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Sample records for chronic intermittent hypoxia

  1. A novel adjustable automated system for inducing chronic intermittent hypoxia in mice

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    Polšek, Dora; Bago, Marcel; Živaljić, Marija; Rosenzweig, Ivana; Lacza, Zsombor

    2017-01-01

    Background Sleep apnea is a chronic, widely underdiagnosed condition characterized by disruption of sleep architecture and intermittent hypoxia due to short cessations of breathing. It is a major independent risk factor for myocardial infarction, congestive heart failure and stroke as well as one of the rare modifiable risk factors for Alzheimer’s Dementia. Reliable animal disease models are needed to understand the link between sleep apnea and the various clinically linked disorders. New method An automated system for inducing hypoxia was developed, in which the major improvement was the possibility to efficiently adjust the length and intensity of hypoxia in two different periods. The chamber used a small volume of gas allowing for fast exchanges of different oxygen levels. The mice were kept in their cages adapted with the system on the cage lid. As a proof of principle, they were exposed to a three week period of intermittent hypoxia for 8 hours a day, with 90 s intervals of 5, 7% and 21% oxygen to validate the model. Treated (n = 8) and control mice (no hypoxia, n = 7) were handled in the same manner and their hippocampal brain regions compared by histology. Results The chamber provided a fast, reliable and precise intermittent hypoxia, without inducing noticeable side effects to the animals. The validation experiment showed that apoptotic neurons in the hippocampus were more numerous in the mice exposed to intermittent hypoxia than in the control group, in all tested hippocampal regions (cornu ammonis 1 (CA1) P neurons in the DG compared to the CA1 and CA3 subfields (P neurons. PMID:28362813

  2. Effect of superoxide anion scavenger on rat hearts with chronic intermittent hypoxia.

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    Pai, Peiying; Lai, Ching Jung; Lin, Ching-Yuang; Liou, Yi-Fan; Huang, Chih-Yang; Lee, Shin-Da

    2016-04-15

    Only very limited information regarding the protective effects of the superoxide anion scavenger on chronic intermittent hypoxia-induced cardiac apoptosis is available. The purpose of this study is to evaluate the effects of the superoxide anion scavenger on cardiac apoptotic and prosurvival pathways in rats with sleep apnea. Forty-two Sprague-Dawley rats were divided into three groups, rats with normoxic exposure (Control, 21% O2, 1 mo), rats with chronic intermittent hypoxia exposure (Hypoxia, 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo), and rats with pretreatment of the superoxide anion scavenger and chronic intermittent hypoxia exposure (Hypoxia-O2 (-)-Scavenger, MnTMPyP pentachloride, 1 mg/kg ip per day; 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo) at 5-6 mo of age. After 1 mo, the protein levels and apoptotic cells of excised hearts from three groups were measured by Western blotting and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay. The superoxide anion scavenger decreased hypoxia-induced myocardial architecture abnormalities, left ventricular hypertrophy, and TUNEL-positive apoptosis. The superoxide anion scavenger decreased hypoxia-induced Fas ligand, Fas death receptors, Fas-associated death domain (FADD), activated caspase-8, and activated caspase-3 (Fas-dependent apoptotic pathway) as well as Bad, activated caspase-9 and activated caspase-3 (mitochondria-dependent apoptotic pathway), endonuclease G (EndoG), apoptosis-inducing factor (AIF), and TUNEL-positive apoptosis. The superoxide anion scavenger increased IGF-1, IGF-1R, p-PI3k, p-Akt, p-Bad, Bcl-2, and Bcl-xL (survival pathway). Our findings imply that the superoxide anion scavenger might prevent cardiac Fas-mediated and mitochondrial-mediated apoptosis and enhance the IGF-1-related survival pathway in chronic intermittent hypoxia. The superoxide anion scavenger may prevent chronic sleep apnea-enhanced cardiac apoptotic pathways and enhances

  3. Chronic intermittent hypoxia and obstructive sleep apnea: an experimental and clinical approach

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    Sforza E

    2016-04-01

    Full Text Available Emilia Sforza, Fréderic Roche Service de Physiologie Clinique et de l'Exercice, Pole NOL, CHU, EA SNA-EPIS 4607, Faculté de Médecine J. Lisfranc, UJM Saint-Etienne, Université de Lyon, Saint-Etienne, France Abstract: Obstructive sleep apnea (OSA is a prevalent sleep disorder considered as an independent risk factor for cardiovascular consequences, such as systemic arterial hypertension, ischemic heart disease, cardiac arrhythmias, metabolic disorders, and cognitive dysfunction. The pathogenesis of OSA-related consequence is assumed to be chronic intermittent hypoxia (IH inducing alterations at the molecular level, oxidative stress, persistent systemic inflammation, oxygen sensor activation, and increase of sympathetic activity. Overall, these mechanisms have an effect on vessel permeability and are considered to be important factors for explaining vascular, metabolic, and cognitive OSA-related consequences. The present review attempts to examine together the research paradigms and clinical studies on the effect of acute and chronic IH and the potential link with OSA. We firstly describe the literature data on the mechanisms activated by acute and chronic IH at the experimental level, which are very helpful and beneficial to explaining OSA consequences. Then, we describe in detail the effect of IH in patients with OSA that we can consider "the human model" of chronic IH. In this way, we can better understand the specific pathophysiological mechanisms proposed to explain the consequences of IH in OSA. Keywords: hypoxia, intermittent hypoxia, experimental studies, obstructive sleep apnea

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

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    Neetu Kushwah

    Full Text Available 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.

  5. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver.

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    Savransky, Vladimir; Bevans, Shannon; Nanayakkara, Ashika; Li, Jianguo; Smith, Philip L; Torbenson, Michael S; Polotsky, Vsevolod Y

    2007-10-01

    Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P diet.

  6. Influence of chronic intermittent hypoxia on growth associated protein 43 expression in the hippocampus of young rats

    Institute of Scientific and Technical Information of China (English)

    Yan Chen; Chunling Zhao; Chunlai Zhang; Lirong Luo; Guang Yu

    2012-01-01

    This study aimed to explore the pathological change to hippocampal neurons and the expression of growth associated protein 43 in 21-day-old young rats following chronic intermittent hypoxia. Hematoxylin-eosin staining results showed varying degrees of degeneration and necrosis in hippocampal neurons depending on the modeling time. Immunohistochemistry revealed that growth associated protein 43 expression in young rats following chronic intermittent hypoxia de-creased, but that levels were still higher than those of normal rats at each time point, especially 4 weeks after modeling. During 1-5 weeks after modeling, a slow growth in rat weight was ob-served. Experimental findings indicate that chronic intermittent hypoxia may induce growth dys-function and necrosis of hippocampal neurons, as well as increase the expression of growth as-sociated protein 43 in young rats.

  7. Influence of chronic intermittent hypoxia on growth associated protein 43 expression in the hippocampus of young rats.

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    Chen, Yan; Zhao, Chunling; Zhang, Chunlai; Luo, Lirong; Yu, Guang

    2012-06-05

    This study aimed to explore the pathological change to hippocampal neurons and the expression of growth associated protein 43 in 21-day-old young rats following chronic intermittent hypoxia. Hematoxylin-eosin staining results showed varying degrees of degeneration and necrosis in hippocampal neurons depending on the modeling time. Immunohistochemistry revealed that growth associated protein 43 expression in young rats following chronic intermittent hypoxia decreased, but that levels were still higher than those of normal rats at each time point, especially 4 weeks after modeling. During 1-5 weeks after modeling, a slow growth in rat weight was observed. Experimental findings indicate that chronic intermittent hypoxia may induce growth dysfunction and necrosis of hippocampal neurons, as well as increase the expression of growth associated protein 43 in young rats.

  8. Effect of chronic intermittent hypoxia on exercise adaptations in healthy subjects.

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    Tonini, Julia; Michallet, Anne-Sophie; Flore, Patrice; Nespoulet, Hugo; Pepin, Jean-Louis; Wuyam, Bernard; Levy, Patrick; Tamisier, Renaud

    2011-12-15

    Reduced exercise tolerance has been reported in obstructive sleep apnea syndrome (OSAS) patients, although the associated hypertension, obesity and/or metabolic disorder may underlie this reduction. Therefore, we evaluated the effects of chronic intermittent hypoxia (CIH) in 12 healthy subjects on exercise capacity, cardio-respiratory responses, and substrate oxidation during maximal and sub-maximal exercise. Subjects were exposed to 30 cycles of hypoxia-reoxygenation per hour for 14 nights. Although exercise capacity was unaltered PETCO(2) was reduced and V˙E/V˙CO(2) increased during both maximal and submaximal exercise tests, indicating a hyperventilatory response. Maximal heart rate was lower and diastolic arterial blood pressure (DBP) was higher in the 1st min of recovery after submaximal exercise. Subjects reached maximal lipid oxidation at a higher power output and had decreased blood lactate for a given power output. This suggests that although the metabolic adaptations to CIH in healthy subjects may improve exercise performance, the cardio-pulmonary modifications are similar to those observed in OSAS patients and could limit exercise capacity.

  9. Vagal cardiac efferent innervation in F344 rats: Effects of chronic intermittent hypoxia.

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    Cheng, Zixi Jack

    2017-03-01

    Chronic intermittent hypoxia (CIH), which is a physiological consequence of obstructive sleep apnea, reduces baroreflex control of heart rate (HR). Previously, we showed that the heart rate (HR) response to electrical stimulation of the vagal efferent nerve was significantly increased following CIH in F344 rats. Since vagal cardiac efferent from the nucleus ambiguus (NA) project to cardiac ganglia and regulate HR, we hypothesized that vagal cardiac efferent innervation of cardiac ganglia is reorganized. Young adult F344 rats were exposed either to room air (RA) or to intermittent hypoxia for 35-50days. Fluorescent tracer DiI was injected into the NA to label vagal efferent innervation of cardiac ganglia which had been counterstained by Fluoro-Gold (FG) injections (i.p). Confocal microscopy was used to examine vagal cardiac efferent axons and terminals in cardiac ganglia. NA axons entered cardiac ganglia and innervated principal neurons (PNs) with robust basket endings in both RA control and CIH animals. In addition, the percentage of PNs which were innervated by DiI-labeled fibers in ganglia was similar. In CIH rats, abnormally large swollen cardiac axon segments and disorganized terminals as well as leaky endings were observed. In general, vagal efferent terminal varicosities around PNs appeared larger and the number of varicosities was significantly increased. Interestingly, some cardiac axons had sprouting-like terminal structures in the cardiac ganglia as well as in cardiac muscle, which had not been found in RA control. Finally, CIH increased the size of PNs and reduced the ratio of nucleus to PN somata. Thus, CIH significantly remodeled the structure of vagal cardiac axons and terminals in cardiac ganglia as well as cardiac PNs.

  10. The effect of oxidative stress in myocardial cell injury in mice exposed to chronic intermittent hypoxia

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    LIU Jian-nan; ZHANG Jie-xin; LIU gan; QIU Yan; YANG Di; YIN Guo-yong; ZHANG Xi-long

    2010-01-01

    Background Obstructive sleep apnea syndrome (OSAS) is an important risk factor for cardiovascular diseases. Chronic intermittent hypoxia (CIH) is considered to be one of the most important causes of cardiovascular diseases in OSA patients. This repeated hypoxia and reoxygenation cycle is similar to hypoxia-reperfusion injury, which initiates oxidative stress. In this study, we observed cardiocytes injury induced by CIH and the effect of N-acetylcysteine (NAC). Methods Thirty ICR mice were randomly assigned to 3 groups: control, CIH and NAC (CIH+NAC) groups. Malondialdehyde (MDA) and superoxide dismutase (SOD) of cardiocyte homogenates were measured. Serum lipids were measured by an instrument method. Serum cardiac troponin I (cTnl) was detected by enzyme-linked immunosorbent assays (ELISA). Myocardium pathological sections were observed.Results (1) The SOD activity and MDA concentration of cardiocyte homogenates in the CIH group were significantly higher than in other groups (P <0.005). The MDA concentration of the NAC group was lower than that of the control group (P <0.01). (2) The serum cTnl concentration of the CIH and NAC groups was significantly higher than that of the control group (P<0.01). (3) Serum triglyceride levels in the NAC group were lower than in the other groups (P<0.01), while there were no significant differences in low density lipoprotein and high density lipoprotein among the three groups. (4) The degeneration of myocardium, transverse striation blurred, and fabric effusion were observed in tissue sections in the CIH and NAC groups. However, normal tissue was found in the control group.Conclusion The oxidative stress induced by CIH can injure cardiocytes and the injury effect can be partially inhibited by NAC.

  11. Changes in carotid body and nTS neuronal excitability following neonatal sustained and chronic intermittent hypoxia exposure.

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    Mayer, C A; Wilson, C G; MacFarlane, P M

    2015-01-01

    We investigated whether pre-treatment with neonatal sustained hypoxia (SH) prior to chronic intermittent hypoxia (SH+CIH) would modify in vitro carotid body (CB) chemoreceptor activity and the excitability of neurons in the caudal nucleus of the solitary tract (nTS). Sustained hypoxia followed by CIH exposure simulates an oxygen paradigm experienced by extremely premature infants who developed persistent apnea. Rat pups were treated with 5 days of SH (11% O2) from postnatal age 1 (P1) followed by 10 days of subsequent chronic intermittent hypoxia (CIH, 5% O2/5 min, 8 h/day, between P6 and P15) as described previously (Mayer et al., Respir. Physiol. Neurobiol. 187(2): 167-75, 2013). At the end of SH+CIH exposure (P16), basal firing frequency was enhanced, and the hypoxic sensory response of single unit CB chemoafferents was attenuated. Further, basal firing frequency and the amplitude of evoked excitatory post-synaptic currents (ESPC's) of nTS neurons was augmented compared to age-matched rats raised in normoxia. These effects were unique to SH+CIH exposure as neither SH or CIH alone elicited any comparable effect on chemoafferent activity or nTS function. These data indicated that pre-treatment with neonatal SH prior to CIH exposure uniquely modified mechanisms of peripheral (CB) and central (nTS) neural function in a way that would be expected to disturb the ventilatory response to acute hypoxia.

  12. Chronic intermittent hypoxia induces atherosclerosis by NF-κB-dependent mechanisms.

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    Song, D; Fang, G; Mao, S-Z; Ye, X; Liu, G; Gong, Y; Liu, S F

    2012-11-01

    Chronic intermittent hypoxia (CIH) causes atherosclerosis in mice fed a high cholesterol diet (HCD). The mechanisms by which CIH promotes atherosclerosis are incompletely understood. This study defined the mechanistic role of NF-κB pathway in CIH+HCD induced atherosclerosis. Wild type (WT) and mice deficient in the p50 subunit of NF-κB (p50-KO) were fed normal chow diet (ND) or HCD, and exposed to sham or CIH. Atherosclerotic lesions on the en face aortic preparation and cross-sections of aortic root were examined. In WT mice, neither CIH nor HCD exposure alone caused, but CIH+HCD caused evident atherosclerotic lesions on both preparations after 20weeks of exposure. WT mice on ND and exposed to CIH for 35.6weeks did not develop atherosclerotic lesions. P50 gene deletion diminished CIH+HCD induced NF-κB activation and abolished CIH+HCD induced atherosclerosis. P50 gene deletion inhibited vascular wall inflammation, reduced hepatic TNF-α level, attenuated the elevation in serum cholesterol level and diminished macrophage foam cell formation induced by CIH+HCD exposure. These results demonstrate that inhibition of NF-κB activation abrogates the activation of three major atherogenic mechanisms associated with an abolition of CIH+HCD induced atherosclerosis. NF-κB may be a central common pathway through which CIH+HCD exposure activates multiple atherogenic mechanisms, leading to atherosclerosis.

  13. Effect of chronic intermittent hypoxia on theophylline metabolism in mouse liver

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    CHEN Xiao-yang; ZENG Yi-ming; ZHANG Yi-xiang; WANG Wan-yu; WU Run-hua

    2013-01-01

    Background Chronic intermittent hypoxia (CIH) has been associated with abnormalities in the liver,which is the most important organ for drug metabolism.This study aimed to investigate the effect of CIH on theophylline metabolism in mouse liver.Methods Eight C57BL/6J mice were exposed to CIH for 12 weeks.Eight C57BL/6J mice were exposed to room air as a control group.Serum levels of alanine aminotransferase and aspartate aminotransferase were measured.Liver histology was observed by light and electron microscopy.Total hepatic cytochrome P450 concentration was measured.Hepatocytes were isolated and incubated with 15 mg/ml theophylline for four hours.After incubation,the theophylline concentration in the supernatant was measured and the theophylline metabolism rate was calculated.Results CIH did not affect the serum transaminase levels.Livers from mice exposed to CIH showed hepatocellular edema,and liver cells had fuzzy rough endoplasmic reticulum under the electron microscope.The theophylline metabolism rate was significantly inhibited by CIH compared with controls; (16.60±2.43)% vs.(21.58±4.52)% (P=0.02).The total liver cytochrome P450 concentration in the CIH group was significantly lower than in the control group;(0.83±0.08) vs.(1.13±0.21) mol/mg microsomal protein (P=0.004).Conclusion CIH decreases theophylline metabolism by mouse hepatocytes,which may correlate with the downregulation of cytochrome P450 expression by CIH.

  14. ERK signaling mediates enhanced angiotensin Ⅱ-induced rat aortic constriction following chronic intermittent hypoxia

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    GUO Xue-ling; DENG Yan; SHANG Jin; LIU Kui; XU Yong-jian; LIU Hui-guo

    2013-01-01

    Background Obstructive sleep apnea (OSA) has been recognized as an independent risk factor for systemic hypertension.The study investigated the functional consequences of chronic intermittent hypoxia (CIH) on aortic constriction induced by angiotensin Ⅱ (Ang Ⅱ) and the possible signaling involving ERK1/2 and contractile proteins such as myosin light chain kinase (MLCK),myosin phosphatase targeting subunit (MYPT1) and myosin light chain (MLC).Methods Male Wistar rats were randomly divided into CIH group and normoxia group and exposed to either CIH procedure or air-air cycles.Phosphorylation of ERK1/2,MYPT1 and MLC was assessed by Western blotting following constrictor studies in the presence or absence of PD98059 (10 μmol/L).Results CIH-exposure resulted in more body weight gain and elevated blood pressure,which could be attenuated by pretreatment with PD98059.Endothelium-removed aortic rings from CIH rats exhibited higher constrictor sensitivity to Ang Ⅱ (Emax:(138.56±5.78)% versus (98.45±5.31)% of KCI; pD2:7.98±0.14 versus 8.14±0.05,respectively).CIH procedure exerted complex effects on ERK expressions (total ERK1/2 decreased whereas the ratio of phosphorylated to total ERK1/2increased).CIH aortas had higher MLCK mRNA and basal phosphorylation of MYPT1 and MLC.In parallel to greater increases in phosphorylation of ERK1/2,MYPT1 and MLC,Ang Ⅱ-induced aortic constriction was significantly enhanced in CIH rats,which was largely reversed by PD98059.However vascular constriction of normoxia rats remained unchanged despite similar but smaller changing tendency of proteins phosphorylation.Conclusion These data suggest that CIH exposure results in aortic hyperresponsiveness to Ang Ⅱ,presumably owing to more activated ERK1/2 signaling pathway.

  15. Adiponectin alleviates contractile dysfunction of genioglossus in rats exposed to chronic intermittent hypoxia

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    WANG Wen-jing; LU Gan; DING Ning; HUANG Han-peng; DING Wen-xiao; ZHANG Xi-long

    2013-01-01

    Background Genioglossal dysfuntion takes an important role in pathogenesis of obstructive sleep apnea hypopnea syndrome (OSAHS) in which chronic intermittent hypoxia (CIH) is the major pathological origin.Recent studies have suggested genioglossal injury induced by CIH might be improved by adiponectin.The aim of this study was to investigate the effects of adiponectin on genioglossus contractile properties in rats exposed to CIH.Methods Thirty-nine healthy male Wistar rats were randomly divided into three groups:normal control (NC),CIH and adiponectin supplement (CIH+Ad) with 13 rats in each.Rats in NC were kept breathing normal air,while rats in CIH and CIH+Ad experienced the same CIH environment eight hours per day for 35 successive days.Rats in CIH+Ad were given intravenous adiponectin of 10 μg twice a week for 30 successive days.Rats in the NC and CIH were injected with normal saline as a control.After 35 days' CIH exposure,the levels of serum adiponectin and genioglossus contractile properties were compared.Results Serum adiponectin level was significantly lower in CIH than in NC (1210 ng/ml vs.2236 ng/ml).Serum adiponectin level in CIH+Ad (1844 ng/ml) was significantly higher than CIH but lower than NC.Twitch tension,time to peak tension,half relaxation time and tetanic tension were significantly lower in CIH than NC and improved in CIH+Ad.All mean tetanic fatigue indices decreased more rapidly in the first 20 seconds than during the subsequent 100 seconds.Tetanic fatigue indices in NC and CIH+Ad were significantly higher compared to CIH.Conclusions CIH could lead to hypoadiponectinaemia,impaired genioglossus contractile properties and decreased fatigue resistance in rats.Such changes could be partially offset by supplementation of adiponectin.

  16. Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle During Adulthood

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    Fiona B Mcdonald

    2016-03-01

    Full Text Available Intermittent hypoxia is a feature of apnea of prematurity, chronic lung disease and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH during postnatal development (pCIH causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 hours of delivery, pups and their respective dams were exposed to CIH: 90s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 hrs per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH, where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

  17. Early life exposure to chronic intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during adulthood.

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    McDonald, Fiona B

    2016-03-01

    Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and\\/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

  18. Impairment of cognitive function and reduced hippocampal cholinergic activity in a rat model of chronic intermittent hypoxia

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    Chunling Zhao; Yan Chen; Chunlai Zhang; Linya Lü; Qian Xu

    2011-01-01

    The present study established a rat model of chronic intermittent hypoxia (CIH) to simulate obstructive sleep apnea syndrome. CIH rats were evaluated for cognitive function using the Morris water maze, and neuronal pathology in the hippocampus was observed using hematoxylin-eosin staining. In addition, hippocampal choline acetyl transferase (ChAT) and nicotinic acetylcholine receptor (nAChR) expression was determined by immunohistochemistry. Our results revealed necrotic hippocampal neurons, decreased ChAT and nAChR expression, as well as cognitive impairment in CIH rats. These results suggest that hippocampal neuronal necrosis and decreased cholinergic activity may be involved in CIH-induced cognitive impairment in rats.

  19. Melatonin reduces microvascular damage and insulin resistance in hamsters due to chronic intermittent hypoxia.

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    Bertuglia, Silvia; Reiter, Russel J

    2009-04-01

    Obstructive sleep apnea (OSA) causes intermittent hypoxia (IH) associated with hypertension, insulin resistance and a systemic inflammatory response. We evaluated the effects of melatonin on vasodilation, capillary perfusion in hamster cheek pouch and insulin resistance, hypertension, and reactive oxygen species (ROS) and nitrate/nitrite levels after IH for 4 wk. Syrian hamsters were divided into four groups: control group (CON), IH group, and melatonin (10 mg/kg) intraperitoneally administered daily for 4 wk/30 min before intermittent air (MEL) or IH (IH + MEL) exposure. IH alone caused elevated blood pressure, increased hematocrit, fasting hyperglycemia, elevated ROS and nitrite/nitrate levels, and vasoconstriction and reduced microvascular perfusion. Melatonin treatment of IH-exposed animals decreased blood pressure, blood glucose, and ROS and nitrite/nitrate levels, and increased vasodilation and capillary perfusion. An oral glucose tolerance test was performed after 4 wk of IH. During the last 30 min of the hyperinsulinemic euglycemic clamp, blood glucose, and insulin levels were identically matched between groups, but the glucose infusion rate was significantly reduced in IH (29.9 +/- 1.9 mg/kg/min) versus IH + MEL group (45.4 +/- 1.5 mg/kg/min, P melatonin. In conclusion, protection induced by melatonin against functional and metabolic impairment in IH is related to the regulation of ROS and nitrite/nitrate levels in the microcirculation. These observations may have importance to OSA pathological changes.

  20. Validation of housekeeping genes in the brains of rats submitted to chronic intermittent hypoxia, a sleep apnea model.

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    Julian, Guilherme Silva; de Oliveira, Renato Watanabe; Perry, Juliana Cini; Tufik, Sergio; Chagas, Jair Ribeiro

    2014-01-01

    Obstructive sleep apnea (OSA) is a syndrome characterized by intermittent nocturnal hypoxia, sleep fragmentation, hypercapnia and respiratory effort, and it has been associated with several complications, such as diabetes, hypertension and obesity. Quantitative real-time PCR has been performed in previous OSA-related studies; however, these studies were not validated using proper reference genes. We have examined the effects of chronic intermittent hypoxia (CIH), which is an experimental model mainly of cardiovascular consequences of OSA, on reference genes, including beta-actin, beta-2-microglobulin, glyceraldehyde-3-phosphate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase and eukaryotic 18S rRNA, in different areas of the brain. All stability analyses were performed using the geNorm, Normfinder and BestKeeper software programs. With exception of the 18S rRNA, all of the evaluated genes were shown to be stable following CIH exposure. However, gene stability rankings were dependent on the area of the brain that was analyzed and varied according to the software that was used. This study demonstrated that CIH affects various brain structures differently. With the exception of the 18S rRNA, all of the tested genes are suitable for use as housekeeping genes in expression analyses.

  1. Validation of housekeeping genes in the brains of rats submitted to chronic intermittent hypoxia, a sleep apnea model.

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    Guilherme Silva Julian

    Full Text Available Obstructive sleep apnea (OSA is a syndrome characterized by intermittent nocturnal hypoxia, sleep fragmentation, hypercapnia and respiratory effort, and it has been associated with several complications, such as diabetes, hypertension and obesity. Quantitative real-time PCR has been performed in previous OSA-related studies; however, these studies were not validated using proper reference genes. We have examined the effects of chronic intermittent hypoxia (CIH, which is an experimental model mainly of cardiovascular consequences of OSA, on reference genes, including beta-actin, beta-2-microglobulin, glyceraldehyde-3-phosphate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase and eukaryotic 18S rRNA, in different areas of the brain. All stability analyses were performed using the geNorm, Normfinder and BestKeeper software programs. With exception of the 18S rRNA, all of the evaluated genes were shown to be stable following CIH exposure. However, gene stability rankings were dependent on the area of the brain that was analyzed and varied according to the software that was used. This study demonstrated that CIH affects various brain structures differently. With the exception of the 18S rRNA, all of the tested genes are suitable for use as housekeeping genes in expression analyses.

  2. Validation of Housekeeping Genes in the Brains of Rats Submitted to Chronic Intermittent Hypoxia, a Sleep Apnea Model

    Science.gov (United States)

    Julian, Guilherme Silva; de Oliveira, Renato Watanabe; Perry, Juliana Cini; Tufik, Sergio; Chagas, Jair Ribeiro

    2014-01-01

    Obstructive sleep apnea (OSA) is a syndrome characterized by intermittent nocturnal hypoxia, sleep fragmentation, hypercapnia and respiratory effort, and it has been associated with several complications, such as diabetes, hypertension and obesity. Quantitative real-time PCR has been performed in previous OSA-related studies; however, these studies were not validated using proper reference genes. We have examined the effects of chronic intermittent hypoxia (CIH), which is an experimental model mainly of cardiovascular consequences of OSA, on reference genes, including beta-actin, beta-2-microglobulin, glyceraldehyde-3-phosphate dehydrogenase, hypoxanthine guanine phosphoribosyl transferase and eukaryotic 18S rRNA, in different areas of the brain. All stability analyses were performed using the geNorm, Normfinder and BestKeeper software programs. With exception of the 18S rRNA, all of the evaluated genes were shown to be stable following CIH exposure. However, gene stability rankings were dependent on the area of the brain that was analyzed and varied according to the software that was used. This study demonstrated that CIH affects various brain structures differently. With the exception of the 18S rRNA, all of the tested genes are suitable for use as housekeeping genes in expression analyses. PMID:25289636

  3. High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation

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    Pauly, Marion; Assense, Allan; Rondon, Aurélie; Thomas, Amandine; Dubouchaud, Hervé; Freyssenet, Damien; Benoit, Henri; Castells, Josiane; Flore, Patrice

    2017-01-01

    Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21–5% FiO2, 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy. PMID:28255159

  4. Effects of Gestational and Postnatal Exposure to Chronic Intermittent Hypoxia on Diaphragm Muscle Contractile Function in the Rat

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    McDonald, Fiona B.; Dempsey, Eugene M.; O'Halloran, Ken D.

    2016-01-01

    Alterations to the supply of oxygen during early life presents a profound stressor to physiological systems with aberrant remodeling that is often long-lasting. Chronic intermittent hypoxia (CIH) is a feature of apnea of prematurity, chronic lung disease, and sleep apnea. CIH affects respiratory control but there is a dearth of information concerning the effects of CIH on respiratory muscles, including the diaphragm—the major pump muscle of breathing. We investigated the effects of exposure to gestational CIH (gCIH) and postnatal CIH (pCIH) on diaphragm muscle function in male and female rats. CIH consisted of exposure in environmental chambers to 90 s of hypoxia reaching 5% O2 at nadir, once every 5 min, 8 h a day. Exposure to gCIH started within 24 h of identification of a copulation plug and continued until day 20 of gestation; animals were studied on postnatal day 22 or 42. For pCIH, pups were born in normoxia and within 24 h of delivery were exposed with dams to CIH for 3 weeks; animals were studied on postnatal day 22 or 42. Sham groups were exposed to normoxia in parallel. Following gas exposures, diaphragm muscle contractile, and endurance properties were examined ex vivo. Neither gCIH nor pCIH exposure had effects on diaphragm muscle force-generating capacity or endurance in either sex. Similarly, early life exposure to CIH did not affect muscle tolerance of severe hypoxic stress determined ex vivo. The findings contrast with our recent observation of upper airway dilator muscle weakness following exposure to pCIH. Thus, the present study suggests a relative resilience to hypoxic stress in diaphragm muscle. Co-ordinated activity of thoracic pump and upper airway dilator muscles is required for optimal control of upper airway caliber. A mismatch in the force-generating capacity of the complementary muscle groups could have adverse consequences for the control of airway patency and respiratory homeostasis. PMID:27462274

  5. Cardiac Response to Chronic Intermittent Hypoxia with a Transition from Adaptation to Maladaptation: The Role of Hydrogen Peroxide

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    Xia Yin

    2012-01-01

    Full Text Available Obstructive sleep apnea (OSA is a highly prevalent respiratory disorder of sleep, and associated with chronic intermittent hypoxia (CIH. Experimental evidence indicates that CIH is a unique physiological state with potentially “adaptive” and “maladaptive” consequences for cardio-respiratory homeostasis. CIH is also a critical element accounting for most of cardiovascular complications of OSA. Cardiac response to CIH is time-dependent, showing a transition from cardiac compensative (such as hypertrophy to decompensating changes (such as failure. CIH-provoked mild and transient oxidative stress can induce adaptation, but severe and persistent oxidative stress may provoke maladaptation. Hydrogen peroxide as one of major reactive oxygen species plays an important role in the transition of adaptive to maladaptive response to OSA-associated CIH. This may account for the fact that although oxidative stress has been recognized as a driver of cardiac disease progression, clinical interventions with antioxidants have had little or no impact on heart disease and progression. Here we focus on the role of hydrogen peroxide in CIH and OSA, trying to outline the potential of antioxidative therapy in preventing CIH-induced cardiac damage.

  6. Mice Exposed to Chronic Intermittent Hypoxia Simulate Clinical Features of Deficiency of both Qi and Yin Syndrome in Traditional Chinese Medicine

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    Chengzhi Chai

    2011-01-01

    Full Text Available Deficiency of both Qi and Yin Syndrome (DQYS is one of the common syndromes in traditional Chinese medicine (TCM, mainly characterized by tiredness, emaciation, anorexia, fidget, palpitation and rapid pulse, and so forth. Currently, there is no available animal model which can reflect the clinical features of this syndrome. In the present paper, we observed the time-course changes of whole behavior, body weight, food intake, locomotive activity and electrocardiogram in mice exposed to chronic intermittent hypoxia for 6 weeks, and measured bleeding time at last according to the clinical features of DQYS and one key pathological factor. The results showed that the mice exposed to intermittent hypoxia for certain time presented lackluster hair, dull looking hair, resistance, attacking, body weight loss, food intake decline, locomotive activity decrease, heart rate quickening and T wave elevating, which were similar to the major clinical features of DQYS. Meanwhile, bleeding time shortening was also found, which was consistent with the clinical fact that DQYS often accompanied with blood stasis. The possible explanation was also outlined according to the available literature. Such findings suggested chronic intermittent hypoxia could induce similar symptoms and signs in mice accorded with the clinical features of DQYS, which provided a suitable animal model for evaluation of drugs for the treatment of this syndrome and further exploration of pathological process or correlation of the syndrome and related diseases.

  7. Mice Exposed to Chronic Intermittent Hypoxia Simulate Clinical Features of Deficiency of both Qi and Yin Syndrome in Traditional Chinese Medicine.

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    Chai, Chengzhi; Kou, Junping; Zhu, Danni; Yan, Yongqing; Yu, Boyang

    2011-01-01

    Deficiency of both Qi and Yin Syndrome (DQYS) is one of the common syndromes in traditional Chinese medicine (TCM), mainly characterized by tiredness, emaciation, anorexia, fidget, palpitation and rapid pulse, and so forth. Currently, there is no available animal model which can reflect the clinical features of this syndrome. In the present paper, we observed the time-course changes of whole behavior, body weight, food intake, locomotive activity and electrocardiogram in mice exposed to chronic intermittent hypoxia for 6 weeks, and measured bleeding time at last according to the clinical features of DQYS and one key pathological factor. The results showed that the mice exposed to intermittent hypoxia for certain time presented lackluster hair, dull looking hair, resistance, attacking, body weight loss, food intake decline, locomotive activity decrease, heart rate quickening and T wave elevating, which were similar to the major clinical features of DQYS. Meanwhile, bleeding time shortening was also found, which was consistent with the clinical fact that DQYS often accompanied with blood stasis. The possible explanation was also outlined according to the available literature. Such findings suggested chronic intermittent hypoxia could induce similar symptoms and signs in mice accorded with the clinical features of DQYS, which provided a suitable animal model for evaluation of drugs for the treatment of this syndrome and further exploration of pathological process or correlation of the syndrome and related diseases.

  8. Chronic intermittent hypoxia from pedo-stage decreases glucose transporter 4 expression in adipose tissue and causes insulin resistance

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    CHEN Lin; CAO Zhao-long; HAN Fang; GAO Zhan-cheng; HE Quan-ying

    2010-01-01

    Background The persistence of sleep disordered breathing (SDB) symptoms after tonsil and/or adenoid (T&A) surgery are common in children with obstructive sleep apnea (OSA). We tested the hypothesis that disturbances of glucose transporters (GLUTs) in intraabdominal adipose tissue caused by chronic intermittent hypoxia (CIH) from the pedo-period could facilitate the appearance of periphery insulin resistance in Sprague-Dawley (SD) rats. We tested the hypothesis that the changes of GLUTs in adipose tissue may be one of the reasons for persistent SDB among clinical OSA children after T&A surgery.Methods Thirty 21-day-old SD rats were randomly divided into a CIH group, a chronic continuous hypoxia (CCH) group, and a normal oxygen group (control group) and exposed for 40 days. The changes of weight, fasting blood glucose and fasting blood insulin levels were measured. Hyperinsulinemic-euglycemic clamp techniques were used to measure insulin resistance in each animal. Real-time quantitative PCR and Westem blotting were used to measure GLUT Mrna and proteins in intraabdominal adipose tissue. Additional intraabdomial white adipose tissue (WAT) was also processed into paraffin sections and directly observed for GLUTs1-4 expression.Results When compared with control group, CIH increased blood fasting insulin levels, (245.07±53.89) pg/ml vs. (168.63±38.70) pg/ml, p=0.038, and decreased the mean glucose infusion rate (GIR), (7.25±1.29) mg·kg~(-1)·min~(-1) vs. (13.34±1.54) mg·kg~(-1)·min~(-1), P<0.001. GLUT-4 Mrna and protein expression was significantly reduced after CIH compared with CCH or normal oxygen rats, 0.002±0.002 vs. 0.039±0.009, P <0.001; 0.642±0.073 vs. 1.000±0.103, P=0.035.Conclusions CIH in young rats could induce insulin resistance via adverse effects on glycometabolism. These findings emphasize the importance of early detection and treatment of insulin insensitivity in obese childhood OSA.

  9. Analysis of the stability of housekeeping gene expression in the left cardiac ventricle of rats submitted to chronic intermittent hypoxia.

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    Julian, Guilherme Silva; Oliveira, Renato Watanabe de; Tufik, Sergio; Chagas, Jair Ribeiro

    2016-01-01

    Obstructive sleep apnea (OSA) has been associated with oxidative stress and various cardiovascular consequences, such as increased cardiovascular disease risk. Quantitative real-time PCR is frequently employed to assess changes in gene expression in experimental models. In this study, we analyzed the effects of chronic intermittent hypoxia (an experimental model of OSA) on housekeeping gene expression in the left cardiac ventricle of rats. Analyses via four different approaches-use of the geNorm, BestKeeper, and NormFinder algorithms; and 2-ΔCt (threshold cycle) data analysis-produced similar results: all genes were found to be suitable for use, glyceraldehyde-3-phosphate dehydrogenase and 18S being classified as the most and the least stable, respectively. The use of more than one housekeeping gene is strongly advised. RESUMO A apneia obstrutiva do sono (AOS) tem sido associada ao estresse oxidativo e a várias consequências cardiovasculares, tais como risco aumentado de doença cardiovascular. A PCR quantitativa em tempo real é frequentemente empregada para avaliar alterações na expressão gênica em modelos experimentais. Neste estudo, analisamos os efeitos da hipóxia intermitente crônica (um modelo experimental de AOS) na expressão de genes de referência no ventrículo cardíaco esquerdo de ratos. Análises a partir de quatro abordagens - uso dos algoritmos geNorm, BestKeeper e NormFinder e análise de dados 2-ΔCt (ciclo limiar) - produziram resultados semelhantes: todos os genes mostraram-se adequados para uso, sendo que gliceraldeído-3-fosfato desidrogenase e 18S foram classificados como o mais e o menos estável, respectivamente. A utilização de mais de um gene de referência é altamente recomendada.

  10. Chronic intermittent hypoxia depresses afferent neurotransmission in NTS neurons by a reduction in the number of active synapses.

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    Almado, Carlos Eduardo L; Machado, Benedito H; Leão, Ricardo M

    2012-11-21

    Long-term synaptic plasticity has been recently described in brainstem areas associated to visceral afferent sensory integration. Chronic intermittent hypoxia (CIH), an animal model for studying obstructive sleep apnea in humans, depresses the afferent neurotransmission in nucleus tractus solitarii (NTS) neurons, which affect respiratory and autonomic regulation. Here we identified the synaptic mechanisms of CIH-induced depression of the afferent neurotransmission in NTS neurons in juvenile rats. We verified that CIH reduced the amplitude of both NMDA and non-NMDA glutamatergic excitatory currents (eEPSCs) evoked by tractus solitarii stimulation (TS-eEPSC) of second-order neurons in the NTS. No changes were observed in release probability, evidenced by absence of any CIH-elicited effects on short-term depression and failures in EPSCs evoked in low calcium. CIH also produced no changes in TS-eEPSC quantal size, since the amplitudes of both low calcium-evoked EPSCs and asynchronous TS-eEPSCs (evoked in the presence of Sr(2+)) were unchanged. Using single TS afferent fiber stimulation in slices from control and CIH rats we clearly show that CIH reduced the quantal content of the TS-eEPSCs without affecting the quantal size or release probability, suggesting a reduction in the number of active synapses as the mechanism of CIH induced TS-eEPSC depression. In accordance with this concept, the input-output relationship of stimulus intensity and TS-eEPSC amplitude shows an early saturation in CIH animals. These findings open new perspectives for a better understanding of the mechanisms underlying the synaptic plasticity in the brainstem sensory neurons under challenges such as those produced by CIH in experimental and pathological conditions.

  11. Intermittent hypoxia can aggravate motor neuronal loss and cognitive dysfunction in ALS mice.

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    Sung-Min Kim

    Full Text Available BACKGROUND: Patients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained can affect the loss of motor neurons or cognitive function in an in vivo model of ALS. OBJECTIVE: To evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice. METHODS: Sixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation. RESULTS: Compared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation. CONCLUSIONS: Chronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in

  12. Adiponectin protects rat myocardium against chronic intermittent hypoxia-induced injury via inhibition of endoplasmic reticulum stress.

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    Wenxiao Ding

    Full Text Available Obstructive sleep apnea syndrome (OSAS is associated with many cardiovascular disorders such as heart failure, hypertension, atherosclerosis, and arrhythmia and so on. Of the many associated factors, chronic intermittent hypoxia (CIH in particular is the primary player in OSAS. To assess the effects of CIH on cardiac function secondary to OSAS, we established a model to study the effects of CIH on Wistar rats. Specifically, we examined the possible underlying cellular mechanisms of hypoxic tissue damage and the possible protective role of adiponectin against hypoxic insults. In the first treatment group, rats were exposed to CIH conditions (nadir O2, 5-6% for 8 hours/day, for 5 weeks. Subsequent CIH-induced cardiac dysfunction was measured by echocardiograph. Compared with the normal control (NC group, rats in the CIH-exposed group experienced elevated levels of left ventricular end-systolic dimension and left ventricular end-systolic volume and depressed levels of left ventricular ejection fraction and left ventricular fractional shortening (p<0.05. However, when adiponectin (Ad was added in CIH + Ad group, we saw a rescue in the elevations of the aforementioned left ventricular function (p<0.05. To assess critical cardiac injury, we detected myocardial apoptosis by Terminal deoxynucleotidyl transfer-mediated dUTP nick end-labeling (TUNEL analysis. It was showed that the apoptosis percentage in CIH group (2.948% was significantly higher than that in NC group (0.4167% and CIH + Ad group (1.219% (p<0.05. Protein expressions of cleaved caspase-3, cleaved caspase-9, and cleaved-caspase-12 validated our TUNEL results (p<0.05. Mechanistically, our results demonstrated that the proteins expressed with endoplasmic reticulum stress and the expression of reactive oxygen species (ROS were significantly elevated under CIH conditions, whereas Ad supplementation partially decreased them. Overall, our results suggested that Ad augmentation could improve CIH

  13. Adiponectin protects the genioglossus of rats against chronic intermittent hypoxia-induced injury via inhibition of endoplasmic reticulum stress

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    ZHANG Xiao-feng; HUANG Han-peng; DING Wen-xiao; DING Ning; LU Gan; LIU Jian-nan; ZHANG Xi-long

    2013-01-01

    Background Obstructive sleep apnea hypopnea syndrome,characterized by chronic intermittent hypoxia (CIH),is closely correlated with genioglossus dysfunction.CIH has been identified to mediate mitochondrial damage in genioglossus.It has been reported that endoplasmic reticulum stress (ERS) could be induced by mitochondrial dysfunction.This study aimed to investigate the role of ERS in CIH-induced genioglossus injury,as well as the possible intervention effect of adiponectin (Ad) supplement in rats.Methods Forty-five male Wistar rats were randomly divided into three groups and submitted to room air (group A,n=15) as a control or CIH (groups B and C,n=15,respectively).Throughout the exposure period,intravenous Ad was given in group C; while intravenous normal saline was simultaneously given in groups A and B.After 35-day exposure,genioglossus samples were obtained from the pentobarbital-anaesthetized rats via surgical dissection,following blood sampling.Western blotting was applied to detect expressions of ERS signals and associated apoptotic pathways in genioglossus.Serum adiponectin levels were assessed via enzyme-linked immunosorbent assay (ELISA).Results Significant hypoadiponectinemia was revealed in group B only (P <0.05).Compared to those in groups A and C,expressions of markers involved in ERS,such as glucose regulated protein 78 (GRP78),p-PERK,phosphorylated eukaryotic initiation factor 2α (p-elF2α),phosphorylated inositol-requiring transmembrane kinase/endoribonuclease 1α (p-IRE1α),spliced X-Box binding protein 1 (XBP1s) and activating transcription factor 6 (ATF6),were significantly enhanced in group B (all P <0.01); while no significant difference was shown between groups A and C (all P >0.05).ERS-associated apoptotic pathways were remarkably activated in group B.The involved markers detected as the expression of CCAAT/enhancer binding protein homologous protein (CHOP),B-cell lymphoma/leukemia associatied X protein (BAX)and caspase-12 were

  14. Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure.

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    Saxena, Ashwini; Little, Joel T; Nedungadi, T Prashant; Cunningham, J Thomas

    2015-03-01

    Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P SCM-injected group exhibited a sustained increase in MAP (P SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/ΔFosB expression in forebrain autonomic nuclei associated with CIH.

  15. Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia

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    Mohammad Badran

    2016-01-01

    Full Text Available Objective. Obstructive sleep apnea (OSA, characterized by chronic intermittent hypoxia (CIH, is often present in diabetic (DB patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH. Methods. Adult male diabetic (BKS.Cg-Dock7m +/+ Leprdb/J (db/db mice (10 weeks old and their heterozygote littermates were subjected to CIH or intermittent air (IA for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic, IH (intermittent hypoxia nondiabetic, IADB (intermittent air diabetic, and IHDB (intermittent hypoxia diabetic groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6, and asymmetric dimethylarginine (ADMA were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE staining. Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group. Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.

  16. Intermittent hypoxia and isoniazid plus rifampicin affect hepatic ultrastructure in mice

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    WU Run-hua; ZENG Yi-ming; CHEN Xiao-yang

    2011-01-01

    Background Chronic intermittent hypoxia is the most important pathophysiologic feature of sleep apnea syndrome.The present study aimed to determine whether chronic intermittent hypoxia,which is associated with sleep apnea syndrome,can cause or increase damage to liver cell ultrastructure induced by isoniazid and rifampicin in mice.Methods Based on a 2x2 full factorial design consisting of two factors of chronic intermittent hypoxia and isoniazid plus rifampicin,32 male C57B6J mice were randomized into the control group,the chronic intermittent hypoxia group,the isoniazid plus rifampicin group,and the chronic intermittent hypoxia + isoniazid plus rifampicin group.Twelve weeks after treatment,we examined the ultrastructure of liver cells and quantitatively analyzed mitochondrial morphology in C57B6J mice.Results Chronic intermittent hypoxia did not significantly affect the ultrastructure of liver cells.The main effect of chronic intermittent hypoxia did not lead to an increase of mean profile area or mean perimeter of mitochondria,and a decrease of numerical density on area of mitochondria (all P >0.05).Isoniazid plus rifampicin significantly affected liver cell ultrastructure.The main effect of isoniazid plus rifampicin resulted in an increase of mean profile area and mean perimeter of mitochondria,and a decrease of numerical density on area of mitochondria (all P <0.05).Moreover,there was a positive interaction among the chronic intermittent hypoxia and the isoniazid plus rifampicin groups for mean profile area,mean perimeter,and numerical density on area of mitochondria (all P<0.05).Conclusion Chronic intermittent hypoxia and isoniazid plus rifampicin treatment lead to synergistic liver cell ultrastructural injury.

  17. Ang Ⅱ type 1 receptor expression in rat aorta exposed to chronic intermittent hypoxia: effects of p38MAPK and ERK1/2 signaling

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    SHANG Jin; YANG Yuan-yuan; GUO Xue-ling; LIU Hui-guo

    2013-01-01

    Background Obstructive sleep apnea is a frequent medical condition consisting of repetitive sleep-related episodes of upper air ways obstruction and can lead to hypertension.Ang Ⅱ type 1 receptor (AT1R) played important roles in hypertension since it binds with Ang Ⅱ,controlling salt-water and blood pressure homeostasis.This study explores rat aorta AT1R expression during intermittent hypoxia (IH) and the signaling pathways involved.Methods A rat model and a cell model used a BioSpherix-OxyCycler A84 system and a ProOx C21 system respectively.The arterial blood pressure was recorded by a Nihon Kohden Polygraph System.Immunohistochemic was used to focus and analyze the expression of AT1R in rat aorta.Real-time PCR and Western blotting were used to explore the signaling pathways that participated in AT1R expression.Results In this study,we found that chronic intermittent hypoxia (CIH) induced AT1R transcription which increased the blood pressure in rat aorta compared to normoxia and to sustained hypoxia.The AT1R protein expression in the aorta was similar to the real-time PCR results.We explored the signaling mechanisms involved in the AT1R induction in both rat aorta and the aortic endothelial cells by real-time PCR and Western blotting.Compared to normoxia,CIH increased ERK1 mRNA transcription but not ERK2 or p38MAPK in the aorta; whereas sustained hypoxia (SH) upregulated ERK2 but not ERK1 or p38MAPK mRNA.In cells,IH induced AT1R expression with ERK1/2 phosphorylation but reduced p38MAPKs phosphorylation,whereas SH induced only ERK1/2 phosphorylation.The ERK1/2 inhibitor PD98059 attenuated the IHinduced AT1R increase but the p38MAPK inhibitor SB203580 did not.Conclusions Our results indicate that CIH induced the elevation of rat blood pressure and aorta AT1R expression.Moreover,AT1R expression in IH and sustained hypoxia might be regulated by different signal transduction pathways,highlighting a novel regulatory function through ERK1/2 signaling in IH.

  18. CaV3.2 T-type Ca2+ channels mediate the augmented calcium influx in carotid body glomus cells by chronic intermittent hypoxia.

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    Makarenko, Vladislav V; Ahmmed, Gias U; Peng, Ying-Jie; Khan, Shakil A; Nanduri, Jayasri; Kumar, Ganesh K; Fox, Aaron P; Prabhakar, Nanduri R

    2016-01-01

    Chronic intermittent hypoxia (CIH) is a hallmark manifestation of sleep apnea. A heightened carotid body activity and the resulting chemosensory reflex mediate increased sympathetic nerve activity by CIH. However, the mechanisms underlying heightened carotid body activity by CIH are not known. An elevation of intracellular calcium ion concentration ([Ca(2+)]i) in glomus cells, the primary oxygen-sensing cells, is an essential step for carotid body activation by hypoxia. In the present study, we examined the effects of CIH on the glomus cell [Ca(2+)]i response to hypoxia and assessed the underlying mechanisms. Glomus cells were harvested from adult rats or wild-type mice treated with 10 days of either room air (control) or CIH (alternating cycles of 15 s of hypoxia and 5 min of room air; 9 episodes/h; 8 h/day). CIH-treated glomus cells exhibited an enhanced [Ca(2+)]i response to hypoxia, and this effect was absent in the presence of 2-(4-cyclopropylphenyl)-N-((1R)-1-[5-[(2,2,2-trifluoroethyl)oxo]-pyridin-2-yl]ethyl)acetamide (TTA-A2), a specific inhibitor of T-type Ca(2+) channels, and in voltage-gated calcium channel, type 3.2 (CaV3.2), null glomus cells. CaV3.2 knockout mice exhibited an absence of CIH-induced hypersensitivity of the carotid body. CIH increased reactive oxygen species (ROS) levels in glomus cells. A ROS scavenger prevented the exaggerated TTA-A2-sensitive [Ca(2+)]i response to hypoxia. CIH had no effect on CaV3.2 mRNA levels. CIH augmented Ca(2+) currents and increased CaV3.2 protein in plasma membrane fractions of human embryonic kidney-293 cells stably expressing CaV3.2, and either a ROS scavenger or brefeldin-A, an inhibitor of protein trafficking, prevented these effects. These findings suggest that CIH leads to an augmented Ca(2+) influx via ROS-dependent facilitation of CaV3.2 protein trafficking to the plasma membrane.

  19. Angiotensin-(1-7 relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis

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    W. Lu

    Full Text Available We aimed to study the renal injury and hypertension induced by chronic intermittent hypoxia (CIH and the protective effects mediated by angiotensin 1-7 [Ang(1-7]. We randomly assigned 32 male Sprague-Dawley rats (body weight 180-200 g to normoxia control, CIH, Ang(1-7-treated normoxia, and Ang(1-7-treated CIH groups. Systolic blood pressure (SBP was monitored at the start and end of each week. Renal sympathetic nerve activity (RSNA was recorded. CTGF and TGF-β were detected by immunohistochemistry and western blotting. Tissue parameters of oxidative stress were also determined. In addition, renal levels of interleukin-6, tumor necrosis factor-α, nitrotyrosine, and hypoxia-inducible factor-1α were determined by immunohistochemistry, immunoblotting, and ELISA. TUNEL assay results and cleaved caspase 3 and 12 were also determined. Ang(1-7 induced a reduction in SBP together with a restoration of RSNA in the rat model of CIH. Ang(1-7 treatment also suppressed the production of reactive oxygen species, reduced renal tissue inflammation, ameliorated mesangial expansion, and decreased renal fibrosis. Thus, Ang(1-7 treatment exerted renoprotective effects on CIH-induced renal injury and was associated with a reduction of oxidative stress, inflammation and fibrosis. Ang(1-7 might therefore represent a promising therapy for obstructive sleep apnea-related hypertension and renal injury.

  20. Immunoreactivity for neuronal NOS and fluorescent indication of NO formation in the NTS of juvenile rats submitted to chronic intermittent hypoxia.

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    Pajolla, Gisela P; Accorsi-Mendonça, Daniela; Lunardi, Claure N; Bendhack, Lusiane M; Machado, Benedito H; Llewellyn-Smith, Ida J

    2009-06-15

    Exposure to chronic intermittent hypoxia (CIH) leads to significant autonomic and respiratory changes, similar to those observed in obstructive sleep apnea. The hypertension associated with CIH is due to sympathoexcitation triggered by long-term exposure to intermittent hypoxia. However, the mechanisms underlying these effects are unknown. Changes in central regulation of sympathetic activity may underlie CIH-induced hypertension. Since NO appears to be mainly sympathoinhibitory in the nucleus of the solitary tract (NTS), we hypothesized that CIH augments sympathetic activity, in part by reducing neuronal nitric oxide synthase (nNOS) expression and consequently nitric oxide (NO) production in this brain region. To test our hypothesis, juvenile male Wistar rats were exposed to CIH for 8 h/day for 10 days and sections of perfused brainstem were either stained to reveal nNOS-immunoreactivity or loaded with DAF 2-DA to label neurons containing NO. CIH rats showed a significant increase in mean arterial pressure and heart rate compared to controls. However, there was no significant difference in the distribution, staining intensity or numbers of nNOS-immunoreactive neurons in the NTS between experimental and control rats. We also found no significant change in NO content in the DAF 2-DA-loaded sections of NTS from CIH rats. Our data show that NO is not altered in the NTS of juvenile CIH rats, suggesting that nitrergic mechanisms, at least in the NTS, are unlikely to be involved in the sympathetic excitation that generates the hypertension observed after 10 days of CIH.

  1. Soluble Receptor for Advanced Glycation End Product Ameliorates Chronic Intermittent Hypoxia Induced Renal Injury, Inflammation, and Apoptosis via P38/JNK Signaling Pathways

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    Xu Wu

    2016-01-01

    Full Text Available Obstructive sleep apnea (OSA associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH triggered tissue damage. Receptor for advanced glycation end product (RAGE and its ligand high mobility group box 1 (HMGB1 are expressed on renal cells and mediate inflammatory responses in OSA-related diseases. To determine their roles in CIH-induced renal injury, soluble RAGE (sRAGE, the RAGE neutralizing antibody, was intravenously administered in a CIH model. We also evaluated the effect of sRAGE on inflammation and apoptosis. Rats were divided into four groups: (1 normal air (NA, (2 CIH, (3 CIH+sRAGE, and (4 NA+sRAGE. Our results showed that CIH accelerated renal histological injury and upregulated RAGE-HMGB1 levels involving inflammatory (NF-κB, TNF-α, and IL-6, apoptotic (Bcl-2/Bax, and mitogen-activated protein kinases (phosphorylation of P38, ERK, and JNK signal transduction pathways, which were abolished by sRAGE but p-ERK. Furthermore, sRAGE ameliorated renal dysfunction by attenuating tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL. These findings suggested that RAGE-HMGB1 activated chronic inflammatory transduction cascades that contributed to the pathogenesis of the CIH-induced renal injury. Inhibition of RAGE ligand interaction by sRAGE provided a therapeutic potential for CIH-induced renal injury, inflammation, and apoptosis through P38 and JNK pathways.

  2. Effect of chronic intermittent hypoxia on the expression of Nip3, cell apoptosis, β-amyloid protein deposit in mice brain cortex

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    ZENG Yi-ming; CAI Kai-jin; CHEN Xiao-yong; WU Minx-ia; LIN Xi

    2009-01-01

    Background Chronic intermittent hypoxia (CIH) is the most important pathophysiologic feature of sleep apnea syndrome (SAS). To explore the relationship between SAS and dementia, the effects of CIH on the expression of Nip3, neuron apoptosis andβ-amyloid protein deposit in the brain cortex of the frontal lobe of mice were evaluated in this study. Methods Thirty male ICR mice were divided into four groups: control group (A, n=-10, sham hypoxia/reoxygenation), 2 weeks CIH group (B, n=-5), 4 weeks CIH group (C, n=-5), and 8 weeks CIH group (D, n=10). The ICR mice were placed in a chamber and exposed to intermittent hypoxia (oxygen concentration changed periodically from (21.72±0.55)% to (6.84±0.47)% every two minutes, eight hours per day). Neuron apoptosis of the cortex of the frontal lobe was detected by means of terminal deoxy-nucleotidyl transferase-mediated in situ end labeling (TUNEL). Immunohistochemical staining was performed for measuring expression of Nip3 and β-amyloid protein. The ultrastructure of neurons was observed under a transmission electron microscope. Results TUNEL positive neurons in each square millimeter in the cortex of the frontal lobe were categorized by median or Ri into group A (1,5.5), group B (133, 13), group C (252, 21), and group D (318, 24). There were significant differences among the above four groups (P=0.000). The significance test was performed between the control group and each CIH group respectively: group A and B (P>0.05); group A and C (P 0.05); groups A and C (P<0.005); and groups A and D (P<0.005). There was no significant difference between groups B and C, groups B and D, and groups C and D. The expression of Nip3 was closely correlated with neuron apoptosis in the brain (P <0.05). The expression ofβ-amyloid protein in the brain of mice was negative in all CIH groups and the control group. Ultrastructure observation showed karyopyknosis of nucleus, swelling of chondriosomes, deposit of lipofuscins and degeneration of

  3. Efficacy of lovastatin on learning and memory deficits caused by chronic intermittent hypoxia-hypercapnia: through regulation of NR2B-containing NMDA receptor-ERK pathway.

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    Xin-long Huo

    Full Text Available BACKGROUND: Chronic intermittent hypoxia-hypercapnia (CIHH exposure leads to learnning and memory deficits in rats. Overactivation of N-methyl-D-aspartate receptors(NMDARs can lead to the death of neurons through a process termed excitotoxicity, which is involved in CIHH-induced cognitive deficits. Excessively activated NR2B (GluN2B-containing NMDARs was reported as the main cause of excitotoxicity. The ERK1/2 (extracellular signal-regulated kinase 1/2 signaling cascade acts as a key component in NMDARs-dependent neuronal plasticity and survival. Ca2+/calmodulin-dependent protein kinase II (CaMKII, synapse-associated protein 102 (SAP102 and Ras GTPase-activating protein (SynGAP have been shown to be involved in the regulation of NMDAR-ERK signalling cascade. Recent studies revealed statins (the HMG-CoA reductase inhibitor have effect on the expression of NMDARs. The present study intends to explore the potential effect of lovastatin on CIHH-induced cognitive deficits and the NR2B-ERK signaling pathway. METHODS AND FINDINGS: Eighty male Sprague Dawley rats were randomly divided into five groups. Except for those in the control group, the rats were exposed to chronic intermittent hypoxia-hypercapnia (CIHH (9 ∼ 11%O2, 5.5 ∼ 6.5%CO2 for 4 weeks. After lovastatin administration, the rats performed better in the Morris water maze test. Electron microscopy showed alleviated hippocampal neuronal synaptic damage. Further observation suggested that either lovastatin or ifenprodil (a selective NR2B antagonist administration similarly downregulated NR2B subunit expression leading to a suppression of CaMKII/SAP102/SynGAP signaling cascade, which in turn enhanced the phosphorylation of ERK1/2. The phosphorylated ERK1/2 induced signaling cascade involving cAMP-response element-binding protein (CREB phosphorylation and brain-derived neurotrophic factor (BDNF activation, which is responsible for neuroprotection. CONCLUSIONS: These findings suggest that the

  4. Chronic intermittent hypoxia increases encoding pigment epithelium-derived factor gene expression, although not that of the protein itself, in the temporal cortex of rats,

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    Guilherme Silva Julian

    2015-02-01

    Full Text Available Objective: Obstructive sleep apnea syndrome is mainly characterized by intermittent hypoxia (IH during sleep, being associated with several complications. Exposure to IH is the most widely used animal model of sleep apnea, short-term IH exposure resulting in cognitive and neuronal impairment. Pigment epithelium-derived factor (PEDF is a hypoxia-sensitive factor acting as a neurotrophic, neuroprotective, and antiangiogenic agent. Our study analyzed performance on learning and cognitive tasks, as well as PEDF gene expression and PEDF protein expression in specific brain structures, in rats exposed to long-term IH. Methods: Male Wistar rats were exposed to IH (oxygen concentrations of 21-5% for 6 weeks-the chronic IH (CIH group-or normoxia for 6 weeks-the control group. After CIH exposure, a group of rats were allowed to recover under normoxic conditions for 2 weeks (the CIH+N group. All rats underwent the Morris water maze test for learning and memory, PEDF gene expression and PEDF protein expression in the hippocampus, frontal cortex, and temporal cortex being subsequently assessed. Results: The CIH and CIH+N groups showed increased PEDF gene expression in the temporal cortex, PEDF protein expression remaining unaltered. PEDF gene expression and PEDF protein expression remained unaltered in the frontal cortex and hippocampus. Long-term exposure to IH did not affect cognitive function. Conclusions: Long-term exposure to IH selectively increases PEDF gene expression at the transcriptional level, although only in the temporal cortex. This increase is probably a protective mechanism against IH-induced injury.

  5. Acute inhibition of glial cells in the NTS does not affect respiratory and sympathetic activities in rats exposed to chronic intermittent hypoxia.

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    Costa, Kauê M; Moraes, Davi J A; Machado, Benedito H

    2013-02-16

    Recent studies suggest that neuron-glia interactions are involved in multiple aspects of neuronal activity regulation. In the nucleus tractus solitarius (NTS) neuron-glia interactions are thought to participate in the integration of autonomic responses to physiological challenges. However, it remains to be shown whether NTS glial cells might influence breathing and cardiovascular control, and also if they could be integral to the autonomic and respiratory responses to hypoxic challenges. Here, we investigated whether NTS glia play a tonic role in the modulation of central respiratory and sympathetic activities as well as in the changes in respiratory-sympathetic coupling induced by exposure to chronic intermittent hypoxia (CIH), a model of central autonomic and respiratory plasticity. We show that bilateral microinjections of fluorocitrate (FCt), a glial cell inhibitor, into the caudal and intermediate subnuclei of the NTS did not alter baseline respiratory and sympathetic parameters in in situ preparations of juvenile rats. Similar results were observed in rats previously exposed to CIH. Likewise, CIH-induced changes in respiratory-sympathetic coupling were unaffected by FCt-mediated inhibition. However, microinjection of FCt into the ventral medulla produced changes in respiratory frequency. Our results show that acute glial inhibition in the NTS does not affect baseline respiratory and sympathetic control. Additionally, we conclude that NTS glial cells may not be necessary for the continuous manifestation of sympathetic and respiratory adaptations to CIH. Our work provides evidence that neuron-glia interactions in the NTS do not participate in baseline respiratory and sympathetic control.

  6. Chronic intermittent hypobaric hypoxia protects the heart against ischemia/reperfusion injury through upregulation of antioxidant enzymes in adult guinea pigs

    Institute of Scientific and Technical Information of China (English)

    Hui-cai GUO; Zhe ZHANG; Li-nan ZHANG; Chen XIONG; Chen FENG; Qian LIU; Xu LIU; Xiao-lu SHI; Yong-li WANG

    2009-01-01

    Aim:To investigate the protection and the anti-oxidative mechanism afforded by chronic intermittent hypobaric hypoxia (CIHH) against ischemia/reperfusion (I/R) injury in guinea pig hearts.Methods:Adult male guinea pigs were exposed to CIHH by mimicking a 5000 m high altitude (pB=404 mmHg,p02=84 mmHg) in a hypobaric chamber for 6 h/day for 28 days.Langendorff-perfused isolated guinea pig hearts were used to measure variables of left ventricular function during baseline perfusion,ischemia and the reperfusion period.The activity and protein expression of antioxidant enzymes in the left myocardium were evaluated using biochemical methods and Western blotting.respectively.Intracellular reactive oxygen species (ROS) were assessed using ROS-sensitive fluorescence.Results:After 30 min of global no-flow ischemia followed by 60 min of reperfusion,myocardial function had better recovery rates in CIHH guinea pig hearts than in control hearts.The activity and protein expression of superoxide dismutase (SOD) and catalase (CAT) were significantly increased in the myocardium of CIHH guinea pigs.Pretreatment of control hearts with an antioxidant mixture containing SOD and CAT exerted cardioprotective effects similar to CIHH.The irreversible CAT inhibitor aminotriazole (ATZ) abolished the cardioprotection of CIHH.Cardiac contractile dysfunction and oxidative stress induced by exogenous hydrogen peroxide (H2O2) were attenuated by CIHH and CAT.Conclusions:These data suggest that CIHH protects the heart against I/R injury through upregulation of antioxidant enzymes in guinea pig.

  7. Chronic intermittent hypoxia increases β cell mass and activates the mammalian target of rapamycin/hypoxia inducible factor 1/vascular endothelial growth factor A pathway in mice pancreatic islet

    Institute of Scientific and Technical Information of China (English)

    GU Chen-juan; LI Min; LI Qing-yun; LI Ning

    2013-01-01

    Background Growing evidence from population and clinic based studies showed that obstructive sleep apnea (OSA) and its characterizing chronic intermittent hypoxia (IH) were independently associated with the development of type 2 diabetes mellitus.However,the pathogenesis by which OSA induces glucose metabolic disorders is not clear.We determined changes in pancreatic β cell mass and the mammalian target of rapamycin (mTOR)/hypoxia inducible factor 1 (HIF-1)/ vascular endothelial growth factor A (VEGF-A) pathway following IH exposure.Methods A controlled gas delivery system regulated the flow of nitrogen and oxygen into a customized cage housing mice during the experiment.Twenty-four male wild C57BL/6J mice were either exposed to IH (n=12) or intermittent air as a control (n=12) for 56 days.Mice were anaesthetized and sacrificed after exposure,pancreas samples were dissected for immunofluorescent staining.Insulin and DAPI staining labelled islet β cells.Insulin positive area and β cell number per islet were measured.P-S6,HIF-1α and VEGF-A staining were performed to detect the activation of mTOR/HIF-1NEGF-A pathway.Results After eight weeks of IH exposure,insulin positive area increased by an average of 18.5% (P <0.05).The β cell number per islet increased (92 vs.55,respectively for IH and the control groups,P <0.05) with no change in the size of individual β cells.Islet expression of HIF-1α and VEGF-A were higher in IH group than control group,and percentage of p-S6 positive β cell also increased after IH exposure (16.8% vs.4.6% respectively for IH and the control groups,P <0.05).Conclusion The number of pancreatic β cells increased as did the activity of the mTOR/HIF-1NEGF-A pathway after exposure to IH.

  8. Beneficial effects of intermittent hypobaric hypoxia on the body

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    Yi ZHANG; Zhao-nian ZHOU

    2012-01-01

    Myocardial ischemia and reperfusion (I/R) is a common problem in clinic and there is no satisfactory method for prevention or treatment of I/R injury so far.Chronic intermittent hypobaric hypoxia (CIHH),similar to the concept of ischemia preconditioning(IPC)or altitude hypoxia adaptation (AHA),has been recognized to confer a protective effect on heart against I/R injury with a longer protective effect than IPC and a less adverse effect than AHA.It has been proved that CIHH increases myocardial tolerance to ischemia or hypoxia,reserving cardiac function and preventing arrhythmia during I/R.Multiple mechanisms or pathway underlying the cardiac protection of ClHH have been proposed,such as induction of heatshock protein,enhancement of myocardial antioxidation capacity,increase of coronary flow and myocardial capillary angiogenesis,activation of adenosine triphosphate (ATP)-sensitive potassium channels,inhibition of mitochondrial permeability transition pores,and activation of protein kinase C (PKC) and induced nitric oxide synthase (iNOS).In addition,CIHH has been found having many beneficial effects on the body,such as promotion of health,increase of oxygen utilization,and prevention or treatment for some diseases.The beneficial effects of ClHH and potential mechanisms are reviewed mainly based on the researches performed by our group.

  9. 慢性间断性缺氧伴二氧化碳潴留小鼠模型的建立%A Mice Mode of Chronic Intermittent Hypoxia with Carbon Dioxide Retention

    Institute of Scientific and Technical Information of China (English)

    刘海林; 张子彦; 郭云云; 李景春; 宋永斌; 徐江涛

    2012-01-01

    目的 建立慢性间断性缺氧伴二氧化碳潴留(chronic intermittent hypoxia with carbon dioxide retention,CIH-CR)小鼠模型.方法 选取雄性昆明小鼠22只,随机分为常氧组(normal control group,NC)和CIH-CR组,每组11只.CIH-CR组小鼠每天CIH-CR处理8h,共4周,实验期间监测箱内O2和CO2浓度及小鼠尾部末端血氧饱和度( SO2).实验终点测定右室肥厚指数并观察心、肺、肾、脑组织病理改变.结果 CIH-CR组箱内O2浓度、CO2浓度和小鼠尾部末端SO2随实验仓的关闭和开启出现周期性的变化;与NC组相比CIH-CR组右心室明显肥大(P<0.01);小鼠心、肺、肾和脑组织均出现明显缺氧改变.结论 成功建立了CIH-CR小鼠模型.%Objective To establish a chronic intermittent hypoxia with carbon dioxide retention (CIH-CR)model in mice. Methods 22 male Kun Ming mice were divided into the normal control (NC) group and CIH-CR group. The mice of CIH-CR group suffered 8 hours intermittent hypoxia everyday for 4 weeks. The concentration of O2 and CO2 in the cabin was detected by oxygen analyzer and Carbon dioxide detector, meanwhile, the blood oxygen saturation were detected by blood oximeter. At the end of the experiment, weight of right and left ventricles was measured. The general pathological changes of myocardium, pulmonary, kidney and brain were observed by HE staining. Result The concentration of O2 and CO2 in the cabin and the SO2in the empennage of mouse accord with the cyclical change process. Compared with the NC group, the right ventricular hypertrophy were increased in the CIH-CR groups ( P < 0. 01 ). The tissue of myocardium, pulmonary, kidney and brain were showen obvious hypoxic change in CIH-CR group. Conclusion A CIH-CR animal model were be established successfully.

  10. 低压氧舱慢性间断性缺氧诱导大鼠膈神经长时程易化%Phrenic long-term facilitation induced by hypobaric chronic intermittent hypoxia in rats

    Institute of Scientific and Technical Information of China (English)

    陈阳; 刘津平; 魏晓燕; 赵彩红; 李柱一; 刘莹莹

    2011-01-01

    Objective: Long-term facilitation (LTF) is an important electrophysiological characteristic indicative of respiratory neuroplasticity, and is tightly related to sleep disorders. Phrenic LTF can be induced by acute intermittent hypoxia (AIH, 3-5 episodic hypoxia), whereas chronic intermittent hypoxia (CIH) lasting for over one week leads to a large enhanced phrenic LTF. CIH rat models is usually prepared with alternately 5 min of 10% O2 + 90% N2, and 5 min of normoxia for 12 h/d for at least 7 d, a process that needs large amount of mixed gases, and is expensive. We aimed to establish an enhanced phrenic LTF model in intact rats in precondition with hypobaric chronic episodic hypoxia. Methods: Adult Sprague-Dawley rats were housed in a chamber and maintained with alternately 5 min of hypobaric hypoxia and 5 min of normoxia for 12 h/d for 7 consecutive days. Hypobaric hypoxia was achieved by air evacuation to gradually reach a pressure of 210-220 mmHg, corresponding to an altitude of around 9000 m. On the eighth day, both CIH and control animals were treated with AIH, to induce phrenic LTF expression. The control animals received AIH challenge only. Alterations of phrenic LIF expressions between two groups were then statistically analysed. Results: Phrenic nerve activity was more sensitive in response to hypoxia in CIH rats than that in control, showing rapid increases in frequency and amplitude during hypoxic period. The integrated amplitudes at 30 min and 60 min after episodic hypoxia were ( 116.3 ±6.5 ) % and ( 106.1 ± 19.2) %, respectively, from baseline in CIH animals, which were significantly different from those (60.4 ± 7.8 ) % and (48.2 ± 11.0) % in control ( P < 0.01 ), indicating a much larger LTF induced by CIH, the enhanced phrenic LTF. Conclusion: We establish an enhanced phrenic LTF model induced by chronic intermittent hypobaric hypoxia in intact rats, which will provide a useful platform for understanding the mechanism of LTF

  11. Intermittent Hypoxia Impairs Endothelial Function in Early Preatherosclerosis.

    Science.gov (United States)

    Tuleta, I; França, C N; Wenzel, D; Fleischmann, B; Nickenig, G; Werner, N; Skowasch, D

    2015-01-01

    Intermittent hypoxia seems to be a major pathomechanism of obstructive sleep apnea-associated progression of atherosclerosis. The goal of the present study was to assess the influence of hypoxia on endothelial function depending on the initial stage of vasculopathy. We used 16 ApoE-/- mice were exposed to a 6-week-intermittent hypoxia either immediately (early preatherosclerosis) or after 5 weeks of high-cholesterol diet (advanced preatherosclerosis). Another 16 ApoE-/- mice under normoxia served as corresponding controls. Endothelial function was measured by an organ bath technique. Blood plasma CD31+/annexin V+ endothelial microparticles as well as sca1/flk1+ endothelial progenitor cells in blood and bone marrow were analyzed by flow cytometry. The findings were that intermittent hypoxia impaired endothelial function (56.6±6.2% of maximal phenylephrine-induced vasoconstriction vs. 35.2±4.1% in control) and integrity (increased percentage of endothelial microparticles: 0.28±0.05% vs. 0.15±0.02% in control) in early preatherosclerosis. Peripheral repair capacity expressed as the number of endothelial progenitor cells in blood was attenuated under hypoxia (2.0±0.5% vs. 5.3±1.9% in control), despite the elevated number of these cells in the bone marrow (2.0±0.4% vs. 1.1±0.2% in control). In contrast, endothelial function, as well as microparticle and endothelial progenitor cell levels were similar under hypoxia vs. control in advanced preatherosclerosis. We conclude that hypoxia aggravates endothelial dysfunction and destruction in early preatherosclerosis.

  12. Xanthine oxidase mediates hypoxia-inducible factor-2α degradation by intermittent hypoxia.

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    Jayasri Nanduri

    Full Text Available Sleep-disordered breathing with recurrent apnea produces chronic intermittent hypoxia (IH. We previously reported that IH leads to down-regulation of HIF-2α protein via a calpain-dependent signaling pathway resulting in oxidative stress. In the present study, we delineated the signaling pathways associated with calpain-dependent HIF-2α degradation in cell cultures and rats subjected to chronic IH. Reactive oxygen species (ROS scavengers prevented HIF-2α degradation by IH and ROS mimetic decreased HIF-2α protein levels in rat pheochromocytoma PC12 cell cultures, suggesting that ROS mediate IH-induced HIF-2α degradation. IH activated xanthine oxidase (XO by increased proteolytic conversion of xanthine dehydrogenase to XO. ROS generated by XO activated calpains, which contributed to HIF-2α degradation by IH. Calpain-induced HIF-2α degradation involves C-terminus but not the N-terminus of the HIF-2α protein. Pharmacological blockade as well as genetic knock down of XO prevented IH induced calpain activation and HIF-2α degradation in PC12 cells. Systemic administration of allopurinol to rats prevented IH-induced hypertension, oxidative stress and XO activation in adrenal medulla. These results demonstrate that ROS generated by XO activation mediates IH-induced HIF-2α degradation via activation of calpains.

  13. Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity.

    Science.gov (United States)

    Drager, Luciano F; Li, Jianguo; Reinke, Christian; Bevans-Fonti, Shannon; Jun, Jonathan C; Polotsky, Vsevolod Y

    2011-11-01

    Obesity causes insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), but the relative contribution of sleep apnea is debatable. The main aim of this study is to evaluate the effects of chronic intermittent hypoxia (CIH), a hallmark of sleep apnea, on IR and NAFLD in lean mice and mice with diet-induced obesity (DIO). Mice (C57BL/6J), 6-8 weeks of age were fed a high fat (n = 18) or regular (n = 16) diet for 12 weeks and then exposed to CIH or control conditions (room air) for 4 weeks. At the end of the exposure, fasting (5 h) blood glucose, insulin, homeostasis model assessment (HOMA) index, liver enzymes, and intraperitoneal glucose tolerance test (1 g/kg) were measured. In DIO mice, body weight remained stable during CIH and did not differ from control conditions. Lean mice under CIH were significantly lighter than control mice by day 28 (P = 0.002). Compared to lean mice, DIO mice had higher fasting levels of blood glucose, plasma insulin, the HOMA index, and had glucose intolerance and hepatic steatosis at baseline. In lean mice, CIH slightly increased HOMA index (from 1.79 ± 0.13 in control to 2.41 ± 0.26 in CIH; P = 0.05), whereas glucose tolerance was not affected. In contrast, in DIO mice, CIH doubled HOMA index (from 10.1 ± 2.1 in control to 22.5 ± 3.6 in CIH; P < 0.01), and induced severe glucose intolerance. In DIO mice, CIH induced NAFLD, inflammation, and oxidative stress, which was not observed in lean mice. In conclusion, CIH exacerbates IR and induces steatohepatitis in DIO mice, suggesting that CIH may account for metabolic dysfunction in obesity.

  14. Intermittent Hypoxia Elicits Prolonged Restoration of Motor Function in Human SCI

    Science.gov (United States)

    2011-10-01

    performed in rats with/without cervical injuries : 1) shelf controls; 2) sham; 3) daily treadmill training for five days; 4) intermittent hypoxia for...combining our results with parallel behavioral studies. 15. SUBJECT TERMS Spinal Injury , Treatment , Intermittent hypoxia, humans, rats, BDNF 16...the translational partnership award is to assess changes in ventral spinal protein expression in rats with cervical spinal injuries following

  15. The role of Foxp3+T cells in chronic intermittent hypoxia induced liver injury%Foxp3+Tregs在慢性间歇低氧所致肝损伤中的作用

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    白晓纯; 王琳; 赵忺; 田建立

    2016-01-01

    Objective To explore the role of Foxp3+ T cells (Tregs) in liver injury induced by chronic intermittent hypoxia. Methods Thirty-two male Wister rats were divided into four groups:control group (A), high-fat diet group (B), intermittent hypoxia group (C), and high-fat diet and intermittent hypoxia group (D). After 4 weeks, blood samples were collected and livers were surgically removed. Using the standard automatic clinical analyzer to test serum levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL- C), alanina aminotransferase (ALT) and aspartato aminotransferase (AST). The MDA content of liver tissue was measured by colorimetrc method. The levels of TNF-αand IL-1βwere measured by radiommunoassay, and the expression of Foxp3 protein was measured by Western blotting technique. Results Serum levels of TC and LDL-C were significantly higher in B group than those of A, C and D groups, and which were higher in D group than those of A and C groups (P<0.05). There were no significant differences in serum levels of TC and LDL-C between A group and C group. Serum levels of ALT, AST, MDA, TNF-αand IL-1βwere significantly higher in C group than those of A group, and which were significantly higher in D group than those of A, B and C groups (P<0.05). There were no significant differences in these indicators between A group and B group, and between B group and C group. Foxp3 protein expression in liver was significantly lower in D group than that of other groups (P<0.05). Conclusion Foxp3+T regulatory cells involve in the regulation of hepatic injury induced by chronic intermittent hypoxia on the basis of a high-fat diet, and which may play an important role in this process of protective immune response.%目的:探讨叉头样转录因子P3(Foxp3)阳性调节性T细胞(Tregs)在慢性间歇低氧诱导的肝损伤中的作用。方法32只雄性Wistar大鼠随机均分为空白对照组(A组)、高脂饮食组(B组)、间歇低氧组

  16. Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation.

    LENUS (Irish Health Repository)

    Garvey, J F

    2012-02-01

    There is increasing evidence that intermittent hypoxia plays a role in the development of cardiovascular risk in obstructive sleep apnoea syndrome (OSAS) through the activation of inflammatory pathways. The development of translational models of intermittent hypoxia has allowed investigation of its role in the activation of inflammatory mechanisms and promotion of cardiovascular disease in OSAS. There are noticeable differences in the response to intermittent hypoxia between body tissues but the hypoxia-sensitive transcription factors hypoxia-inducible factor-1 and nuclear factor-kappaB appear to play a key role in mediating the inflammatory and cardiovascular consequences of OSAS. Expanding our understanding of these pathways, the cross-talk between them and the activation of inflammatory mechanisms by intermittent hypoxia in OSAS will provide new avenues of therapeutic opportunity for the disease.

  17. Insulin production hampered by intermittent hypoxia via impaired zinc homeostasis.

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    Eung-Kwon Pae

    Full Text Available Without zinc, pancreatic beta cells cannot either assemble insulin molecules or precipitate insulin crystals; thus, a lack of zinc concentration in the beta cells would result in a decreased insulin production. ZIP8 is one of the zinc uptake transporters involved in zinc influx into the cytosol of beta cells. Thus, if ZIP8 is down-regulated, a decreased insulin production would result. We assumed that intermittent hypoxic exposure to the beta cells may result in a decreased production of insulin due to a lack of zinc. To test this hypothesis we harvested pancreatic islets from the rats conditioned under intermittent hypoxia (IH (fluctuating between 20.5% and 10% every 4 min for 1 h and compared the results with those from control animals and islets. We also compared their insulin and glucose homeostasis using glucose tolerance tests (GTT after 3 weeks. GTT results show a significant delay (P<0.05 in recovery of the blood glucose level in IH treated pups. ZIP8 expression in the beta cell membrane was down-regulated. The zinc concentration in the cell as well as insulin production was significantly decreased in the islets harvested from IH animals. However, mRNA for insulin and C-peptide/insulin protein levels in the total cell lysates remained the same as those of controls. When we treated the beta cells using siRNA mediated ZIP8, we observed the commensurate results from the IH-treated islets. We conclude that a transient IH exposure could knockdown ZIP8 transporters at mRNA as well as protein levels in the beta cells, which would decrease the level of blood insulin. However, the transcriptional activity of insulin remains the same. We conclude that the precipitation process of insulin crystal may be disturbed by a lack of zinc in the cytosol that is modulated by mainly ZIP8 after IH exposure.

  18. Intermittent hypoxia in childhood: the harmful consequences versus potential benefits of therapeutic uses

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    Tatiana V. Serebrovskaya

    2015-05-01

    Full Text Available Intermittent hypoxia often occurs in early infancy in both preterm and term infants and especially at 36 to 44 weeks postmenstrual age. These episodes of intermittent hypoxia could result from sleep-disordered breathing or may be temporally unrelated to apnea or bradycardia events. There are numerous reports indicating adverse effects of intermittent hypoxia on development, behavior, academic achievement and cognition in children with sleep apnea syndrome. It remains uncertain the exact causative relationship between the neurocognitive and behavioral morbidities and intermittent hypoxia and/or its associated sleep fragmentation. On the other hand, well-controlled and moderate intermittent hypoxia conditioning/training has been used in sick children for treating their various forms of bronchial asthma, allergic dermatoses, autoimmune thyroiditis, cerebral palsy, and obesity. This review article provides an updated and impartial analysis on the currently available evidence in supporting either side of the seemingly contradictory scenarios. We wish to stimulate a comprehensive understanding of such a complex physiological phenomenon as intermittent hypoxia, which may be accompanied by other confounding factors (e.g. hypercapnia, polycythemia, in order to prevent or reduce its harmful consequences, while maximize its potential utility as an effective therapeutic tool in pediatric patients.

  19. The effect of chronic intermittent hypoxia and hyperlipidemia on the heart in rat model%慢性间歇性低氧与高脂血症对大鼠心脏的影响

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    韩茜; 杨思俊; 叶秀文; 麦翠和; 张挪富

    2015-01-01

    Objective Obstructive sleep apnea syndrome (OSAS),with intermittent hypoxia during sleep,is increasingly recognized as an independent risk factor of cardiovascular diseases (CVD).Oxidative stress and inflammation are pathogenic mechanisms in CVD,but majority of studies have focused on the systemic status.The aim of this study was to use an animal model to evaluate oxidative stress and inflammation in response to chronic intermittent hypoxia (CIH) with or without diet-induced hyperlipidemia,with special reference to any difference in the systemic and cardiac response,and the mechanistic pathways involved.Methods Male Sprague-Dawley rats were divided into four groups:regular chow diet or high fat high cholesterol (HFHC) diet plus intermittent air (IA) or IH treatment,and rats were sacrificed at 2 or 4 weeks.Serum and cardiac levels of oxidative and pro-inflammatory markers were assayed with ELISA,the expression of HO-1 was examined by immunohistochemistry and activation of signaling pathways in the heart were analyzed by Western blot.Results IH and HFHC diet alone or together caused time-dependent elevation in serum CINC-1 levels.In contrast,suppression of the cardiac levels of pro-inflammatory markers were seen,accompanied by upregulation of expression of cardiac heam-oxygenase,HO 1,a cytoprotective protein at 4 weeks,when cardiac activations of ERK and Akt were also observed.Conclusions Inflammation resulted from CIH and hyperlipidemia may serve as a potential mechanism underlying OSAS-related CVD.However,the upregulation of HO-1 expression via ERK and Akt activation in cardiac tissues may help to protect the heart from inflammatory insults.%目的 观察慢性间歇性低氧(CIH)及高脂高胆固醇(HFHC)饮食诱导的高脂血症对大鼠全身及心脏局部炎症反应的影响.方法 Sprague-Dawley雄性大鼠64只,随机分为对照组,慢性间歇低氧组+常规饲料喂养组(CIH组),常氧+HFHC饲料喂养组(IA/HFHC组)和慢性间歇低

  20. MUSCLE FIBER SPECIFIC ANTIOXIDATIVE SYSTEM ADAPTATION TO SWIM TRAINING IN RATS: INFLUENCE OF INTERMITTENT HYPOXIA

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    Olga Gonchar

    2005-06-01

    Full Text Available The aim of the present study was to examine the influence of intermittent hypoxia at rest and in combination with long-term high-intensity swimming exercise on lipid peroxidation and antioxidant defense system adaptation in skeletal muscles differing in fiber type composition. High-intensity chronic exercise was performed as swimming training with load that corresponded to ~ 75 % VO2max (30 min·day-1, 5 days·wk-1, for 4 wk. Intermittent hypoxic training (IHT consisted of repeated episodes of hypoxia (12%O2, 15 min, interrupted by equal periods of recovery (5 sessions/day, for 2 wk. Sessions of IHT were used during the first two weeks and during the last two weeks of chronic exercise. Oxidative (red gastrocnemius and soleus, mix and glycolytic (white gastrocnemius muscles were sampled. Our results indicated that high-intensity swim training in combination with sessions of IHT induced more profound antioxidative adaptations in skeletal muscles than the exercise training only. This adaptation has muscle fiber type specificity and is reflected in significantly elevated superoxide dismutase and catalase activities in highly oxidative muscle only. Training adaptation of GSH system (reduced glutathione content, activities of glutathione reductase, glutathione peroxidase, NADPH-supplying enzyme glucose-6-phosphate dehydrogenase occurred both in slow- and fast-twitch muscles. However, this process was more effective in oxidative muscles. IHT attenuated the increase in TBARS content induced by high-intensity swimming training. The test on exercise tolerance demonstrated a significant elevation of the swimming time to exhaustion after IHT at rest and after IHT in conjunction with high-intensity exercise in comparison with untrained and chronically exercised rats. These results confirmed that sessions of IHT might improve exercise tolerance and increase maximal work capacity

  1. Metallothionein as a compensatory component prevents intermittent hypoxia-induced cardiomyopathy in mice

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    Yin, Xia; Zhou, Shanshan [The First Hospital of Jilin University, Changchun, 130021 (China); KCHRI at the Department of Pediatrics, School of Medicine, University of Louisville, Louisville, 40202 (United States); Zheng, Yang, E-mail: zhengyang@jlu.edu.cn [The First Hospital of Jilin University, Changchun, 130021 (China); Tan, Yi [KCHRI at the Department of Pediatrics, School of Medicine, University of Louisville, Louisville, 40202 (United States); Chinese–American Research Institute for Diabetic Complications, Wenzhou Medical College School of Pharmacy, Wenzhou, 325035 (China); Kong, Maiying [Department of Bioinformatics and Biostatistics, School of Public Health and Information Sciences, University of Louisville, Louisville, KY 40202 (United States); Wang, Bo [KCHRI at the Department of Pediatrics, School of Medicine, University of Louisville, Louisville, 40202 (United States); Department of Pathology, Inner Mongolia Forestry General Hospital, Yakeshi, 022150 (China); Feng, Wenke [Department of Medicine, School of Medicine, University of Louisville, Louisville, 40202 (United States); Epstein, Paul N. [KCHRI at the Department of Pediatrics, School of Medicine, University of Louisville, Louisville, 40202 (United States); Cai, Jun, E-mail: j0cai002@louisville.edu [KCHRI at the Department of Pediatrics, School of Medicine, University of Louisville, Louisville, 40202 (United States); Cai, Lu [KCHRI at the Department of Pediatrics, School of Medicine, University of Louisville, Louisville, 40202 (United States); Chinese–American Research Institute for Diabetic Complications, Wenzhou Medical College School of Pharmacy, Wenzhou, 325035 (China); Department of Medicine, School of Medicine, University of Louisville, Louisville, 40202 (United States)

    2014-05-15

    Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (IH) to induce cardiovascular disease, which may be related to oxidative damage. Metallothionein (MT) has been extensively proved to be an endogenous and highly inducible antioxidant protein expressed in the heart. Therefore, we tested the hypotheses that oxidative stress plays a critical role in OSA induced cardiac damage and MT protects the heart from OSA-induced cardiomyopathy. To mimic hypoxia/reoxygenation events that occur in adult OSA patients, mice were exposed to IH for 3 days to 8 weeks. The IH paradigm consisted of alternating cycles of 20.9% O{sub 2}/8% O{sub 2} F{sub I}O{sub 2} (30 episodes per hour) with 20 s at the nadir F{sub I}O{sub 2} for 12 h a day during daylight. IH significantly increased the ratio of heart weight to tibia length at 4 weeks with a decrease in cardiac function from 4 to 8 weeks. Cardiac oxidative damage and fibrosis were observed after 4 and 8 weeks of IH exposures. Endogenous MT expression was up-regulated in response to 3-day IH, but significantly decreased at 4 and 8 weeks of IH. In support of MT as a major compensatory component, mice with cardiac overexpression of MT gene and mice with global MT gene deletion were completely resistant, and highly sensitive, respectively, to chronic IH induced cardiac effects. These findings suggest that chronic IH induces cardiomyopathy characterized by oxidative stress-mediated cardiac damage and the antioxidant MT protects the heart from such pathological and functional changes. - Highlights: • The effect of intermittent hypoxia (IH) on cardiac metallothionein (MT) • Cardiac MT expression was up-regulated in response to 3-day IH. • Exposure to 4- or 8-week IH downregulated cardiac MT expression. • Overexpression of cardiac MT protects from IH-induced cardiac damage. • Global deletion of MT gene made the heart more sensitive to IH damage.

  2. Intermittent Hypoxia-Induced Carotid Body Chemosensory Potentiation and Hypertension Are Critically Dependent on Peroxynitrite Formation

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    Esteban A. Moya

    2016-01-01

    Full Text Available Oxidative stress is involved in the development of carotid body (CB chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH, the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO−, a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO− scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir in the CB, the CB chemosensory discharge, and arterial blood pressure (BP in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day for 7 days. Ebselen (10 mg/kg/day was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u., reduced CB chemosensory response to 5% O2 (266.5 ± 13.4 versus 168.6 ± 16.8 Hz, and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg. Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO− formation.

  3. Hippocampal impairments are associated with intermittent hypoxia of obstructive sleep apnea

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    FENG Jing; WU Qi; ZHANG Dan; CHEN Bao-yuan

    2012-01-01

    Obstructive sleep apnea (OSA),which is the most common sleep-related breathing disorder,is characterized as frequent upper airway collapse and obstruction.It is a treatable disorder but if left untreated is associated with complications in several organ systems.The health risk to OSA patients shows a strong association with acute cardiovascular events,and with chronic conditions.To the central nervous system,OSA causes behavioral and neuropsychologic deficits including daytime sleepiness,depression,impaired memory,mood disorders,cognition deficiencies,language comprehension and expression deficiencies,all of which are compatible with impaired hippocampal function.Furthermore,there exists a significant correlation between disease severity and cognitive deficits in OSA.Children with severe OSA have significantly lower intelligence quotient (IQ) and executive control functions compared to normal children matched for age,gender and ethnicity.This corroborates the findings of several pediatric studies of cognition in childhood OSA,where deficits are reported in general intelligence and some measures of executive function.In studies of OSA,it is difficult to differentiate the effects of its two main pathologic traits,intermittent hypoxia (IH) and sleep fragmentation.Many OSA studies,utilize IH as the only exposure factor in OSA studies.These approaches simplify research process and attain most of the academic goals.IH,continuous hypoxia and intermittent continuous hypoxia can all result in decreases in arterial O2.There are striking differences to them in the response of physiological systems.There are multiple studies showing that IH treatment in a rodent model of OSA can impair performance of standard water maze tests associated with deficits in spatial learning and memory which most likely are hippocampal-dependent.Cellular damage to the hippocampal cornuammonis 1 (CA1) region likely contributes to neuropsychological impairment among OSA patients,since neural circuits

  4. Mechanism of endocannabinoids system in glucose metabolism of rats with chronic intermittent hypoxia%内源性大麻素系统对慢性间歇低氧大鼠糖代谢的影响机制

    Institute of Scientific and Technical Information of China (English)

    肖玲; 陈彦; 张晋源; 王蓓

    2014-01-01

    目的 探讨内源性大麻素系统(ECS)对慢性间歇低氧(CIH)大鼠糖代谢的影响机制.方法 将48只Wistar大鼠采用随机排列表法及实验结束时间分为4、6周正常对照组(充入压缩空气氧浓度为21%),4、6周CIH组(每日CIH暴露8h)及4、6周CIH+利莫那班组[CIH暴露前给予肝脏CB1受体拮抗剂利莫那班腹腔注射(1 mg·kg-1·d-1)]各8只.第4周及第6周结束实验,检测各组大鼠空腹血糖、血清胰岛素、血清C肽水平及肝脏CB1受体表达的变化,评价CIH对糖代谢指标的影响.结果 4、6周CIH组下列指标均显著高于4、6周正常对照组:空腹血糖(8.91±0.40)、(10.61 ±0.36)比(6.48±0.23)、(6.51 ±0.25) mmol/L,血清胰岛素(16.72 ±3.76)、(20.25 ±3.64)比(9.02±2.05)、(9.19 ±2.35) U/L,血清C肽水平(3.53±0.26)、(5.23±0.29)比(1.37±0.26)、(1.41 ±0.41) μg/L,肝脏CB1受体表达(0.290±0.026)、(0.342±0.030)比(0.214±0.023)、(0.221 ±0.026)(均P<0.05);且6周CIH组均显著高于4周CIH组(均P<0.05);而4、6周CIH+利莫那班组上述指标明显降低(均P<0.05).CB1水平与空腹血糖、血清胰岛素、血清C肽水平呈正相关(r=0.856、0.758、0.827,均P<0.05).结论 ECS在CIH引发的糖代谢异常中发挥一定的促进作用.%Objective To explore the mechanism of endocannabinoids system (ECS) in glucose metabolism of rats with chronic intermittent hypoxia (CIH).Methods According to random permutation table and experiment time,a total of 48 Wistar rats were randomly divided into 6 groups of 4/6-week control (filling with compressed air with 21% oxygen),4/6-week CIH (CIH exposure for 8 hours per day) and 4/ 6-week CIH plus rimonabant group [an intraperitoneal injection of CB1 receptor antagonist rimonabant into liver (1 mg · kg-1 · d-1) before CIH exposure] (n =8 each).The levels of fasting plasma glucose,serum insulin,serum C-peptide and the expression of CB1 receptor in liver were detected after 4/6 weeks to evaluate the

  5. Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Intermittent hypoxia has been shown to provide myocardial protection against ishemia/reperfusion-induced injury.Cardiac myocyte loss through apoptosis has been reported in ischemia/reperfusion injury. Our aim was to investigate whether intermittent hypoxia could attenuate ischemia/reperfusion-induced apoptosis in cardiac myocytes and its potential mechanisms. Adult male Sprague-Dawley rats were exposed to hypoxia simulated 5000 m in a hypobaric chamber for 6 h/day, lasting 42 days. Normoxia group rats were kept under normoxic conditions. Isolated perfused hearts from both groups were subjected to 30 min of global ischemia followed by 60 min reperfusion.Incidence of apoptosis in cardiac myocytes was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and DNA agarose gel electrophoresis. Expressions of apoptosis related proteins,Bax and Bcl-2, in cytosolic and membrane fraction were detected by Western Blotting. After ischemia/reperfusion,enhanced recovery of cardiac function was observed in intermittent hypoxia hearts compared with normoxia group.Ischemia/reperfusion-induced apoptosis, as evidenced by TUNEL-positive nuclei and DNA fragmentation, was significantly reduced in intermittent hypoxia group compared with normoxia group. After ischemia/reperfusion,expression of Bax in both cytosolic and membrane fractions was decreased in intermittent hypoxia hearts compared with normoxia group. Although ischemia/reperfusion did not induce changes in the level of Bcl-2 expression in cytosolic fraction between intermittent hypoxia and normoxia groups, the expression of Bcl-2 in membrane fraction was upregulated in intermittent hypoxia group compared with normoxia group. These results indicated that the cardioprotection of intermittent hypoxia against ischemia/reperfusion injury appears to be in part due to reduce myocardial apoptosis. Intermittent hypoxia attenuated ischemia/reperfusion-induced apoptosis via increasing the ratio of Bcl

  6. Thioredoxin and impaired spatial learning and memory in the rats exposed to intermittent hypoxia

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    YANG Xiu-hong; LIU Hui-guo; LIU Xue; CHEN Jun-nan

    2012-01-01

    Background Obstructive sleep apnea (OSA) can cause cognitive dysfunction and may be a reversible cause of cognitive loss in patients with Alzheimer's disease (AD).Chronic exposure to intermittent hypoxia (IH),such as encountered in OSA,is marked by neurodegenerative changes in rat brain.We investigated the change of thioredoxin (Trx),spatial learning and memory in rats exposed to chronic intermittent hypoxia (CIH).Methods Forty healthy male Sprague-Dawley (SD) rats were randomly divided into four groups of ten each:a CIH+normal saline (CIH+NS group),a N-acetylcystein-treated CIH (CIH+NAC) group,a sham CIH group (sham CIH+NS),and a sham NAC-treated sham CIH (CIH+NAC) group.Spatial learning and memory in each group was assessed with the Morris water maze.Real-time PCR and Western blotting were used to examine mRNA and protein expression of Trx in the hippocampus tissue.The terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling (TUNEL) method was used to detect the apoptotic cells of the hippocampus CA1 region.Results ClH-rats showed impaired spatial learning and memory in the Morris water maze,including longer mean latencies for the target platform,reduced numbers of passes over the previous target platform and a smaller percentage of time spent in the target quadrant.Trx mRNA and protein levels were significantly decreased in the CIH-hippocampus,meanwhile,an elevated apoptotic index revealed apoptosis of hippocampal neurons of rats exposed to CIH.The rats,which acted better in the Morris water maze,showed higher levels of the Trx mRNA and protein in the hippocampus;apoptotic index of the neurons in the hippocampus of each group was negatively correlated with the Trx mRNA and protein levels.Conclusion The Trx deficit likely plays an important role in the impaired spatial learning and memory in the rats exposed to CIH and may work through the apoptosis of neurons in the hippocampus.

  7. Intermittent Hypoxia Affects the Spontaneous Differentiation In Vitro of Human Neutrophils into Long-Lived Giant Phagocytes

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    Larissa Dyugovskaya

    2016-01-01

    Full Text Available Previously we identified, for the first time, a new small-size subset of neutrophil-derived giant phagocytes (Gϕ which spontaneously develop in vitro without additional growth factors or cytokines. Gϕ are CD66b+/CD63+/MPO+/LC3B+ and are characterized by extended lifespan, large phagolysosomes, active phagocytosis, and reactive oxygen species (ROS production, and autophagy largely controls their formation. Hypoxia, and particularly hypoxia/reoxygenation, is a prominent feature of many pathological processes. Herein we investigated Gϕ formation by applying various hypoxic conditions. Chronic intermittent hypoxia (IH (29 cycles/day for 5 days completely abolished Gϕ formation, while acute IH had dose-dependent effects. Exposure to 24 h (56 IH cycles decreased their size, yield, phagocytic ability, autophagy, mitophagy, and gp91-phox/p22-phox expression, whereas under 24 h sustained hypoxia (SH the size and expression of LC3B and gp91-phox/p22-phox resembled Gϕ formed in normoxia. Diphenyl iodide (DPI, a NADPH oxidase inhibitor, as well as the PI3K/Akt and autophagy inhibitor LY294002 abolished Gϕ formation at all oxygen conditions. However, the potent antioxidant, N-acetylcysteine (NAC abrogated the effects of IH by inducing large CD66b+/LC3B+ Gϕ and increased both NADPH oxidase expression and phagocytosis. These findings suggest that NADPH oxidase, autophagy, and the PI3K/Akt pathway are involved in Gϕ development.

  8. The Role of Acute Intermittent Hypoxia in Neutrophil-Generated Superoxide, Sympathovagal Balance, and Vascular Function in Healthy Subjects

    Science.gov (United States)

    Almeida, Germana P. L.; Trombetta, Ivani C.; Cepeda, Felipe X.; Hatanaka, Elaine; Curi, Rui; Mostarda, Cristiano; Irigoyen, Maria C.; Barreto-Filho, José A. S.; Krieger, Eduardo M.; Consolim-Colombo, Fernanda M.

    2017-01-01

    Introduction: Recurrent hypoxia (HPX), a hallmark of the obstructive sleep apnea (OSA), impairs autonomic balance, and increases arterial blood pressure (BP). Oxidative stress is one of the mechanisms involved in these alterations. The cumulative effect of acute intermittent HPX and the chronicity may determine whether the response crosses the threshold from having protective value to pathology. However, the impact of acute intermittent HPX–reoxygenation on markers of oxidative stress in healthy individuals remains to be fully understood. Objective: To analyze the effects of the acute intermittent HPX on the generation of neutrophil-derived superoxide, sympathovagal balance, and vascular function in healthy subjects. Methods: We applied six cycles of intermittent HPX (10% O2 and 90% N2) for 5 min followed by 2 min of room-air in 15 healthy volunteers (34 ± 2 years; 22.3 ± 0.46 kg/m2), without OSA (polysomnography), during wakefulness. During the experimental protocol, we recorded O2 saturation, end-tidal CO2, heart rate (HR), systolic, and diastolic BP, cardiac output (CO) and peripheral resistance (PR). Cardiac sympathovagal balance was determined by HR variability analysis (low frequency and high frequency bands, LF/HF). Superoxide generation in polymorphonuclear neutrophil cells were established using relative luminescence units (PMNs RLU) at baseline (pre-HPX) and immediately after hypoxia induction (post-HPX6). Results: The studied subjects had normal levels of BP, plasma glucose, lipid profile, and inflammatory marker (C-reactive protein). Acute intermittent HPX increased HR, systolic BP, CO, and decreased PR. Additionally, acute intermittent HPX increased PMNs RLU, measured post-HPX6 (470 ± 50 vs. 741 ± 135, P < 0.05). We found a similar increase in LF/HF post-HPX6 (0.91 ± 0.11 vs. 2.85 ± 0.40, P < 0.05). PR was diminished from pre-HPX to post-HPX6 (1.0 ± 0.03 vs. 0.85 ± 0.06, P < 0.05). Further analysis showed significant association between O2

  9. Simulating Sleep Apnea by Exposure to Intermittent Hypoxia Induces Inflammation in the Lung and Liver

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    Darlan Pase da Rosa

    2012-01-01

    Full Text Available Sleep apnea is a breathing disorder that results from momentary and cyclic collapse of the upper airway, leading to intermittent hypoxia (IH. IH can lead to the formation of free radicals that increase oxidative stress, and this mechanism may explain the association between central sleep apnea and nonalcoholic steatohepatitis. We assessed the level of inflammation in the lung and liver tissue from animals subjected to intermittent hypoxia and simulated sleep apnea. A total of 12 C57BL/6 mice were divided into two groups and then exposed to IH (n=6 or a simulated IH (SIH (n=6 for 35 days. We observed an increase in oxidative damage and other changes to endogenous antioxidant enzymes in mice exposed to IH. Specifically, the expression of multiple transcription factors, including hypoxia inducible factor (HIF-1α, nuclear factor kappa B (NF-κB, and tumor necrosis factor (TNF-α, inducible NO synthase (iNOS, vascular endothelial growth factor (VEGF, and cleaved caspase 3 were shown to be increased in the IH group. Overall, we found that exposure to intermittent hypoxia for 35 days by simulating sleep apnea leads to oxidative stress, inflammation, and increased activity of caspase 3 in the liver and lung.

  10. Chronic intermittent high altitude exposure, occupation, and body mass index in workers of mining industry.

    Science.gov (United States)

    Esenamanova, Marina K; Kochkorova, Firuza A; Tsivinskaya, Tatyana A; Vinnikov, Denis; Aikimbaev, Kairgeldy

    2014-09-01

    The obesity and overweight rates in population exposed to chronic intermittent exposure to high altitudes are not well studied. The aim of the retrospective study was to evaluate whether there are differences in body mass index in different occupation groups working in intermittent shifts at mining industry at high altitude: 3800-4500 meters above sea level. Our study demonstrated that obesity and overweight are common in workers of high altitude mining industry exposed to chronic intermittent hypoxia. The obesity rate was lowest among miners as compared to blue- and white-collar employees (9.5% vs. 15.6% and 14.7%, p=0.013). Obesity and overweight were associated with older age, higher rates of increased blood pressure (8.79% and 5.72% vs. 1.92%), cholesterol (45.8% and 45.6% vs. 32.8%) and glucose (4.3% and 1.26% vs. 0.57%) levels as compared to normal body mass index category (pmining industry exposed to intermittent high-altitude hypoxia. Therefore, assessment and monitoring of body mass index seems to be essential in those who live and work at high altitudes to supply the correct nutrition, modify risk factors, and prevent related disorders.

  11. 内源性大麻素系统在慢性间歇低氧大鼠心肌肥厚病理过程中的作用%The Pathological Processing of Endocannabinoid System on Cardiac Hypertrophy in a Experimental Rats With Chronic Intermittent Hypoxia

    Institute of Scientific and Technical Information of China (English)

    张晋源; 陈彦; 肖玲; 唐茜; 王蓓; 范艳锋

    2014-01-01

    Objective: To investigate the effect of endocannabinoid system on cardiac hypertrophy in experimental rats with chronic intermittent hypoxia and to study the impact of endocannabinoid antagonist, rimonabant in such pathological processing. Methods: A total of 48 male Wistar rats were divided into 6 groups. 4 and 6 weeks of Normal control group, 4 and 6 weeks of Hypoxia group, 4 and 6 weeks of Hypoxia with rimonabant intervention group. n=8 in each group. The rats were sacrificed to measure left ventricular mass index (LVMI), the myocardial cell morphological changes were observed by optical microscope, the expression of cardiac calcium/calmodulin-dependent protein kinase II (CaMKII) and cardiotrophin-1 (CT-1) were detected by immunohistochemistry at 4 and 6 weeks respectively. Results: Compared with 4 and 6 weeks of Normal control group, the LVMI, cardiac hypertrophy condition, CaMKII and CT-1 were increased in 4 and 6 weeks of Hypoxia group, all P Conclusion: The Chronic intermittent hypoxia could induce myocardial hypertrophy via endocannabinoid system disorders, such pathological processing could be reduced by rimonabant intervention.%目的:探讨内源性大麻素系统在慢性间歇低氧大鼠心肌肥厚中作用及使用内源性大麻素受体拮抗剂利莫那班后对其的影响。  方法:48只雄性Wistar大鼠,根据实验设计在实验4、6周时随机分组,即正常对照4周组、6周组,低氧4周组、6周组,低氧+利莫那班即拮抗低氧4周组、6周组,共6组,随机取8只大鼠,处死后测左心室质量指数(LVMI),光学显微镜下观察心肌细胞形态变化,免疫组化测钙/钙调素依赖性蛋白激酶II(CaMKII)、心肌营养素-1(CT-1)表达。  结果:低氧4周组、6周组分别与正常对照4周组、6周组相比,LVMI、光镜下心肌细胞肥厚及免疫组化下CaMKII、CT-1均明显升高,组间比较差异均有统计学意义(P  结论:慢性间歇

  12. 2种慢性间歇性缺氧小鼠模型模拟气阴两虚证临床指征的比较研究%Comparison of Clinical Indications Simulating Deficiency of Both Qi and Yin Syndrome Induced by Two Types of Chronic Intermittent Hypoxia in Mice

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    王文萍; 柴程芝; 寇俊萍; 余伯阳

    2011-01-01

    目的:比较钠石灰和低压氧仪2种不同缺氧方式诱导的慢性间歇性缺氧小鼠模型的整体行为变化,为进一步构建气阴两虚证动物模型奠定基础.方法:分别采用氧分压从21%逐渐降至6%,平均下降速度为0.5%/min ~ 1%/min的钠石灰缺氧法和氧分压在短时间内骤降后维持在7% ~8%的低压氧仪缺氧法,考察2种缺氧模式对小鼠体重,摄食量,自发活动以及心率、T波等气阴两虚临床相关指标变化的影响.结果:钠石灰和低压氧仪2种不同的缺氧方式均能够导致小鼠体重下降;摄食量减少;行走格数减少,直立次数增加等自发活动改变;心率加快,T波持续抬高等心电图变化,二者对各项指标的影响呈基本一致的趋势,其结果具有显著相关性.结论:钠石灰和低压氧仪2种缺氧方式诱导的慢性间歇性缺氧小鼠模型均能够模拟形体消瘦,食欲不振,体倦乏力,烦躁,心悸,脉细数等气阴两虚证的主要临床特征.%Objective: To establish foundation for constructing a suitable animal model of deficiency of both Qi and Yin syndrome (DQYS) induced by two types of chronic intermittent hypoxia (soda lime and low-pressureoxygen controller) by comparison the whole behavior in mice. Method: The two modes of oxygen scarcity,including oxygen pressure declining continuously from 21% to 7%-8% with the average speed of 0. 5%/min-l% per minute in airtight wide-mouthed bottle and oxygen pressure falling abruptly within short period and then keeping in the level of 7% -8% ,were adopted respectively to observe the time-course changes in body weight, food intake, locomotive activity and electrocardiogram respectively. The experiments were designed for mimicing clinical features of DQYS. Result; The mice exposed to two different modes of chronic intermittent hypoxia for certain duration showed body weight loss, food intake decline, locomotive activity change of ambulation decrease and rearing increase

  13. Developmental programming of O(2) sensing by neonatal intermittent hypoxia via epigenetic mechanisms.

    Science.gov (United States)

    Nanduri, Jayasri; Prabhakar, Nanduri R

    2013-01-01

    Recurrent apnea with intermittent hypoxia (IH) is a major clinical problem in infants born preterm. Carotid body chemo-reflex and catecholamine secretion from adrenal medullary chromaffin cells (AMC) are important for maintenance of cardio-respiratory homeostasis during hypoxia. This article highlights studies on the effects of IH on O(2) sensing by the carotid body and AMC in neonatal rodents. Neonatal IH augments hypoxia-evoked carotid body sensory excitation and catecholamine secretion from AMC which are mediated by reactive oxygen species (ROS)-dependent recruitment of endothelin-1 and Ca(2+) signaling, respectively. The effects of neonatal IH persist into adulthood. Evidence is emerging that neonatal IH initiates epigenetic mechanisms involving DNA hypermethylation contributing to long-lasting increase in ROS levels. Since adult human subjects born preterm exhibit higher incidence of sleep-disordered breathing and hypertension, DNA hypomethylating agents might offer a novel therapeutic intervention to decrease long-term cardio-respiratory morbidity caused by neonatal IH.

  14. [Role of restricted nitric oxide overproduction in the cardioprotective effect of adaptation to intermittent hypoxia].

    Science.gov (United States)

    goriacheva, A V; Belkina, L M; Terekhina, O L; Dawney, H F; Mallet, R T; Smirin, B V; Smirnova, E A; Mashina, S Iu; Manukhina, E B

    2012-01-01

    Adaptation to intermittent normobaric hypoxia is cardioprotective and can stimulate nitric oxide (NO) synthesis. However the role of nitric oxide (NO) in prevention of ischemia-reperfusion (IR) injury of myocardium is controversial. This study was focused on evaluating the effect of adaptation to hypoxia and IR on NO production and development of nitrative stress in the myocardium. Adaptation to hypoxia tended to increase NO production, which was determined by the total level of plasma nitrite and nitrate, and prevented IR-induced NO overproduction. The IR-induced NO overproduction was associated with significant 3-nitrotyrosine (3-NT) accumulation in the left ventricle but not in septum or aorta. In hypoxia-adapted rats, 3-NT after IR was similar to that of control rats without IR. IHC induced marked accumulation of HIF-1alpha in the left ventricle. We suggest that HIF-1alpha contributes to NO-synthase expression during adaptation to hypoxia and thereby facilitates the increase in NO production. NO, in turn, may subsequently prevent NO overproduction during IR by a negative feedback mechanism.

  15. Advancing hypoxic training in team sports: from intermittent hypoxic training to repeated sprint training in hypoxia.

    Science.gov (United States)

    Faiss, Raphaël; Girard, Olivier; Millet, Grégoire P

    2013-12-01

    Over the past two decades, intermittent hypoxic training (IHT), that is, a method where athletes live at or near sea level but train under hypoxic conditions, has gained unprecedented popularity. By adding the stress of hypoxia during 'aerobic' or 'anaerobic' interval training, it is believed that IHT would potentiate greater performance improvements compared to similar training at sea level. A thorough analysis of studies including IHT, however, leads to strikingly poor benefits for sea-level performance improvement, compared to the same training method performed in normoxia. Despite the positive molecular adaptations observed after various IHT modalities, the characteristics of optimal training stimulus in hypoxia are still unclear and their functional translation in terms of whole-body performance enhancement is minimal. To overcome some of the inherent limitations of IHT (lower training stimulus due to hypoxia), recent studies have successfully investigated a new training method based on the repetition of short (training in hypoxia (RSH). The aims of the present review are therefore threefold: first, to summarise the main mechanisms for interval training and repeated sprint training in normoxia. Second, to critically analyse the results of the studies involving high-intensity exercises performed in hypoxia for sea-level performance enhancement by differentiating IHT and RSH. Third, to discuss the potential mechanisms underpinning the effectiveness of those methods, and their inherent limitations, along with the new research avenues surrounding this topic.

  16. 慢性间断性低氧大鼠认知功能和脑胆碱能神经元的进行性变化%The progressive effects of chronic intermittent hypoxia on cognitive function and the cholinergic neuron in rats

    Institute of Scientific and Technical Information of China (English)

    陈燕; 赵春玲; 张春来; 徐倩

    2011-01-01

    Objective: To investigate the relation between the progressive effects of chronic intermittent hypoxia(CIH) on cognitive function and the change of cholinergic neuron. Methods: Forty adult male Sprague-Dawley rats were randomly averagely divided into four groups: control group, CIH 1 week group, CIH 3 week group and CIH 5 week group. The cognitive function was assessed by the Morris Water Maze. The necrosis neurons in prefrontal cortex and hippocampus were observed and counted. The cholin aeetyltransferase(ChAT) immunostained cells in prefrontal cortex and hippocampus were identified and quantitated. Results: The spatial learning and memory impairments progressed from 1 to 5weeks in rats. Compared with the control group, the cognitive impairments in CIH5w group were significant( P < 0.05). The degeneration or necrosis neurons in prefrontal cortex and hippocampus were significantly increased in CIH rats, and worsen gradually along with the hypoxia. The ChAT immunostained cells in prefrontal cortex and hippocampus were gradually reduced. The ChAT immunostained cells of prefrontal cortex and hippocampus in CIH3w group and CIH5w group were less than that in control group ( P <0.05). Conclusion: Chronic intermittent hypoxia induced slowly progressive spatial learning and memory impairments in rats, which maybe associated with the damage of neurons and the reduction of ChAT in prefrontal cortex and hippocampus.%目的:探讨慢性间断性低氧(CIH)大鼠认知功能的进行性变化及其与脑胆碱能神经元变化的关系.方法:成年雄性SD大鼠40只,随机均分为对照组、慢性间断性低氧1,3,5周组.应用Morris水迷宫检测认知功能的变化:利用HE染色在光镜下计数前额叶皮层和海马坏死神经元数;利用免疫组化方法检测前额叶皮层和海马胆碱乙酰转移酶(ChAT)阳性表达.结果:CIH各组大鼠学习记忆能力呈进行性下降趋势;与对照组比较,CIH5w组出现明显学习记忆功能障碍(P<0

  17. Effect of intermittent hypoxia on the reproduction of rats exposed to high altitude in the Chilean Altiplano.

    Science.gov (United States)

    Cikutovic, Marcos; Fuentes, Nelson; Bustos-Obregón, Eduardo

    2009-01-01

    Environmental parameters such as the large day-night temperature differences, high light radiation, and low humidity may have a synergistic effect with low oxygen pressure. To evaluate the effects of the exposure to intermittent chronic hypobaric hypoxia (ICHH) in nature on rat reproduction, a group of rats was alternately moved to a location at 3400 meters over sea level (moml) for 7 days and returned the subsequent week to sea level; this procedure was repeated six times. Hematological and reproductive parameters were measured and analyzed. At the end of the experimental protocol, hematocrit and hemoglobin concentrations were significantly greater in the ICHH group compared to the control group (Nx) (p < 0.05). The diameter of the seminiferous tubule and the height of the spermatogenic epithelium in ICHH rats presented a significant decrease in relation to Nx rats (p < 0.05). Consequently, the number of epididymal spermatozoa in the experimental animals decreased compared to normal rats, with no evidence of recovery after 84 days. The offspring of the different matings between normal and hypoxic animals decreased proportionally to hypoxia exposure. The low oxygen and the changes in testicular temperature homeostasis would provide a novel local mechanism to explain the decrease in sperm cell production and the reduced number of puppies born. The alterations of the reproductive parameters of the hypoxic female, plus testicular injuries and diminished sperm in males, result in a significant decrease in the reproductive activity of the animals.

  18. Distinct mechanisms underlying tolerance to intermittent and constant hypoxia in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Priti Azad

    Full Text Available BACKGROUND: Constant hypoxia (CH and intermittent hypoxia (IH occur during several pathological conditions such as asthma and obstructive sleep apnea. Our research is focused on understanding the molecular mechanisms that lead to injury or adaptation to hypoxic stress using Drosophila as a model system. Our current genome-wide study is designed to investigate gene expression changes and identify protective mechanism(s in D. melanogaster after exposure to severe (1% O(2 intermittent or constant hypoxia. METHODOLOGY/PRINCIPAL FINDINGS: Our microarray analysis has identified multiple gene families that are up- or down-regulated in response to acute CH or IH. We observed distinct responses to IH and CH in gene expression that varied in the number of genes and type of gene families. We then studied the role of candidate genes (up-or down-regulated in hypoxia tolerance (adult survival for longer periods (CH-7 days, IH-10 days under severe CH or IH. Heat shock proteins up-regulation (specifically Hsp23 and Hsp70 led to a significant increase in adult survival (as compared to controls of P-element lines during CH. In contrast, during IH treatment the up-regulation of Mdr49 and l(208717 genes (P-element lines provided survival advantage over controls. This suggests that the increased transcript levels following treatment with either paradigm play an important role in tolerance to severe hypoxia. Furthermore, by over-expressing Hsp70 in specific tissues, we found that up-regulation of Hsp70 in heart and brain play critical role in tolerance to CH in flies. CONCLUSIONS/SIGNIFICANCE: We observed that the gene expression response to IH or CH is specific and paradigm-dependent. We have identified several genes Hsp23, Hsp70, CG1600, l(208717 and Mdr49 that play an important role in hypoxia tolerance whether it is in CH or IH. These data provide further clues about the mechanisms by which IH or CH lead to cell injury and morbidity or adaptation and survival.

  19. HIF-1α activation by intermittent hypoxia requires NADPH oxidase stimulation by xanthine oxidase.

    Science.gov (United States)

    Nanduri, Jayasri; Vaddi, Damodara Reddy; Khan, Shakil A; Wang, Ning; Makarenko, Vladislav; Semenza, Gregg L; Prabhakar, Nanduri R

    2015-01-01

    Hypoxia-inducible factor 1 (HIF-1) mediates many of the systemic and cellular responses to intermittent hypoxia (IH), which is an experimental model that simulates O2 saturation profiles occurring with recurrent apnea. IH-evoked HIF-1α synthesis and stability are due to increased reactive oxygen species (ROS) generated by NADPH oxidases, especially Nox2. However, the mechanisms by which IH activates Nox2 are not known. We recently reported that IH activates xanthine oxidase (XO) and the resulting increase in ROS elevates intracellular calcium levels. Since Nox2 activation requires increased intracellular calcium levels, we hypothesized XO-mediated calcium signaling contributes to Nox activation by IH. We tested this possibility in rat pheochromocytoma PC12 cells subjected to IH consisting alternating cycles of hypoxia (1.5% O2 for 30 sec) and normoxia (21% O2 for 5 min). Kinetic analysis revealed that IH-induced XO preceded Nox activation. Inhibition of XO activity either by allopurinol or by siRNA prevented IH-induced Nox activation, translocation of the cytosolic subunits p47phox and p67phox to the plasma membrane and their interaction with gp91phox. ROS generated by XO also contribute to IH-evoked Nox activation via calcium-dependent protein kinase C stimulation. More importantly, silencing XO blocked IH-induced upregulation of HIF-1α demonstrating that HIF-1α activation by IH requires Nox2 activation by XO.

  20. A Novel Chip for Cyclic Stretch and Intermittent Hypoxia Cell Exposures Mimicking Obstructive Sleep Apnea

    Directory of Open Access Journals (Sweden)

    Noelia Campillo

    2016-07-01

    Full Text Available Intermittent hypoxia (IH, a hallmark of obstructive sleep apnea (OSA, plays a critical role in the pathogenesis of OSA-associated morbidities, especially in the cardiovascular and respiratory systems. Oxidative stress and inflammation induced by IH are suggested as main contributors of end-organ dysfunction in OSA patients and animal models. Since the molecular mechanisms underlying these in vivo pathological responses remain poorly understood, implementation of experimental in vitro cell-based systems capable of inducing high-frequency IH would be highly desirable. Here, we describe the design, fabrication and validation of a versatile chip for subjecting cultured cells to fast changes in gas partial pressure and to cyclic stretch. The chip is fabricated with polydimethylsiloxane (PDMS and consists of a cylindrical well covered by a thin membrane. Cells cultured on top of the membrane can be subjected to fast changes in oxygen concentration (equilibrium time 6 s. Moreover, cells can be subjected to cyclic stretch at cardiac or respiratory frequencies independently or simultaneously. Rat bone marrow-derived mesenchymal stem cells (MSCs exposed to IH mimicking OSA and cyclic stretch at cardiac frequencies revealed that hypoxia-inducible factor 1α (HIF-1α expression was increased in response to both stimuli. Thus, the chip provides a versatile tool for the study of cellular responses to cyclical hypoxia and stretch.

  1. A Novel Chip for Cyclic Stretch and Intermittent Hypoxia Cell Exposures Mimicking Obstructive Sleep Apnea

    Science.gov (United States)

    Campillo, Noelia; Jorba, Ignasi; Schaedel, Laura; Casals, Blai; Gozal, David; Farré, Ramon; Almendros, Isaac; Navajas, Daniel

    2016-01-01

    Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), plays a critical role in the pathogenesis of OSA-associated morbidities, especially in the cardiovascular and respiratory systems. Oxidative stress and inflammation induced by IH are suggested as main contributors of end-organ dysfunction in OSA patients and animal models. Since the molecular mechanisms underlying these in vivo pathological responses remain poorly understood, implementation of experimental in vitro cell-based systems capable of inducing high-frequency IH would be highly desirable. Here, we describe the design, fabrication, and validation of a versatile chip for subjecting cultured cells to fast changes in gas partial pressure and to cyclic stretch. The chip is fabricated with polydimethylsiloxane (PDMS) and consists of a cylindrical well-covered by a thin membrane. Cells cultured on top of the membrane can be subjected to fast changes in oxygen concentration (equilibrium time ~6 s). Moreover, cells can be subjected to cyclic stretch at cardiac or respiratory frequencies independently or simultaneously. Rat bone marrow-derived mesenchymal stem cells (MSCs) exposed to IH mimicking OSA and cyclic stretch at cardiac frequencies revealed that hypoxia-inducible factor 1α (HIF-1α) expression was increased in response to both stimuli. Thus, the chip provides a versatile tool for the study of cellular responses to cyclical hypoxia and stretch. PMID:27524971

  2. 慢性间歇性低压低氧抑制线粒体途径介导的代谢综合征大鼠心肌组织细胞凋亡%Chronic intermittent hypobaric hypoxia ameliorates myocardial apoptosis through inhibiting mitochondrial pathway in rats with metabolism syndrome

    Institute of Scientific and Technical Information of China (English)

    袁芳; 李艳青; 滕旭; 周京京; 郭赞; 王昕; 张自伟; 张翼

    2015-01-01

    Aim To confirm the inhibitory effect of chronic intermittent hypobaric hypoxia ( CIHH) on my-ocardial apoptosis induced by metabolism syndrome ( MS) , and to investigate its mechanism. Methods A rat model of MS induced by fructose was used. The blood pressure and the plasma content of glucose, tri-glyceride, cholesterol, and insulin after 12 h fasting were detected. HE stain were used to detect the cardi-ac structure. The TUNEL staining and activity of caspase-3 were used to detect the apoptosis of myocar-dium. The protein expression of Bcl-2 and Bax was detected by Western blot . Results Compared with the control rats, the blood pressure and the plasma content of glucose, triglyceride, cholesterol, and insu-lin were all increased in rats with MS. In rats with MS, the impairment of cardiac structure and the increase of apoptosis were also observed. The protein expression of Bcl-2 was significantly down-regulated, and that of Bax was significantly up-regulated in MS rats. The ratio of Bcl-2/Bax was also significantly decreased. Interest-ingly, CIHH could ameliorate all of the above issues. There was no significant difference between control group and CIHH group. Conclusion CIHH may im-prove the increased apoptosis in rats with MS via inhib-iting the mitochondrial pathway of apoptosis. This stud-y might provide new targets for therapy and the preven-tion of MS patients.%目的:证实CIHH( chronic intermittent hypobaric hypoxi-a, CIHH)具有改善代谢综合征( metabolism syndrome, MS)大鼠心肌细胞凋亡的作用,并探讨其机制。方法10%果糖水喂养SD大鼠(250~300) g 42 d制备MS模型,检测动脉血压以及空腹血糖、胆固醇、甘油三酯和胰岛素含量,HE染色观察心肌结构,TUNEL染色和caspase-3活性测定检测心肌细胞凋亡, Western blot 检测 Bcl-2和 Bax 的蛋白表达水平。结果与正常大鼠比较,果糖喂养大鼠表现出明显的高血压、高血糖、高甘油三脂血症、高胆固醇血症和高胰

  3. 褪黑素对慢性间歇性缺氧性心肌cTnT及Ca2+-ATPase的影响%Effect of melatonin on the cTnT and Ca2+- AT Pase of chronic intermittent hypoxia cardiac muscular tissues

    Institute of Scientific and Technical Information of China (English)

    董译元; 凌月福; 张耀庭

    2014-01-01

    Objective To investigate whether the melatonin (melatonin,MLT)could protect SD rats’cardiac muscu-lar tissues from chronic intermittent hypoxia damage in the atmospheric pressure.Methods The 24 male,SD rats(5 weeks)were randomly divided into three groups:the Control group,the experimental group A and the experimental group B.The control group rats were fed with normally reared in the air,and the experimental group A and B rats were living in the atmospheric pressure and chronic intermittent hypoxia boxes.The control group rats and the experimental group B rats were fed with normal saline solution (NS ),and the experimental group A rats were fed with melatonin (MLT).After 8 weeks,the cTnT capacity and Ca2+-ATPase activity of each rat were detected,and the right ventri-cles were taken for pathological section.Results ①Comparison of the experimental group B and the experimental group A:The cTnT capacity of the experimental group B was increased (P0.05).There was a small amount of bleeding between myocardial.③Comparison of the experimental group B and the control group:The cTnT capacity of the experimental group B was increased (P<0.05),and the Ca2+-ATPase activity of the experimental group B was decreased (P<0.05).Individual myocardial cell nuclei disappeared.Myocardial cells were hypertrophy,and there was a large amount of bleeding in myocardial.Conclusion MLT can protect rats’cardiac muscular tissue from injury of chronic intermittent hypoxia.%目的:探讨褪黑素(MLT)对常压下慢性间歇性缺氧SD大鼠心肌的保护作用。方法将24只雄性SD大鼠(5周龄)随机分成3组:对照组、实验A组、实验B组。对照组在空气中正常饲养,实验A组和实验B组在常压慢性间歇性低氧箱内,对照组和实验B组灌服生理盐水,实验A组灌服褪黑素。8周后用光电比色法测定血清肌钙蛋白T(cTnT)的浓度和心肌钙离子ATP酶(Ca2+-ATPase)的活性,取大鼠右心室做病理切片

  4. The influence of intermittent hypobaric hypoxia on the brain iron metabolism in adult Sprague dawley rats

    Institute of Scientific and Technical Information of China (English)

    Wu Qiong; Li Yaru; Chang Yanzhong

    2015-01-01

    Objective:Iron is an essential element in all living organisms and is required as a cofactor for oxygen-binding proteins. Iron metabolism, oxygen homeostasis and erythropoiesis are consequently strongly inter-connected. In mammalian cells, exposure to a low-oxygen environment triggers a hypoxic response pathway cen-tered on the regulated expression of the hypoxia-inducible transcription factor ( HIF) . Hypoxia has been shown to increase the expression of a variety of proteins involved in iron homeostasis. However, little is known about brain iron metabolism after intermittent hypobaric hypoxia ( IHH) treatment. In this study, adult Sprague dawley ( SD) rats were treated with IHH for 28 days, 8h per day and then we detected iron homeostasis in different brain areas of SD rats. Results:The protein level of hippocampus transferrin receptor 1 ( TfR1 ) , divalent metal transporter 1 (DMT1) with IRE, DMT1 (-IRE), ferritin-H, iron regulatory protein (IRP) 2 and ceruloplasmin (CP) is ele-vated significantly while ferritin-L decreased. We have also found the down regulation of IRP1. We observe the same results in the cerebral cortex in the brain. Conclusions:We first discover that IHH has an influence on the brain iron homeostasis and the decreased ferritin-L corresponds to the down regulation of IRP1 indicating hypoxia can affect the expression of ferritin-L through IRE/IRP system. Although there is a marked increase in TfR1 ex-pression that would lead to the raised level of LIP in cells. It can finally result in the higher ROS which can damage the cells. The concerned mechanisms involved in it remain to be deliberated.

  5. NF-κB,IL-6 and PGE2 expression in periodontal tissue of rats with periodontitis under chronic intermittent hypoxia%间歇性低氧对牙周炎大鼠牙周组织中 NF-κB、IL-6及 PGE2含量的影响

    Institute of Scientific and Technical Information of China (English)

    王月昊; 王小琴; 苗伟; 柴晶; 程宇钊; 马小雯

    2016-01-01

    Objective:To examine the effects of chronic intermittent hypoxia(CIH)on the NF-κB,IL-6 and PGE2 level in rats with periodontitis.Methods:32 male SD rats(6 weeks old)were randomly divided into 4 groups(n =8),group A(normoxic control),B (normoxic periodontitis),C(CIH)and D(periodontitis +CIH).Periodontitis model was established in the upper second molars by liga-tion technique and high-glucose diet in the rats of group B and D.The rats in the group C and D were subjected to CIH in a cycle of al-ternative nitrogen and oxygen in a closed chamber.The chamber was filled with nadir and zenith ambient oxygen every 1 20 seconds per cycle for 8 hours per day.The rats were sacrificed and the gingival tissues were examined for the detection of IL-6 and PGE2 expression by ELISA,and NF-κB expression by immunohistochemistry.Results:Histology revealed apical migration of junctional epithetlium and crestal alveolar bone resorption in group B and D,and in the above phenomena of group D was the severest.The content of NF-κB,IL-6 and PGE2 in group B,C,D was higher than that in group A(P <0.05),and in group D was the highest(P <0.05).Conclusion:Chro-nic intermittent hypoxia can aggravate the inflammation of periodontitis.%目的:建立慢性间歇性低氧(CIH)及牙周炎大鼠模型,研究 NF-κB、IL-6及 PGE2水平的变化。方法:将32只普通级6周龄雄性 SD 大鼠随机分为4组(n =8):A:常氧空白组、B:常氧牙周炎组、C:CIH 组、D:CIH 合并牙周炎组。B、D 组大鼠上颌第二磨牙进行结扎处理,辅以高糖饮食;A、C 组正常饮食。C、D 组置于低氧舱8 h/d。8周后处死,HE 染色,免疫组化检测牙周组织 NF-κB 含量,ELISA 检测牙龈组织 IL-6、PGE2。结果:HE 染色:8周后 B 组、D 组牙周炎症表现明显。免疫组化:B、C、D 组 NF-κB 表达均高于 A 组(P <0.05);ELISA 检测:B、C、D 组 IL-6、PGE2含量高于 A 组(P <0.05),且 D 组 IL-6

  6. Neuromodulation of Limb Proprioceptive Afferents Decreases Apnea of Prematurity and Accompanying Intermittent Hypoxia and Bradycardia.

    Directory of Open Access Journals (Sweden)

    Kalpashri Kesavan

    Full Text Available Apnea of Prematurity (AOP is common, affecting the majority of infants born at <34 weeks gestational age. Apnea and periodic breathing are accompanied by intermittent hypoxia (IH. Animal and human studies demonstrate that IH exposure contributes to multiple pathologies, including retinopathy of prematurity (ROP, injury to sympathetic ganglia regulating cardiovascular action, impaired pancreatic islet cell and bone development, cerebellar injury, and neurodevelopmental disabilities. Current standard of care for AOP/IH includes prone positioning, positive pressure ventilation, and methylxanthine therapy; these interventions are inadequate, and not optimal for early development.The objective is to support breathing in premature infants by using a simple, non-invasive vibratory device placed over limb proprioceptor fibers, an intervention using the principle that limb movements trigger reflexive facilitation of breathing.Premature infants (23-34 wks gestational age, with clinical evidence of AOP/IH episodes were enrolled 1 week after birth. Caffeine treatment was not a reason for exclusion. Small vibration devices were placed on one hand and one foot and activated in 6 hour ON/OFF sequences for a total of 24 hours. Heart rate, respiratory rate, oxygen saturation (SpO2, and breathing pauses were continuously collected.Fewer respiratory pauses occurred during vibration periods, relative to baseline (p<0.005. Significantly fewer SpO2 declines occurred with vibration (p<0.05, relative to control periods. Significantly fewer bradycardic events occurred during vibration periods, relative to no vibration periods (p<0.05.In premature neonates, limb proprioceptive stimulation, simulating limb movement, reduces breathing pauses and IH episodes, and lowers the number of bradycardic events that accompany aberrant breathing episodes. This low-cost neuromodulatory procedure has the potential to provide a non-invasive intervention to reduce apnea, bradycardia and

  7. 慢性间歇低氧对高脂喂养大鼠心肌天冬氨酸特异性半胱氨酸蛋白酶-3和髓过氧化物酶活性的影响%Effect of chronic intermittent hypoxia on the activities of apoptosis regulating factor cysteine-containing aspartate-specific protease-3 and oxidative stress marker myeloperoxidase in cardiomyocyte in rats fed a high-fat diet

    Institute of Scientific and Technical Information of China (English)

    王卉; 田建立; 张蕴; 王林

    2014-01-01

    Objective To investigate the effect of chronic intermittent hypoxia (CIH) on myocardial tissue pathology,oxidative stress and apoptosis in rat fed a high-fat diet,and to explore the possible mechanism of CIH induced cardiomyocyte injury.Methods A total of 24 male Wistar rats were randomly divided into 3 groups (n=8 each).The control group was fed common rat forage,the high-fat group was fed high-fat forage,and the high-fat plus intermittent hypoxia group was fed high-fat forage combined with a 7h/d intermittent hypoxia treatment.The changes of myocardial tissue pathology and ultrastructure of cardiomyocyte,and the activities of apoptosis regulating factor cysteine-containing aspartate-specific proteases-3 (caspase-3) and oxidative stress marker myeloperoxidase (MPO) were observed in the 3 groups after 4 weeks of treatment.Results There were significant differences in the activities of caspase-3 and MPO among the three group (F=89.94,71.24,both P=0.001).The activities of caspase-3 and MPO were lower in the control group than in the high-fat group and in high fat plus intermittent hypoxia group [(0.21±0.06) vs.(0.80±0.11),(1.15±0.21),(3.20±0.58) vs.(10.87±1.96),(13.17±2.22),P<0.01].The activities of caspase-3 and MPO were higher in the high-fat plus intermittent hypoxia group than in the high fat group[(1.15±0.21) vs.(0.80±0.11),(13.17±2.22) vs.(10.87±1.96),P<0.01].No abnormal findings in the structure of cardiomyocyte were observed in the control group,while multiple pathologic damages in cardiomyocyte were detected in the high-fat group,and more obvious injuries in the high-fat plus intermittent hypoxia group.Conclusions The pathologic damages to cardiomyocyte are more serious in high fat and intermittent hypoxia group than in the high-fat group.Apoptosis induced by oxidative stress may play an important role in the pathogenesis of these injuries.%目的 通过观察慢性间歇低氧对高脂喂养大鼠心肌细胞组织病理学、氧化应激

  8. Protection of Pentoxifylline against Testis Injury Induced by Intermittent Hypobaric Hypoxia

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    Chen Yao

    2016-01-01

    Full Text Available To investigate the effect of pentoxifylline (PTX on spermatogenesis dysfunction induced by intermittent hypobaric hypoxia (IHH and unveil the underlying mechanism, experimental animals were assigned to Control, IHH+Vehicle, and IHH+PTX groups and exposed to 4 cycles of 96 h of hypobaric hypoxia followed by 96 h of normobaric normoxia for 32 days. PTX was administered for 32 days. Blood and tissue samples were collected 7 days thereafter. Serum malondialdehyde levels were used to assess lipid peroxidation; ferric-reducing antioxidant power (FRAP, superoxide dismutase, and catalase and glutathione peroxidase enzyme activities were assessed to determine antioxidant capacity in various samples. Testis histopathology was assessed after hematoxylin-eosin staining by Johnsen’s testicular scoring system. Meanwhile, testosterone synthase and vimentin amounts were assessed by immunohistochemistry. Sperm count, motility, and density were assessed to determine epididymal sperm quality. IHH treatment induced significant pathological changes in testicular tissue and enhanced serum lipid peroxide levels, while reducing serum FRAP, antioxidant enzyme activities, and testosterone synthase expression. Moreover, IHH impaired epididymal sperm quality and vimentin structure in Sertoli cells. Oral administration of PTX improved the pathological changes in the testis. IHH may impair spermatogenesis function of testicular tissues by inducing oxidative stress, but this impairment could be attenuated by administration of PTX.

  9. System for exposing cultured cells to intermittent hypoxia utilizing gas permeable cultureware.

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    Polak, Jan; Studer-Rabeler, Karen; McHugh, Holly; Hussain, Mehboob A; Shimoda, Larissa A

    2015-07-01

    Tissue intermittent hypoxia (IH) occurs in obstructive sleep apnea, sickle cell anemia, physical exercise and other conditions. Poor gas solubility and slow diffusion through culture media hampers mimicking IH-induced transitions of O(2) in vitro. We aimed to develop a system enabling exposure of cultured cells to IH and to validate such exposure by real-time O(2) measurements and cellular responses. Standard 24-well culture plates and plates with bottoms made from a gas permeable film were placed in a heated cabinet. Desired cycling of O(2) levels was induced using programmable solenoids to purge mixtures of 95% N(2) + 5% CO(2) or 95% O(2) + 5% CO(2). Dissolved oxygen, gas pressure, temperature, and water evaporation were measured during cycling. IH-induced cellular effects were evaluated by hypoxia inducible factor (HIF) and NF-κB luciferase reporters in HEK296 cells and by insulin secretion in rat insulinoma cells. Oxygen cycling in the cabinet was translated into identical changes of O(2) at the well bottom in gas permeable, but not in standard cultureware. Twenty-four hours of IH exposure increased HIF (112%), NF-κB (111%) and insulin secretion (44%). Described system enables reproducible and prolonged IH exposure in cultured cells while controlling for important environmental factors.

  10. [Intermittent thrombolytic treatment. Results during severe, chronic arterial diseases].

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    Fiessinger, J N; Aiach, M; Lagneau, P; Cormier, J M; Housset, E

    1975-04-20

    38 patients with severe chronic arteritis of the lower limbs were treated with streptokinase intermittently. All had been refused for surgical operation. One patient died, 4 others had early interruption of treatment. Eleven of the 38 patients had efficient thrombolysis confirmed by arteriography. The facts confirm the possibility of thrombolysis during chronic arterial disease. The fact that the aggravation was recent was favourable factor in prognosis. The eleven patients improved, had severe aggravation of symptomes for less than 2 months. Thus thrombolytic treatment has a place of choice in the treatment of severe arterial disease where surgery is impossible, or dangerous, owing to the uncertain state of the vascular bed below the lesion. Efficacious, it permits reconstructive surgery in cases where it had been at first refused. The use of intermittent treatment, apart from advantages of confort and cost, seems to increase the efficacy of treatment.

  11. Intermittent hypoxia hypobaric exposure minimized oxidative stress and antioxidants in brain cells of Sprague Dawleymice

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    Wardaya Wardaya

    2013-05-01

    Full Text Available AbstrakLatar belakang: Hipoksia hypobaric meningkatkan produksi radikal bebas, terutama spesies oksigen reaktif (ROS. Peningkatan ROS akan menyebabkan stres oksidatif bila tidak disertai dengan peningkatan enzim antioksidan. Kondisi ini dapat dikurangi dengan hipoksia hipobarik intermiten (HHI. Tujuan penelitian ini mengidentifikasi frekuensi IHH yang dapat meminimalkan efek hipoksia hipobarik terhadap stres oksidatif dan aktivitas antioksidan spesifik pada tikus Sprague Dawley.Metode: Penelitian eksperimental pada bulan Februari-April 2010, Subjek terdiri dari satu kelompok kontrol dan empat kelompok paparan pada mencit jantan Sprague Dawley. Setiap kelompok terdiri dari 5 tikus. Kelompok kontrol tidak terpapar IHH. Kelompok terpapar (dengan selang waktu satu minggu terpapar sekali, dua kali, tiga kali, atau empat kali IHH. Semua kelompok paparan dipaparkan hipobarik setara dengan ketinggian: 35.000 ft (1 menit, 25.000 ft (5 menit, dan 18.000 ft (25 menit. Jaringan otak diperiksa untuk 8-OHdG dan SOD.Hasil:Setelah tiga paparan IHH tingkat 8-OHdG sudah kembali ke nilai kontrol (P = 0,843. Tingkat SOD meningkat secara progresif pada dua, tiga, dan empat kali paparan IHH. Bahkan setelah paparan kedua, tingkat SOD sudah sama dengan nilai kontrol, 0,231 ± 0,042 (P = 0,191.Kesimpulan: Tiga kali IHH sudah dapat meminimalkan pengaruh hipoksia hipobarik terhadap stres oksidatif dan aktivitas spesifik antioksidan pada tikus Sprague Dawley.Kata kunci: hipoksia hipobarik intermiten, stres oksidatif, antioksidanAbstractBackground: Hypoxia hypobaric increase the production of free radicals, especially reactive oxygen species (ROS. The increase in ROS would cause oxidative stress when not accompanied by an increase in antioxidant enzymes. This condition may minimize by intermittent hypobaric hypoxia (IHH. This study aimed to identify the number of IHH which may minimize the effect of hypoxia hypobaric on oxidative stress and the specific activity of

  12. Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

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    J.M. Marshall

    1998-07-01

    Full Text Available This review describes the ways in which the primary bradycardia and peripheral vasoconstriction evoked by selective stimulation of peripheral chemoreceptors can be modified by the secondary effects of a chemoreceptor-induced increase in ventilation. The evidence that strong stimulation of peripheral chemoreceptors can evoke the behavioural and cardiovascular components of the alerting or defence response which is characteristically evoked by novel or noxious stimuli is considered. The functional significance of all these influences in systemic hypoxia is then discussed with emphasis on the fact that these reflex changes can be overcome by the local effects of hypoxia: central neural hypoxia depresses ventilation, hypoxia acting on the heart causes bradycardia and local hypoxia of skeletal muscle and brain induces vasodilatation. Further, it is proposed that these local influences can become interdependent, so generating a positive feedback loop that may explain sudden infant death syndrome (SIDS. It is also argued that a major contributor to these local influences is adenosine. The role of adenosine in determining the distribution of O2 in skeletal muscle microcirculation in hypoxia is discussed, together with its possible cellular mechanisms of action. Finally, evidence is presented that in chronic systemic hypoxia, the reflex vasoconstrictor influences of the sympathetic nervous system are reduced and/or the local dilator influences of hypoxia are enhanced. In vitro and in vivo findings suggest this is partly explained by upregulation of nitric oxide (NO synthesis by the vascular endothelium which facilitates vasodilatation induced by adenosine and other NO-dependent dilators and attenuates noradrenaline-evoked vasoconstriction.

  13. Postnatal intermittent hypoxia and developmental programming of hypertension in spontaneously hypertensive rats: the role of reactive oxygen species and L-Ca2+ channels.

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    Soukhova-O'Hare, Galia K; Ortines, Roger V; Gu, Yan; Nozdrachev, Alexander D; Prabhu, Sumanth D; Gozal, David

    2008-07-01

    Obstructive and central apneas during sleep are associated with chronic intermittent hypoxia (CIH) and increased cardiovascular morbidity. Spontaneously hypertensive rats exposed to CIH during postnatal days 4 to 30 develop exaggerated hypertension as adults. We hypothesized that reactive oxygen species and altered L-Ca(2+) channel activity may underlie the postnatal programming of exaggerated blood pressure and cardiac remodeling. Newborn male spontaneously hypertensive rats were exposed to CIH (10% and 21% O(2) alternating every 90 seconds, 12 h/d, for postnatal days 4 to 30) or normoxia (room air). In each condition, spontaneously hypertensive rats received daily (SC) 1 of 3 treatments: L-calcium channel blocker nifedipine (5 mg/kg), superoxide dismutase mimetic MnTMPyP pentachloride (10 mg/kg), or vehicle (polyethylene glycol). Blood pressure was evaluated monthly for 6 months after birth, and echocardiographic assessments were conducted at 6 months of age. CIH vehicle-treated rats presented higher systolic blood pressure (187+/-5 mm Hg) as compared with normoxic vehicle treated controls (163+/-2 mm Hg; Preactive oxygen species-mediated signaling during intermittent hypoxia are critical mechanisms underlying postnatal programming of an increased severity of hypertension and hypertrophic cardiac remodeling in a genetically susceptible rodent model.

  14. Ω3 Supplementation and Intermittent Hypobaric Hypoxia Induce Cardioprotection Enhancing Antioxidant Mechanisms in Adult Rats

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    Emilio A. Herrera

    2015-02-01

    Full Text Available Intermittent hypobaric hypoxia (IH is linked with oxidative stress, impairing cardiac function. However, early IH also activate cardio-protective mechanisms. Omega 3 fatty acids (Ω3 induce cardioprotection by reducing infarct size and reinforcing antioxidant defenses. The aim of this work was to determine the combined effects of IH and Ω3 on cardiac function; oxidative balance and inflammatory state. Twenty-eight rats were randomly divided into four groups: normobaric normoxia (N; N + Ω3 (0.3 g·kg−1·day−1; IH; and IH + Ω3. IH was induced by 4 intercalate periods of hypoxia (4 days—normoxia (4 days in a hypobaric chamber during 32 days. At the end of the exposure, hearts were mounted in a Langendorff system and subjected to 30 min of ischemia followed by 120 min of reperfusion. In addition, we determined HIF-1α and ATP levels, as well as oxidative stress by malondialdehyde and nitrotyrosine quantification. Further, the expression of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase was determined. NF-kappaB and myeloperoxidase levels were assessed in the hearts. Relative to N hearts, IH improved left ventricular function (Left ventricular developed pressure: N; 21.8 ± 3.4 vs. IH; 42.8 ± 7.1 mmHg; p < 0.05; reduced oxidative stress (Malondialdehyde: N; 14.4 ± 1.8 vs. IH; 7.3 ± 2.1 μmol/mg prot.; p < 0.05; and increased antioxidant enzymes expression. Supplementation with Ω3 induces similar responses as IH group. Our findings suggest that both, IH and Ω3 in an independent manner, induce functional improvement by antioxidant and anti-inflammatory mechanisms, establishing cardio-protection.

  15. Kidney EPO expression during chronic hypoxia in aged mice.

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    Benderro, Girriso F; LaManna, Joseph C

    2013-01-01

    In order to maintain normal cellular function, mammalian tissue oxygen concentrations must be tightly regulated within a narrow physiological range. The hormone erythropoietin (EPO) is essential for maintenance of tissue oxygen supply by stimulating red blood cell production and promoting their survival. In this study we compared the effects of 290 Torr atmospheric pressure on the kidney EPO protein levels in young (4-month-old) and aged (24-month-old) C57BL/6 mice. The mice were sacrificed after being anesthetized, and kidney samples were collected and processed by Western blot analysis. Relatively low basal expression of EPO during normoxia in young mice showed significant upregulation in hypoxia and stayed upregulated throughout the hypoxic period (threefold compared to normoxic control), showing a slight decline toward the third week. Whereas, a relatively higher normoxic basal EPO protein level in aged mice did not show significant increase until seventh day of hypoxia, but showed significant upregulation in prolonged hypoxia. Hence, we confirmed that there is a progressively increased accumulation of EPO during chronic hypoxia in young and aged mouse kidney, and the EPO upregulation during hypoxia showed a similarity with the pattern of increase in hematocrit, which we have reported previously.

  16. 参芪花粉片对高原慢性间歇性缺氧暴露期间脱习服的疗效观察%Curative effect observation of Shenqipollen tablet on deacclimatization during exposure period of the chronic intermittent hypoxia in high altitude regions

    Institute of Scientific and Technical Information of China (English)

    娄晓敏; 张雪峰; 周其全; 王胜玉

    2013-01-01

    OBJECTIVE To investigate the intervention effects of Shenqi pollen tablets on deacclimatization during exposure period of chronic plateau intermittent hypoxic hypoxia. METHODS Selected 380 young healthy workers from the plains and low lying areas into the work area altitude 4 300m, with weekly indoor at an altitude of 4 300m for 5 working days, then returned to the elevation of 2 800m fixed base rest mode, continuously observed the intervention effect of Shenqi pollen tablets on symptom occurrence rate of plateau deacclimatization during rest period exposure period of 3 years in the highlands at an altitude of 2 800m. RESULTS The total detectable rate of altitude deacclimatization was 82.37% (313/380); the top 10 symptoms and the order were: lethargy (66.31%) , fatigue (42.37%) , dizziness (35.78%) , insomnia (30.79%) , decreased appetite (29.73%), upset (29.21%), general malaise (28.95%), depression (27.89%), palpitation (27.10%), and chest tightness (24.47%). The crowd in need of treatment with altitude deacclimatization were detected in the total de-acclimation of those 34.18% (107/313). The intervention effect of Shenqi pollen tablets made the symptoms completely disappear in 92.52% (99/ 107) after medication of 15 days, recurrence rate (cured) was 78.79% (78/99) in who without continue medication in half of one year, even?there were some symptoms and self-medication to ease (CR) 21.21% (21/99) , free remission or partial remission, but often needed medication (inactive) had 7.48% (8/107). There were no adverse drug reactions during observation period. CONCLUSION The high altitude deacclimatization during exposure period of chronic plateau intermittent hypoxic hypoxia has a higher prevalence. Shenqi pollen tablets have better short-term effect and long-term prevention, and is an effective disease prevention and treatment.%目的 探讨参芪花粉片对高原慢性间歇性缺氧暴露期间脱习服的干预效果.方法 选择由平原

  17. Epo deficiency alters cardiac adaptation to chronic hypoxia.

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    El Hasnaoui-Saadani, Raja; Marchant, Dominique; Pichon, Aurélien; Escoubet, Brigitte; Pezet, Mylène; Hilfiker-Kleiner, Denise; Hoch, Melanie; Pham, Isabelle; Quidu, Patricia; Voituron, Nicolas; Journé, Clément; Richalet, Jean-Paul; Favret, Fabrice

    2013-04-01

    The involvement of erythropoietin in cardiac adaptation to acute and chronic (CHx) hypoxia was investigated in erythropoietin deficient transgenic (Epo-TAg(h)) and wild-type (WT) mice. Left (LV) and right ventricular functions were assessed by echocardiography and hemodynamics. HIF-1α, VEGF and Epo pathways were explored through RT-PCR, ELISA, Western blot and immunocytochemistry. Epo gene and protein were expressed in cardiomyocytes of WT mice in normoxia and hypoxia. Increase in blood hemoglobin, angiogenesis and functional cardiac adaptation occurred in CHx in WT mice, allowing a normal oxygen delivery (O2T). Epo deficiency induced LV hypertrophy, increased cardiac output (CO) and angiogenesis, but O2T remained lower than in WT mice. In CHx Epo-TAg(h) mice, LV hypertrophy, CO and O2T decreased. HIF-1α and Epo receptor pathways were depressed, suggesting that Epo-TAg(h) mice could not adapt to CHx despite activation of cardioprotective pathways (increased P-STAT-5/STAT-5). HIF/Epo pathway is activated in the heart of WT mice in hypoxia. Chronic hypoxia induced cardiac adaptive responses that were altered with Epo deficiency, failing to maintain oxygen delivery to tissues.

  18. Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS-dependent MAP kinase activation.

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    Makarenko, Vladislav V; Usatyuk, Peter V; Yuan, Guoxiang; Lee, May M; Nanduri, Jayasri; Natarajan, Viswanathan; Kumar, Ganesh K; Prabhakar, Nanduri R

    2014-04-15

    The objective of the present study was to determine the impact of simulated apnea with intermittent hypoxia (IH) on endothelial barrier function and assess the underlying mechanism(s). Experiments were performed on human lung microvascular endothelial cells exposed to IH-consisting alternating cycles of 1.5% O2 for 30s followed by 20% O2 for 5 min. IH decreased transendothelial electrical resistance (TEER) suggesting attenuated endothelial barrier function. The effect of IH on TEER was stimulus dependent and reversible after reoxygenation. IH-exposed cells exhibited stress fiber formation and redistribution of cortactin, vascular endothelial-cadherins, and zona occludens-1 junction proteins along with increased intercellular gaps at cell-cell boundaries. Extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) were phosphorylated in IH-exposed cells. Inhibiting either ERK or JNK prevented the IH-induced decrease in TEER and the reorganization of the cytoskeleton and junction proteins. IH increased reactive oxygen species (ROS) levels, and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride, a membrane-permeable antioxidant, prevented ERK and JNK phosphorylation as well as IH-induced changes in endothelial barrier function. These results demonstrate that IH via ROS-dependent activation of MAP kinases leads to reorganization of cytoskeleton and junction proteins resulting in endothelial barrier dysfunction.

  19. Effects of acute intermittent hypoxia on energy balance and hypothalamic feeding pathways.

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    Moreau, J M; Ciriello, J

    2013-12-01

    This study was done to investigate the effects of acute intermittent hypoxia (IH) on metabolic factors associated with energy balance and body weight, and on hypothalamic satiety-inducing pathways. Adult male Sprague-Dawley rats were exposed to either 8h IH or normoxic control conditions. Food intake, locomotion and body weights were examined after IH. Additionally, plasma levels of leptin, adiponectin corticosterone, insulin and blood glucose were measured following exposure to IH. Furthermore, adipose tissue was removed and analyzed for leptin and adiponectin content. Finally, the hypothalamic arcuate nucleus (ARC) was assessed for alterations in protein signaling associated with satiety. IH reduced body weight, food intake and active cycle locomotion without altering adipose tissue mass. Leptin protein content was reduced while adiponectin content was elevated in adipose tissue after IH. Plasma concentration of leptin was significantly increased while adiponectin decreased after IH. No changes were found in plasma corticosterone, insulin and blood glucose. In ARC, phosphorylation of signal transducer and activator of transcription-3 and pro-opiomelanocortin (POMC) expression were elevated. In addition, POMC-expressing neurons were activated as determined by immediate early gene FRA-1/2 expression. Finally, ERK1/2 and its phosphorylation were reduced in response to IH. These data suggest that IH induces significant alterations to body energy balance through changes in the secretion of leptin which exert effects on satiety-inducing pathways within the hypothalamus.

  20. Intermittent hypobaric hypoxia combined with aerobic exercise improves muscle morphofunctional recovery after eccentric exercise to exhaustion in trained rats.

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    Rizo-Roca, D; Ríos-Kristjánsson, J G; Núñez-Espinosa, C; Santos-Alves, E; Gonçalves, I O; Magalhães, J; Ascensão, A; Pagès, T; Viscor, G; Torrella, J R

    2017-03-01

    Unaccustomed eccentric exercise leads to muscle morphological and functional alterations, including microvasculature damage, the repair of which is modulated by hypoxia. We present the effects of intermittent hypobaric hypoxia and exercise on recovery from eccentric exercise-induced muscle damage (EEIMD). Soleus muscles from trained rats were excised before (CTRL) and 1, 3, 7, and 14 days after a double session of EEIMD protocol. A recovery treatment consisting of one of the following protocols was applied 1 day after the EEIMD: passive normobaric recovery (PNR), a 4-h daily exposure to passive hypobaric hypoxia at 4,000 m (PHR), or hypobaric hypoxia exposure followed by aerobic exercise (AHR). EEIMD produced an increase in the percentage of abnormal fibers compared with CTRL, and it affected the microvasculature by decreasing capillary density (CD, capillaries per mm(2)) and the capillary-to-fiber ratio (CF). After 14 days, AHR exhibited CD and CF values similar to those of CTRL animals (789 and 3.30 vs. 746 and 3.06) and significantly higher than PNR (575 and 2.62) and PHR (630 and 2.92). Furthermore, VEGF expression showed a significant 43% increase in AHR when compared with PNR. Moreover, after 14 days, the muscle fibers in AHR had a more oxidative phenotype than the other groups, with significantly smaller cross-sectional areas (AHR, 3,745; PNR, 4,502; and PHR, 4,790 µm(2)), higher citrate synthase activity (AHR, 14.8; PNR, 13.1; and PHR, 12 µmol·min(-1)·mg(-1)) and a significant 27% increment in PGC-1α levels compared with PNR. Our data show that hypoxia combined with exercise attenuates or reverses the morphofunctional alterations induced by EEIMD.NEW & NOTEWORTHY Our study provides new insights into the use of intermittent hypobaric hypoxia combined with exercise as a strategy to recover muscle damage induced by eccentric exercise. We analyzed the effects of hypobaric exposure combined with aerobic exercise on histopathological features of muscle

  1. Intermittent hypoxia stimulates formation of binuclear neurons in brain cortex- a role of cell fusion in neuroprotection?

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    Paltsyn, Alexander A; Manukhina, Eugenia B; Goryacheva, Anna V; Downey, H Fred; Dubrovin, Ivan P; Komissarova, Svetlana V; Kubatiev, Aslan A

    2014-05-01

    Oligodendrocyte fusion with neurons in the brain cortex is a part of normal ontogenesis and is a possible means of neuroregeneration. Following such fusion, the oligodendrocyte nucleus undergoes neuron-specific reprogramming, resulting in the formation of binuclear neurons, which doubles the functional capability of the neuron. In this study, we tested the hypothesis that the formation of binuclear neurons is involved in long-term adaptation of the brain to intermittent hypobaric hypoxia, which is known to be neuroprotective. Rats were adapted to hypoxia in an altitude chamber at a simulated altitude of 4000 m above sea level for 14 days (30 min increasing to 4 h, daily). One micrometer sections of the left motor cortex were analyzed by light microscopy. Phases of the fusion and reprogramming process were recorded, and the number of binuclear neurons was counted for all section areas containing pyramidal neurons of layers III-V. For the control group subjected to sham hypoxia, the density of binuclear neurons was 4.49 ± 0.32 mm(2). In the hypoxia-adapted group, this density increased to 5.71 ± 0.39 mm(2) (P neurons did not differ from the number observed in the control group. We suggest that the increased content of binuclear neurons may serve as a structural basis for the neuroprotective effects of the adaptation to hypoxia.

  2. Heart rate variability in conscious neonatal swine: spectral features and responses to short-term intermittent hypoxia

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    Zhao Ning

    2006-06-01

    Full Text Available Abstract Background Spectral analysis of the cardiac time series has been used as a tool for assessing levels of parasympathetic and sympathetic modulation of the sinoatrial node. In the present investigation we evaluated daily changes in heart rate variability spectra in conscious neonatal piglets that were either neurally intact (n = 5 or had undergone right stellate ganglionectomy (n = 5. The partial stellectomized animals and their intact litter mates were exposed to four days of intermittent hypoxia, each day comprising nine episodes of hypoxia alternating with nine episodes of normoxia. A time control group (n = 7 comprised animals from different litters that were not exposed to intermittent hypoxia. We hypothesized that exposure to intermittent hypoxia would increase sympathetic efferent neuronal modulation of heart rate variability spectra in neurally intact animals and in those with right stellate ganglionectomy, and that his effect would be observed in heart rate variability spectra computed from baseline recordings. Results Overall, heart rate variability spectra during baseline conditions were dominated by high frequency activity, a reflection of parasympathetic efferent neuronal innervation and linkage to the ventilatory cycle manifested as respiratory sinus arrhythmia. Exposure to intermittent hypoxia did not alter daily baseline spectral features that would indicate an increase of sympathetic cardiac activity: low frequency (0.05 – 0.15 Hz activity was unaffected and the ratio of low- to -high frequency activity remained less than unity indicating a predominance of high frequency activity. The resultant spectra were remarkably similar despite differences in cardiac sympathetic efferent neuronal innervation and experimental treatment. When spectra were computed from cardiac time series during representative hypoxic episodes, significant increases in activity across the low frequency region (0.05 – 0.15 Hz of heart rate

  3. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα in chronic hypoxia- and antigen-mediated pulmonary vascular remodeling

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    Angelini Daniel J

    2013-01-01

    Full Text Available Abstract Background Both chronic hypoxia and allergic inflammation induce vascular remodeling in the lung, but only chronic hypoxia appears to cause PH. We investigate the nature of the vascular remodeling and the expression and role of hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα in explaining this differential response. Methods We induced pulmonary vascular remodeling through either chronic hypoxia or antigen sensitization and challenge. Mice were evaluated for markers of PH and pulmonary vascular remodeling throughout the lung vascular bed as well as HIMF expression and genomic analysis of whole lung. Results Chronic hypoxia increased both mean pulmonary artery pressure (mPAP and right ventricular (RV hypertrophy; these changes were associated with increased muscularization and thickening of small pulmonary vessels throughout the lung vascular bed. Allergic inflammation, by contrast, had minimal effect on mPAP and produced no RV hypertrophy. Only peribronchial vessels were significantly thickened, and vessels within the lung periphery did not become muscularized. Genomic analysis revealed that HIMF was the most consistently upregulated gene in the lungs following both chronic hypoxia and antigen challenge. HIMF was upregulated in the airway epithelial and inflammatory cells in both models, but only chronic hypoxia induced HIMF upregulation in vascular tissue. Conclusions The results show that pulmonary vascular remodeling in mice induced by chronic hypoxia or antigen challenge is associated with marked increases in HIMF expression. The lack of HIMF expression in the vasculature of the lung and no vascular remodeling in the peripheral resistance vessels of the lung is likely to account for the failure to develop PH in the allergic inflammation model.

  4. Intermittent hypoxia in rats reduces activation of Ca2+ sparks in mesenteric arteries.

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    Jackson-Weaver, Olan; Osmond, Jessica M; Naik, Jay S; Gonzalez Bosc, Laura V; Walker, Benjimen R; Kanagy, Nancy L

    2015-12-01

    Ca(+) sparks are vascular smooth muscle cell (VSMC) Ca(2+)-release events that are mediated by ryanodine receptors (RyR) and promote vasodilation by activating large-conductance Ca(2+)-activated potassium channels and inhibiting myogenic tone. We have previously reported that exposing rats to intermittent hypoxia (IH) to simulate sleep apnea augments myogenic tone in mesenteric arteries through loss of hydrogen sulfide (H2S)-induced dilation. Because we also observed that H2S can increase Ca(2+) spark activity, we hypothesized that loss of H2S after IH exposure reduces Ca(2+) spark activity and that blocking Ca(2+) spark generation reduces H2S-induced dilation. Ca(2+) spark activity was lower in VSMC of arteries from IH compared with sham-exposed rats. Furthermore, depolarizing VSMC by increasing luminal pressure (from 20 to 100 mmHg) or by elevating extracellular [K(+)] increased spark activity in VSMC of arteries from sham rats but had no effect in arteries from IH rats. Inhibiting endogenous H2S production in sham arteries prevented these increases. NaHS or phosphodiesterase inhibition increased spark activity to the same extent in sham and IH arteries. Depolarization-induced increases in Ca(2+) spark activity were due to increased sparks per site, whereas H2S increases in spark activity were due to increased spark sites per cell. Finally, inhibiting Ca(2+) spark activity with ryanodine (10 μM) enhanced myogenic tone in arteries from sham but not IH rats and blocked dilation to exogenous H2S in arteries from both sham and IH rats. Our results suggest that H2S regulates RyR activation and that H2S-induced dilation requires Ca(2+) spark activation. IH exposure decreases endogenous H2S-dependent Ca(2+) spark activation to cause membrane depolarization and enhance myogenic tone in mesenteric arteries.

  5. Combined intermittent hypoxia and surface muscle electrostimulation as a method to increase peripheral blood progenitor cell concentration

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    Azqueta Carmen

    2009-10-01

    Full Text Available Abstract Background Our goal was to determine whether short-term intermittent hypoxia exposure, at a level well tolerated by healthy humans and previously shown by our group to increase EPO and erythropoiesis, could mobilize hematopoietic stem cells (HSC and increase their presence in peripheral circulation. Methods Four healthy male subjects were subjected to three different protocols: one with only a hypoxic stimulus (OH, another with a hypoxic stimulus plus muscle electrostimulation (HME and the third with only muscle electrostimulation (OME. Intermittent hypobaric hypoxia exposure consisted of only three sessions of three hours at barometric pressure 540 hPa (equivalent to an altitude of 5000 m for three consecutive days, whereas muscular electrostimulation was performed in two separate periods of 25 min in each session. Blood samples were obtained from an antecubital vein on three consecutive days immediately before the experiment and 24 h, 48 h, 4 days and 7 days after the last day of hypoxic exposure. Results There was a clear increase in the number of circulating CD34+ cells after combined hypobaric hypoxia and muscular electrostimulation. This response was not observed after the isolated application of the same stimuli. Conclusion Our results open a new application field for hypobaric systems as a way to increase efficiency in peripheral HSC collection.

  6. Intermittent hypoxia selects for genotypes and phenotypes that increase survival, invasion, and therapy resistance.

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    Daniel Verduzco

    Full Text Available Hypoxia in tumors correlates with greater risk of metastases, increased invasiveness, and resistance to systemic and radiation therapy. The evolutionary dynamics that links specific adaptations to hypoxia with these observed tumor properties have not been well investigated. While some tumor populations may experience fixed hypoxia, cyclical and stochastic transitions from normoxia to hypoxia are commonly observed in vivo. Although some phenotypic adaptations to this cyclic hypoxia are likely reversible, we hypothesize that some adaptations may become fixed through mutations promoted by hypoxia-induced genomic instability. Here we seek to identify genetic alterations and corresponding stable phenotypes that emerge following cyclic hypoxia. Although these changes may originate as adaptations to this specific environmental stress, their fixation in the tumor genome may result in their observation in tumors from regions of normoxia, a condition known as pseudohypoxia. We exposed several epithelial cell lines to 50 cycles of hypoxia-normoxia, followed by culture in normoxia over a period of several months. Molecular analyses demonstrated permanent changes in expression of several oncogenes and tumor-suppressors, including p53, E-cadherin, and Hif-1α. These changes were associated with increased resistance to multiple cytotoxins, increased survival in hypoxia and increased anchorage-independent growth. These results suggest cycles of hypoxia encountered in early cancers can select for specific and stable genotypic and phenotypic properties that persist even in normoxic conditions, which may promote tumor progression and resistance to therapy.

  7. Spinal 5-HT7 Receptors and Protein Kinase A Constrain Intermittent Hypoxia-Induced Phrenic Long-term Facilitation

    OpenAIRE

    Hoffman, M. S.; Mitchell, G. S.

    2013-01-01

    Phrenic long-term facilitation (pLTF) is a form of serotonin-dependent respiratory plasticity induced by acute intermittent hypoxia (AIH). pLTF requires spinal Gq protein-coupled serotonin-2 receptor (5-HT2) activation, new synthesis of brain-derived neurotrophic factor (BDNF) and activation of its high-affinity receptor, TrkB. Intrathecal injections of selective agonists for Gs protein-coupled receptors (adenosine 2A and serotonin-7; 5-HT7) also induce long-lasting phrenic motor facilitation...

  8. Inducible nitric oxide synthase contributes to intermittent hypoxia against ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Hai-lei DING; Hai-feng ZHU; Jian-wen DONG; Wei-zhong ZHU; Wei-wei YANG; Huang-tian YANG; Zhao-nian ZHOU

    2005-01-01

    Aim: To investigate the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) in the cardioprotection of intermittent hypoxia (IH) against ischemia/reperfusion (I/R) injury. Methods: Langendorff-perfused isolated rat hearts were used to measure variables of left ventricular function during baseline perfusion, ischemia, and reperfusion period. Nitrate plus nitrite (NOx) content in myocardium was measured using a biochemical method, iNOS mRNA and protein expression in rat left ventricles were detected using reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Results: Myocardial function recovered better in IH rat hearts than in normoxic control hearts.The iNOS-selective inhibitor aminoguanidine (AG) (100 μmol/L) significantly inhibited the protective effects of IH, but had no influence on normoxic rat hearts.The baseline content of NOx in IH hearts was higher than that in normoxic hearts.After 30 min ischemia, the NOx level in normoxic hearts increased compared to the corresponding baseline level, whereas there was no significant change in IH hearts. However, the NOx level in IH hearts was still higher than that of normoxic hearts during ischemia and reperfusion period. AG 100 μmol/L significantly diminished the NOx content in IH and normoxic hearts during ischemia and reperfusion period. The baseline levels of iNOS mRNA and protein in IH hearts were higher than those of normoxic hearts. Compared to the corresponding baseline level,iNOS mRNA and protein levels in normoxic rat hearts increased and those in IH rat hearts decreased after reperfusion. The addition of AG 100 μmol/L significantly decreased iNOS mRNA and protein expression in IH rat hearts after I/R.Conclusion: IH upregulated the baseline level of iNOS mRNA and protein expression leading to an increase in NO production, which may play an important role in the cardiac protection of IH against I/R injury.

  9. Effects of cyclic intermittent hypoxia on ET-1 responsiveness and endothelial dysfunction of pulmonary arteries in rats.

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    Zhuo Wang

    Full Text Available Obstructive sleep apnoea (OSA is a risk factor for cardiovascular disorders and in some cases is complication of pulmonary hypertension. We simulated OSA by exposing rats to cyclic intermittent hypoxia (CIH to investigate its effect on pulmonary vascular endothelial dysfunction. Sprague-Dawley Rats were exposed to CIH (FiO2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/wk for 3 wk, and the pulmonary arteries of normoxia and CIH treated rats were analyzed for expression of endothelin-1 (ET-1 and ET receptors by histological, immunohistochemical, RT-PCR and Western Blot analyses, as well as for contractility in response to ET-1. In the pulmonary arteries, ET-1 expression was increased, and ET-1 more potently elicited constriction of the pulmonary artery in CIH rats than in normoxic rats. Exposure to CIH induced marked endothelial cell damage associated with a functional decrease of endothelium-dependent vasodilatation in the pulmonary artery. Compared with normoxic rats, ETA receptor expression was increased in smooth muscle cells of the CIH rats, while the expression of ETB receptors was decreased in endothelial cells. These results demonstrated endothelium-dependent vasodilation was impaired and the vasoconstrictor responsiveness increased by CIH. The increased responsiveness to ET-1 induced by intermittent hypoxia in pulmonary arteries of rats was due to increased expression of ETA receptors predominantly, meanwhile, decreased expression of ETB receptors in the endothelium may also participate in it.

  10. 室旁核中血管紧张素Ⅱ通过活性氧介导慢性间歇性低氧大鼠的升压作用%Angiotensin Ⅱ inparaventricular nucleus contributes to hypertension in chronic intermittent hypoxia rats by reactive oxygen species

    Institute of Scientific and Technical Information of China (English)

    唐志强; 范一菲; 汪金丽; 程文慧; 沈兵; 钟明奎

    2016-01-01

    目的:研究室旁核( PVN)中血管紧张素Ⅱ( Ang Ⅱ)-活性氧(ROS)通路在慢性间歇性低氧(CIH)大鼠的升压作用。方法将雄性SD大鼠随机分为对照组和慢性间歇性低氧组(CIH 组)(8 h/d,连续15 d)。用立体定位仪进行PVN核团定位微量注射,采用颈动脉插管法在体测量大鼠平均动脉压(MAP),ELISA 法测量 PVN 中 Ang Ⅱ、ROS 含量, Western blot 法测定 PVN 中血管紧张素Ⅱ1型受体(AT1R)的蛋白表达,应用试剂盒(羟胺法)测定PVN中的总超氧化物歧化酶(T-SOD)活力。结果与对照组比较,CIH组大鼠PVN中ROS(P<0.05)和Ang Ⅱ含量显著升高(P<0.01),AT1R的表达显著增加(P<0.05),而T-SOD活力则明显下降( P <0.01)。双侧 PVN 内微量注射 Ang Ⅱ(0.3 nmol)可升高两组大鼠的MAP,而CIH大鼠MAP升高更显著(P<0.01);超氧阴离子清除剂Tempol可降低两组大鼠的MAP,而CIH大鼠MAP降低更显著(P<0.01);Tempol预处理可抑制Ang Ⅱ对两组大鼠的升压作用,且在CIH组中抑制作用更加明显( P<0.01)。结论室旁核中ROS介导了Ang Ⅱ在CIH大鼠中的升压作用。%Objective To investigate the effect of Ang II-ROS signal pathway in the hypothalamic paraventricular nucleus ( PVN) on chronic intermittent hypoxia( CIH) induced-hypertension in rats. Methods Male SD rats were randomly divided into control and CIH groups. The control rats were exposed to continuous normoxia, while the CIH rats were submitted to CIH (8 h per day for 15 days) . Rats were fixed on the stereotaxic instrument to conduct microinjection in the PVN according to Paxinos and Watson rat atlas. Mean arterial pressure ( MAP) was recorded in vivo on a PowerLab data acquisition system. We used ELISA kit to measure the content of AngⅡ, ROS, total-superoxide dismutase (T-SOD) and Western blot to measure AngⅡtype 1 receptor (AT1R) protein expression in PVN. Results The contents of PVN ROS(P<0. 05)and AngⅡ(P<0. 01) were significantly higher than

  11. Normobaric Intermittent Hypoxia over 8 Months Does Not Reduce Body Weight and Metabolic Risk Factors - a Randomized, Single Blind, Placebo-Controlled Study in Normobaric Hypoxia and Normobaric Sham Hypoxia

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    Hannes Gatterer

    2015-05-01

    Full Text Available Objective: Both a 1- to 4-week continuous or intermittent stay and moderate exercise in hypoxia versus normoxia can lead to weight loss. We examined the reproducibility and durability of added hypoxic exposure in a feasible health program of several months. Methods: 32 obese persons, randomly assigned to either a hypoxia (age 50.3 ± 10.3 years, BMI 37.9 ± 8.1 kg/m² or a normoxia (age 52.4 ± 7.9 years, BMI 36.3 ± 4.0 kg/m² group, completed 52 exercise sessions within 8 months. Participants exercised for 90 min (65-70% HRpeak either at a simulated altitude of 3,500 m or in normoxia, and rested for further 90 min at 4,500 m or normoxia. Before, after 5 weeks, after 3 months, and after the intervention, body composition and exercise capacity were determined. Risk markers (e.g., blood pressure, cholesterol were measured before, after 3 months, and after the intervention period. Results: Body weight, BMI, waist and hip circumference, Ppeak and BPsys improved over time (p Conclusion: Long-term, moderate intensity exercise and rest in hypoxia does not lead to higher reductions in body weight than normoxia alone. Therefore, for weight loss and metabolic markers hypoxic exposure does not add effects at least when stimuli (i.e., hypoxia dose, exercise intensity/duration are unaltered throughout the intervention.

  12. Intermittent hypoxia leads to functional reorganization of mitochondria and affects cellular bioenergetics in marine molluscs.

    Science.gov (United States)

    Ivanina, Anna V; Nesmelova, Irina; Leamy, Larry; Sokolov, Eugene P; Sokolova, Inna M

    2016-06-01

    Fluctuations in oxygen (O2) concentrations represent a major challenge to aerobic organisms and can be extremely damaging to their mitochondria. Marine intertidal molluscs are well-adapted to frequent O2 fluctuations, yet it remains unknown how their mitochondrial functions are regulated to sustain energy metabolism and prevent cellular damage during hypoxia and reoxygenation (H/R). We used metabolic control analysis to investigate the mechanisms of mitochondrial responses to H/R stress (18 h at <0.1% O2 followed by 1 h of reoxygenation) using hypoxia-tolerant intertidal clams Mercenaria mercenaria and hypoxia-sensitive subtidal scallops Argopecten irradians as models. We also assessed H/R-induced changes in cellular energy balance, oxidative damage and unfolded protein response to determine the potential links between mitochondrial dysfunction and cellular injury. Mitochondrial responses to H/R in scallops strongly resembled those in other hypoxia-sensitive organisms. Exposure to hypoxia followed by reoxygenation led to a strong decrease in the substrate oxidation (SOX) and phosphorylation (PHOS) capacities as well as partial depolarization of mitochondria of scallops. Elevated mRNA expression of a reactive oxygen species-sensitive enzyme aconitase and Lon protease (responsible for degradation of oxidized mitochondrial proteins) during H/R stress was consistent with elevated levels of oxidative stress in mitochondria of scallops. In hypoxia-tolerant clams, mitochondrial SOX capacity was enhanced during hypoxia and continued rising during the first hour of reoxygenation. In both species, the mitochondrial PHOS capacity was suppressed during hypoxia, likely to prevent ATP wastage by the reverse action of FO,F1-ATPase. The PHOS capacity recovered after 1 h of reoxygenation in clams but not in scallops. Compared with scallops, clams showed a greater suppression of energy-consuming processes (such as protein turnover and ion transport) during hypoxia, indicated

  13. Role of chronic hypoxia and hypoxia inducible factor in kidney disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ Cells are endowed with a defensive mechanism against hypoxia,namely hypoxia-inducible factor (HIF) and hypoxia-responsive element (HRE).Under hypoxic conditions,activation of HIF leads to expression of a variety of adaptive genes with HRE in a coordinated manner.

  14. Heart rate and blood pressure responses during hypoxic cycles of a 3-week intermittent hypoxia breathing program in patients at risk for or with mild COPD

    Directory of Open Access Journals (Sweden)

    Faulhaber M

    2015-02-01

    Full Text Available Martin Faulhaber,1 Hannes Gatterer,1 Thomas Haider,2 Tobias Linser,1 Nikolaus Netzer,1 Martin Burtscher11Department of Sport Science, University of Innsbruck, Innsbruck, Austria; 2Institute of Veterinary Physiology, University of Zurich, Zurich, SwitzerlandAbstract: The aim of this study was to provide information on heart rate and blood pressure responses during a 3-week intermittent hypoxia breathing program in COPD patients. Sixteen participants with COPD symptoms were randomly assigned to a hypoxia or control group and completed a 3-week intermittent hypoxia breathing program (five sessions per week, each consisting of three to five breathing cycles, each cycle lasting 3–5 minutes with 3-minute breaks between cycles. During the breathing cycles, the hypoxia group received hypoxic air (inspired fraction of oxygen 15%–12%, whereas the control group received normal air (sham hypoxia. During the breaks, all participants breathed normoxic room air. Arterial oxygen saturation, systolic and diastolic blood pressure, and heart rate were measured during the normoxic and hypoxic/sham hypoxic periods. For each breathing cycle, changes from normoxia to hypoxia/sham hypoxia were calculated, and changes were averaged for each of the 15 sessions and for each week. Changes in arterial oxygen saturation were significantly different between groups in the course of the 3 weeks (two-way analysis of variance for repeated measures, with post hoc differences in weeks 1, 2, and 3. During the course of the intermittent hypoxia application, no between-group differences were detected for blood pressure or rate pressure product values. Changes in heart rate were significantly different between groups in the course of the 3 weeks (two-way analysis of variance for repeated measures, with post hoc differences only in week 3. Averages over all 15 sessions were significantly higher in the hypoxia group for heart rate and rate pressure product, and tended to be

  15. Evidence that chronic hypoxia causes reversible impairment on male fertility

    Institute of Scientific and Technical Information of China (English)

    Vittore Verratti; Francesco Berardinelli; Camillo Di Giulio; Gerardo Bosco; Marisa Cacchio; Mario Pellicciotta; Michele Nicolai; Stefano Martinotti; Raffaele Tenaglia

    2008-01-01

    Aim: To evaluate the effect of chronic hypoxia on human spermatogenic parameters and their recovery time. Methods: Seminological parameters of six male healthy mountain trekkers were evaluated in normoxia at sea level. After 26 days exposure to altitude (ranging from 2 000 m to 5 600 m, Karakorum Expedition) the same parameters were again evaluated after returning to sea level. These parameters were once again evaluated after 1 month and then again after 6 months. Results: Sperm count was found to be lower immediately after returning to sea level (P = 0.0004) and again after a month (P = 0.0008). Normal levels were reached after 6 months. Spermatic motility (%) shows no reduction immediately after returning to sea level (P = 0.0583), whereas after 1 month this reduction was significant (P = 0.0066). After 6 months there was a recovery to pre-hypoxic exposure values. Abnormal or immature sperma- tozoa (%) increased immediately after returning to sea level (P = 0.0067) and then again after 1 month (P=0.0004). After 6 months there was a complete recovery to initial values. The total number of motile sperm in the ejaculate was found to be lower immediately after returning to sea level (P = 0.0024) and then again after 1 month (P = 0.0021). After 6 months there was a recovery to pre-hypoxic exposure values. Conclusion: Chronic hypoxia induces a state of oligospermia and the normalization of such seminological parameters at the restoration of previous normoxic conditions after 6 months indicate the influence of oxygen supply in physiological mechanisms of spermatogenesis and male fertility. (Asian J Androl 2008 Jul; 10: 602-606)

  16. Chronic hypoxia during gestation enhances uterine arterial myogenic tone via heightened oxidative stress.

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    Daliao Xiao

    Full Text Available Chronic hypoxia during gestation has profound adverse effects on the adaptation of uteroplacental circulation in pregnancy. Yet, the underlying mechanisms are not fully understood. The present study tested the hypothesis that enhanced production of reactive oxygen species (ROS in uterine arteries plays a critical role in the maladaptation of uterine circulation associated with chronic hypoxia. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep maintained at sea level (~300 m or exposed to high-altitude (3801 m hypoxia for 110 days. Hypoxia significantly increased ROS production in uterine arteries of pregnant, but not nonpregnant, sheep. This was associated with a significant increase in NADPH oxidase (Nox 2, but not Nox1 or Nox4, protein abundance and total Nox activity in uterine arteries of pregnant animals. Chronic hypoxia significantly increased pressure-dependent uterine arterial myogenic tone in pregnant sheep, which was abrogated by a Nox inhibitor apocynin. Additionally, the hypoxia-induced increase in myogenic reactivity of uterine arteries to phorbol 12,13-dibutyrate in pregnant sheep was blocked by apocynin and tempol. In consistence with the myogenic responses, the hypoxia-mediated down-regulation of BKCa channel activity in uterine arteries of pregnant animals was reversed by apocynin. The findings suggest that heightened oxidative stress in uterine arteries plays a key role in suppressing the BKCa channel activity, resulting in increased myogenic reactivity and maladaptation of uteroplacental circulation caused by chronic hypoxia during gestation.

  17. Human adipocytes are highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, Cormac T. [School of Medicine and Medical Science, The Conway Institute, University College Dublin (Ireland); Kent, Brian D.; Crinion, Sophie J.; McNicholas, Walter T. [School of Medicine and Medical Science, The Conway Institute, University College Dublin (Ireland); Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Dublin (Ireland); Ryan, Silke, E-mail: silke.ryan@ucd.ie [School of Medicine and Medical Science, The Conway Institute, University College Dublin (Ireland); Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Dublin (Ireland)

    2014-05-16

    Highlights: • Intermittent hypoxia (IH) leads to NF-κB activation in human primary adipocytes. • Adipocytes bear higher pro-inflammatory potential than other human primary cells. • IH leads to upregulation of multiple pro-inflammatory genes in human adipocytes. - Abstract: Introduction: Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmented inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages. Methods and results: Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes. Conclusion: Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may be a key

  18. Spinal vascular endothelial growth factor (VEGF) and erythropoietin (EPO) induced phrenic motor facilitation after repetitive acute intermittent hypoxia.

    Science.gov (United States)

    Dale, Erica A; Mitchell, Gordon S

    2013-02-01

    Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) exert neurotrophic and neuroprotective effects in the CNS. We recently demonstrated that VEGF, EPO and their receptors (VEGF-R2, EPO-R) are expressed in phrenic motor neurons, and that cervical spinal VEGF-R2 and EPO-R activation elicit long-lasting phrenic motor facilitation (pMF). Since VEGF, VEGF-R, EPO, and EPO-R are hypoxia-regulated genes, and repetitive exposure to acute intermittent hypoxia (rAIH) up-regulates these molecules in phrenic motor neurons, we tested the hypothesis that 4 weeks of rAIH (10 episodes per day, 3 days per week) enhances VEGF- or EPO-induced pMF. We confirm that cervical spinal VEGF and EPO injections elicit pMF. However, neither VEGF- nor EPO-induced pMF was affected by rAIH pre-conditioning (4 wks). Although our data confirm that spinal VEGF and EPO may play an important role in respiratory plasticity, we provide no evidence that rAIH amplifies their impact. Further experiments with more robust protocols are warranted.

  19. Intermittent Hypoxia Influences Alveolar Bone Proper Microstructure via Hypoxia-Inducible Factor and VEGF Expression in Periodontal Ligaments of Growing Rats

    Science.gov (United States)

    Oishi, Shuji; Shimizu, Yasuhiro; Hosomichi, Jun; Kuma, Yoichiro; Maeda, Hideyuki; Nagai, Hisashi; Usumi-Fujita, Risa; Kaneko, Sawa; Shibutani, Naoki; Suzuki, Jun-ichi; Yoshida, Ken-ichi; Ono, Takashi

    2016-01-01

    Intermittent hypoxia (IH) recapitulates morphological changes in the maxillofacial bones in children with obstructive sleep apnea (OSA). Recently, we found that IH increased bone mineral density (BMD) in the inter-radicular alveolar bone (reflecting enhanced osteogenesis) in the mandibular first molar (M1) region in the growing rats, but the underlying mechanism remains unknown. In this study, we focused on the hypoxia-inducible factor (HIF) pathway to assess the effect of IH by testing the null hypothesis of no significant differences in the mRNA-expression levels of relevant factors associated with the HIF pathway, between control rats and growing rats with IH. To test the null hypothesis, we investigated how IH enhances mandibular osteogenesis in the alveolar bone proper with respect to HIF-1α and vascular endothelial growth factor (VEGF) in periodontal ligament (PDL) tissues. Seven-week-old male Sprague–Dawley rats were exposed to IH for 3 weeks. The microstructure and BMD in the alveolar bone proper of the distal root of the mandibular M1 were evaluated using micro-computed tomography (micro-CT). Expression of HIF-1α and VEGF mRNA in PDL tissues were measured, whereas osteogenesis was evaluated by measuring mRNA levels for alkaline phosphatase (ALP) and bone morphogenetic protein-2 (BMP-2). The null hypothesis was rejected: we found an increase in the expression of all of these markers after IH exposure. The results provided the first indication that IH enhanced osteogenesis of the mandibular M1 region in association with PDL angiogenesis during growth via HIF-1α in an animal model. PMID:27695422

  20. Intermittent Hypoxia Influences Alveolar Bone Proper Microstructure via Hypoxia-Inducible Factor and VEGF Expression in Periodontal Ligaments of Growing Rats

    Directory of Open Access Journals (Sweden)

    Shuji Oishi

    2016-09-01

    Full Text Available Intermittent hypoxia (IH recapitulates morphological changes in the maxillofacial bones in children with obstructive sleep apnea (OSA. Recently, we found that IH increased bone mineral density (BMD in the inter-radicular alveolar bone (reflecting enhanced osteogenesis in the mandibular first molar (M1 region in the growing rats, but the underlying mechanism remains unknown. In this study, we focused on the hypoxia-inducible factor (HIF pathway to assess the effect of IH by testing the null hypothesis of no significant differences in the mRNA-expression levels of relevant factors associated with the HIF pathway, between control rats and growing rats with IH. To test the null hypothesis, we investigated how IH enhances mandibular osteogenesis in the alveolar bone proper with respect to HIF-1α and vascular endothelial growth factor (VEGF in periodontal ligament (PDL tissues. Seven-week-old male Sprague–Dawley rats were exposed to IH for 3 weeks. The microstructure and BMD in the alveolar bone proper of the distal root of the mandibular M1 were evaluated using micro-computed tomography (micro-CT. Expression of HIF-1α and VEGF mRNA in PDL tissues were measured, whereas osteogenesis was evaluated by measuring mRNA levels for alkaline phosphatase (ALP and bone morphogenetic protein-2 (BMP-2. The null hypothesis was rejected: we found an increase in the expression of all of these markers after IH exposure. The results provided the first indication that IH enhanced osteogenesis of the mandibular M1 region in association with PDL angiogenesis during growth via HIF-1α in an animal model.

  1. Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity.

    Science.gov (United States)

    Bouslama, Myriam; Adla-Biassette, Homa; Ramanantsoa, Nelina; Bourgeois, Thomas; Bollen, Bieke; Brissaud, Olivier; Matrot, Boris; Gressens, Pierre; Gallego, Jorge

    2015-01-01

    Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in

  2. Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity

    Directory of Open Access Journals (Sweden)

    Myriam eBouslama

    2015-11-01

    Full Text Available Apnea of prematurity (AOP is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group, a control group exposed to normoxia while separated from the mother (AIR group, and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group. Exposure to moderate IH consisted of 20 hypoxic events/hour, 6 hours per day from postnatal day 6 (P6 to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine

  3. Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity

    Science.gov (United States)

    Bouslama, Myriam; Adle-Biassette, Homa; Ramanantsoa, Nelina; Bourgeois, Thomas; Bollen, Bieke; Brissaud, Olivier; Matrot, Boris; Gressens, Pierre; Gallego, Jorge

    2015-01-01

    Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in

  4. Vascular and hepatic impact of short-term intermittent hypoxia in a mouse model of metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Wojciech Trzepizur

    Full Text Available Experimental models of intermittent hypoxia (IH have been developed during the last decade to investigate the consequences of obstructive sleep apnea. IH is usually associated with detrimental metabolic and vascular outcomes. However, paradoxical protective effects have also been described depending of IH patterns and durations applied in studies. We evaluated the impact of short-term IH on vascular and metabolic function in a diet-induced model of metabolic syndrome (MS.Mice were fed either a standard diet or a high fat diet (HFD for 8 weeks. During the final 14 days of each diet, animals were exposed to either IH (1 min cycle, FiO2 5% for 30s, FiO2 21% for 30s; 8 h/day or intermittent air (FiO2 21%. Ex-vivo vascular reactivity in response to acetylcholine was assessed in aorta rings by myography. Glucose, insulin and leptin levels were assessed, as well as serum lipid profile, hepatic mitochondrial activity and tissue nitric oxide (NO release.Mice fed with HFD developed moderate markers of dysmetabolism mimicking MS, including increased epididymal fat, dyslipidemia, hepatic steatosis and endothelial dysfunction. HFD decreased mitochondrial complex I, II and IV activities and increased lactate dehydrogenase (LDH activity in liver. IH applied to HFD mice induced a major increase in insulin and leptin levels and prevented endothelial dysfunction by restoring NO production. IH also restored mitochondrial complex I and IV activities, moderated the increase in LDH activity and liver triglyceride accumulation in HFD mice.In a mouse model of MS, short-term IH increases insulin and leptin levels, restores endothelial function and mitochondrial activity and limits liver lipid accumulation.

  5. Sildenafil and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets.

    Science.gov (United States)

    Binns-Loveman, Karen M; Kaplowitz, Mark R; Fike, Candice D

    2005-07-01

    Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications.

  6. Autophagy-associated atrophy and metabolic remodeling of the mouse diaphragm after short-term intermittent hypoxia.

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    Christian Giordano

    Full Text Available Short-term intermittent hypoxia (IH is common in patients with acute respiratory disorders. Although prolonged exposure to hypoxia induces atrophy and increased fatigability of skeletal muscle, the response to short-term IH is less well known. We hypothesized that the diaphragm and limb muscles would adapt differently to short-term IH given that hypoxia stimulates ventilation and triggers a superimposed exercise stimulus in the diaphragm.We determined the structural, metabolic, and contractile properties of the mouse diaphragm after 4 days of IH (8 hours per day, 30 episodes per hour to a FiO2 nadir=6%, and compared responses in the diaphragm to a commonly studied reference limb muscle, the tibialis anterior. Outcome measures included muscle fiber size, assays of muscle proteolysis (calpain, ubiquitin-proteasome, and autophagy pathways, markers of oxidative stress and mitochondrial function, quantification of intramyocellular lipid and lipid metabolism genes, type I myosin heavy chain (MyHC expression, and in vitro contractile properties.After 4 days of IH, the diaphragm alone demonstrated significant atrophy (30% decrease of myofiber size together with increased LC3B-II protein (2.4-fold and mRNA markers of the autophagy pathway (LC3B, Gabarapl1, Bnip3, whereas active calpain and E3 ubiquitin ligases (MuRF1, atrogin-1 were unaffected in both muscles. Succinate dehydrogenase activity was significantly reduced by IH in both muscles. However, only the diaphragm exhibited increased intramyocellular lipid droplets (2.5-fold after IH, along with upregulation of genes linked to activated lipid metabolism. In addition, although the diaphragm showed evidence for acute fatigue immediately following IH, it underwent an adaptive fiber type switch toward slow type I MyHC-expressing fibers, associated with greater intrinsic endurance of the muscle during repetitive stimulation in vitro.Short-term IH induces preferential atrophy in the mouse diaphragm

  7. A gloss of Chronic Hypoxia in normal and diseased individuals at high altitude

    Institute of Scientific and Technical Information of China (English)

    Zubieta-Castillo,G.; Zubieta-Calleja,G.R.; Zubieta-Calleja L.

    2004-01-01

    @@ Introduction Millenary populations that live at high altitude in different continents like Asia (1) and South America (8), have endured biological adaptation in very adverse environmental conditions, of which to our understanding, paradoxically, chronic hypoxia is the most tolerable. Patients with pulmonary diseases at high altitude tolerate tissue hypoxia with an arterial tension (PaO2) even as low as 30 mmHg. Current scientific knowledge has made progress in many areas, clarifying many doubts, however due to preconception and lack of broad social studies chronic hypoxia is still not fully understood. Beings that inhabit different areas of the planet earth have lived under a variety of different hostile conditions: intense cold in the polar regions,intense heat in Africa and in the Middle East desserts,great pressure in the depth of the oceans, intense darkness of the caves and naturally the hypoxia of extreme altitudes.

  8. Role of Cyclooxygenase-2 on Intermittent Hypoxia-Induced Lung Tumor Malignancy in a Mouse Model of Sleep Apnea

    Science.gov (United States)

    Campillo, Noelia; Torres, Marta; Vilaseca, Antoni; Nonaka, Paula Naomi; Gozal, David; Roca-Ferrer, Jordi; Picado, César; Montserrat, Josep Maria; Farré, Ramon; Navajas, Daniel; Almendros, Isaac

    2017-01-01

    An adverse role for obstructive sleep apnea (OSA) in cancer epidemiology and outcomes has recently emerged from clinical and animal studies. In animals, intermittent hypoxia (IH) mimicking OSA promotes tumor malignancy both directly and via host immune alterations. We hypothesized that IH could potentiate cancer aggressiveness through activation of the cyclooxygenase-2 (COX-2) pathway and the concomitant increases in prostaglandin E2 (PGE2). The contribution of the COX-2 in IH-induced enhanced tumor malignancy was assessed using celecoxib as a COX-2 specific inhibitor in a murine model of OSA bearing Lewis lung carcinoma (LLC1) tumors. Exposures to IH accelerated tumor progression with a tumor associated macrophages (TAMs) shift towards a pro-tumoral M2 phenotype. Treatment with celecoxib prevented IH-induced adverse tumor outcomes by inhibiting IH-induced M2 polarization of TAMs. Furthermore, TAMs isolated from IH-exposed mice treated with celecoxib reduced the proliferation of LLC1 naïve cells, while the opposite occurred with placebo-treated IH-exposed mice. Finally, in vitro IH exposures of murine macrophages and LLC1 cells showed that both cell types increased PGE2 release in response to IH. These results suggest a crucial role for the COX-2 signaling pathway in the IH-exacerbated malignant processes, and designate macrophages and lung adenocarcinoma cells, as potential sources of PGE2. PMID:28300223

  9. Delivery of In Vivo Acute Intermittent Hypoxia in Neonatal Rodents to Prime Subventricular Zone-derived Neural Progenitor Cell Cultures.

    Science.gov (United States)

    Ross, Heather H; Sandhu, Milap S; Sharififar, Sharareh; Fuller, David D

    2015-11-02

    Extended culture of neural stem/progenitor cells facilitates in vitro analyses to understand their biology while enabling expansion of cell populations to adequate numbers prior to transplantation. Identifying approaches to refine this process, to augment the production of all CNS cell types (i.e., neurons), and to possibly contribute to therapeutic cell therapy protocols is a high research priority. This report describes an easily applied in vivo "pre-conditioning" stimulus which can be delivered to awake, non-anesthetized animals. Thus, it is a non-invasive and non-stressful procedure. Specifically described are the procedures for exposing mouse or rat pups (aged postnatal day 1-8) to a brief (40-80 min) period of intermittent hypoxia (AIH). The procedures included in this video protocol include calibration of the whole-body plethysmography chamber in which pups are placed during AIH and the technical details of AIH exposure. The efficacy of this approach to elicit tissue-level changes in the awake animal is demonstrated through the enhancement of subsequent in vitro expansion and neuronal differentiation in cells harvested from the subventricular zone (SVZ). These results support the notion that tissue level changes across multiple systems could be observed following AIH, and support the continued optimization and establishment of AIH as a priming or conditioning modality for therapeutic cell populations.

  10. Regulation of cerebral blood flow in mammals during chronic hypoxia: a matter of balance.

    Science.gov (United States)

    Ainslie, Philip N; Ogoh, Shigehiko

    2010-02-01

    Respiratory-induced changes in the partial pressures of arterial carbon dioxide (PaCO2) and oxygen (PaO2) play a major role in cerebral blood flow (CBF) regulation. Elevations in PaCO2 (hypercapnia) lead to vasodilatation and increases in CBF, whereas reductions in PaCO2 (hypocapnia) lead to vasoconstriction and decreases in CBF. A fall in PaO2 (hypoxia) below a certain threshold (balance between the myriad of vasodilators and constrictors derived from the endothelium, neuronal innervations and perfusion pressure. This review examines the extent and mechanisms by which hypoxia regulates CBF. Particular focus will be given to the marked influence of hypoxia associated with exposure to high altitude and chronic lung disease. The associated implications of these hypoxia-induced integrative alterations for the regulation of CBF are discussed, and future avenues for research are proposed.

  11. Spinal 5-HT7 receptors and protein kinase A constrain intermittent hypoxia-induced phrenic long-term facilitation.

    Science.gov (United States)

    Hoffman, M S; Mitchell, G S

    2013-10-10

    Phrenic long-term facilitation (pLTF) is a form of serotonin-dependent respiratory plasticity induced by acute intermittent hypoxia (AIH). pLTF requires spinal Gq protein-coupled serotonin-2 receptor (5-HT2) activation, new synthesis of brain-derived neurotrophic factor (BDNF) and activation of its high-affinity receptor, TrkB. Intrathecal injections of selective agonists for Gs protein-coupled receptors (adenosine 2A and serotonin-7; 5-HT7) also induce long-lasting phrenic motor facilitation via TrkB "trans-activation." Since serotonin released near phrenic motor neurons may activate multiple serotonin receptor subtypes, we tested the hypothesis that 5-HT7 receptor activation contributes to AIH-induced pLTF. A selective 5-HT7 receptor antagonist (SB-269970, 5mM, 12 μl) was administered intrathecally at C4 to anesthetized, vagotomized and ventilated rats prior to AIH (3, 5-min episodes, 11% O2). Contrary to predictions, pLTF was greater in SB-269970 treated versus control rats (80 ± 11% versus 45 ± 6% 60 min post-AIH; p5-HT7 receptor inhibition, suggesting that drug effects were localized to the spinal cord. Since 5-HT7 receptors are coupled to protein kinase A (PKA), we tested the hypothesis that PKA inhibits AIH-induced pLTF. Similar to 5-HT7 receptor inhibition, spinal PKA inhibition (KT-5720, 100 μM, 15 μl) enhanced pLTF (99 ± 15% 60 min post-AIH; p5-HT7 receptors constrain AIH-induced pLTF via PKA activity.

  12. Intermittent Hypoxia-Induced Parvalbumin-Immunoreactive Interneurons Loss and Neurobehavioral Impairment is Mediated by NADPH-Oxidase-2.

    Science.gov (United States)

    Yuan, Liang; Wu, Jing; Liu, Jiang; Li, Guowei; Liang, Dong

    2015-06-01

    Obstructive sleep apnea usually contribute to psychiatric diseases and cognitive impairments in adults. Loss of parvalbumin (PV)-immunoreactive interneurons (PV-IN) in the brain cortex is an important feature of psychiatric diseases, such as schizophrenia. Here we investigate the causal contribution of oxidative stress in the brain cortex to neuropathological alterations in a mouse model of sleep apnea. Wild-type (WT) and the NADPH-oxidase-2 (gp91-phox/NOX2) knock-out adult male C57BL/6J mice were exposed to intermittent hypoxia (IH) or standard room air in the same chamber. In vivo we determined the impact (1) of IH exposures on NOX2 expression, (2) of genetic gp91-phox/NOX2 knock-out and (3) of pharmacological NOX2 inhibition on IH-induced neuropathological alterations in adult mice. Endpoints were oxidative stress, PV-IN and neurobehavioral alterations. The results showed IH exposures increased NOX2 expression in the prefrontal cortex of WT mice, which was accompanied with elevations of indirect markers of oxidative stress (HNE, HIF-1α, 8-OHDG). WT mice showed loss of PV-IN in the prefrontal cortex and increased locomotion activity and anxiety levels after exposed to IH, while no change emerged in NOX2 knock-out mice. Treatment of WT mice with the antioxidant/NOX inhibitor apocynin prevented the neuropathological and neurobehavioral alterations induced by IH exposures. Our data suggest that NOX2-derived oxidative stress is involved in the loss of PV-IN in the prefrontal cortex and development of neurobehavioral alterations for adult mice exposed to IH. These results provide a molecular mechanism for the coupling between sleep apnea and brain oxidative stress as well as potential new therapeutic avenues.

  13. Acute and Chronic Sustained Hypoxia Do Not Substantially Regulate Amyloid-β Peptide Generation In Vivo

    Science.gov (United States)

    Heras-Garvín, Antonio; March-Díaz, Rosana; Navarro, Victoria; Vizuete, Marisa; López-Barneo, José; Vitorica, Javier; Pascual, Alberto

    2017-01-01

    Background Recent epidemiological evidence has linked hypoxia with the development of Alzheimer disease (AD). A number of in vitro and in vivo studies have reported that hypoxia can induce amyloid-β peptide accumulation through various molecular mechanisms including the up-regulation of the amyloid-β precursor protein, the β-secretase Bace1, or the γγ-secretase complex components, as well as the down-regulation of Aβ-degrading enzymes. Objectives To investigate the effects of acute and chronic sustained hypoxia in Aβ generation in vivo. Methods 2–3 month-old C57/Bl6J wild-type mice were exposed to either normoxia (21% O2) or hypoxia (9% O2) for either 4 to 72 h (acute) or 21–30 days (chronic sustained) in a hermetic chamber. Brain mRNA levels of Aβ-related genes were measured by quantitative real-time PCR, whereas levels of Bace1 protein, full length AβPP, and its C-terminal fragments (C99/C88 ratio) were measured by Western blot. In addition, 8 and 14-month-old APP/PS1 transgenic mice were subjected to 9% O2 for 21 days and levels of Aβ40, Aβ42, full length AβPP, and soluble AβPPα (sAβPPα) were measured by ELISA or WB. Results Hypoxia (either acute or chronic sustained) did not impact the transcription of any of the Aβ-related genes in young wild-type mice. A significant reduction of Bace1 protein level was noted with acute hypoxia for 16 h but did not correlate with an increased level of full length AβPP or a decreased C99/C83 ratio. Chronic sustained hypoxia did not significantly alter the levels of Bace1, full length AβPP or the C99/C83 ratio. Last, chronic sustained hypoxia did not significantly change the levels of Aβ40, Aβ42, full length AβPP, or sAβPPα in either young or aged APP/PS1 mice. Discussion Our results argue against a hypoxia-induced shift of AβPP proteolysis from the non-amyloidogenic to the amyloidogenic pathways. We discuss the possible methodological caveats of previous in vivo studies. PMID:28099462

  14. Evaluation of anxiolytic effect and withdrawal anxiety in chronic intermittent diazepam treatment in rats.

    Science.gov (United States)

    Açikmeşe, Bariş; Haznedar, Seçil; Hatipoğlu, Iclal; Enginar, Nurhan

    2012-04-01

    This study evaluated the effect of intermittent administration in the development of dependence to diazepam in chronic use of the drug. Gabapentin was used to provide an anxiolytic effect on drug-free days. During a 28-day treatment schedule, rats were given diazepam (15 mg/kg) once daily continuously, or intermittently with saline or gabapentin (50 mg/kg) on days 5, 10, 15, 20, and 25. Anxiety-like behavior was assessed on days 10 and 30 using the elevated plus-maze test and novelty-induced grooming test. Contrary to continuous administration, intermittent diazepam did not provide anxiolytic-like activity on day 10; instead, it prevented withdrawal anxiety on day 30. Gabapentin produced anxiolytic-like effects during the withdrawal period, but not on day 10. These results suggest that intermittent administration of diazepam (given either alone or alternatively with a drug possessing anxiolytic activity) may be of value in preventing the development of physical dependence during the chronic use of the drug. However, further studies are needed to demonstrate that this protocol could effectively produce anxiolytic activity on diazepam-free days.

  15. AMP-Activated Protein Kinase Is Essential for Survival in Chronic Hypoxia

    Science.gov (United States)

    Borger, Darrell R.; Gavrilescu, L. Cristina; Bucur, Maria C.; Ivan, Mircea; DeCaprio, James A.

    2008-01-01

    This study was undertaken to interrogate cancer cell survival during long-term hypoxic stress. Two systems with relevance to carcinogenesis were employed: fully transformed BJ cells, and a renal carcinoma cell line (786-0). The dynamic of AMPK activity was consistent with a prosurvival role during chronic hypoxia. This was further supported by the effects of AMPK agonists and antagonists (AICAR and Compound C). Expression of a dominant-negative AMPK alpha resulted in decreased ATP level, and significantly compromised survival in hypoxia. Dose dependent pro-survival effects of rapamycin were consistent with mTOR inhibition being critical downstream of AMPK in persistent low oxygen. PMID:18359290

  16. Effects of angiotensin II on leptin and downstream leptin signaling in the carotid body during acute intermittent hypoxia.

    Science.gov (United States)

    Moreau, J M; Messenger, S A; Ciriello, J

    2015-12-03

    Angiotensin II (ANG II) is known to promote leptin production and secretion. Although ANG II type 1 receptors (AT1Rs) and leptin are expressed within the carotid body, it is not known whether AT1R and leptin are co-expressed in the same glomus cells nor if these peptides are affected within the carotid body by intermittent hypoxia (IH). This study was done to investigate whether ANG II modulated leptin signaling in the carotid body during IH. Rats were treated with captopril (Capt) or the AT1R blocker losartan (Los) in the drinking water for 3days prior to being exposed to IH (8h) or normoxia (8h). IH induced increases in plasma ANG II and leptin compared to normoxic controls. Capt treatment abolished the plasma leptin changes to IH, whereas Los treatment had no effect on the IH induced increase in plasma leptin. Additionally, carotid body glomus cells containing both leptin and the long form of the leptin receptor (OB-Rb) were found to co-express AT1R protein, and IH increased the expression of only AT1R protein within the carotid body in both Capt- and non-Capt-treated animals. On the other hand, Los treatment did not modify AT1R protein expression to IH. Additionally, Capt and Los treatment eliminated the elevated carotid body leptin protein expression, and the changes in phosphorylated signal transducer and activator of transcription three protein, the short form of the leptin receptor (OB-R100), suppressor of cytokine signaling 3, and phosphorylated extracellular-signal-regulated kinase 1/2 protein expression induced by IH. However, Capt elevated the expression of OB-Rb protein, whereas Los abolished the changes in OB-Rb protein to IH. These findings, taken together with the previous observation that ANG II modifies carotid body chemosensitivity, suggest that the increased circulating levels of ANG II and leptin induced by IH act at the carotid body to alter leptin signaling within the carotid body which in turn may influence chemoreceptor function.

  17. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FAILS TO ALTER FLASH OR PATTERN REVERSAL EVOKED POTENTIALS IN RATS.

    Science.gov (United States)

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Visual disturbances are often reported following exposure to xenobiotics, and cholinesterase-inhibiting compounds have been reported to alter visual functi...

  18. Chronic hypobaric hypoxia mediated skeletal muscle atrophy: role of ubiquitin-proteasome pathway and calpains.

    Science.gov (United States)

    Chaudhary, Pooja; Suryakumar, Geetha; Prasad, Rajendra; Singh, Som Nath; Ali, Shakir; Ilavazhagan, Govindsamy

    2012-05-01

    The most frequently reported symptom of exposure to high altitude is loss of body mass and decreased performance which has been attributed to altered protein metabolism affecting skeletal muscles mass. The present study explores the mechanism of chronic hypobaric hypoxia mediated skeletal muscle wasting by evaluating changes in protein turnover and various proteolytic pathways. Male Sprague-Dawley rats weighing about 200 g were exposed to hypobaric hypoxia (7,620 m) for different durations of exposure. Physical performance of rats was measured by treadmill running experiments. Protein synthesis, protein degradation rates were determined by (14)C-Leucine incorporation and tyrosine release, respectively. Chymotrypsin-like enzyme activity of the ubiquitin-proteasome pathway and calpains were studied fluorimetrically as well as using western blots. Declined physical performance by more than 20%, in terms of time taken in exhaustion on treadmill, following chronic hypobaric hypoxia was observed. Compared to 1.5-fold increase in protein synthesis, the increase in protein degradation was much higher (five-folds), which consequently resulted in skeletal muscle mass loss. Myofibrillar protein level declined from 46.79 ± 1.49 mg/g tissue at sea level to 37.36 ± 1.153 (P calpains (three-fold) has been found to be important factors for the enhanced protein degradation rate. The study provided strong evidences suggesting that elevated protein turnover rate lead to skeletal muscle atrophy under chronic hypobaric hypoxia via ubiquitin-proteasome pathway and calpains.

  19. Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in mice.

    Directory of Open Access Journals (Sweden)

    Eileen M Bauer

    Full Text Available Evidence suggests a role of both innate and adaptive immunity in the development of pulmonary arterial hypertension. The complement system is a key sentry of the innate immune system and bridges innate and adaptive immunity. To date there are no studies addressing a role for the complement system in pulmonary arterial hypertension.Immunofluorescent staining revealed significant C3d deposition in lung sections from IPAH patients and C57Bl6/J wild-type mice exposed to three weeks of chronic hypoxia to induce pulmonary hypertension. Right ventricular systolic pressure and right ventricular hypertrophy were increased in hypoxic vs. normoxic wild-type mice, which were attenuated in C3-/- hypoxic mice. Likewise, pulmonary vascular remodeling was attenuated in the C3-/- mice compared to wild-type mice as determined by the number of muscularized peripheral arterioles and morphometric analysis of vessel wall thickness. The loss of C3 attenuated the increase in interleukin-6 and intracellular adhesion molecule-1 expression in response to chronic hypoxia, but not endothelin-1 levels. In wild-type mice, but not C3-/- mice, chronic hypoxia led to platelet activation as assessed by bleeding time, and flow cytometry of platelets to determine cell surface P-selectin expression. In addition, tissue factor expression and fibrin deposition were increased in the lungs of WT mice in response to chronic hypoxia. These pro-thrombotic effects of hypoxia were abrogated in C3-/- mice.Herein, we provide compelling genetic evidence that the complement system plays a pathophysiologic role in the development of PAH in mice, promoting pulmonary vascular remodeling and a pro-thrombotic phenotype. In addition we demonstrate C3d deposition in IPAH patients suggesting that complement activation plays a role in the development of PAH in humans.

  20. Effects of interleukin-18 and hypoxia-inducible factor-1αin serum and gingival tissues of rat model with periodontitis ;exposed to chronic intermittent hypoxia%慢性间歇低氧对大鼠牙周炎模型血清及牙龈组织中白细胞介素-18和低氧诱导因子-1α的影响

    Institute of Scientific and Technical Information of China (English)

    王斌; 王小琴

    2015-01-01

    目的:观察常氧和慢性间歇低氧下大鼠牙周炎模型中白细胞介素-18(IL-18)和低氧诱导因子(HIF)-1α的表达情况,探讨牙周炎和阻塞性睡眠呼吸暂停低通气综合征(OSAHS)发病相关的可能机制。方法将32只SD大鼠随机分为4组:常氧对照组、常氧牙周炎组、低氧对照组、低氧牙周炎组。通过结扎双侧上颌第二磨牙和高糖饮食的方法建立牙周炎模型。低氧对照组和低氧牙周炎组大鼠置于模拟中重度OSAHS的慢性间歇低氧环境中。8周后处死大鼠,检测各组大鼠的牙周指标,采用酶联免疫吸附测定法检测各组大鼠血清及牙龈组织中IL-18和HIF-1α的质量浓度,分析低氧牙周炎组的牙周附着丧失与IL-18和HIF-1α的相关性。结果低氧牙周炎组的IL-18、HIF-1α的质量浓度较其余3组明显升高(P<0.05);其血清中IL-18、HIF-1α的质量浓度与牙周附着丧失呈正相关,相关系数r分别为0.792和0.753(P<0.05);牙龈组织中IL-18、HIF-1α质量浓度与牙周附着丧失也呈正相关,相关系数r分别为0.817和0.779(P<0.05)。结论慢性间歇低氧能加重牙周炎症,与IL-18、HIF-1α的表达有相关性。%Objective This study evaluates the expression of interleukin-18 (IL-18) and hypoxia-inducible factor (HIF)-1αin 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

  1. Expression profiling reveals novel hypoxic biomarkers in peripheral blood of adult mice exposed to chronic hypoxia.

    Directory of Open Access Journals (Sweden)

    Matias Mosqueira

    Full Text Available Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX, exposed for two weeks to normobaric chronic hypoxia (CH or two weeks of CH followed by two weeks of normoxic recovery (REC. Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off, 230 genes were identified and separated into four distinct temporal categories. Class I contained 1 transcript up-regulated in both CH and REC; Class II contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III contained 9 transcripts down-regulated both in CH and REC; Class IV contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1 by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia.

  2. P2X7 Receptor Antagonism Attenuates the Intermittent Hypoxia-induced Spatial Deficits in a Murine Model of Sleep Apnea Via Inhibiting Neuroinflammation and Oxidative Stress

    Institute of Scientific and Technical Information of China (English)

    Yan Deng; Xue-Ling Guo; Xiao Yuan; Jin Shang; Die Zhu; Hui-Guo Liu

    2015-01-01

    Background:The mechanism of the neural injury caused by chronic intermittent hypoxia (CIH) that characterizes obstructive sleep apnea syndrome (OSAS) is not clearly known.The purpose of this study was to investigate whether P2X7 receptor (P2X7R) is responsible for the CIH-induced neural injury and the possible pathway it involves.Methods:Eight-week-old male C57BL/6 mice were used.For each exposure time point,eight mice divided in room air (RA) and IH group were assigned to the study of P2X7R expression.Whereas in the 21 days-Brilliant Blue G (BBG,a selective P2X7R antagonist) study,48 mice were randomly divided into CIH group,BBG-treated CIH group,RA group and BBG-treated RA group.The hippocampus P2X7R expression was determined by Western blotting and real-time polymerase chain reaction (PCR).The spatial learning was analyzed by Morris water maze.The nuclear factor kappa B (NFκB) and NADPH oxidase 2 (NOX2) expressions were analyzed by Westem blotting.The expressions of tumor necrosis factor α,interleukin 1 β (IL-β),IL-18,and IL-6 were measured by real-time PCR.The malondialdehyde and superoxide dismutase levels were detected by colorimetric method.Cell damage was evaluated by Hematoxylin and Eosin staining and Terminal Transferase dUTP Nick-end Labeling method.Results:The P2X7R mRNA was elevated and sustained after 3-day IH exposure and the P2X7R protein was elevated and sustained after 7-day IH exposure.In the BBG study,the CIH mice showed severer neuronal cell damage and poorer performance in the behavior test.The increased NFκB and NOX2 expressions along with the inflammation injury and oxidative stress were also observed in the CIH group.BBG alleviated CIH-induced neural injury and consequent functional deficits.Conclusions:The P2X7R antagonism attenuates the CIH-induced neuroinflammation,oxidative stress,and spatial deficits,demonstrating that the P2X7R is an important therapeutic target in the cognition deficits accompanied OSAS.

  3. Stress Signal Network between Hypoxia and ER Stress in Chronic Kidney Disease

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    Maekawa, Hiroshi; Inagi, Reiko

    2017-01-01

    Chronic kidney disease (CKD) is characterized by an irreversible decrease in kidney function and induction of various metabolic dysfunctions. Accumulated findings reveal that chronic hypoxic stress and endoplasmic reticulum (ER) stress are involved in a range of pathogenic conditions, including the progression of CKD. Because of the presence of an arteriovenous oxygen shunt, the kidney is thought to be susceptible to hypoxia. Chronic kidney hypoxia is induced by a number of pathogenic conditions, including renal ischemia, reduced peritubular capillary, and tubulointerstitial fibrosis. The ER is an organelle which helps maintain the quality of proteins through the unfolded protein response (UPR) pathway, and ER dysfunction associated with maladaptive UPR activation is named ER stress. ER stress is reported to be related to some of the effects of pathogenesis in kidney, particularly in the podocyte slit diaphragm and tubulointerstitium. Furthermore, chronic hypoxia mediates ER stress in blood vessel endothelial cells and tubulointerstitium via several mechanisms, including oxidative stress, epigenetic alteration, lipid metabolism, and the AKT pathway. In summary, a growing consensus considers that these stresses interact via complicated stress signal networks, which leads to the exacerbation of CKD (Figure 1). This stress signal network might be a target for interventions aimed at ameliorating CKD.

  4. Hypoxia,angiogenesis and liver fibrogenesis in the progression of chronic liver diseases

    Institute of Scientific and Technical Information of China (English)

    Claudia; Paternostro; Ezio; David; Erica; Novo; Maurizio; Parola

    2010-01-01

    Angiogenesis is a dynamic,hypoxia-stimulated and growth factor-dependent process,and is currently referred to as the formation of new vessels from preexisting blood vessels.Experimental and clinical studies have unequivocally reported that hepatic angiogenesis,irrespective of aetiology,occurs in conditions of chronic liver diseases(CLDs) characterized by perpetuation of cell injury and death,inflammatory response and progressive fibrogenesis.Angiogenesis and related changes in liver vascular architecture,th...

  5. Intermittent hypoxia induces the proliferation of rat vascular smooth muscle cell with the increases in epidermal growth factor family and erbB2 receptor

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    Kyotani, Yoji, E-mail: cd147@naramed-u.ac.jp [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522 (Japan); Ota, Hiroyo [Second Department of Internal Medicine, Nara Medical University School of Medicine, Kashihara 634-8522 (Japan); Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Itaya-Hironaka, Asako; Yamauchi, Akiyo; Sakuramoto-Tsuchida, Sumiyo [Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Zhao, Jing; Ozawa, Kentaro; Nagayama, Kosuke; Ito, Satoyasu [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Takasawa, Shin [Department of Biochemistry, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan); Kimura, Hiroshi [Second Department of Internal Medicine, Nara Medical University School of Medicine, Kashihara 634-8522 (Japan); Uno, Masayuki [Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522 (Japan); Yoshizumi, Masanori [Department of Pharmacology, Nara Medical University School of Medicine, Kashihara 634-8521 (Japan)

    2013-11-15

    Obstructive sleep apnea is characterized by intermittent hypoxia (IH), and associated with cardiovascular diseases, such as stroke and heart failure. These cardiovascular diseases have a relation to atherosclerosis marked by the proliferation of vascular smooth muscle cells (VSMCs). In this study, we investigated the influence of IH on cultured rat aortic smooth muscle cell (RASMC). The proliferation of RASMC was significantly increased by IH without changing the level of apoptosis. In order to see what induces RASMC proliferation, we investigated the influence of normoxia (N)-, IH- and sustained hypoxia (SH)-treated cell conditioned media on RASMC proliferation. IH-treated cell conditioned medium significantly increased RASMC proliferation compared with N-treated cell conditioned medium, but SH-treated cell conditioned medium did not. We next investigated the epidermal growth factor (EGF) family as autocrine growth factors. Among the EGF family, we found significant increases in mRNAs for epiregulin (ER), amphiregulin (AR) and neuregulin-1 (NRG1) in IH-treated cells and mature ER in IH-treated cell conditioned medium. We next investigated the changes in erbB family receptors that are receptors for ER, AR and NRG1, and found that erbB2 receptor mRNA and protein expressions were increased by IH, but not by SH. Phosphorylation of erbB2 receptor at Tyr-1248 that mediates intracellular signaling for several physiological effects including cell proliferation was increased by IH, but not by SH. In addition, inhibitor for erbB2 receptor suppressed IH-induced cell proliferation. These results provide the first demonstration that IH induces VSMC proliferation, and suggest that EGF family, such as ER, AR and NRG1, and erbB2 receptor could be involved in the IH-induced VSMC proliferation. - Highlights: ●In vitro system for intermittent hypoxia (IH) and sustained hypoxia (SH). ●IH, but not SH, induces the proliferation of rat vascular smooth muscle cell. ●Epiregulin m

  6. Intermittent targeted therapies and stochastic evolution in patients affected by chronic myeloid leukemia

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    Pizzolato, N.; Persano Adorno, D.; Valenti, D.; Spagnolo, B.

    2016-05-01

    Front line therapy for the treatment of patients affected by chronic myeloid leukemia (CML) is based on the administration of tyrosine kinase inhibitors, namely imatinib or, more recently, axitinib. Although imatinib is highly effective and represents an example of a successful molecular targeted therapy, the appearance of resistance is observed in a proportion of patients, especially those in advanced stages. In this work, we investigate the appearance of resistance in patients affected by CML, by modeling the evolutionary dynamics of cancerous cell populations in a simulated patient treated by an intermittent targeted therapy. We simulate, with the Monte Carlo method, the stochastic evolution of initially healthy cells to leukemic clones, due to genetic mutations and changes in their reproductive behavior. We first present the model and its validation with experimental data by considering a continuous therapy. Then, we investigate how fluctuations in the number of leukemic cells affect patient response to the therapy when the drug is administered with an intermittent time scheduling. Here we show that an intermittent therapy (IT) represents a valid choice in patients with high risk of toxicity, despite an associated delay to the complete restoration of healthy cells. Moreover, a suitably tuned IT can reduce the probability of developing resistance.

  7. Behavioural and neurochemical comparison of chronic intermittent cathinone, mephedrone and MDMA administration to the rat.

    Science.gov (United States)

    Shortall, Sinead E; Macerola, Alice E; Swaby, Rabbi T R; Jayson, Rebecca; Korsah, Chantal; Pillidge, Katharine E; Wigmore, Peter M; Ebling, Francis J P; Richard Green, A; Fone, Kevin C F; King, Madeleine V

    2013-09-01

    The synthetic cathinone derivative, mephedrone, is a controlled substance across Europe. Its effects have been compared by users to 3,4-methylenedioxymethamphetamine (MDMA), but little data exist on its pharmacological properties. This study compared the behavioural and neurochemical effects of mephedrone with cathinone and MDMA in rats. Young-adult male Lister hooded rats received i.p. cathinone (1 or 4 mg/kg), mephedrone (1, 4 or 10mg/kg) or MDMA (10mg/kg) on two consecutive days weekly for 3 weeks or as a single acute injection (for neurochemical analysis). Locomotor activity (LMA), novel object discrimination (NOD), conditioned emotional response (CER) and prepulse inhibition of the acoustic startle response (PPI) were measured following intermittent drug administration. Dopamine, 5-hydroxytryptamine (5-HT) and their major metabolites were measured in striatum, frontal cortex and hippocampus by high performance liquid chromatography 7 days after intermittent dosing and 2h after acute injection. Cathinone (1, 4 mg/kg), mephedrone (10mg/kg) and MDMA (10mg/kg) induced hyperactivity following the first and sixth injections and sensitization to cathinone and mephedrone occurred with chronic dosing. All drugs impaired NOD and mephedrone (10mg/kg) reduced freezing in response to contextual re-exposure during the CER retention trial. Acute MDMA reduced hippocampal 5-HT and 5-HIAA but the only significant effect on dopamine, 5-HT and their metabolites following chronic dosing was altered hippocampal 3,4-dihydroxyphenylacetic acid (DOPAC), following mephedrone (4, 10mg/kg) and MDMA. At the doses examined, mephedrone, cathinone, and MDMA induced similar effects on behaviour and failed to induce neurotoxic damage when administered intermittently over 3 weeks.

  8. Chronic intermittent heroin produces locomotor sensitization and long-lasting enhancement of conditioned reinforcement.

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    Morrison, J; Thornton, V; Ranaldi, R

    2011-09-01

    In a previous study we showed that chronic intermittent heroin in rats enhanced responding with conditioned reinforcement and reversal learning of a conditioned magazine approach task when tested three days after the heroin treatment. Whether or not this enhanced appetitive learning persists after a protracted withdrawal period remains unknown and constitutes the aim of the present study. Forty-eight male Long Evans rats were each exposed to positive pairings of a light stimulus and food for 4 consecutive daily sessions. Then, two groups of rats received saline and two groups received heroin (2 mg/kg) injections before placement in activity monitors for 9 consecutive daily sessions. This was followed by testing in operant conditioning chambers where one lever produced the light stimulus previously paired with food and another no stimulus. For one saline and one heroin group this testing occurred after 2 days of withdrawal while for the other saline and heroin groups it occurred after 30 days of withdrawal. The results indicate that animals treated with heroin displayed progressively and significantly greater locomotor activity across sessions while animals treated with saline displayed locomotor activity that remained low and stable across sessions. In addition, the heroin groups in each withdrawal condition displayed significantly enhanced responding with conditioned reinforcement compared to their respective saline control groups. These results demonstrate that chronic intermittent heroin enhances appetitive learning for natural reinforcers and motivational processes and that this effect persists even after 30-days of withdrawal.

  9. Superficially, longer, intermittent ozone theraphy in the treatment of the chronic, infected wounds.

    Science.gov (United States)

    Białoszewski, Dariusz; Kowalewski, Michał

    2003-10-30

    Background. Ozone therapy - i.e. the treatment of patients by a mixture of oxygen and ozone - has been used for many years as a method ancillary to basic treatment, especially in those cases in which traditional treatment methods do not give satisfactory results, e.g. skin loss in non-healing wounds, ulcers, pressure sores, fistulae, etc. Material and methods. In the Department of Phisiotherapy of the Medical Faculty and the Department of the Orthopedics and Traumatology of the Locomotor System at the Medical University of Warsaw in the period from January 2001 until November 2002, 23 patients with heavy,chronic, antibiotic resistants septic complications after trauma, surgical procedures and secundary skin infetions were treated with ozone. The ozone therapy was administered using an authorial technique of superficially, longer, intermittent ozone application. Results. In the wounds of the all experienced patients the inhibition of septic processes and wound healing was much faster than normal. Conclusions. Our data confirm the advantages wich result from the technique of superficially, longer, intermittent ozone theraphy in combined treatment for septic complications in the soft tissue, especially in the locomotor system. These technique makes posttraumatic infections and promotes quicker healing of post-surgical and post-traumal complications - chronic septic infections. This method also lowers the cost of antibiotic therapy and is sometimes the only available auxiliary technique to support surgical procedures.

  10. High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria.

    Science.gov (United States)

    Pallet, Nicolas; Mami, Iadh; Schmitt, Caroline; Karim, Zoubida; François, Arnaud; Rabant, Marion; Nochy, Dominique; Gouya, Laurent; Deybach, Jean-Charles; Xu-Dubois, Yichum; Thervet, Eric; Puy, Hervé; Karras, Alexandre

    2015-08-01

    Acute intermittent porphyria (AIP) is a genetic disorder of the synthesis of heme caused by a deficiency in hydroxymethylbilane synthase (HMBS), leading to the overproduction of the porphyrin precursors δ-aminolevulinic acid and porphobilinogen. The aim of this study is to describe the clinical and biological characteristics, the renal pathology, and the cellular mechanisms of chronic kidney disease associated with AIP. A total of 415 patients with HMBS deficiency followed up in the French Porphyria Center were enrolled in 2003 in a population-based study. A follow-up study was conducted in 2013, assessing patients for clinical, biological, and histological parameters. In vitro models were used to determine whether porphyrin precursors promote tubular and endothelial cytotoxicity. Chronic kidney disease occurred in up to 59% of the symptomatic AIP patients, with a decline in the glomerular filtration rate of ~1 ml/min per 1.73 m(2) annually. Proteinuria was absent in the vast majority of the cases. The renal pathology was a chronic tubulointerstitial nephropathy, associated with a fibrous intimal hyperplasia and focal cortical atrophy. Our experimental data provide evidence that porphyrin precursors promote endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes in proximal tubular cells. In conclusion, the diagnosis of chronic kidney disease associated with AIP should be considered in cases of chronic tubulointerstitial nephropathy and/or focal cortical atrophy with severe proliferative arteriosclerosis.

  11. Chronic hypoxia impairs muscle function in the Drosophila model of Duchenne's muscular dystrophy (DMD.

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    Matias Mosqueira

    Full Text Available Duchenne's muscular dystrophy (DMD is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH. To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level. Additionally, dmDys and wild type (WT flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips® and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys. These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s to hypoxia may offer a novel therapeutic strategy in DMD.

  12. H,K-ATPase and carbonic anhydrase response to chronic systemic rat gastric hypoxia

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    Ulfah Lutfiah

    2015-11-01

    Full Text Available Background: Hypoxia may induce gastric ulcer associated with excessive hidrogen chloride (HCl secretion. Synthesis of HCl involves 2 enzymes, H,K-ATPase and carbonic anhydrase (CA. This study aimed to clarify the underlying cause of gastric ulcer in chronic hypoxic condition, by investigating the H,K-ATPase and CA9 response in rats.Methods: This study was an in vivo experiment, to know the relationship between hypoxia to expression of H,K-ATPase and CA9 mRNA, and H,K-ATPase and total CA specific activity of chronic systemic rat gastric hypoxia. The result was compared to control. Data was analyzed by SPSS. If the data distribution was normal and homogeneous, ANOVA and LSD post-hoc test were used. However, if the distribution was not normal and not homogeneous, and still as such after transformation, data was treated in non-parametric using Kruskal-Wallis and Mann Whitney test. Twenty five male Sprague-Dawley rats were divided into 5 groups: rats undergoing hypoxia for 1, 3, 5, and 7 days placed in hypoxia chamber (10% O2, 90% N2, and one control group. Following this treatment, stomach of the rats was extracted and homogenized. Expression of H,K-ATPase and CA9 mRNA was measured using real time RT-PCR. Specific activity of H,K-ATPase was measured using phosphate standard solution, and specific activity of total CA was measured using p-nitrophenol solution.Results: The expression of H,K-ATPase mRNA was higher in the first day (2.159, and drastically lowered from the third to seventh day (0.289; 0.108; 0.062. Specific activities of H,K-ATPase was slightly higher in the first day (0.765, then was lowered in the third (0.685 and fifth day (0.655, and was higher in the seventh day (0.884. The expression of CA9 mRNA was lowered progressively from the first to seventh day (0.84; 0.766; 0.736; 0.343. Specific activities of total CA was low in the first day (0.083, and was higher from the third to seventh day (0.111; 0.136; 0.144.Conclusion: In hypoxia

  13. Chronic hypoxia increases TRPC6 expression and basal intracellular Ca2+ concentration in rat distal pulmonary venous smooth muscle.

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    Lei Xu

    Full Text Available Hypoxia causes remodeling and contractile responses in both pulmonary artery (PA and pulmonary vein (PV. Here we explore the effect of hypoxia on PV and pulmonary venous smooth muscle cells (PVSMCs.Chronic hypoxic pulmonary hypertension (CHPH model was established by exposing rats to 10% O2 for 21 days. Rat distal PVSMCs were isolated and cultured for in vitro experiments. The fura-2 based fluorescence calcium imaging was used to measure the basal intracellular Ca2+ concentration ([Ca2+]i and store-operated Ca2+ entry (SOCE. Quantitative RT-PCR and western blotting were performed to measure the expression of mRNA and levels of canonical transient receptor potential (TRPC protein respectively.Hypoxia increased the basal [Ca2+]i and SOCE in both freshly dissociated and serum cultured distal PVSMCs. Moreover, hypoxia increased TRPC6 expression at mRNA and protein levels in both cultured PVSMCs exposed to prolonged hypoxia (4% O2, 60 h and distal PV isolated from CHPH rats. Hypoxia also enhanced proliferation and migration of rat distal PVSMCs.Hypoxia induces elevation of SOCE in distal PVSMCs, leading to enhancement of basal [Ca2+]i in PVSMCs. This enhancement is potentially correlated with the increased expression of TRPC6. Hypoxia triggered intracellular calcium contributes to promoted proliferation and migration of PVSMCs.

  14. Chronic hypoxia in pregnancy affects thymus development in Balb/c mouse offspring via IL2 Signaling.

    Science.gov (United States)

    Zhang, Xiaopeng; Zhou, Xiuwen; Li, Lingjun; Sun, Miao; Gao, Qingqing; Zhang, Pengjie; Tang, Jiaqi; He, Yu; Zhu, Di; Xu, Zhice

    2016-04-01

    Hypoxia during pregnancy can adversely affect development. This study, addressed the impact of prenatal hypoxia on thymus development in the rodent offspring. Pregnant Balb/c mice were exposed to hypoxia or normoxia during pregnancy, and the thymuses of their offspring were tested. Chronic hypoxia during pregnancy resulted in significantly decreased fetal body weight, with an increased thymus-to-body weight ratio. Histological analysis revealed a smaller cortical zone in the thymus of the offspring exposed to hypoxia. A reduction in the cortical T lymphocyte population corresponded to increased mRNA abundance of caspase 3 (Casp3) and decreased expression of the proliferation marker Ki-67 (Mki67). Differences in T lymphocyte sub-populations in the thymus further indicate that thymus development in offspring was retarded or stagnated by prenatal hypoxia. The abundance of IL2 and its receptor was reduced in the thymus following prenatal hypoxia. This was accompanied by an increase in thymus HIF1A and IKKβ and a decrease in phosphorylated NFKB, MAP2K1, and MAPK1/3 compared to control pregnancies. Together, these results implicate deficiencies in IL2-mediated signaling as one source of prenatal-hypoxia-impaired thymus development.

  15. Differential Effects of Chronic and Chronic-Intermittent Ethanol Treatment and Its Withdrawal on the Expression of miRNAs

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    Joanne M. Lewohl

    2013-05-01

    Full Text Available Chronic and excessive alcohol misuse results in changes in the expression of selected miRNAs and their mRNA targets in specific regions of the human brain. These expression changes likely underlie the cellular adaptations to long term alcohol misuse. In order to delineate the mechanism by which these expression changes occur, we have measured the expression of six miRNAs including miR-7, miR-153, miR-152, miR-15B, miR-203 and miR-144 in HEK293T, SH SY5Y and 1321 N1 cells following exposure to ethanol. These miRNAs are predicted to target key genes involved in the pathophysiology of alcoholism. Chronic and chronic-intermittent exposure to ethanol, and its removal, resulted in specific changes in miRNA expression in each cell line suggesting that different expression patterns can be elicited with different exposure paradigms and that the mechanism of ethanol’s effects is dependent on cell type. Specifically, chronic exposure to ethanol for five days followed by a five day withdrawal period resulted in up-regulation of several miRNAs in each of these cell lines similar to expression changes identified in post mortem human brain. Thus, this model can be used to elucidate the role of miRNAs in regulating gene expression changes that occur in response to ethanol exposure.

  16. High-intensity intermittent training in hypoxia: a double-blinded, placebo-controlled field study in youth football players.

    Science.gov (United States)

    Brocherie, Franck; Girard, Olivier; Faiss, Raphael; Millet, Grégoire P

    2015-01-01

    This study examined the effects of 5 weeks (∼60 minutes per training, 2 d·wk) of run-based high-intensity repeated-sprint ability (RSA) and explosive strength/agility/sprint training in either normobaric hypoxia repeated sprints in hypoxia (RSH; inspired oxygen fraction [FIO2] = 14.3%) or repeated sprints in normoxia (RSN; FIO2 = 21.0%) on physical performance in 16 highly trained, under-18 male footballers. For both RSH (n = 8) and RSN (n = 8) groups, lower-limb explosive power, sprinting (10-40 m) times, maximal aerobic speed, repeated-sprint (10 × 30 m, 30-s rest) and repeated-agility (RA) (6 × 20 m, 30-s rest) abilities were evaluated in normoxia before and after supervised training. Lower-limb explosive power (+6.5 ± 1.9% vs. +5.0 ± 7.6% for RSH and RSN, respectively; both p football players, the addition of 10 repeated-sprint training sessions performed in hypoxia vs. normoxia to their regular football practice over a 5-week in-season period was more efficient at enhancing RA ability (including direction changes), whereas it had no additional effect on improvements in lower-limb explosive power, maximal sprinting, and RSA performance.

  17. Reoxygenation, but neither hypoxia nor intermittent ischemia, increases ( sup 125 I)endothelin-1 binding to rat cardiac membranes

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    Liu, J.J.; Gu, X.H.; Casley, D.J.; Nayler, W.G. (Univ. of Melbourne, Heidelberg, Victoria (Australia))

    1990-03-01

    Standard binding techniques were used to establish whether either hypoxia, reoxygenation, perfusion under acidotic conditions, or stunning of the myocardium resembles ischemia and postischemic reperfusion in increasing cardiac membrane ({sup 125}I)endothelin-1 (ET-1) binding site density (Bmax). Membranes from aerobically perfused rat hearts bound ({sup 125}I)ET-1 to a single population of sites, with an affinity (KD) of 0.093 +/- 0.004 nM and a Bmax of 98.8 +/- 5.2 fmol/mg of protein. Bmax was increased (p less than 0.01) after 30 min of global ischemia, and further increased upon reperfusion, without changes in KD or selectivity. Neither three 10 min episodes of ischemia separated by 15 min of perfusion, nor perfusion at pH 6.8 instead of 7.4, nor 60 min of hypoxia altered Bmax, KD, or selectivity. Reoxygenation after 60 min of hypoxia increased Bmax (p less than 0.01) and KD (p less than 0.01) without changing selectivity. These results are interpreted to mean that the ischemia-induced increase in Bmax for ({sup 125}I)ET-1 cannot be explained simply in terms of the ischemia-induced acidosis, or the accompanying reduction in tissue adenosine triphosphate and creatine phosphate.

  18. Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats.

    Science.gov (United States)

    Wallace, Ashley; Pehrson, Alan L; Sánchez, Connie; Morilak, David A

    2014-10-01

    Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.

  19. Mechanisms of cell protection by adaptation to chronic and acute hypoxia: molecular biology and clinical practice.

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    Corbucci, G G; Marchi, A; Lettieri, B; Luongo, C

    2005-11-01

    Several experimental and clinical studies have shown that specific biochemical and molecular pathways are involved in the myocardial and skeletal muscle cell tolerance to acute and/or chronic hypoxic injury. A number of different factors were proposed to play a role in the preservation of tissue viability, but to a few of them a pivotal role in the adaptive mechanisms to hypoxic stimuli could be ascribed. Starting from the observation that mitochondrial electron transport chain (ETC) enzymic complexes are the targets of oxygen reduced availability, most of data are compatible with a mechanism of enzymic adaptation in which the nitric oxide (NO) generation plays the major role. If the partial and reversible NO-induced inhibition of ETC enzymic complexes represents the most rapid and prominent adaptive mechanism in counteracting the damaging effects of hypoxia, the sarcolemmal and mitochondrial K+(ATP) channels activation results to be closely involved in cytoprotection. This process is depending on protein kinase C (PKC) isoform activation triggered by reactive oxygen species (ROS) generation, adenosine triphosphate (ATP) depletion and Ca++ overload. It is well known that all these factors are present in hypoxia-induced oxidative damage and mitochondrial Ca++ altered pools represent powerful stimuli in the damaging processes. The activation of mitochondrial K+(ATP) channels leads to a significant reduction of Ca++ influx and attenuation of mitochondrial Ca++ overload. Closely linked to these adaptive changes signal transduction pathways are involved in the nuclear DNA damage and repair mechanisms. On this context, an essential role is played by the hypoxia-induced factor-1alpha (HIF-1alpha) in terms of key transcription factor involved in oxygen-dependent gene regulation. The knowledge of the biochemical and molecular sequences involved in these adaptive processes call for a re-evaluation of the therapeutic approach to hypoxia-induced pathologies. On this light

  20. Intermittent acute angle closure glaucoma and chronic angle closure following topiramate use with plateau iris configuration

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    Rajjoub LZ

    2014-07-01

    Full Text Available Lamise Z Rajjoub, Nisha Chadha, David A Belyea Department of Ophthalmology, The George Washington University, Washington, DC, USA Abstract: This is a case report describing recurrent intermittent acute angle closure episodes in the setting of topiramate use in a female suffering from migraines. Despite laser peripheral iridotomy placement for the pupillary block component, and the discontinuation of topiramate, the acute angle closure did not resolve in the left eye with chronic angle closure and the patient required urgent trabeculectomy. The right eye responded to laser peripheral iridotomy immediately and further improved after the cessation of topiramate. While secondary angle closure glaucoma due to topiramate use has been widely reported, its effects in patients with underlying primary angle closure glaucoma have not been discussed. Our report highlights the importance of recognizing the often multifactorial etiology of angle closure glaucoma to help guide clinical management. Keywords: angle closure glaucoma, plateau iris, topiramate, secondary glaucoma, drug-induced glaucoma

  1. Chronic cervicogenic tinnitus rapidly resolved by intermittent use of cervical collar

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    Karl eBechter

    2016-03-01

    Full Text Available Introduction:Cervicogenic tinnitus is a not generally accepted pathogenetic subtype, which might be subsumed under the concept of somatosensory tinnitus. After the personal experience of therapy resistant tinnitus in context with a cervical pain syndrome (CS and successful add-on treatment with cervical collar (CC, the idea was persued in several individual treatments in patients.Patients and Methods:Reporting one particular case with chronic tinnitus considered untreatable, but rapidly improved with CC use. Thereafter tinnitus was experimentally replicated by head inclination, the respective neck-head angles and cerebral blood flow measured. Results:Chronic subjective tinnitus of a 20 years duration completely disappeared within 4 weeks with an intermittent short time application of CC. Thereafter, tinnitus was liberately again induced by head inclination, set on with anterior tilt of 14°, reaching maximum strength by 23°. Tinnitus stopped with return to neutral head position. Blood flow in the vertebral arteries on both sides was unchanged during head inclination with prevalent tinnitus, however blood flow was physiologically reduced with head rotation though not accompanied by tinnitus.Discussion:In a single case of chronic tinnitus, we found that treatment with CC rapidly led to full remission. Nevertheless, tinnitus could be resumed by constrained head postures. Experimental tinnitus replication by inclination points to an underscored role of upper posterior cervical muscle groups, matching with animal experiments, working in concert with other triggers including psychological factors. Blood flow reduction in vertebral arteries was unrelated to tinnitus.

  2. Gastric malpositioning and chronic, intermittent vomiting following prophylactic gastropexy in a 20-month-old great Dane dog

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    Sutton, Jessie S.; Steffey, Michele A.; Bonadio, Cecily M.; Marks, Stanley L

    2015-01-01

    A 20-month-old castrated male great Dane dog was presented for evaluation of chronic intermittent vomiting of 2 months’ duration. A prophylactic incisional gastropexy performed at 6 mo of age resulted in gastric malpositioning and subsequent partial gastric outflow tract obstruction.

  3. Increased oxidative metabolism and myoglobin expression in zebrafish muscle during chronic hypoxia

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    Richard T. Jaspers

    2014-07-01

    Full Text Available Fish may be extremely hypoxia resistant. We investigated how muscle fibre size and oxidative capacity in zebrafish (Danio rerio adapt during severe chronic hypoxia. Zebrafish were kept for either 3 or 6 weeks under chronic constant hypoxia (CCH (10% air/90%N2 saturated water. We analyzed cross-sectional area (CSA, succinate dehydrogenase (SDH activity, capillarization, myonuclear density, myoglobin (Mb concentration and Mb mRNA expression of high and low oxidative muscle fibres. After 3 weeks of CCH, CSA, SDH activity, Mb concentration, capillary and myonuclear density of both muscle fibre types were similar as under normoxia. In contrast, staining intensity for Mb mRNA of hypoxic high oxidative muscle fibres was 94% higher than that of normoxic controls (P<0.001. Between 3 and 6 weeks of CCH, CSA of high and low oxidative muscle fibres increased by 25 and 30%, respectively. This was similar to normoxic controls. Capillary and myonuclear density were not changed by CCH. However, in high oxidative muscle fibres of fish maintained under CCH, SDH activity, Mb concentration as well as Mb mRNA content were higher by 86%, 138% and 90%, respectively, than in muscle fibres of fish kept under normoxia (P<0.001. In low oxidative muscle fibres, SDH activity, Mb and Mb mRNA content were not significantly changed. Under normoxia, the calculated interstitial oxygen tension required to prevent anoxic cores in muscle fibres (PO2crit of high oxidative muscle fibres was between 1.0 and 1.7 mmHg. These values were similar at 3 and 6 weeks CCH. We conclude that high oxidative skeletal muscle fibres of zebrafish continue to grow and increase oxidative capacity during CCH. Oxygen supply to mitochondria in these fibres may be facilitated by an increased Mb concentration, which is regulated by an increase in Mb mRNA content per myonucleus.

  4. Increased oxidative metabolism and myoglobin expression in zebrafish muscle during chronic hypoxia

    Science.gov (United States)

    Jaspers, Richard T.; Testerink, Janwillem; Della Gaspera, Bruno; Chanoine, Christophe; Bagowski, Christophe P.; van der Laarse, Willem J.

    2014-01-01

    ABSTRACT Fish may be extremely hypoxia resistant. We investigated how muscle fibre size and oxidative capacity in zebrafish (Danio rerio) adapt during severe chronic hypoxia. Zebrafish were kept for either 3 or 6 weeks under chronic constant hypoxia (CCH) (10% air/90%N2 saturated water). We analyzed cross-sectional area (CSA), succinate dehydrogenase (SDH) activity, capillarization, myonuclear density, myoglobin (Mb) concentration and Mb mRNA expression of high and low oxidative muscle fibres. After 3 weeks of CCH, CSA, SDH activity, Mb concentration, capillary and myonuclear density of both muscle fibre types were similar as under normoxia. In contrast, staining intensity for Mb mRNA of hypoxic high oxidative muscle fibres was 94% higher than that of normoxic controls (P<0.001). Between 3 and 6 weeks of CCH, CSA of high and low oxidative muscle fibres increased by 25 and 30%, respectively. This was similar to normoxic controls. Capillary and myonuclear density were not changed by CCH. However, in high oxidative muscle fibres of fish maintained under CCH, SDH activity, Mb concentration as well as Mb mRNA content were higher by 86%, 138% and 90%, respectively, than in muscle fibres of fish kept under normoxia (P<0.001). In low oxidative muscle fibres, SDH activity, Mb and Mb mRNA content were not significantly changed. Under normoxia, the calculated interstitial oxygen tension required to prevent anoxic cores in muscle fibres (PO2crit) of high oxidative muscle fibres was between 1.0 and 1.7 mmHg. These values were similar at 3 and 6 weeks CCH. We conclude that high oxidative skeletal muscle fibres of zebrafish continue to grow and increase oxidative capacity during CCH. Oxygen supply to mitochondria in these fibres may be facilitated by an increased Mb concentration, which is regulated by an increase in Mb mRNA content per myonucleus. PMID:25063194

  5. Increased oxidative metabolism and myoglobin expression in zebrafish muscle during chronic hypoxia.

    Science.gov (United States)

    Jaspers, Richard T; Testerink, Janwillem; Della Gaspera, Bruno; Chanoine, Christophe; Bagowski, Christophe P; van der Laarse, Willem J

    2014-07-25

    Fish may be extremely hypoxia resistant. We investigated how muscle fibre size and oxidative capacity in zebrafish (Danio rerio) adapt during severe chronic hypoxia. Zebrafish were kept for either 3 or 6 weeks under chronic constant hypoxia (CCH) (10% air/90%N2 saturated water). We analyzed cross-sectional area (CSA), succinate dehydrogenase (SDH) activity, capillarization, myonuclear density, myoglobin (Mb) concentration and Mb mRNA expression of high and low oxidative muscle fibres. After 3 weeks of CCH, CSA, SDH activity, Mb concentration, capillary and myonuclear density of both muscle fibre types were similar as under normoxia. In contrast, staining intensity for Mb mRNA of hypoxic high oxidative muscle fibres was 94% higher than that of normoxic controls (P<0.001). Between 3 and 6 weeks of CCH, CSA of high and low oxidative muscle fibres increased by 25 and 30%, respectively. This was similar to normoxic controls. Capillary and myonuclear density were not changed by CCH. However, in high oxidative muscle fibres of fish maintained under CCH, SDH activity, Mb concentration as well as Mb mRNA content were higher by 86%, 138% and 90%, respectively, than in muscle fibres of fish kept under normoxia (P<0.001). In low oxidative muscle fibres, SDH activity, Mb and Mb mRNA content were not significantly changed. Under normoxia, the calculated interstitial oxygen tension required to prevent anoxic cores in muscle fibres (PO2crit) of high oxidative muscle fibres was between 1.0 and 1.7 mmHg. These values were similar at 3 and 6 weeks CCH. We conclude that high oxidative skeletal muscle fibres of zebrafish continue to grow and increase oxidative capacity during CCH. Oxygen supply to mitochondria in these fibres may be facilitated by an increased Mb concentration, which is regulated by an increase in Mb mRNA content per myonucleus.

  6. Dark Adaptation at High Altitude: An Unexpected Pupillary Response to Chronic Hypoxia in Andean Highlanders.

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    Healy, Katherine; Labrique, Alain B; Miranda, J Jaime; Gilman, Robert H; Danz, David; Davila-Roman, Victor G; Huicho, Luis; León-Velarde, Fabiola; Checkley, William

    2016-09-01

    Healy, Katherine, Alain B. Labrique, J. Jaime Miranda, Robert H. Gilman, David Danz, Victor G. Davila-Roman, Luis Huicho, Fabiola León-Velarde, and William Checkley. Dark adaptation at high altitude: an unexpected pupillary response to chronic hypoxia in Andean highlanders. High Alt Med Biol. 17:208-213, 2016.-Chronic mountain sickness is a maladaptive response to high altitude (>2500 m above sea level) and is characterized by excessive erythrocytosis and hypoxemia resulting from long-term hypobaric hypoxia. There is no known early predictor of chronic mountain sickness and the diagnosis is based on the presence of excessive erythrocytosis and clinical features. Impaired dark adaptation, or an inability to visually adjust from high- to low-light settings, occurs in response to mild hypoxia and may serve as an early predictor of hypoxemia and chronic mountain sickness. We aimed to evaluate the association between pupillary response assessed by dark adaptometry and daytime hypoxemia in resident Andean highlanders aged ≥35 years living in Puno, Peru. Oxyhemoglobin saturation (SpO2) was recorded using a handheld pulse oximeter. Dark adaptation was quantitatively assessed as the magnitude of pupillary contraction to light stimuli of varying intensities (-2.9 to 0.1 log-cd/m(2)) using a portable dark adaptometer. Individual- and stimulus-specific multilevel analyses were conducted using mixed-effect models to elicit the relationship between SpO2 and pupillary responsiveness. Among 93 participants, mean age was 54.9 ± 11.0 years, 48% were male, 44% were night blind, and mean SpO2 was 89.3% ± 3.4%. The magnitude of pupillary contraction was greater with lower SpO2 (p dark-adapted conditions was exaggerated with hypoxemia and may serve as an early predictor of chronic mountain sickness. This unexpected association is potentially explained as an excessive and unregulated sympathetic response to hypoxemia at altitude.

  7. Intermittent hypoxia and diet-induced obesity: effects on oxidative status, sympathetic tone, plasma glucose and insulin levels, and arterial pressure.

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    Olea, Elena; Agapito, Maria Teresa; Gallego-Martin, Teresa; Rocher, Asuncion; Gomez-Niño, Angela; Obeso, Ana; Gonzalez, Constancio; Yubero, Sara

    2014-10-01

    Obstructive sleep apnea (OSA) consists of sleep-related repetitive obstructions of upper airways that generate episodes of recurrent or intermittent hypoxia (IH). OSA commonly generates cardiovascular and metabolic pathologies defining the obstructive sleep apnea syndrome (OSAS). Literature usually links OSA-associated pathologies to IH episodes that would cause an oxidative status and a carotid body-mediated sympathetic hyperactivity. Because cardiovascular and metabolic pathologies in obese patients and those with OSAS are analogous, we used models (24-wk-old Wistar rats) of IH (applied from weeks 22 to 24) and diet-induced obesity (O; animals fed a high-fat diet from weeks 12 to 24) to define the effect of each individual maneuver and their combination on the oxidative status and sympathetic tone of animals, and to quantify cardiovascular and metabolic parameters and their deviation from normality. We found that IH and O cause an oxidative status (increased lipid peroxides and diminished activities of superoxide dismutases), an inflammatory status (augmented C-reactive protein and nuclear factor kappa-B activation), and sympathetic hyperactivity (augmented plasma and renal artery catecholamine levels and synthesis rate); combined treatments worsened those alterations. IH and O augmented liver lipid content and plasma cholesterol, triglycerides, leptin, glycemia, insulin levels, and HOMA index, and caused hypertension; most of these parameters were aggravated when IH and O were combined. IH diminished ventilatory response to hypoxia, and hypercapnia and O created a restrictive ventilatory pattern; a combination of treatments led to restrictive hypoventilation. Data demonstrate that IH and O cause comparable metabolic and cardiovascular pathologies via misregulation of the redox status and sympathetic hyperactivity.

  8. Chronic Intermittent Fasting Improves Cognitive Functions and Brain Structures in Mice

    OpenAIRE

    Liaoliao Li; Zhi Wang; Zhiyi Zuo

    2013-01-01

    Obesity is a major health issue. Obesity started from teenagers has become a major health concern in recent years. Intermittent fasting increases the life span. However, it is not known whether obesity and intermittent fasting affect brain functions and structures before brain aging. Here, we subjected 7-week old CD-1 wild type male mice to intermittent (alternate-day) fasting or high fat diet (45% caloric supplied by fat) for 11 months. Mice on intermittent fasting had better learning and me...

  9. Effects of varying degrees of intermittent hypoxia on proinflammatory cytokines and adipokines in rats and 3T3-L1 adipocytes.

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    Qing He

    Full Text Available OBJECTIVES: Intermittent hypoxia (IH, resulted from recurring episodes of upper airway obstruction, is the hallmark feature and the most important pathophysiologic pathway of obstructive sleep apnea (OSA. IH is believed to be the most important factor causing systemic inflammation. Studies suggest that insulin resistance (IR is positively associated with OSA. In this study, we hypothesized that the recurrence of IH might result in cellular and systemic inflammation, which was manifested through the levels of proinflammatory cytokines and adipokines after IH exposure, and because IR is linked with inflammation tightly, this inflammatory situation may implicate an IR status. METHODS: We developed an IH 3T3-L1 adipocyte and rat model respectively, recapitulating the nocturnal oxygen profile in OSA. In IH cells, nuclear factor kappa B (NF-κB DNA binding reactions, hypoxia-inducible factor-1α (HIF-1α, glucose transporter-1 (Glut-1, necrosis factor alpha (TNF-α, interleukin (IL -6, leptin, adiponectin mRNA transcriptional activities and protein expressions were measured. In IH rats, blood glucose, insulin, TNF-α, IL-6, leptin and adiponectin levels were analyzed. RESULTS: The insulin and blood glucose levels in rats and NF-κB DNA binding activities in cells had significantly statistical results described as severe IH>moderate IH>mild IH>sustained hypoxia>control. The mRNA and protein levels of HIF-1α and Glut-1 in severe IH group were the highest. In cellular and animal models, both the mRNA and protein levels of TNF-α, IL-6 and leptin were the highest in severe IH group, when the lowest in severe IH group for adiponectin. CONCLUSIONS: Oxidative stress and the release of pro-inflammatory cytokines/adipokines, which are the systemic inflammatory markers, are associated with IH closely and are proportional to the severity of IH. Because IR and glucose intolerance are linked with inflammation tightly, our results may implicate the clinical

  10. Enhanced neuropeptide Y synthesis during intermittent hypoxia in the rat adrenal medulla: role of reactive oxygen species-dependent alterations in precursor peptide processing.

    Science.gov (United States)

    Raghuraman, Gayatri; Kalari, Apeksha; Dhingra, Rishi; Prabhakar, Nanduri R; Kumar, Ganesh K

    2011-04-01

    Intermittent hypoxia (IH) associated with recurrent apneas often leads to cardiovascular abnormalities. Previously, we showed that IH treatment elevates blood pressure and increases plasma catecholamines (CAs) in rats via reactive oxygen species (ROS)-dependent enhanced synthesis and secretion from the adrenal medulla (AM). Neuropeptide Y (NPY), a sympathetic neurotransmitter that colocalizes with CA in the AM, has been implicated in blood pressure regulation during persistent stress. Here, we investigated whether IH facilitates NPY synthesis in the rat AM and assessed the role of ROS signaling. IH increased NPY-like immunoreactivity in many dopamine-β-hydroxylase-expressing chromaffin cells with a parallel increase in preproNPY mRNA and protein. IH increased the activities of proNPY-processing enzymes, which were due, in part, to elevated protein expression and increased proteolytic processing. IH increased ROS generation, and antioxidants reversed IH-induced increases in ROS, preproNPY, and its processing to bioactive NPY in the AM. IH treatment increased blood pressure and antioxidants and inhibition of NPY amidation prevented this response. These findings suggest that IH-induced elevation in NPY expression in the rat AM is mediated by ROS-dependent augmentation of preproNPY mRNA expression and proNPY-processing enzyme activities and contributes to IH-induced elevation of blood pressure.

  11. Gene expression, autonomic function and chronic hypoxia:lessons from the Andes.

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    Appenzeller, Otto; Minko, Tamara; Qualls, Clifford; Pozharov, Vitaly; Gamboa, Jorge; Gamboa, Alfredo; Wang, Yang

    2006-06-01

    Autonomic function is altered by altitude in sojourners and natives. We hypothesized that these physiologic responses are modulated by changes in gene expression. We compared gene product levels in 20 natives of Cerro de Pasco (CP), (4338 m), 10 of which had chronic mountain sickness (CMS) established by a CMS-scoring system, with gene products in the same men after 1 h at sea level. We further compared the results with those obtained from 10 US men residing at 1500 m. We measured gene products in white cells by reverse transcription polymerase chain reaction (RT-PCR). We focused on genes important in vascular autonomic physiology, and/or activated by hypoxia; hypoxia inducible factor 1-alpha (HIF 1-alpha), 2 splicing variants of vascular endothelial growth factor (VEGF); VEGF-121, VEGF-165, and phosphoglycerate kinase 1 (PGK 1). Normal CP natives showed high expression of all genes in CP, compared to US controls. Within 1 h of arrival at sea level, they had comparable levels to US residents. In CMS, the gene products were higher in CP. Although gene products decreased in Lima in this group, they never reached US values. VEGF 121 and 165 were correlated (P<0.001). VEGF 165 was higher in CMS in CP (P=0.006), and was positively correlated with CMS-score (R=0.86, P<0.001), and negatively correlated with arterial saturation (R=-0.79, P<0.001). Our findings underscore the changes in gene expression levels in intact humans in response to environmental stress. These changes may support the physiologic alterations induced by the ambient hypoxia at altitude and impact organism survival. They also suggest therapeutic strategies for autonomic and neurodegenerative diseases at sea level.

  12. Overexpression of Extracellular Superoxide Dismutase Protects against Brain Injury Induced by Chronic Hypoxia

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    Zaghloul, Nahla; Patel, Hardik; Codipilly, Champa; Marambaud, Philippe; Dewey, Stephen; Frattini, Stephen; Huerta, Patricio T.; Nasim, Mansoor; Miller, Edmund J.; Ahmed, Mohamed

    2014-01-01

    Extracellular superoxide dismutase (EC-SOD) is an isoform of SOD normally found both intra- and extra-cellularly and accounting for most SOD activity in blood vessels. Here we explored the role of EC-SOD in protecting against brain damage induced by chronic hypoxia. EC-SOD Transgenic mice, were exposed to hypoxia (FiO2.1%) for 10 days (H-KI) and compared to transgenic animals housed in room air (RA-KI), wild type animals exposed to hypoxia (H-WT or wild type mice housed in room air (RA-WT). Overall brain metabolism evaluated by positron emission tomography (PET) showed that H-WT mice had significantly higher uptake of 18FDG in the brain particularly the hippocampus, hypothalamus, and cerebellum. H-KI mice had comparable uptake to the RA-KI and RA-WT groups. To investigate the functional state of the hippocampus, electrophysiological techniques in ex vivo hippocampal slices were performed and showed that H-KI had normal synaptic plasticity, whereas H-WT were severely affected. Markers of oxidative stress, GFAP, IBA1, MIF, and pAMPK showed similar values in the H-KI and RA-WT groups, but were significantly increased in the H-WT group. Caspase-3 assay and histopathological studies showed significant apoptosis/cell damage in the H-WT group, but no significant difference in the H-KI group compared to the RA groups. The data suggest that EC-SOD has potential prophylactic and therapeutic roles in diseases with compromised brain oxygenation. PMID:25268361

  13. Overexpression of extracellular superoxide dismutase protects against brain injury induced by chronic hypoxia.

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    Nahla Zaghloul

    Full Text Available Extracellular superoxide dismutase (EC-SOD is an isoform of SOD normally found both intra- and extra-cellularly and accounting for most SOD activity in blood vessels. Here we explored the role of EC-SOD in protecting against brain damage induced by chronic hypoxia. EC-SOD Transgenic mice, were exposed to hypoxia (FiO2.1% for 10 days (H-KI and compared to transgenic animals housed in room air (RA-KI, wild type animals exposed to hypoxia (H-WT or wild type mice housed in room air (RA-WT. Overall brain metabolism evaluated by positron emission tomography (PET showed that H-WT mice had significantly higher uptake of 18FDG in the brain particularly the hippocampus, hypothalamus, and cerebellum. H-KI mice had comparable uptake to the RA-KI and RA-WT groups. To investigate the functional state of the hippocampus, electrophysiological techniques in ex vivo hippocampal slices were performed and showed that H-KI had normal synaptic plasticity, whereas H-WT were severely affected. Markers of oxidative stress, GFAP, IBA1, MIF, and pAMPK showed similar values in the H-KI and RA-WT groups, but were significantly increased in the H-WT group. Caspase-3 assay and histopathological studies showed significant apoptosis/cell damage in the H-WT group, but no significant difference in the H-KI group compared to the RA groups. The data suggest that EC-SOD has potential prophylactic and therapeutic roles in diseases with compromised brain oxygenation.

  14. Chronic intermittent ethanol induced axon and myelin degeneration is attenuated by calpain inhibition.

    Science.gov (United States)

    Samantaray, Supriti; Knaryan, Varduhi H; Patel, Kaushal S; Mulholland, Patrick J; Becker, Howard C; Banik, Naren L

    2015-10-01

    Chronic alcohol consumption causes multifaceted damage to the central nervous system (CNS), underlying mechanisms of which are gradually being unraveled. In our previous studies, activation of calpain, a calcium-activated neutral protease has been found to cause detrimental alterations in spinal motor neurons following ethanol (EtOH) exposure in vitro. However, it is not known whether calpain plays a pivotal role in chronic EtOH exposure-induced structural damage to CNS in vivo. To test the possible involvement of calpain in EtOH-associated neurodegenerative mechanisms the present investigation was conducted in a well-established mouse model of alcohol dependence - chronic intermittent EtOH (CIE) exposure and withdrawal. Our studies indicated significant loss of axonal proteins (neurofilament light and heavy, 50-60%), myelin proteins (myelin basic protein, 20-40% proteolipid protein, 25%) and enzyme (2', 3'-cyclic-nucleotide 3'-phosphodiesterase, 21-55%) following CIE in multiple regions of brain including hippocampus, corpus callosum, cerebellum, and importantly in spinal cord. These CIE-induced deleterious effects escalated after withdrawal in each CNS region tested. Increased expression and activity of calpain along with enhanced ratio of active calpain to calpastatin (sole endogenous inhibitor) was observed after withdrawal compared to EtOH exposure. Pharmacological inhibition of calpain with calpeptin (25 μg/kg) prior to each EtOH vapor inhalation significantly attenuated damage to axons and myelin as demonstrated by immuno-profiles of axonal and myelin proteins, and Luxol Fast Blue staining. Calpain inhibition significantly protected the ultrastructural integrity of axons and myelin compared to control as confirmed by electron microscopy. Together, these findings confirm CIE exposure and withdrawal induced structural alterations in axons and myelin, predominantly after withdrawal and corroborate calpain inhibition as a potential protective strategy against

  15. Antagonism of Stem Cell Factor/c-kit Signaling Attenuates Neonatal Chronic Hypoxia-Induced Pulmonary Vascular Remodeling

    Science.gov (United States)

    Young, Karen C; Torres, Eneida; Hehre, Dorothy; Wu, Shu; Suguihara, Cleide; Hare, Joshua M.

    2015-01-01

    Background Accumulating evidence suggests that c-kit positive cells are present in the remodeled pulmonary vasculature bed of patients with pulmonary hypertension (PH). Whether stem cell factor (SCF)/ c-kit regulated pathways potentiate pulmonary vascular remodeling is unknown. Here, we tested the hypothesis that attenuated c-kit signaling would decrease chronic hypoxia-induced pulmonary vascular remodeling by decreasing pulmonary vascular cell mitogenesis. Methods Neonatal FVB/NJ mice treated with non-immune IgG (PL), or c-kit neutralizing antibody (ACK2) as well as c-kit mutant mice (WBB6F1- Kit W− v/ +) and their congenic controls, were exposed to normoxia (FiO2=0.21) or hypoxia (FiO2=0.12) for two weeks. Following this exposure, right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), pulmonary vascular cell proliferation and remodeling were evaluated. Results As compared to chronically hypoxic controls, c-kit mutant mice had decreased RVSP, RVH, pulmonary vascular remodeling and proliferation. Consistent with these findings, administration of ACK2 to neonatal mice with chronic hypoxia-induced PH decreased RVSP, RVH, pulmonary vascular cell proliferation and remodeling. This attenuation in PH was accompanied by decreased extracellular signal-regulated protein kinase (ERK) 1/2 activation. Conclusion SCF/c-kit signaling may potentiate chronic hypoxia-induced vascular remodeling by modulating ERK activation. Inhibition of c-kit activity may be a potential strategy to alleviate PH. PMID:26705118

  16. Chronic hypoxia in Andeans; are there lessons for neurology at sea level?

    Science.gov (United States)

    Appenzeller, Otto; Minko, Tamara; Qualls, Clifford; Pozharov, Vitaly; Gamboa, Jorge; Gamboa, Alfredo; Pakunlu, Rafica I

    2006-08-15

    Hypoxia is implicated in aging and neurodegenerative diseases. We posited that changes in gene expression induced by ambient hypoxia at altitude may be neuroprotective to natives of these regions. We studied 30 men. Twenty natives of Cerro de Pasco (CP), altitude 4,338 m were examined in CP; then transported within 6 h to Lima (150 m-sea level) and examined 1 h after arrival. They were assessed by a Chronic Mountain Sickness-score (CMS-sc) in CP, 10 were normal Andeans and 10 had chronic mountain sickness (CMS), a sudden inexplicable loss of adaptation to their native environment. RNA was extracted from venous blood white cells. The Andeans were compared to 10 normal US men living at 1500 m using RT-PCR. We focused on the cyto-neuro-protective genes, Ataxia telangiectasia mutated (ATM), heme-oxygenase-1 (HMOX 1), heat shock protein-70 (HSP-70), heat shock protein-90 (HSP-90), and the neuroprotective enzyme, nicotinamide mononucleotide adenylyl transferase 1 (Nnmat 1). CMS patients had significantly higher levels of gene expression (HMOX-1, HSP-70, ATM) than Andean controls in CP. HSP-90 and Nmnat 1, however, were higher in Andean controls in all locations. Significant reductions of all gene products, within an hour of arriving in normoxia in Lima, were found. In Andean controls, the gene products in Lima fell to levels approaching US controls. Correlation and regression methods showed men with high expression of all gene products had an average CMS-sc=19.8; those with low expression a normal score (9.4, P=0.02). ATM expression was related to age (P<0.001). The natural experiment that unfolds in the mountainous regions of the world provides opportunities to study neuroprotection in intact humans.

  17. Repeated episodes of chronic intermittent ethanol promote insensitivity to devaluation of the reinforcing effect of ethanol.

    Science.gov (United States)

    Lopez, M F; Becker, H C; Chandler, L J

    2014-11-01

    Studies in animal models have shown that repeated episodes of alcohol dependence and withdrawal promote escalation of drinking that is presumably associated with alterations in the addiction neurocircuitry. Using a lithium chloride-ethanol pairing procedure to devalue the reinforcing properties of ethanol, the present study determined whether multiple cycles of chronic intermittent ethanol (CIE) exposure by vapor inhalation also alters the sensitivity of drinking behavior to the devaluation of ethanol's reinforcing effects. The effect of devaluation on operant ethanol self-administration and extinction was examined in mice prior to initiation of CIE (short drinking history) and after repeated cycles of CIE or air control exposure (long drinking history). Devaluation significantly attenuated the recovery of baseline ethanol self-administration when tested either prior to CIE or in the air-exposed controls that had experienced repeated bouts of drinking but no CIE. In contrast, in mice that had undergone repeated cycles of CIE exposure that promoted escalation of ethanol drinking, self-administration was completely resistant to the effect of devaluation. Devaluation had no effect on the time course of extinction training in either pre-CIE or post-CIE mice. Taken together, these results are consistent with the suggestion that repeated cycles of ethanol dependence and withdrawal produce escalation of ethanol self-administration that is associated with a change in sensitivity to devaluation of the reinforcing properties of ethanol.

  18. Treatment with anti-gremlin 1 antibody ameliorates chronic hypoxia/SU5416-induced pulmonary arterial hypertension in mice.

    Science.gov (United States)

    Ciuclan, Loredana; Sheppard, Kellyann; Dong, Liqun; Sutton, Daniel; Duggan, Nicholas; Hussey, Martin; Simmons, Jenny; Morrell, Nicholas W; Jarai, Gabor; Edwards, Matthew; Dubois, Gerald; Thomas, Matthew; Van Heeke, Gino; England, Karen

    2013-11-01

    The expression of the bone morphogenetic protein antagonist, Gremlin 1, was recently shown to be increased in the lungs of pulmonary arterial hypertension patients, and in response to hypoxia. Gremlin 1 released from the vascular endothelium may inhibit endogenous bone morphogenetic protein signaling and contribute to the development of pulmonary arterial hypertension. Here, we investigate the impact of Gremlin 1 inhibition in disease after exposure to chronic hypoxia/SU5416 in mice. We investigated the effects of an anti-Gremlin 1 monoclonal antibody in the chronic hypoxia/SU5416 murine model of pulmonary arterial hypertension. Chronic hypoxic/SU5416 exposure of mice induced upregulation of Gremlin 1 mRNA in lung and right ventricle tissue compared with normoxic controls. Prophylactic treatment with an anti-Gremlin 1 neutralizing mAb reduced the hypoxic/SU5416-dependent increase in pulmonary vascular remodeling and right ventricular hypertrophy. Importantly, therapeutic treatment with an anti-Gremlin 1 antibody also reduced pulmonary vascular remodeling and right ventricular hypertrophy indicating a role for Gremlin 1 in the progression of the disease. We conclude that Gremlin 1 plays a role in the development and progression of pulmonary arterial hypertension in the murine hypoxia/SU5416 model, and that Gremlin 1 is a potential therapeutic target for pulmonary arterial hypertension.

  19. CHRONIC DIETARY EXPOSURE WITH INTERMITTENT SPIKE DOSES OF CHLORPYRIFOS FALLS TO ALTER SOMATOSENSORY EVOKED POTENTIALS, COMPOUND NERVE ACTION POTENTIALS, OR NERVE CONDUCTION VELOCITY IN RATS.

    Science.gov (United States)

    Human exposure to pesticides is often characterized by chronic low level exposure with intermittent spiked higher exposures. Cholinergic transmission is involved in sensory modulation in the cortex and cerebellum, and therefore may be altered following chlorpyrifos (CPF) exposure...

  20. Measuring maximum and standard metabolic rates using intermittent-flow respirometry: a student laboratory investigation of aerobic metabolic scope and environmental hypoxia in aquatic breathers.

    Science.gov (United States)

    Rosewarne, P J; Wilson, J M; Svendsen, J C

    2016-01-01

    Metabolic rate is one of the most widely measured physiological traits in animals and may be influenced by both endogenous (e.g. body mass) and exogenous factors (e.g. oxygen availability and temperature). Standard metabolic rate (SMR) and maximum metabolic rate (MMR) are two fundamental physiological variables providing the floor and ceiling in aerobic energy metabolism. The total amount of energy available between these two variables constitutes the aerobic metabolic scope (AMS). A laboratory exercise aimed at an undergraduate level physiology class, which details the appropriate data acquisition methods and calculations to measure oxygen consumption rates in rainbow trout Oncorhynchus mykiss, is presented here. Specifically, the teaching exercise employs intermittent flow respirometry to measure SMR and MMR, derives AMS from the measurements and demonstrates how AMS is affected by environmental oxygen. Students' results typically reveal a decline in AMS in response to environmental hypoxia. The same techniques can be applied to investigate the influence of other key factors on metabolic rate (e.g. temperature and body mass). Discussion of the results develops students' understanding of the mechanisms underlying these fundamental physiological traits and the influence of exogenous factors. More generally, the teaching exercise outlines essential laboratory concepts in addition to metabolic rate calculations, data acquisition and unit conversions that enhance competency in quantitative analysis and reasoning. Finally, the described procedures are generally applicable to other fish species or aquatic breathers such as crustaceans (e.g. crayfish) and provide an alternative to using higher (or more derived) animals to investigate questions related to metabolic physiology.

  1. Brain-derived neurotrophic factor (BDNF) and TrkB in the piglet brainstem after post-natal nicotine and intermittent hypercapnic hypoxia.

    Science.gov (United States)

    Tang, Samantha; Machaalani, Rita; Waters, Karen A

    2008-09-26

    Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a significant role in the regulation of cell growth, survival and death during central nervous system development. The expression of BDNF and TrkB is affected by noxious insults. Two insults during the early post-natal period that are of interest to our laboratory are exposure to nicotine and to intermittent hypercapnic hypoxia (IHH). Piglet models were used to mimic the conditions associated with the risk factors for the sudden infant death syndrome (SIDS) including post-natal cigarette smoke exposure (nicotine model) and prone sleeping where the infant is subjected to re-breathing of expired gases (IHH model). We aimed to determine the effects of nicotine and IHH, alone or in combination, on pro- and rhBDNF and TrkB expression in the developing piglet brainstem. Four piglet groups were studied, with equal gender ratios in each: control (n=14), nicotine (n=14), IHH (n=10) and nic+IHH (n=14). Applying immunohistochemistry, and studying six nuclei of the caudal medulla, we found that compared to controls, TrkB was the only protein significantly decreased after nicotine and nic+IHH exposure regardless of gender. For pro-BDNF and rhBDNF however, observed changes were more evident in males than females exposed to nicotine and nic+IHH. The implications of these findings are that a prior nicotine exposure makes the developing brainstem susceptible to greater changes in the neurotrophic effects of BDNF and its receptor TrkB in the face of a hypoxic insult, and that the effects are greater in males than females.

  2. The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.

    Science.gov (United States)

    Angelo, Maria Florencia; Aguirre, Alejandra; Avilés Reyes, Rolando X; Villarreal, Alejandro; Lukin, Jerónimo; Melendez, Matías; Vanasco, Virginia; Barker, Phil; Alvarez, Silvia; Epstein, Alberto; Jerusalinsky, Diana; Ramos, Alberto Javier

    2014-01-01

    Sleep apnea (SA) causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH) experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE) and its downstream effector Nuclear Factor Kappa B (NF-κB) have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV)-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE) and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.

  3. Long-term moderate dose exogenous erythropoietin treatment protects from intermittent hypoxia-induced spatial learning deficits and hippocampal oxidative stress in young rats.

    Science.gov (United States)

    Al-Qahtani, Jobran M; Abdel-Wahab, Basel A; Abd El-Aziz, Samy M

    2014-01-01

    Exposure to intermittent hypoxia (IH) is associated with cognitive impairments and oxidative stress in brain regions involved in learning and memory. In earlier studies, erythropoietin (EPO) showed a neuroprotective effect in large doses. The aim of the present study was to explore the effect of smaller doses of EPO, such as those used in the treatment of anemia, on IH-induced cognitive deficits and hippocampal oxidative stress in young rats. The effect of concurrent EPO treatment (500 and 1,000 IU/kg/day ip) on spatial learning and memory deficits induced by long-term exposure to IH for 6 weeks was tested using the Morris water maze (MWM) test and the elevated plus maze (EPM) test. Moreover, the effect on hippocampal glutamate and oxidative stress were assessed. Exposure to IH induced a significant impairment of spatial learning and cognition of animals in both MWM and EPM performance parameters. Moreover, hippocampal glutamate and thiobarbituric acid reactive substances (TBARS) increased while antioxidant defenses (GSH and GSH-Px) decreased. EPO in the tested doses significantly reduced the IH-induced spatial learning deficits in both MWM and EPM tests and dose-dependently antagonized the effects of IH on hippocampal glutamate, TBARS, GSH levels, and GSH-Px activity. Treatment with EPO in moderate doses that used for anemia, concurrently with IH exposure can antagonize IH-induced spatial learning deficits and protect hippocampal neurons from IH-induced lipid peroxidation and oxidative stress-induced damage in young rats, possibly through multiple mechanisms involving a potential antioxidative effect.

  4. Intermittent hypoxia upregulates hepatic heme oxygenase-1 and ferritin-1, thereby limiting hepatic pathogenesis in rats fed a high-fat diet.

    Science.gov (United States)

    Maeda, Hideyuki; Yoshida, Ken-Ichi

    2016-07-01

    Non-alcoholic fatty liver disease (NAFLD) is prevalent in patients with sleep apnea syndrome (SAS). Intermittent hypoxia (IH) and a high-fat diet (HFD) reproduce SAS and NAFLD, respectively, in rodents. In this study, rats were fed either an HFD or a standard diet (SD) for 2 weeks, and breathed either IH air or normoxic air for 4 days (early phase) or 6 weeks (late phase), with the same diets maintained during the exposure. HFD increased hepatic lipid accumulation, as detected by oil-red staining and triglyceride content. However, IH exposure reversed the hepatic steatosis at the late phase in these HFD-rats. IH exposure also increased hepatic expression of HO-1 and iron-binding protein ferritin-1 at the late phase, in association with increase in serum iron, bilirubin, and hepatic levels of lipid peroxides, such as 4-hydroxy-2-nonenal (HNE). IH exposure increased serum levels of hemoglobin (Hb) at the early phase and immunofluorescence of Hb and HO-1 in CD68-positive Kupffer cells (KCs) at the late phase. These findings support that IH induces erythrocytosis, erythro-phagocytosis, and generation of Hb in the KCs. The Hb promotes HO-1 expression in KCs, thereby produces iron, bilirubin, and carbon monoxide (CO). The iron would be either sequestrated by ferritin-1, transferred to the bone marrow for erythropoiesis, or would produce hydroxyradicals and HNE in the liver of rats fed an HFD. HNE might also contribute to the upregulation of HO-1, transferrin-1, and IκB, thereby limiting hepatic steatosis and inflammation via inhibition of nuclear factor κB (NFκB) activation.

  5. Chronic overexpression of cerebral Epo improves the ventilatory response to acute hypoxia during the postnatal development.

    Science.gov (United States)

    Caravagna, Céline; Gasser, Edith M Schneider; Ballot, Orlane; Joseph, Vincent; Soliz, Jorge

    2015-08-01

    Clinicians observed that the treatment of premature human newborns for anemia with erythropoietin (Epo) also improved their respiratory autonomy. This observation is in line with our previous in vitro studies showing that acute and chronic Epo stimulation enhances fictive breathing of brainstem-spinal cord preparations of postnatal day 3-4 mice during hypoxia. Furthermore, we recently reported that the antagonization of the cerebral Epo (by using the soluble Epo receptor; sEpoR) significantly reduced the basal ventilation and the hypoxic ventilatory response of 10 days old mice. In this study, we used transgenic (Tg21) mice to investigate the effect of the chronic cerebral Epo overexpression on the modulation of the normoxic and hypoxic ventilatory drive during the post-natal development. Ventilation was evaluated by whole body plethysmography at postnatal ages 3 (P3), 7 (P7), 15 (P15) and 21 (P21). In addition Epo quantification was performed by RIA and mRNA EpoR was evaluated by qRT-PCR. Our results showed that compared to control animals the chronic Epo overexpression stimulates the hypoxic (but not the normoxic) ventilation assessed as VE/VO2 at the ages of P3 and P21. More interestingly, we observed that at P7 and P15 the chronic Epo stimulation of ventilation was attenuated by the down regulation of the Epo receptor in brainstem areas. We conclude that Epo, by stimulating ventilation in brainstem areas crucially helps tolerating physiological (e.g., high altitude) and/or pathological (e.g., respiratory disorders, prematurity, etc.) oxygen deprivation at postnatal ages.

  6. Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model

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    Constantino Tomas-Sanchez

    2016-01-01

    Full Text Available Acute and subacute administration of zinc exert neuroprotective effects in hypoxia-ischemia animal models; yet the effect of chronic administration of zinc still remains unknown. We addressed this issue by injecting zinc at a tolerable dose (0.5 mg/kg weight, i.p. for 14 days before common carotid artery occlusion (CCAO in a rat. After CCAO, the level of zinc was measured by atomic absorption spectrophotometry, nitrites were determined by Griess method, lipoperoxidation was measured by Gerard-Monnier assay, and mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors was measured by qRT-PCR, whereas nitrotyrosine, chemokines, and their receptors were assessed by ELISA and histopathological changes in the temporoparietal cortex-hippocampus at different time points. Long-term memory was evaluated using Morris water maze. Following CCAO, a significant increase in nitrosative stress, inflammatory chemokines/receptors, and cell death was observed after 8 h, and a 2.5-fold increase in zinc levels was detected after 7 days. Although CXCL12 and FGF2 protein levels were significantly increased, the long-term memory was impaired 12 days after reperfusion in the Zn+CCAO group. Our data suggest that the chronic administration of zinc at tolerable doses causes nitrosative stress, toxic zinc accumulation, and neuroinflammation, which might account for the neuronal death and cerebral dysfunction after CCAO.

  7. Prophylactic Chronic Zinc Administration Increases Neuroinflammation in a Hypoxia-Ischemia Model

    Science.gov (United States)

    Tomas-Sanchez, Constantino; Blanco-Alvarez, Victor Manuel; Gonzalez-Barrios, Juan Antonio; Martinez-Fong, Daniel; Garcia-Robles, Guadalupe; Soto-Rodriguez, Guadalupe; Torres-Soto, Maricela; Gonzalez-Vazquez, Alejandro; Aguilar-Peralta, Ana Karina; Garate-Morales, José-Luis; Aguilar-Carrasco, Luis-Angel; Limón, Daniel I.; Cebada, Jorge

    2016-01-01

    Acute and subacute administration of zinc exert neuroprotective effects in hypoxia-ischemia animal models; yet the effect of chronic administration of zinc still remains unknown. We addressed this issue by injecting zinc at a tolerable dose (0.5 mg/kg weight, i.p.) for 14 days before common carotid artery occlusion (CCAO) in a rat. After CCAO, the level of zinc was measured by atomic absorption spectrophotometry, nitrites were determined by Griess method, lipoperoxidation was measured by Gerard-Monnier assay, and mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors was measured by qRT-PCR, whereas nitrotyrosine, chemokines, and their receptors were assessed by ELISA and histopathological changes in the temporoparietal cortex-hippocampus at different time points. Long-term memory was evaluated using Morris water maze. Following CCAO, a significant increase in nitrosative stress, inflammatory chemokines/receptors, and cell death was observed after 8 h, and a 2.5-fold increase in zinc levels was detected after 7 days. Although CXCL12 and FGF2 protein levels were significantly increased, the long-term memory was impaired 12 days after reperfusion in the Zn+CCAO group. Our data suggest that the chronic administration of zinc at tolerable doses causes nitrosative stress, toxic zinc accumulation, and neuroinflammation, which might account for the neuronal death and cerebral dysfunction after CCAO. PMID:27635404

  8. Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion

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    Ying Yang

    2017-01-01

    Full Text Available Hypoxia inducible factor 1α (HIF-1α, a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH triggered long-lasting accumulation of HIF-1α protein in the hippocampus of rats. However, the role of the stabilized HIF-1α in CCH is obscure. Here, we knock down endogenous HIF-1α to determine whether and how HIF-1α affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1α small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock down HIF-1α gene expression in the hippocampus and other brain areas. Permanent bilateral common carotid artery occlusions, known as 2-vessel occlusions (2VOs, were used to induce CCH in rats. Angiogenesis, oxidative stress, histopathological changes of the brain, and cognitive function were tested. Knockdown of HIF-1α prior to 2VO significantly exacerbates the impairment of learning and memory after four weeks of CCH. Mechanically, reduced cerebral angiogenesis, increased oxidative damage, and increased density of astrocytes and microglia in the cortex and some subregions of hippocampus are also shown after four weeks of CCH. Furthermore, HIF-1α knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-1α-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1α during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit.

  9. Bax/Mcl-1 balance affects neutrophil survival in intermittent hypoxia and obstructive sleep apnea: effects of p38MAPK and ERK1/2 signaling

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    Dyugovskaya Larissa

    2012-10-01

    Full Text Available Abstract Background Prolonged neutrophil survival is evident in various cardiovascular and respiratory morbidities, in hypoxic conditions in-vitro and in patients with obstructive sleep apnea (OSA characterized by nightly intermittent hypoxia (IH. This may lead to persistent inflammation, tissue injury and dysfunction. We therefore investigated by a translational approach the potential contribution of the intrinsic stress-induced mitochondrial pathway in extending neutrophil survival under IH conditions. Thus, neutrophils of healthy individuals treated with IH in-vitro and neutrophils of OSA patients undergoing nightly IH episodes in-vivo were investigated. Specifically, the balance between pro-apoptotic Bax and anti-apoptotic Mcl-1 protein expression, and the potential involvement of p38MAPK and ERK1/2 signaling pathways in the control of Mcl-1 expression were investigated. Methods Purified neutrophils were exposed to IH and compared to normoxia and to sustained hypoxia (SH using a BioSpherix-OxyCycler C42 system. Bax and Mcl-1 levels, and p38MAPK and ERK1/2 phosphorylation were determined by western blotting. Also, Bax/Mcl-1 expression and Bax translocation to the mitochondria were assessed by confocal microscopy in pre-apoptotic neutrophils, before the appearance of apoptotic morphology. Co-localization of Bax and mitochondria was quantified by LSM 510 CarlZeiss MicroImaging using Manders Overlap Coefficient. A paired two-tailed t test, with Bonferroni correction for multiple comparisons, was used for statistical analysis. Results Compared to normoxia, IH and SH up-regulated the anti-apoptotic Mcl-1 by about 2-fold, down-regulated the pro-apoptotic Bax by 41% and 27%, respectively, and inhibited Bax co-localization with mitochondria before visible morphological signs of apoptosis were noted. IH induced ERK1/2 and p38MAPKs phosphorylation, whereas SH induced only p38MAPK phosphorylation. Accordingly, both ERK and p38MAPK inhibitors attenuated

  10. Individually ventilated cages cause chronic low-grade hypoxia impacting mice hematologically and behaviorally

    Science.gov (United States)

    York, Jason M.; McDaniel, Allison W.; Blevins, Neil A.; Guillet, Riley R.; Allison, Sarah O.; Cengel, Keith A.; Freund, Gregory G.

    2012-01-01

    Use of individually ventilated caging (IVC) systems for mouse-based laboratory investigation has dramatically increased. We found that without mice present, intra-cage oxygen concentration was comparable (21%) between IVC housing and ambient environment caging (AEC) that used wire top lids. However, when mice were housed 4-to-a-cage for 1 week, intra-cage oxygen dropped to 20.5% in IVC housing as compared to 21% for AEC housing. IVC intra-cage humidity was also elevated relative to AEC housing. Mice raised in IVC housing as compared to mice raised in AEC housing had higher RBC mass, hematocrit and hemoglobin concentrations. They also had elevated platelet counts but lower white blood cell counts. IVC mice relative to AEC mice had increased saccharin preference and increased fluid consumption but similar locomotion, food intake, social exploration and novel object recognition when tested in an AEC environment. Taken together, these data indicate that ventilated caging systems can have a 0.5% reduction from ambient oxygen concentration that is coupled to mouse red blood cell indices indicative of chronic exposure to a hypoxia. Importantly, IVC housing can impact behavioral testing for depressive-like behavior. PMID:22561683

  11. The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.

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    Maria Florencia Angelo

    Full Text Available Sleep apnea (SA causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE and its downstream effector Nuclear Factor Kappa B (NF-κB have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.

  12. Fetal exposure to a diabetic intrauterine environment resulted in a failure of cord blood endothelial progenitor cell adaptation against chronic hypoxia

    Science.gov (United States)

    Dincer, U Deniz

    2015-01-01

    Gestational diabetes mellitus (GDM) has long-term health consequences, and fetal exposure to a diabetic intrauterine environment increases cardiovascular risk for her adult offspring. Some part of this could be related to their endothelial progenitor cells (EPCs). Understanding the vessel-forming ability of human umbilical cord blood (HUCB)-derived endothelial colony-forming cells (ECFCs) against pathological stress such as GDM response to hypoxia could generate new therapeutic strategies. This study aims to investigate the role of chronic hypoxia in EPCs functional and vessel-forming ability in GDM subjects. Each ECFC was expressed in endothelial and pro-angiogenic specific markers, namely endothelial nitric oxide synthase (eNOS), platelet (PECAM-1) endothelial cell adhesion molecule 1, vascular endothelial-cadherin CdH5 (Ca-dependent cell adhesion molecule), vascular endothelial growth factor A, (VEGFA) and insulin-like growth factor 1 (IGF1). Chronic hypoxia did not affect CdH5, but PECAM1 MRNA expressions were increased in control and GDM subjects. Control hypoxic and GDM normoxic VEGFA MRNA expressions and hypoxia-inducible factor 1-alpha (HIF1α) protein expressions were significantly increased in HUCB ECFCs. GDM resulted in most failure of HUCB ECFC adaptation and eNOS protein expressions against chronic hypoxia. Chronic hypoxia resulted in an overall decline in HUCB ECFCs’ proliferative ability due to reduction of clonogenic capacity and diminished vessel formation. Furthermore, GDM also resulted in most failure of cord blood ECFC adaptation against chronic hypoxic environment. PMID:25565870

  13. Chronic intermittent fasting improves cognitive functions and brain structures in mice.

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    Liaoliao Li

    Full Text Available Obesity is a major health issue. Obesity started from teenagers has become a major health concern in recent years. Intermittent fasting increases the life span. However, it is not known whether obesity and intermittent fasting affect brain functions and structures before brain aging. Here, we subjected 7-week old CD-1 wild type male mice to intermittent (alternate-day fasting or high fat diet (45% caloric supplied by fat for 11 months. Mice on intermittent fasting had better learning and memory assessed by the Barnes maze and fear conditioning, thicker CA1 pyramidal cell layer, higher expression of drebrin, a dendritic protein, and lower oxidative stress than mice that had free access to regular diet (control mice. Mice fed with high fat diet was obese and with hyperlipidemia. They also had poorer exercise tolerance. However, these obese mice did not present significant learning and memory impairment or changes in brain structures or oxidative stress compared with control mice. These results suggest that intermittent fasting improves brain functions and structures and that high fat diet feeding started early in life does not cause significant changes in brain functions and structures in obese middle-aged animals.

  14. Chronic intermittent fasting improves cognitive functions and brain structures in mice.

    Science.gov (United States)

    Li, Liaoliao; Wang, Zhi; Zuo, Zhiyi

    2013-01-01

    Obesity is a major health issue. Obesity started from teenagers has become a major health concern in recent years. Intermittent fasting increases the life span. However, it is not known whether obesity and intermittent fasting affect brain functions and structures before brain aging. Here, we subjected 7-week old CD-1 wild type male mice to intermittent (alternate-day) fasting or high fat diet (45% caloric supplied by fat) for 11 months. Mice on intermittent fasting had better learning and memory assessed by the Barnes maze and fear conditioning, thicker CA1 pyramidal cell layer, higher expression of drebrin, a dendritic protein, and lower oxidative stress than mice that had free access to regular diet (control mice). Mice fed with high fat diet was obese and with hyperlipidemia. They also had poorer exercise tolerance. However, these obese mice did not present significant learning and memory impairment or changes in brain structures or oxidative stress compared with control mice. These results suggest that intermittent fasting improves brain functions and structures and that high fat diet feeding started early in life does not cause significant changes in brain functions and structures in obese middle-aged animals.

  15. Chronic hypoxia promotes pulmonary artery endothelial cell proliferation through H2O2-induced 5-lipoxygenase.

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    Kristi M Porter

    Full Text Available Pulmonary Hypertension (PH is a progressive disorder characterized by endothelial dysfunction and proliferation. Hypoxia induces PH by increasing vascular remodeling. A potential mediator in hypoxia-induced PH development is arachidonate 5-Lipoxygenase (ALOX5. While ALOX5 metabolites have been shown to promote pulmonary vasoconstriction and endothelial cell proliferation, the contribution of ALOX5 to hypoxia-induced proliferation remains unknown. We hypothesize that hypoxia exposure stimulates HPAEC proliferation by increasing ALOX5 expression and activity. To test this, human pulmonary artery endothelial cells (HPAEC were cultured under normoxic (21% O2 or hypoxic (1% O2 conditions for 24-, 48-, or 72 hours. In a subset of cells, the ALOX5 inhibitor, zileuton, or the 5-lipoxygenase activating protein inhibitor, MK-886, was administered during hypoxia exposure. ALOX5 expression was measured by qRT-PCR and western blot and HPAEC proliferation was assessed. Our results demonstrate that 24 and 48 hours of hypoxia exposure have no effect on HPAEC proliferation or ALOX5 expression. Seventy two hours of hypoxia significantly increases HPAEC ALOX5 expression, hydrogen peroxide (H2O2 release, and HPAEC proliferation. We also demonstrate that targeted ALOX5 gene silencing or inhibition of the ALOX5 pathway by pharmacological blockade attenuates hypoxia-induced HPAEC proliferation. Furthermore, our findings indicate that hypoxia-induced increases in cell proliferation and ALOX5 expression are dependent on H2O2 production, as administration of the antioxidant PEG-catalase blocks these effects and addition of H2O2 to HPAEC promotes proliferation. Overall, these studies indicate that hypoxia exposure induces HPAEC proliferation by activating the ALOX5 pathway via the generation of H2O2.

  16. Local Renin-Angiotensin System in the Pancreas: The Significance of Changes by Chronic Hypoxia and Acute Pancreatitis

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    Leung PS

    2001-01-01

    Full Text Available The circulating renin-angiotensin system (RAS plays an important role in the maintenance of blood pressure and fluid homeostasis. Recently, there has been a shift of emphasis from the circulating RAS to the local RAS in the regulation of individual tissue functions via a paracrine and/or autocrine mechanism. In fact, a local RAS has been proposed to be present in an array of tissues including the brain, heart, kidney and gonads. Our previous studies have provided solid evidence that several key elements of the RAS, notably angiotensinogen and renin, are present in the rat pancreas. The data support the existence of an intrinsic RAS in the pancreas and this local RAS may be important for the exocrine/endocrine functions of the pancreas. Interestingly, such a pancreatic RAS has been demonstrated to be markedly activated by experimental rat models of chronic hypoxia and acute pancreatitis. The activation of the pancreatic RAS by chronic hypoxia and experimental pancreatitis could play a role in the physiology and pathophysiology of the pancreas. The significant changes of pancreatic RAS may have clinical relevance to acute pancreatitis and hypoxia-induced injury in the pancreas.

  17. Elevated incidence of suicide in people living at altitude, smokers and patients with chronic obstructive pulmonary disease and asthma: possible role of hypoxia causing decreased serotonin synthesis.

    Science.gov (United States)

    Young, Simon N

    2013-11-01

    Recent research indicates that suicide rates are elevated in those living at higher altitudes in both the United States and South Korea. A possible mechanism that was proposed is metabolic stress associated with hypoxia. This commentary discusses these results, and also the association between elevated suicide rates and other conditions associated with hypoxia (smoking, chronic obstructive pulmonary disease and asthma). Tryptophan hydroxylase may not normally be saturated with oxygen, so mild hypoxia would decrease serotonin synthesis. Low brain serotonin is known to be associated with suicide. Thus, the commentary proposes and discusses the hypothesis that decreased brain serotonin synthesis associated with hypoxia is a mechanism that may contribute to suicide in conditions causing hypoxia. Finally the commentary proposes various studies that could test aspects of this hypothesis.

  18. Complete healing of chronic wounds of a lower leg with haemoglobin spray and regeneration of an accompanying severe dermatoliposclerosis with intermittent normobaric oxygen inhalation (INBOI: a case report

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    Pötzschke, Harald

    2011-01-01

    Full Text Available A new healing procedure has been developed on the basis of the successful treatment of therapy-resistant hypoxic (and practically anoxic leg ulcerations located within a heavy dermatoliposclerosis. The procedure involves an initial intra-ulceral application of haemoglobin followed by the intermittent administration of normobaric oxygen via inhalation. Haemoglobin is capable of externally supplying the granulating wound bed with oxygen at low partial pressure in a physiological manner, like a micro lung, so that oxidative stress can be avoided. A long-term daily administration of oxygen from within – including the peri-ulceral skin – is achieved by intermittent normobaric oxygen inhalation (INBOI regularly throughout the day in the form of 1-hour sessions. Using this combined healing treatment during haemoglobin applications the ulcerations healed within about 1 month, and subsequently with INBOI therapy within further approx. 4 months the peri-ulceral skin regenerated as far as the oxygenation status was concerned: The peri-ulceral transcutaneous oxygen partial pressure (tcPO2 of zero (measured during breathing of normal air rose to a satisfactory value of approx. 35 mmHg. After 28 months of treatment, the completely hypoxic and degenerated skin on the leg had practically returned to normal with a PO2 of 45 mmHg. Furthermore, the skin dermatoliposclerosis regressed. The skin regeneration was long-lasting, which was probably related to cellular tissue regeneration with an increase in the capillary density, whereby it had to be maintained by regular oxygen inhalation (INBOI maintaining treatment. By unintended intra-individual therapy variations it is evidenced that local hypoxia was the reason for skin degeneration: 3 x 1 h oxygen inhalation were sufficient for the healing treatment; 2 x 1 h sufficed for maintenance, whereas 2 x 0.5 h did not. The new procedure carries practically no risks, is simple, cheap and effective. Whereas the

  19. Elevated incidence of suicide in people living at altitude, smokers and patients with chronic obstructive pulmonary disease and asthma: possible role of hypoxia causing decreased serotonin synthesis

    OpenAIRE

    Young, Simon N.

    2013-01-01

    Recent research indicates that suicide rates are elevated in those living at higher altitudes in both the United States and South Korea. A possible mechanism that was proposed is metabolic stress associated with hypoxia. This commentary discusses these results, and also the association between elevated suicide rates and other conditions associated with hypoxia (smoking, chronic obstructive pulmonary disease and asthma). Tryptophan hydroxylase may not normally be saturated with oxygen, so mild...

  20. Chronic Elevation of Liver Enzymes in Acute Intermittent Porphyria Initially Misdiagnosed as Autoimmune Hepatitis

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    A. González Estrada

    2011-01-01

    Full Text Available Autoimmune hepatitis is a disease characterized by an elevation of liver enzymes, as well as specific autoantibodies. It is more common in women than men. We describe a 32-year-old woman with elevated transaminases, autoantibodies, and a liver biopsy result suggestive of autoimmune hepatitis. The indicated treatment was administered without showing a satisfactory response. The patient had a family history of acute intermittent porphyria (AIP so we decided to begin treatment with hematin, achieving a complete remission of the symptoms. Acute intermittent porphyria is a rare condition characterized by neurovisceral symptoms, abdominal pain being the most common of them. The disease has a higher prevalence among young women and certain European countries such as Sweden, Great Britain, and Spain. A correct diagnosis and prompt treatment are essential because patients affected by AIP must have a strict followup due to the fatal outcome of the outbreaks.

  1. Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease.

    Science.gov (United States)

    Li, Hui; Satriano, Joseph; Thomas, Joanna L; Miyamoto, Satoshi; Sharma, Kumar; Pastor-Soler, Núria M; Hallows, Kenneth R; Singh, Prabhleen

    2015-09-01

    Renal hypoxia contributes to chronic kidney disease (CKD) progression, as validated in experimental and human CKD. In the early stages, increased oxygen consumption causes oxygen demand/supply mismatch, leading to hypoxia. Hence, early targeting of the determinants and regulators of oxygen consumption in CKD may alter the disease course before permanent damage ensues. Here, we focus on hypoxia inducible factor-1α (HIF-1α) and AMP-activated protein kinase (AMPK) and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1α activation in the subtotal nephrectomy (STN) model of CKD limits protein synthesis, inhibits apoptosis, and activates autophagy, presumably for improved cell survival. AMPK activation was diminished in the STN kidney and was remarkably restored by HIF-1α activation, demonstrating a novel role for HIF-1α in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1α and AMPK on cell survival and death pathways by utilizing pharmacological and knockdown approaches in cell culture models. We found that the effect of HIF-1α activation on autophagy is independent of AMPK, but on apoptosis it is partially AMPK dependent. The effects of HIF-1α and AMPK activation on inhibiting protein synthesis via the mTOR pathway appear to be additive. These various effects were also observed under hypoxic conditions. In conclusion, HIF-1α and AMPK appear to be linked at a molecular level and may act as components of a concerted cellular response to hypoxic stress in the pathophysiology of CKD.

  2. Chitosan-shelled oxygen-loaded nanodroplets abrogate hypoxia dysregulation of human keratinocyte gelatinases and inhibitors: New insights for chronic wound healing

    Energy Technology Data Exchange (ETDEWEB)

    Khadjavi, Amina [Dipartimento di Neuroscienze, Università di Torino, Torino (Italy); Magnetto, Chiara [Istituto Nazionale di Ricerca Metrologica (INRIM), Torino (Italy); Panariti, Alice [Dipartimento di Scienze della Salute, Università di Milano Bicocca, Monza (Italy); Argenziano, Monica [Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Torino (Italy); Gulino, Giulia Rossana [Dipartimento di Oncologia, Università di Torino, Torino (Italy); Rivolta, Ilaria [Dipartimento di Scienze della Salute, Università di Milano Bicocca, Monza (Italy); Cavalli, Roberta [Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Torino (Italy); Giribaldi, Giuliana [Dipartimento di Oncologia, Università di Torino, Torino (Italy); Guiot, Caterina [Dipartimento di Neuroscienze, Università di Torino, Torino (Italy); Prato, Mauro, E-mail: mauro.prato@unito.it [Dipartimento di Neuroscienze, Università di Torino, Torino (Italy); Dipartimento di Scienze della Sanità Pubblica e Pediatriche, Università di Torino, Torino (Italy)

    2015-08-01

    Background: : In chronic wounds, efficient epithelial tissue repair is hampered by hypoxia, and balances between the molecules involved in matrix turn-over such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are seriously impaired. Intriguingly, new oxygenating nanocarriers such as 2H,3H-decafluoropentane-based oxygen-loaded nanodroplets (OLNs) might effectively target chronic wounds. Objective: : To investigate hypoxia and chitosan-shelled OLN effects on MMP/TIMP production by human keratinocytes. Methods: : HaCaT cells were treated for 24 h with 10% v/v OLNs both in normoxia or hypoxia. Cytotoxicity and cell viability were measured through biochemical assays; cellular uptake by confocal microscopy; and MMP and TIMP production by enzyme-linked immunosorbent assay or gelatin zymography. Results: : Normoxic HaCaT cells constitutively released MMP-2, MMP-9, TIMP-1 and TIMP-2. Hypoxia strongly impaired MMP/TIMP balances by reducing MMP-2, MMP-9, and TIMP-2, without affecting TIMP-1 release. After cellular uptake by keratinocytes, nontoxic OLNs abrogated all hypoxia effects on MMP/TIMP secretion, restoring physiological balances. OLN abilities were specifically dependent on time-sustained oxygen diffusion from OLN core. Conclusion: : Chitosan-shelled OLNs effectively counteract hypoxia-dependent dysregulation of MMP/TIMP balances in human keratinocytes. Therefore, topical administration of exogenous oxygen, properly encapsulated in nanodroplet formulations, might be a promising adjuvant approach to promote healing processes in hypoxic wounds. - Highlights: • Hypoxia impairs MMP9/TIMP1 and MMP2/TIMP2 balances in HaCaT human keratinocytes. • Chitosan-shelled oxygen-loaded nanodroplets (OLNs) are internalised by HaCaT cells. • OLNs are not toxic to HaCaT cells. • OLNs effectively counteract hypoxia effects on MMP/TIMP balances in HaCaT cells. • OLNs appear as promising and cost-effective therapeutic tools for hypoxic

  3. p53 dependent apoptotic cell death induces embryonic malformation in Carassius auratus under chronic hypoxia.

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    Paramita Banerjee Sawant

    Full Text Available Hypoxia is a global phenomenon affecting recruitment as well as the embryonic development of aquatic fauna. The present study depicts hypoxia induced disruption of the intrinsic pathway of programmed cell death (PCD, leading to embryonic malformation in the goldfish, Carrasius auratus. Constant hypoxia induced the early expression of pro-apoptotic/tumor suppressor p53 and concomitant expression of the cell death molecule, caspase-3, leading to high level of DNA damage and cell death in hypoxic embryos, as compared to normoxic ones. As a result, the former showed delayed 4 and 64 celled stages and a delay in appearance of epiboly stage. Expression of p53 efficiently switched off expression of the anti-apoptotic Bcl-2 during the initial 12 hours post fertilization (hpf and caused embryonic cell death. However, after 12 hours, simultaneous downregulation of p53 and Caspase-3 and exponential increase of Bcl-2, caused uncontrolled cell proliferation and prevented essential programmed cell death (PCD, ultimately resulting in significant (p<0.05 embryonic malformation up to 144 hpf. Evidences suggest that uncontrolled cell proliferation after 12 hpf may have been due to downregulation of p53 abundance, which in turn has an influence on upregulation of anti-apoptotic Bcl-2. Therefore, we have been able to show for the first time and propose that hypoxia induced downregulation of p53 beyond 12 hpf, disrupts PCD and leads to failure in normal differentiation, causing malformation in gold fish embryos.

  4. p53 Dependent Apoptotic Cell Death Induces Embryonic Malformation in Carassius auratus under Chronic Hypoxia

    Science.gov (United States)

    Dasgupta, Subrata; Sawant, Bhawesh T.; Chadha, Narinder K.; Pal, Asim K.

    2014-01-01

    Hypoxia is a global phenomenon affecting recruitment as well as the embryonic development of aquatic fauna. The present study depicts hypoxia induced disruption of the intrinsic pathway of programmed cell death (PCD), leading to embryonic malformation in the goldfish, Carrasius auratus. Constant hypoxia induced the early expression of pro-apoptotic/tumor suppressor p53 and concomitant expression of the cell death molecule, caspase-3, leading to high level of DNA damage and cell death in hypoxic embryos, as compared to normoxic ones. As a result, the former showed delayed 4 and 64 celled stages and a delay in appearance of epiboly stage. Expression of p53 efficiently switched off expression of the anti-apoptotic Bcl-2 during the initial 12 hours post fertilization (hpf) and caused embryonic cell death. However, after 12 hours, simultaneous downregulation of p53 and Caspase-3 and exponential increase of Bcl-2, caused uncontrolled cell proliferation and prevented essential programmed cell death (PCD), ultimately resulting in significant (p<0.05) embryonic malformation up to 144 hpf. Evidences suggest that uncontrolled cell proliferation after 12 hpf may have been due to downregulation of p53 abundance, which in turn has an influence on upregulation of anti-apoptotic Bcl-2. Therefore, we have been able to show for the first time and propose that hypoxia induced downregulation of p53 beyond 12 hpf, disrupts PCD and leads to failure in normal differentiation, causing malformation in gold fish embryos. PMID:25068954

  5. Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer.

    Science.gov (United States)

    Danza, Giovanna; Di Serio, Claudia; Ambrosio, Maria Raffaella; Sturli, Niccolò; Lonetto, Giuseppe; Rosati, Fabiana; Rocca, Bruno Jim; Ventimiglia, Giuseppina; del Vecchio, Maria Teresa; Prudovsky, Igor; Marchionni, Niccolò; Tarantini, Francesca

    2013-12-01

    Prostate cancer (PC) is still the second cause of cancer-related death among men. Although patients with metastatic presentation have an ominous outcome, the vast majority of PCs are diagnosed at an early stage. Nonetheless, even among patients with clinically localized disease the outcome may vary considerably. Other than androgen sensitivity, little is known about which other signaling pathways are deranged in aggressive, localized cancers. The elucidation of such pathways may help to develop innovative therapies aimed at specific molecular targets. We report that in a hormone-sensitive PC cell line, LNCaP, Notch3 was activated by hypoxia and sustained cell proliferation and colony formation in soft agar. Hypoxia also modulated cellular cholesterol content and the number and size of lipid rafts, causing a coalescence of small rafts into bigger clusters; under this experimental condition, Notch3 migrated from the non-raft into the raft compartment where it colocalized with the γ-secretase complex. We also looked at human PC biopsies and found that expression of Notch3 positively correlated with Gleason score and with expression of carbonic anhydrase IX, a marker of hypoxia. In conclusion, hypoxia triggers the activation of Notch3, which, in turn, sustains proliferation of PC cells. Notch3 pathway represents a promising target for adjuvant therapy in patients with PC.

  6. Interactions of chronic lead exposure and intermittent stress: consequences for brain catecholamine systems and associated behaviors and HPA axis function.

    Science.gov (United States)

    Virgolini, Miriam B; Chen, Kevin; Weston, Doug D; Bauter, Mark R; Cory-Slechta, Deborah A

    2005-10-01

    Elevated lead (Pb) burden and high stress levels are co-occurring risk factors in low socioeconomic status (SES) children. Our previous work demonstrated that maternal Pb exposure can permanently alter hypothalamic-pituitary-adrenal (HPA) axis function and responsivity to stress challenges in offspring. The current study sought to determine the consequences of chronic Pb exposures initiated later in development combined with variable intermittent stress challenges. Male rats were exposed chronically from weaning to 0, 50, or 150 ppm Pb acetate drinking solutions (producing blood Pb levels of challenges including novelty, cold, and restraint, was measured as changes in Fixed Interval (FI) schedule-controlled behavior in a subset of rats within each group. FI performance was modified by novelty stress only in Pb-treated rats, whereas cold and restraint stress effects were comparable across groups. Novelty elevated corticosterone equivalently across groups, but cold stress markedly increased corticosterone only in Pb-treated groups. The pattern of Pb-induced changes in serotonin (5-HT) or its metabolite 5-HIAA in frontal cortex, nucleus accumbens, striatum, and hypothalamus resembled that observed for basal corticosterone levels indicating a relationship between these variables. In addition to suggesting the potential for HPA axis-mediated effects of Pb on the central nervous system, these findings also raise questions about whether single chemicals studied in isolation from other relevant risk factors can adequately identify neurotoxic hazards.

  7. Phosphorylation of PTEN increase in pathological right ventricular hypertrophy in rats with chronic hypoxia induced pulmonary hypertension

    Institute of Scientific and Technical Information of China (English)

    Nie Xin; Shi Yiwei; Yu Wenyan; Xu Jianying; Hu Xiaoyun; Du Yongcheng

    2014-01-01

    Background Phosphatase and tensin homologue on chromosome ten (PTEN) acts as a convergent nodal signalling point for cardiomyocyte hypertrophy,growth and survival.However,the role of PTEN in cardiac conditions such as right ventricular hypertrophy caused by chronic hypoxic pulmonary,hypertension remains unclear.This study preliminarily discussed the role of PTEN in the cardiac response to increased pulmonary vascular resistance using the hypoxia-induced PH rats.Methods Male Sprague Dawley rats were exposed to 10% oxygen for 1,3,7,14 or 21 days to induce hypertension and right ventricular hypertrophy.Right ventricular systolic pressure was measured via catheterization.Hypertrophy index was calculated as the ratio of right ventricular mass to left ventricle plus septum mass.Tissue morphology and fibrosis were measured using hematoxylin,eosin and picrosirius red staining.The expression and phosphorylation levels of PTEN in ventricles were determined by real time PCR and Western blotting.Results Hypoxic exposure of rats resulted in pathological hypertrophy,interstitial fibrosis and remodelling of the right ventricle.The phosphorylation of PTEN increased significantly in the hypertrophic right ventricle compared to the normoxic control group.There were no changes in protein expression in either ventricle.Conclusion Hypoxia induced pulmonary hypertension developed pathological right ventricular hypertrophy and remodelling probablv related to an increased phosohorvlation of PTEN.

  8. Effects and mechanism of oridonin on pulmonary hypertension induced by chronic hypoxia-hypercapnia in rats

    Institute of Scientific and Technical Information of China (English)

    WANG Liang-xing; SUN Yu; CHEN Chan; HUANG Xiao-ying; LIN Quan; QIAN Guo-qing; DONG Wei; CHEN Yan-fan

    2009-01-01

    Background Pulmonary arterial hypertension (PAH) is characterized by suppressing apoptosis and enhancing cell proliferation in the vascular wall. Inducing pulmonary artery smooth muscle cells (PASMC) apoptosis had been regarded as a therapeutic approach for PAH. Oridonin can cause apoptosis in many cell lines, while little has been done to evaluate its effect on PASMC.Methods Thirty male Sprague-Dawley rats were randomly assigned to three groups: normal control (NC); hypoxia-hypercapnia (HH); Hypoxia-hypercapnia + oridonin (HHO). Flats were exposed to hypoxia-hypercapnia for four weeks. Cultured human PASMC (HPASMC) were assigned to three groups: normoxia (NO); hypoxia (HY); hypoxia+ oridonin (HO). The mean pulmonary artery pressure, mass ratio of right ventricle over left ventricle plus septum (RV/(LV+S)), the ratio of thickness of the pulmonary arteriole wall to vascular external diameter (WT%) and the ratio of the vessel wall area to the total area (WA%) were measured. Morphologic changes of pulmonary arteries were observed under light and electron microscopes. The apoptotic characteristics in vitro and in vivo were detected. Results The mPAP, RV/(LV+S), WT%, and WA% in the HH group were significantly greater than those in the NC (P <0.01) and HHO groups (P <0.01); the activities of caspase-3 and caspase-9, and the expressions of Bex, cyt-C and apoptotic index (AI) in the group HH were less than those in the NC and HHO groups; and the expression of Bcl-2 in group HH was greater than that in the NC and HHO groups. HPASMC mitochondrial membrane potentials in group HO was lower than in group HY (P <0.01), and cyt-C in the cytoplasm, AI, and caspase-9 in the HO group were greater than that in the HY group (P <0.01), but the expression of Bcl-2 in the HO group was less than that in the HY group (P <0.05). Conclusions The results suggest that oridonin can lower pulmonary artery pressure effectively, and inhibit pulmonary artery structural remodeling by inducing smooth

  9. Hypoxia and brain development

    NARCIS (Netherlands)

    Nyakas, Csaba; Buwalda, Bauke; Luiten, P.

    1996-01-01

    Hypoxia threatens brain function during the entire life-span starting from early fetal age up to senescence. This review compares the short-term, long-term and life-spanning effects of fetal chronic hypoxia and neonatal anoxia on several behavioural paradigms including novelty-induced spontaneous an

  10. The effect of protein kinase C on voltage-gated potassium channel in pulmonary artery smooth muscle cells from rats exposed to chronic hypoxia

    Institute of Scientific and Technical Information of China (English)

    张永昶; 倪望; 张珍祥; 徐永健

    2004-01-01

    Background Chronic hypoxia can cause pulmonary hypertension and pulmonary heart disease with high mortality.The signal transduction pathway of protein kinase C (PKC) plays an important role in chronic pulmonary hypertension. So it is necessary to investigate the effect of PKC on voltage-gated potassium (K+) channels in pulmonary artery smooth muscle cells of rats exposed to chronic hypoxia.Methods Male Wistar rats were randomly divided into a control group (group A) and a chronic hypoxia group (group B). Group B received hypoxia [oxygen concentration (10±1)%] eight hours per day for four consecutive weeks. Single pulmonary artery smooth muscle cells were obtained using an acute enzyme separation method. Conventional whole cell patch clamp technique was used to record resting membrane potential, membrane capacitance and voltage-gated K+ currents. The changes in voltage-gated K+ currents before and after applying paramethoxyamphetamine (PMA) (500 nmol/L), an agonist of PKC, and PMA plus carbohydrate mixture of glucose, fructose and xylitol (GFX) (30 nmol/L), an inhibitor of PKC, were compared between the two groups. Results The resting membrane potential in group B was significantly lower than that of group A: -(29.0±4.8) mV (n=18) vs -(42.5±4.6) mV (n=35) (P0.05). The voltage-gated K+ currents were significantly inhibited by PMA in group A, and this effect was reversed by GFX. However, the voltage-gated K+ currents in group B were not affected by PMA.Conclusions The resting membrane potential and voltage-gated K+ currents in pulmonary artery smooth muscle cells from rats exposed to chronic hypoxia decreased significantly. It seems that PKC has different effects on the voltage-gated K+ currents of pulmonary artery smooth muscle cells under different conditions.

  11. Therapeutic efficacy of valproic acid in a combined monocrotaline and chronic hypoxia rat model of severe pulmonary hypertension.

    Directory of Open Access Journals (Sweden)

    Beidi Lan

    Full Text Available Pulmonary hypertension (PH is a serious disease with poor prognosis. Reports show that cells in remodeled pulmonary arteries of PH patients have similar characteristics to cancer cells, such as exuberant inflammation, increased proliferation, and decreased apoptosis. An ideal strategy for developing PH therapies is to directly target pulmonary vascular remodeling. High levels of histone deacetylase (HDAC expression and activity are found in certain cancers, and research has shown the potential of HDAC inhibitors in repressing tumor growth via anti-inflammatory and anti-proliferative effects. To date, little is known about the effectiveness of HDAC inhibitors against pulmonary vascular remodeling in severe PH.To investigate whether class I HDAC inhibitors suppress or reverse the development of severe PH in rats.Male Sprague-Dawley rats were injected with a single, subcutaneous dose of monocrotaline (60 mg/kg, and were exposed to chronic hypoxia to induce severe PH. Valproic acid, a class I HDAC inhibitor, was administered to rats daily via gastric gavage (300 mg/kg in a PH prevention study (during the first 3 weeks or a PH reversal study (from 3 to 5 weeks. At the end of experiment, hemodynamic indices were measured, ventricular hypertrophy indices were calculated and vascular remodeling phenotypes were analyzed.After 3 weeks exposure to a combined stimulation of monocrotaline and chronic hypoxia, rats exhibited a reduced body weight, elevated right ventricular systolic pressure, an increased Fulton index, right ventricle weight ratio, medial wall thickness and muscularized peripheral pulmonary arteries. These parameters for PH evaluation were exacerbated from 3 to 5 weeks. Daily administration of valproic acid therapy prevented and partially reversed the development of severe PH in rats, and decreased inflammation and proliferation in remodeled pulmonary arteries.These data show that class I HDAC inhibitors may be effective for treating severe

  12. Intermittent and continuous high-intensity exercise training induce similar acute but different chronic muscle adaptations.

    Science.gov (United States)

    Cochran, Andrew J R; Percival, Michael E; Tricarico, Steven; Little, Jonathan P; Cermak, Naomi; Gillen, Jenna B; Tarnopolsky, Mark A; Gibala, Martin J

    2014-05-01

    High-intensity interval training (HIIT) performed in an 'all-out' manner (e.g. repeated Wingate tests) is a time-efficient strategy to induce skeletal muscle remodelling towards a more oxidative phenotype. A fundamental question that remains unclear, however, is whether the intermittent or 'pulsed' nature of the stimulus is critical to the adaptive response. In study 1, we examined whether the activation of signalling cascades linked to mitochondrial biogenesis was dependent on the manner in which an acute high-intensity exercise stimulus was applied. Subjects performed either four 30 s Wingate tests interspersed with 4 min of rest (INT) or a bout of continuous exercise (CONT) that was matched for total work (67 ± 7 kJ) and which required ∼4 min to complete as fast as possible. Both protocols elicited similar increases in markers of adenosine monophosphate-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase activation, as well as Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mRNA expression (main effects for time, P ≤ 0.05). In study 2, we determined whether 6 weeks of the CONT protocol (3 days per week) would increase skeletal muscle mitochondrial content to a similar extent to what we have previously reported after 6 weeks of INT. Despite similar acute signalling responses to the CONT and INT protocols, training with CONT did not increase the maximal activity or protein content of a range of mitochondrial markers. However, peak oxygen uptake was higher after CONT training (from 45.7 ± 5.4 to 48.3 ± 6.5 ml kg(-1) min(-1); P muscle adaptations to low-volume, all-out HIIT. Despite the lack of skeletal muscle mitochondrial adaptations, our data show that a training programme based on a brief bout of high-intensity exercise, which lasted <10 min per session including warm-up, and performed three times per week for 6 weeks, improved peak oxygen uptake in young healthy subjects.

  13. Prevalence and severity of pain in adult end-stage renal disease patients on chronic intermittent hemodialysis: a systematic review

    Directory of Open Access Journals (Sweden)

    Brkovic T

    2016-06-01

    Full Text Available Tonci Brkovic,1 Eliana Burilovic,2 Livia Puljak3 1Department of Internal Medicine, Division of Nephrology, 2Department of Psychiatry, University Hospital Split, 3Department of Anatomy, Histology and Embryology, Laboratory for Pain Research, University of Split School of Medicine, Split, Croatia Objectives: Understanding the epidemiology of pain in patients on hemodialysis (HD is crucial for further improvement in managing pain. The aim of this study was to systematically review available evidence on the prevalence and severity of pain in adult end-stage renal disease patients on chronic intermittent HD. Materials and methods: We carried out a systematic review of the literature and developed a comprehensive search strategy based on search terms on pain and HD. We searched the databases MEDLINE, Scopus, PsycINFO, and CINAHL from the earliest date of each database to July 24, 2014. Manuscripts in all languages were taken into consideration. Two authors performed each step independently, and all disagreements were resolved after discussion with the third author. The quality of studies was estimated using the STROBE checklist and Cochrane risk-of-bias tool.Results: We included 52 studies with 6,917 participants. The prevalence of acute and chronic pain in HD patients was up to 82% and 92%, respectively. A considerable number of patients suffered from severe pain. Various locations and causes of pain were described, with most of the studies reporting pain in general, pain related to arteriovenous access, headache, and musculoskeletal pain.Conclusion: The findings of this systematic review indicate high prevalence of pain in HD patients and considerable gaps and limitations in the available evidence. Pain in this population should be recognized as a considerable health concern, and the nephrology community should promote pain management in HD patients as a clinical and research priority to improve patients’ quality of life and pain

  14. 间歇低氧大鼠神经元特异性烯醇化酶蛋白的表达及其对学习记忆功能的影响%Expression of neuron-specific enolase protein in rats after intermittent hypoxia and its influence on learining and memory function

    Institute of Scientific and Technical Information of China (English)

    张盼盼; 韩晓庆; 王红阳; 禹江涛; 李琳; 王立民; 郭秀华

    2014-01-01

    Objective To observe the changes of learning function and neuron-specific enolase (NSE)protein of both brian and serum in rats after intermittent hypoxia,and explore the relation between NSE protein and learning and memory function.Methods Male Wistar adult rats(n=48)were randomly divided into control group (UC group) and 7.5% chronic intermittent hypoxia group (7.5%CIH group).7.5% chronic intermittent hypoxia model in rats were simalated by using the self-made cabin of intermittent hypoxia.At the 2nd,4th,6th,and 8th week respectively,learning and memory function in rat was tested by Morris water maze in two groups.The level of NSE protein in hippocampal CA1 region was detected by immunohistochemical method,and was detected in serum of rats by using enzyme-linked immunosorbent adsorption method.Results Compared with the control group,7.5% CIH group at the 2nd,4th,6th,and 8th week in rats from the second week of the escape latency time was 44.13± 2.84) s,(50.35 ± 1.96) s,(57.47 ± 1.66) s,(62.85 ± 1.80) s,and across the target quadrant time was 48.81 ± 2.09) s,(42.04± 1.84) s,(36.82± 2.07) s,(31.81 ± 1.68) s.From the first two weeks,the longer the hypoxia time prolonged,the longer the rat's escapedlatency (P<0.05) and the shorter the rats acrossed the target quadrant (P <0.05).7.5% CIH group of hippocampal CA1 neurons NSE protein at the 2nd,4th,6th,and 8th week was (9.69±1.37),17.10± 1.87),(24.79± 3.51),(34.16±5.35),respectively,and serum NSE protein at the 2nd,4th,6th,and 8th week respectively was (6.03±0.91) μg/L,(11.04± 1.89) μg/L,(16.39± 1.00) μg/L,(24.22±3.73) μg/L,both of which were more than the control group.The difference was statistically significant (P<0.05).7.5% CIH group of hippocampal CA1 neurons and serum NSE protein expression were significant time differences,and gradually increased over time.The difference was statistically significant (P<0.05).Positive NSE protein expression in hippocampal CA1 region relative

  15. A two-phase model for chronic disease processes under intermittent inspection.

    Science.gov (United States)

    Wu, Ying; Cook, Richard J

    2017-02-26

    A model is developed for chronic diseases with an indolent phase that is followed by a phase with more active disease resulting in progression and damage. The time scales for the intensity functions for the active phase are more naturally based on the time since the start of the active phase, corresponding to a semi-Markov formulation. This two-phase model enables one to fit a separate regression model for the duration of the indolent phase and intensity-based models for the more active second phase. In cohort studies for which the disease status is only known at a series of clinical assessment times, transition times are interval-censored, which means the time origin for phase II is interval-censored. Weakly parametric models with piecewise constant baseline hazard and rate functions are specified, and an expectation-maximization algorithm is described for model fitting. Simulation studies examining the performance of the proposed model show good performance under maximum likelihood and two-stage estimation. An application to data from the motivating study of disease progression in psoriatic arthritis illustrates the procedure and identifies new human leukocyte antigens associated with the duration of the indolent phase. Copyright © 2017 John Wiley & Sons, Ltd.

  16. The effect of ACE inhibition on the pulmonary vasculature in combined model of chronic hypoxia and pulmonary arterial banding in Sprague Dawley rats

    Science.gov (United States)

    Clarke, Shanelle; Baumgardt, Shelley; Molthen, Robert

    2010-03-01

    Microfocal CT was used to image the pulmonary arterial (PA) tree in rodent models of pulmonary hypertension (PH). CT images were used to measure the arterial tree diameter along the main arterial trunk at several hydrostatic intravascular pressures and calculate distensibility. High-resolution planar angiographic imaging was also used to examine distal PA microstructure. Data on pulmonary artery tree morphology improves our understanding of vascular remodeling and response to treatments. Angiotensin II (ATII) has been identified as a mediator of vasoconstriction and proliferative mitotic function. ATII has been shown to promote vascular smooth muscle cell hypertrophy and hyperplasia as well as stimulate synthesis of extracellular matrix proteins. Available ATII is targeted through angiotensin converting enzyme inhibitors (ACEIs), a method that has been used in animal models of PH to attenuate vascular remodeling and decrease pulmonary vascular resistance. In this study, we used rat models of chronic hypoxia to induce PH combined with partial left pulmonary artery occlusion (arterial banding, PLPAO) to evaluate effects of the ACEI, captopril, on pulmonary vascular hemodynamic and morphology. Male Sprague Dawley rats were placed in hypoxia (FiO2 0.1), with one group having underwent PLPAO three days prior to the chronic hypoxia. After the twenty-first day of hypoxia exposure, treatment was started with captopril (20 mg/kg/day) for an additional twenty-one days. At the endpoint, lungs were excised and isolated to examine: pulmonary vascular resistance, ACE activity, pulmonary vessel morphology and biomechanics. Hematocrit and RV/LV+septum ratio was also measured. CT planar images showed less vessel dropout in rats treated with captopril versus the non-treatment lungs. Distensibility data shows no change in rats treated with captopril in both chronic hypoxia (CH) and CH with PLPAO (CH+PLPAO) models. Hemodynamic measurements also show no change in the pulmonary vascular

  17. The efficacy of intermittent cervical traction in patents with chronic neck pain.

    Science.gov (United States)

    Borman, Pinar; Keskin, Dilek; Ekici, Betul; Bodur, Hatice

    2008-10-01

    Previous studies about the usefulness of traction therapy have concluded with conflicting results. The aim of this study was to examine its efficacy in chronic neck pain. Forty-two patients with at least 6 weeks of nonspecific neck pain were selected for the study. Data about demographic characteristics including age, sex, body mass index, duration of cervical pain, working status, smoking status, and regular exercise were recorded. Each patient was randomly assigned to Group 1-receiving only standard physical therapy including hot pack, ultrasound therapy and exercise program and Group 2-treated with traction therapy in addition to standard physical therapy. The patients were reevaluated at the end of the therapy. The main outcome measures of the treatment were pain intensity by visual analog scale (VAS), disability by neck disability index (NDI), and quality of life assessed by Nottingham Health Profile (NHP). Twenty-four female and 18 male patients with mean age of 48.2+/-11.5 years and a mean disease duration of 4.3+/-2.9 years were included to the study. There were no differences between the groups in terms of age, sex, pain intensity, and scores of NHP and NDI at entry. There were 21 patients in both groups. Both groups improved significantly in pain intensity and the scores of NDI and physical subscles of NHP at the end of the therapies (ppain scores in both groups (pneck pain. We suggest the clinicians to consider this condition and to focus on exercise therapy in the management of patients suffering from this condition.

  18. Repeated Cycles of Chronic Intermittent Ethanol Exposure Increases Basal Glutamate in the Nucleus Accumbens of Mice without affecting glutamate transport

    Directory of Open Access Journals (Sweden)

    William C. Griffin

    2015-02-01

    Full Text Available Repeated cycles of chronic intermittent ethanol (CIE exposure increase voluntary consumption of ethanol in mice. Previous work has shown that extracellular glutamate in the nucleus accumbens (NAc is significantly elevated in ethanol dependent mice and that pharmacologically manipulating glutamate concentrations in the NAc will alter ethanol drinking, indicating that glutamate homeostasis plays a crucial role in ethanol drinking in this model. The present studies were designed to measure extracellular glutamate at a time point in which mice would ordinarily be allowed voluntary access to ethanol in the CIE model and, additionally, to measure glutamate transport capacity in the NAc at the same time point. Extracellular glutamate was measured using quantitative microdialysis procedures. Glutamate transport capacity was measured under Na+ dependent and Na+ independent conditions to determine whether the function of excitatory amino acid transporters (EAATs; also known as system XAG or of system Xc- (Glial cysteine-glutamate exchanger was influenced by CIE exposure. The results of the quantitative microdialysis experiment confirm increased extracellular glutamate (~2 –fold in the NAc of CIE exposed mice (i.e. ethanol-dependent compared to non-dependent mice in the NAc, consistent with earlier work. However, the increase in extracellular glutamate was not due to altered transporter function in the NAc of ethanol-dependent mice, because neither Na+ dependent nor Na+ independent glutamate transport was significantly altered by CIE exposure. These findings point to the possibility that hyperexcitability of cortical-striatal pathways underlies the increases in extracellular glutamate found in the nucleus accumbens of ethanol-dependent mice.

  19. Withdrawal from chronic, intermittent access to a highly palatable food induces depressive-like behavior in compulsive eating rats.

    Science.gov (United States)

    Iemolo, Attilio; Valenza, Marta; Tozier, Lisa; Knapp, Clifford M; Kornetsky, Conan; Steardo, Luca; Sabino, Valentina; Cottone, Pietro

    2012-09-01

    The increased availability of highly palatable foods is a major contributing factor toward the development of compulsive eating in obesity and eating disorders. It has been proposed that compulsive eating may develop as a form of self-medication to alleviate the negative emotional state associated with withdrawal from highly palatable foods. This study was aimed at determining whether withdrawal from chronic, intermittent access to a highly palatable food was responsible for the emergence of depressive-like behavior. For this purpose, a group of male Wistar rats was provided a regular chow diet 7 days a week (Chow/Chow), whereas a second group of rats was provided chow for 5 days a week, followed by a 2-day access to a highly palatable sucrose diet (Chow/Palatable). Following 7 weeks of diet alternation, depressive-like behavior was assessed during withdrawal from the highly palatable diet and following renewed access to it, using the forced swim test, the sucrose consumption test, and the intracranial self-stimulation threshold procedure. It was found that Chow/Palatable rats withdrawn from the highly palatable diet showed increased immobility time in the forced swim test and decreased sucrose intake in the sucrose consumption test compared with the control Chow/Chow rats. Interestingly, the increased immobility in the forced swim test was abolished by renewing access to the highly palatable diet. No changes were observed in the intracranial self-stimulation threshold procedure. These results validate the hypothesis that withdrawal from highly palatable food is responsible for the emergence of depressive-like behavior, and they also show that compulsive eating relieves the withdrawal-induced negative emotional state.

  20. Energy intermittency

    CERN Document Server

    Sorensen, Bent

    2014-01-01

    The first book to consider intermittency as a key point of an energy system, Energy Intermittency describes different levels of variability for traditional and renewable energy sources, presenting detailed solutions for handling energy intermittency through trade, collaboration, demand management, and active energy storage. Addressing energy supply intermittency systematically, this practical text:Analyzes typical time-distributions and intervals between episodes of demand-supply mismatch and explores their dependence on system layouts and energy source characteristicsSimulates scenarios regar

  1. Increased eicosanoid levels in the Sugen/chronic hypoxia model of severe pulmonary hypertension.

    Directory of Open Access Journals (Sweden)

    Aysar Al-Husseini

    Full Text Available Inflammation and altered immunity are recognized components of severe pulmonary arterial hypertension in human patients and in animal models of PAH. While eicosanoid metabolites of cyclooxygenase and lipoxygenase pathways have been identified in the lungs from pulmonary hypertensive animals their role in the pathogenesis of severe angioobliterative PAH has not been examined. Here we investigated whether a cyclooxygenase-2 (COX-2 inhibitor or diethylcarbamazine (DEC, that is known for its 5-lipoxygenase inhibiting and antioxidant actions, modify the development of PAH in the Sugen 5416/hypoxia (SuHx rat model. The COX-2 inhibitor SC-58125 had little effect on the right ventricular pressure and did not prevent the development of pulmonary angioobliteration. In contrast, DEC blunted the muscularization of pulmonary arterioles and reduced the number of fully obliterated lung vessels. DEC treatment of SuHx rats, after the lung vascular disease had been established, reduced the degree of PAH, the number of obliterated arterioles and the degree of perivascular inflammation. We conclude that the non-specific anti-inflammatory drug DEC affects developing PAH and is partially effective once angioobliterative PAH has been established.

  2. Increased eicosanoid levels in the Sugen/chronic hypoxia model of severe pulmonary hypertension.

    Science.gov (United States)

    Al-Husseini, Aysar; Wijesinghe, Dayanjan S; Farkas, Laszlo; Kraskauskas, Donatas; Drake, Jennifer I; Van Tassel, Ben; Abbate, Antonio; Chalfant, Charles E; Voelkel, Norbert F

    2015-01-01

    Inflammation and altered immunity are recognized components of severe pulmonary arterial hypertension in human patients and in animal models of PAH. While eicosanoid metabolites of cyclooxygenase and lipoxygenase pathways have been identified in the lungs from pulmonary hypertensive animals their role in the pathogenesis of severe angioobliterative PAH has not been examined. Here we investigated whether a cyclooxygenase-2 (COX-2) inhibitor or diethylcarbamazine (DEC), that is known for its 5-lipoxygenase inhibiting and antioxidant actions, modify the development of PAH in the Sugen 5416/hypoxia (SuHx) rat model. The COX-2 inhibitor SC-58125 had little effect on the right ventricular pressure and did not prevent the development of pulmonary angioobliteration. In contrast, DEC blunted the muscularization of pulmonary arterioles and reduced the number of fully obliterated lung vessels. DEC treatment of SuHx rats, after the lung vascular disease had been established, reduced the degree of PAH, the number of obliterated arterioles and the degree of perivascular inflammation. We conclude that the non-specific anti-inflammatory drug DEC affects developing PAH and is partially effective once angioobliterative PAH has been established.

  3. 间歇缺氧及睡眠剥夺大鼠血管内皮细胞相关指标的变化%Changes in vascular endothelial cells-related indices in rats with intermittent hypoxia and sleep deprivation

    Institute of Scientific and Technical Information of China (English)

    袁春华; 徐劲松; 郭洋琴; 宋宁燕; 夏国际

    2011-01-01

    BACKGROUND: Sleep apnea syndrome has been considered be a significant independent factor that caused outbreaks ofhypertension and coronary heart disease. Vascular endothelial dysfunction may be one of the most important mechanisms for themanifestation of these diseases.OBJECTIVE: To investigate the effects of intermittent hypoxia and sleep deprivation on invasive arterial blood pressure, plasmanitric oxide, endothelin and calcitonin gene related protein levels in rats.METHODS: Sixteen 3-month-old male Sprague-Dawley rats were randomly and evenly divided into two groups: the control groupand the intermittent hypoxia and sleep deprivation group. Rats in the intermittent hypoxia and sleep deprivation group wereplaced in an environment of intermittent hypoxia and sleep deprivation for 10 hours (22:00-08:00) and in an environment ofsimple sleep deprivation for 12 hours (08:00-20:00). During the remaining time, the rats were raised in cages. The control grouprats were raised without sleep deprivation and intermittent hypoxia.RESULTS AND CONCLUSION: After 8 weeks of model establishment, compared with the control group, invasive arterial bloodpressure was significantly higher (P < 0.01), plasma nitric oxide and calcitonin gene related protein levels were significantlydecreased (P < 0.01), and plasma endothelin level was significantly increased (P < 0.01) in the intermittent hypoxia and sleepdeprivation group. These results showed that intermittent hypoxia exposure and sleep deprivation can cause increased bloodpressure and vascular endothelial dysfunction in Sprague-Dawley rats.%背景:血管内皮功能损坏是睡眠呼吸暂停的病理基础.目的:观察间歇缺氧、睡眠剥夺对SD大鼠有创动脉收缩压及血浆一氧化氮、内皮素、降钙素基因相关肽水平的影响.方法:将3月龄雄性SD大鼠16只随机等分为2组,模型组大鼠每天置入睡眠剥夺合并间歇性缺氧条件10 h (22:00-08:00),单纯睡眠剥夺条件12 h(08

  4. Modificaciones hematológicas inducidas por eritropoyetina frente a hipoxia normobárica intermitente Hematologic changes induced by erythropoietin versus intermittent normobaric hypoxia

    Directory of Open Access Journals (Sweden)

    F. Sanchis-Gomar

    2010-12-01

    Full Text Available

    Publicaciones recientes reflejan la preocupación de las autoridades antidopaje por el uso de sistemas simuladores de altitud y la posibilidad de considerarlos métodos dopantes. El objetivo de nuestro estudio fue el de comparar las modificaciones hematológicas inducidas por dos tratamientos con eritropoyetina recombinante humana (rHuEpo a diferentes dosis, frente a un protocolo de hipoxia normobárica intermitente (HNI en un modelo animal.
    Veinticuatro ratas Wistar macho jóvenes fueron divididas en 3 grupos experimentales: grupo sometido a HNI (12h pO2 12% /12h pO2 21% (n=8; grupo tratado con una dosis de 300 UI de rHuEpo (n=8 y grupo tratado con 500 UI de rHuEpo (n=8. Se extrajeron dos muestras de sangre a cada uno de los grupos experimentales (antes y después de los tratamientos. Nuestros resultados muestran incrementos muy similares, y estadísticamente significativos, en los valores de hemoglobina, de hematocrito y de reticulocitos, tanto en el grupo HNI como en el grupo tratado con 300 UI de rHuEpo tras los 15 días de tratamiento. El tratamiento con 500 UI de rHuEpo produjo un incremento significativamente mayor.
    La principal conclusión de nuestro estudio es que las modificaciones de los parámetros hematológicos obtenidas mediante un protocolo de HNI son similares a las obtenidas con un tratamiento con 300 UI de rHuEpo.
    Palabras clave: Hemoglobina, hematocrito, reticulocitos, dopaje

    Recent publications reflect the anti-doping authorities’ concern about the use of altitude simulator systems, since these technologies could be considered as doping methods. The major aim of our study was to compare the effect of two different rHuEpo treatments with a normobaric intermittent hypoxic (NIH protocol regarding the modifications of hemoglobin, hematocrit and reticulocytes values in an animal model. Although these hematological parameters are of secondary nature, some international sport federations

  5. β-adrenergic response modulated by κ-opioid receptor stimulation is attenuated in the cardiomyocytes of rats following chronic hypoxia

    Institute of Scientific and Technical Information of China (English)

    裴建明; 毕辉; 王跃民; 朱妙章; 周京军; 朱运龙

    2003-01-01

    Objective: To study cross-talk between β-opioid receptor and β-adrenoceptor through determination of the intracellular calcium ([Ca2+]i) and cAMP responses in ventricular myocytes of rats subjected to chronic hypoxia for 4 weeks.Methods: Electrically-induced [Ca2+]i transient was measured in single right ventricular myocytes isolated from hearts of chronically hypoxic rats and the age-matched normoxic rats, by using a spectrofluorometric method.Results: β-adrenoceptor stimulation with isoproterenol increased the electrically-induced [Ca2+]i transient and cAMP in myocytes of normoxic rats.U50,488H, a selective β-opioid receptor agonist, at dose (1 μmol/L) which itself had no effect on the [Ca2+]i transient and cAMP, significantly inhibited the effect of isoproterenol.This inhibition was completely abolished in the presence of nor-BNI, a selective κ-opioid receptor antagonist.In the ventricular myocytes of chronically hypoxic rats, the inhibition of U50,488H on the increased [Ca2+]i transient and cAMP with isoproterenol was blunted.Conclusion: Results indicate that the cross-talk between the κ-opioid receptor and β-adrenoceptor is attenuated in the right ventricular myocytes of chronically hypoxic rat.This may be a self-protective mechanism of the heart following chronic hypoxia, which prevents the further decrease of the cardiac function.

  6. 睡眠呼吸暂停模式间歇低氧对心脑血管的影响%The Impact of Intermittent Hypoxia from Obstructive Sleep Apnea on Cardiovascular and Cerebrovascular Diseases

    Institute of Scientific and Technical Information of China (English)

    韩苗苗; 何庆; 施遥; 冯靖; 陈宝元

    2014-01-01

    Obstructive sleep apnea (OSA) is characterized by repeated intermittent hypoxia (IH), hypercapnia, sleep fragmentation and intrathoracic pressure change. IH is related to the clinical pathophysiological processes of hypertension, atherosclerosis, coronary heart disease, arrhythmia, stroke, heart failure and sudden death. IH from OSA can lead to metabol-ic dysregulation, endothelial dysfunction, systemic inflammation, oxidative stress and the change of nerve body fluids, which has been shown to increase the risk of cardiovascular diseases. This study mainly describes the pathogenesis of IH leading to the various cardiovascular diseases.%阻塞性睡眠呼吸暂停(OSA)的特点是睡眠期间反复发生气道阻塞导致间歇性低氧(IH)、高碳酸血症、睡眠片段化和胸内压改变。其中,IH与高血压、动脉粥样硬化、冠心病、心律失常、脑卒中、心衰和猝死等病理生理过程相关。OSA模式下IH会导致代谢调节异常、内皮功能障碍、系统性炎性反应、氧化应激反应及神经体液的变化,可增加心血管疾病的风险。本文主要描述了目前对IH导致各种心血管疾病的发病机制的理解。

  7. Protective effect of intermittent hypobaric hypoxia on cardiomyocytes injury induced by hydrogen peroxide%间歇性低压低氧对过氧化氢心肌细胞损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    郭会彩; 熊晨; 李军霞; 张荣; 赵丽娟; 王永利

    2012-01-01

    Objective: To observe the protective effect and mechnism of intermittent hypobaric hypoxia(IHH) on cardiomyocytes induced by hydrogen dioxide. Methods: Male guinea pigs were divided randomly into two groups (n = 10): intermittent hypoxia gtoup(IHH), and control group( non-IHH). The IHH guinea pigs were exposed to a simulated 5 000 m high altitude and hypoxia in hypobaric chamber for 28 d, 6 h/d. The control guinea pigs were kept in tbe same environment as IHH except hypoxia exposure. Cardiornyocytes were enzymabcally isolated from left ventricle of non-CIHH or CIHH guinea pigs. The contractile was assessed in guinea pigs by a video-based motion edge-detection system. The contents and activities of malondialdehydeC MDA), lactatdehydrogenase(IDH) and anboxidant enzymes were evaluated by using biochemical methods. Results: ①Hydrogen peroxide could induce contractile and diastol dysfunction, the latent period was longer in IHH car-diacmyocytes. ②After hydrogen peroxide(300 μmol/L, 10 min) perfusion, LDH and MDA contents in supernatant increased significantly in non-IHH and CIHH cardiomyocytes (P<0.01), Whereas the contents of MDA and LDH in IHH cardiornyocytes were lower than those in non-IHH cardiomyocytes ( P < 0.01). ③ The activities of superoxide dismutase (SOD) and catalase (CAT) were significantly increased in the myocardium of IHH guinea pigs, after hydrogen peroxide (300 μmol/L, 10 min) perfusion, SOD and CAT activities decreased significantly in non-MH and CIHH cardiomyocytes (p<0.01), whereas the activities of SOD and CAT in CIHH cardiomyocytes were still higher than those in non-IHH cardiomyocytes. Conclusion: Dffl had a protective effect on cardiomyocytes injury induced by hydrogen peroxide, which might relate with its antioxidation effects.%目的:观察慢性间歇性低压低氧对过氧化氢所致心肌细胞损伤的保护作用及其机制.方法:雄性豚鼠20只,随机分为两组(n=10):对照组(non-IHH)、低氧组(IHH).低氧

  8. Chronic hypoxia induces the activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1ΔE9 transgenic mice in vivo

    Science.gov (United States)

    Varela-Nallar, Lorena; Rojas-Abalos, Macarena; Abbott, Ana C.; Moya, Esteban A.; Iturriaga, Rodrigo; Inestrosa, Nibaldo C.

    2014-01-01

    Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin, a key component of the canonical Wnt signaling pathway. Here we studied the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice in vivo. The hypoxia-inducible transcription factor-1α (HIF-1α) was analyzed as a molecular control of the physiological hypoxic response. Exposure to chronic hypoxia (10% oxygen for 6–72 h) stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, Bromodeoxyuridine (BrdU) incorporation and double labeling with doublecortin (DCX). Chronic hypoxia also induced neurogenesis in a double transgenic APPswe-PS1ΔE9 mouse model of Alzheimer’s disease (AD), which shows decreased levels of neurogenesis in the SGZ. Our results show for the first time that exposure to hypoxia in vivo can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorders associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired. PMID:24574965

  9. Chronic hypoxia induces the in vivo activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1deltaE9 transgenic mice

    Directory of Open Access Journals (Sweden)

    Lorena eVarela-Nallar

    2014-02-01

    Full Text Available Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin a key component of the canonical Wnt signaling pathway. Here we studied in vivo the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice. As a molecular control of the physiological hypoxic response the hypoxia-inducible transcription factor-1α (HIF-1α was analyzed. Exposure to chronic hypoxia (10% oxygen for 6-72 h stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, BrdU incorporation and double labeling with doublecortin. Chronic hypoxia also induced neurogenesis in double transgenic APPswe-PS1deltaE9 mouse model of Alzheimer’s disease (AD, which shows decreased levels of neurogenesis at the SGZ. Our results show for the first time that in vivo exposure to hypoxia can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorder associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired.

  10. Hypoxia Room

    Data.gov (United States)

    Federal Laboratory Consortium — The Hypoxia Room is a 8x8x8 ft. clear vinyl plastic and aluminum frame construction enclosure located within USAREIM laboratory 028. The Hypoxia Room (manufactured...

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

    Science.gov (United States)

    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

  12. Effects of maturation, artery size, and chronic hypoxia on 5-HT receptor type in ovine cranial arteries.

    Science.gov (United States)

    Teng, G Q; Williams, J; Zhang, L; Purdy, R; Pearce, W J

    1998-09-01

    To test the hypothesis that variations in cerebrovascular reactivity to 5-HT among arteries of different size or type, during maturation, or during acclimatization to high altitude involve differences in serotonergic receptor subtype, we determined relative agonist potency orders and antagonist affinities in common carotid (Com), main branch middle cerebral (Main), and second branch middle cerebral (2BR) arteries from term fetal lambs and nonpregnant adult sheep acclimatized at sea level or at an altitude of 3,820 m for approximately 110 days. In normoxic adult Com segments, agonist potency order was 5-hydroxytryptamine (5-HT) > 5-carboxamidotryptamine (5-CT) >/= 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT); sumatriptan (Suma) produced no contractile response; and antagonist dissociation constant (pKb) values were 9.4 and 9.5 for ketanserin against 5-HT and 5-CT, 7.5 for GR-127935 against 5-HT, and 7.2 for SB-206553 against 5-HT. In normoxic adult Main segments, agonist potency order was 5-HT > 5-CT >/= Suma >/= DPAT, and pKb values were 9.1 and 9.2 for ketanserin against 5-HT and 5-CT and 7.4 and 8.5 for GR-127935 against 5-HT and Suma, respectively. In the 2BR segments from normoxic adults, agonist potency order was 5-CT > 5-HT > Suma > DPAT and pKb values were 7.4 and 7.2 for ketanserin against 5-HT and 5-CT and 10.0 and 8.7 for GR-127935 against 5-HT and Suma, respectively. Compared with normoxic adults, none of these values were significantly different in hypoxic adults and in fetuses only the pKb values for ketanserin against 5-HT in the 2BR segments (8.8) were greater. From these results we propose that the ratio of 5-HT2 to 5-HT1 receptors is greatest in the Com and decreases progressively to its smallest values in 2BR or smaller segments. Because this gradient appears stable and relatively resistant to the effects of maturation and chronic hypoxia, changes in reactivity associated with these perturbations may involve alterations in receptor density

  13. Intermittent and graded exercise effects on NK cell degranulation markers LAMP-1/LAMP-2 and CD8(+)CD38(+) in chronic fatigue syndrome/myalgic encephalomyelitis.

    Science.gov (United States)

    Broadbent, Suzanne; Coutts, Rosanne

    2017-03-01

    There is substantial evidence of immune system dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) but little is understood of exercise training effects on lymphocyte function in this illness. This study investigated whether graded and intermittent exercise improved CD8(+) lymphocyte activation and natural killer cell degranulation markers compared to no exercise. Twenty-four chronic fatigue syndrome (CFS) patients (50.2 ± 10 year) were randomized to graded exercise (GE), intermittent exercise (IE) or usual care (UC) groups; a control group (CTL) of 18 matched sedentary non-CFS/ME participants were included for immunological variable comparisons. Main outcome measures were pre- and postintervention expression of CD3(+)CD8(+)CD38(+) and CD3(-)CD16(+)56(+)CD107a(+) (LAMP-1) CD107b(+) (LAMP-2) and aerobic exercise capacity. The postintervention percentage of NK cells expressing LAMP-1 and -2 was significantly higher in IE compared to UC, and higher in GE compared to UC and CTL LAMP-1 and LAMP-2 expression (absolute numbers and percent positive) increased significantly pre-to-postintervention for both GE and IE Preintervention, the absolute number of CD8(+)CD38(+) cells was significantly lower in CTL compared to UC and IE There were no significant pre- to postintervention changes in CD8(+)CD38(+) expression for any group. Aerobic exercise capacity was significantly improved by GE and IE Twelve weeks of GE and IE increased the expression of NK cell activation and degranulation markers, suggesting enhanced immunosurveillance. Low-intensity exercise may also reduce CD8(+)CD38(+) expression, a marker of inflammation. Both GE and IE improved exercise capacity without worsening CFS/ME symptoms, and more robust trials of these exercise modalities are warranted.

  14. 睡眠间歇低氧大鼠心室重塑与心肌细胞凋亡和Rho激酶表达的关系%Involvement of sleep intermittent hypoxia in remodeling, apoptosis and expression of Rho kinase in rat myocardial cells

    Institute of Scientific and Technical Information of China (English)

    佟浩; 张曼; 王实; 柏树令

    2011-01-01

    目的 观察睡眠中间歇低氧状态下大鼠心室重塑、血液动力学异常与心肌细胞凋亡和Rho激酶表达的关系,探讨间歇低氧与心室重塑和心力衰竭之间关系的分子机制.方法 24只雄性Wistar大鼠分3组,每组8只.给予适度限制饮食量的普通饮食和每天正常运动量游泳1h,分为常氧(A组)、间歇低氧(B组)、间歇低氧+法舒地尔(C组),60d后检测血液动力学指标、心室重量、体重、形态学检测(HE染色和凋亡细胞检测)和RT-PCR检测Rho激酶mRNA表达.结果 与A组比较,B组血液动力学指标恶化,心室肥厚指数增加,心肌细胞排列紊乱,凋亡明显及Rho激酶表达增加.与B组比较,C组血液动力学指标改善,心室肥厚指数减小,心肌细胞排列紊乱减轻,凋亡减少及Rho激酶表达降低.结论 间歇低氧与心室重塑及心力衰竭的发生、发展密切相关.细胞凋亡和炎症因子Rho激酶表达增加与之密切相关.%Objective To explore the underlying molecular mechanisms relevant to intermittent hypoxia,remodeling and heart failure by observing the changes of remodeling, hemodynamic parameters, apoptosis and the expression of Rho kinase in the myocardial cells of rats with sleep intermittent hypoxia. Methods Male Wistar rats were given limited normal diet ( 20g/d per rat ) and swam for 1hour at 6pm. The rats were divided into 3 groups ( n = 8 per group ): a normal oxygen group ( group A, breathing 21% O2 for 8hours per day ), an intermittent hypoxia group ( group B, breathing 10% O2 and air altered per 90 sec for 8hours per day ) and a fasudil group [ group C, breathing 10% O2 and air altered per 90 see for 8hours per day, 20mg/( kg · d ) fasudil Qd, i. h. ]. Sixty days later, hemodynamic parameters,left ventricular weight and weight of rats were measured. Morphological changes ( HE staining ), apoptosis and the expression of Rho kinase mRNA in rat myocardial cells were examined. Results As compared to group A

  15. Chronic hypoxia increases arterial blood pressure and reduces adenosine and ATP induced vasodilatation in skeletal muscle in healthy humans

    DEFF Research Database (Denmark)

    Calbet, J A L; Boushel, Robert Christopher; Robach, P;

    2014-01-01

    into the femoral artery at sea level and then after 8-12 days of residence at 4559 m above sea level. At sea level, the infusions were carried out while the subjects breathed room air, acute hypoxia (FI O2 = 0.11) and hyperoxia (FI O2 = 1); and at altitude (FI O2 = 0.21 and 1). Skeletal muscle P2Y2 receptor...

  16. Study on Tibetan Chicken embryonic adaptability to chronic hypoxia by revealing differential gene expression in heart tissue

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Oxygen concentration is essential for appropriate metabolism.Hypoxia can exert a significant impact on physiological alteration of the cell and organism.Tibetan Chicken(Gallus gallus) is a Chinese indigenous breed inhabiting in Tibetan areas,which is also a chicken breed living at high altitude for the longest time in the world.It has developed an adaptive mechanism to hypoxia,which is demonstrated by that Tibetan Chicken has much higher hatchability than low-land chicken breeds in high-altitude areas of Tibet.In the present study,Tibetan Chicken fertilized full sib eggs were incubated up to Hamburger-Hamilton stage 43 under 13% and 21% oxygen concentration,respectively.Shouguang Chicken and Dwarf Recessive White Chicken were used as control groups.The hearts in all of the 3 chicken breeds under hypoxic and normoxic conditions were isolated and hybridized to Genechip Chicken Genome Array to study molecular mechanisms underlying the adaptation to high altitude of Tibetan Chicken.As a result,50 transcripts highly expressed in hypoxia are screened out.Among up-regulated genes,some are involved in the gene ontology(GO) such as cell growth,cell difference,muscle contraction and signal transduction.However,the expression levels of 21 transcripts are lower in hypoxia than those in normoxia.Some down-regulated genes take part in cell communication,ion transport,protein amino acid phosphorylation and signal transduction.Interestingly,gene enrichment analyses of these differential gene expressions are mainly associated with immune system response and ion channel activity in response to stimulus.Moreover,the transcriptional expression profiles analyzed by hierarchical clustering and CPP-SOM software in all of the 3 different chicken breeds revealed that Tibetan Chicken is much closely related to Shouguang Chicken rather than Dwarf Recessive White Chicken.In addition,12 transcripts of Tibetan Chicken breed-specific expressed genes were identified,which seem to result in a

  17. Study on Tibetan Chicken embryonic adaptability to chronic hypoxia by revealing differential gene expression in heart tissue

    Institute of Scientific and Technical Information of China (English)

    LI Mei; ZHAO ChunJiang

    2009-01-01

    Oxygen concentration is essential for appropriate metabolism. Hypoxia can exert a significant impact on physiological alteration of the cell and organism. Tibetan Chicken (Gallus gallus) is a Chinese in-digenous breed inhabiting in Tibetan areas, which is also a chicken breed living at high altitude for the longest time in the world. It has developed an adaptive mechanism to hypoxia, which is demonstrated by that Tibetan Chicken has much higher hatchability than low-land chicken breeds in high-altitude areas of Tibet. In the present study, Tibetan Chicken fertilized full sib eggs were incubated up to Ham-burger-Hamilton stage 43 under 13% and 21% oxygen concentration, respectively. Shouguang Chicken and Dwarf Recessive White Chicken were used as control groups. The hearts in all of the 3 chicken breeds under hypoxic and normoxic conditions were isolated and hybridized to GeneChip Chicken Genome Array to study molecular mechanisms underlying the adaptation to high altitude of Tibetan Chicken. As a result, 50 transcripts highly expressed in hypoxia are screened out. Among up-regulated genes, some are involved in the gone ontology (GO) such as cell growth, cell difference, muscle con-traction and signal transduction. However, the expression levels of 21 transcripts are lower in hypoxia than those in normoxia. Some down-regulated genes take part in cell communication, ion transport, protein amino acid phosphorylation and signal transduction. Interestingly, gene enrichment analyses of these differential gone expressions are mainly associated with immune system response and ion channel activity in response to stimulus. Moreover, the transcriptional expression profiles analyzed by hierarchical clustering and CPP-SOM software in all of the 3 different chicken breeds revealed that TI-betan Chicken is much closely related to Shouguang Chicken rather than Dwarf Recessive White Chicken. In addition, 12 transcripts of Tibetan Chicken breed-specific expressed genes were

  18. 不同频率间歇低氧大鼠心脏炎症状态及抗氧化干预的研究%Heart inflammatory status of rat in different frequency of intermittent hypoxia and its study of tempol intervention

    Institute of Scientific and Technical Information of China (English)

    周宁; 陈宝元; 曹洁; 张静; 邓园

    2013-01-01

    Objective To explore the relationship and influencing mechanism in obstructive sleep apnea hypopnea syndrome (OSAHS) combined cardiovascular disease,and to investigate the preventive effect of Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) by observing the changes of inflammation markers interleukin-6 (IL-6),IL-8,tumor necrosis factor-α (TNF-α),and C-reactive protein (CRP) of cardiac muscular tissue in rats exposed to continuous normal oxygen and varying degrees of intermittent hypoxia (IH) circumstances as well as treated with antioxidant intervention.Methods 48 male Wistar rats were divided into six groups by random arrangement table method,including four different frequency IH groups (IH1 group,IH2 group,IH3 group,and IH4 group),a sustained normal oxygen control group (SC group),and a tempol intervention group (IH3T group),each group had eight rats.Each group were given corresponding hypoxia exposure.After exposure of six weeks,the rats were executed,and the hearts were separated immediately.CRP,IL-6,IL-8,and TNF-α in cardiac muscular tissue homogenate were tested by enzyme-linked immune sorbent assay.Results ①The inflammation marker levels of CRP,TNF-α,and IL-8 in the cardiac muscular tissue of rats were significantly elevated in all of IH groups compared with SC group (P <0.05).The comparison among each IH group showed that the levels of IL-6,CRP,TNF-α,and IL-8 in IH3 and IH4 group which had higher frequency of IH were significantly elevated compared with IH1 and IH2 group which had lower frequency of IH,it prompted that the levels of these four inflammation markers in the cardiac muscular tissue of IH rats would be lifted with the increasing degree of IH.②The levels of IL-6,IL-8,CRP,and TNF-α in IH3T group were higher than those in SC group (P <0.05),but lower than those in IH3 group (P <0.05).Conclusions (①The degree of chronic IH could be an important factor influencing the inflammation marker levels of IL-6,IL-8,TNF-α,and CRP in

  19. 间歇缺氧对幼龄大鼠血清中胰岛素样生长因子水平的影响%Study on intermittent hypoxia in children sleep apnea hypopnea syndrome model and insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels in serum

    Institute of Scientific and Technical Information of China (English)

    侯瑾; 闫静; 康全清

    2012-01-01

    目的 利用间歇缺氧条件下饲养的幼龄大鼠研究间歇缺氧与生长发育迟滞的关系.方法 设计制造自动控制环境低氧装置,实现可控的间歇低氧.选取24只25日龄雌性SD大鼠,随机均分为对照组及轻、重度缺氧组.对照组正常喂养;其他两组饲养于间歇低氧箱内,每天循环间歇缺氧8h,共35 d.根据预实验的结果确定间歇低氧的浓度和频度,使轻度组动物每小时发生低氧事件6次,平均最低血氧饱和度降至0.853;重度组动物每小时发生低氧事件24次,平均最低血氧饱和度降至0.776.实验前后均测量体质量及身长,并取静脉血用酶联免疫吸附测定法检测血清胰岛素样生长因子(insulin-like growth factor,IGF)-1及胰岛素样生长因子结合蛋白(insulin-like growth factor binding protein,IGFBP)-3表达水平.结果 3组大鼠实验前后身长和体质量差异均无统计学意义(P值均>0.05).实验前各组血清IGF-1和IGFBP-3水平差异无统计学意义(P值均>0.05),实验35 d后,对照组、轻度缺氧组和重度缺氧组血清中IGF-1((-x)±s,下同)分别为(60.0±18.5)ng/ml、(40.6±9.9) ng/ml和(13.1±8.6)ng/ml,F=25.840,P<0.01;IGFBP-3分别为(1.93±0.23) μg/ml、(1.39±0.30) μg/ml和(0.90±0.21) μg/ml,F=33.929,P<0.01;差异均有统计学意义,且IGF-1及IGFBP-3水平随着缺氧程度加重而降低(P值均<0.05).结论 模拟儿童睡眠呼吸暂停低通气综合征缺氧程度的间歇缺氧幼龄大鼠模型尚未引起大鼠体格发育迟缓,但造成大鼠血清中IGF-1、IGFBP-3水平下 降并随着缺氧程度加重及血氧饱和度降低而降低.%Objective Using rats fed in intermittent hypoxia environment to study the relationship between sleep apnea hypopnea syndrone (SAHS) of children and growth retardation. Methods The hypoxic chamber was designed and manufactured,the control of intermittent hypoxia was achieved.Twentyfour rats were randomly divided into three groups

  20. Distinct Effects of Nalmefene on Dopamine Uptake Rates and Kappa Opioid Receptor Activity in the Nucleus Accumbens Following Chronic Intermittent Ethanol Exposure

    Directory of Open Access Journals (Sweden)

    Jamie H. Rose

    2016-07-01

    Full Text Available The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc κ opioid receptors (KOR in chronic intermittent ethanol (CIE exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood. We investigated the effects of nalmefene on dopamine transmission and KORs using fast scan cyclic voltammetry in NAc brain slices from male C57BL/6J mice following five weeks of CIE or air exposure. Nalmefene concentration-dependently reduced dopamine release similarly in air and CIE groups, suggesting that dynorphin tone may not be present in brain slices. Further, nalmefene attenuated dopamine uptake rates to a greater extent in brain slices from CIE-exposed mice, suggesting that dopamine transporter-KOR interactions may be fundamentally altered following CIE. Additionally, nalmefene reversed the dopamine-decreasing effects of a maximal concentration of a KOR agonist selectively in brain slices of CIE-exposed mice. It is possible that nalmefene may attenuate withdrawal-induced increases in ethanol consumption by modulation of dopamine transmission through KORs.

  1. Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption.

    Science.gov (United States)

    Smith, Maren L; Lopez, Marcelo F; Archer, Kellie J; Wolen, Aaron R; Becker, Howard C; Miles, Michael F

    2016-01-01

    Long lasting abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD). Mechanistically, persistent changes in gene expression are hypothesized to contribute to brain adaptations leading to ethanol toxicity and AUD. We employed repeated chronic intermittent ethanol (CIE) exposure by vapor chamber as a mouse model to simulate the cycles of ethanol exposure and withdrawal commonly seen with AUD. This model has been shown to induce progressive ethanol consumption in rodents. Brain CIE-responsive expression networks were identified by microarray analysis across five regions of the mesolimbic dopamine system and extended amygdala with tissue harvested from 0-hours to 7-days following CIE. Weighted Gene Correlated Network Analysis (WGCNA) was used to identify gene networks over-represented for CIE-induced temporal expression changes across brain regions. Differential gene expression analysis showed that long-lasting gene regulation occurred 7-days after the final cycle of ethanol exposure only in prefrontal cortex (PFC) and hippocampus. Across all brain regions, however, ethanol-responsive expression changes occurred mainly within the first 8-hours after removal from ethanol. Bioinformatics analysis showed that neuroinflammatory responses were seen across multiple brain regions at early time-points, whereas co-expression modules related to neuroplasticity, chromatin remodeling, and neurodevelopment were seen at later time-points and in specific brain regions (PFC or HPC). In PFC a module containing Bdnf was identified as highly CIE responsive in a biphasic manner, with peak changes at 0 hours and 5 days following CIE, suggesting a possible role in mechanisms underlying long-term molecular and behavioral response to CIE. Bioinformatics analysis of this network and several other modules identified Let-7 family microRNAs as potential regulators of gene expression changes induced by CIE. Our results suggest a complex temporal

  2. Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption.

    Directory of Open Access Journals (Sweden)

    Maren L Smith

    Full Text Available Long lasting abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD. Mechanistically, persistent changes in gene expression are hypothesized to contribute to brain adaptations leading to ethanol toxicity and AUD. We employed repeated chronic intermittent ethanol (CIE exposure by vapor chamber as a mouse model to simulate the cycles of ethanol exposure and withdrawal commonly seen with AUD. This model has been shown to induce progressive ethanol consumption in rodents. Brain CIE-responsive expression networks were identified by microarray analysis across five regions of the mesolimbic dopamine system and extended amygdala with tissue harvested from 0-hours to 7-days following CIE. Weighted Gene Correlated Network Analysis (WGCNA was used to identify gene networks over-represented for CIE-induced temporal expression changes across brain regions. Differential gene expression analysis showed that long-lasting gene regulation occurred 7-days after the final cycle of ethanol exposure only in prefrontal cortex (PFC and hippocampus. Across all brain regions, however, ethanol-responsive expression changes occurred mainly within the first 8-hours after removal from ethanol. Bioinformatics analysis showed that neuroinflammatory responses were seen across multiple brain regions at early time-points, whereas co-expression modules related to neuroplasticity, chromatin remodeling, and neurodevelopment were seen at later time-points and in specific brain regions (PFC or HPC. In PFC a module containing Bdnf was identified as highly CIE responsive in a biphasic manner, with peak changes at 0 hours and 5 days following CIE, suggesting a possible role in mechanisms underlying long-term molecular and behavioral response to CIE. Bioinformatics analysis of this network and several other modules identified Let-7 family microRNAs as potential regulators of gene expression changes induced by CIE. Our results suggest a

  3. Altered Wnt Signaling Pathway in Cognitive Impairment Caused by Chronic Intermittent Hypoxia: Focus on Glycogen Synthase Kinase-3β and β-catenin

    Directory of Open Access Journals (Sweden)

    Yue-Ying Pan

    2016-01-01

    Conclusions: Wnt/β-catenin signaling pathway abnormalities possibly play an important role in the development of cognitive deficits among mice exposed to CIH and that LiCl might attenuate CIH-induced cognitive impairment via Wnt/β-catenin signaling pathway.

  4. Mice Exposed to Chronic Intermittent Hypoxia Simulate Clinical Features of Deficiency of both Qi and Yin Syndrome in Traditional Chinese Medicine

    OpenAIRE

    Chengzhi Chai; Junping Kou; Danni Zhu; Yongqing Yan; Boyang Yu

    2011-01-01

    Deficiency of both Qi and Yin Syndrome (DQYS) is one of the common syndromes in traditional Chinese medicine (TCM), mainly characterized by tiredness, emaciation, anorexia, fidget, palpitation and rapid pulse, and so forth. Currently, there is no available animal model which can reflect the clinical features of this syndrome. In the present paper, we observed the time-course changes of whole behavior, body weight, food intake, locomotive activity and electrocardiogram in mice exposed to chron...

  5. On the mechanisms that limit oxygen uptake during exercise in acute and chronic hypoxia: role of muscle mass

    DEFF Research Database (Denmark)

    Calbet, José A L; Rådegran, Göran; Boushel, Robert

    2009-01-01

    Peak aerobic power in humans (VO2,peak) is markedly affected by inspired O2 tension (FIO2). The question to be answered in this study is what factor plays a major role in the limitation of muscle peak VO2 in hypoxia: arterial O2 partial pressure (Pa,O2) or O2 content (Ca,O2)? Thus, cardiac output...... altitude acclimatization. Acclimatization improved Bike peak exercise Pa,O2 from 34 +/- 1 in AH to 45 +/- 1 mmHg in CH(P Pa,O2 from 38 +/- 1 to 55 +/- 2 mmHg(P ... level values (2.65 +/- 0.15 and 1.16 +/- 0.11 l min(-1), respectively) during Knee, but not during Bike. During Knee in CH, leg oxygen delivery was similar to normoxia and, therefore, also VO2,peak in spite of a Pa,O2 of 55 mmHg. Reducing the size of the active mass improves pulmonary gas exchange...

  6. Ethanol withdrawal is required to produce persisting N-methyl-D-aspartate receptor-dependent hippocampal cytotoxicity during chronic intermittent ethanol exposure

    Science.gov (United States)

    Reynolds, Anna R.; Berry, B. Jennifer N.; Sharrett-Field, Lynda; Prendergast, Mark A.

    2015-01-01

    Chronic intermittent ethanol consumption is associated with neurodegeneration and cognitive deficits in preclinical laboratory animals and in the clinical population. While previous work suggests a role for neuroadaptations in the N-methyl-D-aspartate (NMDA) receptor in the development of ethanol dependence and manifestation of withdrawal, the relative roles of ethanol exposure and ethanol withdrawal in producing these effects have not been fully characterized. To examine underlying cytotoxic mechanisms associated with CIE exposure, organotypic hippocampal slices were exposed to 1–3 cycles of ethanol (50 mM) in cell culture medium for 5 days, followed by 24-hours of ethanol withdrawal in which a portion of slices were exposed to competitive NMDA receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV; 40 µM). Cytotoxicity was assessed using immunohistochemical labeling of neuron specific nuclear protein (NeuN; Fox-3), a marker of mature neurons, and thionine (2%) staining of Nissl bodies. Multiple cycles of CIE produced neurotoxicity, as reflected in persisting losses of neuron NeuN immunoreactivity and thionine staining in each of the primary cell layers of the hippocampal formation. Hippocampi aged in vitro were significantly more sensitive to the toxic effects of multiple CIEs than were non-aged hippocampi. This effect was not demonstrated in slices exposed to continuous ethanol, in the absence of withdrawal, or to a single exposure/withdrawal regimen. Exposure to APV significantly attenuated the cytotoxicity observed in the primary cell layers of the hippocampus. The present findings suggest that ethanol withdrawal is required to produce NMDA receptor-dependent hippocampal cytotoxicity, particularly in the aging hippocampus in vitro. PMID:25746220

  7. Blunted inflammation mediated by NF-κB activation in hippocampus alleviates chronic normobaric hypoxia-induced anxiety-like behavior in rats.

    Science.gov (United States)

    Fan, Junming; Fan, Xiaofang; Li, Yang; Guo, Jinbin; Xia, Dongmei; Ding, Lu; Zheng, Qingqing; Wang, Wei; Xue, Feng; Chen, Ran; Liu, Shouting; Hu, Lianggang; Gong, Yongsheng

    2016-04-01

    This study aims to investigate whether inflammation mediated by NF-κB activation is involved in the induction of anxiety-like behavior in chronic normobaric hypoxia (CNH) exposed rats and to investigate the underlying mechanism. To this end, rats were exposed in a normobaric hypoxic chamber with a fraction of inspired oxygen (FIO2) of ∼ 10%, 23 h/d, continues for 2 weeks. Anxiety-like behavior was tested by elevated plus maze and open field, inflammatory response, nucleus translocation of NF-κB, and signaling pathway in hippocampus were examined. CNH induced a significant increase of anxiety- like behavior and inflammation responses, which were ameliorated by NF-κB inhibitor, PDTC pretreatment, suggesting that the anxiogenic effect induced by inflammation is through NF-κB activation. CNH treatment significantly increased nucleus translocation of p65 and p105 in hippocampus, which was suppressed by PDTC pretreatment. In addition, CNH treatment significantly increased Iba-1, iNOS, COX-2, and p-PKA in hippocampus, which were blocked by PDTC pretreatment, suggesting CNH may activate microglia cells in hippocampus through NF-κB pathway. In conclusion, our results illustrate a mechanism that, activation of NF-κB in hippocampus may trigger the proinflammatory response of microglia cells, and iNOS-PKA pathway may involve in anxiogenic effect in CNH exposed rats.

  8. 间歇低氧干预对实验性糖尿病大鼠病症的影响%Effects of Intermittent Hypoxia on the Symptom in Experimental Diabetic Rats

    Institute of Scientific and Technical Information of China (English)

    周燚; 李良鸣; 姚鑫; 石家瑾

    2012-01-01

    OBJECTIVE To study the effect of hypoxia on the blood glucose and symptom in experimental diabetic rats. METHODS The model was established by long-term diet high sugar and fat food, lower dose (30mg/kg body weight) of the streptozocin (STZ) treated rats. They were randomly divided into model control group and hypoxia interfering group. Model control group lived under normal environment while hypoxia interfering group exposed to hypoxia for an hour per day in hypoxic tent (oxygen concentration 15.4% ?0.2%), six days a week for four weeks. RESULTS (1) The rats had the typical symptoms of diabetic. (2) Compared with the rats in Model control group, the ones in hypoxia interfering group had a non-significantly higher fasting blood glucose (FPG) (P > 0.05) and a decreased food intake (P < 0.05) as well as decreased weight (P < 0.05) after four-week intervention period. But there was no significant difference in the drinking, the fat Index, the insulin sensibility index (ISI) and the insulin resistance index (HOMA-IR) between the two groups. CONCLUSION Four-week hypoxia interfering had no improvement to the diabetic symptoms in experimental diabetic rats apparently, in contrast it can result in a quick decrease in weight and an ascendant trend in FPG.%目的 探索低氧干预对实验性糖尿病大鼠血糖及其病症的影响.方法 采用长期高糖高脂膳食加小剂量链脲佐菌素(STZ)的方法建立糖尿病大鼠模型,将复制成功的模型大鼠随机分为模型对照组与低氧干预组.模型对照组在常氧环境下正常生活,低氧干预组大鼠每天在低氧帐篷内低氧暴露1h(O2浓度15.4%±0.2%)、每周休息1d、共干预4周.结果 (1)糖尿病大鼠出现了典型的“三多一少”特征.(2)通过4周实验干预,低氧干预组大鼠血糖稍高于模型对照组(P>0.05)、摄食量明显低于模型对照组(P<0.05)、体重下降显著大于模型对照组(P<0.05)、肥胖指数、饮水量、胰岛素敏感指

  9. Studies on effect of chronic intermittent starvation on neuroendocrinous function in rats%慢性间歇饥饿对大鼠神经内分泌功能的影响

    Institute of Scientific and Technical Information of China (English)

    宋世一; 马宏

    2001-01-01

    探讨了慢性间歇饥饿及重饲过程中神经内分泌功能的动态变化并与急性饥饿进行比较.研究发现慢性间歇饥饿每100克体重垂体重量升高,附性器官无显著变化,重饲后恢复较快,与急性饥饿明显不同;慢性间歇饥饿时血液及垂体催乳素(PRL)无显著变化,PRL诱发反应减弱,与急性饥饿时PRL释放障碍较重,PRL诱发分泌增强有明显不同.结果表明:尽管体重下降程度完全一致,不同的饥饿方式和时程也可能对神经内分泌功能造成不同的影响.%This paper studies the dynamic changes of neuroendcrinous function during chronic intermittent starvation in rats and compares it with the result of acute starvation. The data shows that chronic intermittent starvation causes an elevation in pituitary weight per 100g body weight and no significant changes are found in accessory sex organs ,the changes can return to normal rapidly after refeeding. In chronic intermittent starvation, pituitary PRL and blood PRL show no significant changes, induced PRL serection is attenuated. A significant difference is revealed between chronic starvation and acute starvation. Although the body weight drops in the same degree during the above two kinds of starvation, various ways and periods of starvation can cause different changes in neuroendocrinous function.

  10. Hypoxia and fatty liver.

    Science.gov (United States)

    Suzuki, Tomohiro; Shinjo, Satoko; Arai, Takatomo; Kanai, Mai; Goda, Nobuhito

    2014-11-07

    The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.

  11. Brain dysfunction in mild to moderate hypoxia.

    Science.gov (United States)

    Gibson, G E; Pulsinelli, W; Blass, J P; Duffy, T E

    1981-06-01

    Hypoxia is commonly invoked to explain alterations in mental function, particularly in patients with cardiac pulmonary failure. The effects of acute graded hypoxia or higher integrative functions are well documented experimentally in man. Hypoxia in experimental animal models demonstrates that the pathophysiology is complex. In mild to moderate hypoxia, in contrast to severe hypoxia and to ischemia, the supply of energy for the brain is not impaired; cerebral levels of adenosine triphosphate (ATP) and adenylate energy charge are normal. In contrast, the turnover of several neurotransmitters is altered by mild hypoxia. For example, acetylcholine synthesis is reduced proportionally to the reduction in carbohydrate oxidation. This relationship holds in vitro and with several in vivo models of hypoxia. Pharmacologic and physiologic studies in man and experimental animals are consistent with acetylcholine having an important role in mediating the cerebral effects of mild hypoxia. These observations raise the possibility that treatments directed to cholinergic or other central neurotransmitter systems may benefit patients with cerebral syndromes secondary to chronic hypoxia.

  12. Effects of intermittent hypoxia on the metabolism of glucose, lipid and the function of hypothalamuspituitary-target gland axis%间歇低氧对糖、脂代谢及下丘脑-垂体-靶腺轴功能的影响

    Institute of Scientific and Technical Information of China (English)

    何庆; 韩苗苗; 冯靖; 陈宝元

    2013-01-01

    The main pathophysiological characteristic of obstructive sleep apnea (OSA)--intermittent hypoxia (IH),is related to obesity,dyslipidemia,insulin resistance (IR),type 2 diabetes mellitus (T2DM),the hypothalamus-pituitary-target gland axis (HPT) dysfunction and other related physiological processes of endocrine and metabolic disease.IH from OSA can lead to metabolic dysregulation,endothelial dysfunction,systemic inflammation,oxidative stress and the change of nerve body fluids,which has been shown to increase the risk of cardiovascular and endocrine metabolic diseases.%阻塞性睡眠呼吸暂停(OSA)的主要病理生理学特点——间歇低氧(IH),与肥胖、血脂异常、胰岛素抵抗(IR)、2型糖尿病(T2DM)、下丘脑-垂体-靶腺轴(HPT)功能失调及其他内分泌和代谢紊乱疾病等病理生理过程相关.OSA模式下IH会导致代谢调节异常、内皮功能障碍、系统性炎性反应、氧化应激反应及神经体液的变化,可增加心血管和内分泌代谢疾病的风险.

  13. Acclimatory responses of the Daphnia pulex proteome to environmental changes. I. Chronic exposure to hypoxia affects the oxygen transport system and carbohydrate metabolism

    Directory of Open Access Journals (Sweden)

    Madlung Johannes

    2009-04-01

    Full Text Available Abstract Background Freshwater planktonic crustaceans of the genus Daphnia show a remarkable plasticity to cope with environmental changes in oxygen concentration and temperature. One of the key proteins of adaptive gene control in Daphnia pulex under hypoxia is hemoglobin (Hb, which increases in hemolymph concentration by an order of magnitude and shows an enhanced oxygen affinity due to changes in subunit composition. To explore the full spectrum of adaptive protein expression in response to low-oxygen conditions, two-dimensional gel electrophoresis and mass spectrometry were used to analyze the proteome composition of animals acclimated to normoxia (oxygen partial pressure [Po2]: 20 kPa and hypoxia (Po2: 3 kPa, respectively. Results The comparative proteome analysis showed an up-regulation of more than 50 protein spots under hypoxia. Identification of a major share of these spots revealed acclimatory changes for Hb, glycolytic enzymes (enolase, and enzymes involved in the degradation of storage and structural carbohydrates (e.g. cellubiohydrolase. Proteolytic enzymes remained constitutively expressed on a high level. Conclusion Acclimatory adjustments of the D. pulex proteome to hypoxia included a strong induction of Hb and carbohydrate-degrading enzymes. The scenario of adaptive protein expression under environmental hypoxia can be interpreted as a process to improve oxygen transport and carbohydrate provision for the maintenance of ATP production, even during short episodes of tissue hypoxia requiring support from anaerobic metabolism.

  14. Lung Oxidative Damage by Hypoxia

    Directory of Open Access Journals (Sweden)

    O. F. Araneda

    2012-01-01

    Full Text Available One of the most important functions of lungs is to maintain an adequate oxygenation in the organism. This organ can be affected by hypoxia facing both physiological and pathological situations. Exposure to this condition favors the increase of reactive oxygen species from mitochondria, as from NADPH oxidase, xanthine oxidase/reductase, and nitric oxide synthase enzymes, as well as establishing an inflammatory process. In lungs, hypoxia also modifies the levels of antioxidant substances causing pulmonary oxidative damage. Imbalance of redox state in lungs induced by hypoxia has been suggested as a participant in the changes observed in lung function in the hypoxic context, such as hypoxic vasoconstriction and pulmonary edema, in addition to vascular remodeling and chronic pulmonary hypertension. In this work, experimental evidence that shows the implied mechanisms in pulmonary redox state by hypoxia is reviewed. Herein, studies of cultures of different lung cells and complete isolated lung and tests conducted in vivo in the different forms of hypoxia, conducted in both animal models and humans, are described.

  15. 间歇低氧干预不影响实验性糖尿病大鼠骨骼肌SDH、LDH活性%Intermittent hypoxia did not have effect on the SDH and LDH activities of skeletal muscle in experimental diabetic rats

    Institute of Scientific and Technical Information of China (English)

    周燚; 方彩华; 李良鸣; 石家瑾

    2012-01-01

    目的:探讨间歇低氧干预对糖尿病大鼠骨骼肌糖代谢酶活性的影响。方法:采用长期高糖高脂膳食加小剂量链脲佐菌素(STZ)的方法建立糖尿病大鼠模型,将复制成功的模型大鼠随机分为模型对照组与低氧干预组。模型对照组在常氧环境下正常生活,低氧干预组大鼠每天在低氧帐篷内低氧暴露1h(O2浓度15.4±0.2%)、每周休息1d、共干预28d后36h取股四头肌测试琥珀酸脱氢酶(SDH)、乳酸脱氢酶(LDH)活性。结果:模型对照组大鼠股四头肌SDH活性显著低于正常对照组(P〈0.05),LDH活性高于正常对照组(P〉0.05),低氧干预组SDH、LDH活性与模型对照组比较均无明显差异(P〉0.05)。结论:实验性糖尿病大鼠骨骼肌SDH活性降低,有氧氧化供能能力下降,而LDH活性增强,无氧酵解能力提高;本实验所设计的间歇低氧干预模式对实验性糖尿病大鼠骨骼肌SDH、LDH活性均无明显积极作用。%Objective The purpose of this study was to investigate the effect of intermittent hypoxia on the SDH and LDH activities in skeletal muscle of diabetic rats. Methods The diabetic rat model was established by long-term high sugar and fat diet with low dose (30mg/kg body weight) of the streptozocin (STZ) by intraperitoneal injection only once. The diabetic rats were randomly divided into model control (MC) group and hypoxia interfering (HI) group. The MC rats were living in normal environment while the HI rats were exposed to hypoxia for one hour per day in hypoxic tent (oxygen concentration 15.4 ±0. 2 % ), six days a week for four weeks. The activities of SDH and LDH in the quadriceps femoris rats were measured. Results Compared with the rats in normal control group, the SDH activity reduced significantly ( P 〈 0. 05 ) and LDH activity increased only slightly in model control group. No significant differences of the

  16. 慢性亚致死性缺氧对未成熟脑结构和发育的影响%Chronic sublethal hypoxia: challenge to premature brain in structual and neurological development

    Institute of Scientific and Technical Information of China (English)

    平莉莉; 蒋泽栋

    2010-01-01

    With the advance of modern neonatal management, the increase of survival of infants born with ELBW has resulted in collateral increase in incidence of infants with serious chronic lung disease, typically brnchopulmonary dysplasia (BPD). Long-term sensory, motor and cognitive impairments are common outcomes in survivals with moderate and severe BPD and may persist during school years and adolescence. Increasing evidence suggest that BPD exerts a significant effect on brain growth and development and may be associated with chronic sublethal hypoxia which compond the risk of extended brain injury and NS complications such as cerebral palsy. Animal studies have demonstrated progressive gliosis and cerebral ventriculomegaly, injured subcortical white matter and corpus callosum, dysynchrony synaptic development and disrupted neurotransmitssion in the hypoxia newborn brain. In this literature we built upon the review of neurogical and congnitive outcome in preterm infants with BPD and structural, functional and neurochemical alterations in ainimals following clinical and experimental hypoxia respectively, which may underlie the primary or potential mle for chronic sublethal hypoxia on premature brain development.%现代新生儿学的发展促使极低体质量早产儿的存活率显著提高,同时严重慢性肺部疾病患儿增多,特别是支气管肺发育不良(BPD).中重度BPD患儿多数有远期感觉、运动和认知缺陷.有些功能缺陷可能发展至学龄期或成年甚至持续终生.越来越多的临床数据表明BPD显著影响新生儿脑生长和发育,其病程中伴随的慢性亚致死性缺氧是引起极低体质量早产儿远期脑损伤和脑瘫等神经系统并发症的重要因素之一.动物研究发现慢性缺氧导致新生鼠脑皮层下和胼胝体白质损伤、进行性脑室扩大和胶质增生,突触发育前后失衡及神经递质传导障碍,从而可能显著影响感觉、运动及认知等脑功能发育.

  17. A Novel Rabbit Carotid Body and Common Carotid Artery Model in Vivo for the Simulation of Various Intermittent and Continuous Hypoxia Modes%不同间歇低氧与持续低氧模式家兔在体颈动脉体和颈总动脉模型的建立

    Institute of Scientific and Technical Information of China (English)

    冯靖; 崔林阳; 陈宝元; 郭美南; 曹洁; 孙蓓

    2009-01-01

    Objective To develope a novel rabbit carotid body and carotid common artery model in vivo for the simulation of various intermittent hypoxia (IH) intensities, IH durations, IH reoxygenation (ROX) durations and continuous hypoxia (CH) modes.Methods Forty-five adult New Zealand rabbits (2.5~3.0 kg) were anesthetized while spontaneous breathing kept intact.The tissue surrounding the fight earetid common artery and carotid sinus nerve (CSN) were cleared and "single" chemoreceptor bundle of the CSN was revealed.Then suction electrodes were placed and CSN afferent activity was monitored and recorded carefully.The fight common carotid artery was exposed, cannulated to distal part and its proximal part was ligated.Preparations were challenged by changing the PO2 of the gas mixture equilibrating the perfusate.Alternatively perfusion (2 mL/min) of equilibrated porfusate bubbled with normoxia or hypoxia gas mixtures formed IH/ROX cycles in carotid common artery,simulating the pattern of hypoxic episodes seen in obstructive sleep apnea syndrome (OSAS), or with continuously perfusing hypoxia perfusate to form CH modes.All the perfusing procedures were regulated by a customized computer-controlled set and monitored using O2 gas analyzer.After the systematic exposures, carotid body, carotid common artery part distal to cannula,and carotid bifurcation were harvested as samples.Results The frequencies and average amplitudes of CSN chemoreceptor bundles afferent activities with normoxia peffusion were (0.17±0.03) impulse/s and (46.2±4.4) μV, and with hypoxia perfusion were (0.6±0.09) impulse/s and (87.4±6.6) μV, respectively.PO2 was (139±1.5) nun Hg in normoxia perfusate and (35.2±1.3) mm Hg in hypoxia perfusate.Conclusion This new carotid body and carotid common artery model is a valuable tool to study neurological and biochemical changes in various IH and CH modes.%目的 探讨建立不同间歇低氧(IH)程度、IH时间和再氧合(ROX)时间以及持续低氧(CH)模

  18. Intermittent Oxygen Inhalation with Proper Frequency Improves Overall Health Conditions and Alleviates Symptoms in a Population at High Risk of Chronic Mountain Sickness with Severe Symptoms

    Institute of Scientific and Technical Information of China (English)

    Bin Feng; Wei-Hao Xu; Yu-Qi Gao; Fu-Yu Liu; Peng Li; Shan-Jun Zheng; Lu-Yue Gai

    2016-01-01

    Background:Oxygen inhalation therapy is essential for the treatment of patients with chronic mountain sickness (CMS),but the efficacy of oxygen inhalation for populations at high risk of CMS remains unknown.This research investigated whether oxygen inhalation therapy benefits populations at high risk of CMS.Methods:A total of 296 local residents living at an altitude of 3658 m were included;of which these were 25 diagnosed cases of CMS,8 cases dropped out of the study,and 263 cases were included in the analysis.The subjects were divided into high-risk (180 ≤ hemoglobin (Hb) <210 g/L,n =161) and low-risk (Hb <180 g/L,n =102) groups,and the cases in each group were divided into severe symptom (CMS score ≥6) and mild symptom (CMS score 0-5) subgroups.Severe symptomatic population of either high-or low-risk CMS was randomly assigned to no oxygen intake group (A group) or oxygen intake 7 times/week group (D group);mild symptomatic population of either high-or low-risk CMS was randomly assigned to no oxygen intake group (A group),oxygen intake 2 times/week group (B group),and 4 times/week group (C group).The courses for oxygen intake were all 30 days.The CMS symptoms,sleep quality,physiological biomarkers,biochemical markers,etc.,were recorded on the day before oxygen intake,on the 15th and 30th days of oxygen intake,and on the 15th day after terminating oxygen intake therapy.Results:A total of 263 residents were finally included in the analysis.Among these high-altitude residents,CMS symptom scores decreased for oxygen inhalation methods B,C,and D at 15 and 30 days after oxygen intake and 15 days after termination,including dyspnea,palpitation,and headache index,compared to those before oxygen intake (B group:Z =5.604,5.092,5.741;C group:Z =4.155,4.068,4.809;D group:Z =6.021,6.196,5.331,at the 3 time points respectively;all P < 0.05/3 vs.before intake).However,dyspnea/palpitation (A group:Z =5.003,5.428,5.493,both P < 0.05/3 vs.before intake) and headache (A

  19. Chronic Treatment with a Water-Soluble Extract from the Culture Medium of Ganoderma lucidum Mycelia Prevents Apoptosis and Necroptosis in Hypoxia/Ischemia-Induced Injury of Type 2 Diabetic Mouse Brain

    Directory of Open Access Journals (Sweden)

    Meiyan Xuan

    2015-01-01

    Full Text Available Type 2 diabetes mellitus has been known to increase systemic oxidative stress by chronic hyperglycemia and visceral obesity and aggravate cerebral ischemic injury. On the basis of our previous study regarding a water-soluble extract from the culture medium of Ganoderma lucidum mycelia (designed as MAK, which exerts antioxidative and neuroprotective effects, the present study was conducted to evaluate the preventive effects of MAK on apoptosis and necroptosis (a programmed necrosis induced by hypoxia/ischemia (H/I in type 2 diabetic KKAy mice. H/I was induced by a combination of unilateral common carotid artery ligation with hypoxia (8% O2 for 20 min and subsequent reoxygenation. Pretreatment with MAK (1 g/kg, p.o. for a week significantly reduced H/I-induced neurological deficits and brain infarction volume assessed at 24 h of reoxygenation. Histochemical analysis showed that MAK significantly suppressed superoxide production, neuronal cell death, and vacuolation in the ischemic penumbra, which was accompanied by a decrease in the numbers of TUNEL- or cleaved caspase-3-positive cells. Furthermore, MAK decreased the expression of receptor-interacting protein kinase 3 mRNA and protein, a key molecule for necroptosis. These results suggest that MAK confers resistance to apoptotic and necroptotic cell death and relieves H/I-induced cerebral ischemic injury in type 2 diabetic mice.

  20. Protective effect of the extract of Yi-Qi-Fu-Mai preparation on hypoxia-induced heart injury in mice

    Institute of Scientific and Technical Information of China (English)

    FENG Ya-Qian; JU Ai-Chun; LIU Chun-Hua; WANG Ting; YU Bo-Yang; QI Jin

    2016-01-01

    Yi-Qi-Fu-Mai (YQFM) is extensively used clinically to treat cardiovascular diseases in China.To explore the anti-hypoxia effect of the extract of YQFM preparation (EYQFM),the EYQFM (1.4,2.8,and 5.5 g·kg-1·d-1) was assessed for its heart-protective effect in a chronic intermittent hypoxia (CIH) animal model (oxygen pressure 7%-8%,20 min per day) for 28 days of treatment.Betaloc (0.151 6 g·kg-1·d-1) was used as a positive control.The histopathological analyses of heart in CIH mice were conducted.Several cardiac state parameters,such as left ventricular ejection fractions (EF),stroke volume (SV),expression of creatine kinase (CK),lactate dehydrogenase (LDH),superoxide dismutase (SOD),and malondialdehyde (MDA) were measured.The results showed that treatment with EYQFM markedly reversed swelling of the endothelial cells and vacuolization in the heart when compared with the model group.Further study demonstrated that EYQFM significantly improved ventricular myocardial contractility by increasing EF and SV.In addition,EYQFM inhibited the activity of CK,LDH,decreased the level of MDA and improved SOD activity.The results demonstrated that EYQFM significantly improved the tolerability of myocardium to hypoxia and ameliorated the cardiac damage in the CIH model.

  1. Intermittent degradation and schizotypy

    Directory of Open Access Journals (Sweden)

    Matthew W. Roché

    2015-06-01

    Full Text Available Intermittent degradation refers to transient detrimental disruptions in task performance. This phenomenon has been repeatedly observed in the performance data of patients with schizophrenia. Whether intermittent degradation is a feature of the liability for schizophrenia (i.e., schizotypy is an open question. Further, the specificity of intermittent degradation to schizotypy has yet to be investigated. To address these questions, 92 undergraduate participants completed a battery of self-report questionnaires assessing schizotypy and psychological state variables (e.g., anxiety, depression, and their reaction times were recorded as they did so. Intermittent degradation was defined as the number of times a subject’s reaction time for questionnaire items met or exceeded three standard deviations from his or her mean reaction time after controlling for each item’s information processing load. Intermittent degradation scores were correlated with questionnaire scores. Our results indicate that intermittent degradation is associated with total scores on measures of positive and disorganized schizotypy, but unrelated to total scores on measures of negative schizotypy and psychological state variables. Intermittent degradation is interpreted as potentially derivative of schizotypy and a candidate endophenotypic marker worthy of continued research.

  2. Defining "intermittent UVR exposure"

    DEFF Research Database (Denmark)

    Bodekær, Mette; Philipsen, Peter Alshede; Petersen, Bibi Øager;

    2016-01-01

    to define and quantify “intermittent UVR exposure” by an objective measure. Methods: A broad study population of adults and children had data collected during a summer period. Data were personal UVR dosimetry measurements, from which the number of “intermittent days” was derived, sun behaviour diaries.......001). The corresponding numbers for prediction of nevi and lentigo density by retrospective questionnaire data was lower (R2 = 0.11, R2 = 0.26, p defined objective measure of intermittent UVR exposure. This measure may provide a better prediction of solar skin damage and CMM...

  3. Intermittent Explosive Disorder

    Directory of Open Access Journals (Sweden)

    Lut Tamam

    2011-09-01

    Full Text Available Intermittent explosive disorder is an impulse control disorder characterized by the occurrence of discrete episodes of failure to resist aggressive impulses that result in violent assault or destruction of property. Though the prevalence intermittent explosive disorder has been reported to be relatively rare in frontier studies on the field, it is now common opinion that intermittent explosive disorder is far more common than previously thought especially in clinical psychiatry settings. Etiological studies displayed the role of both psychosocial factors like childhood traumas and biological factors like dysfunctional neurotransmitter systems and genetics. In differential diagnosis of the disorder, disorders involving agression as a symptom such as alcohol and drug intoxication, antisocial and borderline personality disorders, personality changes due to general medical conditions and behavioral disorder should be considered. A combination of pharmacological and psychotherapeutic approaches are suggested in the treatment of the disorder. This article briefly reviews the historical background, diagnostic criteria, epidemiology, etiology and treatment of intermittent explosive disorder.

  4. Migraine induced by hypoxia

    DEFF Research Database (Denmark)

    Arngrim, Nanna; Schytz, Henrik Winther; Britze, Josefine

    2016-01-01

    Migraine with aura is prevalent in high-altitude populations suggesting an association between migraine aura and hypoxia. We investigated whether experimental hypoxia triggers migraine and aura attacks in patients suffering from migraine with aura. We also investigated the metabolic and vascular...... response to hypoxia. In a randomized double-blind crossover study design, 15 migraine with aura patients were exposed to 180 min of normobaric hypoxia (capillary oxygen saturation 70-75%) or sham on two separate days and 14 healthy controls were exposed to hypoxia. Glutamate and lactate concentrations...... in the visual cortex were measured by proton magnetic resonance spectroscopy. The circumference of cranial arteries was measured by 3 T high-resolution magnetic resonance angiography. Hypoxia induced migraine-like attacks in eight patients compared to one patient after sham (P = 0.039), aura in three...

  5. Selective vulnerability in brain hypoxia

    DEFF Research Database (Denmark)

    Cervos-Navarro, J.; Diemer, Nils Henrik

    1991-01-01

    Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis......Neuropathology, selective vulnerability, brain hypoxia, vascular factors, excitotoxicity, ion homeostasis...

  6. Intermittent Hypoxia Promote the Formation of Atherosclerosis by Increasing Expression of Lipoprotein-Associated Phospholipase A2 and Oxidized Low Density Lipoprotein%间歇性低氧通过上调脂蛋白相关磷脂酶A2和氧化型低密度脂蛋白表达促进动脉粥样硬化形成

    Institute of Scientific and Technical Information of China (English)

    李月春; 刘国荣; 王宝军; 郝喜娃; 张京芬; 庞江霞; 闫洁

    2012-01-01

    目的 研究间歇性低氧及高脂饮食通过上调脂蛋白相关磷脂酶A2(Lp-PLA2)、氧化型低密度脂蛋白(ox-LDL)的表达促进动脉粥样硬化的形成.方法 采用随机对照、前瞻性动物实验和析因设计的方法,建立间歇性低氧和高脂饮食兔动物模型,将24只4月龄新西兰大耳白兔随机分为四组:对照组、间歇性低氧组(IH组)、高脂饮食组(HFD组)和间歇性低氧+高脂饮食组(IH+ HFD组),每组6只.IH组和IH +HFD组置于间歇性低氧舱中,每天8h,每循环5min,舱内最低氧浓度8%,最高氧浓度21%,HFD组和IH +HFD组给予高脂饲料饲养,间歇性低氧和高脂饮食干预12周,利用酶联免疫吸附法测定间歇性低氧和高脂饮食干预0、4、8和12周血浆中Lp-PLA2和ox-LDL含量的变化,在实验终点12周取主动脉弓和腹主动脉观察动脉粥样硬化的形成情况.结果 在第8周和12周时,IH组、HFD组和IH+ HFD组Lp-PLA2含量较对照组和第4周时升高(P<0.05);在第4、8和12周时IH+ HFD组Lp-PLA2含量分别较对照组、IH组和HFD组升高(P<0.05);间歇性低氧和高脂饮食分别在第4、8和12周对Lp-PLA2的影响存在交互效应(P=0.000,P=0.001,P=0.000).在第4、8和12周时,IH组、HFD组和IH+ HFD组ox-LDL含量较对照组均升高(P<0.05),在第4周时明显高于第8周和12周(P<0.05);在第4、8和12周时IH +HFD组ox-LDL含量分别较对照组、IH组和HFD组升高(P<0.05);间歇性低氧和高脂饮食在第4周时对ox-LDL的影响存在交互效应(P=0.000),在第8周和12周时不存在交互效应(P=0.104和P=0.166).间歇性低氧和高脂饮食干预下腹主动脉油红“O”染色及主动脉弓和腹主动脉组织HE染色后可观察到动脉粥样硬化的形成.结论 间歇性低氧和高脂饮食可能通过上调血浆中Lp-PLA2和ox-LDL表达促进动脉粥样硬化形成.%Aim To investigate the intermittent hypoxia and high-fat diet promoting the formation of atherosclerosis through

  7. Ultrastructural modifications in the mitochondria of hypoxia-adapted Drosophila melanogaster.

    Science.gov (United States)

    Perkins, Guy; Hsiao, Yu-hsin; Yin, Songyue; Tjong, Jonathan; Tran, My T; Lau, Jenna; Xue, Jin; Liu, Siqi; Ellisman, Mark H; Zhou, Dan

    2012-01-01

    Chronic hypoxia (CH) occurs under certain physiological or pathological conditions, including in people who reside at high altitude or suffer chronic cardiovascular or pulmonary diseases. As mitochondria are the predominant oxygen-consuming organelles to generate ATP through oxidative phosphorylation in cells, their responses, through structural or molecular modifications, to limited oxygen supply play an important role in the overall functional adaptation to hypoxia. Here, we report the adaptive mitochondrial ultrastructural modifications and the functional impacts in a recently generated hypoxia-adapted Drosophila melanogaster strain that survives severe, otherwise lethal, hypoxic conditions. Using electron tomography, we discovered increased mitochondrial volume density and cristae abundance, yet also cristae fragmentation and a unique honeycomb-like structure in the mitochondria of hypoxia-adapted flies. The homeostatic levels of adenylate and energy charge were similar between hypoxia-adapted and naïve control flies and the hypoxia-adapted flies remained active under severe hypoxia as quantified by negative geotaxis behavior. The equilibrium ATP level was lower in hypoxia-adapted flies than those of the naïve controls tested under severe hypoxia that inhibited the motion of control flies. Our results suggest that the structural rearrangement in the mitochondria of hypoxia-adapted flies may be an important adaptive mechanism that plays a critical role in preserving adenylate homeostasis and metabolism as well as muscle function under chronic hypoxic conditions.

  8. Ultrastructural modifications in the mitochondria of hypoxia-adapted Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Guy Perkins

    Full Text Available Chronic hypoxia (CH occurs under certain physiological or pathological conditions, including in people who reside at high altitude or suffer chronic cardiovascular or pulmonary diseases. As mitochondria are the predominant oxygen-consuming organelles to generate ATP through oxidative phosphorylation in cells, their responses, through structural or molecular modifications, to limited oxygen supply play an important role in the overall functional adaptation to hypoxia. Here, we report the adaptive mitochondrial ultrastructural modifications and the functional impacts in a recently generated hypoxia-adapted Drosophila melanogaster strain that survives severe, otherwise lethal, hypoxic conditions. Using electron tomography, we discovered increased mitochondrial volume density and cristae abundance, yet also cristae fragmentation and a unique honeycomb-like structure in the mitochondria of hypoxia-adapted flies. The homeostatic levels of adenylate and energy charge were similar between hypoxia-adapted and naïve control flies and the hypoxia-adapted flies remained active under severe hypoxia as quantified by negative geotaxis behavior. The equilibrium ATP level was lower in hypoxia-adapted flies than those of the naïve controls tested under severe hypoxia that inhibited the motion of control flies. Our results suggest that the structural rearrangement in the mitochondria of hypoxia-adapted flies may be an important adaptive mechanism that plays a critical role in preserving adenylate homeostasis and metabolism as well as muscle function under chronic hypoxic conditions.

  9. Intermittency and exotic channels

    CERN Document Server

    Bialas, A

    1994-01-01

    It is pointed out that accurate measurements of short-range two-particle correlations in like-charge K\\pi and in \\pi^ 0\\pi^ 0 channels should be very helpful in determining the origin of the \\lq\\lq intermittency\\rq\\rq\\ phenomenon observed recently for the like-charge pion pairs.

  10. Functioning of the mitochondrial ATP-dependent potassium channel in rats varying in their resistance to hypoxia. Involvement of the channel in the process of animal's adaptation to hypoxia.

    Science.gov (United States)

    Mironova, Galina D; Shigaeva, Maria I; Gritsenko, Elena N; Murzaeva, Svetlana V; Gorbacheva, Olga S; Germanova, Elena L; Lukyanova, Ludmila D

    2010-12-01

    The mechanism of tissue protection from ischemic damage by activation of the mitochondrial ATP-dependent K(+) channel (mitoK(ATP)) remains unexplored. In this work, we have measured, using various approaches, the ATP-dependent mitochondrial K(+) transport in rats that differed in their resistance to hypoxia. The transport was found to be faster in the hypoxia-resistant rats as compared to that in the hypoxia-sensitive animals. Adaptation of animals to the intermittent normobaric hypoxia increased the rate of transport. At the same time, the intramitochondrial concentration of K(+) in the hypoxia-sensitive rats was higher than that in the resistant and adapted animals. This indicates that adaptation to hypoxia stimulates not only the influx of potassium into mitochondria, but also K(+)/H(+) exchange. When mitoK(ATP) was blocked, the rate of the mitochondrial H(2)O(2) production was found to be significantly higher in the hypoxia-resistant rats than that in the hypoxia-sensitive animals. The natural flavonoid-containing adaptogen Extralife, which has an evident antihypoxic effect, increased the rate of the mitochondrial ATP-dependent K(+) transport in vitro and increased the in vivo tolerance of hypoxia-sensitive rats to acute hypoxia 5-fold. The involvement of the mitochondrial K(+) transport in the mechanism of cell adaptation to hypoxia is discussed.

  11. Chronic intermittent ethanol exposure alters stress effects on (3α,5α-3-hydroxy-pregnan-20-one (3α,5α-THP immunolabeling of amygdala neurons in C57BL/6J mice

    Directory of Open Access Journals (Sweden)

    Antoniette M Maldonado-Devincci

    2016-03-01

    Full Text Available The GABAergic neuroactive steroid (3α,5α-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone is decreased in various brain regions of C57BL/6J mice following exposure to an acute stressor or chronic intermittent ethanol (CIE exposure and withdrawal. It is well established that there are complex interactions between stress and ethanol drinking, with mixed literature regarding the effects of stress on ethanol intake. However, there is little research examining how chronic ethanol exposure alters stress responses. The present work examined the impact of CIE exposure and withdrawal on changes in brain levels of 3α,5α-THP, hormonal, and behavioral responses to forced swim stress (FSS. Adult male C57BL/6J mice were exposed to four cycles of CIE to induce ethanol dependence. Following 8 or 72 hr withdrawal, mice were subjected to FSS for 10 min, and 50 min later brains were collected for immunohistochemical analysis of cellular 3α,5α-THP. Behavioral and circulating corticosterone responses to the FSS were quantified. Following 8 hr withdrawal, ethanol exposure potentiated the corticosterone response to FSS. Following 72 hr withdrawal, this difference was no longer observed. Following 8 hr withdrawal, stress-exposed mice showed no differences in immobility, swimming or struggling behavior. However, following 72 hr withdrawal, ethanol-exposed mice showed less immobility and greater swimming behavior compared to air-exposed mice. Interestingly, cellular 3α,5α-THP levels were increased in the lateral amygdala 8 hr and 72 hr post-withdrawal in stressed ethanol-exposed mice compared to ethanol-exposed/non-stressed mice. In the paraventricular nucleus of the hypothalamus, stress exposure decreased 3α,5α-THP levels compared to controls following 72 hr withdrawal, but no differences were observed 8 hr post-withdrawal. There were no differences in cellular 3α,5α-THP levels in the nucleus accumbens shell at either withdrawal time point. These data

  12. Mild hypoxia affects synaptic connectivity in cultured neuronal networks.

    Science.gov (United States)

    Hofmeijer, Jeannette; Mulder, Alex T B; Farinha, Ana C; van Putten, Michel J A M; le Feber, Joost

    2014-04-01

    Eighty percent of patients with chronic mild cerebral ischemia/hypoxia resulting from chronic heart failure or pulmonary disease have cognitive impairment. Overt structural neuronal damage is lacking and the precise cause of neuronal damage is unclear. As almost half of the cerebral energy consumption is used for synaptic transmission, and synaptic failure is the first abrupt consequence of acute complete anoxia, synaptic dysfunction is a candidate mechanism for the cognitive deterioration in chronic mild ischemia/hypoxia. Because measurement of synaptic functioning in patients is problematic, we use cultured networks of cortical neurons from new born rats, grown over a multi-electrode array, as a model system. These were exposed to partial hypoxia (partial oxygen pressure of 150Torr lowered to 40-50Torr) during 3 (n=14) or 6 (n=8) hours. Synaptic functioning was assessed before, during, and after hypoxia by assessment of spontaneous network activity, functional connectivity, and synaptically driven network responses to electrical stimulation. Action potential heights and shapes and non-synaptic stimulus responses were used as measures of individual neuronal integrity. During hypoxia of 3 and 6h, there was a statistically significant decrease of spontaneous network activity, functional connectivity, and synaptically driven network responses, whereas direct responses and action potentials remained unchanged. These changes were largely reversible. Our results indicate that in cultured neuronal networks, partial hypoxia during 3 or 6h causes isolated disturbances of synaptic connectivity.

  13. 慢性间歇性缺氧对高脂饮食导致的动脉粥样硬化的影响%The effect of high-adiposed diet on arteriosclerosis mold caused by chronic intermittent hypoxia

    Institute of Scientific and Technical Information of China (English)

    荣耀; 杨宇; 罗荧荃

    2008-01-01

    目的:在慢性间歇缺氧的条件下,用高脂饮食方法建立兔的动脉粥样硬化模型,探讨相关致病机制.方法:24只新西兰兔,随机分为对照组、缺氧组、高脂饮食组、高脂饮食合并缺氧组.每组6只.观察各组兔第0周、第6周、第10周外周血血脂指标和C反应蛋白变化;实验第10周取各组兔主动脉光镜下观察病理学变化.结果:各实验组第6周时的血脂学指标与实验开始时比较均显著升高(P高脂饮食组>缺氧组.结论:单纯慢性缺氧10周可使兔动脉产生动脉粥样硬化的早期病变;慢性间歇缺氧合并高脂饮食10周时可使兔主动脉形成动脉粥样硬化斑块.

  14. Fate in intermittent claudication

    DEFF Research Database (Denmark)

    Jelnes, Rolf; Gaardsting, O; Hougaard Jensen, K

    1986-01-01

    The fate of 257 consecutive patients (100 women) aged 36-85 years (mean 65) first seen with intermittent claudication in 1977 was analysed after a mean of 6.5 (SD 0.5) years. When first seen none of the patients complained of rest pain or had ulcers or gangrenous lesions on the feet. At follow up....... The rate of clinical progression of the arteriosclerotic disease (that is, rest pain or gangrene) of the worst affected leg was 7.5% in the first year after referral. Thereafter the rate was 2.2% a year. An ankle systolic blood pressure below 70 mm Hg, a toe systolic blood pressure below 40 mm Hg......, or an ankle/arm pressure index below 50% were individually significantly associated with progression of the arteriosclerotic disease. These findings show the importance of peripheral blood pressure measurements in the management of patients with intermittent claudication due to arteriosclerotic disease....

  15. Análise de variáveis fisiológicas de adolescentes com diagnóstico clínico de asma leve intermitente ou leve persistente quando submetidos a hipóxia aguda e teste de esforço máximo Analysis of physiological variables during acute hypoxia and maximal stress test in adolescents clinically diagnosed with mild intermittent or mild persistent asthma

    Directory of Open Access Journals (Sweden)

    Martin Maldonado

    2011-12-01

    -sectional study involving 48 adolescents (12-14 years of age who were divided into three groups: mild intermittent asthma (MIA, n = 12; mild persistent asthma (MPA, n = 12; and control (n = 24. All subjects were induced to acute hypoxia and were submitted to maximal stress testing. Anthropometric data were collected, and functional variables were assessed before and after the maximal stress test. During acute hypoxia, the time to a decrease in SpO2 and the time to recovery of SpO2 (at rest were determined. RESULTS: No significant differences were found among the groups regarding the anthropometric variables or regarding the ventilatory variables during the stress test. Significant differences were found in oxygen half-saturation pressure of hemoglobin prior to the test and in PaO2 prior to the test between the MPA and control groups (p = 0.0279 and p = 0.0116, respectively, as was in the oxygen extraction tension prior to the test between the MIA and MPA groups (p = 0.0419. There were no significant differences in terms of the SpO2 times under any of the conditions studied. Oxygen consumption and respiratory efficiency were similar among the groups. The use of a bronchodilator provided no significant benefit during the hypoxia test. No correlations were found between the hypoxia test results and the physiological variables. CONCLUSIONS: Our findings suggest that adolescents with mild persistent asthma have a greater capacity to adapt to hypoxia than do those with other types of asthma.

  16. Past Occurrences of Hypoxia in the Baltic Sea

    Science.gov (United States)

    Zillen, L.; Conley, D. J.; Bjorck, S.

    2007-12-01

    The hypoxic zone in the Baltic Sea has increased in area by about four times since 1950. Widespread oxygen deficiency below the halocline has severely reduced macro benthic communities in the Baltic Proper and the Gulf of Finland over the past decades and negatively effected food chain dynamics, fish habitats and fisheries in the entire Baltic Sea. In addition, hypoxia alters nutrient biogeochemical cycles. The cause of the increased hypoxia is believed to be enhanced eutrophication through increased anthropogenic input of nutrients, such as phosphorous and nitrogen. Conditions prior to the 1950s are considered as the benchmark and some authors suggest that the earlier Baltic Sea was an oligothrophic, clear-water body with oxygenated deep waters. By contrast, studies of short sediment cores reveal that hypoxia has been present in some of the deepest basins for at least the last 100-200 years. In addition, long sediment cores suggest that hypoxia in the Baltic Sea has occurred intermittently in deep basins over the last c. 8500 years. Thus, the occurrence of present day hypoxia in the deeper basins need not necessarily be attributed to human activity but rather to natural oceanographic, geologic and climate conditions. We present a compilation of previous publications that reported the occurrence of laminated sediments (i.e. a palaeo-proxy for hypoxia) in the Baltic Sea. This review shows that the deeper parts of the Baltic Sea have experienced either intermittent or more regular hypoxia during most of the Holocene and that more continuous laminations started to form c. 7800-8500 cal. yr BP ago, in association with the establishment of a permanent halocline during the transition from the Ancylus Lake to the Littorina Sea. Laminated sediments were more common during the early and late Holocene and coincided with intervals of high organic productivity (high TOC content) and high salinity during the Holocene Thermal Maximum and the Medieval Climate Optimum. This study

  17. Hypoxia-mediated metastasis.

    Science.gov (United States)

    Chang, Joan; Erler, Janine

    2014-01-01

    Metastasis is responsible for more than 90 % of deaths among cancer patient. It is a highly complex process that involves the interplay between cancer cells, the tumor microenvironment, and even noncancerous host cells. Metastasis can be seen as a step-wise process: acquisition of malignant phenotype, invasion into surrounding tissue, intravasation into blood vessels, survival in circulation, extravasation to distant sites, and colonization of new organs. Before the actual metastatic process, the secondary site is also prepared for the arrival of the cancer cells through formation of "premetastatic niches." Hypoxia (low oxygen tension) is commonly found in solid tumors more than a few millimeters cubed and often is associated with a poor prognosis. Hypoxia increases angiogenesis, cancer cell survival, and metastasis. This chapter described how hypoxia regulates each step of the metastatic process and how blocking hypoxia-driven metastasis through targeting hypoxia-inducible factor 1, or downstream effector molecules such as the lysyl oxidase family may represent highly effective preventive strategies against metastasis in cancer patients.

  18. Heart disease link to fetal hypoxia and oxidative stress.

    Science.gov (United States)

    Giussani, Dino A; Niu, Youguo; Herrera, Emilio A; Richter, Hans G; Camm, Emily J; Thakor, Avnesh S; Kane, Andrew D; Hansell, Jeremy A; Brain, Kirsty L; Skeffington, Katie L; Itani, Nozomi; Wooding, F B Peter; Cross, Christine M; Allison, Beth J

    2014-01-01

    The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia.

  19. Quality of life and functional status after revascularization or conservative treatment in patients with intermittent claudication

    DEFF Research Database (Denmark)

    Hedeager Momsen, Anne-Mette; Bach Jensen, Martin; Norager, Charlotte Buchard;

    2011-01-01

    Revascularization of patients with intermittent claudication (IC) is recommended only for selected patients who have chronic pain or disabling disease. However, improvement in the quality of life (QoL) could justify more widespread use.......Revascularization of patients with intermittent claudication (IC) is recommended only for selected patients who have chronic pain or disabling disease. However, improvement in the quality of life (QoL) could justify more widespread use....

  20. Comment on "Intermittent plate tectonics?".

    Science.gov (United States)

    Korenaga, Jun

    2008-06-01

    Silver and Behn (Reports, 4 January 2008, p. 85) proposed that intermittent plate tectonics may resolve a long-standing paradox in Earth's thermal evolution. However, their analysis misses one important term, which subsequently brings their main conclusion into question. In addition, the Phanerozoic eustasy record indicates that the claimed effect of intermittency is probably weak.

  1. Assessment of hypoxia-inducible factor-1α mRNA expression in mantis shrimp as a biomarker of environmental hypoxia exposure.

    Science.gov (United States)

    Kodama, Keita; Rahman, Md Saydur; Horiguchi, Toshihiro; Thomas, Peter

    2012-04-23

    Efforts to assess the ecological impacts of the marked increase in coastal hypoxia worldwide have been hampered by a lack of biomarkers of hypoxia exposure in marine benthic organisms. Here, we show that hypoxia-inducible factor-1α (HIF-1α) transcript levels in the heart and cerebral ganglion of mantis shrimp (Oratosquilla oratoria) collected from hypoxic sites in Tokyo Bay are elevated several-fold over those in shrimp collected from normoxic sites. Upregulation of HIF-1α mRNA levels in the heart after exposure to sub-lethal hypoxia was confirmed in controlled laboratory experiments. HIF-1α transcript levels were increased at approximately threefold after 7 and 14 days of hypoxia exposure and declined to control levels within 24 h of restoration to normoxic conditions. The results provide the first evidence for upregulation of HIF-1α transcript levels in two hypoxia-sensitive organs, heart and cerebral ganglion, in a marine invertebrate exposed to environmental hypoxia. These results suggest that upregulation of HIF-1α transcript levels is an important component in adaptation of mantis shrimp to chronic hypoxia and is a potentially useful biomarker of environmental hypoxia exposure.

  2. Acute Intermittent Porphyria (AIP)

    Science.gov (United States)

    ... attacks, but are usually not chronic. Wearing a Medic Alert bracelet is advisable for patients who have ... Week is ONE Month Away! Mar 17, 2017 Access to Care Toolkit for the Acute Porphyrias is ...

  3. Acute intermittent porphyria.

    Science.gov (United States)

    Herrick, Ariane L; McColl, Kenneth E L

    2005-04-01

    Acute intermittent porphyria (AIP) is characterised by neurovisceral crises the most common clinical presentation of which is abdominal pain. It is an autosomal dominant condition with incomplete penetrance and is potentially life-threatening. The key point in management is to suspect and confirm the diagnosis as early as possible in order to treat the attack and to avoid inappropriate treatments which may exacerbate the crisis. In this chapter we briefly outline the haem biosynthetic pathway and how deficiencies in individual enzymes give rise to the different porphyrias. We then describe the clinical features and diagnosis of AIP, followed by a discussion of pathogenesis, highlighting advances in the molecular biology of AIP and introducing the debate as to whether neurovisceral crises might result from porphyrin precursor neurotoxicity or from haem deficiency. Finally we discuss management, including family screening, avoidance of triggering factors, analgesia, maintenance of a high calorie intake, and administration of haem derivatives.

  4. Hypoxia and dehydroepiandrosterone in old age: a mouse survival study

    Directory of Open Access Journals (Sweden)

    Quillard Janine

    2006-12-01

    Full Text Available Abstract Background Survival remains an issue in pulmonary hypertension, a chronic disorder that often affects aged human adults. In young adult mice and rats, chronic 50% hypoxia (11% FIO2 or 0.5 atm induces pulmonary hypertension without threatening life. In this framework, oral dehydroepiandrosterone was recently shown to prevent and reverse pulmonary hypertension in rats within a few weeks. To evaluate dehydroepiandrosterone therapy more globally, in the long term and in old age, we investigated whether hypoxia decreases lifespan and whether dehydroepiandrosterone improves survival under hypoxia. Methods 240 C57BL/6 mice were treated, from the age of 21 months until death, by normobaric hypoxia (11% FIO2 or normoxia, both with and without dehydroepiandrosterone sulfate (25 mg/kg in drinking water (4 groups, N = 60. Survival, pulmonary artery and heart remodeling, weight and blood patterns were assessed. Results In normoxia, control mice reached the median age of 27 months (median survival: 184 days. Hypoxia not only induced cardiopulmonary remodeling and polycythemia in old animals but also induced severe weight loss, trembling behavior and high mortality (p Conclusion Dehydroepiandrosterone globally reduced what may be called an age-related frailty induced by hypoxic pulmonary hypertension. This interestingly recalls an inverse correlation found in the prospective PAQUID epidemiological study, between dehydroepiandrosterone blood levels and mortality in aged human smokers and former smokers.

  5. Dopamine does not limit fetal cerebrovascular responses to hypoxia.

    Science.gov (United States)

    Mayock, Dennis E; Bennett, Rachel; Robinson, Roderick D; Gleason, Christine A

    2007-01-01

    Dopamine is used clinically to stabilize mean arterial blood pressure (MAP) in sick infants. One goal of this therapeutic intervention is to maintain adequate cerebral blood flow (CBF) and perfusion pressure. High-dose intravenous dopamine has been previously demonstrated to increase cerebrovascular resistance (CVR) in near-term fetal sheep. We hypothesized that this vascular response might limit cerebral vasodilatation during acute isocapnic hypoxia. We studied nine near-term chronically catheterized unanesthetized fetal sheep. Using radiolabeled microspheres to measure fetal CBF, we calculated CVR at baseline, during fetal hypoxia, and then with the addition of an intravenous dopamine infusion at 2.5, 7.5, and 25 microg.kg(-1).min(-1) while hypoxia continued. During acute isocapnic fetal hypoxia, CBF increased 73.0 +/- 14.1% and CVR decreased 38.9 +/- 4.9% from baseline. Dopamine infusion at 2.5 and 7.5 microg.kg(-1).min(-1), begun during hypoxia, did not alter CVR or MAP, but MAP increased when dopamine infusion was increased to 25 microg.kg(-1).min(-1). Dopamine did not alter CBF or affect the CBF response to hypoxia at any dose. However, CVR increased at a dopamine infusion rate of 25 microg.kg(-1).min(-1). This increase in CVR at the highest dopamine infusion rate is likely an autoregulatory response to the increase in MAP, similar to our previous findings. Therefore, in chronically catheterized unanesthetized near-term fetal sheep, dopamine does not alter the expected cerebrovascular responses to hypoxia.

  6. High-Intensity Intermittent Exercise: Effect on Young People's Cardiometabolic Health and Cognition.

    Science.gov (United States)

    Cooper, Simon B; Dring, Karah J; Nevill, Mary E

    2016-01-01

    With only a quarter of young people currently meeting physical activity guidelines, two key areas of concern are the effects of exercise on cardiometabolic health and cognition. Despite the fact that physical activity in young people is typically high intensity and intermittent in nature, much of the literature examines traditional endurance-type exercise. This review provides an update on the effects of high-intensity intermittent exercise on young people's cardiometabolic health and cognition. High-intensity intermittent exercise has acute beneficial effects on endothelial function and postprandial lipemia and chronic positive effects on weight management. In addition, there is emerging evidence regarding chronic benefits on the blood lipid profile, blood pressure, and proinflammatory and anti-inflammatory cytokines. Furthermore, emerging evidence suggests beneficial acute and chronic effects of high-intensity intermittent exercise on cognition. However, further research is required in both cardiometabolic health and cognition, particularly regarding the impact of school-based interventions in adolescents.

  7. Intermedia and Intermittency

    Directory of Open Access Journals (Sweden)

    Veres Bálint

    2014-12-01

    Full Text Available It is commonly known that medial reflections have been initiated by attempts to secure the borders of discrete medial forms and to define the modus operandi of each essentialized medial area. Later on, the focus of study has shifted to plurimedial formations and the interactions between predefined medial genres. In the last few decades, taxonomic approaches to various multi-, inter-, and transmedial phenomena dominated the discussions, which offered invaluable support in mapping the terrain, but at the same time hindered the analysis of the ephemeral, time-dependent aspects of plurimedial operations. While we explore the properties of each medial configuration, we lose sight of the actual historical drivers that produce ever-new configurations. My thesis is that any discourse on intermediality should be paralleled by a discourse on cultural intermittency, and consequently, media studies should involve an approach that focuses on the “ecosystem” of the constantly renewing media configurations from the point of view of their vitalizing potential and capability to trigger heightened experiences. This approach draws much inspiration from K. Ludwig Pfeiffer’s media anthropology that gives orientation in my paper.

  8. Intermittency in spiral Poiseuille flow

    Energy Technology Data Exchange (ETDEWEB)

    Heise, M; Abshagen, J; Menck, A; Pflster, G [Institute of Experimental and Applied Physics, University of Kiel, 24098 Kiel (Germany)

    2005-01-01

    The results of an experimental study on intermittent spiral vortices observed in a counter-rotating Taylor-Couette system with an additional axial through flow, i.e. Spiral-Poiseuille flow, are presented. Convectively unstable upstream propagating spiral vortices appear in the laminar basic flow from an oscillatory instability and in general become absolutely unstable at higher inner cylinder Reynolds number. It is found that at Reynolds numbers above the absolute stability border the spiral vortices become unstable and a complex flow state showing intermittent bursts appears. The intermittent flow state is characterised by an irregular alternation between clearly distinguishable 'laminar' phases corresponding to up-and downstream propagating spiral vortices as well as propagating Taylor vortices. For a sufficiently high rate of axial through flow it is found that intermittency can occur directly from the convectively unstable regime of the upstream propagating spiral vortices.

  9. RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature

    Science.gov (United States)

    Viollet, Coralie; Davis, David A.; Tekeste, Shewit S.; Reczko, Martin; Pezzella, Francesco; Ragoussis, Jiannis

    2017-01-01

    Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases. PMID:28046107

  10. Eeffects of Coptis Chinensis on vasoconstrictive activity of isolated thoracic aorta of normoxic and chronic intermittent hypobaric hypoxic rats%黄连对正常氧和慢性间歇性低压低氧大鼠离体胸主动脉收缩活动的影响

    Institute of Scientific and Technical Information of China (English)

    张鹏; 宋士军; 刘威兰; 李连连; 赵卫丽; 张翼

    2011-01-01

    Objective: To observe the effects of Coptis Chinensis on vasoconstrictive activity of isolated thoracic aorta rings of normoxic and chronic intermittent hypobaric hypoxic(CIHH) rats, and to investigate the underlying mechanisms. Methods: Young male Sprague-Dawley rats were randomly divided into normoxic group and QHH group: the former were not given any special treatment; the latter were exposed to hypoxia in a hypobaric chamber simulating 5000 m altitude (PB = 404 mmHg, PO2= 84 mmHg, 11.1% O2), 6 hours daily for 28 days. The isolated thoracic aorta rings of rats were prepared and perfused in thermostat, and the effects of Coptis on vasoconstrictive activity of aorta rings were recorded, the mechanisms were investigated simultaneouly. Results: Coptis Chinensis significantly decreased NE and KCl-induced vaso-constriction of normoxic and QHH rats' isolated aortic rings, but the inhibitive effects had no obvious discrepancy between the two groups. The contractive amplitude had no marked change after the removal of endothelium. When calculated by Logit Loglinear analysis, IC50 of NE and KCl-induced contractive amplitude in normoxic group were respectively 2.99 g/L and 6.14 g/L, while they were 3.45 g/L and 5.81 g/L in CIHH group. The inhibitive effect of Coptis on vasoconstrictive activity of both groups could be partly decreased by Glibenclamide and nitro-L-arginine methyl ester; Indomethacin suppressed the effect on normoxic group as well. Also Coptis significantly inhibited NE-induced both intra-cellular and extracellular calciumion-depended vasoconstriction. Conclusion: Coptis Chinensis obviously relaxes isolated thoracic aorta rings of normoxic and CIHH rats, but the effects are endothelium-independent and have no marked discrepancy between the two groups. The mechanisms of the effects may be related to the opening of ATP-sensitive K+ channel, raise of nitric oxide concentration in both groups, and the increasing of PGI2 in normoxic group. Besides, Coptis may

  11. Alpha-lipoic acid inhibits mitochondrial oxidative stress in the rat skeletal muscle with chronic hypoxia exposure%α-硫辛酸抑制慢性低氧大鼠骨骼肌线粒体的氧化应激**

    Institute of Scientific and Technical Information of China (English)

    肖频; 庞奕辉; 彭朋; 薄海

    2013-01-01

    BACKGROUND: α-lipoic acid is named as “nature antioxidant” and “mitochondrial nutrition”. But it is unclear whether α-lipoic acid can be used to protect skeletal muscle with chronic hypoxia exposure, as wel as the relative mechanism. OBJECTIVE: To observe the effect of α-lipoic acid on the antioxidant enzymes and oxidative stress in rat skeletal muscle with chronic hypoxia exposure, and to investigate the relative signaling pathway of α-lipoic acid. METHODS: Thirty-six Sprague Dawley rats were randomly divided into three groups: normoxia control group, hypoxia control group, and hypoxia+α-lipoic acid group. Rats in the hypoxia control group were subjected to hypoxia exposure in normobaric hypoxic tent with 11.3% oxygen concentration. Rats in the hypoxia+α-lipoic acid group were induced by adding α-lipoic acid (0.25%) in the normal diet. Al the interventions were lasted for 4 weeks. RESULTS AND CONCLUSION: α-lipoic acid in hypoxia could markedly enhance the mitochondrial Sirtuin-3 expression, improve the mitochondrial adenosine triphosphate synthesis activity and membrane potential, up-regulate the mitochondrial state 3 respiratory rate, respiratory control ratio and ratio of phosphorus to oxygen, down-regulate the mitochondrial state 4 respiratory rate and promote and up-regulate the activity of mitochondrial antioxidant enzymes such as manganese superoxide dismutase, glutathione peroxidase and catalase, thus inhibiting mitochondrial H2O2 generation rate and reducing mitochondrial malondialdehyde level. The results indicated that α-lipoic acid could improve the efficiency of energy metabolism of chronic hypoxia skeletal muscle mitochondria and inhibit reactive oxygen generation, and it could inhibit the oxidative stress through improving antioxidant enzyme activity of mitochondria. The protection mechanism of α-lipoic acid on hypoxia skeletal muscle mitochondria may be related to the increasing of mitochondrial state 3 respiratory rate.%  背

  12. Acidosis, hypoxia and bone.

    Science.gov (United States)

    Arnett, Timothy R

    2010-11-01

    Bone homeostasis is profoundly affected by local pH and oxygen tension. It has long been recognised that the skeleton contains a large reserve of alkaline mineral (hydroxyapatite), which is ultimately available to neutralise metabolic H(+) if acid-base balance is not maintained within narrow limits. Bone cells are extremely sensitive to the direct effects of pH: acidosis inhibits mineral deposition by osteoblasts but it activates osteoclasts to resorb bone and other mineralised tissues. These reciprocal responses act to maximise the availability of OH(-) ions from hydroxyapatite in solution, where they can buffer excess H(+). The mechanisms by which bone cells sense small pH changes are likely to be complex, involving ion channels and receptors in the cell membrane, as well as direct intracellular effects. The importance of oxygen tension in the skeleton has also long been known. Recent work shows that hypoxia blocks the growth and differentiation of osteoblasts (and thus bone formation), whilst strongly stimulating osteoclast formation (and thus bone resorption). Surprisingly, the resorptive function of osteoclasts is unimpaired in hypoxia. In vivo, tissue hypoxia is usually accompanied by acidosis due to reduced vascular perfusion and increased glycolytic metabolism. Thus, disruption of the blood supply can engender a multiple negative impact on bone via the direct actions of reduced pO(2) and pH on bone cells. These observations may contribute to our understanding of the bone disturbances that occur in numerous settings, including ageing, inflammation, fractures, tumours, anaemias, kidney disease, diabetes, respiratory disease and smoking.

  13. Regulation of hypoxia-inducible factor-α isoforms and redox state by carotid body neural activity in rats.

    Science.gov (United States)

    Peng, Ying-Jie; Yuan, Guoxiang; Khan, Shakil; Nanduri, Jayasri; Makarenko, Vladislav V; Reddy, Vaddi Damodara; Vasavda, Chirag; Kumar, Ganesh K; Semenza, Gregg L; Prabhakar, Nanduri R

    2014-09-01

    Previous studies reported that chronic intermittent hypoxia (CIH) results in an imbalanced expression of hypoxia-inducible factor-α (HIF-α) isoforms and oxidative stress in rodents, which may be due either to the direct effect of CIH or indirectly via hitherto uncharacterized mechanism(s). As neural activity is a potent regulator of gene transcription, we hypothesized that carotid body (CB) neural activity contributes to CIH-induced HIF-α isoform expression and oxidative stress in the chemoreflex pathway. Experiments were performed on adult rats exposed to CIH for 10 days. Rats exposed to CIH exhibited: increased HIF-1α and decreased HIF-2α expression; increased NADPH oxidase 2 and decreased superoxide dismutase 2 expression; and oxidative stress in the nucleus tractus solitarius and rostral ventrolateral medulla as well as in the adrenal medulla (AM), a major end organ of the sympathetic nervous system. Selective ablation of the CB abolished these effects. In the AM, sympathetic activation by the CB chemoreflex mediates CIH-induced HIF-α isoform imbalance via muscarinic acetylcholine receptor-mediated Ca(2+) influx, and the resultant activation of mammalian target of rapamycin pathway and calpain proteases. Rats exposed to CIH presented with hypertension, elevated sympathetic activity and increased circulating catecholamines. Selective ablation of either the CB (afferent pathway) or sympathetic innervation to the AM (efferent pathway) abolished these effects. These observations uncover CB neural activity-dependent regulation of HIF-α isoforms and the redox state by CIH in the central and peripheral nervous systems associated with the chemoreflex.

  14. Bursts in intermittent aeolian saltation

    CERN Document Server

    Carneiro, M V; Herrmann, H J

    2014-01-01

    Close to the onset of Aeolian particle transport through saltation we find in wind tunnel experiments a regime of intermittent flux characterized by bursts of activity. Scaling laws are observed in the time delay between each burst and in the measurements of the wind fluctuations at the critical Shields number $\\theta_c$. The time delay between each burst decreases on average with the increase of the Shields number until saltation becomes non-intermittent and the sand flux becomes continuous. A numerical model for saltation including the wind-entrainment from the turbulent fluctuations can reproduce these observations and gives insight about their origin. We present here also for the first time measurements showing that with feeding it becomes possible to sustain intermittent flux even below the threshold $\\theta_c$ for natural saltation initiation.

  15. Intermittency in spherical Couette dynamos

    CERN Document Server

    Raynaud, Raphaël; 10.1103/PhysRevE.87.033011

    2013-01-01

    We investigate dynamo action in three-dimensional numerical simulations of turbulent spherical Couette flows. Close to the onset of dynamo action, the magnetic field exhibits an intermittent behavior, characterized by a series of short bursts of the magnetic energy separated by low-energy phases. We show that this behavior corresponds to the so-called on-off intermittency. This behavior is here reported for dynamo action with realistic boundary conditions. We investigate the role of magnetic boundary conditions in this phenomenon.

  16. Regulation of human skeletal muscle perfusion and its heterogeneity during exercise in moderate hypoxia

    DEFF Research Database (Denmark)

    Heinonen, Ilkka H; Kemppainen, Jukka; Kaskinoro, Kimmo

    2010-01-01

    Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine...... healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to approximately 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion...

  17. Transcriptome analysis of the spalax hypoxia survival response includes suppression of apoptosis and tight control of angiogenesis

    Directory of Open Access Journals (Sweden)

    Malik Assaf

    2012-11-01

    Full Text Available Abstract Background The development of complex responses to hypoxia has played a key role in the evolution of mammals, as inadequate response to this condition is frequently associated with cardiovascular diseases, developmental disorders, and cancers. Though numerous studies have used mice and rats in order to explore mechanisms that contribute to hypoxia tolerance, these studies are limited due to the high sensitivity of most rodents to severe hypoxia. The blind subterranean mole rat Spalax is a hypoxia tolerant rodent, which exhibits unique longevity and therefore has invaluable potential in hypoxia and cancer research. Results Using microarrays, transcript abundance was measured in brain and muscle tissues from Spalax and rat individuals exposed to acute and chronic hypoxia for varying durations. We found that Spalax global gene expression response to hypoxia differs from that of rat and is characterized by the activation of functional groups of genes that have not been strongly associated with the response to hypoxia in hypoxia sensitive mammals. Using functional enrichment analysis of Spalax hypoxia induced genes we found highly significant overrepresentation of groups of genes involved in anti apoptosis, cancer, embryonic/sexual development, epidermal growth factor receptor binding, coordinated suppression and activation of distinct groups of transcription factors and membrane receptors, in addition to angiogenic related processes. We also detected hypoxia induced increases of different critical Spalax hub gene transcripts, including antiangiogenic genes associated with cancer tolerance in Down syndrome human individuals. Conclusions This is the most comprehensive study of Spalax large scale gene expression response to hypoxia to date, and the first to use custom Spalax microarrays. Our work presents novel patterns that may underlie mechanisms with critical importance to the evolution of hypoxia tolerance, with special relevance to

  18. Restraint Stress Intensifies Interstitial K+ Accumulation during Severe Hypoxia

    Science.gov (United States)

    Schnell, Christian; Janc, Oliwia A.; Kempkes, Belinda; Callis, Carolina Araya; Flügge, Gabriele; Hülsmann, Swen; Müller, Michael

    2012-01-01

    Chronic stress affects neuronal networks by inducing dendritic retraction, modifying neuronal excitability and plasticity, and modulating glial cells. To elucidate the functional consequences of chronic stress for the hippocampal network, we submitted adult rats to daily restraint stress for 3 weeks (6 h/day). In acute hippocampal tissue slices of stressed rats, basal synaptic function and short-term plasticity at Schaffer collateral/CA1 neuron synapses were unchanged while long-term potentiation was markedly impaired. The spatiotemporal propagation pattern of hypoxia-induced spreading depression episodes was indistinguishable among control and stress slices. However, the duration of the extracellular direct current potential shift was shortened after stress. Moreover, K+ fluxes early during hypoxia were more intense, and the postsynaptic recoveries of interstitial K+ levels and synaptic function were slower. Morphometric analysis of immunohistochemically stained sections suggested hippocampal shrinkage in stressed rats, and the number of cells that are immunoreactive for glial fibrillary acidic protein was increased in the CA1 subfield indicating activation of astrocytes. Western blots showed a marked downregulation of the inwardly rectifying K+ channel Kir4.1 in stressed rats. Yet, resting membrane potentials, input resistance, and K+-induced inward currents in CA1 astrocytes were indistinguishable from controls. These data indicate an intensified interstitial K+ accumulation during hypoxia in the hippocampus of chronically stressed rats which seems to arise from a reduced interstitial volume fraction rather than impaired glial K+ buffering. One may speculate that chronic stress aggravates hypoxia-induced pathophysiological processes in the hippocampal network and that this has implications for the ischemic brain. PMID:22470344

  19. Impaired response of mature adipocytes of diabetic mice to hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Seok Jong, E-mail: seok-hong@northwestern.edu; Jin, Da P.; Buck, Donald W.; Galiano, Robert D.; Mustoe, Thomas A., E-mail: tmustoe@nmh.org

    2011-10-01

    Adipose tissue contains various cells such as infiltrated monocytes/macrophages, endothelial cells, preadipocytes, and adipocytes. Adipocytes have an endocrine function by secreting adipokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-{alpha}, leptin, and adiponectin. Dysregulation of adipokines in adipose tissues leads to a chronic low-grade inflammation which could result in atherosclerosis, hypertension, and type 2 diabetes. A sustained inflammatory state, which is characterized by prolonged persistence of macrophages and neutrophils, is found in diabetic wounds. In addition, subcutaneous adipocytes are enormously increased in amount clinically in type 2 diabetes. However, the function of subcutaneous adipocytes, which play an important role in injured tissue subjected to hypoxia, has not been well characterized in vitro due to the difficulty of maintaining mature adipocytes in culture using conventional methods because of their buoyancy. In this study, we established a novel in vitro culture method of mature adipocytes by enclosing them in a hyaluronan (HA) based hydrogel to study their role in response to stress such as hypoxia. BrdU labeling and Ki67 immunostaining experiments showed that hydrogel enclosed mature adipocytes proliferate in vitro. Both mRNA and protein expression analyses for hypoxia regulated genes, such as vascular endothelial growth factor (VEGF) and heme oxygenase 1 (HO1), showed that mature adipocytes of wild type mice respond to hypoxia. In contrast, mature adipocytes of diabetic db/db and TallyHo mice did not efficiently respond to hypoxia. Our studies suggest that mature adipocytes are functionally active cells, and their abnormal function to hypoxia can be one of underlining mechanisms in type 2 diabetes.

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

    Science.gov (United States)

    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.

  1. Hypoxia and hypoxia-inducible factors in leukaemias

    Directory of Open Access Journals (Sweden)

    Margaux eDeynoux

    2016-02-01

    Full Text Available Despite huge improvements in the treatment of leukaemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukaemic stem cells (LSCs within the bone marrow, which are able to self-renew and therefore re-establish the full tumour. The marrow microenvironment contributes considerably in supporting the protection and development of leukaemic cells. LSCs share specific niches with normal haematopoietic stem cells with the niche itself being composed of a variety of cell types including mesenchymal stem/stromal cells, bone cells, immune cells, neuronal cells and vascular cells. A hallmark of the haematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of HSCs. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor family. In solid tumours, it has been well-established that hypoxia triggers intrinsic metabolic changes and microenvironmental modifications, such as the stimulation of angiogenesis, through activation of HIFs. As leukaemia is not considered a solid tumour, the role of oxygen in the disease was presumed to be inconsequential and remained long overlooked. This view has now been revised since hypoxia has been shown to influence leukaemic cell proliferation, differentiation and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumour suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukaemic development and therapeutic resistance, and to discuss the recent hypoxia-based strategies proposed to eradicate leukaemias.

  2. Immunoreactivity of neurogenic factor in the guinea pig brain after prenatal hypoxia.

    Science.gov (United States)

    Chung, Yoonyoung; So, Keumyoung; Kim, Eunyoung; Kim, Seokwon; Jeon, Yonghyun

    2015-07-01

    Chronic prenatal hypoxia is considered to cause perinatal brain injury. It can result in neurological disorders such as cerebral palsy or learning disabilities. These neurological problems are related to chronic placental insufficiency (CPI), which leads to chronic hypoxemia and hypoglycemia. The effects of hypoxia on neurogenesis during development have been a matter of controversy. We therefore investigated the effect of chronic prenatal hypoxia in the brain of the fetal guinea pig using the guinea pig CPI model. Chronic placental insufficiency was induced by unilateral uterine artery ligation at 30-32 days of gestation (dg: with term defined as ∼67dg). At 50 and 60dg, fetuses were sacrificed and assigned to either the growth-restricted (GR) or control (no ligation) group. Immunohistochemistry was performed with HIF-1α, PCNA, NeuN and BDNF antibodies in the cerebral cortex and dentate gyrus. The number of NeuN-IR and BDNF-IR cells was lesser in GR fetuses than in controls in the cerebral cortex and dentate gyrus at 60dg (pcerebral cortex is decreased by chronic prenatal hypoxia at 60dg.

  3. Intermittent exotropia: Surgical treatment strategies

    Directory of Open Access Journals (Sweden)

    Jai Aditya Kelkar

    2015-01-01

    Full Text Available Surgical management of intermittent exotropias (IXTs is ambiguous, with techniques of management varying widely between institutions. This review aims to examine available literature on the surgical management of IXT. A literature search was performed using PubMed, Web of Knowledge, LILACS, and the University of Liverpool Orthoptic Journals and Conference Transactions Database. All English-language papers published between 1958 and the present day were considered.

  4. Power-constrained intermittent control

    OpenAIRE

    Gawthrop, P.; Wagg, D.; Neild, S.; Wang, L

    2013-01-01

    In this article, input power, as opposed to the usual input amplitude, constraints are introduced in the context of intermittent control. They are shown to result in a combination of quadratic optimisation and quadratic constraints. The main motivation for considering input power constraints is its similarity with semi-active control. Such methods are commonly used to provide damping in mechanical systems and structures. It is shown that semi-active control can be re-expressed and generalised...

  5. Non-injurious neonatal hypoxia confers resistance to brain senescence in aged male rats.

    Directory of Open Access Journals (Sweden)

    Nicolas Martin

    Full Text Available Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia (100% N₂, 5 min on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence. We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus involving activation of Erk1/2 and repression of p38 and death-associated protein (DAP kinase. At 21 days of age, increased thicknesses and cell densities were recorded in various subregions, with strong synapsin activation. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity, and with increases of their key regulators, i.e. Erk1/2, the transcription factor EGR-1/Zif-268 and Src kinase. Moreover, the significantly higher interactions between PSD-95 scaffolding protein and NMDA receptors measured in the hippocampus of 720-day-old male animals strengthen the conclusion of increased synaptic functional activity and plasticity associated with neonatal hypoxia. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.

  6. Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans.

    Directory of Open Access Journals (Sweden)

    Kemal Erdem Basaran

    Full Text Available Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400 mg every 8 hrs or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m. Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease.

  7. LIFE-SPANNING BEHAVIORAL AND ADRENAL DYSFUNCTION INDUCED BY PRENATAL HYPOXIA IN THE RAT IS PREVENTED BY THE CALCIUM-ANTAGONIST NIMODIPINE

    NARCIS (Netherlands)

    NYAKAS, C; BUWALDA, B; MARKEL, E; KORTE, SM; LUITEN, PGM

    1994-01-01

    The long-term behavioural effects of prenatal chronic anaemic hypoxia were investigated in young (5 months old), late adult (19 months) and aged Wistar rats (23 - 26 months). Sodium nitrite (2 g/l) offered in the drinking water during the second half of pregnancy served to evoke prenatal hypoxia. In

  8. The effects of pentoxifylline on skeletal muscle contractility and neuromuscular transmission during hypoxia

    Directory of Open Access Journals (Sweden)

    Simsek-Duran Fatma

    2009-01-01

    Full Text Available Objectives : The objective of this study was to investigate the effects of pentoxifylline (PTX, a drug that is mainly used for indications related to tissue hypoxia, on hypoxia-induced inhibition of skeletal muscle contractility and neuromuscular transmission in mice. We hypothesized that chronic PTX treatment alters skeletal muscle contractility and hypoxia-induced dysfunction. Materials and Methods : Mice were treated with 50 mg/kg PTX or saline intraperitoneally for a week. Following ether anesthesia, diaphragm muscles were removed; isometric muscle contractions and action potentials were recorded. Time to reach neuromuscular blockade and the rate of recovery of muscle contractility were assessed during hypoxia and re-oxygenation. Results : The PTX group displayed 90% greater twitch amplitudes (P < 0.01. Hypoxia depressed twitch contractions and caused neuromuscular blockade in both groups. However, neuromuscular blockade occurred earlier in PTX-treated animals (P < 0.05. Muscle contractures developed during hypoxia were more pronounced in the PTX group (P < 0.05. Re-oxygenation reduced contracture and indirect muscle contractions resumed. The rate of recovery of contractions was faster (P < 0.05 and the amplitude of contractions was greater (P < 0.01 in the PTX group. PTX treatment increased amplitude (P < 0.05 and shortened action potential (P < 0.05 without altering resting membrane potential, excitation threshold, and neurotransmitter release. Conclusion : Chronic PTX treatment increases diaphragm contractility, but amplifies hypoxia-induced contractile dysfunction in mice. These results may implicate important clinical consequences for clinical usage of PTX in hypoxia-related conditions.

  9. FDG uptake, a surrogate of tumour hypoxia?

    NARCIS (Netherlands)

    Dierckx, Rudi Andre; de Wiele, Christophe Van

    2008-01-01

    Introduction Tumour hyperglycolysis is driven by activation of hypoxia-inducible factor-1 (HIF-1) through tumour hypoxia. Accordingly, the degree of 2-fluro-2-deoxy-D-glucose (FDG) uptake by tumours might indirectly reflect the level of hypoxia, obviating the need for more specific radiopharmaceutic

  10. INTRAUTERINE HYPOXIA OF FETUS - INFLUENCE OF ULTRA-LOW DOSES OF ANTIOXIDANT (EXPERIMENTAL RESEARCH

    Directory of Open Access Journals (Sweden)

    ZARINA KHAYBULLINA

    2011-08-01

    Full Text Available Oxygensensing mechanisms have been developed to maintain cell and tissue homeostasis, as well as to adapt to the chronic lowoxygen condition, but intensive production of reactive oxygen species (ROS can cause cell destruction. Previous studies revealed that the hypoxia induces oxidative stress and neurodegeneration, which is associated with memory, behavioral, and learningeducation impairment in children. In the view of the abovestated concept, the study of influence of ultra low doses of antioxidant on ROS generation and activity of enzymes of antioxidant protection in a brain and blood at intrauterine hypoxia of a fetus appears appealing. The effect of Fenozan in ultra low doses was evaluated in the rats underwent intrauterine hypoxia. Research was made on white rats, 66 pregnant females and 279 infant rats (021 days. It was established, that chronic prenatal hypoxia is accompanied by accumulation of malondialdehyde in brain tissue, blood and subcellular fractions of a liver, with the subsequent spontaneous normalization of its maintenance by 21st day in a brain and blood.Fenozan injection in ultra low doses leads to appreciable decrease in MDA level and increase of the ROSscavenging enzymes at first in a brain and peripheral blood, and then in microsomal and mitochondrial fractions of the liver, that is the precondition for normalization of pathological process in earlier terms. Significance of this data argues that ultra low doses of Fenozan can be less invasive and effective in the treatment of chronic intrauterine hypoxia and suggest the directions for further research.

  11. 腺苷受体激动剂降低低氧大鼠肺动脉高压及对诱导型一氧化氮合酶-一氧化氮和肾素-血管紧张素的影响%Adenosine receptors agonists mitigated PAH of rats induced by chronic hypoxia through reduction of renin activity/angiotensin Ⅱ levels and increase of inducible nitric oxide synthase-nitric oxide levels

    Institute of Scientific and Technical Information of China (English)

    谭建新; 黄秀兰; 王波; 方兴; 黄迪南

    2012-01-01

    Objective Recent studies showed that adenosine played important roles in vasodilation.This study aimed to investigate the effects of adenosine,its A1 and A2b receptor agonists on pulmonary artery hypertension (PAH) induced by chronic hypoxia in rats by continuously subcutaneous administration with an osmotic pump for 14 days,and to see if rennin angiotensin system and inducible nitric oxygen synthase (iNOS)/nitric oxide (NO) mediate the effects.Method Fifty-six male SD rats were randomly assigned to seven groups.Each group included eight rats.They were normoxic group,hypoxic group,adenosine-treated group [adenosine was administered at a dose of 150 μg(kg · min) under the hypoxic condition],adenosine A1 receptor agonist CPA-treated group [CPA was administered at a dose of 20 μg/(kg · min)under the hypoxic condition],CPA plus selective adenosine A1 antagonist DPCPX-treated group [CPA and DPCPX were administered simultaneously under the hypoxic condition,the dose of CPA was the same as the above,and the dose of DPCPX was 25 μg/(kg · min)],adenosine A2b receptor agonist NECA-treated group [NECA was administered at a dose of 30 μg/(kg · min) under the hypoxic condition],NECA plus selective adenosine A2b receptor antagonist MRS-treated group [NECA and MRS1754 were administered simultaneously under the hypoxic condition,the dose of NECA was the same as the above,and the dose of MRS1754 was 50 μg/(kg · min)].Osmotic pumps containing adenosine or selective adenosine A1 receptor agonist (CPA),or nonselective but potent adenosine A2b receptor agonist (NECA) were placed subcutaneously 7 days after hypoxia and continuously administered the agents for 14 days.Mean pulmonary artery pressure (mPAP) was detected after administration of the agents.Then blood samples were taken from heart for measurement of renin activity,angiotensin Ⅱ (Ang Ⅱ) and endothelin-1 (ET-1) concentration by radioimmunoassay,NO by measuring nitrate.Small pulmonary arteries were prepared for

  12. LPCES对慢性低压缺氧兔颏舌肌肌球蛋白重链和SR Ca2+摄取-释放动力学的影响%Electrical stimulation at lower physiological frequency induces myosin heavy chain isoform transformation and improves sarcoplasmic reticulum Ca2+ uptake/release in genioglossus of rabbits exposed to chronic hypoxia

    Institute of Scientific and Technical Information of China (English)

    刘熙; 刘刚; 张妮; 欧娜; 张鹏

    2011-01-01

    Objective To identify the effect of chronic electrical stimulation at a lower physiological frequency on the expressions of myosin heavy chain (MHC) isoforms and kinetics of sarcoplasmic reticulum (SR) Ca2 + uptake/release in the genioglossus of rabbits exposed to chronic hypoxia. Methods Twenty-four adult rabbits were randomized into control group ( A), chronic hypoxia group ( B ), 2.5 Hz electrical stimulation group (C) and (2.5 + 40) Hz electrical stimulation group (low frequency plus physical frequency, D).After the rabbits from group B, C and D had been fed with free access to food and water in a hypoxia cabin ( simulating 5 000 m altitude) in 10 h a day for 4 weeks, the rabbits in group C and D received electrical stimulation in their genioglossus at a frequency of 2.5 Hz and (2.5 +40) Hz respectively in 10 h per day for 14 d,while those in group B received no electrical stimulation. Expressions of MHC isoforms in the genioglossus of rabbits in 4 groups were detected by Western blotting, and Fura-2 fluorophotometry was used to assay the kinetics changes of SR Ca2 + uptake-release. Restlts The expression level of MHC l a was significantly higher while that of MHC I was significantly lower in group B than that in group A (P < 0.05 ). Meanwhile,the genioglossus SR Ca2+ uptake/release velocity in group B was significantly decreased compared with that in group A ( P < 0. 05 ). The expression levels of MHC Ⅱ a and MHC I in group C and D after electrical stimulation were significantly higher, while those of MHC Ⅱ b, especially in group D, were significantly lower than those in group B (P < 0.05 ). The genioglossus SR Ca2+ uptake/release velocity in group C and D, especially in group D, was significantly increased compared with that in group B ( P < 0.05 ). No significant difference was found in expression levels of MHC Ⅱ a and MHC I between group C and D after electrical stimulation ( P > 0.05). Conclusion MHC Ⅱb in the genioglossus of rabbits with

  13. COMPARISON OF LIVE HIGH: TRAIN LOW ALTITUDE AND INTERMITTENT HYPOXIC EXPOSURE

    Directory of Open Access Journals (Sweden)

    Clare E. Humberstone-Gough

    2013-09-01

    Full Text Available Live High:Train Low (LHTL altitude training is a popular ergogenic aid amongst athletes. An alternative hypoxia protocol, acute (60-90 min daily Intermittent Hypoxic Exposure (IHE, has shown potential for improving athletic performance. The aim of this study was to compare directly the effects of LHTL and IHE on the running and blood characteristics of elite triathletes. Changes in total haemoglobin mass (Hbmass, maximal oxygen consumption (VO2max, velocity at VO2max (vVO2max, time to exhaustion (TTE, running economy, maximal blood lactate concentration ([La] and 3 mM [La] running speed were compared following 17 days of LHTL (240 h of hypoxia, IHE (10.2 h of hypoxia or Placebo treatment in 24 Australian National Team triathletes (7 female, 17 male. There was a clear 3.2 ± 4.8% (mean ± 90% confidence limits increase in Hbmass following LHTL compared with Placebo, whereas the corresponding change of -1.4 ± 4.5% in IHE was unclear. Following LHTL, running economy was 2.8 ± 4.4% improved compared to IHE and 3mM [La] running speed was 4.4 ± 4.5% improved compared to Placebo. After IHE, there were no beneficial changes in running economy or 3mM [La] running speed compared to Placebo. There were no clear changes in VO2max, vVO2max and TTE following either method of hypoxia. The clear difference in Hbmass response between LHTL and IHE indicated that the dose of hypoxia in IHE was insufficient to induce accelerated erythropoiesis. Improved running economy and 3mM [La] running speed following LHTL suggested that this method of hypoxic exposure may enhance performance at submaximal running speeds. Overall, there was no evidence to support the use of IHE in elite triathletes

  14. Plasma volume in acute hypoxia

    DEFF Research Database (Denmark)

    Poulsen, T D; Klausen, T; Richalet, J P

    1998-01-01

    Exposure to acute hypoxia is associated with changes in body fluid homeostasis and plasma volume (PV). This study compared a dye dilution technique using Evans' blue (PV[Evans']) with a carbon monoxide (CO) rebreathing method (PV[CO]) for measurements of PV in ten normal subjects at sea level...

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

    Science.gov (United States)

    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.

  16. Emerging evidence of the physiological role of hypoxia in mammary development and lactation

    Institute of Scientific and Technical Information of China (English)

    Yong Shao; Feng-Qi Zhao

    2014-01-01

    Hypoxia is a physiological or pathological condition of a deficiency of oxygen supply in the body as a whole or within a tissue. During hypoxia, tissues undergo a series of physiological responses to defend themselves against a low oxygen supply, including increased angiogenesis, erythropoiesis, and glucose uptake. The effects of hypoxia are mainly mediated by hypoxia-inducible factor 1 (HIF-1), which is a heterodimeric transcription factor consisting ofαandβsubunits. HIF-1βis constantly expressed, whereas HIF-1αis degraded under normal oxygen conditions. Hypoxia stabilizes HIF-1αand the HIF complex, and HIF then translocates into the nucleus to initiate the expression of target genes. Hypoxia has been extensively studied for its role in promoting tumor progression, and emerging evidence also indicates that hypoxia may play important roles in physiological processes, including mammary development and lactation. The mammary gland exhibits an increasing metabolic rate from pregnancy to lactation to support mammary growth, lactogenesis, and lactation. This process requires increasing amounts of oxygen consumption and results in localized chronic hypoxia as confirmed by the binding of the hypoxia marker pimonidazole HCl in mouse mammary gland. We hypothesized that this hypoxic condition promotes mammary development and lactation, a hypothesis that is supported by the following several lines of evidence:i) Mice with an HIF-1αdeletion selective for the mammary gland have impaired mammary differentiation and lipid secretion, resulting in lactation failure and striking changes in milk compositions;ii) We recently observed that hypoxia significantly induces HIF-1α-dependent glucose uptake and GLUT1 expression in mammary epithelial cells, which may be responsible for the dramatic increases in glucose uptake and GLUT1 expression in the mammary gland during the transition period from late pregnancy to early lactation;and ii ) Hypoxia and HIF-1αincrease the

  17. Hyperglycemia suppresses the sympatho-adrenal response to hypoxia, but not to handling stress

    NARCIS (Netherlands)

    Benthem, L; Taborsky, G.J.

    1998-01-01

    We hypothesized that the ability of prior hyperglycemia to suppress the sympatho-adrenal response would depend on the type of stress. To test this hypothesis, hyperglycemia was induced in chronically catheterized rats, before submitting them to either hypoxia (7.5% O-2) or handling stress. Central v

  18. Hypoxia in the Baltic Sea: biogeochemical cycles, benthic fauna, and management.

    Science.gov (United States)

    Carstensen, Jacob; Conley, Daniel J; Bonsdorff, Erik; Gustafsson, Bo G; Hietanen, Susanna; Janas, Urzsula; Jilbert, Tom; Maximov, Alexey; Norkko, Alf; Norkko, Joanna; Reed, Daniel C; Slomp, Caroline P; Timmermann, Karen; Voss, Maren

    2014-02-01

    Hypoxia has occurred intermittently over the Holocene in the Baltic Sea, but the recent expansion from less than 10 000 km(2) before 1950 to >60 000 km(2) since 2000 is mainly caused by enhanced nutrient inputs from land and atmosphere. With worsening hypoxia, the role of sediments changes from nitrogen removal to nitrogen release as ammonium. At present, denitrification in the water column and sediments is equally important. Phosphorus is currently buried in sediments mainly in organic form, with an additional contribution of reduced Fe-phosphate minerals in the deep anoxic basins. Upon the transition to oxic conditions, a significant proportion of the organic phosphorus will be remineralized, with the phosphorus then being bound to iron oxides. This iron-oxide bound phosphorus is readily released to the water column upon the onset of hypoxia again. Important ecosystems services carried out by the benthic fauna, including biogeochemical feedback-loops and biomass production, are also lost with hypoxia. The results provide quantitative knowledge of nutrient release and recycling processes under various environmental conditions in support of decision support tools underlying the Baltic Sea Action Plan.

  19. Prediction of Critical Power and W' in Hypoxia: Application to Work-Balance Modelling.

    Science.gov (United States)

    Townsend, Nathan E; Nichols, David S; Skiba, Philip F; Racinais, Sebastien; Périard, Julien D

    2017-01-01

    Purpose: Develop a prediction equation for critical power (CP) and work above CP (W') in hypoxia for use in the work-balance ([Formula: see text]) model. Methods: Nine trained male cyclists completed cycling time trials (TT; 12, 7, and 3 min) to determine CP and W' at five altitudes (250, 1,250, 2,250, 3,250, and 4,250 m). Least squares regression was used to predict CP and W' at altitude. A high-intensity intermittent test (HIIT) was performed at 250 and 2,250 m. Actual and predicted CP and W' were used to compute W' during HIIT using differential ([Formula: see text]) and integral ([Formula: see text]) forms of the [Formula: see text] model. Results: CP decreased at altitude (P study are suitable for use with the [Formula: see text] model in acute hypoxia. This enables the application of [Formula: see text] modelling to training prescription and competition analysis at altitude.

  20. Radiation characteristics of intermittence exhaust noise

    Institute of Scientific and Technical Information of China (English)

    ZHAO Shengdun; SHANG Chunyang; ZHAO Zhigang; SHI Weixiang

    2000-01-01

    Aerodynamic characteristics, the noise characteristics in the course of intermittence exhaust are investigated and the expressions for sound pressure level of the noise generated by single-pole source and quadrupole source in the intermittence exhaust noise are established. The effects of all parameters in pneumatic system on the noise are also comprehensively studied.

  1. COHO SALMON DEPENDENCE ON INTERMITTENT STREAMS

    Science.gov (United States)

    In February 2006, the US Supreme Court heard cases that may affect whether intermittent streams are jurisdictional waters under the Clean Water Act. In June 2006, however, the cases were remanded to the circuit court, leaving the status of intermittent streams uncertain once agai...

  2. Disodium cromoglycate attenuates hypoxia induced enlargement of end-expiratory lung volume in rats.

    Science.gov (United States)

    Maxová, H; Hezinová, A; Vízek, M

    2011-01-01

    Mechanism responsible for the enlargement of end-expiratory lung volume (EELV) induced by chronic hypoxia remains unclear. The fact that the increase in EELV persists after return to normoxia suggests involvement of morphological changes. Because hypoxia has been also shown to activate lung mast cells, we speculated that they could play in the mechanism increasing EELV similar role as in vessel remodeling in hypoxic pulmonary hypertension (HPH). We, therefore, tested an effect of mast cells degranulation blocker disodium cromoglycate (DSCG) on hypoxia induced EELV enlargement. Ventilatory parameters, EELV and right to left heart weight ratio (RV/LV+S) were measured in male Wistar rats. The experimental group (H+DSCG) was exposed to 3 weeks of normobaric hypoxia and treated with DSCG during the first four days of hypoxia, control group was exposed to hypoxia only (H), two others were kept in normoxia as non-treated (N) and treated (N+DSCG) groups. DSCG treatment significantly attenuated the EELV enlargement (H+DSCG = 6.1+/-0.8; H = 9.2+/-0.9; ml +/-SE) together with the increase in minute ventilation (H + DSCG = 190+/-8; H = 273 +/- 10; ml/min +/- SE) and RV/LV + S (H + DSCG = 0.39 +/- 0.03; H = 0.50 +/- 0.06).

  3. Influence of moderate hypoxia on vaccine efficacy against Vibrio anguillarum in Oreochromis niloticus (Nile tilapia).

    Science.gov (United States)

    Gallage, Sanchala; Katagiri, Takayuki; Endo, Makoto; Futami, Kunihiko; Endo, Masato; Maita, Masashi

    2016-04-01

    Hypoxia is known as a potential immunomodulator in fish. This study therefore assesses the impact of chronic, moderate hypoxia on vaccine efficacy in Oreochromis niloticus. Serum antibody titer was used as a surrogate marker to detect vaccine efficacy. The fish were acclimatized to either moderate hypoxia (55 ± 5% DO) or normoxia (85 ± 5%DO) and immunized with formalin inactivated Vibrio anguillarum. Significantly, a higher antibody titer was found in normoxic fish than in moderate hypoxia. The normoxic group titer peaked at 14th dpv (days post vaccination) while the moderate hypoxic group peaked at 21st or 28th dpv. The absolute blood lymphocyte counts and serum bactericidal activities against V. anguillarum were significantly higher in normoxic fish. Serum killing of V. anguillarum appeared to be mainly via antibody-dependent classical complement pathway. Furthermore, the first week following vaccination appears critical for antibody production. This view was further supported by results obtained from gene expression assay, where the transcription level of all the detected immune related genes (IgM, IL-1 β, TCR-β, MHC-II β), except B cell activating factor, were significantly suppressed following exposure to moderate hypoxia. The overall results highlight that even though moderate hypoxia is not easily detectable in Oreochromis niloticus, it negatively affects antibody production by suppressing and delaying antibody response, ultimately affecting vaccine efficacy.

  4. Kinetic intermittency in magnetized plasma turbulence

    CERN Document Server

    Teaca, Bogdan; Told, Daniel; Jenko, Frank

    2016-01-01

    We employ magnetized plasma turbulence, described by a gyrokinetic formalism in an interval ranging from the end of the fluid scales to the electron gyroradius, to introduce the first study of kinetic intermittency, in which nonlinear structures formed directly in the distribution functions are analyzed by accounting for velocity space correlations generated by linear (Landau resonance) and nonlinear phase mixing. Electron structures are found to be strongly intermittent and dominated by linear phase mixing, while nonlinear phase mixing dominates the weakly intermittent ions. This is the first time spatial intermittency and linear phase mixing are shown to be self-consistently linked for the electrons and, as the magnetic field follows the intermittency of the electrons at small scales, explain why magnetic islands are places dominated by Landau damping in steady state turbulence.

  5. Optical diagnostics of intermittent flows

    DEFF Research Database (Denmark)

    Okulov, V.L.; Naumov, I.V.; Sørensen, Jens Nørkær

    2007-01-01

    The efficiency of combined use of different optical techniques for flow diagnostics is demonstrated with the practically important case of intense swirling flows. It is shown that, when applied separately, commonly used optical measuring techniques, such as laser Doppler anemometry and particle...... image velocimetry, frequently give erroneous results, especially for the transition flow and developed nonstationary flow. However, their combined use in diagnostics of unsteady (intermittent) flows significantly improves both the temporal and spatial resolution of measurements. Such a complex approach...... is for the first time applied for diagnostics of the flow pattern in a closed cylinder with a rotating end face with the aim of studying the changeover from the steady axisymmetric to unsteady asymmetric flow over a wide range of flow parameters. It is found that such a transition is notable for azimuthal...

  6. Lattice splitting under intermittent flows

    CERN Document Server

    Schläpfer, Markus

    2010-01-01

    We study the splitting of regular square lattices subject to stochastic intermittent flows. By extensive Monte Carlo simulations we reveal how the time span until the occurence of a splitting depends on various flow patterns imposed on the lattices. Increasing the flow fluctuation frequencies shortens this time span which reaches a minimum before rising again due to inertia effects incorporated in the model. The size of the largest connected component after the splitting is rather independent of the flow fluctuations but sligthly decreases with the link capacities. Our results are relevant for assessing the robustness of real-life systems, such as electric power grids with a large share of renewable energy sources including wind turbines and photovoltaic systems.

  7. Intermittent transport in edge plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Garcia, O.E.; Naulin, V.; Nielsen, A.H.; Juul Rasmussen, J. [Association EURATOM-Riso National Laboratory, Optics and Plasma Research, Roskilde (Denmark)

    2004-07-01

    The properties of low-frequency convective fluctuations and transport are investigated for the boundary region of magnetized plasmas. We employ a two-dimensional fluid model for the evolution of the global plasma quantities in a geometry and with parameters relevant to the scrape-off layer of confined toroidal plasmas. Strongly intermittent plasma transport is regulated by self-consistently generated sheared poloidal flows and is mediated by burst ejection of particles and heat from the bulk plasma in the form of blobs. Coarse grained probe signals reveal a highly skewed and flat distribution on short time scales, but tends towards a normal distribution at large time scales. Conditionally averaged signals are in perfect agreement with experimental measurements. (authors)

  8. Cooperative controls with intermittent communication

    Science.gov (United States)

    Shen, Dan; Chen, Genshe; Cruz, Jose B., Jr.; Pham, Khanh; Blasch, Erik; Lynch, Robert

    2010-04-01

    In this paper, we propose a solution to the cooperative path planning with limited communication problem in two phases. In the first (offline) phase, a Pareto-optimal path problem is formulated to find a reference path and the graph cuts minimization method is used to speedily calculate the optimal solution. In the second (online) phase, a foraging algorithm is used to dynamically refine the reference path to meet the dynamic constraints of unmanned aerial vehicle (UAVs), during which an open-loop feedback optimal (OLFO) controller is used to estimate the states which may be unavailable due to infrequent battlefield information updates. Furthermore, an adaptive Markov decision process is proposed to deal with intermittent asynchronous information flow. The method is demonstrated in a simulation for a swarm of Unmanned Air Vehicle (UAV) teams with various communication ranges.

  9. Viral and host factors related with histopathologyc activity in patients with chronic hepatitis B and moderate or intermittently elevated alanine aminotransferase levels Influencia de factores virales y del huésped en la actividad histológica en pacientes con hepatitis crónica por virus de la hepatitis B y elevación moderada o intermitente de alanina aminotransferasa

    Directory of Open Access Journals (Sweden)

    E. Molina Pérez

    2010-09-01

    Full Text Available Objective: viral and host factors are related with progression of pathological lesion in chronic hepatitis B. We analyzed these factors in patients with moderate or intermittently elevated ALT levels, and its threshold that determinate significant histological activity. Patients and methods: retrospective analyses of viral and host parameters in 89 consecutive chronic hepatitis B patients biopsied because of moderate or intermittently elevated ALT levels [1-2 x ULN (ULN = 39 IU/mL] and/or DNA-HBV > 2 x 10³ IU/mL in AntiHBe+ patients. It was analyzed age, gender, ALT levels, HBeAg, viral load and genotype. It was considered advanced histological lesion a Knodell Score (KS > 7 and histological lesion indicating treatment, lobular inflammation ≥ 2 or fibrosis ≥ 2 according to Scheuer Classification. Results: KS > 7 and histological lesion indicating treatment was found in 47.8 and 60.7% respectively. It was observed relationship between age, male gender, ALT levels and viral load with histological damage (p ULN (69.1 vs. 47.1%, p = 0.04. There were not significant upper frequencies of advanced lesion when a cut-off of 40 years or DNA-HBV > 2 x 10³ IU/mL viral load or serological status HBeAg was considerate. Histological activity was lesser in genotype D patients than those infected with others genotypes (p Objetivo: analizar factores virales y del huésped relacionados con actividad histológica en un subgrupo de pacientes con hepatitis crónica B y elevación intermitente o moderada de alanina aminotransferasa (ALT, y el umbral que determine daño histológico indicativo de tratamiento. Pacientes y métodos: análisis retrospectivo de parámetros virales y del huésped en 89 pacientes con hepatitis crónica B biopsiados consecutivamente por elevación intermitente o moderada de ALT [1-2 x USN (USN = 39 UI/mL]. Fueron analizados edad, sexo, ALT, HBeAg, carga viral y genotipo. Se consideró como lesion histologica avanzada un Índice de

  10. Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors.

    Science.gov (United States)

    Dilly, Ashok K; Lee, Yong J; Zeh, Herbert J; Guo, Zong Sheng; Bartlett, David L; Choudry, Haroon A

    2016-03-01

    Excessive accumulation of mucin 2 (MUC2; a gel-forming secreted mucin) protein in the peritoneal cavity is the major cause of morbidity and mortality in pseudomyxoma peritonei (PMP). Hypoxia (hypoxia-inducible factor-1α; HIF-1α) has been shown to regulate the expression of similar mucins (eg, MUC5AC). We hypothesized that hypoxia (HIF-1α) drives MUC2 expression in PMP and is therefore a novel target to reduce mucinous tumor growth. The regulation of MUC2 by 2% hypoxia (HIF-1α) was evaluated in MUC2-secreting LS174T cells. The effect of BAY 87-2243, an inhibitor of HIF-1α, on MUC2 expression and mucinous tumor growth was evaluated in LS174T cells, PMP explant tissue, and in a unique intraperitoneal murine xenograft model of PMP. In vitro exposure of LS174T cells to hypoxia increased MUC2 messenger RNA (mRNA) and protein expression and increased HIF-1α binding to the MUC2 promoter. Hypoxia-mediated MUC2 protein overexpression was downregulated by transfected HIF-1α small interfering RNA (siRNA) compared with scrambled siRNA in LS174T cells. BAY 87-2243 inhibited hypoxia-induced MUC2 mRNA and protein expression in LS174T cells and PMP explant tissue. In a murine xenograft model of PMP, chronic oral therapy with BAY 87-2243 inhibited mucinous tumor growth and MUC2, HIF-1α expression in the tumor tissue. Our data suggest that hypoxia (HIF-1α) induces MUC2 promoter activity to increase MUC2 expression. HIF-1α inhibition decreases MUC2 production and mucinous tumor growth, providing a preclinical rationale for the use of HIF-1α inhibitors to treat patients with PMP.

  11. Hyperplasia and hypertrophy of pulmonary neuroepithelial bodies, presumed airway hypoxia sensors, in hypoxia-inducible factor prolyl hydroxylase-deficient mice.

    Science.gov (United States)

    Pan, Jie; Bishop, Tammie; Ratcliffe, Peter J; Yeger, Herman; Cutz, Ernest

    2016-01-01

    Pulmonary neuroepithelial bodies (NEBs), presumed polymodal airway sensors, consist of innervated clusters of amine (serotonin) and peptide-producing cells. While NEB responses to acute hypoxia are mediated by a membrane-bound O2 sensor complex, responses to sustained and/or chronic hypoxia involve a prolyl hydroxylase (PHD)-hypoxia-inducible factor-dependent mechanism. We have previously reported hyperplasia of NEBs in the lungs of Phd1-/- mice associated with enhanced serotonin secretion. Here we use a novel multilabel immunofluorescence method to assess NEB distribution, frequency, and size, together with the number and size of NEB cell nuclei, and to colocalize multiple cytoplasmic and nuclear epitopes in the lungs of Phd1-/-, Phd2+/-, and Phd3-/- mice and compare them with wild-type controls. To define the mechanisms of NEB cell hyperplasia, we used antibodies against Mash1 and Prox1 (neurogenic genes involved in NEB cell differentiation/maturation), hypoxia-inducible factor-1alpha, and the cell proliferation marker Ki67. Morphometric analysis of (% total lung area) immunostaining for synaptophysin (% synaptophysin), a cytoplasmic marker of NEB cells, was significantly increased in Phd1-/- and Phd3-/- mice compared to wild-type mice. In addition, NEB size and the number and size of NEB nuclei were also significantly increased, indicating that deficiency of Phds is associated with striking hyperplasia and hypertrophy of NEBs. In Phd2+/- mice, while mean % synaptophysin was comparable to wild-type controls, the NEB size was moderately increased, suggesting an effect even in heterozygotes. NEBs in all Phd-deficient mice showed increased expression of Mash1, Prox1, Ki67, and hypoxia-inducible factor-1alpha, in keeping with enhanced differentiation from precursor cells and a minor component of cell proliferation. Since the loss of PHD activity mimics chronic hypoxia, our data provide critical information on the potential role of PHDs in the pathobiology and

  12. Analytical approach to continuous and intermittent bottleneck flows

    DEFF Research Database (Denmark)

    Helbing, D.; Johansson, A.; Mathiesen, Joachim Kaj;

    2006-01-01

    Many-particle-inspired theory, Continuous and Intermittent Bottleneck Flows Udgivelsesdato: Oct. 20......Many-particle-inspired theory, Continuous and Intermittent Bottleneck Flows Udgivelsesdato: Oct. 20...

  13. Hypoxia, Monitoring, and Mitigation System

    Science.gov (United States)

    2015-08-01

    22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply...unlimited. 13. SUPPLEMENTARY NOTES The original document contains color images . 14. ABSTRACT The Hypoxia Monitoring, Alert and Mitigation System...was started in May. Optional Tasks 3, 4 and 5 have not been exercised . The second iteration of the arm mounted prototype is being fabricated and tested

  14. Hypoxia Impairs Vasodilation in the Lung

    OpenAIRE

    Norbert F Voelkel; McMurtry, Ivan F.; Reeves, John T.

    1981-01-01

    Alveolar hypoxia causes pulmonary vasoconstriction; we investigated whether hypoxia could also impair pulmonary vasodilation. We found in the isolated perfused rat lung a delay in vasodilation following agonist-induced vasoconstriction. The delay was not due to erythrocyte or plasma factors, or to alterations in base-line lung perfusion pressure. Pretreating lungs with arachidonic acid abolished hypoxic vasoconstriction, but did not influence the hypoxia-induced impairment of vasodilation aft...

  15. Intermittent hypoxia and prolonged suboxia measured in situ in a marine sponge

    Directory of Open Access Journals (Sweden)

    Adi Lavy

    2016-12-01

    Full Text Available High Microbial Abundance (HMA sponges constitute a guild of suspension-feeding sponges that host vast populations of symbiotic microbes. These symbionts mediate a complex series of biogeochemical transformations that fuel the holobiont’s metabolism. Although sponges are aerobic animals, suboxic and anaerobic bacteria are known to reside within their bodies. However, little is known about the chemical characteristics of the sponge environment in which they occur and almost no data are available regarding the dissolved oxygen (DO dynamics inside the holobiont in its natural habitat. In this study we examined the oxygen dynamics in situ in the HMA sponge Theonella swinhoei. A submersed data-logging system equipped with micro-sensors was used to continuously record DO concentrations inside the sponge body and in its outflowing water for up to 48 hours. Actively pumping sponges exhibited high DO removal rates punctuated with short bursts of extreme DO uptake (>90 µmol DO Lpumped-1, never before observed in sponges. Such a high DO removal rate indicates the consumption of a considerable amount of reduced matter, far exceeding the available sources in the surrounding water of the oligotrophic coral-reef ecosystem inhabited by this sponge. The inner body of the sponge remained suboxic throughout the experiments, with short events of further rapid DO concentration decline. Moreover, DO concentrations measured in the body and in the outflowing water were found to be uncorrelated. Our findings support a previous hypothesis of bacterial symbiont farming by the sponge as a potential source for acquiring reduced material. Moreover, this suggests a complex and highly localized control of the holobiont’s metabolism, probably associated with the microbial community’s metabolism. Our results indicate that temporal micro-environments exist in the sponge at alternating locations, providing suitable conditions for the activity of its anaerobic microbial symbionts.

  16. Assessing Relative Volatility/Intermittency/Energy Dissipation

    DEFF Research Database (Denmark)

    Barndorff-Nielsen, Ole E.; Pakkanen, Mikko; Schmiegel, Jürgen

    We introduce the notion of relative volatility/intermittency and demonstrate how relative volatility statistics can be used to estimate consistently the temporal variation of volatility/intermittency even when the data of interest are generated by a non-semimartingale, or a Brownian semistationary...... process in particular. While this estimation method is motivated by the assessment of relative energy dissipation in empirical data of turbulence, we apply it also to energy price data. Moreover, we develop a probabilistic asymptotic theory for relative power variations of Brownian semistationary...... processes and Ito semimartingales and discuss how it can be used for inference on relative volatility/intermittency....

  17. Hypoxia facilitates neurogenic dural plasma protein extravasation in mice: a novel animal model for migraine pathophysiology.

    Science.gov (United States)

    Hunfeld, Anika; Segelcke, Daniel; Bäcker, Ingo; Mecheri, Badreddine; Hemmer, Kathrin; Dlugosch, Elisabeth; Andriske, Michael; Paris, Frank; Zhu, Xinran; Lübbert, Hermann

    2015-12-08

    Migraine animal models generally mimic the onset of attacks and acute treatment processes. A guinea pig model used the application of meta-chlorophenylpiperazine (mCPP) to trigger immediate dural plasma protein extravasation (PPE) mediated by 5-HT2B receptors. This model has predictive value for antimigraine drugs but cannot explain the delayed onset of efficacy of 5-HT2B receptor antagonists when clinically used for migraine prophylaxis. We found that mCPP failed to induce dural PPE in mice. Considering the role 5-HT2B receptors play in hypoxia-induced pulmonary vessel muscularization, we were encouraged to keep mice under hypoxic conditions and tested whether this treatment will render them susceptible to mCPP-induced dural PPE. Following four-week of hypoxia, PPE, associated with increased transendothelial transport, was induced by mCPP. The effect was blocked by sumatriptan. Chronic application of 5-HT2B receptor or nitric oxide synthase blockers during hypoxia prevented the development of susceptibility. Here we present a migraine model that distinguishes between a migraine-like state (hypoxic mice) and normal, normoxic mice and mimics processes that are related to chronic activation of 5-HT2B receptors under hypoxia. It seems striking, that chronic endogenous activation of 5-HT2B receptors is crucial for the sensitization since 5-HT2B receptor antagonists have strong, albeit delayed migraine prophylactic efficacy.

  18. Hypoxia primes human normal prostate epithelial cells and cancer cell lines for the NLRP3 and AIM2 inflammasome activation.

    Science.gov (United States)

    Panchanathan, Ravichandran; Liu, Hongzhu; Choubey, Divaker

    2016-05-10

    The molecular mechanisms by which hypoxia contributes to prostatic chronic inflammation (PCI) remain largely unknown. Because hypoxia stimulates the transcriptional activity of NF-κB, which "primes" cells for inflammasome activation by inducing the expression of NLRP3 or AIM2 receptor and pro-IL-1β, we investigated whether hypoxia could activate the NLRP3 and AIM2 inflammasome in human normal prostate epithelial cells (PrECs) and cancer cell lines. Here we report that hypoxia (1% O2) treatment of PrECs, prostate cell lines, and a macrophage cell line (THP-1) increased the levels of NLRP3, AIM2, and pro-IL-1β. Further, hypoxia in cells potentiated activation of the NLRP3 and AIM2 inflammasome activity. Notably, hypoxia "primed" cells for NLRP3 and AIM2 inflammasome activation through stimulation of the NF-κB activity. Our observations support the idea that hypoxia in human prostatic tumors contributes to PCI, in part, by priming cells for the activation of NLRP3 and AIM2 inflammasome.

  19. Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis

    Science.gov (United States)

    Maron, Bradley A.; Oldham, William M.; Chan, Stephen Y.; Vargas, Sara O.; Arons, Elena; Zhang, Ying-Yi; Loscalzo, Joseph; Leopold, Jane A.

    2014-01-01

    Background The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension (PAH), suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in PAH. Methods and Results Patients with PAH, rats with Sugen/hypoxia-PAH, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia-StAR signaling in HPAECs. Hypoxia (2.0% FiO2) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography-mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos/c-Jun binding to the proximal activator protein (AP-1) site of the StAR promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR-siRNA or treated with the AP-1 inhibitor, SR-11302, hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro, and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in Conclusions Our findings identify autonomous aldosterone synthesis in HPAECs due to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular

  20. Sky dancer: an intermittent system

    Science.gov (United States)

    Cros, Anne; Rodríguez Romero, Jesse Alexander; Damián Díaz Andrade, Oscar

    2009-11-01

    Sky dancers attract people sight to make advertising. What is the origin of those large vertical tubes fluctuations above an air blower? This study complements the previous one [1] about the system analysis from a dynamical system point of view. As a difference from the ``garden hose-instability'' [2], the tube shape has got ``break points''. Those ``break points'' separate the air-filled bottom tube portion from its deflated top portion. We record the tube dynamics with a high-speed videocamera simultaneously that we measure the pressure at the air blower exit. The intermittent pressure evolution displays picks when the tube fluctuates. We compare those overpressure values with the ones that appears in a rigid tube whose exit is partially obstructed. [1] F. Castillo Flores & A. Cros ``Transition to chaos of a vertical collapsible tube conveying air flow'' J. Phys.: Conf. Ser. 166, 012017 (2009). [2] A. S. Greenwald & J. Dungundji ``Static and dynamic instabilities of a propellant line'' MIT Aeroelastic and Structures Research Lab, AFOSR Sci. Report: AFOSR 67-1395 (1967).

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

    Science.gov (United States)

    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

  2. On-line intermittent connector anomaly detection

    Data.gov (United States)

    National Aeronautics and Space Administration — This paper investigates a non-traditional use of differential current sensor and current sensor to detect intermittent disconnection problems in connectors. An...

  3. Improved Intermittency Analysis of Single Event Data

    OpenAIRE

    Janik, R. A.; Ziaja, B.

    1998-01-01

    The intermittency analysis of single event data (particle moments) in multiparticle production is improved, taking into account corrections due to the reconstruction of history of a particle cascade. This approach is tested within the framework of the $\\alpha$-model.

  4. Intermittent preventive treatment of malaria in pregnancy

    DEFF Research Database (Denmark)

    Mbonye, A.K.; Bygbjerg, Ib Christian; Magnussen, Pascal

    2008-01-01

    OBJECTIVE: To assess whether traditional birth attendants, drug-shop vendors, community reproductive-health workers, or adolescent peer mobilizers could administer intermittent preventive treatment (IPTp) for malaria with sulfadoxine-pyrimethamine to pregnant women. METHODS: A non-randomized comm......OBJECTIVE: To assess whether traditional birth attendants, drug-shop vendors, community reproductive-health workers, or adolescent peer mobilizers could administer intermittent preventive treatment (IPTp) for malaria with sulfadoxine-pyrimethamine to pregnant women. METHODS: A non...

  5. [Pulsed hypoxia in the treatment of obstructive lung diseases].

    Science.gov (United States)

    Sil'vestrov, V P; Kovalenko, E A; Krysin, Iu S

    1993-01-01

    A new approach to the treatment of chronic nonspecific pulmonary diseases is proposed: helium-oxygen therapy combined with repeated interrupted hypoxic stimuli. Helium inclusion into hypoxic gas mixture leads to reduced air density. Gas mixture containing 10-15% of oxygen is more effective at the level of alveolocapillary membrane. When conducted in normal atmospheric pressure, the method involved no complications and produced positive responses in coronary heart disease, hypertension, alimentary diseases. The mixture of helium with oxygen (85-90% of helium, 10-15% oxygen) in combination with impulse normobaric hypoxia has been tried in 25 chronics with obstructive bronchitis and bronchial asthma. The results were indicative of the treatment efficacy: bronchial permeability improved in 67% of the cases, forced vital capacity of the lungs increased, inspiratory reserve volume grew, dyspnea and cough diminished, sputum discharge improved, general tonicity and performance status changed positively. Six-month follow-up evidenced positive shifts too.

  6. Kinetic modeling in PET imaging of hypoxia

    DEFF Research Database (Denmark)

    Li, Fan; Jørgensen, Jesper Tranekjær; Hansen, Anders E

    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...... analysis for PET imaging of hypoxia....

  7. Prolonged hypoxia increases survival even in Zebrafish (Danio rerio showing cardiac arrhythmia.

    Directory of Open Access Journals (Sweden)

    Renate Kopp

    Full Text Available Tolerance towards hypoxia is highly pronounced in zebrafish. In this study even beneficial effects of hypoxia, specifically enhanced survival of zebrafish larvae, could be demonstrated. This effect was actually more pronounced in breakdance mutants, which phenotypically show cardiac arrhythmia. Breakdance mutants (bre are characterized by chronically reduced cardiac output. Despite an about 50% heart rate reduction, they become adults, but survival rate significantly drops to 40%. Normoxic bre animals demonstrate increased hypoxia inducible factor 1 a (Hif-1α expression, which indicates an activated hypoxic signaling pathway. Consequently, cardiovascular acclimation, like cardiac hypertrophy and increased erythrocyte concentration, occurs. Thus, it was hypothesized, that under hypoxic conditions survival might be even more reduced. When bre mutants were exposed to hypoxic conditions, they surprisingly showed higher survival rates than under normoxic conditions and even reached wildtype values. In hypoxic wildtype zebrafish, survival yet exceeded normoxic control values. To specify physiological acclimation, cardiovascular and metabolic parameters were measured before hypoxia started (3 dpf, when the first differences in survival rate occurred (7 dpf and when survival rate plateaued (15 dpf. Hypoxic animals expectedly demonstrated Hif-1α accumulation and consequently enhanced convective oxygen carrying capacity. Moreover, bre animals showed a significantly enhanced heart rate under hypoxic conditions, which reached normoxic wildtype values. This improvement in convective oxygen transport ensured a sufficient oxygen and nutrient supply and was also reflected in the significantly higher mitochondrial activity. The highly optimized energy metabolism observed in hypoxic zebrafish larvae might be decisive for periods of higher energy demand due to organ development, growth and increased activity. However, hypoxia increased survival only during a

  8. VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

    Energy Technology Data Exchange (ETDEWEB)

    Garcia-Roman, Jonathan; Ibarra-Sanchez, Alfredo; Lamas, Monica [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico); Gonzalez Espinosa, Claudia, E-mail: cgonzal@cinvestav.mx [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico)

    2010-10-15

    Research highlights: {yields} Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. {yields} CoCl{sub 2}-induced VEGF secretion in mast cells occurs by a Ca{sup 2+}-insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. {yields} Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits Fc{epsilon}RI-dependent anaphylactic degranulation in mast cells. {yields} Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl{sub 2}) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl{sub 2} promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl{sub 2}-induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl{sub 2}-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl{sub 2} in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals

  9. The Response of Macrophages and Neutrophils to Hypoxia in the Context of Cancer and Other Inflammatory Diseases

    Directory of Open Access Journals (Sweden)

    Antje Egners

    2016-01-01

    Full Text Available Lack of oxygen (hypoxia is a hallmark of a multitude of acute and chronic diseases and can be either beneficial or detrimental for organ restitution and recovery. In the context of inflammation, hypoxia is particularly important and can significantly influence the course of inflammatory diseases. Macrophages and neutrophils, the chief cellular components of innate immunity, display distinct properties when exposed to hypoxic conditions. Virtually every aspect of macrophage and neutrophil function is affected by hypoxia, amongst others, morphology, migration, chemotaxis, adherence to endothelial cells, bacterial killing, differentiation/polarization, and protumorigenic activity. Prominent arenas of macrophage and neutrophil function, for example, acute/chronic inflammation and the microenvironment of solid tumors, are characterized by low oxygen levels, demonstrating the paramount importance of the hypoxic response for proper function of these cells. Members of the hypoxia-inducible transcription factor (HIF family emerged as pivotal molecular regulators of macrophages and neutrophils. In this review, we will summarize the molecular responses of macrophages and neutrophils to hypoxia in the context of cancer and other chronic inflammatory diseases and discuss the potential avenues for therapeutic intervention that arise from this knowledge.

  10. Oxygen sensing by the carotid body: mechanisms and role in adaptation to hypoxia.

    Science.gov (United States)

    López-Barneo, José; González-Rodríguez, Patricia; Gao, Lin; Fernández-Agüera, M Carmen; Pardal, Ricardo; Ortega-Sáenz, Patricia

    2016-04-15

    Oxygen (O2) is fundamental for cell and whole-body homeostasis. Our understanding of the adaptive processes that take place in response to a lack of O2(hypoxia) has progressed significantly in recent years. The carotid body (CB) is the main arterial chemoreceptor that mediates the acute cardiorespiratory reflexes (hyperventilation and sympathetic activation) triggered by hypoxia. The CB is composed of clusters of cells (glomeruli) in close contact with blood vessels and nerve fibers. Glomus cells, the O2-sensitive elements in the CB, are neuron-like cells that contain O2-sensitive K(+)channels, which are inhibited by hypoxia. This leads to cell depolarization, Ca(2+)entry, and the release of transmitters to activate sensory fibers terminating at the respiratory center. The mechanism whereby O2modulates K(+)channels has remained elusive, although several appealing hypotheses have been postulated. Recent data suggest that mitochondria complex I signaling to membrane K(+)channels plays a fundamental role in acute O2sensing. CB activation during exposure to low Po2is also necessary for acclimatization to chronic hypoxia. CB growth during sustained hypoxia depends on the activation of a resident population of stem cells, which are also activated by transmitters released from the O2-sensitive glomus cells. These advances should foster further studies on the role of CB dysfunction in the pathogenesis of highly prevalent human diseases.

  11. HIF-1α mediates tumor hypoxia to confer a perpetual mesenchymal phenotype for malignant progression.

    Science.gov (United States)

    Yoo, Young-Gun; Christensen, Jared; Gu, Jie; Huang, L Eric

    2011-06-21

    Although tumor progression involves genetic and epigenetic alterations to normal cellular biology, the underlying mechanisms of these changes remain obscure. Numerous studies have shown that hypoxia-inducible factor 1α (HIF-1α) is overexpressed in many human cancers and up-regulates a host of hypoxia-responsive genes for cancer growth and survival. We recently identified an alternative mechanism of HIF-1α function that induces genetic alterations by suppressing DNA repair. Here, we show that long-term hypoxia, which mimics the tumor microenvironment, drives a perpetual epithelial-mesenchymal transition (EMT) through up-regulation of the zinc finger E-box binding homeobox protein ZEB2, whereas short-term hypoxia induces a reversible EMT that requires the transcription factor Twist1. Moreover, we show that the perpetual EMT driven by chronic hypoxia depends on HIF-1α induction of genetic alterations rather than its canonical transcriptional activator function. These mesenchymal tumor cells not only acquire tumorigenicity but also display characteristics of advanced cancers, including necrosis, aggressive invasion, and metastasis. Hence, these results reveal a mechanism by which HIF-1α promotes a perpetual mesenchymal phenotype, thereby advancing tumor progression.

  12. Hypoxia and oxidative stress markers in pediatric patients undergoing hemodialysis: cross section study

    Directory of Open Access Journals (Sweden)

    Hamed Enas A

    2012-10-01

    Full Text Available Abstract Background Tissue injury due to hypoxia and/or free radicals is common in a variety of disease processes. This cross-sectional study aimed to investigate effect of chronic kidney diseases (CKD and hemodialysis (HD on hypoxia and oxidative stress biomarkers. Methods Forty pediatric patients with CKD on HD and 20 healthy children were recruited. Plasma hypoxia induced factor-1α (HIF-1α, vascular endothelial growth factor (VEGF were measured by specific ELISA kits while, total antioxidant capacity (TAC, total peroxide (TPX, pyruvate and lactate by enzymatic/chemical colorimetric methods. Oxidative stress index (OSI and lactate/pyruvate (L/P ratio were calculated. Results TAC was significantly lower while TPX, OSI and VEGF were higher in patients at before- and after-dialysis session than controls. Lactate and HIF-1α levels were significantly higher at before-dialysis session than controls. Before dialysis, TAC and L/P ratio were lower than after-dialysis. In before-dialysis session, VEGF correlated positively with pyruvate, HIF-1α and OSI correlated positively with TPX, but, negatively with TAC. In after-dialysis session, HIF-1α correlated negatively with TPX and OSI; while, OSI correlated positively with TPX. Conclusions CKD patients succumb considerable tissue hypoxia with oxidative stress. Hemodialysis ameliorated hypoxia but lowered antioxidants as evidenced by decreased levels of HIF-1α and TAC at before- compared to after-dialysis levels.

  13. Assessment of intermittent trace element pollution by moss bags

    Energy Technology Data Exchange (ETDEWEB)

    Cesa, M. [Dipartimento di Biologia, Universita di Trieste, Via Giorgieri 10, I-34127 Trieste (Italy)]. E-mail: mcesa@units.it; Bizzotto, A. [ARPAV Dipartimento di Vicenza, Servizio Territoriale di Bassano del Grappa, Via Cereria 15, I-36061 Bassano del Grappa (VI) (Italy); Ferraro, C. [ARPAV Dipartimento di Vicenza, Servizio Territoriale di Bassano del Grappa, Via Cereria 15, I-36061 Bassano del Grappa (VI) (Italy); Fumagalli, F. [Dipartimento di Biologia, Universita di Trieste, Via Giorgieri 10, I-34127 Trieste (Italy); Nimis, P.L. [Dipartimento di Biologia, Universita di Trieste, Via Giorgieri 10, I-34127 Trieste (Italy)

    2006-12-15

    Moss bags of the aquatic bryophyte Rhynchostegium riparioides (Hedw.) C. Jens. were transplanted into an irrigation ditch in the Province of Vicenza (NE Italy), affected by intermittent trace element contamination due to galvanics. The study aimed at: (a) testing the ability of mosses to detect different patterns of pollution (b) providing information about intensity and temporal extension of pollution events, and (c) localising the main sources. Moss bags were collected after 20, 34, 48 and 62 days of exposure. The concentrations of As, Cd, Cr, Cu, Hg, Mn, Ni, Pb and Zn in the desiccated apical shoots of mosses were determined by atomic absorption spectrophotometry. The mean concentrations measured in non-contaminated stations of a previous work were adopted as background values, to calculate the contamination factor (CF). Transplants were able to: (a) detect spatial patterns of bioaccumulation (b) reveal chronic contamination by Pb and Cu, intermittent contamination by Cr, Zn, and Ni, and a release of Cd by moss bags, and (c) localise the main emission sources. - Transplanted bryophytes are able to detect accidental trace element pollution in freshwaters of industrial areas.

  14. Beneficial effects of intermittent suction and pressure treatment in intermittent claudication

    DEFF Research Database (Denmark)

    Mehlsen, J; Himmelstrup, H; Himmelstrup, Bodil;

    1993-01-01

    The present study reports on the effects of a physical treatment modality in patients with intermittent claudication. During this treatment a major part of the skin surface is subjected to intermittent suction and pressure. In a previous, preliminary study the authors found a beneficial effect of...

  15. Intermittent ephemeral river-breaching

    Science.gov (United States)

    Reniers, A. J.; MacMahan, J. H.; Gallagher, E. L.; Shanks, A.; Morgan, S.; Jarvis, M.; Thornton, E. B.; Brown, J.; Fujimura, A.

    2012-12-01

    In the summer of 2011 we performed a field experiment in Carmel River State Beach, CA, at a time when the intermittent natural breaching of the ephemeral Carmel River occurred due to an unusually rainy period prior to the experiment associated with El Nino. At this time the river would fill the lagoon over the period of a number of days after which a breach would occur. This allowed us to document a number of breaches with unique pre- and post-breach topographic surveys, accompanying ocean and lagoon water elevations as well as extremely high flow (4m/s) velocities in the river mouth during the breaching event. The topographic surveys were obtained with a GPS-equipped backpack mounted on a walking human and show the evolution of the river breaching with a gradually widening and deepening river channel that cuts through the pre-existing beach and berm. The beach face is qualified as a steep with an average beach slope of 1:10 with significant reflection of the incident waves (MacMahan et al., 2012). The wave directions are generally shore normal as the waves refract over the deep canyon that is located offshore of the beach. The tide is mixed semi-diurnal with a range on the order of one meter. Breaching typically occurred during the low-low tide. Grain size is highly variable along the beach with layers of alternating fine and coarse material that could clearly be observed as the river exit channel was cutting through the beach. Large rocky outcroppings buried under the beach sand are also present along certain stretches of the beach controlling the depth of the breaching channel. The changes in the water level measured within the lagoon and the ocean side allows for an estimate of the volume flux associated with the breach as function of morphology, tidal elevation and wave conditions as well as an assessment of the conditions and mechanisms of breach closure, which occurred on the time scale of O(0.5 days). Exploratory model simulations will be presented at the

  16. Intermittent changing axis deviation with intermittent left anterior hemiblock during atrial flutter with subclinical hyperthyroidism.

    Science.gov (United States)

    Patanè, Salvatore; Marte, Filippo

    2009-06-26

    Subclinical hyperthyroidism is an increasingly recognized entity that is defined as a normal serum free thyroxine and free triiodothyronine levels with a thyroid-stimulating hormone level suppressed below the normal range and usually undetectable. It has been reported that subclinical hyperthyroidism is not associated with CHD or mortality from cardiovascular causes but it is usually associated with a higher heart rate and a higher risk of supraventricular arrhythmias including atrial fibrillation and atrial flutter. Intermittent changing axis deviation during atrial fibrillation has also rarely been reported. We present a case of intermittent changing axis deviation with intermittent left anterior hemiblock in a 59-year-old Italian man with atrial flutter and subclinical hyperthyroidism. To our knowledge, this is the first report of intermittent changing axis deviation with intermittent left anterior hemiblock in a patient with atrial flutter.

  17. Intermittency in 2D soap film turbulence

    CERN Document Server

    Cerbus, R T

    2013-01-01

    The Reynolds number dependency of intermittency for 2D turbulence is studied in a flowing soap film. The Reynolds number used here is the Taylor microscale Reynolds number R_{\\lambda}, which ranges from 20 to 800. Strong intermittency is found for both the inverse energy and direct enstrophy cascades as measured by (a) the pdf of velocity differences P(\\delta u(r)) at inertial scales r, (b) the kurtosis of P(\\partial_x u), and (c) the scaling of the so-called intermittency exponent \\mu, which is zero if intermittency is absent. Measures (b) and (c) are quantitative, while (a) is qualitative. These measurements are in disagreement with some previous results but not all. The velocity derivatives are nongaussian at all R_{\\lambda} but show signs of becoming gaussian as R_{\\lambda} increases beyond the largest values that could be reached. The kurtosis of P(\\delta u(r)) at various r indicates that the intermittency is scale dependent. The structure function scaling exponents also deviate strongly from the Kraichn...

  18. Endoscopic excision of a prolapsing malignant polyp which caused intermittent gastric outlet obstruction

    Institute of Scientific and Technical Information of China (English)

    Huqh J Freeman

    2005-01-01

    A 69-year-old male with chronic lymphocytic leukemia presented with iron deficiency anemia and post-prandial abdominal fullness. Endoscopy showed a large polyp on a stalk, protruding through the pylorus into the duodenum causing intermittent gastric outlet obstruction. While prolapsing gastric antral polyps are usually benign and hyperplastic, inflammatory or regenerative in type, excisional snare polypectomy here led to complete resolution of his symptoms, but showed a malignant polyp.

  19. TanshinoneIIA and cryptotanshinone protect against hypoxia-induced mitochondrial apoptosis in H9c2 cells.

    Directory of Open Access Journals (Sweden)

    Hyou-Ju Jin

    Full Text Available Mitochondrial apoptosis pathway is an important target of cardioprotective signalling. Tanshinones, a group of major bioactive compounds isolated from Salvia miltiorrhiza, have been reported with actions against inflammation, oxidative stress, and myocardial ischemia reperfusion injury. However, the actions of these compounds on the chronic hypoxia-related mitochondrial apoptosis pathway have not been investigated. In this study, we examined the effects and molecular mechanisms of two major tanshonones, tanshinone IIA (TIIA and cryptotanshinone (CT on hypoxia induced apoptosis in H9c2 cells. Cultured H9c2 cells were treated with TIIA and CT (0.3 and 3 μΜ 2 hr before and during an 8 hr hypoxic period. Chronic hypoxia caused a significant increase in hypoxia inducible factor 1α expression and the cell late apoptosis rate, which was accompanied with an increase in caspase 3 activity, cytochrome c release, mitochondria membrane potential and expression of pro-apoptosis proteins (Bax and Bak. TIIA and CT (0.3 and 3 μΜ, in concentrations without affecting the cell viability, significantly inhibited the late apoptosis and the changes of caspase 3 activity, cytochrome c release, and mitochondria membrane potential induced by chronic hypoxia. These compounds also suppressed the overexpression of Bax and reduced the ratio of Bax/Bcl-2. The results indicate that TIIA and CT protect against chronic hypoxia induced cell apoptosis by regulating the mitochondrial apoptosis signaling pathway, involving inhibitions of mitochondria hyperpolarization, cytochrome c release and caspase 3 activity, and balancing anti- and pro-apoptotic proteins in Bcl-2 family proteins.

  20. Chronic penile strangulation

    Directory of Open Access Journals (Sweden)

    Lopes Roberto I

    2003-01-01

    Full Text Available Chronic penile strangulation is exceedingly rare with only 5 cases previously reported. We report an additional case of progressive penile lymphedema due to chronic intermittent strangulation caused by a rubber band applied to the penile base for 6 years. A 49-year-old man presented incapacity to exteriorize the glans penis. For erotic purposes, he had been using a rubber-enlarging band placed in the penile base for 6 years. With chronic use, he noticed that his penis swelled. Physical examination revealed lymphedema of the penis, phimosis and a stricture in the penile base. The patient was submitted to circumcision and the lymphedema remained stable 10 months postoperatively. Chronic penile incarceration usually causes penile lymphedema and urinary disturbance. Treatment consists of removal of foreign devices and surgical treatment of lymphedema.

  1. Intermittency in Switching Power Converters: Theoretical Analysis

    Institute of Scientific and Technical Information of China (English)

    ZHOU Yu-fei; CHEN Jun-ning; TSE Chi K.; QIU Shui-sheng; KE Dao-ming; SHI Long-xing; SUN Wei-feng

    2006-01-01

    In view of reasonable explanation of intermittent subharmonics and chaos that can be gained from coupling filter between circuits,this paper discusses a method that maps time bifurcation with parameter bifurcation.Based on this mapping method,the general analysis method of characteristic multiplier,which is originally aimed at parameter bifurcation,can be used for the study of intermittency,i.e.,time bifurcation.In this paper,all researches coming from characteristic multipliers,parameter-bifurcation diagrams,and the largest Lyapunov exponent indicate the same results as those produced by simulation and experiment.Thus,it is proved theoretically that the intermittency in switching power converter can be explained in terms of coupling of spurious interference.

  2. Intermittent rainfall in dynamic multimedia fate modeling.

    Science.gov (United States)

    Hertwich, E G

    2001-03-01

    It has been shown that steady-state multimedia models (level III fugacity models) lead to a substantial underestimate of air concentrations for chemicals with a low Henry's law constant (H multimedia models are used to estimate the spatial range or inhalation exposure. A dynamic model of pollutant fate is developed for conditions of intermittent rainfall to calculate the time profile of pollutant concentrations in different environmental compartments. The model utilizes a new, mathematically efficient approach to dynamic multimedia fate modeling that is based on the convolution of solutions to the initial conditions problem. For the first time, this approach is applied to intermittent conditions. The investigation indicates that the time-averaged pollutant concentrations under intermittent rainfall can be approximated by the appropriately weighted average of steady-state concentrations under conditions with and without rainfall.

  3. The Yo-Yo intermittent recovery test

    DEFF Research Database (Denmark)

    Bangsbo, Jens; Iaia, F. Marcello; Krustrup, Peter

    2008-01-01

    The two Yo-Yo intermittent recovery (IR) tests evaluate an individual's ability to repeatedly perform intense exercise. The Yo-Yo IR level 1 (Yo-Yo IR1) test focuses on the capacity to carry out intermittent exercise leading to a maximal activation of the aerobic system, whereas Yo-Yo IR level 2...... (Yo-Yo IR2) determines an individual's ability to recover from repeated exercise with a high contribution from the anaerobic system. Evaluations of elite athletes in various sports involving intermittent exercise showed that the higher the level of competition the better an athlete performs in the Yo-Yo...... IR tests. Performance in the Yo-Yo IR tests for young athletes increases with rising age. The Yo-Yo IR tests have shown to be a more sensitive measure of changes in performance than maximum oxygen uptake. The Yo-Yo IR tests provide a simple and valid way to obtain important information...

  4. Chaos synchronization based on intermittent state observer

    Institute of Scientific and Technical Information of China (English)

    Li Guo-Hui; Zhou Shi-Ping; Xu De-Ming

    2004-01-01

    This paper describes the method of synchronizing slave to the master trajectory using an intermittent state observer by constructing a synchronizer which drives the response system globally tracing the driving system asymptotically. It has been shown from the theory of synchronization error-analysis that a satisfactory result of chaos synchronization is expected under an appropriate intermittent period and state observer. Compared with continuous control method,the proposed intermittent method can target the desired orbit more efficiently. The application of the method is demonstrated on the hyperchaotic Rossler systems. Numerical simulations show that the length of the synchronization interval rs is of crucial importance for our scheme, and the method is robust with respect to parameter mismatch.

  5. Magnetic field generation by intermittent convection

    CERN Document Server

    Chertovskih, R; Chimanski, E V

    2016-01-01

    Magnetic field generation by convective flows in transition to weak turbulence is studied numerically. By fixing the Prandtl number at P=0.3 and varying the Rayleigh number (Ra) as a control parameter in three-dimensional Rayleigh-Benard convection of an electrically conducting fluid, a recently reported route to hyperchaos involving quasiperiodic regimes, crises and chaotic intermittent attractors is followed, and the critical magnetic Prandtl number ($P_m^c$) for dynamo action is determined as a function of Ra. A mechanism for the onset of on-off intermittency in the magnetic energy is described, the most beneficial convective regimes for dynamo action are identified, and how intermittency affects the dependence of $P_m^c$ on Ra is discussed.

  6. Synchronization of Intermittently Coupled Dynamical Networks

    Directory of Open Access Journals (Sweden)

    Gang Zhang

    2013-01-01

    Full Text Available This paper investigates the synchronization phenomenon of an intermittently coupled dynamical network in which the coupling among nodes can occur only at discrete instants and the coupling configuration of the network is time varying. A model of intermittently coupled dynamical network consisting of identical nodes is introduced. Based on the stability theory for impulsive differential equations, some synchronization criteria for intermittently coupled dynamical networks are derived. The network synchronizability is shown to be related to the second largest and the smallest eigenvalues of the coupling matrix, the coupling strength, and the impulsive intervals. Using the chaotic Chua system and Lorenz system as nodes of a dynamical network for simulation, respectively, the theoretical results are verified and illustrated.

  7. Assessing relative volatility/intermittency/energy dissipation

    DEFF Research Database (Denmark)

    Barndorff-Nielsen, Ole E.; Pakkanen, Mikko S.; Schmiegel, Jürgen

    2014-01-01

    We introduce the notion of relative volatility/intermittency and demonstrate how relative volatility statistics can be used to estimate consistently the temporal variation of volatility/intermittency when the data of interest are generated by a non-semimartingale, or a Brownian semistationary...... process in particular. This estimation method is motivated by the assessment of relative energy dissipation in empirical data of turbulence, but it is also applicable in other areas. We develop a probabilistic asymptotic theory for realised relative power variations of Brownian semistationary processes......, and introduce inference methods based on the theory. We also discuss how to extend the asymptotic theory to other classes of processes exhibiting stochastic volatility/intermittency. As an empirical application, we study relative energy dissipation in data of atmospheric turbulence....

  8. Hypoxia: Exposure Time Until Significant Performance Effects

    Science.gov (United States)

    2016-03-07

    and self-reported symptoms. Additionally, the PowerLab computer system interfaced with the gas analyzer to measure levels of carbon dioxide (CO2) and...processing by hypoxia. Ergonomics , 36(6), 727-35. 4. Fowler, B., Elcombe, D.D., Kelso, B., & Porlier, G. (1987). The threshold for hypoxia effects on... Ergonomics , 25(3), 189-201. 9. Gold, R.E. & Kulak, L.L. (1972). Effect of hypoxia on aircraft pilot performance. Aerospace Medicine, 43(2), 180-3

  9. [Chronic inflammatory bowel diseases in cats].

    Science.gov (United States)

    Ghermai, A K

    1989-01-01

    The aetiology of chronic idiopathic intestinal inflammation is unknown. It is characterized by a diffuse infiltration with inflammatory cells into the intestinal mucosa and sometimes submucosa. Cats with chronic intermittent vomiting and diarrhoea, later on accompanied by anorexia and weight loss, are presented. Definitive diagnosis can be obtained by intestinal biopsy only. An immune pathogenesis is suspected, which is supported by the fact, that chronic inflammatory bowel disease responds to steroid therapy.

  10. Intermittently connected mobile ad hoc networks

    CERN Document Server

    Jamalipour, Abbas

    2011-01-01

    In the last few years, there has been extensive research activity in the emerging area of Intermittently Connected Mobile Ad Hoc Networks (ICMANs). By considering the nature of intermittent connectivity in most real word mobile environments without any restrictions placed on users' behavior, ICMANs are eventually formed without any assumption with regard to the existence of a end-to-end path between two nodes wishing to communicate. It is different from the conventional Mobile Ad Hoc Networks (MANETs), which have been implicitly viewed as a connected graph with established complete paths betwe

  11. Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism *

    Science.gov (United States)

    Thompson, A.A.R.; Dickinson, R.S.; Murphy, F.; Thomson, J. P.; Marriott, H.M.; Tavares, A.; Willson, J.; Williams, L.; Lewis, A.; Mirchandani, A.; Dos Santos Coelho, P.; Doherty, C.; Ryan, E.; Watts, E.; Morton, N. M.; Forbes, S.; Stimson, R. H.; Hameed, A. G.; Arnold, N.; Preston, J.A.; Lawrie, A.; Finisguerra, V.; Mazzone, M.; Sadiku, P.; Goveia, J.; Taverna, F.; Carmeliet, P.; Foster, S.J.; Chilvers, E.R.; Cowburn, A.S.; Dockrell, D.H.; Johnson, R.S.; Meehan, R. R.; Whyte, M.K.B.; Walmsley, S.R.

    2017-01-01

    Hypoxia and bacterial infection frequently co-exist, in both acute and chronic clinical settings, and typically result in adverse clinical outcomes. To ameliorate this morbidity, we investigated the interaction between hypoxia and the host response. In the context of acute hypoxia, both S. aureus and S. pneumoniae infections rapidly induced progressive neutrophil mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, prior to infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes. Specifically, perturbation of HIF pathway and glycolysis genes by hypoxic preconditioning was associated with reduced leukocyte glucose utilisation, resulting in systemic rescue from a global negative energy state and myocardial protection. Thus we demonstrate that hypoxia preconditions the innate immune response and determines survival outcomes following bacterial infection through suppression of HIF-1α and neutrophil metabolism. The therapeutic implications of this work are that in the context of systemic or tissue hypoxia therapies that target the host response could improve infection associated morbidity and mortality. PMID:28386604

  12. Wheatgrass extract inhibits hypoxia-inducible factor-1-mediated epithelial-mesenchymal transition in A549 cells

    Science.gov (United States)

    Do, Nam Yong; Shin, Hyun-Jae

    2017-01-01

    BACKGROUND/OBJECTIVES Epithelial-mesenchymal transition (EMT) is involved in not only cancer development and metastasis but also non-cancerous conditions. Hypoxia is one of the proposed critical factors contributing to formation of chronic rhinosinusitis or nasal polyposis. Wheatgrass (Triticum aestivum) has antioxidant, anti-aging, and anti-inflammatory effects. In this study, we analyzed whether wheatgrass has an inhibitory effect on the EMT process in airway epithelial cells. MATERIALS/METHODS A549 human lung adenocarcinoma cells were incubated in hypoxic conditions (CO2 5%/O2 1%) for 24 h in the presence of different concentrations of wheatgrass extract (50, 75, 100, and 150 µg/mL) and changes in expression of epithelial or mesenchymal markers were evaluated by immunoblotting and immunofluorescence. Accordingly, associated EMT-related transcriptional factors, Snail and Smad, were also evaluated. RESULTS Hypoxia increased expression of N-cadherin and reduced expression of E-cadherin. Mechanistically, E-cadherin levels were recovered during hypoxia by silencing hypoxia inducible factor (HIF)-1α or administering wheatgrass extract. Wheatgrass inhibited the hypoxia-mediated EMT by reducing the expression of phosphorylated Smad3 (pSmad3) and Snail. It suppressed the hypoxia-mediated EMT processes of airway epithelial cells via HIF-1α and the pSmad3 signaling pathway. CONCLUSION These results suggest that wheatgrass has potential as a therapeutic or supplementary agent for HIF-1-related diseases.

  13. Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury.

    Science.gov (United States)

    Kobayashi, Hanako; Gilbert, Victoria; Liu, Qingdu; Kapitsinou, Pinelopi P; Unger, Travis L; Rha, Jennifer; Rivella, Stefano; Schlöndorff, Detlef; Haase, Volker H

    2012-05-15

    Renal fibrosis and inflammation are associated with hypoxia, and tissue pO(2) plays a central role in modulating the progression of chronic kidney disease. Key mediators of cellular adaptation to hypoxia are hypoxia-inducible factor (HIF)-1 and -2. In the kidney, they are expressed in a cell type-specific manner; to what degree activation of each homolog modulates renal fibrogenesis and inflammation has not been established. To address this issue, we used Cre-loxP recombination to activate or to delete both Hif-1 and Hif-2 either globally or cell type specifically in myeloid cells. Global activation of Hif suppressed inflammation and fibrogenesis in mice subjected to unilateral ureteral obstruction, whereas activation of Hif in myeloid cells suppressed inflammation only. Suppression of inflammatory cell infiltration was associated with downregulation of CC chemokine receptors in renal macrophages. Conversely, global deletion or myeloid-specific inactivation of Hif promoted inflammation. Furthermore, prolonged hypoxia suppressed the expression of multiple inflammatory molecules in noninjured kidneys. Collectively, we provide experimental evidence that hypoxia and/or myeloid cell-specific HIF activation attenuates renal inflammation associated with chronic kidney injury.

  14. 2004 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  15. 2002 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  16. Triptolide protects astrocytes from hypoxia/ reoxygenation injury

    Institute of Scientific and Technical Information of China (English)

    Minfang Guo; Hongcui Fan; Jiezhong Yu; Ning Ji; Yongsheng Sun; Liyun Liang; Baoguo Xiao; Cungen Ma

    2011-01-01

    Astrocytes in an in vitro murine astrocyte model of oxygen and glucose deprivation/hypoxia and reoxygenation were treated with different concentrations of triptolide (250, 500, 1 000 ng/mL) in a broader attempt to elucidate the protection and mechanism underlying triptolide treatment on astrocytes exposed to hypoxia/reoxygenation injury. The results showed that the matrix metalloproteinase-9, interleukin-1β, tumor necrosis factor α and interleukin-6 expressions were significantly decreased after triptolide treatment in the astrocytes exposed to hypoxia/ reoxygenation injury, while interleukin-10 expression was upregulated. In addition, the vitality of the injured astrocytes was enhanced, the triptolide's effect was apparent at 500 ng/mL. These experimental findings indicate that triptolide treatment could protect astrocytes against hypoxia/ reoxygenation injury through the inhibition of inflammatory response and the reduction of matrix metalloproteinase-9 expression.

  17. 2001 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  18. 2005 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  19. 2003 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  20. 2006 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  1. 2007 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  2. 慢性间歇性低压低氧对成年和幼年大鼠缺血/再灌注心脏保护作用的比较%Comparison of cardioprotection of chronic intermittent hypobaric hypoxia against ischemia/reperfusion injury between adult and young rats

    Institute of Scientific and Technical Information of China (English)

    马会杰; 李茜; 王福伟; 王璐; 马慧娟; 史敏; 张浩; 张翼

    2010-01-01

    目的 观察慢性间歇性低压低氧(CIHH)对成年和幼年大鼠心脏缺血/再灌注损伤的保护作用的异同点.方法 ♂成年和新生Sprague-Dawlay (SD)大鼠随机分为4组:对照28 d组(CON28)、对照42 d组(CON42)、CIHH处理28 d组(CIHH28)和CIHH处理42 d组(CIHH42).间歇性低氧处理组动物于低压氧舱分别接受28 d、42 d模拟3 000米海拔高度(P_B=525 mmHg,P_(O_2)=108.8 mmHg)的低压低氧处理,每天5 h.对照组动物除了不接受低氧处理外,其它处理均与间歇性低氧组动物相同.应用Langendorff离体心脏灌流技术,给予心脏缺血(停灌30 min)/再灌注(复灌60 min)处理,记录离体大鼠心脏在不同时期的心功能变化.心功能参数包括左室发展压(left ventricular developing pressure,LVDP)、左室压力最大变化速率(maximum change rate of LVDP,±LVdp/dt_(max))、左室舒张末压(left ventricular end diastolic pressure, LVEDP) 、冠脉流量(coronary flow,CF)和心率(heartrate,HR).结果 ①对成年大鼠,基础状态和缺血/再灌注状态下CIHH 28 d组各心功能参数与CON 28 d组相比差异均无统计学意义.CIHH 42 d组各心功能参数均好于CON 42 d组,表现为LVDP、LVEDP、±LVdp/dt_(max)和CF恢复均增加(P<0.05).② 对幼年大鼠,基础状态下,CIHH大鼠CF较对照大鼠明显增多,其余心功能参数与对照大鼠无差异.CIHH大鼠缺血/再灌注后心脏功能的恢复明显好于对照动物,表现为LVDP、LVEDP、±LVdp/dt_(max)和CF恢复均增加(P<0.05),且CIHH 42 d组比CIHH 28 d组心功能改善更明显.结论 CIHH可增强成年和幼年大鼠抗心肌缺血/再灌注损伤的能力,具有明显的心脏保护作用,CIHH 42 d组保护作用更为明显;CIHH的心脏保护作用有明显的年龄差异,在幼年大鼠更易产生保护作用.

  3. Raisanberine protected pulmonary arterial rings and cardiac myocytes of rats against hypoxia injury by suppressing NADPH oxidase and calcium influx

    Institute of Scientific and Technical Information of China (English)

    Jie GAO; Yi-qun TANG; De-zai DAI; Yu-si CHENG; Guo-lin ZHANG; Can ZHANG; Yin DAI

    2012-01-01

    To investigate the protection of pulmonary arterial rings and cardiac myocytes of rats by raisanberine (RS),a derivative of berberine,against hypoxia injury and to elucidate the action mechanisms.Methods:Adult SD rats were exposed to intermittent hypoxia for 17 d or 28 d.The pulmonary arterial rings were isolated and vascular activity was measured using a transducer and computer-aided system.The difference in the tension produced by phenylephrine in the presence and absence of L-nitroarginine (10 μmol/L) was referred to as the NO bioavailability; the maximum release of NO was assessed by the ratio of the maximal dilatation caused by ACh to those caused by sodium nitroprusside.After the lungs were fixed,the internal and the external diameters of the pulmonary arterioles were measured using a graphic analysis system.Cultured cardiac myocytes from neonatal rats were exposed to H2O2 (10 μmol/L) to mimic hypoxia injury.ROS generation and [Ca2+]i level in the myocytes were measured using DHE and Fluo-3 fluorescence,respectively.Results:Oral administration of RS (80 mg/kg),the NADPH oxidase inhibitor apocynin (APO,80 mg/kg) or Ca2+ channel blocker nifedipine (Nif,10 mg/kg,) significantly alleviated the abnormal increase in the vasoconstriction force and endothelium-related vasodilatation induced by the intermittent hypoxia.The intermittent hypoxia markedly decreased the NO bioavailability and maximal NO release from pulmonary arterial rings,which were reversed by APO or RS administration.However,RS administration did not affect the NO bioavailability and maximal NO release from pulmonary arterial rings of normal rats.RS,Nif or APO administration significantly attenuated the pulmonary arteriole remodeling.Treatment of cultured cardiac myocytes with RS (10 μmol/L) suppressed the ROS generation and [Ca2+]i increase induced by H2O2,which were comparable to those caused by APO (10 μmol/L) or Nif (0.1 μmol/L).Conclusion:Raisanberine relieved hypoxic/oxidant insults to the

  4. Patterns of fetal lamb regional cerebral blood flow during and after prolonged hypoxia.

    Science.gov (United States)

    Ashwal, S; Majcher, J S; Vain, N; Longo, L D

    1980-10-01

    In an effort to determine to what extent cerebral blood flow (CBF) varies in different parts of the brain during prolonged fetal hypoxia, we measured flow to 34 regions in 12 chronically catheterized fetal lambs 130 to 140 days gestation. Control values of PO2, PCO2 pH, heart rate, and blood pressure were obtained, and CBF was measured by use of radioactive labeled microspheres during a control period, during (15-, 30-, and 90-min) reduction of maternal inspired O2 concentration (fetal arterial PO2 was maintained at 12 to 15 torr), and 60 min after returning the ewe to room air. control blood flow to cortical, subcortical, and brainstem structures equaled 134, 186, and 254 ml x min-1 x 100 g-1, respectively. During hypoxia, CBF increased 92%, and 60 min after fetal oxygenation was restored, it remained 50% above control values. We noted a similar response in regional CBF to the cortex, subcortex, and brainstem during and after hypoxia. Blood flow to smaller areas within the three major regions were quite homogenous and had a similar pattern of response to hypoxia. We conclude that: (1) significant fetal regional CBF differences occurred in utero with brainstem and subcortical flows being substantially greater than flows to other regions of the brain; (2) during prolonged intrauterine hypoxia, total regional CBF increased 92%; (3) 1 hr after fetal oxygenation was restored, CBF still remained 50% above control values; and finally, (4) there was no significant preferential shunting of regional CBF during prolonged hypoxia in utero.

  5. Hypoxia independent drivers of melanoma angiogenesis

    Directory of Open Access Journals (Sweden)

    Svenja eMeierjohann

    2015-05-01

    Full Text Available Tumor angiogenesis is a process which is traditionally regarded as the tumor`s response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a prerequisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia independent mechanisms of tumor angiogenesis in melanoma.

  6. Pharm GKB: Porphyria, Acute Intermittent [PharmGKB

    Lifescience Database Archive (English)

    Full Text Available Overview Alternate Names: PharmGKB Accession Id: PA166048717 External Vocabularies NDFRT: Porphyria, Acute... Intermittent (N0000003536) Common Searches Search Medline Plus Search CTD Pharm GKB: Porphyria, Acute Intermittent ...

  7. Current drive induced by intermittent trapping

    Energy Technology Data Exchange (ETDEWEB)

    Nakach, R. [Association Euratom-CEA, CEA/Cadarache, Dept. de Recherches sur la Fusion Controlee (DRFC), 13 - Saint-Paul-lez-Durance (France); Gell, Y. [CET, Israel (Israel)

    1999-02-01

    We propose a mechanism for driving a current in a dispersive plasma based on intermittent trapping of electrons in a ponderomotive well generated by two- counterpropagating electron cyclotron waves. By choosing properly the parameters of the system, this mechanism is expected to induce a high efficiency current drive. (authors)

  8. Intermittent demand : Linking forecasting to inventory obsolescence

    NARCIS (Netherlands)

    Teunter, Ruud H.; Syntetos, Aris A.; Babai, M. Zied

    2011-01-01

    The standard method to forecast intermittent demand is that by Croston. This method is available in ERP-type solutions such as SAP and specialised forecasting software packages (e.g. Forecast Pro), and often applied in practice. It uses exponential smoothing to separately update the estimated demand

  9. Intermittent resistive faults in digital cmos circuits

    NARCIS (Netherlands)

    Kerkhoff, Hans G.; Ebrahimi, H.

    2015-01-01

    A major threat in extremely dependable high-end process node integrated systems in e.g. Avionics are no failures found (NFF). One category of NFFs is the intermittent resistive fault, often originating from bad (e.g. Via or TSV-based) interconnections. This paper will show the impact of these faults

  10. Intermittent Swimming with a Flexible Propulsor

    Science.gov (United States)

    Akoz, Emre; Zeyghami, Samane; Moored, Keith

    2016-11-01

    Some animals propel themselves by using an intermittent swimming gait known as a burst-and-glide or a burst-and-coast motion. These swimmers tend to have a more pronounced pitching of their caudal fins than heaving leading to low non-dimensional heave-to-pitch ratios. Recent work has shown that when this ratio is sufficiently low the efficiency of an intermittently heaving/pitching airfoil can be significantly improved over a continuously oscillating airfoil. However, fish that swim with an intermittent gait, such as cod and saithe, do not have rigid fins, but instead have highly flexible fins. To examine the performance and flow structures of an intermittent swimmer with a flexible propulsor, a fast boundary element method solver strongly coupled with a torsional-spring structural model was developed. A self-propelled virtual body combined with a flexible-hinged pitching airfoil is used to model a free-swimming animal and its flexible caudal fin. The duty cycle of the active to the coasting phase of motion, the torsional spring flexibility and the forcing frequency are all varied. The cost-of-transport and the swimming speed are measured and connected to the observed wake patterns. Supported by the Office of Naval Research under Program Director Dr. Bob Brizzolara, MURI Grant Number N00014-14-1-0533.

  11. Management of patients with intermittent claudication

    NARCIS (Netherlands)

    S. Spronk (Sandra)

    2008-01-01

    textabstractIntermittent claudication is the first and mildest manifestation of peripheral arterial disease, caused by the atherosclerotic process of progressive narrowing of one or more of the arteries of the peripheral circulation.1 If the arterial system fails, it results in a progressive oxygen

  12. Sensing and surviving hypoxia in vertebrates.

    Science.gov (United States)

    Jonz, Michael G; Buck, Leslie T; Perry, Steve F; Schwerte, Thorsten; Zaccone, Giacomo

    2016-02-01

    Surviving hypoxia is one of the most critical challenges faced by vertebrates. Most species have adapted to changing levels of oxygen in their environment with specialized organs that sense hypoxia, while only few have been uniquely adapted to survive prolonged periods of anoxia. The goal of this review is to present the most recent research on oxygen sensing, adaptation to hypoxia, and mechanisms of anoxia tolerance in nonmammalian vertebrates. We discuss the respiratory structures in fish, including the skin, gills, and air-breathing organs, and recent evidence for chemosensory neuroepithelial cells (NECs) in these tissues that initiate reflex responses to hypoxia. The use of the zebrafish as a genetic and developmental model has allowed observation of the ontogenesis of respiratory and chemosensory systems, demonstration of a putative intracellular O2 sensor in chemoreceptors that may initiate transduction of the hypoxia signal, and investigation into the effects of extreme hypoxia on cardiorespiratory development. Other organisms, such as goldfish and freshwater turtles, display a high degree of anoxia tolerance, and these models are revealing important adaptations at the cellular level, such as the regulation of glutamatergic and GABAergic neurotransmission in defense of homeostasis in central neurons.

  13. Hypobaric Hypoxia Imbalances Mitochondrial Dynamics in Rat Brain Hippocampus

    Directory of Open Access Journals (Sweden)

    Khushbu Jain

    2015-01-01

    Full Text Available Brain is predominantly susceptible to oxidative stress and mitochondrial dysfunction during hypobaric hypoxia, and therefore undergoes neurodegeneration due to energy crisis. Evidences illustrate a high degree of association for mitochondrial fusion/fission imbalance and mitochondrial dysfunction. Mitochondrial fusion/fission is a recently reported dynamic mechanism which frequently occurs among cellular mitochondrial network. Hence, the study investigated the temporal alteration and involvement of abnormal mitochondrial dynamics (fusion/fission along with disturbed mitochondrial functionality during chronic exposure to hypobaric hypoxia (HH. The Sprague-Dawley rats were exposed to simulated high altitude equivalent to 25000 ft for 3, 7, 14, 21, and 28 days. Mitochondrial morphology, distribution within neurons, enzyme activity of respiratory complexes, Δψm, ADP: ATP, and expression of fission/fusion key proteins were determined. Results demonstrated HH induced alteration in mitochondrial morphology by damaged, small mitochondria observed in neurons with disturbance of mitochondrial functionality and reduced mitochondrial density in neuronal processes manifested by excessive mitochondrial fragmentation (fission and decreased mitochondrial fusion as compared to unexposed rat brain hippocampus. The study suggested that imbalance in mitochondrial dynamics is one of the noteworthy mechanisms occurring in hippocampal neurons during HH insult.

  14. Shuttle-run sprint training in hypoxia for youth elite soccer players: a pilot study.

    Science.gov (United States)

    Gatterer, Hannes; Philippe, Marc; Menz, Verena; Mosbach, Florian; Faulhaber, Martin; Burtscher, Martin

    2014-12-01

    The purposes of the present study were to investigate if a) shuttle-run sprint training performed in a normobaric hypoxia chamber of limited size (4.75x2.25m) is feasible, in terms of producing the same absolute training load, when compared to training in normoxia, and b) if such training improves the repeated sprint ability (RSA) and the Yo-Yo intermittent recovery (YYIR) test outcome in young elite soccer players. Players of an elite soccer training Centre (age: 15.3 ± 0.5 years, height: 1.73 ± 0.07 m, body mass: 62.6 ± 6.6 kg) were randomly assigned to a hypoxia or a normoxia training group. Within a 5-week period, players, who were not informed about the hypoxia intervention, performed at least 7 sessions of identical shuttle-run sprint training either in a normal training room (FiO2 = 20.95%) or in a hypoxic chamber (FiO2 = 14.8%; approximately 3300m), both equipped with the same floor. Each training session comprised 3 series of 5x10s back and forth sprints (4.5m) performed at maximal intensity. Recovery time between repetitions was 20s and between series 5min. Before and after the training period the RSA (6 x 40m shuttle sprint with 20 s rest between shuttles) and the YYIR test were performed. The size of the chamber did not restrict the training intensity of the sprint training (both groups performed approximately 8 shuttles during 10s). Training in hypoxia resulted in a lower fatigue slope which indicates better running speed maintenance during the RSA test (p = 0.024). YYIR performance increased over time (p = 0.045) without differences between groups (p > 0.05). This study showed that training intensity of the shuttle-run sprint training was not restricted in a hypoxic chamber of limited size which indicates that such training is feasible. Furthermore, hypoxia compared to normoxia training reduced the fatigue slope during the RSA test in youth soccer players. Key PointsShuttle-run sprint training is feasible in hypoxic chambers of limited size (i

  15. Intermittent Aeration in Biological Treatment of Wastewater

    Directory of Open Access Journals (Sweden)

    H. Doan

    2009-01-01

    Full Text Available Problem statement: E-coating process is widely used to provide a protective coating layer on metal parts in the automotive and metal finishing industry. The wastewater from the coating process contains organic compounds that are used in the cleaning, pretreatment and coating steps. Organic pollutants can be removed biologically. In the aerobic biological treatment, water aeration accounts for a significant portion of the total operating cost of the treatment process. Intermittent aeration is thus of benefit since it would reduce the energy consumption in the wastewater treatment. In the present study, wastewater from an electro-coating process was treated biologically using a packed column as an aerator where the wastewater was aerated by a countercurrent air flow. The objective was to obtain an optimum aeration cycle. Approach: Intermittent aeration time was varied at different preset cycles. An operational optimum of the aeration time (or air-water contacting time in the column was determined from the BOD5 removal after a certain treatment period. For continuous aeration of the wastewater, the air-liquid contacting time in the column was 52 min for 24 h of treatment. A unit energy consumption for pumping liquid and air, which was defined as the energy consumption per percent BOD5 removed, was used as a criterion to determine the optimum contacting time. Results: Optimum air-liquid contacting times were found to be about 38, 26 and 22 min for the treatment times of 24, 48 and 72 h, consecutively. This indicates that 27-58% saving on the unit energy consumption can be achieved using intermittent aeration of the wastewater. On the basis of the overall BOD5 removal, 17% and 23% savings in energy were observed with the intermittent aeration as compared to the continuous aeration of the wastewater for 48 and 72 h. Conclusion: The results obtained indicate that an appropriate intermittent aeration cycle can bring about a substantial energy saving

  16. 40 CFR 51.119 - Intermittent control systems.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 2 2010-07-01 2010-07-01 false Intermittent control systems. 51.119... Intermittent control systems. (a) The use of an intermittent control system (ICS) may be taken into account in... of any constant pollution control system which was in use before December 31, 1970, or the...

  17. An update of clinical management of acute intermittent porphyria

    Directory of Open Access Journals (Sweden)

    Pischik E

    2015-09-01

    mutation-positive family members. C, management of patients with recurrent attacks: 1 evaluation of the lifestyle, 2 evaluation of hormonal therapy in women, 3 prophylactic heme therapy, and 4 liver transplantation in patients with severe recurrent attacks. D, follow-up of the AIP patients for long-term complications: chronic hypertension, chronic kidney insufficiency, chronic pain syndrome, and hepatocellular carcinoma. Keywords: porphyria, acute intermittent porphyria, neuropathy, treatment, heme

  18. Renal Overexpression of Atrial Natriuretic Peptide and Hypoxia Inducible Factor-1α as Adaptive Response to a High Salt Diet

    OpenAIRE

    Silvana Lorena Della Penna; Gabriel Cao; Andrea Carranza; Elsa Zotta; Susana Gorzalczany; Carolina Susana Cerrudo; Natalia Lucía Rukavina Mikusic; Alicia Correa; Verónica Trida; Jorge Eduardo Toblli; María Inés Rosón; Belisario Enrique Fernández

    2014-01-01

    In the kidney, a high salt intake favors oxidative stress and hypoxia and causes the development of fibrosis. Both atrial natriuretic peptide (ANP) and hypoxia inducible factor (HIF-1α) exert cytoprotective effects. We tested the hypothesis that renal expression of ANP and HIF-1α is involved in a mechanism responding to the oxidative stress produced in the kidneys of rats chronically fed a high sodium diet. Sprague-Dawley rats were fed with a normal salt (0.4% NaCl) (NS) or a high salt (8% Na...

  19. Hypoxia inducible factor 1α promotes survival of mesenchymal stem cells under hypoxia

    Science.gov (United States)

    Lv, Bingke; Li, Feng; Fang, Jie; Xu, Limin; Sun, Chengmei; Han, Jianbang; Hua, Tian; Zhang, Zhongfei; Feng, Zhiming; Jiang, Xiaodan

    2017-01-01

    Mesenchymal stem cells (MSCs) are ideal materials for cell therapy. Research has indicated that hypoxia benefits MSC survival, but little is known about the underlying mechanism. This study aims to uncover potential mechanisms involving hypoxia inducible factor 1α (HIF1A) to explain the promoted MSC survival under hypoxia. MSCs were obtained from Sprague-Dawley rats and cultured under normoxia or hypoxia condition. The overexpression vector or small interfering RNA of Hif1a gene was transfected to MSCs, after which cell viability, apoptosis and expression of HIF1A were analyzed by MTT assay, flow cytometry, qRT-PCR and Western blot. Factors in p53 pathway were detected to reveal the related mechanisms. Results showed that hypoxia elevated MSCs viability and up-regulated HIF1A (P cell CLL/lymphoma 2 (BCL2) expression had the opposite pattern (P cell therapy.

  20. Hypoxia-inducible factor-1 modulates the expression of vascular endothelial growth factor and endothelial nitric oxide synthase induced by eccentric exercise.

    Science.gov (United States)

    Rodriguez-Miguelez, Paula; Lima-Cabello, Elena; Martínez-Flórez, Susana; Almar, Mar; Cuevas, María J; González-Gallego, Javier

    2015-04-15

    The present study investigated the effects of acute and chronic eccentric exercise on the hypoxia-inducible factor (HIF)-1α activation response and the concomitant modulation of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression in rat skeletal muscle. Twenty-four male Wistar rats were randomly assigned to three experimental groups: rested control group, acutely exercised group after an intermittent downhill protocol for 90 min, and acutely exercise group with a previous eccentric training of 8 wk. HIF-1α activation, VEGF and eNOS gene expression, protein content, and promoter activation were assessed in vastus lateralis muscle biopsies. Acute eccentric exercise induced a marked activation of HIF-1α and resulted in increased VEGF and eNOS mRNA level and protein concentration. The binding of HIF-1α to the VEGF and eNOS promoters, measured by a chromatin immunoprecipitation assay, was undetectable in rested rats, whereas it was evident in acutely exercised animals. Acute exercise also increased myeloperoxidase, toll-like receptor-4, tumor necrosis factor-α, and interleukin-1β protein content, suggesting a contribution of proinflammatory stimuli to HIF-1α activation and VEGF overexpression. All of these effects were partially abolished by training. Moreover, training resulted in an increased capillary density. In summary, our findings indicate that eccentric exercise prompts an HIF-1α response in untrained skeletal muscle that contributes to the upregulation of VEGF and eNOS gene expression and is attenuated after an eccentric training program.

  1. Hypoxia-on-a-chip

    Directory of Open Access Journals (Sweden)

    Busek Mathias

    2016-09-01

    Full Text Available In this work a microfluidic cell cultivation device for perfused hypoxia assays as well as a suitable controlling unit are presented. The device features active components like pumps for fluid actuation and valves for fluid direction as well as an oxygenator element to ensure a sufficient oxygen transfer. It consists of several individually structured layers which can be tailored specifically to the intended purpose. Because of its clearness, its mechanical strength and chemical resistance as well as its well-known biocompatibility polycarbonate was chosen to form the fluidic layers by thermal diffusion bonding. Several oxygen sensing spots are integrated into the device and monitored with fluorescence lifetime detection. Furthermore an oxygen regulator module is implemented into the controlling unit which is able to mix different process gases to achieve a controlled oxygenation. First experiments show that oxygenation/deoxygenation of the system is completed within several minutes when pure nitrogen or air is applied to the oxygenator. Lastly the oxygen input by the pneumatically driven micro pump was quantified by measuring the oxygen content before and after the oxygenator.

  2. Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis.

    Science.gov (United States)

    Madsen, Chris D; Pedersen, Jesper T; Venning, Freja A; Singh, Lukram Babloo; Moeendarbary, Emad; Charras, Guillaume; Cox, Thomas R; Sahai, Erik; Erler, Janine T

    2015-10-01

    Cancer-associated fibroblasts (CAFs) interact with tumour cells and promote growth and metastasis. Here, we show that CAF activation is reversible: chronic hypoxia deactivates CAFs, resulting in the loss of contractile force, reduced remodelling of the surrounding extracellular matrix and, ultimately, impaired CAF-mediated cancer cell invasion. Hypoxia inhibits prolyl hydroxylase domain protein 2 (PHD2), leading to hypoxia-inducible factor (HIF)-1α stabilisation, reduced expression of αSMA and periostin, and reduced myosin II activity. Loss of PHD2 in CAFs phenocopies the effects of hypoxia, which can be prevented by simultaneous depletion of HIF-1α. Treatment with the PHD inhibitor DMOG in an orthotopic breast cancer model significantly decreases spontaneous metastases to the lungs and liver, associated with decreased tumour stiffness and fibroblast activation. PHD2 depletion in CAFs co-injected with tumour cells similarly prevents CAF-induced metastasis to lungs and liver. Our data argue that reversion of CAFs towards a less active state is possible and could have important clinical implications.

  3. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... alcohol abuse over many years. Repeated episodes of acute ... chronic pancreatitis. Genetics may be a factor in some cases. ...

  4. Insights from intermittent binocular rivalry and EEG

    Directory of Open Access Journals (Sweden)

    Michael A Pitts

    2011-09-01

    Full Text Available Novel stimulation and analytical approaches employed in EEG studies of ambiguous figures have recently been applied to binocular rivalry. The combination of intermittent stimulus presentation and EEG source imaging has begun to shed new light on the neural underpinnings of binocular rivalry. Here, we review the basics of the intermittent paradigm and highlight methodological issues important for interpreting previous results and designing future experiments. We then outline current analytical approaches, including EEG microstates, event-related potentials, and statistically-based source estimation, and propose a spatio-temporal model that integrates findings from several studies. Finally, we discuss the advantages and limitations of using binocular rivalry as a tool to investigate the neural basis of perceptual awareness.

  5. Towards an intermittency-friendly energy system

    DEFF Research Database (Denmark)

    Blarke, Morten

    2012-01-01

    Distributed cogeneration has played a key role in the implementation of sustainable energy policies for three decades. However, increasing penetration levels of intermittent renewables is challenging that position. The paradigmatic case of West Denmark indicates that distributed operators...... are capitulating as wind power penetration levels are moving above 25%; some operators are retiring cogeneration units entirely, while other operators are making way for heat-only boilers. This development is jeopardizing the system-wide energy, economic, and environmental benefits that distributed cogeneration....... However, well-designed heat pump concepts are more cost-effective than electric boilers, and in future markets where the gas/electricity price ratio is likely to increase, compression heat pumps in combination with intermediate thermal storages represent a superior potential for combining an intermittency...

  6. INTERMITTENCY AND SCALING IN TURBULENT CONVECTION

    Institute of Scientific and Technical Information of China (English)

    Emily S. C. CHING

    2003-01-01

    Both the velocity and temperature measurements taken in turbulent Rayleigh-B'enard convection experiments have been analyzed. It is found that both the velocity and temperature fluctuations are intermittent and can be well-described by the She-Leveque hierarchical structure. A positive correlation between the vertical velocity and the temperature differences is found both at the center,near the sidewall and near the bottom of the convection cell, supporting that buoyancy is significant in the Bolgiano regime. Moreover, the intermittent nature of the temperature fluctuations in the Bolgiano regime can be attributed to the variations in the temperature dissipation rate. However, the relations between the velocity and temperature structure functions and their correlations implied by the Bolgiano-Obukhov scaling are not supported by experimental measurements.

  7. A simple model for turbulence intermittencies

    CERN Document Server

    Rimbert, Nicolas

    2009-01-01

    Whether turbulence intermittencies shall be described by a log-Poisson, a log-stable pdf or other distributions is still debated nowadays. In this paper, a bridge between polymer physics, self-avoiding walk and random vortex stretching is established which may help in getting a new insight on this topics. Actually a very simple relationship between stability index of the stable law and the well known Flory exponent stemming from polymer physics is established. Moreover the scaling of turbulence intermittencies with Reynolds number is also obtained and the overall picture is very close to Tennekes' simple model for the fine scale structure of turbulence [Phys. Fluids, 11, 3 (1968)] : vortex tubes of Kolmogorov length width are bend by bigger vortices of Taylor length scale. This thus results in both a simple and sound model with no fitting parameter needed.

  8. Scaling and Intermittency in Animal Behavior

    CERN Document Server

    Harnos, A; Lawrence, A B; Vattay, G

    1999-01-01

    Scale-invariant spatial or temporal patterns and Lévy flight motion have been observed in a large variety of biological systems. It has been argued that animals in general might perform Lévy flight motion with power law distribution of times between two changes of the direction of motion. Here we study the temporal behaviour of nesting gilts. The time spent by a gilt in a given form of activity has power law probability distribution without finite average. Further analysis reveals intermittent eruption of certain periodic behavioural sequences which are responsible for the scaling behaviour and indicates the existence of a critical state. We show that this behaviour is in close analogy with temporal sequences of velocity found in turbulent flows, where random and regular sequences alternate and form an intermittent sequence.

  9. Preparation and Preservation of Hypoxia UW Solution

    Institute of Scientific and Technical Information of China (English)

    WAN Chidang; WANG Chunyou; LIU Tan; CHENG Rui; YANG Zhiyong

    2007-01-01

    In order to explore the method to prepare hypoxia UW solution and the stability and preservation of hypoxia UW solution, UW solution was purged by argon or air for 15 min or 60 at a flow rate of 0.8 or 2 L/min, and the oxygen partial pressure of UW solution was detected. The hy-poxia UW solution was exposed to the air or sealed up to preserve by using different methods, and the changes of oxygen partial pressure was tested. The results showed that oxygen partial pressure of 50 mL UW solution, purged by argon for 15 min at a flow rate of 2 L/min, was declined from 242±6 mmHg to 83±10 mmHg. After exposure to the air, oxygen partial pressure of hypoxia UW solution was gradually increased to 160±7 mmHg at 48 h. After sealed up by the centrifuge tube and plastic bad filled with argon, oxygen partial pressure of hypoxia UW solution was stable, about 88±13 mmHg at 72 h. It was concluded that oxygen of UW solution could be purged by argon efficiently. Sealed up by the centrifuge tube and plastic bag filled with argon, oxygen partial pressure of UW so- lution could be stabilized.

  10. Hypoxia-regulated target genes implicated in tumor metastasis

    Directory of Open Access Journals (Sweden)

    Tsai Ya-Ping

    2012-12-01

    Full Text Available Abstract Hypoxia is an important microenvironmental factor that induces cancer metastasis. Hypoxia/hypoxia-inducible factor-1α (HIF-1α regulates many important steps of the metastatic processes, especially epithelial-mesenchymal transition (EMT that is one of the crucial mechanisms to cause early stage of tumor metastasis. To have a better understanding of the mechanism of hypoxia-regulated metastasis, various hypoxia/HIF-1α-regulated target genes are categorized into different classes including transcription factors, histone modifiers, enzymes, receptors, kinases, small GTPases, transporters, adhesion molecules, surface molecules, membrane proteins, and microRNAs. Different roles of these target genes are described with regards to their relationship to hypoxia-induced metastasis. We hope that this review will provide a framework for further exploration of hypoxia/HIF-1α-regulated target genes and a comprehensive view of the metastatic picture induced by hypoxia.

  11. Treatment of febrile seizures with intermittent clobazam

    OpenAIRE

    1997-01-01

    Fifty children, 24 female and 26 male, with ages varying from 6 to 72 months (mean=23.7 m.) that experienced at least one febrile seizure (FS) entered a prospective study of intermittent therapy with clobazam. Cases with severe neurological abnormalities, progressive neurological disease, afebrile seizures, symptomatic seizures of other nature, or seizures during a central nervous system infection were excluded. Seizures were of the simple type in 25 patients, complex in 20 and unclassified i...

  12. Bladder calculi complicating intermittent clean catheterization.

    Science.gov (United States)

    Amendola, M A; Sonda, L P; Diokno, A C; Vidyasagar, M

    1983-10-01

    Eight male patients on clean intermittent catheterization programs for neurogenic bladder dysfunction developed vesical calculi around pubic hairs inadvertently introduced into the bladder, acting as a nidus for incrustation. In three patients, the radiographic appearance of serpentine calcifications in the pelvis was highly consistent with calcareous deposits on strands of hair. Familiarity with this radiologic appearance should suggest the diagnosis in the appropriate clinical setting and help avoid misinterpretation of these calcifications, atypical of usual bladder stones.

  13. Intermittent chaotic chimeras for coupled rotators.

    Science.gov (United States)

    Olmi, Simona; Martens, Erik A; Thutupalli, Shashi; Torcini, Alessandro

    2015-09-01

    Two symmetrically coupled populations of N oscillators with inertia m display chaotic solutions with broken symmetry similar to experimental observations with mechanical pendulums. In particular, we report evidence of intermittent chaotic chimeras, where one population is synchronized and the other jumps erratically between laminar and turbulent phases. These states have finite lifetimes diverging as a power law with N and m. Lyapunov analyses reveal chaotic properties in quantitative agreement with theoretical predictions for globally coupled dissipative systems.

  14. Intermittent radio galaxies and source statistics

    CERN Document Server

    Reynolds, C S

    1997-01-01

    We suggest that extragalactic radio sources are intermittent on timescales of 10^4-10^5 yr. Using a simple spherical model of a cocoon/shock system, it is found that inactive sources fade rapidly in radio luminosity but the shock in the ambient medium continues to expand supersonically, thereby keeping the whole source structure intact during the inactive phases. The fading of inactive sources, and the effect of the intermittency on the expansion velocity, can readily explain the observed over-abundance of small radio sources. In particular, the plateau in the observed distribution of sizes found by O'Dea & Baum (1997) can be interpreted as being due to intermittency. The model predicts that very young sources will be particularly radio luminous, once the effects of absorption have been accounted for. Furthermore, it predicts the existence of a significant number of faint `coasting' sources. These might be detectable in deep, low-frequency radio maps, or via the X-ray and optical emission line properties ...

  15. Rat reaction to hypokinesia after prior adaptation to hypoxia

    Science.gov (United States)

    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.

  16. Overexpression of Hypoxia-Inducible Factor-1α Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

    Directory of Open Access Journals (Sweden)

    Pei Wang

    2013-09-01

    Full Text Available Background/Aims: The mechanisms involved in endothelial barrier dysfunction induced by hypoxia are incompletely understood. There is debate about the role of hypoxia-inducible factor-1α (HIF-1α in endothelial barrier disruption. The aim of this study was to investigate the effect of genetic overexpression of HIF-1α on barrier function and the underlying mechanisms in hypoxic endothelial cells. Methods: The plasmid pcDNA3.1/V5-His-HIF-1α was stably transfected into human endothelial cells. The cells were exposed to normoxia or hypoxia. The mRNA and protein expressions of HIF-1α were detected by RT-PCR and Western blot respectively. The barrier function was assessed by measuring the transendothelial electrical resistance (TER. The Western blot analysis was used to determine the protein expression of glucose transporter-1 (GLUT-1, zonular occludens-1 (ZO-1, occludin, and myosin light chain kinase (MLCK in endothelial cells. The mRNA expression of proinflammatory cytokines was detected by qRT-PCR. Results: Genetic overexpression of HIF-1α significantly increased the mRNA and protein expression of HIF-1α in endothelial cells. The overexpression of HIF-1α enhanced the hypoxia-induced increase of HIF-1α and GLUT-1 protein expression. HIF-1α overexpression not only exacerbated hypoxia-induced endothelial barrier dysfunction but also augmented hypoxia-induced up-regulation of MLCK protein expression. HIF-1α overexpression also enhanced IL-1β, IL-6 and TNF-α mRNA expression. Conclusion: We provide evidence that genetic overexpression of HIF-1α aggravates the hypoxia-induced endothelial barrier dysfunction via enhancing the up-regulation of MLCK protein expression caused by hypoxia, suggesting a potential role for HIF-1α in the pathogenesis of endothelial barrier dysfunction in hypoxia.

  17. Analysis of hypoxia and hypoxia-like states through metabolite profiling.

    Directory of Open Access Journals (Sweden)

    Julie E Gleason

    Full Text Available BACKGROUND: In diverse organisms, adaptation to low oxygen (hypoxia is mediated through complex gene expression changes that can, in part, be mimicked by exposure to metals such as cobalt. Although much is known about the transcriptional response to hypoxia and cobalt, little is known about the all-important cell metabolism effects that trigger these responses. METHODS AND FINDINGS: Herein we use a low molecular weight metabolome profiling approach to identify classes of metabolites in yeast cells that are altered as a consequence of hypoxia or cobalt exposures. Key findings on metabolites were followed-up by measuring expression of relevant proteins and enzyme activities. We find that both hypoxia and cobalt result in a loss of essential sterols and unsaturated fatty acids, but the basis for these changes are disparate. While hypoxia can affect a variety of enzymatic steps requiring oxygen and heme, cobalt specifically interferes with diiron-oxo enzymatic steps for sterol synthesis and fatty acid desaturation. In addition to diiron-oxo enzymes, cobalt but not hypoxia results in loss of labile 4Fe-4S dehydratases in the mitochondria, but has no effect on homologous 4Fe-4S dehydratases in the cytosol. Most striking, hypoxia but not cobalt affected cellular pools of amino acids. Amino acids such as aromatics were elevated whereas leucine and methionine, essential to the strain used here, dramatically decreased due to hypoxia induced down-regulation of amino acid permeases. CONCLUSIONS: These studies underscore the notion that cobalt targets a specific class of iron proteins and provide the first evidence for hypoxia effects on amino acid regulation. This research illustrates the power of metabolite profiling for uncovering new adaptations to environmental stress.

  18. Hypoxia tolerance, nitric oxide, and nitrite

    DEFF Research Database (Denmark)

    Fago, Angela; Jensen, Frank Bo

    2015-01-01

    Among vertebrates able to tolerate periods of oxygen deprivation, the painted and red-eared slider turtles (Chrysemys picta and Trachemys scripta) and the crucian carp (Carassius carassius) are the most extreme and can survive even months of total lack of oxygen during winter. The key to hypoxia ...... of NO and nitrite signaling in the adaptive response to hypoxia in vertebrate animals....... survival resides in concerted physiological responses, including strong metabolic depression, protection against oxidative damage and – in air breathing animals - redistribution of blood flow. Each of these responses is known to be tightly regulated by nitric oxide (NO) and during hypoxia by its metabolite...... nitrite. The aim of this review is to highlight recent work illustrating the widespread roles of NO and nitrite in the tolerance to extreme oxygen deprivation, in particular in the red-eared slider turtle and crucian carp, but also in diving marine mammals. The emerging picture underscores the importance...

  19. Role of hypoxia-induced anorexia and right ventricular hypertrophy on lactate transport and MCT expression in rat muscle.

    Science.gov (United States)

    Py, Guillaume; Eydoux, Nicolas; Lambert, Karen; Chapot, Rachel; Koulmann, Natahlie; Sanchez, Hervé; Bahi, Lahoucine; Peinnequin, André; Mercier, Jacques; Bigard, André-Xavier

    2005-05-01

    To dissect the independent effects of altitude-induced hypoxemia and anorexia on the capacity for cardiac lactate metabolism, we examined the effects of 21 days of chronic hypobaric hypoxia (CHH) and its associated decrease in food intake and right ventricle (RV) hypertrophy on the monocarboxylate transporter 1 and 4 (MCT) expression, the rate of lactate uptake into sarcolemmal vesicles, and the activity of lactate dehydrogenase isoforms in rat muscles. In comparison with control rats (C), 1 mmol/L lactate transport measured on skeletal muscle sarcolemmal vesicles increased by 33% and 58% in hypoxic (CHH, barometric pressure = 495 hPa) and rats pair-fed an equivalent quantity of food to that consumed by hypoxic animals, respectively. The increased lactate transport was higher in PF than in CHH animals ( P < .05). No associated change in the expression of MCT1 protein was observed in skeletal muscles, whereas MCT1 mRNA decreased in CHH rats, in comparison with C animals (42%, P < .05), partly related to caloric restriction (30%, P < .05). MCT4 mRNA and protein increased during acclimatization to hypoxia only in slow-oxidative muscles (68%, 72%, P < .05, respectively). The MCT4 protein content did not change in the plantaris muscle despite a decrease in transcript levels, related to hypoxia and caloric restriction. In both the left and right ventricles, the MCT1 protein content was unaffected by ambient hypoxia or restricted food consumption. These results suggest that MCT1 and MCT4 gene expression in fast-glycolytic muscles is mainly regulated by posttranscriptional mechanisms. Moreover, the results emphasize the role played by caloric restriction on the control of gene expression in response to chronic hypoxia and suggest that hypoxia-induced right ventricle hypertrophy failed to alter MCT proteins.

  20. The von Hippel-Lindau Chuvash mutation in mice causes carotid-body hyperplasia and enhanced ventilatory sensitivity to hypoxia.

    Science.gov (United States)

    Slingo, Mary E; Turner, Philip J; Christian, Helen C; Buckler, Keith J; Robbins, Peter A

    2014-04-01

    The hypoxia-inducible factor (HIF) family of transcription factors coordinates diverse cellular and systemic responses to hypoxia. Chuvash polycythemia (CP) is an autosomal recessive disorder in humans in which there is impaired oxygen-dependent degradation of HIF, resulting in long-term systemic elevation of HIF levels at normal oxygen tensions. CP patients demonstrate the characteristic features of ventilatory acclimatization to hypoxia, namely, an elevated baseline ventilation and enhanced acute hypoxic ventilatory response (AHVR). We investigated the ventilatory and carotid-body phenotype of a mouse model of CP, using whole-body plethysmography, immunohistochemistry, and electron microscopy. In keeping with studies in humans, CP mice had elevated ventilation in euoxia and a significantly exaggerated AHVR when exposed to 10% oxygen, with or without the addition of 3% carbon dioxide. Carotid-body immunohistochemistry demonstrated marked hyperplasia of the oxygen-sensing type I cells, and the cells themselves appeared enlarged with more prominent nuclei. This hypertrophy was confirmed by electron microscopy, which also revealed that the type I cells contained an increased number of mitochondria, enlarged dense-cored vesicles, and markedly expanded rough endoplasmic reticulum. The morphological and ultrastructural changes seen in the CP mouse carotid body are strikingly similar to those observed in animals exposed to chronic hypoxia. Our study demonstrates that the HIF pathway plays a major role, not only in regulating both euoxic ventilatory control and the sensitivity of the response to hypoxia, but also in determining the morphology of the carotid body.

  1. An immunohistochemical study of the expression of the hypoxia markers Glut-1 and Ca-IX in canine sarcomas.

    Science.gov (United States)

    Abbondati, E; Del-Pozo, J; Hoather, T M; Constantino-Casas, F; Dobson, J M

    2013-11-01

    Tumor hypoxia has been associated with increased malignancy, likelihood of metastasis, and increased resistance to radiotherapy and chemotherapy in human medicine. Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor that is induced by tumor hypoxia and regulates the pathways involved in cellular response and adaptation to the hostile tumor microenvironment. HIF-1 induces transcription of different proteins, including Ca-IX and Glut-1, which are considered endogenous markers of chronic hypoxia in solid tumors in humans. In this study, sections from 40 canine sarcomas (20 histiocytic sarcomas and 20 low-grade soft-tissue sarcomas) were immunostained for these markers. Expression of Glut-1 was scored based on percentage of positive staining cells (0 = 50%) and intensity of cellular staining (1 = weak; 2 = strong); Ca-IX was scored based on percentage of positive cells (0 = 30%). Intratumoral microvessel density was measured using CD31 to assess intratumoral neoangiogenesis. Histiocytic sarcomas showed statistically significant higher Glut-1 immunoreactivity and angiogenesis than did low-grade soft-tissue sarcomas. Intratumoral microvessel density in histiocytic sarcomas was positively associated with Glut-1 immunoreactivity score. These findings suggest a potential role of hypoxia in the biology of these tumors and may provide a base for investigation of the potential prognostic use of these markers in naturally occurring canine tumors.

  2. Shuttle-Run Sprint Training in Hypoxia for Youth Elite Soccer Players: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Hannes Gatterer

    2014-12-01

    Full Text Available The purposes of the present study were to investigate if a shuttle-run sprint training performed in a normobaric hypoxia chamber of limited size (4.75x2.25m is feasible, in terms of producing the same absolute training load, when compared to training in normoxia, and b if such training improves the repeated sprint ability (RSA and the Yo-Yo intermittent recovery (YYIR test outcome in young elite soccer players. Players of an elite soccer training Centre (age: 15.3 ± 0.5 years, height: 1.73 ± 0.07 m, body mass: 62.6 ± 6.6 kg were randomly assigned to a hypoxia or a normoxia training group. Within a 5-week period, players, who were not informed about the hypoxia intervention, performed at least 7 sessions of identical shuttle-run sprint training either in a normal training room (FiO2 = 20.95% or in a hypoxic chamber (FiO2 = 14.8%; approximately 3300m, both equipped with the same floor. Each training session comprised 3 series of 5x10s back and forth sprints (4.5m performed at maximal intensity. Recovery time between repetitions was 20s and between series 5min. Before and after the training period the RSA (6 x 40m shuttle sprint with 20 s rest between shuttles and the YYIR test were performed. The size of the chamber did not restrict the training intensity of the sprint training (both groups performed approximately 8 shuttles during 10s. Training in hypoxia resulted in a lower fatigue slope which indicates better running speed maintenance during the RSA test (p = 0.024. YYIR performance increased over time (p = 0.045 without differences between groups (p > 0.05. This study showed that training intensity of the shuttle-run sprint training was not restricted in a hypoxic chamber of limited size which indicates that such training is feasible. Furthermore, hypoxia compared to normoxia training reduced the fatigue slope during the RSA test in youth soccer players.

  3. Measuring and monitoring eutrophication and hypoxia

    Digital Repository Service at National Institute of Oceanography (India)

    Naqvi, S.W.A.; Heidemeier, J.

    stream_size 16126 stream_content_type text/plain stream_name Hypoxia_Nutrient_Reduct_Coast_Zone_2011_27.pdf.txt stream_source_info Hypoxia_Nutrient_Reduct_Coast_Zone_2011_27.pdf.txt Content-Encoding UTF-8 Content-Type text... by legal (individual licensing stipulating requirement or restrictions) and technical measures (building or upgrading of treatment plants, changing production practices). In many highly susceptible areas, such as the Bay of Bengal and Andaman Sea...

  4. Mild hypoxia in vivo regulates cardioprotective SUR2A: A role for Akt and LDH.

    Science.gov (United States)

    Mohammed Abdul, Khaja Shameem; Jovanović, Sofija; Du, Qingyou; Sukhodub, Andriy; Jovanović, Aleksandar

    2015-05-01

    High-altitude residents have lower mortality rates for ischaemic heart disease and this is ascribed to cardiac gene remodelling by chronic hypoxia. SUR2A is a cardioprotective ABC protein serving as a subunit of sarcolemmal ATP-sensitive K(+) channels. The purpose of this study was to determine whether SUR2A is regulated by mild hypoxia in vivo and to elucidate the underlying mechanism. Mice were exposed to either 21% (control) or 18% (mild hypoxia) oxygen for 24h. Exposure to 18% oxygen did not affect partial pressure of O(2) (PO(2)) and CO(2) (PCO(2)) in the blood, haematocrit or level of ATP in the heart. However, hypoxia increased myocardial lactate dehydrogenase (LDH) and lactate as well as NAD(+) without affecting total NAD. SUR2A levels were significantly increased as well as myocardial resistance to ischaemia-reperfusion. Exposure to 18% oxygen did not phosphorylate extracellular signal regulated kinases (ERK1/2) or AMP activated protein kinase (AMPK), but it phosphorylated protein kinase B (Akt). An inhibitor of phosphoinositide 3-kinases (PI3K), LY294002 (0.2mg/mouse), abolished all observed effects of hypoxia. LDH inhibitors, galloflavin (50 μM) and sodium oxamate (80 mM) significantly decreased levels of SUR2A in heart embryonic H9c2 cells, while inactive mutant LDH form, gly193-M-LDH increased cellular sensitivity towards stress induced by 2,4-dinitrophenol (10mM). Treatment of H9c2 cells with sodium lactate (30 mM) increased intracellular lactate, but did not affect LDH activity or SUR2A levels. We conclude that PI3K/Akt signalling pathway and LDH play a crucial role in increase of cardiac SUR2A induced by in vivo exposure to 18% oxygen.

  5. Analysis of liver stiffness measurement in chronic hepatitis B patients with persistently normal ALT and persistently or intermittently elevated ALT%ALT持续正常及持续或间断升高的慢性乙型肝炎患者肝脏硬度值分析

    Institute of Scientific and Technical Information of China (English)

    钟曼华; 梁携儿; 陈永鹏; 杨淑玲; 彭劼; 谭文娟; 于文轩; 孙剑

    2014-01-01

    目的:目前ALT持续正常(PNALT)以及持续或间断升高(PIEALT)的慢性乙型肝炎(CHB)患者肝脏硬度值(LSM)的数据十分有限。本研究对该组患者LSM范围及其影响因素进行了探讨,以供临床应用参考。方法将在2012年9月-2013年3月于本院就诊的208例初治CHB患者纳入研究,均接受瞬时弹性扫描仪(FS)检查。PNALT组:在最近1 a随访至少3次,每次间隔2个月以上,ALT水平均正常,入组时ALT正常;PIEALT组进一步分为ALT轻度升高(过去1 a随访中ALT水平至少有1次升高但<2×ULN)以及ALT明显升高(过去1 a随访中ALT水平至少有1次升高>2×ULN),入组时ALT<2×ULN。根据现有的研究结果,当ALT<2×ULN时,用于诊断以及排除进展性肝纤维化的标准分别为LSM≥10.6 kPa和LSM<7.4 kPa。计量资料分析采用t检验、方差分析和秩和检验,计数资料采用χ2检验,相关因素采用双变量相关分析及Logistic回归分析。结果受试人群平均LSM为(6.2±2.9) kPa。在PNALT患者中,LSM≥7.4 kPa占14.3%(18/126),LSM≥10.6 kPa占2.4%(3/126)。在总体PIEALT患者中,这个比例分别是35.4%(29/82)以及13.4%(11/82)。多元回归分析中,ALT>1×ULN(OR=2.63,P=0.037)、男性(OR=5.29,P=0.012)是LSM≥7.4 kPa的独立影响因素;HBV DNA定量>5 log10拷贝/ml是LSM≥10.6 kPa唯一的独立影响因素(OR=13.84,P=0.046)。结论在PIEALT和PNALT的CHB患者中,分别有35%及14%的患者不能排除进展性肝纤维化的可能;大约13%的PIEALT患者根据LSM结果可判断为进展性肝纤维化。对于ALT>1×ULN、HBV DNA拷贝数的对数值大于5的男性CHB患者,建议对其进行密切随访。%Objective Data on liver stiffness measurement (LSM)in chronic hepatitis B (CHB)patients with persistently normal alanine amin-otransferase (ALT

  6. Intermittent hypoxic exposure does not improve sleep at 4300 m.

    Science.gov (United States)

    Jones, Juli E; Muza, Stephen R; Fulco, Charles S; Beidleman, Beth A; Tapia, Michael L; Cymerman, Allen

    2008-01-01

    The purpose of this study was to determine in sea-level residents if 6 to 7 consecutive days of normobaric intermittent hypoxic exposure (IHE) (hypoxia room: 2-h ambient PO2=90 mmHg sedentary and 1-h ambient PO2=110 mmHg exercising at 80+/-5% of maximum heart rate) improved sleep quality (awakenings per hour) and quantity at altitude (4300 m). We hypothesized that IHE would improve sleep arterial oxygen saturation (SaO2) levels and decrease desaturation events, thereby contributing to improvements in sleep quality and quantity during subsequent exposure to high altitude. Ten sea-level residents (mean+/-SE: 22+/-1 yr, 179+/-2 cm, 79+/-3 kg) were assigned to an IHE group and six to a SHAM group (20+/-0.5 yr, 180+/-3 cm, 77+/-4 kg). Sleep quantity, SaO2, and heart rate (HR) were monitored at sea level and during high altitude (i.e., 4300 m in a hypobaric chamber) before pretest (PRE-T) and 60 h after posttest (POST-T) for the last IHE or SHAM treatment. Over the 6 to 7 days of IHE, resting SaO2 increased from 75+/-1% to 81+/-3% in the IHE group, while the SHAM group remained at 98+/-1%. From PRE-T to POST-T at 4300-m exposure, both the IHE and SHAM groups had significantly higher sleep SaO2, fewer desaturation events per hour, and an increase in the percentage of time asleep while sleeping (sleep percent). The IHE group, but not the SHAM group, had significantly lower sleep HR and a trend to more awakenings during the POST-T 4300-m exposure. These results indicate that although IHE treatment induced significant ventilatory acclimatization, relative to the SHAM group, IHE did not further improve sleep SaO2 quality and quantity following rapid ascent to 4300 m. Rather, it is likely that the acquired ventilatory acclimatization was lost in the 60 h between the last IHE session and the POST-T altitude exposure.

  7. Steroids for Chronic Inflammatory Demyelinating Polyneuropathy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-03-01

    Full Text Available The efficacy and safety of high-dose, intermittent IV methylprednisolone (IVMP as initial and long-term maintenance therapy for chronic inflammatory demyelinating polyneuropathy (CIDP were analyzed by a retrospective review of outcome data derived from patients’ medical records between 1992 and 2003 at Washington University School of Medicine, St Louis, MO.

  8. Body temperature regulation during acclimation to cold and hypoxia in rats.

    Science.gov (United States)

    Cadena, V; Tattersall, G J

    2014-12-01

    Extreme environmental conditions present challenges for thermoregulation in homoeothermic organisms such as mammals. Such challenges are exacerbated when two stressors are experienced simultaneously and each stimulus evokes opposing physiological responses. This is the case of cold, which induces an increase in thermogenesis, and hypoxia, which suppresses metabolism conserving oxygen and preventing hypoxaemia. As an initial approach to understanding the thermoregulatory responses to cold and hypoxia in a small mammal, we explored the effects of acclimation to these two stressors on the body temperature (Tb) and the daily and ultradian Tb variations of Sprague-Dawley rats. As Tb is influenced by sleep-wake cycles, these Tb variations reflect underlying adjustments in set-point and thermosensitivity. The Tb of rats decreased precipitously during initial hypoxic exposure which was more pronounced in cold (Tb=33.4 ± 0.13) than in room temperature (Tb=35.74 ± 0.17) conditions. This decline was followed by an increase in Tb stabilising at a new level ~0.5°C and ~1.4°C below normoxic values at room and cold temperatures, respectively. Daily Tb variations were blunted during hypoxia with a greater effect in the cold. Ultradian Tb variations exhibited daily rhythmicity that disappeared under hypoxia, independent of ambient temperature. The adjustments in Tb during hypoxia and/or cold are in agreement with the hypothesis that an initial decrease in the Tb set-point is followed by its partial re-establishment with chronic hypoxia. This rebound of the Tb set-point might reflect cellular adjustments that would allow animals to better deal with low oxygen conditions, diminishing the drive for a lower Tb set-point. Cold and hypoxia are characteristic of high altitude environments. Understanding how mammals cope with changes in oxygen and temperature will shed light into their ability to colonize new environments along altitudinal clines and increase our understanding of how

  9. Significant molecular and systemic adaptations after repeated sprint training in hypoxia.

    Directory of Open Access Journals (Sweden)

    Raphael Faiss

    Full Text Available While intermittent hypoxic training (IHT has been reported to evoke cellular responses via hypoxia inducible factors (HIFs but without substantial performance benefits in endurance athletes, we hypothesized that repeated sprint training in hypoxia could enhance repeated sprint ability (RSA performed in normoxia via improved glycolysis and O(2 utilization. 40 trained subjects completed 8 cycling repeated sprint sessions in hypoxia (RSH, 3000 m or normoxia (RSN, 485 m. Before (Pre- and after (Post- training, muscular levels of selected mRNAs were analyzed from resting muscle biopsies and RSA tested until exhaustion (10-s sprint, work-to-rest ratio 1:2 with muscle perfusion assessed by near-infrared spectroscopy. From Pre- to Post-, the average power output of all sprints in RSA was increased (p<0.01 to the same extent (6% vs 7%, NS in RSH and in RSN but the number of sprints to exhaustion was increased in RSH (9.4±4.8 vs. 13.0±6.2 sprints, p<0.01 but not in RSN (9.3±4.2 vs. 8.9±3.5. mRNA concentrations of HIF-1α (+55%, carbonic anhydrase III (+35% and monocarboxylate transporter-4 (+20% were augmented (p<0.05 whereas mitochondrial transcription factor A (-40%, peroxisome proliferator-activated receptor gamma coactivator 1α (-23% and monocarboxylate transporter-1 (-36% were decreased (p<0.01 in RSH only. Besides, the changes in total hemoglobin variations (Δ[tHb] during sprints throughout RSA test increased to a greater extent (p<0.01 in RSH. Our findings show larger improvement in repeated sprint performance in RSH than in RSN with significant molecular adaptations and larger blood perfusion variations in active muscles.

  10. Hypoxia tolerance and partitioning of bimodal respiration in the striped catfish (Pangasianodon hypophthalmus).

    Science.gov (United States)

    Lefevre, Sjannie; Huong, Do Thi Thanh; Wang, Tobias; Phuong, Nguyen Thanh; Bayley, Mark

    2011-02-01

    Air-breathing fish are common in the tropics, and their importance in Asian aquaculture is increasing, but the respiratory physiology of some of the key species such as the striped catfish, Pangasianodon hypophthalmus Sauvage 1878 is unstudied. P. hypophthalmus is an interesting species as it appears to possess both well-developed gills and a modified swim bladder that functions as an air-breathing organ indicating a high capacity for both aquatic and aerial respiration. Using newly developed bimodal intermittent-closed respirometry, the partitioning of oxygen consumption in normoxia and hypoxia was investigated in P. hypophthalmus. In addition the capacity for aquatic breathing was studied through measurements of oxygen consumption when access to air was denied, both in normoxia and hypoxia, and the critical oxygen tension, Pcrit, was also determined during these experiments. Finally, gill ventilation and air-breathing frequency were measured in a separate experiment with pressure measurements from the buccal cavity. The data showed that P. hypophthalmus is able to maintain standard metabolic rate (SMR) through aquatic breathing alone in normoxia, but that air-breathing is important during hypoxia. Gill ventilation was reduced during air-breathing, which occurred at oxygen levels below 8 kPa, coinciding with the measured Pcrit of 7.7 kPa. The findings in this study indicate that the introduction of aeration into the aquaculture of P. hypophthalmus could potentially reduce the need to air-breathe. The possibility of reducing air-breathing frequency may be energetically beneficial for the fish, leaving more of the aerobic scope for growth and other activities, due to the proposed energetic costs of surfacing behavior.

  11. UNSTEADY INTERMITTENT FLOW IN A ROTATING CURVED PIPE

    Institute of Scientific and Technical Information of China (English)

    YIN Jian-an; SHEN Xin-rong; CHEN Hua-jun; ZHANG Ben-zhao

    2004-01-01

    The effects of rotation and intermittent fre quency on the flow transition of secondary flow and, main flow were examined in detail. Certain hitherto unknown flow patterns were found. A numerical study was performed to study the characteristics of unsteady intermittent flow in a rotating curved pipe. Due to the rotation, both the Coriolis force and the centrifugal force could contribute to the unsteady intermittent flow and some complicated phenomena can be found. The results indicate that the unsteady intermittent flow are mainly characterized by five parameters: the Dean number Dn , the curvatureκ, the maximal force ratio F (of the Coriolis force to the centrifugal force in a cycle), the intermittent frequency parameter η(the ratio of a pulslating time to the cycle period), and the Womersley number α. Present works shows the natures of the unsteady intermittent flow in a rotating curved pipe.

  12. Infiltration Effects on Residential Pollutant Concentrations for Continuous and Intermittent Mechanical Ventilation Approaches

    Energy Technology Data Exchange (ETDEWEB)

    Sherman, Max; Logue, Jennifer; Singer, Brett

    2010-06-01

    The prevailing residential ventilation standard in North America, American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) Standard 62.2, specifies volumetric airflow requirements as a function of the overall size of the home and the number of bedrooms, assumes a fixed, minimal amount of infiltration, and requires mechanical ventilation to achieve the remainder. The standard allows for infiltration credits and intermittent ventilation patterns that can be shown to provide comparable performance. Whole-house ventilation methods have a substantial effect on time-varying indoor pollutant concentrations. If alternatives specified by Standard 62.2, such as intermittent ventilation, are used, short-term pollutant concentrations could exceed acute health standards even if chronic health standards are met.The authors present a methodology for comparing ASHRAE- and non-ASHRAE-specified ventilation scenarios on relative indoor pollutant concentrations. We use numerical modeling to compare the maximum time-averaged concentrations for acute exposure relevant (1-hour, 8-hour, 24-hour ) and chronic exposure relevant (1-year) time periods for four different ventilation scenarios in six climates with a range of normalized leakage values. The results suggest that long-term concentrations are the most important metric for assessing the effectiveness of whole-house ventilation systems in meeting exposure standards and that, if chronic health exposure standards are met, acute standards will also be met.

  13. Clinical investigation of surgery for intermittent exotropia

    Institute of Scientific and Technical Information of China (English)

    Chong-qing YANG; Ye SHEN; Yang-shun GU; Wei HAN

    2008-01-01

    Objective: To investigate the time and postoperative binocular vision of strabismus surgery for children with intermittent exotropia (X (T)). Methods: A retrospective investigation was conducted in 80 child patients with intermittent exotropia. Pre- and postoperative angles of deviation fixating at near (33cm) and distant targets (6m) were measured with the prolonged alternate cover testing. The binocular function was assessed with synoptophore. Twenty-one patients took the postoperative synoptophore exercise. Results: (1) A week after surgery, 96.2% of the 80 patients had binocular normotopia, while a year after surgery, 91.3% of the 80 patients had binocular normotopia; (2) Preoperatively, 58 patients had near stereoacuity, while postoperatively, 72 patients achieved near stereoacuity (P<0.05); (3) Preoperatively, 64 patients had Grade I for the synoptophore evaluation and postoperatively, 76 patients achieved Grade I. Meanwhile, 55 patients had Grade Ⅱpreoperatively and 72 achieved Grade Ⅱ postoperatively. For Grade Ⅲ, there were 49 patients preoperatively and 64 patients postoperatively (P<0.05); (4) Patients of 5~8 years old had a significantly better recovery rate of binocular vision than those of 9~18 years old (P<0.05); (5)Patients taking postoperative synoptophore exercise had a better binocular vision than those taking no exercise (P<0.05). Conclusions: (1) Strabismus surgery can help to preserve or restore the binocular vision for intermittent exotropia; (2) Receiving the surgery at young ages may develop better postoperative binocular vision; (3) The postoperative synoptophore exercise can help to restore the binocular vision.

  14. Hovering and intermittent flight in birds

    Energy Technology Data Exchange (ETDEWEB)

    Tobalske, Bret W, E-mail: bret.tobalske@mso.umt.ed [Field Research Station at Fort Missoula, Division of Biological Sciences, University of Montana, Missoula, MT 59812 (United States)

    2010-12-15

    Two styles of bird locomotion, hovering and intermittent flight, have great potential to inform future development of autonomous flying vehicles. Hummingbirds are the smallest flying vertebrates, and they are the only birds that can sustain hovering. Their ability to hover is due to their small size, high wingbeat frequency, relatively large margin of mass-specific power available for flight and a suite of anatomical features that include proportionally massive major flight muscles (pectoralis and supracoracoideus) and wing anatomy that enables them to leave their wings extended yet turned over (supinated) during upstroke so that they can generate lift to support their weight. Hummingbirds generate three times more lift during downstroke compared with upstroke, with the disparity due to wing twist during upstroke. Much like insects, hummingbirds exploit unsteady mechanisms during hovering including delayed stall during wing translation that is manifest as a leading-edge vortex (LEV) on the wing and rotational circulation at the end of each half stroke. Intermittent flight is common in small- and medium-sized birds and consists of pauses during which the wings are flexed (bound) or extended (glide). Flap-bounding appears to be an energy-saving style when flying relatively fast, with the production of lift by the body and tail critical to this saving. Flap-gliding is thought to be less costly than continuous flapping during flight at most speeds. Some species are known to shift from flap-gliding at slow speeds to flap-bounding at fast speeds, but there is an upper size limit for the ability to bound ({approx}0.3 kg) and small birds with rounded wings do not use intermittent glides.

  15. Acute intermittent porphyria in the puerperium

    Directory of Open Access Journals (Sweden)

    Sparić Radmila

    2010-01-01

    Full Text Available Introduction. Acute intermittent porphyria emerges as a result of partial defect of porphobilinogen deaminase and is manifested by repeated episodes of somatic, psychiatric and neurological disorders. The disease is conducted via the autosomaldominant gene of variable penetration, so most of the carriers never experience seizures. Timely making of diagnosis, screening of blood relatives of the patient and education of patients on avoidance of provoking factors are the key to adequate treatment. Case Outline. A 23-year-old patient having born the third child was hospitalized due to pains in the abdomen and convulsive seizures nine days after the vaginal delivery. At admittance, she suffered a generalized convulsive seizure of clonic-tonic type. The patient immediately underwent a complete clinical, laboratory, bacteriological and ultrasound examination. Bearing in mind the fact that the patient had several convulsive seizures even after the given neurological therapy, haem-arginate was introduced into therapy during four days. The administration of haem-arginate led to the normalization of blood pressure, pulse and bowel function. The administration of haem-arginate led to the normalization of blood pressure, pulse and bowel function. The patient was treated by a team of doctors, in the intensive care ward, with the use of medicaments, which are allowed in the case of acute porphyria. Sixteen days after the admittance, with clean neurological status and gynaecological and ultra-sound findings, she was released for ambulatory treatment. Conclusion. The presented case exhibits the gravity of making a diagnosis of acute intermittent porphyria in puerperium and the necessity of multi-disciplinary approach in treating this disease. Acute intermittent porphyria should be considered in cases of ambiguous abdominal pain, as well as in patients having abdominal pains followed by neuro-psychiatric disorders.

  16. Frequently asked questions in hypoxia research

    Directory of Open Access Journals (Sweden)

    Wenger RH

    2015-09-01

    Full Text Available Roland H Wenger,1,2 Vartan Kurtcuoglu,1,2 Carsten C Scholz,1,2 Hugo H Marti,3 David Hoogewijs1,2,4 1Institute of Physiology and Zurich Center for Human Physiology (ZIHP, University of Zurich, 2National Center of Competence in Research “Kidney.CH”, Zurich, Switzerland; 3Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, 4Institute of Physiology, University of Duisburg-Essen, Essen, Germany Abstract: “What is the O2 concentration in a normoxic cell culture incubator?” This and other frequently asked questions in hypoxia research will be answered in this review. Our intention is to give a simple introduction to the physics of gases that would be helpful for newcomers to the field of hypoxia research. We will provide background knowledge about questions often asked, but without straightforward answers. What is O2 concentration, and what is O2 partial pressure? What is normoxia, and what is hypoxia? How much O2 is experienced by a cell residing in a culture dish in vitro vs in a tissue in vivo? By the way, the O2 concentration in a normoxic incubator is 18.6%, rather than 20.9% or 20%, as commonly stated in research publications. And this is strictly only valid for incubators at sea level. Keywords: gas laws, hypoxia-inducible factor, Krogh tissue cylinder, oxygen diffusion, partial pressure, tissue oxygen levels

  17. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Nicole Horrée

    2007-01-01

    Full Text Available Background: Hypoxia-inducible factor 1α (HIF-1α plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. Methods: Expression of HIF-1α and proteins in the HIF-1α pathway (Glut-1, CAIX, VEGF in paraffin-embedded specimens of normal (n = 17, premalignant (n = 17 and endometrioid endometrial carcinoma (n = 39 was explored by immunohistochemistry, in relation to microvessel density (MVD. Results: HIF-1α overexpression was absent in inactive endometrium but present in hyperplasia (61% and carcinoma (87%, with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium, in contrast with expression in hyperplasia (Glut-1 0%, CAIX 61%, only focal and diffuse and carcinoma (Glut-1 94.6%, CAIX 92%, both mostly perinecrotically. Diffuse HIF-1α was accompanied by activation of downstream targets. VEGF was significantly higher expressed in hyperplasias and carcinomas compared to inactive endometrium. MVD was higher in hyperplasias and carcinomas than in normal endometrium (p < 0.001. Conclusion: HIF-1α and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1α in endometrial carcinogenesis.

  18. Hypoxia, HIF-1 Regulation and Cancer Therapy

    NARCIS (Netherlands)

    Groot, A.J.

    2008-01-01

    Oxygen insufficiency (hypoxia) is a common feature of human cancer and associated with tumor aggressiveness and poor clinical outcome. Furthermore, hypoxic tumors are more resistant to ionizing radiation and chemotherapy contributing to their unfavorable prognosis. The oxygen sensing pathway is cont

  19. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M;

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...... experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O2 in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U.l-1, post-hypoxia 10.24 (SEM 0.95) U.l-1, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO2...... (10% Co2 with 10% O2) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVA P > 0.05). Hypocapnic normoxia, produced...

  20. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M;

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...... exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVA P = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other...... experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O2 in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U.l-1, post-hypoxia 10.24 (SEM 0.95) U.l-1, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO2...

  1. Intermittent Microwave Drying of Wheat (Triticum aestivum L.) Seeds

    OpenAIRE

    Yan Li; Tao Zhang; Chenglai Wu; Chunqing Zhang

    2014-01-01

    The purpose of present study was to characterize the intermittent microwave drying of wheat seeds. Results revealed that microwave on time percentage (MOTP) and initial moisture content were the main parameters which influenced the intermittent microwave drying rate and the germination capacity of dried seeds. Best intermittent microwave drying (power: 800 W; seed sample weight: 100 g, microwave on time in each cycle: 32 s) without significantly decreasing the germination rate was...

  2. Long term and transitional intermittent smokers: a longitudinal study.

    OpenAIRE

    Lindström, Martin; Isacsson, Sven-Olof

    2002-01-01

    Objective: To investigate differences in snuff consumption, sociodemographic and psychosocial characteristics between baseline intermittent smokers that had become daily smokers, stopped smoking or remained intermittent smokers at the one year follow up. Design/setting/participants/measurements: A population of 12 507 individuals interviewed at baseline in 1992-94 and at a one year follow up, aged 45-69 years, was investigated in a longitudinal study. The three groups of baseline intermittent...

  3. Intermittent fasting: a "new" historical strategy for controlling seizures?

    Science.gov (United States)

    Hartman, Adam L; Rubenstein, James E; Kossoff, Eric H

    2013-05-01

    In antiquity, fasting was a treatment for epilepsy and a rationale for the ketogenic diet (KD). Preclinical data indicate the KD and intermittent fasting do not share identical anticonvulsant mechanisms. We implemented an intermittent fasting regimen in six children with an incomplete response to a KD. Three patients adhered to the combined intermittent fasting/KD regimen for 2 months and four had transient improvement in seizure control, albeit with some hunger-related adverse reactions.

  4. The hypoxia signaling pathway and hypoxic adaptation in fishes.

    Science.gov (United States)

    Xiao, Wuhan

    2015-02-01

    The hypoxia signaling pathway is an evolutionarily conserved cellular signaling pathway present in animals ranging from Caenorhabditis elegans to mammals. The pathway is crucial for oxygen homeostasis maintenance. Hypoxia-inducible factors (HIF-1α and HIF-2α) are master regulators in the hypoxia signaling pathway. Oxygen concentrations vary a lot in the aquatic environment. To deal with this, fishes have adapted and developed varying strategies for living in hypoxic conditions. Investigations into the strategies and mechanisms of hypoxia adaptation in fishes will allow us to understand fish speciation and breed hypoxia-tolerant fish species/strains. This review summarizes the process of the hypoxia signaling pathway and its regulation, as well as the mechanism of hypoxia adaptation in fishes.

  5. Physiological responses of three species of unionid mussels to intermittent exposure to elevated carbon dioxide

    Science.gov (United States)

    Hannan, Kelly D.; Jeffrey, Jennifer D.; Hasler, Caleb T.; Suski, Cory D.

    2016-01-01

    Freshwater systems are at risk owing to increasing carbon dioxide (CO2) levels, and one of the possible reasons for these elevations is the deployment of non-physical fish barriers to prevent invasive fish movements. Carbon dioxide barriers have the potential to create short, chronic and intermittent exposures of CO2 for surrounding freshwater biota. Although intermittent exposures to a stressor may be more ecologically relevant, the majority of laboratory tests use chronic or short-term time periods to determine how organisms will respond to an environmental stressor. Mea