 h of severe hypoxia (0.35 mg O2 l-1 in the respiratory water, 24 C). Thus, the epaulette shark differs from other hypoxia- and anoxia-tolerant species studied: there is no adenosine-mediated increase in cerebral blood flow such as that occurring in freshwater turtles and cyprinid fish. However, blood pressure showed a 50 % decrease in the epaulette shark during hypoxia, indicating that a compensatory cerebral vasodilatation occurs to maintain cerebral blood flow. We observed an increase in cerebral blood flow velocity when superfusing the normoxic brain with adenosine (making sharks the oldest vertebrate group in which this mechanism has been found). The adenosine-induced increase in cerebral blood flow velocity was reduced by the adenosine receptor antagonist aminophylline. Aminophylline had no effect upon the maintenance of cerebral blood flow during hypoxia, however, indicating that adenosine is not involved in maintaining cerebral blood flow in the epaulette shark during hypoxic hypotension.

Alteration of carotid body chemoreflexes after neonatal intermittent hypoxia and caffeine treatment in rat pups.

PubMed

Julien, Cécile A; Joseph, Vincent; Bairam, Aida

2011-08-15

In human neonates, caffeine therapy for apnoea of prematurity, especially when associated with hypoxemia, is maintained for several weeks after birth. In the present study, we used newborn rats and whole-body plethysmography to test whether chronic exposure to neonatal caffeine treatment (NCT), alone or combined with neonatal intermittent hypoxia (n-IH) alters: (1) baseline ventilation and response to hypoxia (12% O(2), 20 min); and (2) response to acute i.p. injection of caffeine citrate (20 mg/kg) or domperidone, a peripheral dopamine D2 receptor antagonist (1 mg/kg). Four groups of rats were studied as follows: raised under normal conditions with daily gavage with water (NWT) or NCT, or exposed to n-IH (n-IH+NWT and n-IH+NCT) from postnatal days 3 to 12. In n-IH+NCT rats, baseline ventilation was higher than in the other groups. Caffeine or domperidone enhanced baseline ventilation only in NWT and n-IH+NWT rats, but neither caffeine nor domperidone affected the hypoxic ventilatory response in these groups. In n-IH+NWT rats, the response during the early phase of hypoxia (<10 min) was higher than in other groups. During the late response phase to hypoxia (20 min), ventilation was lower in n-IH+NWT and n-IH+NCT rats compared to NWT or NCT, and were not affected by caffeine or domperidone injection. NCT or caffeine injection decreased baseline apnoea frequency in all groups. These data suggest that chronic exposure to NCT alters both carotid body dopaminergic and adenosinergic systems and central regulation of breathing under baseline conditions and in response to hypoxia. Copyright © 2011 Elsevier B.V. All rights reserved.

pO{sub 2} Fluctuation Pattern and Cycling Hypoxia in Human Cervical Carcinoma and Melanoma Xenografts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ellingsen, Christine; Ovrebo, Kirsti Marie; Galappathi, Kanthi

2012-07-15

Purpose: Blood perfusion in tumors is spatially and temporally heterogeneous, resulting in local fluctuations in tissue oxygen tension (pO{sub 2}) and tissue regions showing cycling hypoxia. In this study, we investigated whether the pO{sub 2} fluctuation pattern and the extent of cycling hypoxia differ between tumor types showing high (e.g., cervical carcinoma xenograft) and low (e.g., melanoma xenograft) fractions of connective tissue-associated blood vessels. Methods and Materials: Two cervical carcinoma lines (CK-160 and TS-415) and two melanoma lines (A-07 and R-18) transplanted into BALB/c nu/nu mice were included in the study. Tissue pO{sub 2} was measured simultaneously in two positionsmore » in each tumor by using a two-channel OxyLite fiber-optic oxygen-sensing device. The extent of acute and chronic hypoxia was assessed by combining a radiobiological and a pimonidazole-based immunohistochemical assay of tumor hypoxia. Results: The proportion of tumor regions showing pO{sub 2} fluctuations, the pO{sub 2} fluctuation frequency in these regions, and the relative amplitude of the pO{sub 2} fluctuations were significantly higher in the melanoma xenografts than in the cervical carcinoma xenografts. Cervical carcinoma and melanoma xenografts did not differ significantly in the fraction of acutely hypoxic cells or the fraction of chronically hypoxic cells. However, the ratio between fraction of acutely hypoxic cells and fraction of chronically hypoxic cells was significantly higher in melanoma than in cervical carcinoma xenografts. Conclusions: Temporal heterogeneity in blood flow and tissue pO{sub 2} in tumors may depend on tumor histology. Connective tissue surrounding microvessels may stabilize blood flow and pO{sub 2} and, thus, protect tumor tissue from cycling hypoxia.« less

[Hypoxia and memory. Specific features of nootropic agents effects and their use].

PubMed

Voronina, T A

2000-01-01

Hypoxia and hypoxic adaptation are powerful factors of controlling memory and behavior processes. Acute hypoxia exerts a differential impact on different deficits of mnestic and cognitive functions. Instrumental reflexes of active and passive avoidance, negative learning, behavior with a change in the stereotype of learning are more greatly damaged. Memory with spatial and visual differentiation and their rearrangement change to a lesser extent and conditional reflexes are not deranged. In this contract, altitude hypoxic adaptation enhances information fixation and increases the degree and duration of retention of temporary relations. Nootropic agents with an antihypoxic action exert a marked effect on hypoxia-induced cognitive and memory disorders and the magnitude of this effect depends on the ration of proper nootropic to antihypoxic components in the spectrum of the drugs' pharmacological activity. The agents that combine a prevailing antiamnestic effect and a marked and moderate antihypoxic action (mexidole, nooglutil, pyracetam, beglymin, etc.) are most effective in eliminating different hypoxia-induced cognitive and memory disorders, nootropic drugs that have a pronounced antiamnestic activity (centrophenoxine, etc.) and no antihypoxic component also restore the main types of mnestic disorders after hypoxia, but to a lesser extent.

Differential sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy.

PubMed

de Theije, C C; Langen, R C J; Lamers, W H; Gosker, H R; Schols, A M W J; Köhler, S E

2015-01-15

Hypoxia as a consequence of acute and chronic respiratory disease has been associated with muscle atrophy. This study investigated the sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy. Male mice were exposed to 8% normobaric oxygen for up to 21 days. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were isolated, weighed, and assayed for expression profiles of the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF1α) signaling. Fiber-type composition and the capillary network were investigated. Hypoxia-induced muscle atrophy was more prominent in the EDL than the soleus muscle. Although increased expression of HIF1α target genes showed that both muscle types sensed hypoxia, their adaptive responses differed. Atrophy consistently involved a hypoxia-specific effect (i.e., not attributable to a hypoxia-mediated reduction of food intake) in the EDL only. Hypoxia-specific activation of the UPS and ALP and increased expression of the glucocorticoid receptor (Gr) and its target genes were also mainly observed in the EDL. In the soleus, stimulation of gene expression of those pathways could be mimicked to a large extent by food restriction alone. Hypoxia increased the number of capillary contacts per fiber cross-sectional area in both muscles. In the EDL, this was due to type II fiber atrophy, whereas in the soleus the absolute number of capillary contacts increased. These responses represent two distinct modes to improve oxygen supply to muscle fibers, but may aggravate muscle atrophy in chronic obstructive pulmonary disease patients who have a predominance of type II fibers. Copyright © 2015 the American Physiological Society.

Acute Lipotoxicity Regulates Severity of Biliary Acute Pancreatitis without Affecting Its Initiation

PubMed Central

Durgampudi, Chandra; Noel, Pawan; Patel, Krutika; Cline, Rachel; Trivedi, Ram N.; DeLany, James P.; Yadav, Dhiraj; Papachristou, Georgios I.; Lee, Kenneth; Acharya, Chathur; Jaligama, Deepthi; Navina, Sarah; Murad, Faris; Singh, Vijay P.

2015-01-01

Obese patients have worse outcomes during acute pancreatitis (AP). Previous animal models of AP have found worse outcomes in obese rodents who may have a baseline proinflammatory state. Our aim was to study the role of acute lipolytic generation of fatty acids on local severity and systemic complications of AP. Human postpancreatitis necrotic collections were analyzed for unsaturated fatty acids (UFAs) and saturated fatty acids. A model of biliary AP was designed to replicate the human variables by intraductal injection of the triglyceride glyceryl trilinoleate alone or with the chemically distinct lipase inhibitors orlistat or cetilistat. Parameters of AP etiology and outcomes of local and systemic severity were measured. Patients with postpancreatitis necrotic collections were obese, and 13 of 15 had biliary AP. Postpancreatitis necrotic collections were enriched in UFAs. Intraductal glyceryl trilinoleate with or without the lipase inhibitors resulted in oil red O–positive areas, resembling intrapancreatic fat. Both lipase inhibitors reduced the glyceryl trilinoleate–induced increase in serum lipase, UFAs, pancreatic necrosis, serum inflammatory markers, systemic injury, and mortality but not serum alanine aminotransferase, bilirubin, or amylase. We conclude that UFAs are enriched in human necrotic collections and acute UFA generation via lipolysis worsens pancreatic necrosis, systemic inflammation, and injury associated with severe AP. Inhibition of lipolysis reduces UFA generation and improves these outcomes of AP without interfering with its induction. PMID:24854864

Hypoxia delays hematopoiesis: retention of embryonic hemoglobin and erythrocytes in larval rainbow trout, Oncorhynchus mykiss, during chronic hypoxia exposure.

PubMed

Bianchini, Kristin; Wright, Patricia A

2013-12-01

In rainbow trout development, a switch occurs from high-affinity embryonic hemoglobin (Hb) and round, embryonic erythrocytes to lower-affinity adult Hb and oval, adult erythrocytes. Our study investigated the early ontogeny of rainbow trout blood properties and the hypoxia response. We hypothesized that hypoxia exposure would delay the ontogenetic turnover of Hb and erythrocytes because retention of high-affinity embryonic Hb would facilitate oxygen loading. To test this hypothesis we developed a method of efficiently extracting blood from individual embryos and larvae and optimized several techniques for measuring hematological parameters on microliter (0.5-2.0 μl) blood samples. In chronic hypoxia (30% of oxygen saturation), stage-matched embryos and larvae possessed half the Hb concentration, erythrocyte counts and hematocrit observed in normoxia. Hypoxia-reared larvae also had threefold to sixfold higher mRNA expression of the embryonic Hb α-1, β-1 and β-2 subunits relative to stage-matched normoxia-reared larvae. Furthermore, in hypoxia, the round embryonic erythrocytic shape persisted into later developmental stages. Despite these differences, Hb-oxygen affinity (P50), cooperativity and the Root effect were unaltered in hypoxia-reared O. mykiss. The data support our hypothesis that chronic hypoxia delays the ontogenetic turnover of Hb and erythrocytes, but without the predicted functional consequences (i.e. higher than expected P50). These results also suggest that the Hb-oxygen affinity is protected during development in chronic hypoxia to favor oxygen unloading at the tissues. We conclude that in early trout development, the blood-oxygen transport system responds very differently to chronic hypoxia relative to adults, possibly because respiration depends relatively more on oxygen diffusion than convection.

Carbamylated erythropoietin ameliorates the metabolic stress induced in vivo by severe chronic hypoxia

PubMed Central

Fantacci, Monica; Bianciardi, Paola; Caretti, Anna; Coleman, Thomas R.; Cerami, Anthony; Brines, Michael; Samaja, Michele

2006-01-01

Ischemia and chronic hypoxia (CH) trigger a variety of adverse effects arising from metabolic stress that injures cells. In response to reduced O2, hypoxia-inducible factor 1α (HIF-1α) activates erythropoietin (Epo) as well as many other target genes that counteract the effects of O2 deficiency. Epo produced by the kidney stimulates erythrocyte production, leading to decreased HIF-1α production by improved tissue O2 delivery. However, Epo is produced by many other tissues, and it is currently unclear to what extent, if any, locally produced Epo modulates HIF-1α expression. Derivatives of Epo that possess tissue-protective activities but do not stimulate erythropoiesis [e.g., carbamylated Epo (CEpo)] are useful tools with which to determine whether exogenous Epo modulates HIF-1α in the absence of changes in hemoglobin concentration. We compared the effects of CH (6.5% O2 for 10 days) with or without CEpo administered by daily s.c. injection (10 μg/kg of body weight). CEpo administration did not alter the survival rate, weight loss, or increased hemoglobin concentration associated with CH. Therefore, CEpo does not directly suppress HIF-mediated erythropoiesis. CEpo does, however, prevent CH-induced neuronal increases of HIF-1α and Epo receptor-associated immunoreactivity (a measure of stress) while reducing the apoptotic index. In contrast, the myocardium did not exhibit increased HIF-1α expression during CH, although CEpo did reduce the apoptotic index. These observations therefore demonstrate that CEpo administration reduces the metabolic stress caused by severe CH, resulting in improved cellular survival independent of erythrocyte production. PMID:17090665

Neonatal hypoxia, hippocampal atrophy, and memory impairment: evidence of a causal sequence.

PubMed

Cooper, Janine M; Gadian, David G; Jentschke, Sebastian; Goldman, Allan; Munoz, Monica; Pitts, Georgia; Banks, Tina; Chong, W Kling; Hoskote, Aparna; Deanfield, John; Baldeweg, Torsten; de Haan, Michelle; Mishkin, Mortimer; Vargha-Khadem, Faraneh

2015-06-01

Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life. © The Author 2013. Published by Oxford University Press.

Cerebral Oxygenation in Awake Rats during Acclimation and Deacclimation to Hypoxia: An In Vivo Electron Paramagnetic Resonance Study

PubMed Central

Khan, Mohammad N.; Hou, Huagang G.; Merlis, Jennifer; Abajian, Michelle A.; Demidenko, Eugene; Grinberg, Oleg Y.; Swartz, Harold M.

2011-01-01

Abstract Dunn, J. F., N. Khan, H. G. Hou, J. Merlis, M. A. Abajian, E. Demidenko, O.Y. Grinberg, and H. M. Swartz. Cerebral oxygenation in awake rats during acclimation and deacclimation to hypoxia: an in vivo EPR study. High Alt. Med. Biol. 12:71–77, 2011.— Exposure to high altitude or hypobaric hypoxia results in a series of metabolic, physiologic, and genetic changes that serve to acclimate the brain to hypoxia. Tissue Po2 (Pto2) is a sensitive index of the balance between oxygen delivery and utilization and can be considered to represent the summation of such factors as cerebral blood flow, capillary density, hematocrit, arterial Po2, and metabolic rate. As such, it can be used as a marker of the extent of acclimation. We developed a method using electron paramagnetic resonance (EPR) to measure Pto2 in unanesthetized subjects with a chronically implanted sensor. EPR was used to measure rat cortical tissue Pto2 in awake rats during acute hypoxia and over a time course of acclimation and deacclimation to hypobaric hypoxia. This was done to simulate the effects on brain Pto2 of traveling to altitude for a limited period. Acute reduction of inspired O2 to 10% caused a decline from 26.7 ± 2.2 to 13.0 ± 1.5 mmHg (mean ± SD). Addition of 10% CO2 to animals breathing 10% O2 returned Pto2 to values measured while breathing 21% O2, indicating that hypercapnia can reverse the effects of acute hypoxia. Pto2 in animals acclimated to 10% O2 was similar to that measured preacclimation when breathing 21% O2. Using a novel, individualized statistical model, it was shown that the T1/2 of the Pto2 response during exposure to chronic hypoxia was approximately 2 days. This indicates a capacity for rapid adaptation to hypoxia. When subjects were returned to normoxia, there was a transient hyperoxygenation, followed by a return to lower values with a T1/2 of deacclimation of 1.5 to 3 days. These data indicate that exposure to hypoxia results in significant

Sleeping in moderate hypoxia at home for prevention of acute mountain sickness (AMS): a placebo-controlled, randomized double-blind study.

PubMed

Dehnert, Christoph; Böhm, Astrid; Grigoriev, Igor; Menold, Elmar; Bärtsch, Peter

2014-09-01

Acclimatization at natural altitude effectively prevents acute mountain sickness (AMS). It is, however, unknown whether prevention of AMS is also possible by only sleeping in normobaric hypoxia. In a placebo-controlled, double-blind study 76 healthy unacclimatized male subjects, aged 18 to 50 years, slept for 14 consecutive nights at either a fractional inspired oxygen (Fio2) of 0.14 to 0.15 (average target altitude 3043 m; treatment group) or 0.209 (control group). Four days later, AMS scores and incidence of AMS were assessed during a 20-hour exposure in normobaric hypoxia at Fio2 = 0.12 (equivalent to 4500 m). Because of technical problems with the nitrogen generators, target altitude was not achieved in the tents and only 21 of 37 subjects slept at an average altitude considered sufficient for acclimatization (>2200 m; average, 2600 m). Therefore, in a subgroup analysis these subjects were compared with the 21 subjects of the control group with the lowest sleeping altitude. This analysis showed a significantly lower AMS-C score (0.38; 95% CI, 0.21 to 0.54) vs 1.10; 95% CI, 0.57 to 1.62; P = .04) and lower Lake Louise Score (3.1; 95% CI, 2.2 to 4.1 vs 5.1; 95% CI, 3.6 to 6.6; P = .07) for the treatment subgroup. The incidence of AMS defined as an AMS-C score greater than 0.70 was also significantly lower (14% vs 52%; P < .01). Sleeping 14 consecutive nights in normobaric hypoxia (equivalent to 2600 m) reduced symptoms and incidence of AMS 4 days later on exposure to 4500 m. Copyright © 2014 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

In vivo retinal and choroidal hypoxia imaging using a novel activatable hypoxia-selective near-infrared fluorescent probe.

PubMed

Fukuda, Shinichi; Okuda, Kensuke; Kishino, Genichiro; Hoshi, Sujin; Kawano, Itsuki; Fukuda, Masahiro; Yamashita, Toshiharu; Beheregaray, Simone; Nagano, Masumi; Ohneda, Osamu; Nagasawa, Hideko; Oshika, Tetsuro

2016-12-01

Retinal hypoxia plays a crucial role in ocular neovascular diseases, such as diabetic retinopathy, retinopathy of prematurity, and retinal vascular occlusion. Fluorescein angiography is useful for identifying the hypoxia extent by detecting non-perfusion areas or neovascularization, but its ability to detect early stages of hypoxia is limited. Recently, in vivo fluorescent probes for detecting hypoxia have been developed; however, these have not been extensively applied in ophthalmology. We evaluated whether a novel donor-excited photo-induced electron transfer (d-PeT) system based on an activatable hypoxia-selective near-infrared fluorescent (NIRF) probe (GPU-327) responds to both mild and severe hypoxia in various ocular ischemic diseases animal models. The ocular fundus examination offers unique opportunities for direct observation of the retina through the transparent cornea and lens. After injection of GPU-327 in various ocular hypoxic diseases of mouse and rabbit models, NIRF imaging in the ocular fundus can be performed noninvasively and easily by using commercially available fundus cameras. To investigate the safety of GPU-327, electroretinograms were also recorded after GPU-327 and PBS injection. Fluorescence of GPU-327 increased under mild hypoxic conditions in vitro. GPU-327 also yielded excellent signal-to-noise ratio without washing out in vivo experiments. By using near-infrared region, GPU-327 enables imaging of deeper ischemia, such as choroidal circulation. Additionally, from an electroretinogram, GPU-327 did not cause neurotoxicity. GPU-327 identified hypoxic area both in vivo and in vitro.

Management of patients after recovering from acute severe biliary pancreatitis.

PubMed

Dedemadi, Georgia; Nikolopoulos, Manolis; Kalaitzopoulos, Ioannis; Sgourakis, George

2016-09-14

Cholelithiasis is the most common cause of acute pancreatitis, accounting 35%-60% of cases. Around 15%-20% of patients suffer a severe attack with high morbidity and mortality rates. As far as treatment is concerned, the optimum method of late management of patients with severe acute biliary pancreatitis is still contentious and the main question is over the correct timing of every intervention. Patients after recovering from an acute episode of severe biliary pancreatitis can be offered alternative options in their management, including cholecystectomy, endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy, or no definitive treatment. Delaying cholecystectomy until after resolution of the inflammatory process, usually not earlier than 6 wk after onset of acute pancreatitis, seems to be a safe policy. ERCP and sphincterotomy on index admission prevent recurrent episodes of pancreatitis until cholecystectomy is performed, but if used for definitive treatment, they can be a valuable tool for patients unfit for surgery. Some patients who survive severe biliary pancreatitis may develop pseudocysts or walled-off necrosis. Management of pseudocysts with minimally invasive techniques, if not therapeutic, can be used as a bridge to definitive operative treatment, which includes delayed cholecystectomy and concurrent pseudocyst drainage in some patients. A management algorithm has been developed for patients surviving severe biliary pancreatitis according to the currently published data in the literature.

Systematic review of severe acute liver injury caused by terbinafine.

PubMed

Yan, Jun; Wang, Xiaolin; Chen, Shengli

2014-08-01

Terbinafine is an effective antimicrobial agent against dermatophytes, cryptococcus and other fungi. It is the preferred drug to treat onychomycosis. However, severe acute hepatitis from oral terbinafine administration has been recently reported. To describe a representative case, and review the literature regarding the best evidence on treatment and prognosis of severe acute hepatitis caused by oral terbinafine. The literature was searched for publications on severe hepatitis caused by terbinafine using MEDLINE, China Biology Medicine Disc, and the VIP Medical Information Resource System. Related references were searched manually. Seventeen English and three Chinese references of case reports were included after eliminating duplicate publications. No randomized control studies were found. Liver enzyme levels were found to have been increased significantly. Abdominal ultrasound demonstrated cholestasis. Severe acute liver injury is a known, but unusual complication of terbinafine exposure. The prognosis is often good with appropriate treatment. Liver function assessment before treatment and periodic monitoring 4-6 weeks after initiation of treatment is recommended.

Association between serum interleukin-35 levels and severity of acute pancreatitis

PubMed Central

Zhang, Yi-Li; Zhou, Xiu-Yun; Guo, Xian-Yang; Tu, Jun-Wei

2015-01-01

Inflammatory cytokines have been reported to be associated with pathogenesis of acute pancreatitis. The aim of this study was to measure the serum IL-35 levels in patients with acute pancreatitis and analyze the relationship between IL-35 levels and the disease severity. Thirty-two patients with acute pancreatitis and 32 healthy control subjects were included into the study. The serum levels of IL-35 were measured by enzyme-linked immunosorbent assay upon admission and the following seven days. The relationships with severity and etiology during the clinical course were analyzed. Serum IL-35 levels in patients with acute pancreatitis at the time of admission (5.25±0.37 ng/mL) were significantly higher than those in healthy controls (1.93±0.16 ng/mL, P<0.001). Moreover, serum IL-35 levels in patients with severe attacks (7.15±0.48 ng/mL) were significantly higher than those with moderately severe attacks (5.14±0.49 ng/mL, P=0.01) and mild attacks (3.69±0.53 ng/mL, P<0.001). However, there was no significant difference of serum IL-35 levels among patients with acute pancreatitis due of alcohol, gallstone and idiopathy. In addition, the peak serum concentrations of IL-35 were on day 1 after admission. Our results demonstrate that increased serum IL-35 levels may be related to the inflammatory response in patients with acute pancreatitis, suggesting that IL-35 may be used for a potential biomarker of acute pancreatitis. PMID:26221286

Comparative and Experimental Studies on the Genes Altered by Chronic Hypoxia in Human Brain Microendothelial Cells

PubMed Central

Mata-Greenwood, Eugenia; Goyal, Dipali; Goyal, Ravi

2017-01-01

Background : Hypoxia inducible factor 1 alpha (HIF1A) is a master regulator of acute hypoxia; however, with chronic hypoxia, HIF1A levels return to the normoxic levels. Importantly, the genes that are involved in the cell survival and viability under chronic hypoxia are not known. Therefore, we tested the hypothesis that chronic hypoxia leads to the upregulation of a core group of genes with associated changes in the promoter DNA methylation that mediates the cell survival under hypoxia. Results : We examined the effect of chronic hypoxia (3 days; 0.5% oxygen) on human brain micro endothelial cells (HBMEC) viability and apoptosis. Hypoxia caused a significant reduction in cell viability and an increase in apoptosis. Next, we examined chronic hypoxia associated changes in transcriptome and genome-wide promoter methylation. The data obtained was compared with 16 other microarray studies on chronic hypoxia. Nine genes were altered in response to chronic hypoxia in all 17 studies. Interestingly, HIF1A was not altered with chronic hypoxia in any of the studies. Furthermore, we compared our data to three other studies that identified HIF-responsive genes by various approaches. Only two genes were found to be HIF dependent. We silenced each of these 9 genes using CRISPR/Cas9 system. Downregulation of EGLN3 significantly increased the cell death under chronic hypoxia, whereas downregulation of ERO1L, ENO2, adrenomedullin, and spag4 reduced the cell death under hypoxia. Conclusions : We provide a core group of genes that regulates cellular acclimatization under chronic hypoxic stress, and most of them are HIF independent. PMID:28620317

Midcervical neuronal discharge patterns during and following hypoxia

PubMed Central

Sandhu, M. S.; Baekey, D. M.; Maling, N. G.; Sanchez, J. C.; Reier, P. J.

2014-01-01

Anatomical evidence indicates that midcervical interneurons can be synaptically coupled with phrenic motoneurons. Accordingly, we hypothesized that interneurons in the C3–C4 spinal cord can display discharge patterns temporally linked with inspiratory phrenic motor output. Anesthetized adult rats were studied before, during, and after a 4-min bout of moderate hypoxia. Neuronal discharge in C3–C4 lamina I–IX was monitored using a multielectrode array while phrenic nerve activity was extracellularly recorded. For the majority of cells, spike-triggered averaging (STA) of ipsilateral inspiratory phrenic nerve activity based on neuronal discharge provided no evidence of discharge synchrony. However, a distinct STA phrenic peak with a 6.83 ± 1.1 ms lag was present for 5% of neurons, a result that indicates a monosynaptic connection with phrenic motoneurons. The majority (93%) of neurons changed discharge rate during hypoxia, and the diverse responses included both increased and decreased firing. Hypoxia did not change the incidence of STA peaks in the phrenic nerve signal. Following hypoxia, 40% of neurons continued to discharge at rates above prehypoxia values (i.e., short-term potentiation, STP), and cells with initially low discharge rates were more likely to show STP (P < 0.001). We conclude that a population of nonphrenic C3–C4 neurons in the rat spinal cord is synaptically coupled to the phrenic motoneuron pool, and these cells can modulate inspiratory phrenic output. In addition, the C3–C4 propriospinal network shows a robust and complex pattern of activation both during and following an acute bout of hypoxia. PMID:25552641

Systemic oxidative-nitrosative-inflammatory stress during acute exercise in hypoxia; implications for microvascular oxygenation and aerobic capacity.

PubMed

Woodside, John D S; Gutowski, Mariusz; Fall, Lewis; James, Philip E; McEneny, Jane; Young, Ian S; Ogoh, Shigehiko; Bailey, Damian M

2014-12-01

Exercise performance in hypoxia may be limited by a critical reduction in cerebral and skeletal tissue oxygenation, although the underlying mechanisms remain unclear. We examined whether increased systemic free radical accumulation during hypoxia would be associated with elevated microvascular deoxygenation and reduced maximal aerobic capacity (V̇O2 max ). Eleven healthy men were randomly assigned single-blind to an incremental semi-recumbent cycling test to determine V̇O2 max in both normoxia (21% O2) and hypoxia (12% O2) separated by a week. Continuous-wave near-infrared spectroscopy was employed to monitor concentration changes in oxy- and deoxyhaemoglobin in the left vastus lateralis muscle and frontal cerebral cortex. Antecubital venous blood samples were obtained at rest and at V̇O2 max to determine oxidative (ascorbate radical by electron paramagnetic resonance spectroscopy), nitrosative (nitric oxide metabolites by ozone-based chemiluminescence and 3-nitrotyrosine by enzyme-linked immunosorbent assay) and inflammatory stress biomarkers (soluble intercellular/vascular cell adhesion 1 molecules by enzyme-linked immunosorbent assay). Hypoxia was associated with increased cerebral and muscle tissue deoxygenation and lower V̇O2 max (P < 0.05 versus normoxia). Despite an exercise-induced increase in oxidative-nitrosative-inflammatory stress, hypoxia per se did not have an additive effect (P > 0.05 versus normoxia). Consequently, we failed to observe correlations between any metabolic, haemodynamic and cardiorespiratory parameters (P > 0.05). Collectively, these findings suggest that altered free radical metabolism cannot explain the elevated microvascular deoxygenation and corresponding lower V̇O2 max in hypoxia. Further research is required to determine whether free radicals when present in excess do indeed contribute to the premature termination of exercise in hypoxia. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

[Fatal acute pancreatitis caused by severe hypertriglyceridaemia].

PubMed

Abed, Osama Karim; Lindberg, Mats; Andos, Shadi

2014-04-14

We report a case of fatal acute pancreatitis caused by severe hypertriglyceridaemia in a 27-year-old male who was treated with quetiapine. The blood samples were milk-like with markedly elevated triglycerides (> 55 mmol/l). Computer tomography revealed a severe pancreatitis without bile stones or cholestasis. In spite of treatment the patient's condition rapidly worsened and he died 48 hours after admission. We discuss the option of treating hypertriglyceridaemia-induced pancreatitis with apheresis.

Acute salicylate poisoning: risk factors for severe outcome.

PubMed

Shively, Rachel M; Hoffman, Robert S; Manini, Alex F

2017-03-01

Salicylate poisoning remains a significant public health threat with more than 20,000 exposures reported annually in the United States. We aimed to establish early predictors of severe in-hospital outcomes in Emergency Department patients presenting with acute salicylate poisoning. This was a secondary data analysis of adult salicylate overdoses from a prospective cohort study of acute drug overdoses at two urban university teaching hospitals from 2009 to 2013. Patients were included based on confirmed salicylate ingestion and enrolled consecutively. Demographics, clinical parameters, treatment and disposition were collected from the medical record. Severe outcome was defined as a composite occurrence of acidemia (pH <7.3 or bicarbonate <16 mEq/L), hemodialysis, and/or death. Out of 1997 overdoses screened, 48 patients met inclusion/exclusion criteria. Patient characteristics were 43.8% male, median age 32 (range 18-87), mean initial salicylate concentration 28.1 mg/dL (SD 26.6), and 20.8% classified as severe outcome. Univariate analysis indicated that age, respiratory rate, lactate, coma, and the presence of co-ingestions were significantly associated with severe outcome, while initial salicylate concentration alone had no association. However, when adjusted for salicylate concentration, only age (OR 1.13; 95% CI 1.02-1.26) and respiratory rate (OR 1.29; 95% CI 1.02-1.63) were independent predictors. Additionally, lactate showed excellent test characteristics to predict severe outcome, with an optimal cutpoint of 2.25 mmol/L (78% sensitivity, 67% specificity). In adult Emergency Department patients with acute salicylate poisoning, independent predictors of severe outcome were older age and increased respiratory rate, as well as initial serum lactate, while initial salicylate concentration alone was not predictive.

HRGFish: A database of hypoxia responsive genes in fishes

NASA Astrophysics Data System (ADS)

Rashid, Iliyas; Nagpure, Naresh Sahebrao; Srivastava, Prachi; Kumar, Ravindra; Pathak, Ajey Kumar; Singh, Mahender; Kushwaha, Basdeo

2017-02-01

Several studies have highlighted the changes in the gene expression due to the hypoxia response in fishes, but the systematic organization of the information and the analytical platform for such genes are lacking. In the present study, an attempt was made to develop a database of hypoxia responsive genes in fishes (HRGFish), integrated with analytical tools, using LAMPP technology. Genes reported in hypoxia response for fishes were compiled through literature survey and the database presently covers 818 gene sequences and 35 gene types from 38 fishes. The upstream fragments (3,000 bp), covered in this database, enables to compute CG dinucleotides frequencies, motif finding of the hypoxia response element, identification of CpG island and mapping with the reference promoter of zebrafish. The database also includes functional annotation of genes and provides tools for analyzing sequences and designing primers for selected gene fragments. This may be the first database on the hypoxia response genes in fishes that provides a workbench to the scientific community involved in studying the evolution and ecological adaptation of the fish species in relation to hypoxia.

Minocycline blocks glial cell activation and ventilatory acclimatization to hypoxia

PubMed Central

Arbogast, Tara E.; Moya, Esteban A.; Fu, Zhenxing; Powell, Frank L.

2017-01-01

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation, which persists upon return to normoxia and involves plasticity in both central nervous system respiratory centers and peripheral chemoreceptors. We investigated the role of glial cells in VAH in male Sprague-Dawley rats using minocycline, an antibiotic that inhibits microglia activation and has anti-inflammatory properties, and barometric pressure plethysmography to measure ventilation. Rats received either minocycline (45mg/kg ip daily) or saline beginning 1 day before and during 7 days of chronic hypoxia (CH, PiO2 = 70 Torr). Minocycline had no effect on normoxic control rats or the hypercapnic ventilatory response in CH rats, but minocycline significantly (P < 0.001) decreased ventilation during acute hypoxia in CH rats. However, minocycline administration during only the last 3 days of CH did not reverse VAH. Microglia and astrocyte activation in the nucleus tractus solitarius was quantified from 30 min to 7 days of CH. Microglia showed an active morphology (shorter and fewer branches) after 1 h of hypoxia and returned to the control state (longer filaments and extensive branching) after 4 h of CH. Astrocytes increased glial fibrillary acidic protein antibody immunofluorescent intensity, indicating activation, at both 4 and 24 h of CH. Minocycline had no effect on glia in normoxia but significantly decreased microglia activation at 1 h of CH and astrocyte activation at 24 h of CH. These results support a role for glial cells, providing an early signal for the induction but not maintenance of neural plasticity underlying ventilatory acclimatization to hypoxia. NEW & NOTEWORTHY The signals for neural plasticity in medullary respiratory centers underlying ventilatory acclimatization to chronic hypoxia are unknown. We show that chronic hypoxia activates microglia and subsequently astrocytes. Minocycline, an antibiotic that blocks microglial activation and has anti

Network-based association of hypoxia-responsive genes with cardiovascular diseases

NASA Astrophysics Data System (ADS)

Wang, Rui-Sheng; Oldham, William M.; Loscalzo, Joseph

2014-10-01

Molecular oxygen is indispensable for cellular viability and function. Hypoxia is a stress condition in which oxygen demand exceeds supply. Low cellular oxygen content induces a number of molecular changes to activate regulatory pathways responsible for increasing the oxygen supply and optimizing cellular metabolism under limited oxygen conditions. Hypoxia plays critical roles in the pathobiology of many diseases, such as cancer, heart failure, myocardial ischemia, stroke, and chronic lung diseases. Although the complicated associations between hypoxia and cardiovascular (and cerebrovascular) diseases (CVD) have been recognized for some time, there are few studies that investigate their biological link from a systems biology perspective. In this study, we integrate hypoxia genes, CVD genes, and the human protein interactome in order to explore the relationship between hypoxia and cardiovascular diseases at a systems level. We show that hypoxia genes are much closer to CVD genes in the human protein interactome than that expected by chance. We also find that hypoxia genes play significant bridging roles in connecting different cardiovascular diseases. We construct a hypoxia-CVD bipartite network and find several interesting hypoxia-CVD modules with significant gene ontology similarity. Finally, we show that hypoxia genes tend to have more CVD interactors in the human interactome than in random networks of matching topology. Based on these observations, we can predict novel genes that may be associated with CVD. This network-based association study gives us a broad view of the relationships between hypoxia and cardiovascular diseases and provides new insights into the role of hypoxia in cardiovascular biology.

Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury.

PubMed

Yang, Yunwen; Yu, Xiaowen; Zhang, Yue; Ding, Guixia; Zhu, Chunhua; Huang, Songming; Jia, Zhanjun; Zhang, Aihua

2018-04-16

Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active, small-molecule HIF PHD inhibitor for the treatment of anemia in patients with chronic kidney disease (CKD). The current study aimed to evaluate the effect of FG-4592 (Roxadustat) on cis -diamminedichloroplatinum (cisplatin)-induced kidney injury. In mice, pretreatment with FG-4592 markedly ameliorated cisplatin-induced kidney injury as shown by the improved renal function (blood urea nitrogen (BUN), serum creatinine (Scr), and cystatin C) and kidney morphology (periodic acid-Schiff (PAS) staining) in line with a robust blockade of renal tubular injury markers of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Meanwhile, the renal apoptosis and inflammation induced by cisplatin were also strikingly attenuated in FG-4592-treated mice. Along with the protective effects shown above, FG-4592 pretreatment strongly enhanced HIF-1α in tubular cells, as well as the expressions of HIF target genes. FG-4592 alone did not affect the renal function and morphology in mice. In vitro , FG-4592 treatment significantly up-regulated HIF-1α and protected the tubular cells against cisplatin-induced apoptosis. In summary, FG-4592 treatment remarkably ameliorated the cisplatin-induced kidney injury possibly through the stabilization of HIF. Thus, besides the role in treating CKD anemia, the clinical use of FG-4592 also could be extended to AKI. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical

Temporal dynamics of lactate concentration in the human brain during acute inspiratory hypoxia

PubMed Central

Harris, Ashley D; Roberton, Victoria H; Huckle, Danielle L; Saxena, Neeraj; Evans, C John; Murphy, Kevin; Hall, Judith E; Bailey, Damian M; Mitsis, Georgios; Edden, Richard A E; Wise, Richard G

2012-01-01

Purpose To demonstrate the feasibility of measuring the temporal dynamics of cerebral lactate concentration and examine these dynamics in human subjects using MRS during hypoxia. Methods A respiratory protocol consisting of 10 min baseline normoxia, 20 min inspiratory hypoxia and ending with 10 min normoxic recovery was used, throughout which lactate-edited MRS was performed. This was repeated four times in three subjects. A separate session was performed to measure blood lactate. Impulse response functions using end-tidal oxygen and blood lactate as system inputs and cerebral lactate as the system output were examined to describe the dynamics of the cerebral lactate response to a hypoxic challenge. Results The average lactate increase was 20%±15% during the last half of the hypoxic challenge. Significant changes in cerebral lactate concentration were observed after 400s. The average relative increase in blood lactate was 188%±95%. The temporal dynamics of cerebral lactate concentration was reproducibly demonstrated with 200s time bins of MRS data (coefficient of variation 0.063±0.035 between time bins in normoxia). The across subject coefficient of variation was 0.333. Conclusions The methods for measuring the dynamics of the cerebral lactate response developed here would be useful to further investigate the brain’s response to hypoxia. PMID:23197421

Shared Genetic Signals of Hypoxia Adaptation in Drosophila and in High-Altitude Human Populations

PubMed Central

Jha, Aashish R.; Zhou, Dan; Brown, Christopher D.; Kreitman, Martin; Haddad, Gabriel G.; White, Kevin P.

2016-01-01

The ability to withstand low oxygen (hypoxia tolerance) is a polygenic and mechanistically conserved trait that has important implications for both human health and evolution. However, little is known about the diversity of genetic mechanisms involved in hypoxia adaptation in evolving populations. We used experimental evolution and whole-genome sequencing in Drosophila melanogaster to investigate the role of natural variation in adaptation to hypoxia. Using a generalized linear mixed model we identified significant allele frequency differences between three independently evolved hypoxia-tolerant populations and normoxic control populations for approximately 3,800 single nucleotide polymorphisms. Around 50% of these variants are clustered in 66 distinct genomic regions. These regions contain genes that are differentially expressed between hypoxia-tolerant and normoxic populations and several of the differentially expressed genes are associated with metabolic processes. Additional genes associated with respiratory and open tracheal system development also show evidence of directional selection. RNAi-mediated knockdown of several candidate genes’ expression significantly enhanced survival in severe hypoxia. Using genomewide single nucleotide polymorphism data from four high-altitude human populations—Sherpas, Tibetans, Ethiopians, and Andeans, we found that several human orthologs of the genes under selection in flies are also likely under positive selection in all four high-altitude human populations. Thus, our results indicate that selection for hypoxia tolerance can act on standing genetic variation in similar genes and pathways present in organisms diverged by hundreds of millions of years. PMID:26576852

Hypoxia promotes apoptosis of neuronal cells through hypoxia-inducible factor-1α-microRNA-204-B-cell lymphoma-2 pathway

PubMed Central

Wang, Xiuwen; Li, Ji; Wu, Dongjin; Bu, Xiangpeng

2015-01-01

Neuronal cells are highly sensitive to hypoxia and may be subjected to apoptosis when exposed to hypoxia. Several apoptosis-related genes and miRNAs involve in hypoxia-induced apoptosis. This study aimed to examine the role of HIF1α-miR-204-BCL-2 pathway in hypoxia-induced apoptosis in neuronal cells. Annexin V/propidium iodide assay was performed to analyze cell apoptosis in AGE1.HN and PC12 cells under hypoxic or normoxic conditions. The expression of BCL-2 and miR-204 were determined by Western blot and qRT-PCR. The effects of miR-204 overexpression or knockdown on the expression of BCL-2 were evaluated by luciferase assay and Western blot under hypoxic or normoxic conditions. HIF-1α inhibitor YC-1 and siHIF-1α were employed to determine the effect of HIF-1α on the up-regulation of miR-204 and down-regulation of BCL-2 induced by hypoxia. Apoptosis assay showed the presence of apoptosis induced by hypoxia in neuronal cells. Moreover, we found that hypoxia significantly down-regulated the expression of BCL-2, and increased the mRNA level of miR-204 in neuronal cells than that in control. Bioinformatic analysis and luciferase reporter assay demonstrated that miR-204 directly targeted and regulated the expression of BCL-2. Specifically, the expression of BCL-2 was inhibited by miR-204 mimic and enhanced by miR-204 inhibitor. Furthermore, we detected that hypoxia induced cell apoptosis via HIF-1α/miR-204/BCL-2 in neuronal cells. This study demonstrated that HIF-1α-miR-204-BCL-2 pathway contributed to apoptosis of neuronal cells induced by hypoxia, which could potentially be exploited to prevent spinal cord ischemia–reperfusion injury. PMID:26350953

Factors predicting mortality in severe acute pancreatitis.

PubMed

Compañy, L; Sáez, J; Martínez, J; Aparicio, J R; Laveda, R; Griñó, P; Pérez-Mateo, M

2003-01-01

Acute pancreatitis (AP) is a common disorder in which ensuing serious complications may lead to a fatal outcome in patients. To describe a large series of patients with severe AP (SAP) who were admitted to our hospital and to identify factors predicting mortality. In a retrospective study, all patients with SAP diagnosed between February 1996 and October 2000 according to the Atlanta criteria were studied. Out of a total of 363 AP patients, 67 developed SAP. The mean age of the patients was 69; the commonest etiology was biliary; 55.2% developed necrosis; the commonest systemic complication was respiratory failure (44.7%), followed by acute renal failure (35.8%) and shock (20.9%). A total of 31.3% of the patients died. Factors significantly related to mortality were age, upper digestive tract bleeding, acute renal failure, respiratory failure and shock by univariate analysis. However, pseudocysts seemed to have a protective effect. By multivariate analysis, independent prognostic factors were age, acute renal failure and respiratory failure. Patients with SAP mainly died due to systemic complications, especially acute renal failure and respiratory failure. Necrosis (in the absence or presence of infection) was not correlated with increased mortality. A pseudocyst was found to be a protective factor, probably because the definition itself led to the selection of patients who had survived multiorgan failure. Copyright 2003 S. Karger AG, Basel and IAP

Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation.

PubMed

Dellinger, E Patchen; Forsmark, Christopher E; Layer, Peter; Lévy, Philippe; Maraví-Poma, Enrique; Petrov, Maxim S; Shimosegawa, Tooru; Siriwardena, Ajith K; Uomo, Generoso; Whitcomb, David C; Windsor, John A

2012-12-01

To develop a new international classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of published evidence, and worldwide consultation. The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of pancreatologists but suboptimal because these definitions are based on empiric description of occurrences that are merely associated with severity. A personal invitation to contribute to the development of a new international classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensivists, and radiologists who are currently active in clinical research on acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global Web-based survey was conducted and a dedicated international symposium was organized to bring contributors from different disciplines together and discuss the concept and definitions. The new international classification is based on the actual local and systemic determinants of severity, rather than description of events that are correlated with severity. The local determinant relates to whether there is (peri)pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another such that the presence of both infected (peri)pancreatic necrosis and persistent organ failure have a greater effect on severity than either determinant alone. The derivation of a classification based on the above principles results in 4 categories of severity-mild, moderate, severe, and critical. This classification is the result of a consultative process amongst pancreatologists from 49 countries spanning North America, South America, Europe, Asia, Oceania, and Africa. It provides

Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing.

PubMed

Sommer, Natascha; Hüttemann, Maik; Pak, Oleg; Scheibe, Susan; Knoepp, Fenja; Sinkler, Christopher; Malczyk, Monika; Gierhardt, Mareike; Esfandiary, Azadeh; Kraut, Simone; Jonas, Felix; Veith, Christine; Aras, Siddhesh; Sydykov, Akylbek; Alebrahimdehkordi, Nasim; Giehl, Klaudia; Hecker, Matthias; Brandes, Ralf P; Seeger, Werner; Grimminger, Friedrich; Ghofrani, Hossein A; Schermuly, Ralph T; Grossman, Lawrence I; Weissmann, Norbert

2017-08-04

Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as a critical step in the signaling pathway underlying HPV. However, the identity of the primary oxygen sensor and the mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary oxygen sensing, remain unresolved. To investigate the role of the pulmonary-specific isoform 2 of subunit 4 of the mitochondrial complex IV (Cox4i2) and the subsequent mediators superoxide and hydrogen peroxide for pulmonary oxygen sensing and signaling. Isolated ventilated and perfused lungs from Cox4i2 -/- mice lacked acute HPV. In parallel, pulmonary arterial smooth muscle cells (PASMCs) from Cox4i2 -/- mice showed no hypoxia-induced increase of intracellular calcium. Hypoxia-induced superoxide release which was detected by electron spin resonance spectroscopy in wild-type PASMCs was absent in Cox4i2 -/- PASMCs and was dependent on cysteine residues of Cox4i2. HPV could be inhibited by mitochondrial superoxide inhibitors proving the functional relevance of superoxide release for HPV. Mitochondrial hyperpolarization, which can promote mitochondrial superoxide release, was detected during acute hypoxia in wild-type but not Cox4i2 -/- PASMCs. Downstream signaling determined by patch-clamp measurements showed decreased hypoxia-induced cellular membrane depolarization in Cox4i2 -/- PASMCs compared with wild-type PASMCs, which could be normalized by the application of hydrogen peroxide. In contrast, chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling were not or only slightly affected by Cox4i2 deficiency, respectively. Cox4i2 is essential for acute but not chronic pulmonary oxygen sensing by triggering mitochondrial hyperpolarization and release of mitochondrial superoxide which, after conversion

Hypoxia potentiates microRNA-mediated gene silencing through posttranslational modification of Argonaute2.

PubMed

Wu, Connie; So, Jessica; Davis-Dusenbery, Brandi N; Qi, Hank H; Bloch, Donald B; Shi, Yang; Lagna, Giorgio; Hata, Akiko

2011-12-01

Hypoxia contributes to the pathogenesis of various human diseases, including pulmonary artery hypertension (PAH), stroke, myocardial or cerebral infarction, and cancer. For example, acute hypoxia causes selective pulmonary artery (PA) constriction and elevation of pulmonary artery pressure. Chronic hypoxia induces structural and functional changes to the pulmonary vasculature, which resembles the phenotype of human PAH and is commonly used as an animal model of this disease. The mechanisms that lead to hypoxia-induced phenotypic changes have not been fully elucidated. Here, we show that hypoxia increases type I collagen prolyl-4-hydroxylase [C-P4H(I)], which leads to prolyl-hydroxylation and accumulation of Argonaute2 (Ago2), a critical component of the RNA-induced silencing complex (RISC). Hydroxylation of Ago2 is required for the association of Ago2 with heat shock protein 90 (Hsp90), which is necessary for the loading of microRNAs (miRNAs) into the RISC, and translocation to stress granules (SGs). We demonstrate that hydroxylation of Ago2 increases the level of miRNAs and increases the endonuclease activity of Ago2. In summary, this study identifies hypoxia as a mediator of the miRNA-dependent gene silencing pathway through posttranslational modification of Ago2, which might be responsible for cell survival or pathological responses under low oxygen stress.

Role of Recurrent Hypoxia-Ischemia in Preterm White Matter Injury Severity

PubMed Central

Hagen, Matthew W.; Riddle, Art; McClendon, Evelyn; Gong, Xi; Shaver, Daniel; Srivastava, Taasin; Dean, Justin M.; Bai, Ji-Zhong; Fowke, Tania M.; Gunn, Alistair J.; Jones, Daniel F.; Sherman, Larry S.; Grafe, Marjorie R.; Hohimer, A. Roger; Back, Stephen A.

2014-01-01

Objective Although the spectrum of white matter injury (WMI) in preterm infants is shifting from cystic necrotic lesions to milder forms, the factors that contribute to this changing spectrum are unclear. We hypothesized that recurrent hypoxia-ischemia (rHI) will exacerbate the spectrum of WMI defined by markers of inflammation and molecules related to the extracellular matrix (hyaluronan (HA) and the PH20 hyaluronidase) that regulate maturation of the oligodendrocyte (OL) lineage after WMI. Methods We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. The response to rHI was compared against corresponding early or later single episodes of HI. An ordinal rating scale of WMI was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microglial activation. Late oligodendrocyte progenitors (preOLs) were quantified by stereology. Analysis of hyaluronan and the hyaluronidase PH20 defined the progressive response of the extracellular matrix to WMI. Results rHI resulted in a more severe spectrum of WMI with a greater burden of necrosis, but an expanded population of preOLs that displayed reduced susceptibility to cell death. WMI from single episodes of HI or rHI was accompanied by elevated HA levels and increased labeling for PH20. Expression of PH20 in fetal ovine WMI was confirmed by RT-PCR and RNA-sequencing. Conclusions rHI is associated with an increased risk for more severe WMI with necrosis, but reduced risk for preOL degeneration compared to single episodes of HI. Expansion of the preOL pool may be linked to elevated hyaluronan and PH20. PMID:25390897

A Four-Way Comparison of Cardiac Function with Normobaric Normoxia, Normobaric Hypoxia, Hypobaric Hypoxia and Genuine High Altitude

PubMed Central

Boos, Christopher John; O’Hara, John Paul; Mellor, Adrian; Hodkinson, Peter David; Tsakirides, Costas; Reeve, Nicola; Gallagher, Liam; Green, Nicholas Donald Charles; Woods, David Richard

2016-01-01

Background There has been considerable debate as to whether different modalities of simulated hypoxia induce similar cardiac responses. Materials and Methods This was a prospective observational study of 14 healthy subjects aged 22–35 years. Echocardiography was performed at rest and at 15 and 120 minutes following two hours exercise under normobaric normoxia (NN) and under similar PiO2 following genuine high altitude (GHA) at 3,375m, normobaric hypoxia (NH) and hypobaric hypoxia (HH) to simulate the equivalent hypoxic stimulus to GHA. Results All 14 subjects completed the experiment at GHA, 11 at NN, 12 under NH, and 6 under HH. The four groups were similar in age, sex and baseline demographics. At baseline rest right ventricular (RV) systolic pressure (RVSP, p = 0.0002), pulmonary vascular resistance (p = 0.0002) and acute mountain sickness (AMS) scores were higher and the SpO2 lower (p<0.0001) among all three hypoxic groups (GHA, NH and HH) compared with NN. At both 15 minutes and 120 minutes post exercise, AMS scores, Cardiac output, septal S’, lateral S’, tricuspid S’ and A’ velocities and RVSP were higher and SpO2 lower with all forms of hypoxia compared with NN. On post-test analysis, among the three hypoxia groups, SpO2 was lower at baseline and 15 minutes post exercise with GHA (89.3±3.4% and 89.3±2.2%) and HH (89.0±3.1 and (89.8±5.0) compared with NH (92.9±1.7 and 93.6±2.5%). The RV Myocardial Performance (Tei) Index and RVSP were significantly higher with HH than NH at 15 and 120 minutes post exercise respectively and tricuspid A’ was higher with GHA compared with NH at 15 minutes post exercise. Conclusions GHA, NH and HH produce similar cardiac adaptations over short duration rest despite lower SpO2 levels with GHA and HH compared with NH. Notable differences emerge following exercise in SpO2, RVSP and RV cardiac function. PMID:27100313

Chronic hypoxia up-regulates expression of adenosine A1 receptors in DDT1-MF2 cells.

PubMed

Hammond, Lucy C; Bonnet, Claire; Kemp, Paul J; Yates, Michael S; Bowmer, Christopher J

2004-02-01

As the first step to understand how chronic hypoxia might regulate smooth muscle function in health and disease, we have employed an established immortalised cell model of smooth muscle, DDT1-MF2 cells, to address the hypothesis that adenosine A1 receptor density is modulated by O2 availability. Maximal specific binding (Bmax) of the selective adenosine A1 receptor antagonist, [3H]-DPCPX, to cell membranes increased 3.5-fold from 0.48 +/- 0.02 pmol/mg to 1.7 +/- 0.5 pmol/mg protein after 16 hr of hypoxia and this effect was not accompanied by any statistically significant changes in either binding affinity (0.84 +/- 0.2 nM vs. 1.2 +/- 0.3 nM) or Hill coefficient (1.1 +/- 0.1 vs. 0.99 +/- 0.03). Hypoxia-evoked increases in membrane receptor density were paralleled in intact DDT1-MF2 cells. In addition, the increase in [3H]-DPCPX binding to intact cells was inhibited by co-incubation during hypoxia with the translational inhibitor cycloheximide, the transcriptional blocker actinomycin D and the NFkappaB inhibitor sulphasalazine. Together, these data show that adenosine A1 receptor density is modulated, at least in part, by O2-dependent activation of the transcription factor NFkappaB and adds to the list of processes dynamically regulated by ambient oxygen availability. Since hypoxia is an initiating factor in acute renal failure, similar changes in transcription may account for up-regulation of adenosine A1 receptors noted previously in the renal vasculature of rats with acute renal failure.

[Multidisciplinar international classification of the severity of acute pancreatitis: Italian version 2013].

PubMed

Uomo, G; Patchen Dellinger, E; Forsmark, C E; Layer, P; Lévy, P; Maravì-Poma, E; Shimosegawa, T; Siriwardena, A K; Whitcomb, D C; Windsor, J A; Petrov, M S

2013-12-01

The aim of this paper was to present the 2013 Italian edition of a new international classification of acute pancreatitis severity. The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of pancreatologists but suboptimal because these definitions are based on empiric description of occurrences that are merely associated with severity. A personal invitation to contribute to the development of a new international classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensivists, and radiologists who are currently active in clinical research on acute pancreatitis. A global web-based survey was conducted and a dedicated international symposium was organized to bring contributors from different disciplines together and discuss the concept and definitions. The new international classification is based on the actual local and systemic determinants of severity, rather than description of events that are correlated with severity. The local determinant relates to whether there is (peri)pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another such that the presence of both infected (peri)pancreatic necrosis and persistent organ failure have a greater effect on severity than either determinant alone. The derivation of a classification based on the above principles results in 4 categories of severity-mild, moderate, severe, and critical. This classification provides a set of concise up-to-date definitions of all the main entities pertinent to classifying the severity of acute pancreatitis in clinical practice and research.

Severe Hypertriglyceridemia in Diabetic Ketoacidosis Accompanied by Acute Pancreatitis: Case Report

PubMed Central

Hahn, Suk Jae; Park, Jung-hyun; Lee, Jong Ho; Lee, Jun Kyu

2010-01-01

We report a case of diabetic ketoacidosis (DKA) and hypertriglyceridemia (severely elevated to 15,240 mg/dL) complicated by acute pancreatitis, which was treated successfully with insulin therapy and conservative management. A 20-yr-old woman with a history of type 1 diabetes came to the emergency department 7 months after discontinuing insulin therapy. DKA, severe hypertriglyceridemia and acute pancreatitis were diagnosed, with DKA suspected of contributing to the development of the other conditions. In Korea, two cases of DKA-induced hypertriglyceridemia and 13 cases of hypertriglyceridemia-induced acute pancreatitis have been previously reported separately. PMID:20808685

Severe hypertriglyceridemia in diabetic ketoacidosis accompanied by acute pancreatitis: case report.

PubMed

Hahn, Suk Jae; Park, Jung-hyun; Lee, Jong Ho; Lee, Jun Kyu; Kim, Kyoung-Ah

2010-09-01

We report a case of diabetic ketoacidosis (DKA) and hypertriglyceridemia (severely elevated to 15,240 mg/dL) complicated by acute pancreatitis, which was treated successfully with insulin therapy and conservative management. A 20-yr-old woman with a history of type 1 diabetes came to the emergency department 7 months after discontinuing insulin therapy. DKA, severe hypertriglyceridemia and acute pancreatitis were diagnosed, with DKA suspected of contributing to the development of the other conditions. In Korea, two cases of DKA-induced hypertriglyceridemia and 13 cases of hypertriglyceridemia-induced acute pancreatitis have been previously reported separately.

VGKC complex antibodies in pediatric severe acute encephalitis: a study and literature review.

PubMed

Lin, Jainn-Jim; Lin, Kuang-Lin; Hsia, Shao-Hsuan; Wang, Huei-Shyong; Chiu, Cheng-Hsun; CHEESE Study Group

2013-08-01

Antibodies to surface proteins like voltage-gated potassium channel (VGKC) complexes are increasingly found in different neurologic diseases and encephalitis in adults and recently, in children. Detecting such antibodies can help identify forms of encephalitis that may respond to immuno-therapies. However, there are few reports on VGKC complex antibodies in pediatric severe acute encephalitis. This study retrospectively reviewed antibodies to VGKC, leucine-rich glioma-inactivated 1 (Lgi1), and contactin-associated protein-like 2 (Caspr2) in 46 children with severe acute encephalitis. Published cases of VGKC complex antibodies in pediatric encephalitis in the period of 2000-2012 were also reviewed. Elevated VGKC complex antibodies (>100pM) were detected in one of the 46 children with severe acute encephalitis. The 4-year and 6-month-old girl presented with seizure and disturbed consciousness. Viral PCR/culture and serologic evidence of influenza A infection was noted. She also had complications of epilepsy, impaired cognition, and altered behavior and psychology. Antibodies to Lgi1 and Caspr2 were not detected. Ten previously published reports revealed that VGKC complex antibodies can occur in children with limbic encephalitis and acute or sub-acute encephalitis. The incidence of VGKC complex antibodies in pediatric severe acute encephalitis is not high with only one (2.2%) of 46 children in this study. And, this is the first report on the association of VGKC complex antibodies and patients with influenza A-related severe acute encephalitis. The mechanism of VGKC complex antibodies in pediatric severe acute encephalitis warrants further study. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Severe asthma exacerbation: role of acute Chlamydophila pneumoniae and Mycoplasma pneumoniae infection.

PubMed

Cosentini, Roberto; Tarsia, Paolo; Canetta, Ciro; Graziadei, Giovanna; Brambilla, Anna Maria; Aliberti, Stefano; Pappalettera, Maria; Tantardini, Francesca; Blasi, Francesco

2008-05-30

Chlamydophila pneumoniae and Mycoplasma pneumoniae are associated with acute exacerbation of bronchial asthma (AEBA). The aim of this study was to evaluate the correlation between these acute bacterial infections and the severity of AEBA. We prospectively analysed consecutive patients admitted to the Emergency Department with acute asthma exacerbation. In every patient peak expiratory flow (PEF) measurement was performed on admission, and spirometry during follow-up. Serology for Chlamydophila and Mycoplasma pneumoniae was performed on admission and after 4-8 weeks. Fifty-eight patients completed the study. Acute atypical infections (AAI) was observed in 22/58 cases; we found single acute C. pneumoniae in 19 cases, single acute M. pneumoniae in 2 cases, and double acute infection in one case. Functional impairment on admission was greater in patients with AAI than in patients without AAI (PEF 205 +/- 104 L/min vs 276 +/- 117 p = 0.02) and persisted until visit 2 (FEV1% 76.30 +/- 24.54 vs FEV1% 92.91 +/- 13.89, p = 0.002). Moreover, the proportion of patients who presented with severe AEBA was significantly greater in the group with AAI than in the group without AAI (15/22 vs 12/36, p = 0.01; OR 4.29, 95% CI 1.38-13.32). Our data suggest an association between acute atypical infection and a more severe AEBA.

Hypoxia activates muscle-restricted coiled-coil protein (MURC) expression via transforming growth factor-β in cardiac myocytes.

PubMed

Shyu, Kou-Gi; Cheng, Wen-Pin; Wang, Bao-Wei; Chang, Hang

2014-03-01

The expression of MURC (muscle-restricted coiled-coil protein), a hypertrophy-regulated gene, increases during pressure overload. Hypoxia can cause myocardial hypertrophy; however, how hypoxia affects the regulation of MURC in cardiomyocytes undergoing hypertrophy is still unknown. The aim of the present study was to test the hypothesis that hypoxia induces MURC expression in cardiomyocytes during hypertrophy. The expression of MURC was evaluated in cultured rat neonatal cardiomyocytes subjected to hypoxia and in an in vivo model of AMI (acute myocardial infarction) to induce myocardial hypoxia in adult rats. MURC protein and mRNA expression were significantly enhanced by hypoxia. MURC proteins induced by hypoxia were significantly blocked after the addition of PD98059 or ERK (extracellular-signal-regulated kinase) siRNA 30 min before hypoxia. Gel-shift assay showed increased DNA-binding activity of SRF (serum response factor) after hypoxia. PD98059, ERK siRNA and an anti-TGF-β (transforming growth factor-β) antibody abolished the SRF-binding activity enhanced by hypoxia or exogenous administration of TGF-β. A luciferase promoter assay demonstrated increased transcriptional activity of SRF in cardiomyocytes by hypoxia. Increased βMHC (β-myosin heavy chain) and BNP (B-type natriuretic peptide) protein expression and increased protein synthesis was identified after hypoxia with the presence of MURC in hypertrophic cardiomyocytes. MURC siRNA inhibited the hypertrophic marker protein expression and protein synthesis induced by hypoxia. AMI in adult rats also demonstrated increased MURC protein expression in the left ventricular myocardium. In conclusion, hypoxia in cultured rat neonatal cardiomyocytes increased MURC expression via the induction of TGF-β, SRF and the ERK pathway. These findings suggest that MURC plays a role in hypoxia-induced hypertrophy in cardiomyocytes.

Hypoxia Regulates mTORC1-Mediated Keratinocyte Motility and Migration via the AMPK Pathway

PubMed Central

Yan, Tiantian; Zhang, Junhui; Tang, Di; Zhang, Xingyue; Jiang, Xupin; Zhao, Liping; Zhang, Qiong; Zhang, Dongxia; Huang, Yuesheng

2017-01-01

Keratinocyte migration, the initial event and rate-limiting step in wound healing, plays a vital role in restoration of the intact skin barrier, also known as re-epithelialization. After acute tissue injury, hypoxic microenvironment gradually develops and acts as an early stimulus to initiate the healing process. Although we have previously found that hypoxia induces keratinocyte migration, the underlying mechanism remains unknown. Here, we first observed that hypoxia increased mTORC1 activity. Recombinant lentivirus vector and Rapamycin were used for silencing mTORC1 in HaCaT cells and primary mouse keratinocytes (MKs). Using cell migration assay and a Zeiss chamber equipped with imaging system, we also demonstrated that mTORC1 downregulation reversed hypoxia-induced keratinocyte motility and lateral migration. Importantly, hypoxia-activated mTORC1 was accompanied by the AMPK downregulation, and we found that the AMPK pathway activators Metformin (Met) and 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) decreased the mTORC1 activity, cell motility and lateral migration. Thus, our results suggest that hypoxia regulates mTORC1-mediated keratinocyte motility and migration via the AMPK pathway. PMID:28068384

Red blood cell antibody-induced anemia causes differential degrees of tissue hypoxia in kidney and brain.

PubMed

Mistry, Nikhil; Mazer, C David; Sled, John G; Lazarus, Alan H; Cahill, Lindsay S; Solish, Max; Zhou, Yu-Qing; Romanova, Nadya; Hare, Alexander G M; Doctor, Allan; Fisher, Joseph A; Brunt, Keith R; Simpson, Jeremy A; Hare, Gregory M T

2018-04-01

Moderate anemia is associated with increased mortality and morbidity, including acute kidney injury (AKI), in surgical patients. A red blood cell (RBC)-specific antibody model was utilized to determine whether moderate subacute anemia could result in tissue hypoxia as a potential mechanism of injury. Cardiovascular and hypoxic cellular responses were measured in transgenic mice capable of expressing hypoxia-inducible factor-1α (HIF-1α)/luciferase activity in vivo. Antibody-mediated anemia was associated with mild intravascular hemolysis (6 h) and splenic RBC sequestration ( day 4), resulting in a nadir hemoglobin concentration of 89 ± 13 g/l on day 4. At this time point, renal tissue oxygen tension (P t O 2 ) was decreased in anemic mice relative to controls (13.1 ± 4.3 vs. 20.8 ± 3.7 mmHg, P < 0.001). Renal tissue hypoxia was associated with an increase in HIF/luciferase expression in vivo ( P = 0.04) and a 20-fold relative increase in renal erythropoietin mRNA transcription ( P < 0.001) but no increase in renal blood flow ( P = 0.67). By contrast, brain P t O 2 was maintained in anemic mice relative to controls (22.7 ± 5.2 vs. 23.4 ± 9.8 mmHg, P = 0.59) in part because of an increase in internal carotid artery blood flow (80%, P < 0.001) and preserved cerebrovascular reactivity. Despite these adaptive changes, an increase in brain HIF-dependent mRNA levels was observed (erythropoietin: P < 0.001; heme oxygenase-1: P = 0.01), providing evidence for subtle cerebral tissue hypoxia in anemic mice. These data demonstrate that moderate subacute anemia causes significant renal tissue hypoxia, whereas adaptive cerebrovascular responses limit the degree of cerebral tissue hypoxia. Further studies are required to assess whether hypoxia is a mechanism for acute kidney injury associated with anemia.

Neuroepithelial cells and the hypoxia emersion response in the amphibious fish Kryptolebias marmoratus.

PubMed

Regan, Kelly S; Jonz, Michael G; Wright, Patricia A

2011-08-01

Teleost fish have oxygen-sensitive neuroepithelial cells (NECs) in the gills that appear to mediate physiological responses to hypoxia, but little is known about oxygen sensing in amphibious fish. The mangrove rivulus, Kryptolebias marmoratus, is an amphibious fish that respires via the gills and/or the skin. First, we hypothesized that both the skin and gills are sites of oxygen sensing in K. marmoratus. Serotonin-positive NECs were abundant in both gills and skin, as determined by immunohistochemical labelling and fluorescence microscopy. NECs retained synaptic vesicles and were found near nerve fibres labelled with the neuronal marker zn-12. Skin NECs were 42% larger than those of the gill, as estimated by measurement of projection area, and 45% greater in number. Moreover, for both skin and gill NECs, NEC area increased significantly (30-60%) following 7 days of exposure to hypoxia (1.5 mg l(-1) dissolved oxygen). Another population of cells containing vesicular acetylcholine transporter (VAChT) proteins were also observed in the skin and gills. The second hypothesis we tested was that K. marmoratus emerse in order to breathe air cutaneously when challenged with severe aquatic hypoxia, and this response will be modulated by neurochemicals associated chemoreceptor activity. Acute exposure to hypoxia induced fish to emerse at 0.2 mg l(-1). When K. marmoratus were pre-exposed to serotonin or acetylcholine, they emersed at a significantly higher concentration of oxygen than untreated fish. Pre-exposure to receptor antagonists (ketanserin and hexamethonium) predictably resulted in fish emersing at a lower concentration of oxygen. Taken together, these results suggest that oxygen sensing occurs at the branchial and/or cutaneous surfaces in K. marmoratus and that serotonin and acetylcholine mediate, in part, the emersion response.

Severe acute malnutrition and infection

PubMed Central

Jones, Kelsey D J; Berkley, James A

2014-01-01

Severe acute malnutrition (SAM) is associated with increased severity of common infectious diseases, and death amongst children with SAM is almost always as a result of infection. The diagnosis and management of infection are often different in malnourished versus well-nourished children. The objectives of this brief are to outline the evidence underpinning important practical questions relating to the management of infectious diseases in children with SAM and to highlight research gaps. Overall, the evidence base for many aspects covered in this brief is very poor. The brief addresses antimicrobials; antipyretics; tuberculosis; HIV; malaria; pneumonia; diarrhoea; sepsis; measles; urinary tract infection; nosocomial Infections; soil transmitted helminths; skin infections and pharmacology in the context of SAM. The brief is structured into sets of clinical questions, which we hope will maximise the relevance to contemporary practice. PMID:25475887

Kinetic modeling in PET imaging of hypoxia

PubMed Central

Li, Fan; Joergensen, Jesper T; Hansen, Anders E; Kjaer, Andreas

2014-01-01

Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET contains additional valuable information on the temporal changes in tracer distribution. Kinetic modeling can be used to extract relevant pharmacokinetic parameters of tracer behavior in vivo that reflects relevant physiological processes. In this paper, we review the potential contribution of kinetic analysis for PET imaging of hypoxia. PMID:25250200

Brief Report: Incubation Period Duration and Severity of Clinical Disease Following Severe Acute Respiratory Syndrome Coronavirus Infection.

PubMed

Virlogeux, Victor; Fang, Vicky J; Wu, Joseph T; Ho, Lai-Ming; Peiris, J S Malik; Leung, Gabriel M; Cowling, Benjamin J

2015-09-01

Few previous studies have investigated the association between the severity of an infectious disease and the length of incubation period. We estimated the association between the length of the incubation period and the severity of infection with the severe acute respiratory syndrome coronavirus, using data from the epidemic in 2003 in Hong Kong. We estimated the incubation period of severe acute respiratory syndrome based on a subset of patients with available data on exposure periods and a separate subset of patients in a putative common source outbreak, and we found associations between shorter incubation period and greater severity in both groups after adjusting for potential confounders. Our findings suggest that patients with a shorter incubation period went on to have more severe disease. Further studies are needed to investigate potential biological mechanisms for this association.

Preterm birth and oxidative stress: Effects of acute physical exercise and hypoxia physiological responses.

PubMed

Martin, Agnès; Faes, Camille; Debevec, Tadej; Rytz, Chantal; Millet, Grégoire; Pialoux, Vincent

2018-05-01

Preterm birth is a global health issue that can induce lifelong medical sequela. Presently, at least one in ten newborns are born prematurely. At birth, preterm newborns exhibit higher levels of oxidative stress (OS) due to the inability to face the oxygen rich environment in which they are born into. Moreover, their immature respiratory, digestive, immune and antioxidant defense systems, as well as the potential numerous medical interventions following a preterm birth, such as oxygen resuscitation, nutrition, phototherapy and blood transfusion further contribute to high levels of OS. Although the acute effects seem well established, little is known regarding the long-term effects of preterm birth on OS. This matter is especially important given that chronically elevated OS levels may persist into adulthood and consequently contribute to the development of numerous non-communicable diseases observed in people born preterm such as diabetes, hypertension or lung disorders. The purpose of this review is to summarize the current knowledge regarding the consequences of preterm birth on OS levels from newborn to adulthood. In addition, the effects of physical activity and hypoxia, both known to disrupt redox balance, on OS modulation in preterm individuals are also explored. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

[International multidisciplinary classification of acute pancreatitis severity: the 2013 Spanish edition].

PubMed

Maraví-Poma, E; Patchen Dellinger, E; Forsmark, C E; Layer, P; Lévy, P; Shimosegawa, T; Siriwardena, A K; Uomo, G; Whitcomb, D C; Windsor, J A; Petrov, M S

2014-05-01

To develop a new classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of the published evidence, and worldwide consultation. The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of specialist in pancreatic diseases, but are suboptimal because these definitions are based on the empiric description of events not associated with severity. A personal invitation to contribute to the development of a new classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensivists and radiologists currently active in the field of clinical acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global web-based survey was conducted, and a dedicated international symposium was organized to bring contributors from different disciplines together and discuss the concept and definitions. The new classification of severity is based on the actual local and systemic determinants of severity, rather than on the description of events that are non-causally associated with severity. The local determinant relates to whether there is (peri) pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another, whereby the presence of both infected (peri) pancreatic necrosis and persistent organ failure has a greater impact upon severity than either determinant alone. The derivation of a classification based on the above principles results in four categories of severity: mild, moderate, severe, and critical. This classification is the result of a consultative process among specialists in pancreatic diseases from 49 countries spanning North America, South America, Europe, Asia, Oceania and

Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs

PubMed Central

Terry, Michael H.; Merritt, Travis A.; Papamatheakis, Demosthenes G.; Blood, Quintin; Ross, Jonathon M.; Power, Gordon G.; Longo, Lawrence D.; Wilson, Sean M.

2013-01-01

Exposure to chronic hypoxia during gestation predisposes infants to neonatal pulmonary hypertension, but the underlying mechanisms remain unclear. Here, we test the hypothesis that moderate continuous hypoxia during gestation causes changes in the rho-kinase pathway that persist in the newborn period, altering vessel tone and responsiveness. Lambs kept at 3,801 m above sea level during gestation and the first 2 wk of life were compared with those with gestation at low altitude. In vitro studies of isolated pulmonary arterial rings found a more forceful contraction in response to KCl and 5-HT in high-altitude compared with low-altitude lambs. There was no difference between the effects of blockers of various pathways of extracellular Ca2+ entry in low- and high-altitude arteries. In contrast, inhibition of rho-kinase resulted in significantly greater attenuation of 5-HT constriction in high-altitude compared with low-altitude arteries. High-altitude lambs had higher baseline pulmonary artery pressures and greater elevations in pulmonary artery pressure during 15 min of acute hypoxia compared with low-altitude lambs. Despite evidence for an increased role for rho-kinase in high-altitude arteries, in vivo studies found no significant difference between the effects of rho-kinase inhibition on hypoxic pulmonary vasoconstriction in intact high-altitude and low-altitude lambs. We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin. PMID:23152110

Sensors, transmitters, and targets in mitochondrial oxygen shortage-a hypoxia-inducible factor relay story.

PubMed

Dehne, Nathalie; Brüne, Bernhard

2014-01-10

Cells sense and respond to a shortage of oxygen by activating the hypoxia-inducible transcription factors HIF-1 and HIF-2 and evoking adaptive responses. Mitochondria are at the center of a hypoxia sensing and responding relay system. Under normoxia, reactive oxygen species (ROS) and nitric oxide (NO) are HIF activators. As their individual flux rates determine their diffusion-controlled interaction, predictions how these radicals affect HIF appear context-dependent. Considering that the oxygen requirement for NO formation limits its role in activating HIF to conditions of ambient oxygen tension. Given the central role of mitochondrial complex IV as a NO target, especially under hypoxia, allows inhibition of mitochondrial respiration by NO to spare oxygen thus, raising the threshold for HIF activation. HIF targets seem to configure a feedback-signaling circuit aimed at gradually adjusting mitochondrial function. In hypoxic cancer cells, mitochondria redirect Krebs cycle intermediates to preserve their biosynthetic ability. Persistent HIF activation lowers the entry of electron-delivering compounds into mitochondria to reduce Krebs cycle fueling and β-oxidation, attenuates the expression of electron transport chain components, limits mitochondria biosynthesis, and provokes their removal by autophagy. Mitochondria can be placed central in a hypoxia sensing-hypoxia responding circuit. We need to determine to which extent and how mitochondria contribute to sense hypoxia, explore whether modulating their oxygen-consuming capacity redirects hypoxic responses in in vivo relevant disease conditions, and elucidate how the multiple HIF targets in mitochondria shape conditions of acute versus chronic hypoxia.

Developing vascular and hypoxia based theranostics in solid tumors

NASA Astrophysics Data System (ADS)

Koonce, Nathan A.

Tissue hypoxia was recognized for its biological attenuating effects on ionizing radiation over a century ago and is a characteristic feature of many solid tumors. Clinical and experimental evidence indicates tumor hypoxia plays diverse and key roles in tumor progression, angiogenesis, and resistance to chemotherapy/radiotherapy. Hypoxia has known effects on progression and resistance to several standard treatment approaches and the significant history of study might suggest diagnostic imaging and therapeutic interventions would be routine in oncological practice. Curiously, this is not the case and the research results involved in this report will attempt to better understand and contribute to why this gap in knowledge exists and a rationale for harnessing the potential of detecting and targeting hypoxia. Despite the addition of oxygen and reversal of hypoxia being known as the best radiosensitizer, hypoxia remains unexploited in clinical cancer therapy. The studies reported herein detail development of a novel imaging technique to detect a subtype of tumor hypoxia, vascular hypoxia or hypoxemia, with a 17-fold increase (p<0.05) in uptake of pimonidazole targeted microbubbles observed compared to controls. This technique creates the potential to study the role of hypoxemia in progression and therapeutic response. Additionally, description of a nanoparticle-based therapy that targets tumor areas associated with tumor hypoxia and the tumor microenvironment in general is reported. TNF-loaded nanoparticles combined with radiotherapy resulted in a 5.25-fold growth delay that was found to be synergistic (p<0.05) and suggests clinical evaluation is warranted. An additional study to evaluate an approach to use thermal ablation of intratumoral hypoxia by an image-guided technique developed in our group is described along with a sequence dependence of radiation preceding ablation. A final study on the use of galectin-1 antagonist to significantly decrease (p<0.05) hypoxia

21-Aminosteroids prevent the down-regulation of hepatic cytochrome P450 induced by hypoxia and inflammation in conscious rabbits

PubMed Central

Galal, Ahmed; du Souich, Patrick

1999-01-01

This study was conducted to assess whether a 21-aminosteroid, U74389G, could prevent the down-regulation of hepatic cytochrome P450 (P450) induced by acute moderate hypoxia or an inflammatory reaction.The rabbits of two groups (n=6 per group) were subjected to acute moderate hypoxia (PaO2≈35 mmHg), one pre-treated with U74389G (3 mg kg−1 i.v. every 6 h, for 48 h). The rabbits of two other groups received 5 ml of turpentine s.c., one of them being pre-treated with U74389G (3 mg kg−1 i.v. every 6 h, for 72 h). The kinetics of theophylline (2.5 mg kg−1) were assessed to evaluate the activity of the P450. Once the rabbits were sacrificed, the P450 content and the amount of thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, were estimated in the liver.Compared with control rabbits, hypoxia and inflammation increased theophylline plasma concentrations, as a result of a decrease in theophylline systemic clearance (P<0.05). Both experimental conditions reduced hepatic content of P450 by 40–50% (P<0.05) and increased the amount of hepatic TBARS by around 50% (P<0.05). Pre-treatment with U74389G prevented the hypoxia- and inflammation-induced decrease in theophylline systemic clearance, the down-regulation of hepatic P450, and the increase in liver TBARS.It is concluded that in the rabbit, U74389G prevents hepatic P450 depression produced by acute moderate hypoxia and a turpentine-induced inflammatory reaction, possibly by eliciting a radical quenching antioxidant activity. PMID:10510447

Impact of Fetal Versus Perinatal Hypoxia on Sex Differences in Childhood Outcomes: Developmental Timing Matters

PubMed Central

Anastario, Michael; Salafia, Carolyn M.; Fitzmaurice, Garrett; Goldstein, Jill M.

2013-01-01

Purpose To examine how the timing of hypoxic exposure results in specific childhood outcomes and whether there is a differential effect by sex. Methods A sample of 10,879 prospectively followed pregnancies was drawn from the Boston and Providence sites (New England-NE) of the National Collaborative Perinatal Project. Based on placental pathology, we developed and validated a measure of probable chronic fetal hypoxia (CHP) and contrasted the effects of acute perinatal hypoxia on age 7 emotional, behavioral, and cognitive outcomes. Results Perinatal hypoxia had a significant impact on multiple behavioral and cognitive outcomes in boys and girls by age 7, in contrast to probable CHP which had a differential effect on girls and boys such that there was decreased verbal IQ and increased inhibition in females alone. Conclusions Findings underscore the importance of considering the timing of obstetric complications and offspring sex in investigations of the impact of fetal and perinatal hypoxia on offspring’s outcomes throughout the life course. PMID:21327969

Severe asthma exacerbation: role of acute Chlamydophila pneumoniae and Mycoplasma pneumoniae infection

PubMed Central

Cosentini, Roberto; Tarsia, Paolo; Canetta, Ciro; Graziadei, Giovanna; Brambilla, Anna Maria; Aliberti, Stefano; Pappalettera, Maria; Tantardini, Francesca; Blasi, Francesco

2008-01-01

Background Chlamydophila pneumoniae and Mycoplasma pneumoniae are associated with acute exacerbation of bronchial asthma (AEBA). The aim of this study was to evaluate the correlation between these acute bacterial infections and the severity of AEBA. Methods We prospectively analysed consecutive patients admitted to the Emergency Department with acute asthma exacerbation. In every patient peak expiratory flow (PEF) measurement was performed on admission, and spirometry during follow-up. Serology for Chlamydophila and Mycoplasma pneumoniae was performed on admission and after 4–8 weeks. Results Fifty-eight patients completed the study. Acute atypical infections (AAI) was observed in 22/58 cases; we found single acute C. pneumoniae in 19 cases, single acute M. pneumoniae in 2 cases, and double acute infection in one case. Functional impairment on admission was greater in patients with AAI than in patients without AAI (PEF 205 ± 104 L/min vs 276 ± 117 p = 0.02) and persisted until visit 2 (FEV1% 76.30 ± 24.54 vs FEV1% 92.91 ± 13.89, p = 0.002). Moreover, the proportion of patients who presented with severe AEBA was significantly greater in the group with AAI than in the group without AAI (15/22 vs 12/36, p = 0.01; OR 4.29, 95% CI 1.38–13.32). Conclusion Our data suggest an association between acute atypical infection and a more severe AEBA. PMID:18513407

Thrombopoietin as Early Biomarker of Disease Severity in Patients With Acute Pancreatitis.

PubMed

Lupia, Enrico; Pigozzi, Luca; Pivetta, Emanuele; Bosco, Ornella; Vizio, Barbara; Loiacono, Maria; Lucchiari, Manuela; Battista, Stefania; Morello, Fulvio; Moiraghi, Corrado; Mengozzi, Giulio; Montrucchio, Giuseppe

2017-02-01

To study the concentrations of thrombopoietin (TPO), a growth factor recently involved in the pathogenesis of experimental acute pancreatitis (AP), and its potential role as an early diagnostic and prognostic biomarker in patients with AP. Thrombopoietin was measured in 44 AP patients, 18 patients with nonpancreatic acute abdominal pain, and 18 healthy volunteers. Acute pancreatitis severity was classified on the basis of the 2012 International Atlanta Symposium on Acute Pancreatitis criteria. Thrombopoietin levels did not differ between AP patients and control subjects, whereas these were higher in patients with moderately severe or severe AP compared with those with mild AP. Receiver operating characteristic curve analysis of TPO for severe AP diagnosis showed an area under the curve of 0.80. A cutoff value of 31.48 pg/mL showed the highest sensitivity, allowing to rule out severe AP when TPO was lower, whereas TPO higher than 98.23 pg/mL was associated with severe AP with high specificity (93.5%). Furthermore, TPO levels were greater in AP patients developing organ dysfunction or sepsis and in nonsurvivors compared with survivors. Our data provide the first evidence for TPO as potential early prognostic biomarker in AP patients. High TPO levels at hospital admission may predict organ dysfunction, sepsis, and fatal outcome in AP patients.

Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome.

PubMed

Ferrari, Michele; Jain, Isha H; Goldberger, Olga; Rezoagli, Emanuele; Thoonen, Robrecht; Cheng, Kai-Hung; Sosnovik, David E; Scherrer-Crosbie, Marielle; Mootha, Vamsi K; Zapol, Warren M

2017-05-23

The most common pediatric mitochondrial disease is Leigh syndrome, an episodic, subacute neurodegeneration that can lead to death within the first few years of life, for which there are no proven general therapies. Mice lacking the complex I subunit, Ndufs4, develop a fatal progressive encephalopathy resembling Leigh syndrome and die at ≈60 d of age. We previously reported that continuously breathing normobaric 11% O 2 from an early age prevents neurological disease and dramatically improves survival in these mice. Here, we report three advances. First, we report updated survival curves and organ pathology in Ndufs4 KO mice exposed to hypoxia or hyperoxia. Whereas normoxia-treated KO mice die from neurodegeneration at about 60 d, hypoxia-treated mice eventually die at about 270 d, likely from cardiac disease, and hyperoxia-treated mice die within days from acute pulmonary edema. Second, we report that more conservative hypoxia regimens, such as continuous normobaric 17% O 2 or intermittent hypoxia, are ineffective in preventing neuropathology. Finally, we show that breathing normobaric 11% O 2 in mice with late-stage encephalopathy reverses their established neurological disease, evidenced by improved behavior, circulating disease biomarkers, and survival rates. Importantly, the pathognomonic MRI brain lesions and neurohistopathologic findings are reversed after 4 wk of hypoxia. Upon return to normoxia, Ndufs4 KO mice die within days. Future work is required to determine if hypoxia can be used to prevent and reverse neurodegeneration in other animal models, and to determine if it can be provided in a safe and practical manner to allow in-hospital human therapeutic trials.

Hypoxia Inducible Factor-2 Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS).

PubMed

Dötsch, Annika; Eisele, Lewin; Rabeling, Miriam; Rump, Katharina; Walstein, Kai; Bick, Alexandra; Cox, Linda; Engler, Andrea; Bachmann, Hagen S; Jöckel, Karl-Heinz; Adamzik, Michael; Peters, Jürgen; Schäfer, Simon T

2017-06-14

Hypoxia-inducible-factor-2α (HIF-2α) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902) are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs' prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2α or PHD2 genes are (1) common, and (2) independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay) and HIF-2α -polymorphism (restriction digest + agarose-gel visualization), and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2α CC-carriers (CG: 0.38%; GG: 0%), 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%; CC: 78.8%), and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%; CC: 52.4%). PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09-10.22; p = 0.034) within 30-days, whereas the other SNPs had no significant impact ( p = ns). The homozygous HIF-2α GG-genotype was not present in our Caucasian ARDS cohort; however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS.

[Effects of interleukin-18 and hypoxia-inducible factor-1α in serum and gingival tissues of rat model with periodontitis exposed to chronic intermittent hypoxia].

PubMed

Wang, Bin; Wang, Xiaoqin

2015-08-01

This study evaluates the expression of interleukin-18 (IL-18) and hypoxia-inducible factor (HIF)-lα in rat periodontitis model exposed to normoxia and chronic intermittent hypoxia (CIH) environments. The possible correlation between periodontitis and obstructive sleep apnea-hypopnea syndrome (OSAHS) was also investigated. Methods: Thirty-two Sprague-Dawley (SD) rats were randomly assigned into four groups: normoxia control, normoxia periodontitis, hypoxia control, and hypoxia periodontitis groups. The periodontitis models were established by ligating the bilateral maxillary second molars and employing high-carbohydrate diets. Rats in hypoxia control and hypoxia periodontitis groups were exposed to CIH treatment mimicking a moderately severe OSAHS condition. All animals were sacrificed after eight weeks, and the clinical periodontal indexes were detected. The levels of IL-18 and HIF-1α in serum and gingival tissues were determined using enzyme-linked immunosorbent assay (ELISA). The correlation between attachment loss (AL) and the levels of IL-18 and HIF-lα in hypoxia periodontitis group was evaluated. The levels of IL-18 and HIF-lα in hypoxia periodontitis group were significantly higher than that in normoxia periodontitis and hypoxia control groups (P<0.05). Furthermore, the levels of IL-18 and HIF-lα in serum (r-0.792, r=0.753, P<0.05) and gingival tissues (r-0.817, r=0.779, P<0.05) were positively correlated with AL. CIH could aggravate the destruction of periodontal tissues, which is correlated with IL-18 and HIF-lα levels.

Minocycline blocks glial cell activation and ventilatory acclimatization to hypoxia.

PubMed

Stokes, Jennifer A; Arbogast, Tara E; Moya, Esteban A; Fu, Zhenxing; Powell, Frank L

2017-04-01

Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation, which persists upon return to normoxia and involves plasticity in both central nervous system respiratory centers and peripheral chemoreceptors. We investigated the role of glial cells in VAH in male Sprague-Dawley rats using minocycline, an antibiotic that inhibits microglia activation and has anti-inflammatory properties, and barometric pressure plethysmography to measure ventilation. Rats received either minocycline (45mg/kg ip daily) or saline beginning 1 day before and during 7 days of chronic hypoxia (CH, Pi O 2  = 70 Torr). Minocycline had no effect on normoxic control rats or the hypercapnic ventilatory response in CH rats, but minocycline significantly ( P < 0.001) decreased ventilation during acute hypoxia in CH rats. However, minocycline administration during only the last 3 days of CH did not reverse VAH. Microglia and astrocyte activation in the nucleus tractus solitarius was quantified from 30 min to 7 days of CH. Microglia showed an active morphology (shorter and fewer branches) after 1 h of hypoxia and returned to the control state (longer filaments and extensive branching) after 4 h of CH. Astrocytes increased glial fibrillary acidic protein antibody immunofluorescent intensity, indicating activation, at both 4 and 24 h of CH. Minocycline had no effect on glia in normoxia but significantly decreased microglia activation at 1 h of CH and astrocyte activation at 24 h of CH. These results support a role for glial cells, providing an early signal for the induction but not maintenance of neural plasticity underlying ventilatory acclimatization to hypoxia. NEW & NOTEWORTHY The signals for neural plasticity in medullary respiratory centers underlying ventilatory acclimatization to chronic hypoxia are unknown. We show that chronic hypoxia activates microglia and subsequently astrocytes. Minocycline, an antibiotic that blocks microglial activation and has anti

Modulation of K(ATP) currents in rat ventricular myocytes by hypoxia and a redox reaction.

PubMed

Yan, Xi-Sheng; Ma, Ji-Hua; Zhang, Pei-Hua

2009-10-01

The present study investigated the possible regulatory mechanisms of redox agents and hypoxia on the K(ATP) current (I(KATP)) in acutely isolated rat ventricular myocytes. Single-channel and whole-cell patch-clamp techniques were used to record the K(ATP) current (I(KATP)) in acutely isolated rat ventricular myocytes. Oxidized glutathione (GSSG, 1 mmol/L) increased the I(KATP), while reduced glutathione (GSH, 1 mmol/L) could reverse the increased I(KATP) during normoxia. To further corroborate the effect of the redox agent on the K(ATP) channel, we employed the redox couple DTT (1 mmol/L)/H2O2 (0.3, 0.6, and 1 mmol/L) and repeated the previous processes, which produced results similar to the previous redox couple GSH/GSSG during normoxia. H2O2 increased the I(KATP) in a concentration dependent manner, which was reversed by DTT (1 mmol/L). In addition, our results have shown that 15 min of hypoxia increased the I(KATP), while GSH (1 mmol/L) could reverse the increased I(KATP). Furthermore, in order to study the signaling pathways of the I(KATP) augmented by hypoxia and the redox agent, we applied a protein kinase C(PKC) inhibitor bisindolylmaleimide VI (BIM), a protein kinase G(PKG) inhibitor KT5823, a protein kinase A (PKA) inhibitor H-89, and Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitors KN-62 and KN-93. The results indicated that BIM, KT5823, KN-62, and KN-93, but not H-89, inhibited the I(KATP) augmented by hypoxia and GSSG; in addition, these results suggest that the effects of both GSSG and hypoxia on K(ATP) channels involve the activation of the PKC, PKG, and CaMK II pathways, but not the PKA pathway. The present study provides electrophysiological evidence that hypoxia and the oxidizing reaction are closely related to the modulation of I(KATP).

Acute severe asthma: performance of ventilator at simulated altitude.

PubMed

Tourtier, Jean-Pierre; Forsans, Emma; Leclerc, Thomas; Libert, Nicolas; Ramsang, Solange; Tazarourte, Karim; Man, Michel; Borne, Marc

2011-04-01

Exacerbation of asthma can be seen during air transport. Severe patients, not responding to conventional therapy, require ventilator support. We evaluated the performance of two transport ventilators, built with turbine technology, the T-birdVSO2 and the LTV-1000, for use during aeromedical evacuation of acute severe asthma. We have assessed the ability of both the ventilators to deliver to an acute severe asthma model a tidal volume (Vt) set at different simulated altitudes, by changing the ambient air pressure. The simulated cabin altitudes were 1500, 2500, and 3000 m (decompression chamber). Vt was set at 700 and 400 ml in an acute severe asthma lung model. Comparisons of the preset with the actual measured values were accomplished using a t-test. Comparisons between the actual delivered Vt and set Vt showed a significant difference starting at 1500 m for both the ventilators. The T-birdVSO2 showed a decrease in the volume delivered, with a negative variation of more than 10% compared with the Vt set. The LTV-1000 showed mostly an increase in the volume delivered. The delivered Vt remained within 10% of the set Vt. The accuracy of Vt delivery was superior with the LTV-1000 than with the T-birdVSO2, but the higher delivered Vt of the LTV-1000 are likely to be more harmful than lower delivered Vt of the T-birdVSO2.

Hypoxia induces copper stable isotope fractionation in hepatocellular carcinoma, in a HIF-independent manner.

PubMed

Bondanese, Victor P; Lamboux, Aline; Simon, Melanie; Lafont, Jérôme E; Albalat, Emmanuelle; Pichat, Sylvain; Vanacker, Jean-Marc; Telouk, Philippe; Balter, Vincent; Oger, Philippe; Albarède, Francis

2016-11-09

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, with increasing incidence worldwide. The unrestrained proliferation of tumour cells leads to tumour hypoxia which in turn promotes cancer aggressiveness. While changes in the concentration of copper (Cu) have long been observed upon cancerization, we have recently reported that the isotopic composition of copper is also altered in several types of cancer. In particular, we showed that in hepatocellular carcinoma, tumour tissue contains heavier copper compared to the surrounding parenchyma. However, the reasons behind such isotopic signature remained elusive. Here we show that hypoxia causes heavy copper enrichment in several human cell lines. We also demonstrate that this effect of hypoxia is pH, HIF-1 and -2 independent. Our data identify a previously unrecognized cellular process associated with hypoxia, and suggests that in vivo tumour hypoxia determines copper isotope fractionation in HCC and other solid cancers.

Cardiac beta-adrenergic receptors and coronary hemodynamics in the conscious dog during hypoxic hypoxia.

NASA Technical Reports Server (NTRS)

Erickson, H. H.; Stone, H. L.

1972-01-01

The mechanisms by which acute hypoxia (10% and 5% oxygen) mediates changes in coronary blood flow and cardiac function were investigated in the conscious dog. When the dogs breathed hypoxic gas mixtures through a tracheostomy, both arterial and coronary sinus oxygen tensions were significantly decreased. With 5% oxygen, there were significant increases in heart rate (25%), maximum left ventricular dP/dt (39%), left circumflex coronary artery blood flow (163%), and left ventricular oxygen consumption (52%), which were attenuated by beta-adrenergic blockage with propranolol. When electrical pacing was used to keep the ventricular rate constant during hypoxia, there was no significant difference in coronary blood flow before and after beta blockade. Beta-adrenergic receptor activity in the myocardium participates in the integrated response to hypoxia although it may not cause active vasodilation of the coronary vessels.

Acute Kidney Injury in Pediatric Severe Sepsis: An Independent Risk Factor for Death and New Disability.

PubMed

Fitzgerald, Julie C; Basu, Rajit K; Akcan-Arikan, Ayse; Izquierdo, Ledys M; Piñeres Olave, Byron E; Hassinger, Amanda B; Szczepanska, Maria; Deep, Akash; Williams, Duane; Sapru, Anil; Roy, Jason A; Nadkarni, Vinay M; Thomas, Neal J; Weiss, Scott L; Furth, Susan

2016-12-01

The prevalence of septic acute kidney injury and impact on functional status of PICU survivors are unknown. We used data from an international prospective severe sepsis study to elucidate functional outcomes of children suffering septic acute kidney injury. Secondary analysis of patients in the Sepsis PRevalence, OUtcomes, and Therapies point prevalence study: acute kidney injury was defined on the study day using Kidney Disease Improving Global Outcomes definitions. Patients with no acute kidney injury or stage 1 acute kidney injury ("no/mild acute kidney injury") were compared with those with stage 2 or 3 acute kidney injury ("severe acute kidney injury"). The primary outcome was a composite of death or new moderate disability at discharge defined as a Pediatric Overall Performance Category score of 3 or higher and increased by 1 from baseline. One hundred twenty-eight PICUs in 26 countries. Children with severe sepsis in the Sepsis PRevalence, OUtcomes, and Therapies study. None. One hundred two (21%) of 493 patients had severe acute kidney injury. More than twice as many patients with severe acute kidney injury died or developed new moderate disability compared with those with no/mild acute kidney injury (64% vs 30%; p < 0.001). Severe acute kidney injury was independently associated with death or new moderate disability (adjusted odds ratio, 2.5; 95% CI, 1.5-4.2; p = 0.001) after adjustment for age, region, baseline disability, malignancy, invasive mechanical ventilation, albumin administration, and the pediatric logistic organ dysfunction score. In a multinational cohort of critically ill children with severe sepsis and high mortality rates, septic acute kidney injury is independently associated with further increased death or new disability.

Intermittent Hypoxia Enhances Functional Connectivity of Midcervical Spinal Interneurons

PubMed Central

Streeter, Kristi A.; Sunshine, Michael D.; Patel, Shreya; Gonzalez-Rothi, Elisa J.; Reier, Paul J.

2017-01-01

Brief, intermittent oxygen reductions [acute intermittent hypoxia (AIH)] evokes spinal plasticity. Models of AIH-induced neuroplasticity have focused on motoneurons; however, most midcervical interneurons (C-INs) also respond to hypoxia. We hypothesized that AIH would alter the functional connectivity between C-INs and induce persistent changes in discharge. Bilateral phrenic nerve activity was recorded in anesthetized and ventilated adult male rats and a multielectrode array was used to record C4/5 spinal discharge before [baseline (BL)], during, and 15 min after three 5 min hypoxic episodes (11% O2, H1–H3). Most C-INs (94%) responded to hypoxia by either increasing or decreasing firing rate. Functional connectivity was examined by cross-correlating C-IN discharge. Correlograms with a peak or trough were taken as evidence for excitatory or inhibitory connectivity between C-IN pairs. A subset of C-IN pairs had increased excitatory cross-correlations during hypoxic episodes (34%) compared with BL (19%; p < 0.0001). Another subset had a similar response following each episode (40%) compared with BL (19%; p < 0.0001). In the latter group, connectivity remained elevated 15 min post-AIH (30%; p = 0.0002). Inhibitory C-IN connectivity increased during H1–H3 (4.5%; p = 0.0160), but was reduced 15 min post-AIH (0.5%; p = 0.0439). Spike-triggered averaging indicated that a subset of C-INs is synaptically coupled to phrenic motoneurons and excitatory inputs to these “pre-phrenic” cells increased during AIH. We conclude that AIH alters connectivity of the midcervical spinal network. To our knowledge, this is the first demonstration that AIH induces plasticity within the propriospinal network. SIGNIFICANCE STATEMENT Acute intermittent hypoxia (AIH) can trigger spinal plasticity associated with sustained increases in respiratory, somatic, and/or autonomic motor output. The impact of AIH on cervical spinal interneuron (C-IN) discharge and connectivity is unknown. Our

An experimental research on chronic intermittent hypoxia leading to liver injury.

PubMed

Feng, Shu-zhi; Tian, Jian-li; Zhang, Qiang; Wang, Hui; Sun, Ning; Zhang, Yun; Chen, Bao-yuan

2011-09-01

Sleep apnea-hypopnea syndrome and its chronic intermittent hypoxia component may cause multi-system-targeted injury. The latest finding shows that liver is one of the injured organs. The purpose of the study is to observe the dynamic process of the influence that chronic intermittent hypoxia plays on rat liver enzyme, hepatic histology, and ultrastructure based on lipid disorders. A total of 72 male Wistar rats were randomly divided into three groups. The control group was fed with a regular chow diet, the high fat group with a high fat diet, and the high fat plus intermittent hypoxia group with a high fat diet with a 7-h/day intermittent hypoxia treatment. Changes were observed in rat liver enzyme, hepatic histology, and ultrastructure of the three groups on the third, sixth, and ninth weeks, respectively. The liver paraffin sections were detected with myeloperoxidase. The liver function and structure of the control group were found to be normal; the liver enzyme level of the high fat group was significantly higher than that of the control group on the sixth and ninth weeks; and the liver enzyme level of the high fat plus intermittent hypoxia group was significantly higher than that of the control group and the high fat group on the third, sixth, and ninth weeks (all P < 0.01). Observed by a light microscope and a transmission electron microscope, the high fat group and the high fat plus intermittent hypoxia group were all characterized by nonalcoholic fatty liver disease: the high fat group was characterized by simple fatty liver on the third and sixth weeks and by steatohepatitis on the ninth week; the damage of the high fat plus intermittent hypoxia group was significantly more severe than that of the high fat group in all the monitoring points, characterized by steatohepatitis on the sixth week and by obvious liver fibrosis on the ninth week; the myeloperoxidase level of the high fat plus intermittent hypoxia group was significantly higher than that of the

Heat acclimation attenuates physiological strain and the HSP72, but not HSP90α, mRNA response to acute normobaric hypoxia.

PubMed

Gibson, Oliver R; Turner, Gareth; Tuttle, James A; Taylor, Lee; Watt, Peter W; Maxwell, Neil S

2015-10-15

Heat acclimation (HA) attenuates physiological strain in hot conditions via phenotypic and cellular adaptation. The aim of this study was to determine whether HA reduced physiological strain, and heat shock protein (HSP) 72 and HSP90α mRNA responses in acute normobaric hypoxia. Sixteen male participants completed ten 90-min sessions of isothermic HA (40°C/40% relative humidity) or exercise training [control (CON); 20°C/40% relative humidity]. HA or CON were preceded (HYP1) and proceeded (HYP2) by a 30-min normobaric hypoxic exposure [inspired O2 fraction = 0.12; 10-min rest, 10-min cycling at 40% peak O2 uptake (V̇O2 peak), 10-min cycling at 65% V̇O2 peak]. HA induced greater rectal temperatures, sweat rate, and heart rates (HR) than CON during the training sessions. HA, but not CON, reduced resting rectal temperatures and resting HR and increased sweat rate and plasma volume. Hemoglobin mass did not change following HA nor CON. HSP72 and HSP90α mRNA increased in response to each HA session, but did not change with CON. HR during HYP2 was lower and O2 saturation higher at 65% V̇O2 peak following HA, but not CON. O2 uptake/HR was greater at rest and 65% V̇O2 peak in HYP2 following HA, but was unchanged after CON. At rest, the respiratory exchange ratio was reduced during HYP2 following HA, but not CON. The increase in HSP72 mRNA during HYP1 did not occur in HYP2 following HA. In CON, HSP72 mRNA expression was unchanged during HYP1 and HYP2. In HA and CON, increases in HSP90α mRNA during HYP1 were maintained in HYP2. HA reduces physiological strain, and the transcription of HSP72, but not HSP90α mRNA in acute normobaric hypoxia. Copyright © 2015 the American Physiological Society.

Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models.

PubMed

Benito, Juliana; Ramirez, Marc S; Millward, Niki Zacharias; Velez, Juliana; Harutyunyan, Karine G; Lu, Hongbo; Shi, Yue-Xi; Matre, Polina; Jacamo, Rodrigo; Ma, Helen; Konoplev, Sergej; McQueen, Teresa; Volgin, Andrei; Protopopova, Marina; Mu, Hong; Lee, Jaehyuk; Bhattacharya, Pratip K; Marszalek, Joseph R; Davis, R Eric; Bankson, James A; Cortes, Jorge E; Hart, Charles P; Andreeff, Michael; Konopleva, Marina

2016-04-01

To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models. Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models. Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. ©2015 American Association for Cancer Research.

Stochastic Petri Net Modeling of Hypoxia Pathway Predicts a Novel Incoherent Feed-Forward Loop Controlling SDF-1 Expression in Acute Kidney Injury.

PubMed

Heidary, Zarifeh; Ghaisari, Jafar; Moein, Shiva; Naderi, Mahmood; Gheisari, Yousof

2016-01-01

Homing of stem cells to the sites of injury is crucial for tissue regeneration. Stromal derived factor 1 (SDF-1) is among the most important chemokines recruiting these cells. Unexpectedly, our previous experimental data on mouse models of acute kidney injury showed that SDF-1 has a declining trend following ischemic kidney insult. To describe this unforeseen observation, a stochastic Petri net model of SDF-1 regulation in the hypoxia pathway was constructed based on main related components extracted from literature. Using this strategy, predictions regarding the underlying mechanisms of SDF-1 kinetics are generated and a novel incoherent feed forward loop regulating SDF-1 expression is proposed. The computational approach suggested here can be exploited to propose novel therapies for debilitating disorders such as kidney injury.

Hypoxia inducible factors in hepatocellular carcinoma

PubMed Central

Chen, Chu; Lou, Tao

2017-01-01

Hepatocellular carcinoma is one of the most prevalent and lethal cancers with limited therapeutic options. Pathogenesis of this disease involves tumor hypoxia and the activation of hypoxia inducible factors. In this review, we describe the current understanding of hypoxia signaling pathway and summarize the expression, function and target genes of hypoxia inducible factors in hepatocellular carcinoma. We also highlight the recent progress in hypoxia-targeted therapeutic strategies in hepatocellular carcinoma and discuss further the future efforts for the study of hypoxia and/or hypoxia inducible factors in this deadly disease. PMID:28493839

[Multiple organ failure complicating a severe acute necrotising pancreatitis secondary of a severe hypertriglyceridemia: a case report].

PubMed

Degardin, J; Pons, B; Ardisson, F; Gallego, J-P; Thiery, G

2013-09-01

We report the case of a 42-year-old man admitted for a multi-organ failure with a coma, a hemodynamic instability, a respiratory distress syndrome, an acute renal failure and a thrombocytopenia. The blood samples highlighted a milky serum and allowed to diagnose an acute pancreatitis associated with a major dyslipidemia: hypertriglyceridemia 11,800 mg/dL and hypercholesterolemia 1195 mg/dL. The CT-scans do not reveal any cerebral abnormalities but highlighted pancreatic lesions without biliary obstruction. A multi-organ failure complicating a severe acute pancreatitis secondary of a major hypertriglyceridemia was mentioned. Despite the absence of clear guidelines, a session of plasma exchange was started in emergency. Symptomatic treatment with protective ventilation, vasopressors, continuous heparin and insulin was continued. The clinical and biological course was good in parallel of the normalization of lipid abnormalities. The patient was discharged at day 17 with a lipid-lowering therapy. We discuss the various treatments available for the management of acute pancreatitis complicating a severe hypertriglyceridemia and their actual relevance in the absence of clear recommendations. Copyright © 2013. Published by Elsevier SAS.

Differential Responses of Hippocampal Neurons and Astrocytes to Nicotine and Hypoxia in the Fetal Guinea Pig

PubMed Central

Blutstein, Tamara; Castello, Michael A.; Viechweg, Shaun S.; Hadjimarkou, Maria M.; McQuail, Joseph A.; Holder, Mary; Thompson, Loren P.; Mong, Jessica A.

2012-01-01

In utero exposure to cigarette smoke has severe consequences for the developing fetus, including increased risk of birth complications and behavioral and learning disabilities later in life. Evidence from animal models suggests that the cognitive deficits may be a consequence of in utero nicotine exposure in the brain during critical developmental periods. However, maternal smoking exposes the fetus to not only nicotine but also a hypoxic intrauterine environment. Thus, both nicotine and hypoxia are capable of initiating cellular cascades, leading to long-term changes in synaptic patterning that have the potential to affect cognitive functions. The present study investigates the combined effect of in utero exposure to nicotine and hypoxia on neuronal and glial elements in the hippocampal CA1 field. Fetal guinea pigs were exposed in utero to normoxic or hypoxic conditions in the presence or absence of nicotine. Hypoxia increased the protein levels of matrix metalloproteinase-9 (MMP-9) and synaptophysin and decreased the neural density as measured by NeuN immunoreactivity (ir). Nicotine exposure had no effect on these neuronal parameters but dramatically increased the density of astrocytes immunopositive for glial fibrillary acidic protein (GFAP). Further investigation into the effects of in utero nicotine exposure revealed that both GFAP-ir and NeuN-ir in the CA1 field were significantly reduced in adulthood. Taken together, our data suggest that prenatal exposure to nicotine and hypoxia not only alters synaptic patterning acutely during fetal development, but that nicotine also has long-term consequences that are observed well into adulthood. Moreover, these effects most likely take place through distinct mechanisms. PMID:23192463

Soluble CD40 ligand in prediction of acute severe pancreatitis

PubMed Central

Frossard, Jean Louis; Morel, Philippe; Kwak, Brenda; Pastor, Catherine; Berney, Thierry; Buhler, Léo; Von Laufen, Alain; Demulder, Sandrine; Mach, Francois

2006-01-01

AIM: To assess the early predictability of the soluble CD40L (sCD40L) in pancreatitis severity. METHODS: Between February 2000 and February 2003, 279 consecutive patients with acute pancreatitis were prospectively enrolled in our study. In this report, 40 patients with mild and 40 patients with severe pancreatitis were randomly studied. sCD40L concentrations were measured 48 hours after admission. RESULTS: sCD40L levels were significantly higher 48 hours after admission in severe pancreatitis than in mild pancreatitis. Using a cutoff of 1 000 pg/L, the sensitivity and specificity of sCD40L to detect a severe course of the disease were 78% and 62% respectively compared to 72% and 81% for CRP. Logistic regression analysis found that CRP was the only statistically significant marker able to detect a severe course of the disease. CONCLUSION: These findings indicate that CRP remains a valuable marker to determine the severity and prognosis of acute pancreatitis whereas sCD40L levels should be assessed in further studies. PMID:16570356

Hypoxia, Blackwater and Fish Kills: Experimental Lethal Oxygen Thresholds in Juvenile Predatory Lowland River Fishes

PubMed Central

Small, Kade; Kopf, R. Keller; Watts, Robyn J.; Howitt, Julia

2014-01-01

Hypoxia represents a growing threat to biodiversity in freshwater ecosystems. Here, aquatic surface respiration (ASR) and oxygen thresholds required for survival in freshwater and simulated blackwater are evaluated for four lowland river fishes native to the Murray-Darling Basin (MDB), Australia. Juvenile stages of predatory species including golden perch Macquaria ambigua, silver perch Bidyanus bidyanus, Murray cod Maccullochella peelii, and eel-tailed catfish Tandanus tandanus were exposed to experimental conditions of nitrogen-induced hypoxia in freshwater and hypoxic blackwater simulations using dried river red gum Eucalyptus camaldulensis leaf litter. Australia's largest freshwater fish, M. peelii, was the most sensitive to hypoxia but given that we evaluated tolerances of juveniles (0.99±0.04 g; mean mass ±SE), the low tolerance of this species could not be attributed to its large maximum attainable body mass (>100,000 g). Concentrations of dissolved oxygen causing 50% mortality (LC50) in freshwater ranged from 0.25±0.06 mg l−1 in T. tandanus to 1.58±0.01 mg l−1 in M. peelii over 48 h at 25–26°C. Logistic models predicted that first mortalities may start at oxygen concentrations ranging from 2.4 mg l−1 to 3.1 mg l−1 in T. tandanus and M. peelii respectively within blackwater simulations. Aquatic surface respiration preceded mortality and this behaviour is documented here for the first time in juveniles of all four species. Despite the natural occurrence of hypoxia and blackwater events in lowland rivers of the MDB, juvenile stages of these large-bodied predators are vulnerable to mortality induced by low oxygen concentration and water chemistry changes associated with the decomposition of organic material. Given the extent of natural flow regime alteration and climate change predictions of rising temperatures and more severe drought and flooding, acute episodes of hypoxia may represent an underappreciated risk to riverine fish communities. PMID

Hypoxia, blackwater and fish kills: experimental lethal oxygen thresholds in juvenile predatory lowland river fishes.

PubMed

Small, Kade; Kopf, R Keller; Watts, Robyn J; Howitt, Julia

2014-01-01

Hypoxia represents a growing threat to biodiversity in freshwater ecosystems. Here, aquatic surface respiration (ASR) and oxygen thresholds required for survival in freshwater and simulated blackwater are evaluated for four lowland river fishes native to the Murray-Darling Basin (MDB), Australia. Juvenile stages of predatory species including golden perch Macquaria ambigua, silver perch Bidyanus bidyanus, Murray cod Maccullochella peelii, and eel-tailed catfish Tandanus tandanus were exposed to experimental conditions of nitrogen-induced hypoxia in freshwater and hypoxic blackwater simulations using dried river red gum Eucalyptus camaldulensis leaf litter. Australia's largest freshwater fish, M. peelii, was the most sensitive to hypoxia but given that we evaluated tolerances of juveniles (0.99 ± 0.04 g; mean mass ±SE), the low tolerance of this species could not be attributed to its large maximum attainable body mass (>100,000 g). Concentrations of dissolved oxygen causing 50% mortality (LC50) in freshwater ranged from 0.25 ± 0.06 mg l(-1) in T. tandanus to 1.58 ± 0.01 mg l(-1) in M. peelii over 48 h at 25-26 °C. Logistic models predicted that first mortalities may start at oxygen concentrations ranging from 2.4 mg l(-1) to 3.1 mg l(-1) in T. tandanus and M. peelii respectively within blackwater simulations. Aquatic surface respiration preceded mortality and this behaviour is documented here for the first time in juveniles of all four species. Despite the natural occurrence of hypoxia and blackwater events in lowland rivers of the MDB, juvenile stages of these large-bodied predators are vulnerable to mortality induced by low oxygen concentration and water chemistry changes associated with the decomposition of organic material. Given the extent of natural flow regime alteration and climate change predictions of rising temperatures and more severe drought and flooding, acute episodes of hypoxia may represent an underappreciated risk to riverine fish communities.

Response of skeletal muscle mitochondria to hypoxia.

PubMed

Hoppeler, Hans; Vogt, Michael; Weibel, Ewald R; Flück, Martin

2003-01-01

This review explores the current concepts relating the structural and functional modifications of skeletal muscle mitochondria to the molecular mechanisms activated when organisms are exposed to a hypoxic environment. In contrast to earlier assumptions it is now established that permanent or long-term exposure to severe environmental hypoxia decreases the mitochondrial content of muscle fibres. Oxidative muscle metabolism is shifted towards a higher reliance on carbohydrates as a fuel, and intramyocellular lipid substrate stores are reduced. Moreover, in muscle cells of mountaineers returning from the Himalayas, we find accumulations of lipofuscin, believed to be a mitochondrial degradation product. Low mitochondrial contents are also observed in high-altitude natives such as Sherpas. In these subjects high-altitude performance seems to be improved by better coupling between ATP demand and supply pathways as well as better metabolite homeostasis. The hypoxia-inducible factor 1 (HIF-1) has been identified as a master regulator for the expression of genes involved in the hypoxia response, such as genes coding for glucose transporters, glycolytic enzymes and vascular endothelial growth factor (VEGF). HIF-1 achieves this by binding to hypoxia response elements in the promoter regions of these genes, whereby the increase of HIF-1 in hypoxia is the consequence of a reduced degradation of its dominant subunit HIF-1a. A further mechanism that seems implicated in the hypoxia response of muscle mitochondria is related to the formation of reactive oxygen species (ROS) in mitochondria during oxidative phosphorylation. How exactly ROS interfere with HIF-1a as well as MAP kinase and other signalling pathways is debated. The current evidence suggests that mitochondria themselves could be important players in oxygen sensing.

HIF-1 and ventilatory acclimatization to chronic hypoxia

PubMed Central

Powell, Frank L.; Fu, Zhenxing

2008-01-01

Ventilatory acclimatization to hypoxia (VAH) is a time-dependent increase in ventilation and ventilatory O2-sensitivity that involves plasticity in carotid body chemoreceptors and CNS respiratory centers. Hypoxia inducible factor-1α (HIF-1α) controls the expression of several genes that increase physiological O2 supply. Studies using transgenic mice show HIF-1α expression in the carotid bodies and CNS with chronic sustained and intermittent hypoxia is important for VAH. Other O2-sensitive transcription factors such as HIF-2α may be important for VAH by reducing metabolic O2 demands also. Specific gene targets of HIF-1α shown to be involved in VAH include erythropoietin, endothelin-1, neuronal nitric oxide synthase and tyrosine hydroxylase. Other HIF-1α targets that may be involved in VAH include vascular endothelial growth factor, heme oxygenase 1 and cytoglobin. Interactions between these multiple pathways and feedback control of HIF-1α expression from some of the targets support a complex and powerful role for HIF-1α in neural plasticity of physiological control circuits with chronic hypoxia. PMID:18708172

Does inducible NOS have a protective role against hypoxia/reoxygenation injury in rat heart?

PubMed

Rus, Alma; del Moral, Maria Luisa; Molina, Francisco; Peinado, Maria Angeles

2011-01-01

The present study analyzes the role of the nitric oxide (NO) derived from inducible NO synthase (iNOS) under cardiac hypoxia/reoxygenation situations. For this, we have designed a follow-up study of different parameters of cell and tissue damage in the heart of Wistar rats submitted for 30 min to acute hypobaric hypoxia, with or without prior treatment with the selective iNOS inhibitor N-(3-(aminomethyl)benzyl) acetamidine or 1400W (10 mg/kg). The rats were studied at 0 h, 12 h, and 5 days of reoxygenation, analyzing NO production (NOx), lipid peroxidation, apoptosis, and protein nitration expression and location. This is the first time-course study which analyzes the effects of the iNOS inhibition by 1400W during hypoxia/reoxygenation in the adult rat heart. The results show that when 1400W was administered before the hypoxic episode, NOx levels fell, while both the lipid peroxidation level and the percentage of apoptotic cells rose throughout the reoxygenation period. Levels of nitrated proteins expression fell only at 12 h post-hypoxia. The inhibition of iNOS raises the peroxidative and apoptotic level in the hypoxic heart indicating that this isoform may have a protective effect on this organ against hypoxia/reoxygenation injuries, and challenging the conventional wisdom that iNOS is deleterious under these conditions. These findings could help in the design of new treatments based on NO pharmacology against hypoxia/reoxygenation dysfunctions. Copyright © 2011 Elsevier Inc. All rights reserved.

Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome

PubMed Central

Ferrari, Michele; Jain, Isha H.; Goldberger, Olga; Rezoagli, Emanuele; Thoonen, Robrecht; Cheng, Kai-Hung; Sosnovik, David E.; Scherrer-Crosbie, Marielle; Mootha, Vamsi K.; Zapol, Warren M.

2017-01-01

The most common pediatric mitochondrial disease is Leigh syndrome, an episodic, subacute neurodegeneration that can lead to death within the first few years of life, for which there are no proven general therapies. Mice lacking the complex I subunit, Ndufs4, develop a fatal progressive encephalopathy resembling Leigh syndrome and die at ≈60 d of age. We previously reported that continuously breathing normobaric 11% O2 from an early age prevents neurological disease and dramatically improves survival in these mice. Here, we report three advances. First, we report updated survival curves and organ pathology in Ndufs4 KO mice exposed to hypoxia or hyperoxia. Whereas normoxia-treated KO mice die from neurodegeneration at about 60 d, hypoxia-treated mice eventually die at about 270 d, likely from cardiac disease, and hyperoxia-treated mice die within days from acute pulmonary edema. Second, we report that more conservative hypoxia regimens, such as continuous normobaric 17% O2 or intermittent hypoxia, are ineffective in preventing neuropathology. Finally, we show that breathing normobaric 11% O2 in mice with late-stage encephalopathy reverses their established neurological disease, evidenced by improved behavior, circulating disease biomarkers, and survival rates. Importantly, the pathognomonic MRI brain lesions and neurohistopathologic findings are reversed after 4 wk of hypoxia. Upon return to normoxia, Ndufs4 KO mice die within days. Future work is required to determine if hypoxia can be used to prevent and reverse neurodegeneration in other animal models, and to determine if it can be provided in a safe and practical manner to allow in-hospital human therapeutic trials. PMID:28483998

Processes of care associated with acute stroke outcomes.

PubMed

Bravata, Dawn M; Wells, Carolyn K; Lo, Albert C; Nadeau, Steven E; Melillo, Jean; Chodkowski, Diane; Struve, Frederick; Williams, Linda S; Peixoto, Aldo J; Gorman, Mark; Goel, Punit; Acompora, Gregory; McClain, Vincent; Ranjbar, Noshene; Tabereaux, Paul B; Boice, John L; Jacewicz, Michael; Concato, John

2010-05-10

Many processes of care have been proposed as metrics to evaluate stroke care. We sought to identify processes of stroke care that are associated with improved patient outcomes after adjustment for both patient characteristics and other process measures. This retrospective cohort study included patients 18 years or older with an ischemic stroke or transient ischemic attack (TIA) onset no more than 2 days before admission and a neurologic deficit on admission. Patients were excluded if they resided in a skilled nursing facility, were already admitted to the hospital at stroke onset, or were transferred from another acute-care facility. The combined outcome included in-hospital mortality, discharge to hospice, or discharge to a skilled nursing facility. Seven processes of stroke care were evaluated: fever management, hypoxia management, blood pressure management, neurologic evaluation, swallowing evaluation, deep vein thrombosis (DVT) prophylaxis, and early mobilization. Risk adjustment included age, comorbidity (medical history), concomitant medical illness present at admission, preadmission symptom course, prestroke functional status, code status, stroke severity, nonneurologic status, modified APACHE (Acute Physiology and Chronic Health Evaluation) III score, and admission brain imaging findings. Among 1487 patients, the outcome was observed in 239 (16%). Three processes of care were independently associated with an improvement in the outcome after adjustment: swallowing evaluation (adjusted odds ratio [OR], 0.64; 95% confidence interval [CI], 0.43-0.94); DVT prophylaxis (adjusted OR, 0.60; 95% CI, 0.37-0.96); and treating all episodes of hypoxia with supplemental oxygen (adjusted OR, 0.26; 95% CI, 0.09-0.73). Outcomes among patients with ischemic stroke or TIA can be improved by attention to swallowing function, DVT prophylaxis, and treatment of hypoxia.

Intermittent hypercapnic hypoxia during sleep does not induce ventilatory long-term facilitation in healthy males.

PubMed

Deacon, Naomi L; McEvoy, R Doug; Stadler, Daniel L; Catcheside, Peter G

2017-09-01

Intermittent hypoxia-induced ventilatory neuroplasticity is likely important in obstructive sleep apnea pathophysiology. Although concomitant CO 2 levels and arousal state critically influence neuroplastic effects of intermittent hypoxia, no studies have investigated intermittent hypercapnic hypoxia effects during sleep in humans. Thus the purpose of this study was to investigate if intermittent hypercapnic hypoxia during sleep induces neuroplasticity (ventilatory long-term facilitation and increased chemoreflex responsiveness) in humans. Twelve healthy males were exposed to intermittent hypercapnic hypoxia (24 × 30 s episodes of 3% CO 2 and 3.0 ± 0.2% O 2 ) and intermittent medical air during sleep after 2 wk washout period in a randomized crossover study design. Minute ventilation, end-tidal CO 2 , O 2 saturation, breath timing, upper airway resistance, and genioglossal and diaphragm electromyograms were examined during 10 min of stable stage 2 sleep preceding gas exposure, during gas and intervening room air periods, and throughout 1 h of room air recovery. There were no significant differences between conditions across time to indicate long-term facilitation of ventilation, genioglossal or diaphragm electromyogram activity, and no change in ventilatory response from the first to last gas exposure to suggest any change in chemoreflex responsiveness. These findings contrast with previous intermittent hypoxia studies without intermittent hypercapnia and suggest that the more relevant gas disturbance stimulus of concomitant intermittent hypercapnia frequently occurring in sleep apnea influences acute neuroplastic effects of intermittent hypoxia. These findings highlight the need for further studies of intermittent hypercapnic hypoxia during sleep to clarify the role of ventilatory neuroplasticity in the pathophysiology of sleep apnea. NEW & NOTEWORTHY Both arousal state and concomitant CO 2 levels are known modulators of the effects of intermittent hypoxia on

Nocturnal intermittent hypoxia and C reactive protein among middle-aged community residents: a cross-sectional survey.

PubMed

Muraki, Isao; Tanigawa, Takeshi; Yamagishi, Kazumasa; Sakurai, Susumu; Ohira, Tetsuya; Imano, Hironori; Kitamura, Akihiko; Kiyama, Masahiko; Sato, Shinichi; Shimamoto, Takashi; Konishi, Masamitsu; Iso, Hiroyasu

2010-06-01

There are conflicting results for the association between obstructive sleep apnoea and raised C reactive protein (CRP) levels. A study was undertaken to investigate whether nocturnal intermittent hypoxia, a surrogate marker for obstructive sleep apnoea, was associated with CRP levels among a community-dwelling Japanese population. Among participants in the Circulatory Risk in Communities Study (CIRCS), 1422 male and 2466 female community residents aged 40-69 years were tested during sleep. No nocturnal intermittent hypoxia, mild nocturnal intermittent hypoxia and moderate to severe nocturnal intermittent hypoxia were defined using 3% oxygen desaturation index cut-off points at 5 and 15 events/h, respectively. High-sensitivity CRP levels were measured using a latex particle-enhanced immunonephelometric assay. Multivariate analysis was adjusted for age, sex, body mass index, smoking status, current alcohol intake, hypertension, hypercholesterolaemia, diabetes mellitus and menopausal status for women. Multivariable-adjusted mean CRP levels among men were 0.70 mg/l (95% CI 0.65 to 0.75) for no nocturnal intermittent hypoxia, 0.82 mg/l (95% CI 0.74 to 0.89) for mild nocturnal intermittent hypoxia and 0.84 mg/l (95% CI 0.70 to 1.00) for moderate to severe nocturnal intermittent hypoxia (p for trend=0.03). The values for women were 0.59 mg/l (95% CI 0.57 to 0.62), 0.66 mg/l (95% CI 0.59 to 0.73) and 0.82 mg/l (95% CI 0.62 to 1.03), respectively (p for trend=0.008). Compared with no nocturnal intermittent hypoxia, the prevalence of a high CRP level (>or=1.0 mg/l) was 1.4-1.7-fold higher for mild to severe nocturnal intermittent hypoxia in both sexes. Nocturnal intermittent hypoxia is associated with raised serum CRP levels among middle-aged Japanese subjects.

Interspecific variation in hypoxia tolerance, swimming performance and plasticity in cyprinids that prefer different habitats.

PubMed

Fu, Shi-Jian; Fu, Cheng; Yan, Guan-Jie; Cao, Zhen-Dong; Zhang, An-Jie; Pang, Xu

2014-02-15

This study quantified and compared hypoxia tolerance and swim performance among cyprinid fish species from rapid-, slow- and intermediate-flow habitats (four species per habitat) in China. In addition, we explored the effects of short-term acclimation on swim performance, maximum metabolic rate (M(O2,max)) and gill remodelling to detect habitat-associated patterns of plastic response to hypoxia. Indices of hypoxia tolerance included oxygen threshold for loss of equilibrium (LOE50) and aquatic surface respiration (ASR50), and critical oxygen tension for routine metabolic rate (Pcrit). Critical swimming speed (Ucrit) and M(O2,max) were measured under normoxic and hypoxic conditions after 48 h acclimation to normoxia and hypoxia, and gill remodelling was estimated after 48 h of hypoxia exposure. Both traditional ANCOVA and phylogenetically independent contrast (PDANOVA) analyses showed that fish species from rapid-flow habitats exhibited lower LOE50 compared with fish from intermediate- and slow-flow habitats. Habitat-specific differences in Pcrit and Ucrit were detected using PDANOVA but not traditional ANCOVA analyses, with fish species from rapid-flow habitats exhibiting lower Pcrit but higher Ucrit values compared with fish from intermediate- and slow-flow habitats. Fish species from rapid-flow habitats were also characterized by less plasticity in swim performance and gill morphology in response to hypoxia acclimation compared with species from slow-flow habitats, but a greater drop in swim performance in response to acute hypoxia exposure. The study detected a habitat-specific difference in hypoxia tolerance, swimming performance and its plasticity among fish from habitats with different flow conditions, possibly because of the long-term adaptation to the habitat caused by selection stress. The PDANOVA analyses were more powerful than traditional statistical analyses according to the habitat effects in both hypoxia tolerance and swimming performance in this

Effect of repeated normobaric hypoxia exposures during sleep on acute mountain sickness, exercise performance, and sleep during exposure to terrestrial altitude.

PubMed

Fulco, Charles S; Muza, Stephen R; Beidleman, Beth A; Demes, Robby; Staab, Janet E; Jones, Juli E; Cymerman, Allen

2011-02-01

There is an expectation that repeated daily exposures to normobaric hypoxia (NH) will induce ventilatory acclimatization and lessen acute mountain sickness (AMS) and the exercise performance decrement during subsequent hypobaric hypoxia (HH) exposure. However, this notion has not been tested objectively. Healthy, unacclimatized sea-level (SL) residents slept for 7.5 h each night for 7 consecutive nights in hypoxia rooms under NH [n = 14, 24 ± 5 (SD) yr] or "sham" (n = 9, 25 ± 6 yr) conditions. The ambient percent O(2) for the NH group was progressively reduced by 0.3% [150 m equivalent (equiv)] each night from 16.2% (2,200 m equiv) on night 1 to 14.4% (3,100 m equiv) on night 7, while that for the ventilatory- and exercise-matched sham group remained at 20.9%. Beginning at 25 h after sham or NH treatment, all subjects ascended and lived for 5 days at HH (4,300 m). End-tidal Pco(2), O(2) saturation (Sa(O(2))), AMS, and heart rate were measured repeatedly during daytime rest, sleep, or exercise (11.3-km treadmill time trial). From pre- to posttreatment at SL, resting end-tidal Pco(2) decreased (P < 0.01) for the NH (from 39 ± 3 to 35 ± 3 mmHg), but not for the sham (from 39 ± 2 to 38 ± 3 mmHg), group. Throughout HH, only sleep Sa(O(2)) was higher (80 ± 1 vs. 76 ± 1%, P < 0.05) and only AMS upon awakening was lower (0.34 ± 0.12 vs. 0.83 ± 0.14, P < 0.02) in the NH than the sham group; no other between-group rest, sleep, or exercise differences were observed at HH. These results indicate that the ventilatory acclimatization induced by NH sleep was primarily expressed during HH sleep. Under HH conditions, the higher sleep Sa(O(2)) may have contributed to a lessening of AMS upon awakening but had no impact on AMS or exercise performance for the remainder of each day.

Enhanced muscular oxygen extraction in athletes exaggerates hypoxemia during exercise in hypoxia.

PubMed

Van Thienen, Ruud; Hespel, Peter

2016-02-01

High rate of muscular oxygen utilization facilitates the development of hypoxemia during exercise at altitude. Because endurance training stimulates oxygen extraction capacity, we investigated whether endurance athletes are at higher risk to developing hypoxemia and thereby acute mountain sickness symptoms during exercise at simulated high altitude. Elite athletes (ATL; n = 8) and fit controls (CON; n = 7) cycled for 20 min at 100 W (EX100W), as well as performed an incremental maximal oxygen consumption test (EXMAX) in normobaric hypoxia (0.107 inspired O2 fraction) or normoxia (0.209 inspired O2 fraction). Cardiorespiratory responses, arterial Po2 (PaO2), and oxygenation status in m. vastus lateralis [tissue oxygenation index (TOIM)] and frontal cortex (TOIC) by near-infrared spectroscopy, were measured. Muscle O2 uptake rate was estimated from change in oxyhemoglobin concentration during a 10-min arterial occlusion in m. gastrocnemius. Maximal oxygen consumption in normoxia was 70 ± 2 ml·min(-1·)kg(-1) in ATL vs. 43 ± 2 ml·min(-1·)kg(-1) in CON, and in hypoxia decreased more in ATL (-41%) than in CON (-25%, P < 0.05). Both in normoxia at PaO2 of ∼95 Torr, and in hypoxia at PaO2 of ∼35 Torr, muscle O2 uptake was twofold higher in ATL than in CON (0.12 vs. 0.06 ml·min(-1)·100 g(-1); P < 0.05). During EX100W in hypoxia, PaO2 dropped to lower (P < 0.05) values in ATL (27.6 ± 0.7 Torr) than in CON (33.5 ± 1.0 Torr). During EXMAX, but not during EX100W, TOIM was ∼15% lower in ATL than in CON (P < 0.05). TOIC was similar between the groups at any time. This study shows that maintenance of high muscular oxygen extraction rate at very low circulating PaO2 stimulates the development of hypoxemia during submaximal exercise in hypoxia in endurance-trained individuals. This effect may predispose to premature development of acute mountain sickness symptoms during exercise at altitude. Copyright © 2016 the American Physiological Society.

Neuroprotective Role of Intermittent Hypobaric Hypoxia in Unpredictable Chronic Mild Stress Induced Depression in Rats

PubMed Central

Deep, Satayanarayan; Prasad, Dipti; Singh, Shashi Bala; Khan, Nilofar

2016-01-01

Hypoxic exposure results in several pathophysiological conditions associated with nervous system, these include acute and chronic mountain sickness, loss of memory, and high altitude cerebral edema. Previous reports have also suggested the role of hypoxia in pathogenesis of depression and related psychological conditions. On the other hand, sub lethal intermittent hypoxic exposure induces protection against future lethal hypoxia and may have beneficial effect. Therefore, the present study was designed to explore the neuroprotective role of intermittent hypobaric hypoxia (IHH) in Unpredictable Chronic Mild Stress (UCMS) induced depression like behaviour in rats. The IHH refers to the periodic exposures to hypoxic conditions interrupted by the normoxic or lesser hypoxic conditions. The current study examines the effect of IHH against UCMS induced depression, using elevated plus maze (EPM), open field test (OFT), force swim test (FST), as behavioural paradigm and related histological and molecular approaches. The data indicated the UCMS induced depression like behaviour as evident from decreased exploration activity in OFT with increased anxiety levels in EPM, and increased immobility time in the FST; whereas on providing the IHH (5000m altitude, 4hrs/day for two weeks) these behavioural changes were ameliorated. The morphological and molecular studies also validated the neuroprotective effect of IHH against UCMS induced neuronal loss and decreased neurogenesis. Here, we also explored the role of Brain-Derived Neurotrophic Factor (BDNF) in anticipatory action of IHH against detrimental effect of UCMS as upon blocking of BDNF-TrkB signalling the beneficial effect of IHH was nullified. Taken together, the findings of our study demonstrate that the intermittent hypoxia has a therapeutic potential similar to an antidepressant in animal model of depression and could be developed as a preventive therapeutic option against this pathophysiological state. PMID:26901349

Tet1 facilitates hypoxia tolerance by stabilizing the HIF-α proteins independent of its methylcytosine dioxygenase activity.

PubMed

Wang, Jing; Zhang, Dawei; Du, Juan; Zhou, Chi; Li, Zhi; Liu, Xing; Ouyang, Gang; Xiao, Wuhan

2017-12-15

Because of the requirement of oxygen (O2) to produce energy, aerobic organisms developed mechanisms to protect themselves against a shortage of oxygen in both acute status and chronic status. To date, how organisms tolerate acute hypoxia and the underlying mechanisms remain largely unknown. Here, we identify that Tet1, one member of the ten-eleven translocation (TET) family of methylcytosine dioxygenases, is required for hypoxia tolerance in zebrafish and mice. Tet1-null zebrafish and mice are more sensitive to hypoxic conditions compared with their wild-type siblings. We demonstrate that Tet1 stabilizes hypoxia-inducible factor α (HIF-α) and enhances HIF-α transcription activity independent of its enzymatic activity. In addition, we show that Tet1 modulates HIF-2α and HIF-1α through different mechanisms. Tet1 competes with prolyl hydroxylase protein 2 (PHD2) to bind to HIF-2α, resulting in a reduction of HIF-2α hydroxylation by PHD2. For HIF-1α, however, Tet1 has no effect on HIF-1α hydroxylation, but rather it appears to stabilize the C-terminus of HIF-1α by affecting lysine site modification. Furthermore, we found that Tet1 enhances rather than prevents poly-ubiquitination on HIF-α. Our results reveal a previously unrecognized function of Tet1 independent of its methylcytosine dioxygenase activity in hypoxia signaling. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Carbohydrate management, anaerobic metabolism, and adenosine levels in the armoured catfish, Liposarcus pardalis (castelnau), during hypoxia.

PubMed

Maccormack, Tyson James; Lewis, Johanne Mari; Almeida-Val, Vera Maria Fonseca; Val, Adalberto Luis; Driedzic, William Robert

2006-04-01

The armoured catfish, Liposarcus pardalis, tolerates severe hypoxia at high temperatures. Although this species can breathe air, it also has a strong anaerobic metabolism. We assessed tissue to plasma glucose ratios and glycogen and lactate in a number of tissues under "natural" pond hypoxia, and severe aquarium hypoxia without aerial respiration. Armour lactate content and adenosine in brain and heart were also investigated. During normoxia, tissue to plasma glucose ratios in gill, brain, and heart were close to one. Hypoxia increased plasma glucose and decreased tissue to plasma ratios to less than one, suggesting glucose phosphorylation is activated more than uptake. High normoxic white muscle glucose relative to plasma suggests gluconeogenesis or active glucose uptake. Excess muscle glucose may serve as a metabolic reserve since hypoxia decreased muscle to plasma glucose ratios. Mild pond hypoxia changed glucose management in the absence of lactate accumulation. Lactate was elevated in all tissues except armour following aquarium hypoxia; however, confinement in aquaria increased armour lactate, even under normoxia. A stress-associated acidosis may contribute to armour lactate sequestration. High plasma lactate levels were associated with brain adenosine accumulation. An increase in heart adenosine was triggered by confinement in aquaria, although not by hypoxia alone.

Optimizing Severe Acute Respiratory Syndrome Response Strategies: Lessons Learned From Quarantine

PubMed Central

Wang, Tsung-Hsi; Wei, Kuo-Chen; Hsiung, Chao Agnes; Maloney, Susan A.; Eidex, Rachel Barwick; Posey, Drew L.; Chou, Wei-Hui; Shih, Wen-Yi; Kuo, Hsu-Sung

2007-01-01

Taiwan used quarantine as 1 of numerous interventions implemented to control the outbreak of severe acute respiratory syndrome in 2003. From March 18 to July 31, 2003, 147 526 persons were placed under quarantine. Quarantining only persons with known exposure to people infected with severe acute respiratory syndrome could have reduced the number of persons quarantined by approximately 64%. Focusing quarantine efforts on persons with known or suspected exposure can greatly decrease the number of persons placed under quarantine, without substantially compromising its yield and effectiveness. PMID:17413071

Hypoxia and fetal heart development.

PubMed

Patterson, A J; Zhang, L

2010-10-01

Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not the only gene involved in adaptation to hypoxia, its role places it as a central figure in orchestrating events needed for adaptation to hypoxic stress. Although "normal" hypoxia (lower oxygen tension in the fetus as compared with the adult) is essential in heart formation, further abnormal hypoxia in utero adversely affects cardiogenesis. Prenatal hypoxia alters myocardial structure and causes a decline in cardiac performance. Not only are the effects of hypoxia apparent during the perinatal period, but prolonged hypoxia in utero also causes fetal programming of abnormality in the heart's development. The altered expression pattern of cardioprotective genes such as protein kinase c epsilon, heat shock protein 70, and endothelial nitric oxide synthase, likely predispose the developing heart to increased vulnerability to ischemia and reperfusion injury later in life. The events underlying the long-term changes in gene expression are not clear, but likely involve variation in epigenetic regulation.

Hypoxia and Mucosal Inflammation

PubMed Central

Colgan, Sean P.; Campbell, Eric L.; Kominsky, Douglas J.

2016-01-01

Sites of inflammation are defined by significant changes in metabolic activity. Recent studies have suggested that O2 metabolism and hypoxia play a prominent role in inflammation so-called “inflammatory hypoxia,” which results from a combination of recruited inflammatory cells (e.g., neutrophils and monocytes), the local proliferation of multiple cell types, and the activation of multiple O2-consuming enzymes during inflammation. These shifts in energy supply and demand result in localized regions of hypoxia and have revealed the important function off the transcription factor HIF (hypoxia-inducible factor) in the regulation of key target genes that promote inflammatory resolution. Analysis of these pathways has provided multiple opportunities for understanding basic mechanisms of inflammation and has defined new targets for intervention. Here, we review recent work addressing tissue hypoxia and metabolic control of inflammation and immunity. PMID:27193451

Fetal in vivo continuous cardiovascular function during chronic hypoxia

PubMed Central

Allison, B. J.; Brain, K. L.; Niu, Y.; Kane, A. D.; Herrera, E. A.; Thakor, A. S.; Botting, K. J.; Cross, C. M.; Itani, N.; Skeffington, K. L.; Beck, C.

2016-01-01

Key points The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and large an enigma because no technology has been available to induce significant and prolonged fetal hypoxia whilst recording longitudinal changes in fetal regional blood flow as the hypoxic pregnancy is developing.We introduce a new technique able to maintain chronically instrumented maternal and fetal sheep preparations under isobaric chronic hypoxia for most of gestation, beyond levels that can be achieved by high altitude and of relevance in magnitude to the human intrauterine growth‐restricted fetus.This technology permits wireless recording in free‐moving animals of longitudinal maternal and fetal cardiovascular function, including beat‐to‐beat alterations in pressure and blood flow signals in regional circulations.The relevance and utility of the technique is presented by testing the hypotheses that the fetal circulatory brain sparing response persists during chronic fetal hypoxia and that an increase in reactive oxygen species in the fetal circulation is an involved mechanism. Abstract Although the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O2) hypoxia, yielding fetal mean PaO2 levels (11.5 ± 0.6 mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery

Prone Positioning Improves Oxygenation in Adult Burn Patients with Severe Acute Respiratory Distress Syndrome

DTIC Science & Technology

2012-01-01

Prone positioning improves oxygenation in adult burn patients with severe acute respiratory distress syndrome Diane F. Hale, MD, Jeremy W. Cannon, MD...Kevin K. Chung, MD, San Antonio, Texas BACKGROUND: Prone positioning (PP) improves oxygenation and may provide a benefit in patients with acute... positioning improves oxygenation in adult burn patients with severe acute respiratory distress syndrome 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM

Hypoxia-induced changes in standing balance.

PubMed

Wagner, Linsey S; Oakley, Sarah R; Vang, Pao; Noble, Brie N; Cevette, Michael J; Stepanek, Jan P

2011-05-01

A few studies in the literature have reported postural changes with hypoxia, but none have quantified the magnitude of change. Further understanding of this condition could have implications for patients at risk for falls, individuals undergoing acute altitude exposure, and pilots and commercial passengers. The objective of this study was to evaluate the effect of different levels of hypoxia (oxygen nitrogen mixtures) on postural standing balance using the computerized dynamic posturography (CDP) system. This improves upon previous protocols by manipulating vision and standing balance with a sway-referenced visual field and/or platform. Additionally, normative data were available for comparison with the cumulative test scores and scores for each condition. Altitude hypoxia was simulated by use of admixing nitrogen to the breathing gas to achieve equivalent altitudes of 1524 m, 2438 m, and 3048 m. Subjects were evaluated using the CDP system. Subjects showed an overall trend toward decreased performance at higher simulated altitudes consistent with the initial hypothesis. Composite standing balance sway scores for the sensory organization subtest of CDP were decreased compared to baseline for simulated altitudes as low as 2438 m (mean sway scores: 81.92 at baseline; 81.85 at 1524 m; 79.15 at 2438 m; 79.15 at 3048 m). Reaction times to unexpected movements in the support surface for the motor control subtest (MCT) increased compared to baseline (mean composite scores: 133.3 at baseline; 135.9 ms at 1524 m; 138.0 ms at 2438 m; 140.9 ms at 3048 m). The CDP testing provided a reliable objective measurement of degradation of balance under hypoxic conditions.

Severe Acute Respiratory Syndrome (SARS) Prevention in Taiwan

ERIC Educational Resources Information Center

Liu, Hsueh-Erh

2004-01-01

Severe Acute Respiratory Syndrome (SARS) is a newly identified respiratory disease that threatened Taiwan between April 14 and July 5, 2003. Chang Gung University experienced various SARS-related episodes, such as the postponement of classes for 7 days, the reporting of probable SARS cases, and the isolation of students under Level A and B…

Hypoxia regulates alternative splicing of HIF and non-HIF target genes.

PubMed

Sena, Johnny A; Wang, Liyi; Heasley, Lynn E; Hu, Cheng-Jun

2014-09-01

Hypoxia is a common characteristic of many solid tumors. The hypoxic microenvironment stabilizes hypoxia-inducible transcription factor 1α (HIF1α) and 2α (HIF2α/EPAS1) to activate gene transcription, which promotes tumor cell survival. The majority of human genes are alternatively spliced, producing RNA isoforms that code for functionally distinct proteins. Thus, an effective hypoxia response requires increased HIF target gene expression as well as proper RNA splicing of these HIF-dependent transcripts. However, it is unclear if and how hypoxia regulates RNA splicing of HIF targets. This study determined the effects of hypoxia on alternative splicing (AS) of HIF and non-HIF target genes in hepatocellular carcinoma cells and characterized the role of HIF in regulating AS of HIF-induced genes. The results indicate that hypoxia generally promotes exon inclusion for hypoxia-induced, but reduces exon inclusion for hypoxia-reduced genes. Mechanistically, HIF activity, but not hypoxia per se is found to be necessary and sufficient to increase exon inclusion of several HIF targets, including pyruvate dehydrogenase kinase 1 (PDK1). PDK1 splicing reporters confirm that transcriptional activation by HIF is sufficient to increase exon inclusion of PDK1 splicing reporter. In contrast, transcriptional activation of a PDK1 minigene by other transcription factors in the absence of endogenous HIF target gene activation fails to alter PDK1 RNA splicing. This study demonstrates a novel function of HIF in regulating RNA splicing of HIF target genes. ©2014 American Association for Cancer Research.

Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302.

PubMed

Wojtkowiak, Jonathan W; Cornnell, Heather C; Matsumoto, Shingo; Saito, Keita; Takakusagi, Yoichi; Dutta, Prasanta; Kim, Munju; Zhang, Xiaomeng; Leos, Rafael; Bailey, Kate M; Martinez, Gary; Lloyd, Mark C; Weber, Craig; Mitchell, James B; Lynch, Ronald M; Baker, Amanda F; Gatenby, Robert A; Rejniak, Katarzyna A; Hart, Charles; Krishna, Murali C; Gillies, Robert J

2015-01-01

Hypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, to date, have begun to show clinical efficacy. However, clinical HAPs activity could be improved. In this study, we sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models. Three human PDAC cell lines with varying sensitivity to TH-302 (Hs766t > MiaPaCa-2 > SU.86.86) were used to establish PDAC xenograft models. PDAC cells were metabolically profiled in vitro and in vivo using the Seahorse XF system and hyperpolarized (13)C pyruvate MRI, respectively, in addition to quantitative immunohistochemistry. The effect of exogenous pyruvate on tumor oxygenation was determined using electroparamagnetic resonance (EPR) oxygen imaging. Hs766t and MiaPaCa-2 cells exhibited a glycolytic phenotype in comparison to TH-302 resistant line SU.86.86. Supporting this observation is a higher lactate/pyruvate ratio in Hs766t and MiaPaCa xenografts as observed during hyperpolarized pyruvate MRI studies in vivo. Coincidentally, response to exogenous pyruvate both in vitro (Seahorse oxygen consumption) and in vivo (EPR oxygen imaging) was greatest in Hs766t and MiaPaCa models, possibly due to a higher mitochondrial reserve capacity. Changes in oxygen consumption and in vivo hypoxic status to pyruvate were limited in the SU.86.86 model. Combination therapy of pyruvate plus TH-302 in vivo significantly decreased tumor growth and increased survival in the MiaPaCa model and improved survival in Hs766t tumors. Using metabolic profiling, functional imaging, and computational modeling, we show improved TH-302 activity by transiently increasing tumor hypoxia metabolically with exogenous pyruvate. Additionally, this work identified a set of biomarkers that may be used clinically to predict which tumors will be most responsive to

Hypoxia-independent upregulation of placental hypoxia inducible factor-1α gene expression contributes to the pathogenesis of preeclampsia.

PubMed

Iriyama, Takayuki; Wang, Wei; Parchim, Nicholas F; Song, Anren; Blackwell, Sean C; Sibai, Baha M; Kellems, Rodney E; Xia, Yang

2015-06-01

Accumulation of hypoxia inducible factor-1α (HIF-1α) is commonly an acute and beneficial response to hypoxia, whereas chronically elevated HIF-1α is associated with multiple disease conditions, including preeclampsia, a serious hypertensive disease of pregnancy. However, the molecular basis underlying the persistent elevation of placental HIF-1α in preeclampsia and its role in the pathogenesis of preeclampsia are poorly understood. Here we report that Hif-1α mRNA and HIF-1α protein were elevated in the placentas of pregnant mice infused with angiotensin II type I receptor agonistic autoantibody, a pathogenic factor in preeclampsia. Knockdown of placental Hif-1α mRNA by specific siRNA significantly attenuated hallmark features of preeclampsia induced by angiotensin II type I receptor agonistic autoantibody in pregnant mice, including hypertension, proteinuria, kidney damage, impaired placental vasculature, and elevated maternal circulating soluble fms-like tyrosine kinase-1 levels. Next, we discovered that Hif-1α mRNA levels and HIF-1α protein levels were induced in an independent preeclampsia model with infusion of the inflammatory cytokine tumor necrosis factor superfamily member 14 (LIGHT). SiRNA knockdown experiments also demonstrated that elevated HIF-1α contributed to LIGHT-induced preeclampsia features. Translational studies with human placentas showed that angiotensin II type I receptor agonistic autoantibody or LIGHT is capable of inducing HIF-1α in a hypoxia-independent manner. Moreover, increased HIF-1α was found to be responsible for angiotensin II type I receptor agonistic autoantibody or LIGHT-induced elevation of Flt-1 gene expression and production of soluble fms-like tyrosine kinase-1 in human villous explants. Overall, we demonstrated that hypoxia-independent stimulation of HIF-1α gene expression in the placenta is a common pathogenic mechanism promoting disease progression. Our findings reveal new insight to preeclampsia and highlight

Differential regulation of the slow and rapid components of guinea-pig cardiac delayed rectifier K+ channels by hypoxia

PubMed Central

Hool, Livia C

2004-01-01

The aim of this study was to examine the effects of acute hypoxia on the slow (IKs) and rapid (IKr) components of the native delayed rectifier K+ channel in the absence and presence of the β-adrenergic receptor agonist isoproterenol (isoprenaline; Iso) using the whole-cell configuration of the patch-clamp technique. Hypoxia reversibly inhibited basal IKs. The effect could be mimicked by exposing the cells to the thiol-specific reducing agent dithiothreitol (DTT) and attenuated upon exposure of cells to the membrane-impermeant thiol-specific oxidizing compound 5,5′-dithio-bis[2-nitrobenzoic acid] (DTNB). In the presence of hypoxia, the K0.5 for activation of IKs by Iso was significantly decreased from 18.3 to 1.9 nm. DTT mimicked the effect of hypoxia on the sensitivity of IKs to Iso while DTNB had no effect. Hypoxia increased the sensitivity of IKs to histamine and forskolin suggesting that the effect of hypoxia is not occurring at the β-adrenergic receptor. The increase in sensitivity of IKs to Iso could be attenuated with addition of PKCβ peptide to the pipette solution. While hypoxia and DTT inhibited basal IKs they were without effect on IKr. In addition, Iso did not appear to alter the magnitude of IKr in the absence or presence of hypoxia. These data suggest that hypoxia regulates native IKs through two distinct mechanisms: direct inhibition of basal IKs and an increase in sensitivity to Iso that occurs downstream from the β-adrenergic receptor. Both mechanisms appear to involve redox modification of thiol groups. In contrast native IKr does not appear to be regulated by Iso, hypoxia or redox state. PMID:14634203

Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia

PubMed Central

Hansen, Jim; Sander, Mikael

2003-01-01

Acute exposure to hypoxia causes chemoreflex activation of the sympathetic nervous system. During acclimatization to high altitude hypoxia, arterial oxygen content recovers, but it is unknown to what degree sympathetic activation is maintained or normalized during prolonged exposure to hypoxia. We therefore measured sympathetic nerve activity directly by peroneal microneurography in eight healthy volunteers (24 ± 2 years of age) after 4 weeks at an altitude of 5260 m (Chacaltaya, Bolivian Andes) and at sea level (Copenhagen). The subjects acclimatized well to altitude, but in every subject sympathetic nerve activity was highly elevated at altitude vs. sea level (48 ± 5 vs. 16 ± 3 bursts min−1, respectively, P < 0.05), coinciding with increased mean arterial blood pressure (87 ± 3 vs. 77 ± 2 mmHg, respectively, P < 0.05). To examine the underlying mechanisms, we administered oxygen (to eliminate chemoreflex activation) and saline (to reduce cardiopulmonary baroreflex deactivation). These interventions had minor effects on sympathetic activity (48 ± 5 vs. 38 ± 4 bursts min−1, control vs. oxygen + saline, respectively, P < 0.05). Moreover, sympathetic activity was still markedly elevated (37 ± 5 bursts min−1) when subjects were re-studied under normobaric, normoxic and hypervolaemic conditions 3 days after return to sea level. In conclusion, acclimatization to high altitude hypoxia is accompanied by a striking and long-lasting sympathetic overactivity. Surprisingly, chemoreflex activation by hypoxia and baroreflex deactivation by dehydration together could account for only a small part of this response, leaving the major underlying mechanisms unexplained. PMID:12563015

Developmental study of the distribution of hypoxia-induced factor-1 alpha and microtubule-associated protein 2 in children's brainstem: comparison between controls and cases with signs of perinatal hypoxia.

PubMed

Coveñas, R; González-Fuentes, J; Rivas-Infante, E; Lagartos-Donate, M J; Cebada-Sánchez, S; Arroyo-Jiménez, M M; Insausti, R; Marcos, P

2014-06-20

Perinatal asphyxia and hypoxia are common causes of morbidity in neonates. Prenatal birth associated with hypoxemia often results in several disorders because of the lack of oxygen in the brain. Survival rates from perinatal hypoxia have improved, but appropriate treatments for recovery are still limited, with great impact on patients, their families, society in general and health systems. The aim of this work is to contribute to a better understanding of the cellular mechanisms underlying the brainstem responses to hypoxia. For this purpose, distributions of two proteins, hypoxia-inducible factor-1 alpha (HIF-1α) and microtubule-associated protein 2 (MAP-2) were analyzed in brainstems of 11 children, four of them showing neuropathological evidence of brain hypoxia. They were included in control or hypoxic groups, and then in several subgroups according to their age. Immunohistochemical labeling for these proteins revealed only cell bodies containing HIF-1α, and both cell bodies and fibers positive for MAP-2 in the children's brainstems. The distribution of HIF-1α was more restricted than that of MAP-2, and it can be suggested that the expression of HIF-1α increased with age. The distribution pattern of MAP-2 in the medulla oblongata could be more due to age-related changes than to a response to hypoxic damage, whereas in the pons several regions, such as the nucleus ambiguus or the solitary nucleus, showed different immunolabeling patterns in controls and hypoxic cases. The distribution patterns of these two proteins suggest that some brainstem regions, such as the reticular formation or the central gray, could be less affected by conditions of hypoxia. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Acute care clinical indicators associated with discharge outcomes in children with severe traumatic brain injury.

PubMed

Vavilala, Monica S; Kernic, Mary A; Wang, Jin; Kannan, Nithya; Mink, Richard B; Wainwright, Mark S; Groner, Jonathan I; Bell, Michael J; Giza, Christopher C; Zatzick, Douglas F; Ellenbogen, Richard G; Boyle, Linda Ng; Mitchell, Pamela H; Rivara, Frederick P

2014-10-01

The effect of the 2003 severe pediatric traumatic brain injury (TBI) guidelines on outcomes has not been examined. We aimed to develop a set of acute care guideline-influenced clinical indicators of adherence and tested the relationship between these indicators during the first 72 hours after hospital admission and discharge outcomes. Retrospective multicenter cohort study. Five regional pediatric trauma centers affiliated with academic medical centers. Children under 18 years with severe traumatic brain injury (admission Glasgow Coma Scale score ≤ 8, International Classification of Diseases, 9th Edition, diagnosis codes of 800.0-801.9, 803.0-804.9, 850.0-854.1, 959.01, 950.1-950.3, 995.55, maximum head abbreviated Injury Severity Score ≥ 3) who received tracheal intubation for at least 48 hours in the ICU between 2007 and 2011 were examined. None. Total percent adherence to the clinical indicators across all treatment locations (prehospital, emergency department, operating room, and ICU) during the first 72 hours after admission to study center were determined. Main outcomes were discharge survival and Glasgow Outcome Scale score. Total adherence rate across all locations and all centers ranged from 68% to 78%. Clinical indicators of adherence were associated with survival (adjusted hazard ratios, 0.94; 95% CI, 0.91-0.96). Three indicators were associated with survival: absence of prehospital hypoxia (adjusted hazard ratios, 0.20; 95% CI, 0.08-0.46), early ICU start of nutrition (adjusted hazard ratios, 0.06; 95% CI, 0.01-0.26), and ICU PaCO2 more than 30 mm Hg in the absence of radiographic or clinical signs of cerebral herniation (adjusted hazard ratios, 0.22; 95% CI, 0.06-0.8). Clinical indicators of adherence were associated with favorable Glasgow Outcome Scale among survivors (adjusted hazard ratios, 0.99; 95% CI, 0.98-0.99). Three indicators were associated with favorable discharge Glasgow Outcome Scale: all operating room cerebral perfusion pressure

Low sodium intake does not impair renal compensation of hypoxia-induced respiratory alkalosis.

PubMed

Höhne, Claudia; Boemke, Willehad; Schleyer, Nora; Francis, Roland C; Krebs, Martin O; Kaczmarczyk, Gabriele

2002-05-01

Acute hypoxia causes hyperventilation and respiratory alkalosis, often combined with increased diuresis and sodium, potassium, and bicarbonate excretion. With a low sodium intake, the excretion of the anion bicarbonate may be limited by the lower excretion rate of the cation sodium through activated sodium-retaining mechanisms. This study investigates whether the short-term renal compensation of hypoxia-induced respiratory alkalosis is impaired by a low sodium intake. Nine conscious, tracheotomized dogs were studied twice either on a low-sodium (LS = 0.5 mmol sodium x kg body wt-1 x day-1) or high-sodium (HS = 7.5 mmol sodium x kg body wt-1 x day-1) diet. The dogs breathed spontaneously via a ventilator circuit during the experiments: first hour, normoxia (inspiratory oxygen fraction = 0.21); second to fourth hour, hypoxia (inspiratory oxygen fraction = 0.1). During hypoxia (arterial PO2 34.4 +/- 2.1 Torr), plasma pH increased from 7.37 +/- 0.01 to 7.48 +/- 0.01 (P < 0.05) because of hyperventilation (arterial PCO2 25.6 +/- 2.4 Torr). Urinary pH and urinary bicarbonate excretion increased irrespective of the sodium intake. Sodium excretion increased more during HS than during LS, whereas the increase in potassium excretion was comparable in both groups. Thus the quick onset of bicarbonate excretion within the first hour of hypoxia-induced respiratory alkalosis was not impaired by a low sodium intake. The increased sodium excretion during hypoxia seems to be combined with a decrease in plasma aldosterone and angiotensin II in LS as well as in HS dogs. Other factors, e.g., increased mean arterial blood pressure, minute ventilation, and renal blood flow, may have contributed.

Antenatal Hypoxia and Pulmonary Vascular Function and Remodeling

PubMed Central

Papamatheakis, Demosthenes G.; Blood, Arlin B.; Kim, Joon H.; Wilson, Sean M.

2015-01-01

This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression. PMID:24063380

Severe acute malnutrition.

PubMed

Nel, E D

2016-05-01

The mortality and morbidity associated with severe acute malnutrition (SAM) remain high. A summary of recent studies that are of interest to clinicians treating children with SAM is provided. Three important themes emerged in 2015: the use of anthropometry in the diagnosis of SAM and its correlation with body composition; the composition of ready-to-use therapeutic feeds (RUTF); and an improved understanding of the pathophysiology of SAM. Standard anthropometry does not accurately predict body composition and mid-upper arm circumference more accurately reflects fat mass in children. As single measure, mid-upper arm circumference identifies those children who are most likely to die from SAM and is not influenced by dehydration. However, a significant proportion of SAM children requiring treatment will not be detected. Present RUTF formulations are deficient in long chain polyunsaturated fatty acids. Current evidence suggests that preformed docosahexaenoic acid should be added and/or the content of linoleic acid reduced in RUTF. In contrast to an animal model, stabile children with SAM have the same cardiac index as children without SAM. The situation in haemodynamically unstable children is unknown, continued conservative use of intravenous fluids seems advisable. A reduction in variability of the faecal DNA virome may account for increased susceptibility to malnutrition in vulnerable children.

Home-based therapy for severe acute malnutrition with ready-to-use food

USDA-ARS?s Scientific Manuscript database

Severe acute malnutrition is a devastating condition afflicting children under 5 years in many developing countries, but concentrated in sub-Saharan Africa. This paper examines the development of home-based lipid-nutrient therapeutic foods for the treatment of acute malnutrition in sub-Saharan Afric...

Language features in the acute phase of poststroke severe aphasia could predict the outcome.

PubMed

Glize, Bertrand; Villain, Marie; Richert, Laura; Vellay, Maeva; de Gabory, Isabelle; Mazaux, Jean-Michel; Dehail, Patrick; Sibon, Igor; Laganaro, Marina; Joseph, Pierre-Alain

2017-04-01

Aphasia recovery remains difficult to predict initially in particular for the most severe cases. The features of impaired verbal communication which are the basis for cognitive-linguistic diagnosis and treatment could be part of prediction of recovery from aphasia. This study investigated whether some components of language screening in the acute phase of stroke are reliable prognostic factors for language recovery in the post-acute phase. Monocentric prospective study. University hospital stroke unit. Eighty-six patients aged between 21 and 92 years (mean=67.4, SD=15.3) were admitted after a first left hemisphere stroke with aphasia and were consecutively included. Language assessment was performed in the acute phase and 3 months post-stroke with the LAnguage Screening Test (LAST) and the Aphasia Severity Rating Scale (ASRS) of the Boston Diagnostic Aphasia Examination (BDAE). Severe aphasia was defined as ASRS<3. Good recovery was defined as an ASRS≥4. Language scores and other potential predictors of recovery were analysed by comparing groups of patients with good versus poor recovery and as predictors of change with multiple regression approaches. LAST Total score as well as all the individual items of LAST, NIHSS and ASRS measured in the acute phase significantly differentiated good and poor recovery from aphasia at three months for all aphasic patients and for the most severe cases. In multivariable analyses the repetition score of LAST at the acute phase was significantly associated with the delta of ASRS between the acute phase and 3 months after the stroke reflecting changes in symptom severity. For patients with initial severe aphasia, word repetition from a language screening task seems to be a more relevant predictor of recovery than initial severity to enrich the prognosis of poststroke aphasia recovery three month after a stroke. These findings show the importance of phonological perception and production as well as speech motor components in the

Acute Severe Aortic Regurgitation: Imaging with Pathological Correlation.

PubMed

Janardhanan, Rajesh; Pasha, Ahmed Khurshid

2016-03-01

Acute aortic regurgitation (AR) is an important finding associated with a wide variety of disease processes. Its timely diagnosis is of utmost importance. Delay in diagnosis could prove fatal. We describe a case of acute severe AR that was timely diagnosed using real time three-dimensional (3D) transesophageal echocardiogram (3D TEE). Not only did it diagnose but also the images obtained by 3D TEE clearly matched with the pathologic specimen. Using this sophisticated imaging modality that is mostly available at the tertiary centers helped in the timely diagnosis, which lead to the optimal management saving his life. Echocardiography and especially 3D TEE can diagnose AR very accurately. Surgical intervention is the definitive treatment but medical therapy is utilized to stabilize the patient initially.

[Experimental study of acute brain swelling under acute intracranial hypertension (author's transl)].

PubMed

Shigemori, M; Watanabe, M; Kuramoto, S

1976-12-01

There are many problems about the cause, pathophysiology and treatment of acute brain swelling under intracranial hypertension frequently encountered in the neurosurgical clinics. Generally, rapid increase of the cerebral vasoparesis caused by unknown etiology is thought to be the main cause of acute brain swelling under intracranial hypertension. Moreover, disturbance of the cerebral venous circulatory system is discussed recently by many authors. But, research from the point of systemic respiration and hemodynamics is necessary for resolving these problems. This experiment was designed to study the effects of respiration and hemodynamics on the cerebral vasoparesis. Using 22 adult dogs, acute intracranial hypertension was produced by epidural balloon inflation sustained at the level of 300 - 400 mmH2O. Simultaneously with measurement of intracranial pressure at the epidural space, superior sagittal sinus pressure, respirogram, systemic blood pressure (femoral artery), central venous pressure, common carotid blood flow, EKG and bipolar lead EEG were monitored continuously. The experimental group was divided by the respiratory loading into 5 groups as follows: control (6 cases), 10% CO2 hypercapnia (4 cases), 10% O2 hypoxia (4 cases), stenosis of airway (5 cases), 100% O2-controled respiration (3 cases). 1) Cerebral vasoparesis under acute intracranial hypertension took place earlier and showed more rapid progression in groups of stenosis of airway, hypercapnia and hypoxia than control group of spontaneous respiration in room air. No occurrence of cerebral vasoparesis was found out in a group of 100% O2 controlled respiration. It is proved that increased airway resistance or asphyxia, hypercapnia and hypoxia have strictly reference to the occurrence and progression of cerebral vasoparesis and for the prevention of cerebral vasoparesis, correct 100% O2 cont rolled respiration is effective. 2) From the hemodynamic change, the progression of rapid increase of cerebral

Differential Expression of miRNAs in the Respiratory Tree of the Sea Cucumber Apostichopus japonicus Under Hypoxia Stress.

PubMed

Huo, Da; Sun, Lina; Li, Xiaoni; Ru, Xiaoshang; Liu, Shilin; Zhang, Libin; Xing, Lili; Yang, Hongsheng

2017-11-06

The sea cucumber, an important economic species, has encountered high mortality since 2013 in northern China because of seasonal environmental stress such as hypoxia, high temperature, and low salinity. MicroRNAs (miRNAs) are important in regulating gene expression in marine organisms in response to environmental change. In this study, high-throughput sequencing was used to investigate alterations in miRNA expression in the sea cucumber under different levels of dissolved oxygen (DO). Nine small RNA libraries were constructed from the sea cucumber respiratory trees. A total of 26 differentially expressed miRNAs, including 12 upregulated and 14 downregulated miRNAs, were observed in severe hypoxia (DO 2 mg/L) compared with mild hypoxia (DO 4 mg/L) and normoxic conditions (DO 8 mg/L). Twelve differentially expressed miRNAs were clustered in severe hypoxia. In addition, real-time PCR revealed that 14 randomly selected differentially expressed miRNAs showed significantly increased expressions in severe hypoxia and the expressions of nine miRNAs, including key miRNAs such as Aja-miR-1, Aja-miR-2008, and Aja-miR-184, were consistent with the sequencing results. Moreover, gene ontology and pathway analyses of putative target genes suggest that these miRNAs are important in redox, transport, transcription, and hydrolysis under hypoxia stress. Notably, novel-miR-1, novel-miR-2, and novel-miR-3 were specifically clustered and upregulated in severe hypoxia, which may provide new insights into novel "hypoxamiR" identification. These results will provide a basis for future studies of miRNA regulation and molecular adaptive mechanisms in sea cucumbers under hypoxia stress. Copyright © 2017 Huo et al.

[Characterization of severe acute occupational poisoning accidents in China between 1989 and 2003].

PubMed

Zhang, Min; Li, Tao; Wang, Huan-Qiang; Wang, Hong-Fei; Chen, Shu-Yang; Du, Xie-Yi; Zhang, Shuang; Qin, Jian

2006-12-01

To analyze severe acute occupational poisoning accidents reported in China between 1989 and 2003, and to study the characteristics of severe acute occupational poisoning accidents and provide scientific evidences for prevention and control strategies. The data from the national occupational poisoning case reporting system were analyzed with descriptive methods. (1) There were 506 acute severe occupational poisoning accidents for 15 years with 4 657 workers poisoned. The total poisoning rate was 54.8%, and the total mortality was 16.5%. The average poisoning age was (31.9 +/- 9.8) years old and the average death age was (33.7 +/- 10.3) years old. The poisoning accidents occurred more in men than in women. (2) There were more than 112 chemicals which caused these poisoning accidents. Most of the accidents caused by hydrogen sulfide, carbon monoxide, benzene and homologs, metal and metalloid and carbon dioxide, and the types of chemicals varied in different types of industries. (3) The accidents mainly occurred in chemical industry, manufacture, water disposal industry, mining and construction industry, and the risk was higher in some jobs than others, such as cleanout, machine maintenance and repair, production, mine and digging. The accidents occurred more frequently from April to August each year. (1) The control over the severe acute occupational poisoning is urgent. (2) The trend of the characteristics of severe acute occupational poisoning accidents is centralized in the high risk industries, poisons and jobs. (3) The characteristics of the accidents varied in different types of industries. (4) It is the key point to strengthen the supervision on poisoning.

Water permeability is a measure of severity in acute appendicitis.

PubMed

Pini, Nicola; Pfeifle, Viktoria A; Kym, Urs; Keck, Simone; Galati, Virginie; Holland-Cunz, Stefan; Gros, Stephanie J

2017-12-01

Acute appendicitis is the most common indication for pediatric abdominal emergency surgery. Determination of the severity of appendicitis on clinical grounds is challenging. Complicated appendicitis presenting with perforation, abscess or diffuse peritonitis is not uncommon. The question remains why and when acute appendicitis progresses to perforation. The aim of this study was to assess the impact of water permeability on the severity of appendicitis. We show that AQP1 expression and water permeability in appendicitis correlate with the stage of inflammation and systemic infection parameters, leading eventually to perforation of the appendix. AQP1 is also expressed within the ganglia of the enteric nervous system and ganglia count increases with inflammation. Severity of appendicitis can be correlated with water permeability measured by AQP1 protein expression and increase of ganglia count in a progressive manner. This introduces the question if regulation of water permeability can present novel curative or ameliorating therapeutic options.

Severe acute bovine viral diarrhea in Ontario, 1993-1995.

PubMed

Carman, S; van Dreumel, T; Ridpath, J; Hazlett, M; Alves, D; Dubovi, E; Tremblay, R; Bolin, S; Godkin, A; Anderson, N

1998-01-01

In 1993, noncytopathic bovine viral diarrhea virus (BVDV) strains with enhanced virulence caused unprecedented outbreaks of severe acute bovine viral diarrhea (BVD) in dairy, beef, and veal herds in Ontario (Canada). Fever, pneumonia, diarrhea, and sudden death occurred in all age groups of cattle. Abortions often occurred in pregnant animals. Gross lesions in the alimentary tract were similar to those associated with mucosal disease, especially in animals >6 months of age. Cattle of all age groups had microscopic lesions in the alimentary tract similar to those seen with mucosal disease. The epidemic peaked in the summer of 1993, with 15% of all bovine accessions from diseased cattle presented to the diagnostic laboratory being associated with BVDV. The virus strains involved in the outbreak were analyzed using monoclonal and polyclonal antibodies and the polymerase chain reaction. The virus isolates from these outbreaks of severe disease were determined to be type 2 BVDV. Type 2 BVDV has been present in Ontario at least since 1981 without causing widespread outbreaks of severe acute BVD, which suggests that type 2 designation in itself does not imply enhanced virulence. Cattle properly vaccinated with type 1 BVDV vaccines appear to be protected from clinical disease.

Hypoxia-Inducible Factor Prolyl Hydroxylases are Oxygen Sensors in the Brain

DTIC Science & Technology

2005-03-01

astrocytes. It has been appreciated that increased HIF-1α protein levels are commonly found in several cancer types (Zhong, De Marzo et al. 1999...A 98(17): 9630-5. Zhong, H., A. M. De Marzo , et al. (1999). "Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their...rat brain” Discussion 17-23 Bibliography 24 -31 ix INTRODUCTION Vertebrate cells possess adaptive responses to hypoxia

Sex-specific respiratory effects of acute and chronic caffeine administration in newborn rats.

PubMed

Kouchi, Hayet; Uppari, NagaPraveena; Joseph, Vincent; Bairam, Aida

2017-06-01

Caffeine is widely used for the treatment of apnea of prematurity (AoP) but whether this effect varies with sex is unknown. To shed some light on this question, we present a summary of data obtained on the effects of caffeine on the respiratory chemoreflexes and apnea frequency in 1- and 12-days old male and female rats. Caffeine was either administered as a single acute injection (10mg/kg, i.p.) or for 10 consecutive days (7.5mg/kg/day between 3 and 12days of life by gavage, simulating its clinical use). Acute caffeine had little effects on breathing in 1-day old male and female rats. In 12-days old female rats caffeine reduced the response to hypercapnia (not hypoxia) compared to males. During the steady state of hypoxia females had a lower frequency of apneas than males, and acute injection of caffeine decreased the frequency of apnea, suppressing the differences between males and females. In 12-days old rats chronic administration of caffeine stimulated basal breathing and decreased the frequency of apnea similarly in males and females. In response to hypoxia, chronic caffeine administration also masked the difference in respiratory frequency between males and females observed in control rats. Female rats had lower frequency of apnea than males with or without caffeine treatment. These observations indicate that sex influences the respiratory responses to caffeine and this effect seems to depend on the modality of administration (acute vs chronic) and environmental oxygen (normoxia vs hypoxia). Copyright © 2017 Elsevier B.V. All rights reserved.

Different susceptibility of rat pancreatic alpha and beta cells to hypoxia.

PubMed

Bloch, Konstantin; Vennäng, Julia; Lazard, Daniel; Vardi, Pnina

2012-06-01

Insulin-producing beta cells are known to be highly susceptible to hypoxia, which is a major factor in their destruction after pancreatic islet transplantation. However, whether the glucagon-producing pancreatic islet alpha cells are sensitive to hypoxia is not known. Our objective was to compare the sensitivity of alpha and beta cells to hypoxia. Isolated rat pancreatic islets were exposed to hypoxia (1% oxygen, 94% N(2), 5% CO(2)) for 3 days. The viability of the alpha and beta cells, as well as the stimulus-specific secretion of glucagon and insulin, was evaluated. A quantitative analysis of the proportion of beta to alpha cells indicated that, under normoxic conditions, islet cells were composed mainly of beta cells (87 ± 3%) with only 13 ± 3% alpha cells. Instead, hypoxia treatment significantly increased the proportion of alpha cells (40 ± 13%) and decreased the proportion of beta cells to 60 ± 13%. Using the fluorescent TUNEL assay we found that only a few percent of beta cells and alpha cells were apoptotic in normoxia. In contrast, hypoxia induced an abundance of apoptotic beta cells (61 ± 22%) and had no effect on the level of apoptosis in alpha cells. In conclusion, this study demonstrates that hypoxia results in severe functional abnormality in both beta and alpha cells while alpha cells display significantly decreased rate of apoptosis compared to intensive apoptotic injury of beta cells. These findings have implications for the understanding of the possible role of hypoxia in the pathophysiology of diabetes.

NIV-Helmet in Severe Hypoxemic Acute Respiratory Failure.

PubMed

Martins, Joana; Nunes, P; Silvestre, C; Abadesso, C; Loureiro, H; Almeida, H

2015-01-01

Noninvasive ventilation (NIV) is a method to be applied in acute respiratory failure, given the possibility of avoiding tracheal intubation and conventional ventilation. A previous healthy 5-month-old boy developed low-grade intermittent fever, flu-like symptoms, and dry cough for 3 days. On admission, he showed severe respiratory distress with SpO2/FiO2 ratio of 94. Subsequent evaluation identified an RSV infection complicated with an increase of inflammatory parameters (reactive C protein 15 mg/dL). Within the first hour after NIV-helmet CPAP SpO2/FiO2 ratio increased to 157. This sustained improvement allowed the continuing of this strategy. After 102 h, he was disconnected from the helmet CPAP device. The NIV use in severe hypoxemic acute respiratory failure should be carefully monitored as the absence of clinical improvement has a predictive value in the need to resume to intubation and mechanical ventilation. We emphasize that SpO2/FiO2 ratio is a valuable monitoring instrument. Helmet interface use represents a more comfortable alternative for providing ventilatory support, particularly to small infants, which constitute a sensitive group within pediatric patients.

Severe and acute complications of biologics in psoriasis.

PubMed

Oussedik, Elias; Patel, Nupur U; Cash, Devin R; Gupta, Angela S; Feldman, Steven R

2017-12-01

Biologic therapies have revolutionized the approach to immune-mediated diseases such as psoriasis. Due to their favorable safety profiles and excellent efficacy, biologic agents are considered the gold standard for moderate-to-severe psoriasis. The aim of this paper is to saliently review the severe and acute complications of the Food and Drug Administration (FDA) approved biologic agents for psoriasis. Reviewed agents include tumor necrosis factor alpha inhibitors (etanercept, infliximab, and adalimumab), interleukin 12/23 inhibitors (ustekinumab), and interleukin 17 (IL-17) inhibitors (secukinumab and ixekizumab). While malignancies, serious infections, and major adverse cardiovascular events have been reported, their association with biologic therapy are not hypothesized as causal. However, IL-17 inhibitors appear to cause exacerbations and new cases of inflammatory bowel disease. While more long-term studies are warranted in understanding the biologic's long-term side effect profile, short-term studies have confirmed that the biologics are some of the safest treatment options for psoriasis. Nevertheless, certain populations yield higher risk to acute complications with the biologics than others - physicians must use their judgement and vigilance when monitoring and treating patients undergoing therapy with biological agents.

AltitudeOmics: cerebral autoregulation during ascent, acclimatization, and re-exposure to high altitude and its relation with acute mountain sickness.

PubMed

Subudhi, Andrew W; Fan, Jui-Lin; Evero, Oghenero; Bourdillon, Nicolas; Kayser, Bengt; Julian, Colleen G; Lovering, Andrew T; Panerai, Ronney B; Roach, Robert C

2014-04-01

Cerebral autoregulation (CA) acts to maintain brain blood flow despite fluctuations in perfusion pressure. Acute hypoxia is thought to impair CA, but it is unclear if CA is affected by acclimatization or related to the development of acute mountain sickness (AMS). We assessed changes in CA using transfer function analysis of spontaneous fluctuations in radial artery blood pressure (indwelling catheter) and resulting changes in middle cerebral artery blood flow velocity (transcranial Doppler) in 21 active individuals at sea level upon arrival at 5,260 m (ALT1), after 16 days of acclimatization (ALT16), and upon re-exposure to 5,260 m after 7 days at 1,525 m (POST7). The Lake Louise Questionnaire was used to evaluate AMS symptom severity. CA was impaired upon arrival at ALT1 (P < 0.001) and did not change with acclimatization at ALT16 or upon re-exposure at POST7. CA was not associated with AMS symptoms (all R < 0.50, P > 0.05). These findings suggest that alterations in CA are an intrinsic consequence of hypoxia and are not directly related to the occurrence or severity of AMS.

Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent Manner*

PubMed Central

Chen, Rui; Dioum, Elhadji M.; Hogg, Richard T.; Gerard, Robert D.; Garcia, Joseph A.

2011-01-01

Hypoxia-inducible factors (HIFs) are stress-responsive transcriptional regulators of cellular and physiological processes involved in oxygen metabolism. Although much is understood about the molecular machinery that confers HIF responsiveness to oxygen, far less is known about HIF isoform-specific mechanisms of regulation, despite the fact that HIF-1 and HIF-2 exhibit distinct biological roles. We recently determined that the stress-responsive genetic regulator sirtuin 1 (Sirt1) selectively augments HIF-2 signaling during hypoxia. However, the mechanism by which Sirt1 maintains activity during hypoxia is unknown. In this report, we demonstrate that Sirt1 gene expression increases in a HIF-dependent manner during hypoxia in Hep3B and in HT1080 cells. Impairment of HIF signaling affects Sirt1 deacetylase activity as decreased HIF-1 signaling results in the appearance of acetylated HIF-2α, which is detected without pharmacological inhibition of Sirt1. We also find that Sirt1 augments HIF-2 mediated, but not HIF-1 mediated, transcriptional activation of the isolated Sirt1 promoter. These data in summary reveal a bidirectional link of HIF and Sirt1 signaling during hypoxia. PMID:21345792

Acute Severe Aortic Regurgitation: Imaging with Pathological Correlation

PubMed Central

Janardhanan, Rajesh; Pasha, Ahmed Khurshid

2016-01-01

Context: Acute aortic regurgitation (AR) is an important finding associated with a wide variety of disease processes. Its timely diagnosis is of utmost importance. Delay in diagnosis could prove fatal. Case Report: We describe a case of acute severe AR that was timely diagnosed using real time three-dimensional (3D) transesophageal echocardiogram (3D TEE). Not only did it diagnose but also the images obtained by 3D TEE clearly matched with the pathologic specimen. Using this sophisticated imaging modality that is mostly available at the tertiary centers helped in the timely diagnosis, which lead to the optimal management saving his life. Conclusion: Echocardiography and especially 3D TEE can diagnose AR very accurately. Surgical intervention is the definitive treatment but medical therapy is utilized to stabilize the patient initially. PMID:27114975

Gill and lung ventilation responses to steady-state aquatic hypoxia and hyperoxia in the bullfrog tadpole.

PubMed

West, N H; Burggren, W W

1982-02-01

Gill ventilation frequency (fG), the pressure amplitude (PBC) and stroke volume (VS) of buccal ventilation cycles, the frequency of air breaths (fL), water flow over the gills (VW), gill oxygen uptake (MGO2), oxygen utilization (U), and heart frequency (fH) have been measured in unanaesthetized, air breathing Rana catesbeiana tadpoles (stage XVI-XIX). The animals were unrestrained except for ECG leads or cannulae, and were able to surface voluntarily for air breathing. They were subjected to aquatic normoxia, hyperoxia and three levels of aquatic hypoxia, and their respiratory responses recorded in the steady state. The experiments were performed at 20 +/- 0.5 degrees C. In hyperoxia there was an absence of air breathing, and fG, PBC and VW fell from the normoxic values, while U increased, resulting in no significant change in MGO2. Animals in normoxia showed a very low fL which increased in progressively more hypoxic states. VW increased from the normoxic value in mild hypoxia (PO2 = 96 +/- 2 mm Hg), but fell, associated with a reduction in PBC, in moderate (PO2 = 41 +/- 1 mm Hg) and severe (PO2 = 21 +/- 3 mm Hg) hypoxia in the presence of lung ventilation. Gill MGO2 was not significantly different from the normoxic value in mild hypoxia but fell in moderate hypoxia, while in severe hypoxia oxygen was lost to the ventilating water from the blood perfusing the gills. There was no significant change in fH from the normoxic value in either hypoxia or hyperoxia. These data indicate, that in the bimodally breathing bullfrog tadpole, aquatic PO2 exerts a strong control over both gill and lung ventilation. Furthermore, there is an interaction between gill and lung ventilation such that the onset of a high frequency of lung ventilation in moderate and severe hypoxia promotes a suppression of gill ventilation cycles.

Is hypoxia training good for muscles and exercise performance?

PubMed

Vogt, Michael; Hoppeler, Hans

2010-01-01

Altitude training has become very popular among athletes as a means to further increase exercise performance at sea level or to acclimatize to competition at altitude. Several approaches have evolved during the last few decades, with "live high-train low" and "live low-train high" being the most popular. This review focuses on functional, muscular, and practical aspects derived from extensive research on the "live low-train high" approach. According to this, subjects train in hypoxia but remain under normoxia for the rest of the time. It has been reasoned that exercising in hypoxia could increase the training stimulus. Hypoxia training studies published in the past have varied considerably in altitude (2300-5700 m) and training duration (10 days to 8 weeks) and the fitness of the subjects. The evidence from muscle structural, biochemical, and molecular findings point to a specific role of hypoxia in endurance training. However, based on the available performance capacity data such as maximal oxygen uptake (Vo(2)max) and (maximal) power output, hypoxia as a supplement to training is not consistently found to be advantageous for performance at sea level. Stronger evidence exists for benefits of hypoxic training on performance at altitude. "Live low-train high" may thus be considered when altitude acclimatization is not an option. In addition, the complex pattern of gene expression adaptations induced by supplemental training in hypoxia, but not normoxia, suggest that muscle tissue specifically responds to hypoxia. Whether and to what degree these gene expression changes translate into significant changes in protein concentrations that are ultimately responsible for observable structural or functional phenotypes remains open. It is conceivable that the global functional markers such as Vo(2)max and (maximal) power output are too coarse to detect more subtle changes that might still be functionally relevant, at least to high-level athletes.

Soluble CD163 is increased in patients with acute pancreatitis independent of disease severity.

PubMed

Karrasch, Thomas; Brünnler, Tanja; Hamer, Okka W; Schmid, Karin; Voelk, Markus; Herfarth, Hans; Buechler, Christa

2015-10-01

Macrophages are crucially involved in the pathophysiology of acute pancreatitis. Soluble CD163 (sCD163) is specifically released from macrophages and systemic levels are increased in inflammatory diseases. Here, sCD163 was measured in serum of 50 patients with acute pancreatitis to find out possible associations with disease activity. Admission levels of systemic sCD163 were nearly three-fold higher in patients with acute pancreatitis compared to controls. In patients sCD163 did not correlate with C-reactive protein and leukocyte count as established markers of inflammation. Levels were not associated with disease severity assessed by the Schroeder score, Balthazar score, Acute Physiology, Age, and Chronic Health Evaluation (Apache) II score and peripancreatic necrosis score. Soluble CD163 was not related to complications of acute pancreatitis. These data show that serum sCD163 is increased in acute pancreatitis indicating activation of macrophages but is not associated with disease severity and outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

Role of Kv7 channels in responses of the pulmonary circulation to hypoxia.

PubMed

Sedivy, Vojtech; Joshi, Shreena; Ghaly, Youssef; Mizera, Roman; Zaloudikova, Marie; Brennan, Sean; Novotna, Jana; Herget, Jan; Gurney, Alison M

2015-01-01

Hypoxic pulmonary vasoconstriction (HPV) is a beneficial mechanism that diverts blood from hypoxic alveoli to better ventilated areas of the lung, but breathing hypoxic air causes the pulmonary circulation to become hypertensive. Responses to airway hypoxia are associated with depolarization of smooth muscle cells in the pulmonary arteries and reduced activity of K(+) channels. As Kv7 channels have been proposed to play a key role in regulating the smooth muscle membrane potential, we investigated their involvement in the development of HPV and hypoxia-induced pulmonary hypertension. Vascular effects of the selective Kv7 blocker, linopirdine, and Kv7 activator, flupirtine, were investigated in isolated, saline-perfused lungs from rats maintained for 3-5 days in an isobaric hypoxic chamber (FiO2 = 0.1) or room air. Linopirdine increased vascular resistance in lungs from normoxic, but not hypoxic rats. This effect was associated with reduced mRNA expression of the Kv7.4 channel α-subunit in hypoxic arteries, whereas Kv7.1 and Kv7.5 were unaffected. Flupirtine had no effect in normoxic lungs but reduced vascular resistance in hypoxic lungs. Moreover, oral dosing with flupirtine (30 mg/kg/day) prevented short-term in vivo hypoxia from increasing pulmonary vascular resistance and sensitizing the arteries to acute hypoxia. These findings suggest a protective role for Kv7.4 channels in the pulmonary circulation, limiting its reactivity to pressor agents and preventing hypoxia-induced pulmonary hypertension. They also provide further support for the therapeutic potential of Kv7 activators in pulmonary vascular disease. Copyright © 2015 the American Physiological Society.

Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferrari, Michele; Jain, Isha H.; Goldberger, Olga

The most common pediatric mitochondrial disease is Leigh syn-drome, an episodic, subacute neurodegeneration that can lead to death within the first few years of life, for which there are no proven general therapies. Mice lacking the complex I subunit, Ndufs4, develop a fatal progressive encephalopathy resembling Leigh syndrome and die at ≈60 d of age. We previously reported that contin-uously breathing normobaric 11% O 2 from an early age prevents neurological disease and dramatically improves survival in these mice. Here, we report three advances. First, we report updated sur-vival curves and organ pathology in Ndufs4 KO mice exposed to hypoxiamore » or hyperoxia. Whereas normoxia-treated KO mice die from neurodegeneration at about 60 d, hypoxia-treated mice eventually die at about 270 d, likely from cardiac disease, and hyperoxia-treated mice die within days from acute pulmonary edema. Second, we report that more conservative hypoxia regimens, such as contin-uous normobaric 17% O 2 or intermittent hypoxia, are ineffective in preventing neuropathology. Finally, we show that breathing normobaric 11% O 2 in mice with late-stage encephalopathy re-verses their established neurological disease, evidenced by im-proved behavior, circulating disease biomarkers, and survival rates. Importantly, the pathognomonic MRI brain lesions and neurohistopathologic findings are reversed after 4 wk of hyp-oxia. Upon return to normoxia, Ndufs4 KO mice die within days. Future work is required to determine if hypoxia can be used to prevent and reverse neurodegeneration in other animal models, and to determine if it can be provided in a safe and practical manner to allow in-hospital human therapeutic trials.« less

Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome

DOE PAGES

Ferrari, Michele; Jain, Isha H.; Goldberger, Olga; ...

2017-05-08

The most common pediatric mitochondrial disease is Leigh syn-drome, an episodic, subacute neurodegeneration that can lead to death within the first few years of life, for which there are no proven general therapies. Mice lacking the complex I subunit, Ndufs4, develop a fatal progressive encephalopathy resembling Leigh syndrome and die at ≈60 d of age. We previously reported that contin-uously breathing normobaric 11% O 2 from an early age prevents neurological disease and dramatically improves survival in these mice. Here, we report three advances. First, we report updated sur-vival curves and organ pathology in Ndufs4 KO mice exposed to hypoxiamore » or hyperoxia. Whereas normoxia-treated KO mice die from neurodegeneration at about 60 d, hypoxia-treated mice eventually die at about 270 d, likely from cardiac disease, and hyperoxia-treated mice die within days from acute pulmonary edema. Second, we report that more conservative hypoxia regimens, such as contin-uous normobaric 17% O 2 or intermittent hypoxia, are ineffective in preventing neuropathology. Finally, we show that breathing normobaric 11% O 2 in mice with late-stage encephalopathy re-verses their established neurological disease, evidenced by im-proved behavior, circulating disease biomarkers, and survival rates. Importantly, the pathognomonic MRI brain lesions and neurohistopathologic findings are reversed after 4 wk of hyp-oxia. Upon return to normoxia, Ndufs4 KO mice die within days. Future work is required to determine if hypoxia can be used to prevent and reverse neurodegeneration in other animal models, and to determine if it can be provided in a safe and practical manner to allow in-hospital human therapeutic trials.« less

Effects of different acute hypoxic regimens on tissue oxygen profiles and metabolic outcomes.

PubMed

Reinke, Christian; Bevans-Fonti, Shannon; Drager, Luciano F; Shin, Mi-Kyung; Polotsky, Vsevolod Y

2011-09-01

Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) during sleep. Both obesity and OSA are associated with insulin resistance and systemic inflammation, which may be attributable to tissue hypoxia. We hypothesized that a pattern of hypoxic exposure determines both oxygen profiles in peripheral tissues and systemic metabolic outcomes, and that obesity has a modifying effect. Lean and obese C57BL6 mice were exposed to 12 h of intermittent hypoxia 60 times/h (IH60) [inspired O₂ fraction (Fi(O₂)) 21-5%, 60/h], IH 12 times/h (Fi(O₂) 5% for 15 s, 12/h), sustained hypoxia (SH; Fi(O₂) 10%), or normoxia while fasting. Tissue oxygen partial pressure (Pti(O₂)) in liver, skeletal muscle and epididymal fat, plasma leptin, adiponectin, insulin, blood glucose, and adipose tumor necrosis factor-α (TNF-α) were measured. In lean mice, IH60 caused oxygen swings in the liver, whereas fluctuations of Pti(O₂) were attenuated in muscle and abolished in fat. In obese mice, baseline liver Pti(O₂) was lower than in lean mice, whereas muscle and fat Pti(O₂) did not differ. During IH, Pti(O₂) was similar in obese and lean mice. All hypoxic regimens caused insulin resistance. In lean mice, hypoxia significantly increased leptin, especially during SH (44-fold); IH60, but not SH, induced a 2.5- to 3-fold increase in TNF-α secretion by fat. Obesity was associated with striking increases in leptin and TNF-α, which overwhelmed effects of hypoxia. In conclusion, IH60 led to oxygen fluctuations in liver and muscle and steady hypoxia in fat. IH and SH induced insulin resistance, but inflammation was increased only by IH60 in lean mice. Obesity caused severe inflammation, which was not augmented by acute hypoxic regimens.

Effects of different acute hypoxic regimens on tissue oxygen profiles and metabolic outcomes

PubMed Central

Bevans-Fonti, Shannon; Drager, Luciano F.; Shin, Mi-Kyung; Polotsky, Vsevolod Y.

2011-01-01

Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) during sleep. Both obesity and OSA are associated with insulin resistance and systemic inflammation, which may be attributable to tissue hypoxia. We hypothesized that a pattern of hypoxic exposure determines both oxygen profiles in peripheral tissues and systemic metabolic outcomes, and that obesity has a modifying effect. Lean and obese C57BL6 mice were exposed to 12 h of intermittent hypoxia 60 times/h (IH60) [inspired O2 fraction (FiO2) 21–5%, 60/h], IH 12 times/h (FiO2 5% for 15 s, 12/h), sustained hypoxia (SH; FiO2 10%), or normoxia while fasting. Tissue oxygen partial pressure (PtiO2) in liver, skeletal muscle and epididymal fat, plasma leptin, adiponectin, insulin, blood glucose, and adipose tumor necrosis factor-α (TNF-α) were measured. In lean mice, IH60 caused oxygen swings in the liver, whereas fluctuations of PtiO2 were attenuated in muscle and abolished in fat. In obese mice, baseline liver PtiO2 was lower than in lean mice, whereas muscle and fat PtiO2 did not differ. During IH, PtiO2 was similar in obese and lean mice. All hypoxic regimens caused insulin resistance. In lean mice, hypoxia significantly increased leptin, especially during SH (44-fold); IH60, but not SH, induced a 2.5- to 3-fold increase in TNF-α secretion by fat. Obesity was associated with striking increases in leptin and TNF-α, which overwhelmed effects of hypoxia. In conclusion, IH60 led to oxygen fluctuations in liver and muscle and steady hypoxia in fat. IH and SH induced insulin resistance, but inflammation was increased only by IH60 in lean mice. Obesity caused severe inflammation, which was not augmented by acute hypoxic regimens. PMID:21737828

Acute respiratory failure requiring mechanical ventilation in severe chronic obstructive pulmonary disease (COPD)

PubMed Central

Gadre, Shruti K.; Duggal, Abhijit; Mireles-Cabodevila, Eduardo; Krishnan, Sudhir; Wang, Xiao-Feng; Zell, Katrina; Guzman, Jorge

2018-01-01

Abstract There are limited data on the epidemiology of acute respiratory failure necessitating mechanical ventilation in patients with severe chronic obstructive pulmonary disease (COPD). The prognosis of acute respiratory failure requiring invasive mechanical ventilation is believed to be grim in this population. The purpose of this study was to illustrate the epidemiologic characteristics and outcomes of patients with underlying severe COPD requiring mechanical ventilation. A retrospective study of patients admitted to a quaternary referral medical intensive care unit (ICU) between January 2008 and December 2012 with a diagnosis of severe COPD and requiring invasive mechanical ventilation for acute respiratory failure. We evaluated 670 patients with an established diagnosis of severe COPD requiring mechanical ventilation for acute respiratory failure of whom 47% were male with a mean age of 63.7 ± 12.4 years and Acute physiology and chronic health evaluation (APACHE) III score of 76.3 ± 27.2. Only seventy-nine (12%) were admitted with a COPD exacerbation, 27(4%) had acute respiratory distress syndrome (ARDS), 78 (12%) had pneumonia, 78 (12%) had sepsis, and 312 (47%) had other causes of respiratory failure, including pulmonary embolism, pneumothorax, etc. Eighteen percent of the patients received a trial of noninvasive positive pressure ventilation. The median duration of mechanical ventilation was 3 days (interquartile range IQR 2–7); the median duration for ICU length of stay (LOS) was 5 (IQR 2–9) days and the median duration of hospital LOS was 12 (IQR 7–22) days. The overall ICU mortality was 25%. Patients with COPD exacerbation had a shorter median duration of mechanical ventilation (2 vs 4 days; P = .04), ICU (3 vs 5 days; P = .01), and hospital stay (10 vs 13 days; P = .01). The ICU mortality (9% vs 27%; P < .001), and the hospital mortality (17% vs 32%; P = .004) for mechanically ventilated patients with an acute

Acute respiratory failure requiring mechanical ventilation in severe chronic obstructive pulmonary disease (COPD).

PubMed

Gadre, Shruti K; Duggal, Abhijit; Mireles-Cabodevila, Eduardo; Krishnan, Sudhir; Wang, Xiao-Feng; Zell, Katrina; Guzman, Jorge

2018-04-01

There are limited data on the epidemiology of acute respiratory failure necessitating mechanical ventilation in patients with severe chronic obstructive pulmonary disease (COPD). The prognosis of acute respiratory failure requiring invasive mechanical ventilation is believed to be grim in this population. The purpose of this study was to illustrate the epidemiologic characteristics and outcomes of patients with underlying severe COPD requiring mechanical ventilation.A retrospective study of patients admitted to a quaternary referral medical intensive care unit (ICU) between January 2008 and December 2012 with a diagnosis of severe COPD and requiring invasive mechanical ventilation for acute respiratory failure.We evaluated 670 patients with an established diagnosis of severe COPD requiring mechanical ventilation for acute respiratory failure of whom 47% were male with a mean age of 63.7 ± 12.4 years and Acute physiology and chronic health evaluation (APACHE) III score of 76.3 ± 27.2. Only seventy-nine (12%) were admitted with a COPD exacerbation, 27(4%) had acute respiratory distress syndrome (ARDS), 78 (12%) had pneumonia, 78 (12%) had sepsis, and 312 (47%) had other causes of respiratory failure, including pulmonary embolism, pneumothorax, etc. Eighteen percent of the patients received a trial of noninvasive positive pressure ventilation. The median duration of mechanical ventilation was 3 days (interquartile range IQR 2-7); the median duration for ICU length of stay (LOS) was 5 (IQR 2-9) days and the median duration of hospital LOS was 12 (IQR 7-22) days. The overall ICU mortality was 25%. Patients with COPD exacerbation had a shorter median duration of mechanical ventilation (2 vs 4 days; P = .04), ICU (3 vs 5 days; P = .01), and hospital stay (10 vs 13 days; P = .01). The ICU mortality (9% vs 27%; P < .001), and the hospital mortality (17% vs 32%; P = .004) for mechanically ventilated patients with an acute exacerbation of severe

A method for measuring brain partial pressure of oxygen in unanesthetized unrestrained subjects: the effect of acute and chronic hypoxia on brain tissue PO(2).

PubMed

Ortiz-Prado, E; Natah, Siraj; Srinivasan, Sathyanarayanan; Dunn, Jeff F

2010-11-30

The level of tissue oxygenation provides information related to the balance between oxygen delivery, oxygen utilization, tissue reactivity and morphology during physiological conditions. Tissue partial pressure of oxygen (PtO(2)) is influenced by the use of anesthesia or restraint. These factors may impact the absolute level of PtO(2). In this study we present a novel fiber optic method to measure brain PtO(2). This method can be used in unanesthetized, unrestrained animals, provides absolute values for PO(2), has a stable calibration, does not consume oxygen and is MRI compatible. Brain PtO(2) was studied during acute hypoxia, as well as before and after 28 days of high altitude acclimatization. A sensor was chronically implanted in the frontal cortex of eight Wistar rats. It is comprised of a fiber optic probe with a tip containing material that fluoresces with an oxygen dependent lifetime. Brain PtO(2) declines by 80% and 76% pre- and post-acclimatization, respectively, when the fraction of inspired oxygen declines from 0.21 to 0.08. In addition, a linear relationship between brain PtO(2) and inspired O(2) levels was demonstrated r(2)=0.98 and r(2)=0.99 (pre- and post-acclimatization). Hypoxia acclimatization resulted in an increase in the overall brain PtO(2) by approximately 35%. This paper demonstrates the use of a novel chronically implanted fiber optic based sensor for measuring absolute PtO(2). It shows a very strong linear relationship in awake animals between inspired O(2) and tissue O(2), and shows that there is a proportional increase in PtO(2) over a range of inspired values after exposure to chronic hypoxia. Copyright © 2010 Elsevier B.V. All rights reserved.

Spontaneous acute spinal subdural hematoma: spontaneous recovery from severe paraparesis--case report and review.

PubMed

Payer, Michael; Agosti, Reto

2010-11-01

Spontaneous idiopathic acute spinal subdural hematomas are highly exceptional. Neurological symptoms are usually severe, and rapid diagnosis with MRI is mandatory. Surgical evacuation has frequently been used therapeutically; however, spontaneous recovery in mild cases has also been reported. We present a case of spontaneous recovery from severe paraparesis after spontaneous acute SSDH, and review the English-speaking literature.

Severe Acute Respiratory Syndrome–associated Coronavirus Infection

PubMed Central

Ip, Margaret; Ng, KC; Wu, Alan; Lee, Nelson; Rainer, Timothy H.; Joynt, Gavin M.; Sung, Joseph J. Y.; Tam, John S.

2003-01-01

Whether severe acute respiratory syndrome–associated coronavirus (SARS-CoV) infection can be asymptomatic is unclear. We examined the seroprevalence of SARS-CoV among 674 healthcare workers from a hospital in which a SARS outbreak had occurred. A total of 353 (52%) experienced mild self-limiting illnesses, and 321 (48%) were asymptomatic throughout the course of these observations. None of these healthcare workers had antibody to SARS CoV, indicating that subclinical or mild infection attributable to SARS CoV in adults is rare. PMID:14718090

Severe acute hypophosphatemia during renal replacement therapy adversely affects outcome of critically ill patients with acute kidney injury.

PubMed

Schiffl, Helmut; Lang, Susanne M

2013-02-01

Hypophosphatemia during renal replacement therapy (RRT) is common in critically ill patients with acute kidney injury (AKI). The clinical consequences of RRT-induced phosphate depletion are not well defined in this patient population, and there is no evidence that intravenous sodium phosphate supplementation (PS) prevents the clinical sequelae of acute hypophosphatemia. The purpose of this retrospective analysis of the Acute Renal Support Registry of the University of Munich was to examine the association between severe hypophosphatemia and severity of and recovery from AKI. 289 ICU patients with AKI on intermittent hemodialysis (IHD) were included in the study. One hundred and forty-nine patients received PS during IHD. Outcomes were short-term (at discharge) and long-term (at 1 year) recovery of renal function and mortality. The two patient groups did not differ in demographics, clinical features, renal characteristics, and frequency of hypophosphatemia at initiation of IHD. Without PS, the frequency of hypophosphatemia increased from 20 to 35%. Severe hypophosphatemia was found in 50% of these patients. By comparison, PS was not associated with an increased frequency of hypophosphatemia. Compared with patients with acute phosphate depletion, patients receiving PS developed less oliguria during IHD, had shorter duration of AKI, higher incidence of complete renal recovery at discharge, and a lower risk of de novo chronic kidney disease. Hypophosphatemia was associated with higher all-cause in-hospital mortality and higher risk of long-term mortality. This multicenter study indicates for the first time that hypophosphatemia during IHD adversely affects short- and long-term outcome of critically-ill patients with AKI. The clinical consequences of the acute hypophosphatemic syndrome may be prevented by PS.

Serological diagnosis and prognosis of severe acute pancreatitis by analysis of serum glycoprotein 2.

PubMed

Roggenbuck, Dirk; Goihl, Alexander; Hanack, Katja; Holzlöhner, Pamela; Hentschel, Christian; Veiczi, Miklos; Schierack, Peter; Reinhold, Dirk; Schulz, Hans-Ulrich

2017-05-01

Glycoprotein 2 (GP2), the pancreatic major zymogen granule membrane glycoprotein, was reported to be elevated in acute pancreatitis in animal models. Enzyme-linked immunosorbent assays (ELISAs) were developed to evaluate human glycoprotein 2 isoform alpha (GP2a) and total GP2 (GP2t) as specific markers for acute pancreatitis in sera of 153 patients with acute pancreatitis, 26 with chronic pancreatitis, 125 with pancreatic neoplasms, 324 with non-pancreatic neoplasms, 109 patients with liver/biliary disease, 67 with gastrointestinal disease, and 101 healthy subjects. GP2a and GP2t levels were correlated with procalcitonin and C-reactive protein in 152 and 146 follow-up samples of acute pancreatitis patients, respectively. The GP2a ELISA revealed a significantly higher assay accuracy in contrast to the GP2t assay (sensitivity ≤3 disease days: 91.7%, specificity: 96.7%, positive likelihood ratio [LR+]: 24.6, LR-: 0.09). GP2a and GP2t levels as well as prevalences were significantly elevated in early acute pancreatitis (≤3 disease days) compared to all control cohorts (p<0.05, respectively). GP2a and GP2t levels were significantly higher in patients with severe acute pancreatitis at admission compared with mild cases (p<0.05, respectively). Odds ratio for GP2a regarding mild vs. severe acute pancreatitis with lethal outcome was 7.8 on admission (p=0.0222). GP2a and GP2t levels were significantly correlated with procalcitonin [Spearman's rank coefficient of correlation (ρ)=0.21, 0.26; p=0.0110, 0.0012; respectively] and C-reactive protein (ρ=0.37, 0.40; p<0.0001; respectively). Serum GP2a is a specific marker of acute pancreatitis and analysis of GP2a can aid in the differential diagnosis of acute upper abdominal pain and prognosis of severe acute pancreatitis.

Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination.

PubMed

Rofstad, Einar K; Gaustad, Jon-Vidar; Egeland, Tormod A M; Mathiesen, Berit; Galappathi, Kanthi

2010-10-01

Clinical studies have shown that patients with highly hypoxic primary tumors may have poor disease-free and overall survival rates. Studies of experimental tumors have revealed that acutely hypoxic cells may be more metastatic than normoxic or chronically hypoxic cells. In the present work, causal relations between acute cyclic hypoxia and metastasis were studied by periodically exposing BALB/c nu/nu mice bearing A-07 human melanoma xenografts to a low oxygen atmosphere. The hypoxia treatment consisted of 12 cycles of 10 min of 8% O(2) in N(2) followed by 10 min of air for a total of 4 hr, began on the first day after tumor cell inoculation and was given daily until the tumors reached a volume of 100 mm(3). Twenty-four hours after the last hypoxia exposure, the primary tumors were subjected to dynamic contrast-enhanced magnetic resonance imaging for assessment of blood perfusion before being resected and processed for immunohistochemical examinations of microvascular density and expression of proangiogenic factors. Mice exposed to acute cyclic hypoxia showed increased incidence of pulmonary metastases, and the primary tumors of these mice showed increased blood perfusion, microvascular density and vascular endothelial growth factor-A (VEGF-A) expression; whereas, the expression of interleukin-8, platelet-derived endothelial cell growth factor and basic fibroblast growth factor was unchanged. The increased pulmonary metastasis was most likely a consequence of hypoxia-induced VEGF-A upregulation, which resulted in increased angiogenic activity and blood perfusion in the primary tumor and thus facilitated tumor cell intravasation and hematogenous transport into the general circulation.

Acute hypoxia-induced alterations of calbindin-D28k immunoreactivity in cerebellar Purkinje cells of the guinea pig fetus at term.

PubMed

Katsetos, C D; Spandou, E; Legido, A; Taylor, M L; Zanelli, S A; de Chadarevian, J P; Christakos, S; Mishra, O P; Delivoria-Papadopoulos, M

2001-05-01

Purkinje cells (PCs) are vulnerable to hypoxic/ischemic insults and rich in calcium and calcium-buffering/sequestering systems, including calcium-binding proteins (CaBPs). Calbindin-D28k is an EF-hand CaBP, which is highly expressed in PCs where it acts primarily as a cellular Ca++ buffer. Elevation of [Ca++] in the cytosol and nuclei of PCs is pivotal in hypoxic/ischemic cell death. We hypothesize that hypoxia results in decreased concentration, or availability of calbindin-D28k in PCs, thereby decreasing their buffering capacity and resulting in increase of intracellular and intranuclear [Ca++]. Cerebellar tissues from normoxic fetuses were compared to fetuses obtained from term pregnant guinea pigs exposed to hypoxia [7% FiO2] for 60 min. The pregnant guinea pigs were either killed upon delivery immediately following hypoxia (Hx0h) or were subsequently allowed to recover for 24 h (Hx24h) or 72 h (Hx72h). Fetal brain hypoxia was documented biochemically by a decrease in brain tissue levels of ATP and phosphocreatine. Compared to normoxic fetuses, there is a predominantly somatodendritic loss or decrease of calbindin-D28k immunohistochemical staining in PCs of Hx0h (p < 0.005), Hx24h (p < 0.05), and Hx72h (p < 0.005) fetuses. Hypoxia-induced alterations of calbindin-D28k immunoreactivity are qualitatively similar at all time points and include a distinctive intranuclear localization in subpopulations of PCs. A similar trend is demonstrated by immunoblotting. Subpopulations of TUNEL+/calbindin-D28k- PCs lacking morphologic features of apoptosis or necrosis are demonstrated in Hx24h and Hx72h fetuses. The present study demonstrates an abrogating effect of perinatal hypoxia on calbindin-D28k immunoreactivity in cerebellar PCs. The perturbation of this Ca++ buffer protein in hypoxia-induced neuronal injury may herald delayed cell death or degeneration.

Sestrin2 Induced by Hypoxia Inducible Factor 1 alpha protects the Blood-Brain Barrier via Inhibiting VEGF after Severe Hypoxic-Ischemic Injury in Neonatal Rats

PubMed Central

Shi, Xudan; Doycheva, Desislava Met; Xu, Liang; Tang, Jiping; Yan, Min; Zhang, John H

2016-01-01

Objective Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injury. Methods Rat pups underwent common carotid artery ligation followed by either 150 min (severe model) or 100 min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) were used to examine their roles on BBB permeability. Results Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. Conclusions rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α’s effects as a prodeath or prosurvival signal were influenced by the severity of HI injury. PMID:27425892

Dopamine D2 receptor status assessed by IBZM SPECT - A sensitive indicator for cerebral hypoxia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tatsch, K.; Schwarz, J.; Welz, A.

1995-05-01

The striatum is highly sensitive to tissue hypoxia. Thus, it may be suggested that cerebral hypoxia could affect the integrity of the striatal receptor system. Purpose of the current SPECT investigations with IBZM was to evaluate whether hypoxic conditions cause detectable changes in the D2 receptor status. 25 controls and 30 pts with history of cerebral hypoxia (resuscitation after cardiac arrest: n=19, CABG surgery under cardiopulmonary bypass: n=11) were investigated with SPECT 2h p.i. of 185 MBq I-123 IBZM. For semiquant, evaluation transverse slices corrected for attenuation were used to calculate striatal to frontal cortex (S/FC) ratios. In 13/19 ptsmore » with cerebral hypoxia due to cardiac arrest IBZM binding was severely reduced after successful resuscitation. 7 died, 5 were in a vegetative state, 1 remained severely disabled. In 6/19 S/FC ratios were normal/mildly reduced, 2 of them had a good outcome, 4 were moderatley disabled. In pts with CABG IBZM binding was preoperatively normal. After hypoxia due to cardiac surgery striatal S/FC ratios decreased slightly, persisting on this level even 6 months after surgery. Neuropsychological/psychiatric testing showed only minor or transient changes in this group of patients. The striatal D2 receptor status seems to be a sensitive indicator for cerebral hypoxia. After hypoxia due to cardiac arrest IBZM results well correlate (in contrast to morphological or SEP findings) with the clinical outcome and thus may serve as early predictor of the individual prognosis. The moderate decline in IBZM binding following CABG surgery suggests mild cerebral hypoxia despite of protective hypothermia. Sensitively indicating cerebral hypoxia changes in the D2 receptor status assessed by IBZM SPECT may serve as a valuable diagnostic tool for testing neuroprotective drugs or modified surgical techniques.« less

Role of maximal heart rate and arterial O2 saturation on the decrement of VO2max in moderate acute hypoxia in trained and untrained men.

PubMed

Mollard, P; Woorons, X; Letournel, M; Cornolo, J; Lamberto, C; Beaudry, M; Richalet, J-P

2007-03-01

We aimed to evaluate 1) the altitude where maximal heart rate (HR (max)) decreases significantly in both trained and untrained subjects in moderate acute hypoxia, and 2) if the HR (max) decrease could partly explain the drop of V.O (2max). Seventeen healthy males, nine trained endurance athletes (TS) and eight untrained individuals (US) were studied. Subjects performed incremental exercise tests at sea level and at 5 simulated altitudes (1000, 1500, 2500, 3500, 4500 meters). Power output (PO), heart rate (HR), arterial oxygen saturation (SaO (2)), oxygen uptake (V.O (2)), arterialized blood pH and lactate were measured. Both groups showed a progressive reduction in V.O (2max). The decrement in HR (max) (DeltaHR (max)) was significant from 1000 m for TS and 2500 m for US and more important in TS than US (at 1500 m and 3500 m). At maximal exercise, TS had a greater reduction in SaO (2) (DeltaSaO (2)) at each altitude. DeltaHR (max) observed in TS was correlated with DeltaSaO (2). When the two groups were pooled, simple regressions showed that DeltaV.O (2max) was correlated with both DeltaSaO (2) and DeltaHR (max). However, a multiple regression analysis demonstrated that DeltaSaO (2) alone may account for DeltaV.O (2max). Furthermore, in spite of a greater reduction in SaO (2) and HR (max) in TS, no difference was evidenced in relative DeltaV.O (2max) between groups. Thus, in moderate acute hypoxia, the reduction in SaO (2) is the primary factor to explain the drop of V.O (2max) in trained and untrained subjects.

Role of chemoreception in cardiorespiratory acclimatization to, and deacclimatization from, hypoxia.

PubMed

Dempsey, Jerome A; Powell, Frank L; Bisgard, Gerald E; Blain, Gregory M; Poulin, Marc J; Smith, Curtis A

2014-04-01

During sojourn to high altitudes, progressive time-dependent increases occur in ventilation and in sympathetic nerve activity over several days, and these increases persist upon acute restoration of normoxia. We discuss evidence concerning potential mediators of these changes, including the following: 1) correction of alkalinity in cerebrospinal fluid; 2) increased sensitivity of carotid chemoreceptors; and 3) augmented translation of carotid chemoreceptor input (at the level of the central nervous system) into increased respiratory motor output via sensitization of hypoxic sensitive neurons in the central nervous system and/or an interdependence of central chemoreceptor responsiveness on peripheral chemoreceptor sensory input. The pros and cons of chemoreceptor sensitization and cardiorespiratory acclimatization to hypoxia and intermittent hypoxemia are also discussed in terms of their influences on arterial oxygenation, the work of breathing, sympathoexcitation, systemic blood pressure, and exercise performance. We propose that these adaptive processes may have negative implications for the cardiovascular health of patients with sleep apnea and perhaps even for athletes undergoing regimens of "sleep high-train low"!

Pulmonary hemodynamics responses to hypoxia and/or CO2 inhalation during moderate exercise in humans.

PubMed

Doutreleau, Stéphane; Enache, Irina; Pistea, Cristina; Geny, Bernard; Charloux, Anne

2018-03-03

In this study, we hypothesized that adding CO 2 to an inhaled hypoxic gas mixture will limit the rise of pulmonary artery pressure (PAP) induced by a moderate exercise. Eight 20-year-old males performed four constant-load exercise tests on cycle at 40% of maximal oxygen consumption in four conditions: ambient air, normobaric hypoxia (12.5% O 2 ), inhaled CO 2 (4.5% CO 2 ), and combination of hypoxia and inhaled CO 2 . Doppler echocardiography was used to measure systolic (s)PAP, cardiac output (CO). Total pulmonary resistance (TPR) was calculated. Arterialized blood pH was 7.40 at exercise in ambient and hypoxia conditions, whereas CO 2 inhalation and combined conditions showed acidosis. sPAP increases from rest in ambient air to exercise ranged as follows: ambient + 110%, CO 2 inhalation + 135%, combined + 184%, hypoxia + 217% (p < 0.001). CO was higher when inhaling O 2 -poor gas mixtures with or without CO 2 (~ 17 L min -1 ) than in the other conditions (~ 14 L min -1 , p < 0.001). Exercise induced a significant decrease in TPR in the four conditions (p < 0.05) but less marked in hypoxia (- 19% of the resting value in ambient air) than in ambient (- 33%) and in both CO 2 inhalation and combined condition (- 29%). We conclude that (1) acute CO 2 inhalation did not significantly modify pulmonary hemodynamics during moderate exercise. (2) CO 2 adjunction to hypoxic gas mixture did not modify CO, despite a higher CaO 2 in combined condition than in hypoxia. (3) TPR was lower in combined than in hypoxia condition, limiting sPAP increase in combined condition.

Adenosine and Hypoxia-Inducible Factor Signaling in Intestinal Injury and Recovery

PubMed Central

Eltzschig, Holger K.

2013-01-01

The gastrointestinal mucosa has proven to be an interesting tissue in which to investigate disease-related metabolism. In this review, we outline some of the evidence that implicates hypoxia-mediated adenosine signaling as an important signature within both healthy and diseased mucosa. Studies derived from cultured cell systems, animal models, and human patients have revealed that hypoxia is a significant component of the inflammatory microenvironment. These studies have revealed a prominent role for hypoxia-induced factor (HIF) and hypoxia signaling at several steps along the adenine nucleotide metabolism and adenosine receptor signaling pathways. Likewise, studies to date in animal models of intestinal inflammation have demonstrated an almost uniformly beneficial influence of HIF stabilization on disease outcomes. Ongoing studies to define potential similarities with and differences between innate and adaptive immune responses will continue to teach us important lessons about the complexity of the gastrointestinal tract. Such information has provided new insights into disease pathogenesis and, importantly, will provide insights into new therapeutic targets. PMID:21942704

Analysis of factors influencing survival in patients with severe acute pancreatitis.

PubMed

Kim, Yeon Ji; Kim, Dae Bum; Chung, Woo Chul; Lee, Ji Min; Youn, Gun Jung; Jung, Yun Duk; Choi, Sooa; Oh, Jung Hwan

2017-08-01

Acute pancreatitis (AP) ranges from a mild and self-limiting disease to a fulminant illness with significant morbidity and mortality. Severe acute pancreatitis (SAP) is defined as persistent organ failure lasting for 48 h. We aimed to determine the factors that predict survival and mortality in patients with SAP. We reviewed a consecutive series of patients who were admitted with acute pancreatitis between January 2003 and January 2013. A total of 1213 cases involving 660 patients were evaluated, and 68 cases with SAP were selected for the study. Patients were graded based on the Computer Tomography Severity Index (CTSI), the bedside index for severity (BISAP), and Ranson's criteria. The frequency of SAP was 5.6% (68/1213 cases). Among these patients, 17 died due to pancreatitis-induced causes. We compared several factors between the survivor (n = 51) and non-survivor (n = 17) groups. On multivariate analysis, there were significant differences in the incidence of diabetes mellitus (p = .04), Ranson score (p = .03), bacteremia (p = .05) and body mass index (BMI) (p = .02) between the survivor and non-survivor groups. Bacteremia, high Ranson score, DM, and lower BMI were closely associated with mortality in patients with SAP. When patients with SAP show evidence of bacteremia or diabetes, aggressive treatment is necessary. For the prediction of disease mortality, the Ranson score might be a useful tool in SAP.

Chronic intermittent hypoxia-hypercapnia blunts heart rate responses and alters neurotransmission to cardiac vagal neurons.

PubMed

Dyavanapalli, Jhansi; Jameson, Heather; Dergacheva, Olga; Jain, Vivek; Alhusayyen, Mona; Mendelowitz, David

2014-07-01

Patients with obstructive sleep apnoea experience chronic intermittent hypoxia-hypercapnia (CIHH) during sleep that elicit sympathetic overactivity and diminished parasympathetic activity to the heart, leading to hypertension and depressed baroreflex sensitivity. The parasympathetic control of heart rate arises from pre-motor cardiac vagal neurons (CVNs) located in nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX). The mechanisms underlying diminished vagal control of heart rate were investigated by studying the changes in blood pressure, heart rate, and neurotransmission to CVNs evoked by acute hypoxia-hypercapnia (H-H) and CIHH. In vivo telemetry recordings of blood pressure and heart rate were obtained in adult rats during 4 weeks of CIHH exposure. Retrogradely labelled CVNs were identified in an in vitro brainstem slice preparation obtained from adult rats exposed either to air or CIHH for 4 weeks. Postsynaptic inhibitory or excitatory currents were recorded using whole cell voltage clamp techniques. Rats exposed to CIHH had increases in blood pressure, leading to hypertension, and blunted heart rate responses to acute H-H. CIHH induced an increase in GABAergic and glycinergic neurotransmission to CVNs in NA and DMNX, respectively; and a reduction in glutamatergic neurotransmission to CVNs in both nuclei. CIHH blunted the bradycardia evoked by acute H-H and abolished the acute H-H evoked inhibition of GABAergic transmission while enhancing glycinergic neurotransmission to CVNs in NA. These changes with CIHH inhibit CVNs and vagal outflow to the heart, both in acute and chronic exposures to H-H, resulting in diminished levels of cardioprotective parasympathetic activity to the heart as seen in OSA patients. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Specific prognostic factors for secondary pancreatic infection in severe acute pancreatitis.

PubMed

Armengol-Carrasco, M; Oller, B; Escudero, L E; Roca, J; Gener, J; Rodríguez, N; del Moral, P; Moreno, P

1999-01-01

The aim of the present study was to investigate whether there are specific prognostic factors to predict the development of secondary pancreatic infection (SPI) in severe acute pancreatitis in order to perform a computed tomography-fine needle aspiration with bacteriological sampling at the right moment and confirm the diagnosis. Twenty-five clinical and laboratory parameters were determined sequentially in 150 patients with severe acute pancreatitis (SAP) and univariate, and multivariate regression analyses were done looking for correlation with the development of SPI. Only APACHE II score and C-reactive protein levels were related to the development of SPI in the multivariate analysis. A regression equation was designed using these two parameters, and empiric cut-off points defined the subgroup of patients at high risk of developing secondary pancreatic infection. The results showed that it is possible to predict SPI during SAP allowing bacteriological confirmation and early treatment of this severe condition.

Hypoxia induces pulmonary fibroblast proliferation through NFAT signaling.

PubMed

Senavirathna, Lakmini Kumari; Huang, Chaoqun; Yang, Xiaoyun; Munteanu, Maria Cristina; Sathiaseelan, Roshini; Xu, Dao; Henke, Craig A; Liu, Lin

2018-02-09

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and typically fatal lung disease with a very low survival rate. Excess accumulation of fibroblasts, myofibroblasts and extracellular matrix creates hypoxic conditions within the lungs, causing asphyxiation. Hypoxia is, therefore, one of the prominent features of IPF. However, there have been few studies concerning the effects of hypoxia on pulmonary fibroblasts. In this study, we investigated the molecular mechanisms of hypoxia-induced lung fibroblast proliferation. Hypoxia increased the proliferation of normal human pulmonary fibroblasts and IPF fibroblasts after exposure for 3-6 days. Cell cycle analysis demonstrated that hypoxia promoted the G1/S phase transition. Hypoxia downregulated cyclin D1 and A2 levels, while it upregulated cyclin E1 protein levels. However, hypoxia had no effect on the protein expression levels of cyclin-dependent kinase 2, 4, and 6. Chemical inhibition of hypoxia-inducible factor (HIF)-2 reduced hypoxia-induced fibroblast proliferation. Moreover, silencing of Nuclear Factor Activated T cell (NFAT) c2 attenuated the hypoxia-mediated fibroblasts proliferation. Hypoxia also induced the nuclear translocation of NFATc2, as determined by immunofluorescence staining. NFAT reporter assays showed that hypoxia-induced NFAT signaling activation is dependent on HIF-2, but not HIF-1. Furthermore, the inhibition or silencing of HIF-2, but not HIF-1, reduced the hypoxia-mediated NFATc2 nuclear translocation. Our studies suggest that hypoxia induces the proliferation of human pulmonary fibroblasts through NFAT signaling and HIF-2.

Cancer cell-associated cytoplasmic B7–H4 is induced by hypoxia through hypoxia-inducible factor-1α and promotes cancer cell proliferation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeon, You-Kyoung; Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735; Park, Sae-Gwang

2015-04-03

Aberrant B7–H4 expression in cancer tissues serves as a novel prognostic biomarker for poor survival in patients with cancer. However, the factor(s) that induce cancer cell-associated B7–H4 remain to be fully elucidated. We herein demonstrate that hypoxia upregulates B7–H4 transcription in primary CD138{sup +} multiple myeloma cells and cancer cell lines. In support of this finding, analysis of the Multiple Myeloma Genomics Portal (MMGP) data set revealed a positive correlation between the mRNA expression levels of B7–H4 and the endogenous hypoxia marker carbonic anhydrogenase 9. Hypoxia-induced B7–H4 expression was detected in the cytoplasm, but not in cancer cell membranes. Chromatinmore » immunoprecipitation analysis demonstrated binding of hypoxia-inducible factor-1α (HIF-1α) to proximal hypoxia-response element (HRE) sites within the B7–H4 promoter. Knockdown of HIF-1α and pharmacological inhibition of HIF-1α diminished B7–H4 expression. Furthermore, knockdown of cytoplasmic B7–H4 in MCF-7 decreased the S-phase cell population under hypoxia. Finally, MMGP analysis revealed a positive correlation between the transcript levels of B7–H4 and proliferation-related genes including MKI67, CCNA1, and Myc in several patients with multiple myeloma. Our results provide insight into the mechanisms underlying B7–H4 upregulation and its role in cancer cell proliferation in a hypoxic tumor microenvironment. - Highlights: • Hypoxia upregulates B7–H4 transcription and protein expression. • Hypoxia-induced B7–H4 is detected in the cytoplasm, but not on membrane. • ChIP assay reveals a binding of HIF-1α to B7–H4 promoter at HRE site. • Knockdown and pharmacological inhibition of HIF-1α reduce B7–H4 expression. • B7–H4 knockdown decrease the number of cells in S-phase of cell cycle.« less

The hypoxia signalling pathway in haematological malignancies

PubMed Central

Irigoyen, Marta; García-Ruiz, Juan Carlos; Berra, Edurne

2017-01-01

Haematological malignancies are tumours that affect the haematopoietic and the lymphatic systems. Despite the huge efforts to eradicate these tumours, the percentage of patients suffering resistance to therapies and relapse still remains significant. The tumour environment favours drug resistance of cancer cells, and particularly of cancer stem/initiating cells. Hypoxia promotes aggressiveness, metastatic spread and relapse in most of the solid tumours. Furthermore, hypoxia is associated with worse prognosis and resistance to conventional treatments through activation of the hypoxia-inducible factors. Haematological malignancies are not considered solid tumours, and therefore, the role of hypoxia in these diseases was initially presumed to be inconsequential. However, hypoxia is a hallmark of the haematopoietic niche. Here, we will review the current understanding of the role of both hypoxia and hypoxia-inducible factors in different haematological tumours. PMID:28415662

Effects of hyperthermia on ventilation and metabolism during hypoxia in conscious mice.

PubMed

Iwase, Michiko; Izumizaki, Masahiko; Kanamaru, Mitsuko; Homma, Ikuo

2004-02-01

Hyperthermia and hypoxia influence ventilation and metabolism; however, their synergistic effects remain unanswered. We hypothesized that an enhancement of ventilation induced by hyperthermia is competitive with hypoxic hypometabolism. We then examined the relationship of body temperature, hypoxia, and respiration in conscious mice, measuring minute ventilation (VE), aerobic metabolism, and arterial blood gases. All parameters were measured at two different body temperatures (BTs), approximately 37 degrees C (normothermia) and 39 degrees C (hyperthermia), under both normoxia (room air inhalation) and hypoxia (7% O2 inhalation). Under normoxia, VE and O2 consumption (VO2) were lower at hyperthermia than at normothermia, and the VE-VO2 ratio remained constant. PaCO2 values were normal at both BTs under normoxia. Hypoxic gas inhalation increased VE, which reached a peak in 2 min, then decreased at both BTs. VE remained at a higher level during hyperthermia than during normothermia throughout the 10 min experiment. VO2 decreased during hypoxia at both BTs. Hypoxia increased the VE-VO2 ratio because of relatively high VE with respect to the decreased VO2, which means hyperventilation. At hypoxia under hyperthermia, serious hyperventilation occurred with a further increase in VE. The augmented ventilation may be due to the thermal stimulus and a lowered thermoregulatory set point for hypoxia. Thus hyperthermia reduces ventilation and metabolism to maintain normocapnia; as a result, thermogenesis is reduced under normoxia. Hyperthermia augments hyperventilation induced by hypoxia, leading to severe hypoxic hypocapnia. Thermal stimuli may impair the adjustment of ventilation and metabolism when O2 is limited.

Effect of oral nitrate supplementation on pulmonary hemodynamics during exercise and time trial performance in normoxia and hypoxia: a randomized controlled trial

PubMed Central

Bourdillon, Nicolas; Fan, Jui-Lin; Uva, Barbara; Müller, Hajo; Meyer, Philippe; Kayser, Bengt

2015-01-01

Background: Hypoxia-induced pulmonary vasoconstriction increases pulmonary arterial pressure (PAP) and may impede right heart function and exercise performance. This study examined the effects of oral nitrate supplementation on right heart function and performance during exercise in normoxia and hypoxia. We tested the hypothesis that nitrate supplementation would attenuate the increase in PAP at rest and during exercise in hypoxia, thereby improving exercise performance. Methods: Twelve trained male cyclists [age: 31 ± 7 year (mean ± SD)] performed 15 km time-trial cycling (TT) and steady-state submaximal cycling (50, 100, and 150 W) in normoxia and hypoxia (11% inspired O2) following 3-day oral supplementation with either placebo or sodium nitrate (0.1 mmol/kg/day). We measured TT time-to-completion, muscle tissue oxygenation during TT and systolic right ventricle to right atrium pressure gradient (RV-RA gradient: index of PAP) during steady state cycling. Results: During steady state exercise, hypoxia elevated RV-RA gradient (p > 0.05), while oral nitrate supplementation did not alter RV-RA gradient (p > 0.05). During 15 km TT, hypoxia lowered muscle tissue oxygenation (p < 0.05). Nitrate supplementation further decreased muscle tissue oxygenation during 15 km TT in hypoxia (p < 0.05). Hypoxia impaired time-to-completion during TT (p < 0.05), while no improvements were observed with nitrate supplementation in normoxia or hypoxia (p > 0.05). Conclusion: Our findings indicate that oral nitrate supplementation does not attenuate acute hypoxic pulmonary vasoconstriction nor improve performance during time trial cycling in normoxia and hypoxia. PMID:26528189

Relationship of Renal Function Tests and Electrolyte Levels with Severity of Dehydration in Acute Diarrhea.

PubMed

Gauchan, E; Malla, K K

2015-01-01

Acute diarrheal illness constitutes a major cause of morbidity and mortality in children in developing countries. Most of the complications of diarrhea occur due to excessive fluid and electrolyte loss; adverse complications are seen more with increasing severity of dehydration. This study was conducted to identify the relation of renal function and electrolyte abnormalities in children with varying severity of dehydration. This study was carried out in Manipal Teaching Hospital, Pokhara, Nepal over duration of one year. The aims were to find out the association of renal function and electrolyte disturbances with type of diarrhea, severity of dehydration and their relation to outcome. All children more than one month and less than 15 years with acute diarrhea were included in the study. Data were entered and analyzed by SPSS version 19. Statistical analysis applied was Chi-square test. A p-value of <0.05 was taken as significant. Acute watery diarrhea was the commonest type of diarrhea in children. Dehydration was associated more with Acute Watery Diarrhea than with Invasive Diarrhea. Renal function and electrolyte abnormalities were seen more in Acute Watery Diarrhea with increasing levels of blood urea, serum creatinine and abnormal levels of serum sodium seen with increased severity of dehydration. Abnormalities in renal function and electrolytes correlated significantly with severity of dehydration. The outcome of patients correlated with severity of dehydration with mortality occurring in 18.1% of patients with Severe dehydration, 0.8% of Some dehydration with no mortality in the No dehydration group.

Postconditioning with repeated mild hypoxia protects neonatal hypoxia-ischemic rats against brain damage and promotes rehabilitation of brain function.

PubMed

Deng, Qingqing; Chang, Yanqun; Cheng, Xiaomao; Luo, Xingang; Zhang, Jing; Tang, Xiaoyuan

2018-05-01

Mild hypoxia conditioning induced by repeated episodes of transient ischemia is a clinically applicable method for protecting the brain against injury after hypoxia-ischemic brain damage. To assess the effect of repeated mild hypoxia postconditioning on brain damage and long-term neural functional recovery after hypoxia-ischemic brain damage. Rats received different protocols of repeated mild hypoxia postconditioning. Seven-day-old rats with hypoxia ischemic brain damage (HIBD) from the left carotid ligation procedure plus 2 h hypoxic stress (8% O 2 at 37 °C) were further receiving repeated mild hypoxia intermittently. The gross anatomy, functional analyses, hypoxia inducible factor 1 alpha (HIF-1a) expression, and neuronal apoptosis of the rat brains were subsequently examined. Compared to the HIBD group, rats postconditioned with mild hypoxia had elevated HIF-1a expression, more Nissl-stain positive cells in their brain tissue and their brains functioned better in behavioral analyses. The recovery of the brain function may be directly linked to the inhibitory effect of HIF-1α on neuronal apoptosis. Furthermore, there were significantly less neuronal apoptosis in the hippocampal CA1 region of the rats postconditioned with mild hypoxia, which might also be related to the higher HIF-1a expression and better brain performance. Overall, these results suggested that postconditioning of neonatal rats after HIBD with mild hypoxia increased HIF-1a expression, exerted a neuroprotective effect and promoted neural functional recovery. Repeated mild hypoxia postconditioning protects neonatal rats with HIBD against brain damage and improves neural functional recovery. Our results may have clinical implications for treating infants with HIBD. Copyright © 2018 Elsevier Inc. All rights reserved.

β-Adrenergic or parasympathetic inhibition, heart rate and cardiac output during normoxic and acute hypoxic exercise in humans

PubMed Central

Hopkins, Susan R; Bogaard, Harm J; Niizeki, Kyuichi; Yamaya, Yoshiki; Ziegler, Michael G; Wagner, Peter D

2003-01-01

Acute hypoxia increases heart rate (HR) and cardiac output () at a given oxygen consumption () during submaximal exercise. It is widely believed that the underlying mechanism involves increased sympathetic activation and circulating catecholamines acting on cardiac β receptors. Recent evidence indicating a continued role for parasympathetic modulation of HR during moderate exercise suggests that increased parasympathetic withdrawal plays a part in the increase in HR and during hypoxic exercise. To test this, we separately blocked the β-sympathetic and parasympathetic arms of the autonomic nervous system (ANS) in six healthy subjects (five male, one female; mean ± s.e.m. age = 31.7 ± 1.6 years, normoxic maximal () = 3.1 ± 0.3 l min−1) during exercise in conditions of normoxia and acute hypoxia (inspired oxygen fraction = 0.125) to . Data were collected on different days under the following conditions: (1)control, (2) after 8.0 mg propranolol I.V. and (3) after 0.8 mg glycopyrrolate I.V. was measured using open-circuit acetylene uptake. Hypoxia increased venous [adrenaline] and [noradrenaline] but not [dopamine] at a given (P < 0.05, P < 0.01 and P = 0.2, respectively). HR/ and / increased during hypoxia in all three conditions (P < 0.05). Unexpectedly, the effects of hypoxia on HR and were not significantly different from control with either β-sympathetic or parasympathetic inhibition. These data suggest that although acute exposure to hypoxia increases circulating [catecholamines], the effects of hypoxia on HR and do not necessarily require intact cardiac muscarinic and β receptors. It may be that cardiac α receptors play a primary role in elevating HR and during hypoxic exercise, or perhaps offer an alternative mechanism when other ANS pathways are blocked. PMID:12766243

Acute diabetes insipidus in severe head injury: a prospective study.

PubMed

Hadjizacharia, Pantelis; Beale, Elizabeth O; Inaba, Kenji; Chan, Linda S; Demetriades, Demetrios

2008-10-01

The incidence and risk factors for acute diabetes insipidus after severe head injury and the effect of this complication on outcomes have not been evaluated in any large prospective studies. We conducted a prospective study of all patients admitted to the surgical ICU of a Level I trauma center with severe head injury (head Abbreviated Injury Score [AIS] >or= 3). The following potential risk factors with p < 0.2 on bivariate analysis were included in a stepwise logistic regression to identify independent risk factors for diabetes insipidus and its association with mortality: age, mechanism of injury (blunt or penetrating), blood pressure, Glasgow Coma Scale, Injury Severity Score, head and other body area AIS, skull fracture, cerebral edema and shift, intracranial hemorrhage, and pneumocephaly. There were 436 patients (blunt injuries, 392; penetrating injuries, 44); 387 patients had isolated head injury. Diabetes insipidus occurred in 15.4% of all patients (blunt, 12.5%; penetrating, 40.9%; p < 0.0001) and in 14.7% of patients with isolated head injury (blunt, 11.8%; penetrating, 39.5%; p < 0.0001). The presence of major extracranial injuries did not influence the incidence of diabetes insipidus. Independent risk factors for diabetes insipidus in isolated head injury were Glasgow Coma Scale3. Diabetes insipidus was an independent risk factor for death (adjusted odds ratio, 3.96; 95% CI [1.65, 9.72]; adjusted p value = 0.002). The incidence of acute diabetes insipidus in severe head injury is high, especially in penetrating injuries. Independent risk factors for diabetes insipidus include a Glasgow Coma Scale3. Acute diabetes insipidus was associated with significantly increased mortality.

Substrate modulation of fatty acid effects on energization and respiration of kidney proximal tubules during hypoxia/reoxygenation.

PubMed

Bienholz, Anja; Al-Taweel, Ahmad; Roeser, Nancy F; Kribben, Andreas; Feldkamp, Thorsten; Weinberg, Joel M

2014-01-01

Kidney proximal tubules subjected to hypoxia/reoxygenation develop a nonesterified fatty acid-induced energetic deficit characterized by persistent partial mitochondrial deenergization that can be prevented and reversed by citric acid cycle substrates. To further assess the role of competition between fatty acids and substrates on inner membrane substrate carriers in the deenergization and the contribution to deenergization of fatty acid effects on respiratory function, digitonin-permeabilized rabbit and mouse tubules were studied using either addition of exogenous oleate after control normoxic incubation or increases of endogenous fatty acids produced by hypoxia/reoxygenation. The results demonstrated major effects of matrix oxaloacetate accumulation on succinate-supported energization and respiration and their modification by fatty acids. Improvements of energization in the presence of fatty acids by glutamate were shown to result predominantly from lowering matrix oxaloacetate rather than from amelioration of transmembrane cycling of fatty acids and uncoupling. Mouse tubules had 2.5 fold higher rates of succinate utilization, which resulted in stronger effects of oxaloacetate accumulation than rabbit tubules. Hypoxia/reoxygenation induced respiratory inhibition that was more severe for complex I-dependent substrates. Fatty acids themselves did not acutely contribute to this respiratory inhibition, but lowering them during 60 min. reoxygenation to allow recovery of ATP during that period alleviated it. These data clarify the basis for the nonesterified fatty acid-induced mitochondrial energetic deficit in kidney proximal tubules that impairs structural and functional recovery and provide insight into interactions that need to be considered in the design of substrate-based interventions to improve mitochondrial function.

Preconditioning Triggered by Carbon Monoxide (CO) Provides Neuronal Protection Following Perinatal Hypoxia-Ischemia

PubMed Central

Widerøe, Marius; Alves, Paula M.; Vercelli, Alessandro; Vieira, Helena L. A.

2012-01-01

Perinatal hypoxia-ischemia is a major cause of acute mortality in newborns and cognitive and motor impairments in children. Cerebral hypoxia-ischemia leads to excitotoxicity and necrotic and apoptotic cell death, in which mitochondria play a major role. Increased resistance against major damage can be achieved by preconditioning triggered by subtle insults. CO, a toxic molecule that is also generated endogenously, may have a role in preconditioning as low doses can protect against inflammation and apoptosis. In this study, the role of CO-induced preconditioning on neurons was addressed in vitro and in vivo. The effect of 1 h of CO treatment on neuronal death (plasmatic membrane permeabilization and chromatin condensation) and bcl-2 expression was studied in cerebellar granule cells undergoing to glutamate-induced apoptosis. CO's role was studied in vivo in the Rice-Vannucci model of neonatal hypoxia-ischemia (common carotid artery ligature +75 min at 8% oxygen). Apoptotic cells, assessed by Nissl staining were counted with a stereological approach and cleaved caspase 3-positive profiles in the hippocampus were assessed. Apoptotic hallmarks were analyzed in hippocampal extracts by Western Blot. CO inhibited excitotoxicity-induced cell death and increased Bcl-2 mRNA in primary cultures of neurons. In vivo, CO prevented hypoxia-ischemia induced apoptosis in the hippocampus, limited cytochrome c released from mitochondria and reduced activation of caspase-3. Still, Bcl-2 protein levels were higher in hippocampus of CO pre-treated rat pups. Our results show that CO preconditioning elicits a molecular cascade that limits neuronal apoptosis. This could represent an innovative therapeutic strategy for high-risk cerebral hypoxia-ischemia patients, in particular neonates. PMID:22952602

Extracorporeal Life Support for Severe Acute Respiratory Distress Syndrome in Adults

PubMed Central

Hemmila, Mark R.; Rowe, Stephen A.; Boules, Tamer N.; Miskulin, Judiann; McGillicuddy, John W.; Schuerer, Douglas J.; Haft, Jonathan W.; Swaniker, Fresca; Arbabi, Saman; Hirschl, Ronald B.; Bartlett, Robert H.

2004-01-01

Objective: Severe acute respiratory distress syndrome (ARDS) is associated with a high level of mortality. Extracorporeal life support (ECLS) during severe ARDS maintains oxygen and carbon dioxide gas exchange while providing an optimal environment for recovery of pulmonary function. Since 1989, we have used a protocol-driven algorithm for treatment of severe ARDS, which includes the use of ECLS when standard therapy fails. The objective of this study was to evaluate our experience with ECLS in adult patients with severe ARDS with respect to mortality and morbidity. Methods: We reviewed our complete experience with ELCS in adults from January 1, 1989, through December 31, 2003. Severe ARDS was defined as acute onset pulmonary failure, with bilateral infiltrates on chest x-ray, and PaO2/fraction of inspired oxygen (FiO2) ratio ≤100 or A-aDO2 >600 mm Hg despite maximal ventilator settings. The indication for ECLS was acute severe ARDS unresponsive to optimal conventional treatment. The technique of ECLS included veno-venous or veno-arterial vascular access, lung “rest” at low FiO2 and inspiratory pressure, minimal anticoagulation, and optimization of systemic oxygen delivery. Results: During the study period, ECLS was used for 405 adult patients age 17 or older. Of these 405 patients, 255 were placed on ECLS for severe ARDS refractory to all other treatment. Sixty-seven percent were weaned off ECLS, and 52% survived to hospital discharge. Multivariate logistic regression analysis identified the following pre-ELCS variables as significant independent predictors of survival: (1) age (P = 0.01); (2) gender (P = 0.048); (3) pH ≤7.10 (P = 0.01); (4) PaO2/FiO2 ratio (P = 0.03); and (5) days of mechanical ventilation (P < 0.001). None of the patients who survived required permanent mechanical ventilation or supplemental oxygen therapy. Conclusion: Extracorporeal life support for severe ARDS in adults is a successful therapeutic option in those patients who do not

Acute Chest Syndrome in Children with Sickle Cell Disease

PubMed Central

Bakshi, Nitya; Krishnamurti, Lakshmanan

2017-01-01

Acute chest syndrome (ACS) is a frequent cause of acute lung disease in children with sickle cell disease (SCD). Patients may present with ACS or may develop this complication during the course of a hospitalization for acute vaso-occlusive crises (VOC). ACS is associated with prolonged hospitalization, increased risk of respiratory failure, and the potential for developing chronic lung disease. ACS in SCD is defined as the presence of fever and/or new respiratory symptoms accompanied by the presence of a new pulmonary infiltrate on chest X-ray. The spectrum of clinical manifestations can range from mild respiratory illness to acute respiratory distress syndrome. The presence of severe hypoxemia is a useful predictor of severity and outcome. The etiology of ACS is often multifactorial. One of the proposed mechanisms involves increased adhesion of sickle red cells to pulmonary microvasculature in the presence of hypoxia. Other commonly associated etiologies include infection, pulmonary fat embolism, and infarction. Infection is a common cause in children, whereas adults usually present with pain crises. Several risk factors have been identified in children to be associated with increased incidence of ACS. These include younger age, severe SCD genotypes (SS or Sβ0 thalassemia), lower fetal hemoglobin concentrations, higher steady-state hemoglobin levels, higher steady-state white blood cell counts, history of asthma, and tobacco smoke exposure. Opiate overdose and resulting hypoventilation can also trigger ACS. Prompt diagnosis and management with intravenous fluids, analgesics, aggressive incentive spirometry, supplemental oxygen or respiratory support, antibiotics, and transfusion therapy, are key to the prevention of clinical deterioration. Bronchodilators should be considered if there is history of asthma or in the presence of acute bronchospasm. Treatment with hydroxyurea should be considered for prevention of recurrent episodes. This review evaluates the

Acute Chest Syndrome in Children with Sickle Cell Disease.

PubMed

Jain, Shilpa; Bakshi, Nitya; Krishnamurti, Lakshmanan

2017-12-01

Acute chest syndrome (ACS) is a frequent cause of acute lung disease in children with sickle cell disease (SCD). Patients may present with ACS or may develop this complication during the course of a hospitalization for acute vaso-occlusive crises (VOC). ACS is associated with prolonged hospitalization, increased risk of respiratory failure, and the potential for developing chronic lung disease. ACS in SCD is defined as the presence of fever and/or new respiratory symptoms accompanied by the presence of a new pulmonary infiltrate on chest X-ray. The spectrum of clinical manifestations can range from mild respiratory illness to acute respiratory distress syndrome. The presence of severe hypoxemia is a useful predictor of severity and outcome. The etiology of ACS is often multifactorial. One of the proposed mechanisms involves increased adhesion of sickle red cells to pulmonary microvasculature in the presence of hypoxia. Other commonly associated etiologies include infection, pulmonary fat embolism, and infarction. Infection is a common cause in children, whereas adults usually present with pain crises. Several risk factors have been identified in children to be associated with increased incidence of ACS. These include younger age, severe SCD genotypes (SS or Sβ 0 thalassemia), lower fetal hemoglobin concentrations, higher steady-state hemoglobin levels, higher steady-state white blood cell counts, history of asthma, and tobacco smoke exposure. Opiate overdose and resulting hypoventilation can also trigger ACS. Prompt diagnosis and management with intravenous fluids, analgesics, aggressive incentive spirometry, supplemental oxygen or respiratory support, antibiotics, and transfusion therapy, are key to the prevention of clinical deterioration. Bronchodilators should be considered if there is history of asthma or in the presence of acute bronchospasm. Treatment with hydroxyurea should be considered for prevention of recurrent episodes. This review evaluates the