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Sample records for chronic intermittent hypoxia

  1. Neural Control of Blood Pressure in Chronic Intermittent Hypoxia.

    Science.gov (United States)

    Shell, Brent; Faulk, Katelynn; Cunningham, J Thomas

    2016-03-01

    Sleep apnea (SA) is increasing in prevalence and is commonly comorbid with hypertension. Chronic intermittent hypoxia is used to model the arterial hypoxemia seen in SA, and through this paradigm, the mechanisms that underlie SA-induced hypertension are becoming clear. Cyclic hypoxic exposure during sleep chronically stimulates the carotid chemoreflexes, inducing sensory long-term facilitation, and drives sympathetic outflow from the hindbrain. The elevated sympathetic tone drives hypertension and renal sympathetic activity to the kidneys resulting in increased plasma renin activity and eventually angiotensin II (Ang II) peripherally. Upon waking, when respiration is normalized, the sympathetic activity does not diminish. This is partially because of adaptations leading to overactivation of the hindbrain regions controlling sympathetic outflow such as the nucleus tractus solitarius (NTS), and rostral ventrolateral medulla (RVLM). The sustained sympathetic activity is also due to enhanced synaptic signaling from the forebrain through the paraventricular nucleus (PVN). During the waking hours, when the chemoreceptors are not exposed to hypoxia, the forebrain circumventricular organs (CVOs) are stimulated by peripherally circulating Ang II from the elevated plasma renin activity. The CVOs and median preoptic nucleus chronically activate the PVN due to the Ang II signaling. All together, this leads to elevated nocturnal mean arterial pressure (MAP) as a response to hypoxemia, as well as inappropriately elevated diurnal MAP in response to maladaptations. PMID:26838032

  2. Respiratory plasticity in the behaving rat following chronic intermittent hypoxia.

    Science.gov (United States)

    Edge, Deirdre; Skelly, J Richard; Bradford, Aidan; O'Halloran, Ken D

    2010-01-01

    Chronic intermittent hypoxia (CIH), a feature of obstructive sleep apnoea (OSA) has been shown to have myriad effects on the respiratory control system. The effects on breathing are of great clinical significance for the sleep apnoea patient. We sought to determine the effect of CIH on normoxic ventilation. Both male and female adult Wistar rats were studied due to the evident sex difference in the prevalence of OSA. A role for oxidative stress in respiratory modifications was also explored. Adult male (n = 30) and female (n = 16) rats were exposed to alternating periods of N(2) and O(2) for 90 s each, bringing the ambient oxygen concentration to 5% at nadir (CIH) group. Sham groups were subject to cycles of air/air under identical experimental conditions. A subset of male rats (8 controls, 8 CIH) had free access to water containing 1 mM Tempol (SOD-mimetic) at all times. Treatments were carried out for 8 hours a day for 9 days. Following treatment, normoxic ventilation was assessed by whole body plethysmography in sleeping animals. Baseline normoxic ventilation was increased in both male and female treated rats but this did not achieve statistical significance. However, ventilatory drive (V(T)/Ti) was significantly increased in male rats. Chronic treatment with Tempol abolished this effect. Conversely, CIH had no significant effect on VT/Ti in female rats. Our results indicate subtle effects of intermittent hypoxia on breathing in conscious behaving rats. We speculate the increased ventilatory drive following CIH represents a form a neural plasticity - a ROS dependent phenomenon - with sexual dimorphism. PMID:20217363

  3. Gene expression and phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia

    OpenAIRE

    Fan, Chenhao; Iacobas, Dumitru A.; Zhou, Dan; Chen, Qiaofang; Lai, James K.; Gavrialov, Orit; Haddad, Gabriel G.

    2005-01-01

    Chronic constant hypoxia (CCH), such as in pulmonary diseases or high altitude, and chronic intermittent hypoxia (CIH), such as in sleep apnea, can lead to major changes in the heart. Molecular mechanisms underlying these cardiac alterations are not well understood. We hypothesized that changes in gene expression could help to delineate such mechanisms. The current study used a neonatal mouse model in CCH or CIH combined with cDNA microarrays to determine changes in gene expression in the CCH...

  4. Chronic intermittent hypoxia alters ventilatory and metabolic responses to acute hypoxia in rats.

    Science.gov (United States)

    Morgan, Barbara J; Adrian, Russell; Wang, Zun-Yi; Bates, Melissa L; Dopp, John M

    2016-05-15

    We determined the effects of chronic exposure to intermittent hypoxia (CIH) on chemoreflex control of ventilation in conscious animals. Adult male Sprague-Dawley rats were exposed to CIH [nadir oxygen saturation (SpO2), 75%; 15 events/h; 10 h/day] or normoxia (NORM) for 21 days. We assessed the following responses to acute, graded hypoxia before and after exposures: ventilation (V̇e, via barometric plethysmography), V̇o2 and V̇co2 (analysis of expired air), heart rate (HR), and SpO2 (pulse oximetry via neck collar). We quantified hypoxia-induced chemoreceptor sensitivity by calculating the stimulus-response relationship between SpO2 and the ventilatory equivalent for V̇co2 (linear regression). An additional aim was to determine whether CIH causes proliferation of carotid body glomus cells (using bromodeoxyuridine). CIH exposure increased the slope of the V̇e/V̇co2/SpO2 relationship and caused hyperventilation in normoxia. Bromodeoxyuridine staining was comparable in CIH and NORM. Thus our CIH paradigm augmented hypoxic chemosensitivity without causing glomus cell proliferation. PMID:26917692

  5. Diaphragm Muscle Remodeling in a Rat Model of Chronic Intermittent Hypoxia

    OpenAIRE

    Shortt, Christine M.; Fredsted, Anne; Bradford, Aidan; O’Halloran, Ken D.

    2013-01-01

    Respiratory muscle remodeling occurs in human sleep apnea—a common respiratory disorder characterized by chronic intermittent hypoxia (CIH) due to recurrent apnea during sleep. We sought to determine if CIH causes remodeling in rat sternohyoid (upper airway dilator) and diaphragm muscles. Adult male Wistar rats were exposed to CIH (n=8), consisting of 90 sec of hypoxia (5% at the nadir; SaO2 ~80%)/90 sec of normoxia, 8 hr per day, for 7 consecutive days. Sham animals (n=8) were exposed to alt...

  6. The impact of chronic intermittent hypoxia on hematopoiesis and the bone marrow microenvironment

    OpenAIRE

    Alvarez-Martins, Inês; Remédio, Leonor; Matias, Inês; Diogo, Lucília N; Monteiro, Emília C; Dias, Sérgio

    2016-01-01

    Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder which is associated with patient morbidity and an elevated risk of developing hypertension and cardiovascular diseases. There is ample evidence for the involvement of bone marrow (BM) cells in the pathophysiology of cardiovascular diseases but a connection between OSA and modulation of the BM microenvironment had not been established. Here, we studied how chronic intermittent hypoxia (CIH) affected hematopoie...

  7. Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus

    OpenAIRE

    Rukhadze, Irma; FENIK, Victor B.; Benincasa, Kate E.; Price, Andrea; Kubin, Leszek

    2010-01-01

    Rationale: Patients with obstructive sleep apnea (OSA) adapt to the anatomical vulnerability of their upper airway by generating increased activity in upper airway–dilating muscles during wakefulness. Norepinephrine (NE) and serotonin (5-HT) mediate, through α1-adrenergic and 5-HT2A receptors, a wake-related excitatory drive to upper airway motoneurons. In patients with OSA, this drive is necessary to maintain their upper airway open. We tested whether chronic intermittent hypoxia (CIH), a ma...

  8. Chronic Intermittent Hypoxia Induces 11Beta-Hydroxysteroid Dehydrogenase in Rat Heart

    Czech Academy of Sciences Publication Activity Database

    Klusoňová, Petra; Řeháková, Lenka; Borchert, Gudrun H.; Vagnerová, Karla; Neckář, Jan; Ergang, Peter; Mikšík, Ivan; Kolář, František; Pácha, Jiří

    2009-01-01

    Roč. 150, č. 9 (2009), s. 4270-4277. ISSN 0013-7227 R&D Projects: GA ČR(CZ) GA305/07/0328; GA ČR(CZ) GA305/07/0875; GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : heart * corticosteroids * chronic intermittent hypoxia Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.752, year: 2009

  9. CHRONIC INTERMITTENT HYPOXIA AFFECTS INTEGRATION OF SENSORY INPUT BY NEURONS IN THE NUCLEUS TRACTUS SOLITARII

    OpenAIRE

    Kline, David D.

    2010-01-01

    The autonomic nervous and respiratory systems, as well as their coupling, adapt over a wide range of conditions. Chronic intermittent hypoxia (CIH) is a model for recurrent apneas and induces alterations in breathing and increases in sympathetic nerve activity which may ultimately result in hypertension if left untreated. These alterations are believed to be due to increases in the carotid body chemoreflex pathway. Here we present evidence that the nucleus tractus solitarii (nTS), the central...

  10. Neuromolecular Mechanisms Mediating the Effects of Chronic Intermittent Hypoxia on Adrenal Medulla

    OpenAIRE

    Kumar, Ganesh K.; Nanduri, Jayasri; Peng, Ying-Jie; Prabhakar, Nanduri R.

    2015-01-01

    Sleep disordered breathing (SDB) with recurrent apnea is a major health problem affecting several million adult men and women. Humans with SDB are prone to develop hypertension. Studies on rodents established that exposure to chronic intermittent hypoxia (CIH) alone is sufficient to induce hypertension similar to that seen in patients with SDB. Available evidence from studies on experimental animals suggests that catecholamines secreted from adrenal medulla (AM), an end-organ of the sympathet...

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

    Directory of Open Access Journals (Sweden)

    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

  12. Sustained acclimatization in Chilean mine workers subjected to chronic intermittent hypoxia.

    Science.gov (United States)

    Farias, Jorge G; Osorio, Jorge; Soto, Gustavo; Brito, Julio; Siques, Patricia; Reyes, Juan G

    2006-01-01

    Farias, Jorge G., Jorge Osorio, Gustavo Soto, Julio Brito, Patricia Siques, and Juan G. Reyes. Sustained acclimatization in Chilean mine workers subjected to chronic intermittent hypoxia. High Alt. Med. Biol. 7:302-306, 2006--We wanted to know if sea-level mine workers exposed previously to chronic intermittent hypoxia reached a steady acclimatization at 36 months under hypobaric hypoxia. An intermittently exposed group of mine workers (IE, n = 25) were subjected to submaximal exercise (100 W) at 4500 m. Their systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and hemoglobin oxygen saturation (HbSatO(2)) were monitored. Two comparison groups of unacclimatized sea-level workers (n = 17) were studied. A nonexposed group (NE) performed 5 min of submaximal exercise at sea level. Some kind of exercise was performed both by an acutely exposed group (AE) and IE group at 4500 m. No statistical differences were found for HR, SBP, and DBP (p > 0.05) during exercise between IE and AE groups. Resting HbSatO(2) of IE (87 +/- 6%) was lower than NE (97 +/- 3%) (p < 0.05), but was higher than AE (82 +/- 4%) (p < 0.05). In the exercise condition, HbSatO(2) of IE (85 +/- 5%) was lower than NE (95 +/- 3%) (p < 0.05), but was higher than AE (76 +/- 2%) (p < 0.05). These responses were maintained through the 6 months of the study period. Thus, mine workers subjected to intermittent hypobaric condition for 3 years showed a good degree of acclimatization that was maintained through time. PMID:17173515

  13. The effects of acute intermittent hypoxia on cardiovascular parameters in normotensive and chronic hypobaric hypoxia-induced hypertensive rabbits.

    Science.gov (United States)

    Yaman, Muhittin O; Guner, Ibrahim; Uzun, Hafize; Sahin, Gulderen; Yelmen, Nermin

    2014-01-01

    The effects of both chronic hypoxia and acute intermittent hypoxia (AIH) on cardiovascular system are unclear. We designed this study to develop a rabbit model of hypertension by exposure to chronic hypobaric hypoxia (CHH) and to investigate the effects of AIH on hypertensive rabbits. Present study was performed in 13 albino rabbits that divided into CHH and control groups. To develop hypertension, the rabbits were placed in a hypobaric chamber (390 mmHg; 22 hours/day, 30 days). Afterwards, AIH protocol was applied (8% FIO2 (Fraction of Inspired Oxygen) 1 min + 5 min normoxia, 20 cycles, 2 hours) to rabbits anesthetized with urethane and alpha-chloralose. Mean arterial pressure (MAP), heart rate (HR) and hematocrit values have been determined. Also asymmetric dimethylarginine (ADMA), endothelial nitric oxide synthase (eNOS), endothelin-1 and norepinephrine values have been analyzed in blood. We developed a model of hypertension in rabbits via exposure to severe CHH and we believe that ADMA is an important parameter in the development and permanence of CHH-induced hypertension. The main finding of this sudy was the depressor effect of AIH on blood pressure and heart rate in CHH- induced hypertension model. Finally, we believe that AIH protocol may be applicable for prevention and treatment of hypertension if properly developed. PMID:24448370

  14. Neuromolecular mechanisms mediating the effects of chronic intermittent hypoxia on adrenal medulla.

    Science.gov (United States)

    Kumar, Ganesh K; Nanduri, Jayasri; Peng, Ying-Jie; Prabhakar, Nanduri R

    2015-04-01

    Sleep disordered breathing (SDB) with recurrent apnea is a major health problem affecting several million adult men and women. Humans with SDB are prone to develop hypertension. Studies on rodents established that exposure to chronic intermittent hypoxia (CIH) alone is sufficient to induce hypertension similar to that seen in patients with SDB. Available evidence from studies on experimental animals suggests that catecholamines secreted from adrenal medulla (AM), an end-organ of the sympathetic nervous system is a major contributor to CIH-induced hypertension. In this article, we present an overview of our current understanding on how CIH reconfigures AM function and highlight recent findings on the underlying cellular and molecular mechanisms. PMID:25583660

  15. Intermittent hypoxia and neurorehabilitation.

    Science.gov (United States)

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

    2015-12-15

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

  16. Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity

    OpenAIRE

    Gilmartin, G. S.; Lynch, M; Tamisier, R.; Weiss, J W

    2010-01-01

    Chronic intermittent hypoxia (CIH) is thought to be responsible for the cardiovascular disease associated with obstructive sleep apnea (OSA). Increased sympathetic activation, altered vascular function, and inflammation are all putative mechanisms. We recently reported (Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas RJ, Levy P, Weiss JW. J Appl Physiol 107: 17–24, 2009) a new model of CIH in healthy humans that is associated with both increases in blood pressure and augme...

  17. Chronic intermittent hypoxia activates nuclear factor-κB in cardiovascular tissues in vivo

    International Nuclear Information System (INIS)

    Obstructive sleep apnea (OSA) is an important risk factor for cardiovascular morbidity and mortality. The mechanisms through which OSA promotes the development of cardiovascular disease are poorly understood. In this study, we tested the hypotheses that chronic exposure to intermittent hypoxia and reoxygenation (CIH) is a major pathologic factor causing cardiovascular inflammation, and that CIH-induces cardiovascular inflammation and pathology by activating the NF-κB pathway. We demonstrated that exposure of mice to CIH activated NF-κB in cardiovascular tissues, and that OSA patients had markedly elevated monocyte NF-κB activity, which was significantly decreased when obstructive apneas and their resultant CIH were eliminated by nocturnal CPAP therapy. The elevated NF-κB activity induced by CIH is accompanied by and temporally correlated to the increased expression of iNOS protein, a putative and important NF-κB-dependent gene product. Thus, CIH-mediated NF-κB activation may be a molecular mechanism linking OSA and cardiovascular pathologies seen in OSA patients

  18. Chronic intermittent hypoxia creates the perfect storm with calamitous consequences for respiratory control.

    Science.gov (United States)

    O'Halloran, Ken D

    2016-06-01

    Obstructive sleep apnoea syndrome (OSAS) is a common respiratory disorder with devastating consequences for integrative body systems. A picture is emerging to illustrate wide-ranging deleterious consequences of disordered breathing during sleep for major homeostatic control systems, with considerable interest in cardiorespiratory and autonomic morbidity underpinning the development of hypertension. The vista is bleak when one also considers the link between OSAS and a host of other maladies. Exposure to chronic intermittent hypoxia (CIH), resulting from repeated obstructions of the pharyngeal airway, is a hallmark feature of OSAS that appears, in animal models, to drive the development and maintenance of several key morbidities. A growing body of evidence now points to aberrant respiratory plasticity at multiple levels following exposure to CIH. Herein, we review the experimental data revealing that CIH causes: respiratory muscle weakness and fatigue; impaired motor control of the upper airway; and, discordant respiratory rhythm and pattern generation. This multifaceted conspiracy creates the perfect storm with the potential to exacerbate OSAS-serving to establish an inescapable cycle of respiratory morbidity. Several pharmacological interventions in animal models appear wholly effective in preventing the calamitous consequences of CIH and may have application as adjunctive therapies in the treatment of OSAS. PMID:26528897

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

    Institute of Scientific and Technical Information of China (English)

    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.

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

    Institute of Scientific and Technical Information of China (English)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

    Institute of Scientific and Technical Information of China (English)

    Hui XIE; Wing-ho YUNG

    2012-01-01

    Obstructive sleep apnea (OSA) is well known for its metabolic as well as neurobehavioral consequences.Chronic intermittent hypoxia (IH) is a major component of OSA.In recent years,substantial advances have been made in elucidating the cellular and molecular mechanisms underlying the effect of chronic IH on neurocognitive functions,many of which are based on studies in animal models.A number of hypotheses have been put forward to explain chronic IH-induced neurological dysfunctions.Among these,the roles of oxidative stress and apoptosis-related neural injury are widely accepted.Here,focusing on results derived from animal studies,we highlight a possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH.The possible relationship between BDNF and previous findings on this subject will be elucidated.

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

    Institute of Scientific and Technical Information of China (English)

    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.

  4. Role of oxidative stress in PKC-delta upregulation and cardioprotection induced by chronic intermittent hypoxia

    Czech Academy of Sciences Publication Activity Database

    Kolář, František; Ježková, J.; Balková, P.; Břeh, J.; Neckář, Jan; Novák, F.; Nováková, O.; Tomášová, H.; Srbová, M.; Ošťádal, Bohuslav; Wilhelm, J.; Herget, J.

    2007-01-01

    Roč. 292, č. 1 (2007), H224-H230. ISSN 0363-6135 R&D Projects: GA ČR GA305/04/0465 Grant ostatní: GA UK(CZ) 153/2005/B-Bio/PrF Institutional research plan: CEZ:AV0Z50110509 Keywords : ischemia -reperfusion * protein kinase C * chronic hypoxia Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 3.973, year: 2007

  5. Role of protein kinases in chronic intermittent hypoxia-induced cardioprotection

    Czech Academy of Sciences Publication Activity Database

    Kolář, František; Novák, F.; Neckář, Jan; Nováková, O.; Ošťádal, Bohuslav; Musters, R.J.P.

    Hauppauge, N.Y : Nova Science, 2009 - (Xi, L.; Serebrovskaya, T.), s. 213-230 ISBN 978-1-60876-127-2 R&D Projects: GA ČR(CZ) GA305/07/0875; GA ČR(CZ) GP305/06/P372 Institutional research plan: CEZ:AV0Z50110509 Keywords : chronic hypoxia * cardioprotection * protein kinases Subject RIV: ED - Physiology

  6. Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory

    OpenAIRE

    Xu, Lin-Hao; Xie, Hui; Shi, Zhi-Hui; Du, Li-Da; Wing, Yun-Kwok; Li, Albert M.; Ke, Ya; Yung, Wing-Ho

    2015-01-01

    Aims: This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits. Results: Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12...

  7. Effect of chronic intermittent hypoxia on the reflex recruitment of the genioglossus during airway obstruction in the anesthetized rat.

    Science.gov (United States)

    Edge, Deirdre; McDonald, Fiona B; Jones, James F X; Bradford, Aidan; O'Halloran, Ken D

    2014-01-01

    We sought to test the hypothesis that chronic intermittent hypoxia (CIH)-a feature of sleep-disordered breathing in humans-impairs reflex recruitment of the genioglossus (GG, pharyngeal dilator) during obstructive airway events. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5% O2 at nadir) per hour, 8h a day for 7 days (CIH, N=7). The sham group (N=7) were exposed to normoxia in parallel. Following gas treatments, rats were anesthetized with an i.p. injection of urethane (1.5g/kg; 20%, w/v). Fine concentric needle electrodes were inserted into the GG and the costal diaphragm. Discriminated GG motor unit potentials and whole electromyograph (EMG), together with arterial blood pressure and arterial O2 saturation, were recorded during quiet basal breathing and during nasal airway occlusion. Airway occlusion significantly increased GG EMG activity in all animals; but there was no difference in the reflex response to airway occlusion between sham and CIH-treated animals (+105±22% vs. +105±17%, mean±SEM for area under the curve of integrated GG EMG, % increase from baseline, p=0.99). Occluded breaths were characterized by a significant increase in the firing frequency of phasically active units and the recruitment of large motor units that were quiescent under basal conditions. Though there are reports of impaired control of the upper airway following CIH in the rat, we conclude that reflexly evoked motor discharge to the GG is not affected by 7 days of CIH, a paradigm that we have shown increases apnea index in sleeping rats. PMID:24746047

  8. Changes in genioglossus and their association with serum adiponectin levels in rats subjected to chronic intermittent hypoxia

    Institute of Scientific and Technical Information of China (English)

    ZHANG Xiao-feng; WANG Ya-hui; LI Qin; ZHANG Xi-long; SHEN Jiu-cheng; LI Chong; LIU Hao

    2010-01-01

    Background The genioglossus (GG) is involved in the maintenance of an open airway for effective breathing.Although the pathogenesis of obstructive sleep apnea hypopnea syndrome (OSAHS) was closely associated with GG dysfunction,its causes and possible treatment have not been elucidated.The aim of the study was to investigate the effects of chronic intermittent hypoxia (CIH) on serum adiponectin levels, electromyograph (EMG) activity and ultrastructure of GG, as well as the effect of an adiponectin supplement in anesthetized rats.Methods Forty-two healthy male Wistar rats were randomly divided into normal control (A), CIH (B) and adiponectin treatment (C) groups, 14 rats in each group.CIH was performed eight hours per day for five weeks in both groups B and C.Group C received transvenous injection of adiponectin at the dosage of 10 μg per injection, twice a week for five weeks.At the end of the 5th week the GG EMG voltage was measured and compared among the three groups.Transmission electron microscope was used to observe the ultrastructure of the GG.Results CIH caused significant hypoadiponectinemia, weakened activity of GG EMG at both baseline and hypoxia stimulation, and induced ultrastructural pathological changes, such as, myofibril discontinuities, lysis of myofilament,edema of mitochondria and disruption of cristae, vacuolus and lysis of some mitochondria.Venous supplement of adiponectin improved the above pathological changes resulting from CIH.Conclusion CIH resulted in pathological changes in GG's EMG and ultrastructure, which could be improved by supplement of adiponectin and be associated with hypoadiponectinemia caused by ClH.

  9. Chronic intermittent hypoxia stimulates 11HSD2 in rat heart myocardium

    Czech Academy of Sciences Publication Activity Database

    Řeháková, Lenka; Klusoňová, Petra; Kolář, František; Borchert, Gudrun H.; Neckář, Jan; Pácha, Jiří

    Neuherberg : German Research Center for Environmental Health, 2008. P23-P23. [Workshop on Pre-receptor steroid metabolism as target for pharmacological treatment. 26.05.2008-28.05.2008, Neuherberg] R&D Projects: GA ČR(CZ) GA305/07/0328; GA ČR(CZ) GA305/07/0875 Institutional research plan: CEZ:AV0Z50110509 Keywords : spo2 * corticosteroids * hypoxia Subject RIV: ED - Physiology

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

    Institute of Scientific and Technical Information of China (English)

    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.

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

    Institute of Scientific and Technical Information of China (English)

    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

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

    Institute of Scientific and Technical Information of China (English)

    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.

  13. Glucoregulatory consequences and cardiorespiratory parameters in rats exposed to chronic-intermittent hypoxia: Effects of the duration of exposure and losartan

    Directory of Open Access Journals (Sweden)

    LeszekKubin

    2012-04-01

    Full Text Available Background: Obstructive sleep apnea (OSA is associated with glucose intolerance. Both chronic sleep disruption and recurrent blood oxygen desaturations (chronic-intermittent hypoxia – CIH may cause, or exacerbate, metabolic derangements. Methods: To assess the impact of CIH alone, without accompanying upper airway obstructions, on the counter-regulatory response to glucose load and cardiorespiratory parameters, we exposed adult male Sprague-Dawley rats to CIH or sham room air exchanges for 10 h/day for 7, 21 or 35 days and then, one day after conclusion of CIH exposure, conducted intravenous glucose tolerance tests (ivgtt under urethane anesthesia. Additional rats underwent 35 days of CIH followed by 35 days of regular housing, or had 35 day-long CIH exposure combined with daily administration of the type 1 angiotensin II receptor antagonist, losartan (15 mg/kg, p.o., and then were also subjected to ivgtt. Results: Compared with the corresponding control groups, CIH rats had progressively reduced glucose-stimulated insulin release and impaired glucose clearance, only mildly elevated heart rate and/or arterial blood pressure and slightly reduced respiratory rate. The differences in insulin release between the CIH and sham-treated rats disappeared in the rats normally housed for 35 days after 35 days of CIH/sham exposure. The losartan-treated rats had improved insulin sensitivity, with no evidence of suppressed insulin release in the CIH group. Conclusions: In adult rats, the glucose-stimulated insulin release is gradually suppressed with the duration of exposure to CIH, but the effect is reversible. Elimination of the detrimental effect of CIH on insulin release by losartan suggests that CIH disrupts glucoregulation through angiotensin/catecholaminergic pathways. Accordingly, treatment with continuous positive airway pressure may ameliorate pre-diabetic conditions in OSA patients, in part, by reducing sympathoexcitatory effects of recurrent

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

    Science.gov (United States)

    Julian, Guilherme Silva; de Oliveira, Renato Watanabe; Favaro, Vanessa Manchim; de Oliveira, Maria Gabriela Menezes; Perry, Juliana Cini; Tufik, Sergio; Chagas, Jair Ribeiro

    2015-01-01

    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. PMID:25750673

  15. Insulin resistance is associated with tissue-specific regulation of HIF-1α and HIF-2α during mild chronic intermittent hypoxia.

    Science.gov (United States)

    Sacramento, J F; Ribeiro, M J; Rodrigues, T; Guarino, M P; Diogo, L N; Seiça, R; Monteiro, E C; Matafome, P; Conde, S V

    2016-07-01

    Chronic intermittent hypoxia (CIH) is a feature of obstructive sleep apnea (OSA). Whereas clinical studies have demonstrated the association between OSA and insulin resistance, the molecular mechanisms behind it are still unknown. Herein we investigated the effect of mild CIH on insulin sensitivity and we evaluated the changes in insulin and HIF signaling pathways that occur in CIH-induced insulin resistance. We showed that mild CIH obtained by 5/6 hypoxic (5%O2) cycles/h, 10.5h/day during 28 and 35 days increased arterial blood pressure. Insulin resistance and insulinemia increased with CIH duration, being significantly different after 35 days of CIH. Thirty-five days of CIH decreased insulin receptor expression and phosphorylation in skeletal muscle and adipose tissue, but not in the liver. Conversely, Glut2 expression increased in the liver of CIH-animals. Thirty-five days of CIH up-regulated HIF-1α in the liver and down-regulated HIF-1α and HIF-2α in skeletal muscle. We concluded that the effect of CIH on insulin sensitivity and signaling is time-dependent and is associated with changes in HIF signaling in insulin-sensitive tissues. PMID:26993367

  16. Global Gene Expression Profiling in Three Tumor Cell Lines Subjected to Experimental Cycling and Chronic Hypoxia

    OpenAIRE

    Olbryt, Magdalena; Habryka, Anna; Student, Sebastian; Jarząb, Michał; Tyszkiewicz, Tomasz; Lisowska, Katarzyna Marta

    2014-01-01

    Hypoxia is one of the most important features of the tumor microenvironment, exerting an adverse effect on tumor aggressiveness and patient prognosis. Two types of hypoxia may occur within the tumor mass, chronic (prolonged) and cycling (transient, intermittent) hypoxia. Cycling hypoxia has been shown to induce aggressive tumor cell phenotype and radioresistance more significantly than chronic hypoxia, though little is known about the molecular mechanisms underlying this phenomenon. The aim o...

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

    Institute of Scientific and Technical Information of China (English)

    Yue-Ying Pan; Yan Deng; Sheng Xie; Zhi-Hua Wang; Yu Wang; Jie Ren; Hui-Guo Liu

    2016-01-01

    Background:Cognitive impairment is a severe complication caused by obstructive sleep apnea (OSA).The mechanisms of causation are still unclear.The Wnt/β-catenin signaling pathway is involved in cognition,and abnormalities in it are implicated in neurological disorders.Here,we explored the Wnt/β-catenin signaling pathway abnormalities caused by chronic intermittent hypoxia (CIH),the most characteristic pathophysiological component of OSA.Methods:We divided 32 4-week-old male C57/BL mice into four groups of eight each:a CIH + normal saline (NS) group,CIH + LiC1 group,sham CIH + NS group,and a sham CIH + LiC1 group.The spatial learning performance of each group was assessed by using the Morris water maze (MWM).Protein expressions of glycogen synthase kinase-3β (GSK-3β) and β-catenin in the hippocampus were examined using the Western blotting test.EdU labeling and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining methods were used,respectively,to determine the proliferation and apoptosis of neurons in the hippocampal dentate gyrus region.Results:Mice exposed to CIH showed impaired spatial learning performance in the MWM,including increased mean escape latencies to reach the target platform,decreased mean times passing through the target platform and mean duration in the target quadrant.The GSK-3β activity increased,and expression of β-catenin decreased significantly in the hippocampus of the CIH-exposed mice.Besides,CIH significantly increased hippocampal neuronal apoptosis,with an elevated apoptosis index.Meanwhile,LiCl decreased the activity of GSK-3β and increased the expression of β-catenin and partially reversed the spatial memory deficits in MWM and the apoptosis caused by CIH.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

  18. Increased vasopressin transmission from the paraventricular nucleus to the rostral medulla augments cardiorespiratory outflow in chronic intermittent hypoxia-conditioned rats.

    Science.gov (United States)

    Kc, Prabha; Balan, Kannan V; Tjoe, Steven S; Martin, Richard J; Lamanna, Joseph C; Haxhiu, Musa A; Dick, Thomas E

    2010-02-15

    A co-morbidity of sleep apnoea is hypertension associated with elevated sympathetic nerve activity (SNA) which may result from conditioning to chronic intermittent hypoxia (CIH). Our hypothesis is that SNA depends on input to the rostral ventrolateral medulla (RVLM) from neurons in the paraventricular nucleus (PVN) that release arginine vasopressin (AVP) and specifically, that increased SNA evoked by CIH depends on this excitatory input. In two sets of neuroanatomical experiments, we determined if AVP neurons project from the PVN to the RVLM and if arginine vasopressin (V(1A)) receptor expression increases in the RVLM after CIH conditioning (8 h per day for 10 days). In the first set, cholera toxin beta subunit (CT-beta) was microinjected into the RVLM to retrogradely label the PVN neurons. Immunohistochemical staining demonstrated that 14.6% of CT-beta-labelled PVN neurons were double-labelled with AVP. In the second set, sections of the medulla were immunolabelled for V(1A) receptors, and the V(1A) receptor-expressing cell count was significantly greater in the RVLM (P EMG)) and genioglossus muscle (GG(EMG)) activity were recorded in anaesthetized, ventilated and vagotomized rats. The PVN was disinhibited by microinjecting a GABA(A) receptor antagonist, bicuculline (BIC, 0.1 nmol), before and after blocking V(1A) receptors within the RVLM and rVRC with SR49059 (0.2 nmol). In RA-conditioned rats, disinhibition of the PVN increased BP, HR, minute D(EMG) and GG(EMG) activity and these increases were attenuated after blocking V(1A) receptors. In CIH-conditioned rats, a significantly greater dose of blocker (0.4 nmol) was required to blunt these physiological responses (P < 0.05). Further, this dose normalized the baseline BP. In summary, AVP released by a subset of PVN neurons modulates cardiorespiratory output via V(1A) receptors in the RVLM and rVRC, and increased SNA in CIH-conditioned animals depends on up-regulation of V(1A) receptors in the RVLM. PMID:20051497

  19. Intermittent hypoxia with or without hypercapnia is associated with tumorigenesis by decreasing the expression of brain derived neurotrophic factor and miR-34a in rats

    Institute of Scientific and Technical Information of China (English)

    Zhang Jing; Guo Xu; Shi Yanwei; Ma Jing; Wang Guangfa

    2014-01-01

    Background Very recent studies revealed that obstructive sleep apnoea (OSA) is a contributor of the increased incidence and mortality of cancer in humans,but mechanisms of how OSA promotes tumorigenesis remains largely unknown.We investigated whether intermittent hypoxia with and without hypercapnia plays a role in tumorigenesis.Methods First,Sprague-Dawley (SD) male rats (12 weeks old) were subjected to different hypoxia exposures:intermittent hypoxia and intermittent hypoxia with hypercapnia; continuous hypoxia and normal air.The systemic application of chronic fast rate hypoxia with or without hypercapnia mimicked severe OSA patients with apnoea/hypopnea index equivalent to 60 events per hour.Then routine blood tests were performed and the levels of brain derived neurotrophic factor (BDNF) and miR-34a were examined.Results In contrast to intermittent hypoxia with hypercapnia,both intermittent hypoxia and continuous hypoxia treatments caused significantly higher levels of haematology parameters than normoxia treatments.Compared to normoxia,intermittent hypoxia with hypercapnia exposure resulted in substantial decrease of serum BDNF and,miR-34a in the lower brainstem,while less pronounced results were found in intermittent hypoxia and continuous hypoxia exposure.Conclusions The exposure of intermittent hypoxia with or without hypercapnia,mimicking the situations in severe OSA patients,was associated with,or even promoted tumorigenesis.

  20. Intermittent hypoxia maintains glycemia in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Chen, Xiaofei; Zhao, Tong; Huang, Xin; Wu, Liying; Wu, Kuiwu; Fan, Ming; Zhu, Lingling

    2016-05-01

    Increasing studies have shown protective effects of intermittent hypoxia on brain injury and heart ischemia. However, the effect of intermittent hypoxia on blood glucose metabolism, especially in diabetic conditions, is rarely observed. The aim of this study was to investigate whether intermittent hypoxia influences blood glucose metabolism in type 1 diabetic rats. Streptozotocin-induced diabetic adult rats and age-matched control rats were treated with intermittent hypoxia (at an altitude of 3 km, 4 h per day for 3 weeks) or normoxia as control. Fasting blood glucose, body weight, plasma fructosamine, plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), pancreas β-cell mass, and hepatic and soleus glycogen were measured. Compared with diabetic rats before treatment, the level of fasting blood glucose in diabetic rats after normoxic treatment was increased (19.88 ± 5.69 mmol/L vs. 14.79 ± 5.84 mmol/L, p  0.05). Meanwhile, fasting blood glucose in diabetic rats after hypoxic treatment was also lower than that in diabetic rats after normoxic treatment (13.14 ± 5.77 mmol/L vs. 19.88 ± 5.69 mmol/L, pintermittent hypoxia was significantly lower than that in diabetic rats receiving normoxia (1.28 ± 0.11 vs. 1.39 ± 0.11, p intermittent hypoxia showed effect on the increase of soleus glycogen but not hepatic glycogen. We conclude that intermittent hypoxia maintains glycemia in streptozotocin-induced diabetic rats and its regulation on muscular glycogenesis may play a role in the underlying mechanism. PMID:26902078

  1. Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats Causes an Imbalance in the Asymmetric Dimethylarginine/Nitric Oxide Pathway and ROS Activity: A Possible Synergistic Mechanism for Altitude Pulmonary Hypertension?

    Science.gov (United States)

    Lüneburg, Nicole; Siques, Patricia; Brito, Julio; Arriaza, Karem; Pena, Eduardo; Klose, Hans; Leon-Velarde, Fabiola; Böger, Rainer H.

    2016-01-01

    Chronic intermittent hypoxia (CIH) and chronic hypoxia (CH) are associated with high-altitude pulmonary hypertension (HAPH). Asymmetric dimethylarginine (ADMA), a NO synthase (NOS) inhibitor, may contribute to HAPH. This study assessed changes in the ADMA/NO pathway and the underlying mechanisms in rat lungs following exposure to CIH or CH simulated in a hypobaric chamber at 428 Torr. Twenty-four adult Wistar rats were randomly assigned to three groups: CIH2x2 (2 days of hypoxia/2 days of normoxia), CH, and NX (permanent normoxia), for 30 days. All analyses were performed in whole lung tissue. L-Arginine and ADMA were analyzed using LC-MS/MS. Under both hypoxic conditions right ventricular hypertrophy was observed (p < 0.01) and endothelial NOS mRNA increased (p < 0.001), but the phosphorylated/nonphosphorylated vasodilator-stimulated phosphoprotein (VASP) ratio was unchanged. ADMA increased (p < 0.001), whereas dimethylarginine dimethylaminohydrolase (DDAH) activity decreased only under CH (p < 0.05). Although arginase activity increased (p < 0.001) and L-arginine exhibited no changes, the L-arginine/ADMA ratio decreased significantly (p < 0.001). Moreover, NOX4 expression increased only under CH (p < 0.01), but malondialdehyde (MDA) increased (up to 2-fold) equally in CIH2x2 and CH (p < 0.001). Our results suggest that ADMA and oxidative stress likely reduce NO bioavailability under altitude hypoxia, which implies greater pulmonary vascular reactivity and tone, despite the more subdued effects observed under CIH. PMID:27313889

  2. Sleep state dependence of ventilatory long-term facilitation following acute intermittent hypoxia in Lewis rats

    OpenAIRE

    Nakamura, A.; Olson, E B; Terada, J.; Wenninger, J. M.; Bisgard, G. E.; Mitchell, G.S.

    2010-01-01

    Ventilatory long-term facilitation (vLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia (AIH). Although vLTF has been reported in unanesthetized animals, little is known concerning the effects of vigilance state on vLTF expression. We hypothesized that AIH-induced vLTF is preferentially expressed in sleeping vs. awake male Lewis rats. Vigilance state was assessed in unanesthetized rats with chronically implanted EEG and nuchal EMG electrodes, while tidal volume, fr...

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

    OpenAIRE

    Olga Gonchar

    2005-01-01

    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 o...

  4. Spinal Plasticity following Intermittent Hypoxia: Implications for Spinal Injury

    OpenAIRE

    Dale-Nagle, Erica A.; Hoffman, Michael S.; MacFarlane, Peter M.; Satriotomo, Irawan; Lovett-Barr, Mary Rachael; Vinit, Stéphane; Mitchell, Gordon S.

    2010-01-01

    Plasticity is a fundamental property of the neural system controlling breathing. One frequently studied model of respiratory plasticity is long-term facilitation of phrenic motor output (pLTF) following acute intermittent hypoxia (AIH). pLTF arises from spinal plasticity, increasing respiratory motor output through a mechanism that requires new synthesis of brain derived neurotrophic factor (BDNF), activation of its high affinity receptor, tropomyosin-related kinase B (TrkB) and extracellular...

  5. Effect of Intermittent Hypoxia and Rimonabant on Glucose Metabolism in Rats: Involvement of Expression of GLUT4 in Skeletal Muscle

    OpenAIRE

    Wang, Xiaoya; Yu, Qin; Yue, Hongmei; Zeng, Shuang; Cui, Fenfen

    2015-01-01

    Background Obstructive sleep apnea (OSA) and its main feature, chronic intermittent hypoxia (IH) during sleep, is closely associated with insulin resistance (IR) and diabetes. Rimonabant can regulate glucose metabolism and improve IR. The present study aimed to assess the effect of IH and rimonabant on glucose metabolism and insulin sensitivity, and to explore the possible mechanisms. Material/Methods Thirty-two rats were randomly assigned into 4 groups: Control group, subjected to intermitte...

  6. CORRECTION ON "CHRONIC INTERMITTENT ANOXIA...".

    Science.gov (United States)

    Halstead, W C

    1945-08-10

    The writer is embarrassed by his discovery that in revising a manuscript entitled "Chronic Intermittent Anoxia and Impairment of Peripheral Vision," an important paragraph was inadvertently omitted from the version which appeared in Science for June 15, 1945. In checking back it becomes evident that the omission arose in the author's final copy, and that the editors of Science are in no way responsible. The paragraph which should have been inserted between the two paragraphs of column 2, page 615, is as follows: Serial determinations of alveolar gas tensions for each visual test day were carried out on sixteen of the twenty subjects by Dr. Wright Adams, but no relationship could be established with the impairment of peripheral vision. Similarly, in a smaller number of subjects no clear relationship could be established between the visual effect and renal vascular changes (Dr. Alf S. Alving), cardio-vascular changes (Dr. Emmet B. Bay), blood chemistry (Dr. Guzmán E. S. Barrón), psychiatric changes (Dr. Hugh T. Carmichael), electroencephalograms (Dr. Theodore Case), peripheral blood flow (Dr. Milton Landowne), certain metabolic effects (Drs. Henry T. Ricketts and A. Hughes Bryan), and certain additional neuropsychological indicators. Through omission of the above paragraph, inadequate representation was given to the scope of the total war research project in which the psychological studies carried out by the writer constituted one aspect. In addition to their particular lines of investigation, each of the above men contributed generously of specialized knowledge and of time and energy to insure adequate clinical supervision of the experimental subjects and a valid interpretation of the impairment of peripheral vision as reported. PMID:17802440

  7. Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period

    OpenAIRE

    Carreras, Alba; Kayali, Foaz; Zhang, Jing; Hirotsu, Camila; Wang, Yang; Gozal, David

    2012-01-01

    Intermittent hypoxia (IH) is a frequent occurrence in sleep and respiratory disorders. Both human and murine studies show that IH may be implicated in metabolic dysfunction. Although the effects of nocturnal low-frequency intermittent hypoxia (IHL) have not been extensively examined, it would appear that IHL and high-frequency intermittent hypoxia (IHH) may elicit distinct metabolic adaptations. To this effect, C57BL/6J mice were randomly assigned to IHH (cycles of 90 s 6.4% O2 and 90 s 21% O...

  8. Relationship between nocturnal chronic intermittent hypoxia and fatty liver in hypertensive patients%夜间间歇性低血氧与高血压患者脂肪肝的关系

    Institute of Scientific and Technical Information of China (English)

    邵亮; 李南方; 姚晓光; 洪静; 周克明

    2013-01-01

    Objective To investigate the relationship between nocturnal chronic intermittent hypoxia and fatty liver in hypertensive patients.Methods 168 patients with hypertension who underwent both polysomnography and liver ultrasonography were enrolled from July 2004 to March 2006.The main clinical features as well as apneahypnea index(AHI) and the lowest oxygen saturation (LSaO2),were compared between patients with and without fatty liver,and the potential risk factors of fatty liver were discussed.Results 101 out of 168 cases were diagnosed as fatty liver,in which the body mass index,fasting blood glucose,triglyceride,alanine aminotransferase (ALT),aspartate amino-transferase(AST),Gamma-glutamyl transpeptidase(GGT) and mean AHI were significantly higher,while the LSaO2 [(79.37 + 9.19) % vs.(83.12 + 6.40) %,P < 0.05] was much lower compared with patients without fatty liver.The multivariate logistic regression indicated that the fasting blood glucose [OR (95% CI):3.794 (1.678-8.578)],LSaO2 [OR (95% CI):3.378 (1.464-7.796)] were possible contributing risk factors of fatty liver in patients with hypertension.Conclusion Nocturnal chronic intermittent hypoxia may play a role in the pathogenesis of fatty liver disease in hypertensive patients.%目的 探讨高血压患者夜间间歇性低血氧与脂肪肝的关系.方法 选择行多导睡眠监测的原发性高血压患者168例,并根据肝脏超声影像学的诊断结果分组,比较两组间临床、实验室资料及多导睡眠监测指标中的睡眠呼吸暂停低通气指数(AHI)、最低血氧饱和度(LSaO2),分析脂肪肝形成的相关因素.结果 脂肪肝组(101例)较非脂肪肝组(67例)的体重指数、空腹血糖、甘油三酯、丙氨酸氨基转移酶、门冬氨酸氨基转移酶、谷酰转肽酶明显增高(P<0.05),但LSaO2水平明显降低[(79.37±9.19)% vs.(83.12±6.40)%,P<0.05].Logistic回归分析表明空腹血糖、LSaO2可能是高血压患者脂肪肝的形成

  9. 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.

  10. The study of genistein attenuating genioglossus muscle fatigue under chronic intermittent hypoxia%金雀异黄素减弱慢性间歇性低氧大鼠颏舌肌疲劳的实验研究

    Institute of Scientific and Technical Information of China (English)

    丁王辉; 李文; 陈小燕; 施洁珺

    2016-01-01

    目的 探讨金雀异黄素对慢性间歇性低氧(chronic intermittent hypoxia,CIH)大鼠颏舌肌功能及核因子-E2相关因子(nuclear factor erythroid 2 related factor 2,Nrf-2)/抗氧化反应元件(antioxidant responsive element, ARE)信号通路的影响,以期找到药物治疗阻塞性睡眠呼吸暂停低通气综合征的方法.方法 8周龄健康雌性SD大鼠30只,去势1周后用随机数字表法分为对照组、CIH组(低氧组)、CIH+金雀异黄素治疗组(治疗组),每组10只.后两组建立CIH动物模型(8 h/d,5周).电生理法检测并计算大鼠颏舌肌强直收缩20、40、60、80和100s时抗疲劳性,实时定量反转录PCR及蛋白质印迹法检测Nrf-2基因及蛋白表达.结果 与对照组相比,低氧组大鼠各时间点颏舌肌抗疲劳性显著降低(P<0.05);与低氧组相比,治疗组颏舌肌各时间点抗疲劳性显著增强(P<0.05),但仍显著小于对照组(P<0.05).低氧组大鼠颏舌肌Nrf-2基因及蛋白表达(0.54±0.11和0.35±0.13)显著低于对照组(1.00±0.00和1.00±0.00) (P<0.05),治疗组Nrf-2基因及蛋白表达(0.76±0.16和0.63±0.14)相对低氧组上调(P<0.05),但仍显著低于对照组(P<0.05).结论 CIH通过抑制Nrf-2/ARE信号通路降低大鼠颏舌肌的抗疲劳能力,金雀异黄素通过增强Nrf-2基因及蛋白表达发挥对颏舌肌的保护作用.%Objective To investigate the effects of genistein on genioglossus muscle function and nuclear factor erythroid 2 related factor 2(Nrf-2)/antioxidant responsive element(ARE) signaling pathway in rats under chronic intermittent hypoxia(CIH) condition in order to find medication treatment of obstructive sleep apnea/hyponea syndrome.Methods Thirty female Sprague-Dawley(SD) rats (8 weeks old) were randomly(random number table) divided into three groups 1 week after ovariectomy: control group(NC group), CIH group, and CIH+genistein treatment group(T group).Rats in the latter two groups were exposed to CIH for 8 h/d for 5

  11. Enhanced carotid body chemosensory activity and the cardiovascular alterations induced by intermittent hypoxia

    Directory of Open Access Journals (Sweden)

    Rodrigo eIturriaga

    2014-12-01

    Full Text Available The carotid body (CB plays a main role in the maintenance of the oxygen homeostasis. The hypoxic stimulation of the CB increases the chemosensory discharge, which in turn elicits reflex sympathetic, cardiovascular and ventilatory adjustments. An exacerbate carotid chemosensory activity has been associated with human sympathetic-mediated diseases such as hypertension, insulin resistance, heart failure and obstructive sleep apnea (OSA. Indeed, the CB chemosensory discharge becomes tonically hypereactive in experimental models of OSA and heart failure. Chronic intermittent hypoxia (CIH, a main feature of OSA, enhances CB chemosensory baseline discharges in normoxia and in response to hypoxia, inducing sympathetic overactivity and hypertension. Oxidative stress, increased levels of ET-1, Angiotensin II and pro-inflammatory cytokines, along with a reduced production of NO in the CB, have been associated with the enhanced carotid chemosensory activity. In this review, we will discuss new evidence supporting a main role for the CB chemoreceptor in the autonomic and cardiorespiratory alterations induced by intermittent hypoxia, as well as the molecular mechanisms involved in the CB chemosensory potentiation.

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

    International Nuclear Information System (INIS)

    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% O2/8% O2 FIO2 (30 episodes per hour) with 20 s at the nadir FIO2 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

  13. Cardioprotective adaptation of rats to intermittent hypobaric hypoxia is accompanied by the increased association of hexokinase with mitochondria.

    Science.gov (United States)

    Waskova-Arnostova, Petra; Elsnicova, Barbara; Kasparova, Dita; Hornikova, Daniela; Kolar, Frantisek; Novotny, Jiri; Zurmanova, Jitka

    2015-12-15

    Chronic hypoxia increases the myocardial resistance to acute ischemia-reperfusion injury by affecting the mitochondrial redox balance. Hexokinase (HK) bears a high potential to suppress the excessive formation of reactive oxygen species because of its increased association with mitochondria, thereby inhibiting the membrane permeability transition pore opening and preventing cell death. The purpose of this study was to determine the effect of severe intermittent hypobaric hypoxia (7,000 m, 8 h/day, 5 wk) on the function and colocalization of HK isoforms with mitochondria in the left (LV) and right ventricles of rat myocardium. The real-time RT-PCR, Western blot, enzyme coupled assay, and quantitative immunofluorescence techniques were used. Our results showed significantly elevated expression of HK isoforms (HK1 and HK2) in the hypoxic LV. In addition, intermittent hypoxia increased the total HK activity and the association of HK isoforms with mitochondria in both ventricles. These findings suggest that HK may contribute to the cardioprotective phenotype induced by adaptation to severe intermittent hypobaric hypoxia. PMID:26494452

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

    Directory of Open Access Journals (Sweden)

    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

  15. Transient Intermittent Hypoxia Exposure Disrupts Neonatal Bone Strength

    Science.gov (United States)

    Kim, Gyuyoup; Elnabawi, Omar; Shin, Daehwan; Pae, Eung-Kwon

    2016-01-01

    A brief intermittent hypoxia (IH, ambient O2 levels alternating between room air and 12% O2) for 1 h immediately after birth resulted in pancreatic islet dysfunction associated with zinc deficiency as previously reported. We hypothesized that IH exposure modulates zinc homeostasis in bone as well, which leads to increased bone fragility. To test this hypothesis, we used neonatal rats and human osteoblasts (HObs). To examine IH influences on osteoblasts devoid of neural influences, we quantified amounts of alkaline phosphatase and mineralization in IH-treated HObs. Bones harvested from IH-treated animals showed significantly reduced hardness and elasticity. The IH group also showed discretely decreased levels of alkaline phosphatase and mineralization amounts. The IH group showed a decreased expression of ZIP8 or Zrt and Irt-like protein 8 (a zinc uptake transporter), Runx2 (or Runt-related transcription factor 2, a master protein in bone formation), Collagen-1 (a major protein comprising the extracellular matrix of the bone), osteocalcin, and zinc content. When zinc was eliminated from the media containing HObs using a zinc chelate and added later with zinc sulfate, Runx2, ZIP8, and osteocalcin expression decreased first, and recovered with zinc supplementation. Adenovirus-mediated ZIP8 over-expression in osteoblasts increased mineralization significantly as well. We conclude that IH impairs zinc homeostasis in bones and osteoblasts, and that such disturbances decrease bone strength, which can be recovered by zinc supplementation. PMID:27014665

  16. Construction of An Experimental Hypogiossal Nerve Signals Record Platform in Rat Model of Chronic Intermittent Hypoxia in Vivo%慢性间歇低氧大鼠模型在体舌下神经电信号记录实验平台的建立

    Institute of Scientific and Technical Information of China (English)

    赵景景; 文芳静; 王念; 范慧; 万志辉; 胡克

    2012-01-01

    Objective: To establish an experimental platform of the rat model of chronic intermittent hy-poxia simulating obstructive sleep apnea syndrome and to explore the activity of the hypoglossal nerve signals in vivo. Methods: Experiments were performed in the rat model of chronic intermittent hypoxia. These preparations included the gas source, the gas control delivery system, the intermittent hypoxia animal chambers, and the rats. In accordance with the requirement of experiment, the rats were given nitrogen and air alternately for 8 hours per day and the experiment lasted for 7 weeks. After the experiment, the hypoglossal nerve was isolated and the average peak amplitude and frequency of hypoglossal nerve discharges were recorded and analyzed with medical biological signal processor (MedLab U/C 501H). Results: The pre-test results showed that chronic intermittent hypoxia rat model could simulate the pathophysiological characteristics of the obstructive sleep apnea hypopnea syndrome in human, and the recorded signals from hypoglossal nerve are stable and reliable. Conclusion; The chronic intermittent hypoxia model proved simple, easy, practical, and reproducible, and the recorded signals of hypoglossal nerve are stable and reliable. The system is ideally suited for studies.%目的:建立一种以模拟阻塞性睡眠呼吸暂停低通气综合征的慢性间歇低氧大鼠模型为基础、探讨在体舌下神经电信号活动的实验平台.方法:慢性间歇低氧大鼠模型由气源(氮气及空气)、电磁阀控制系统、间歇低氧动物仓、以及实验动物(大鼠)组成,按照实验要求对大鼠交替给予氮气和空气,每天8h,连续处理7周后,分离舌下神经,应用多通道生物信号采集与处理系统对舌下神经电信号进行处理与分析.结果:预实验结果显示,慢性间歇低氧大鼠模型能够模拟人体阻塞性睡眠呼吸暂停低通气综合征的病理生理特征,所记录的电信号稳定、可靠.结论:

  17. Deletion of Metallothionein Exacerbates Intermittent Hypoxia-Induced Oxidative and Inflammatory Injury in Aorta

    Directory of Open Access Journals (Sweden)

    Shanshan Zhou

    2014-01-01

    Full Text Available The present study was to explore the effect of metallothionein (MT on intermittent hypoxia (IH induced aortic pathogenic changes. Markers of oxidative damages, inflammation, and vascular remodeling were observed by immunohistochemical staining after 3 days and 1, 3, and 8 weeks after IH exposures. Endogenous MT was induced after 3 days of IH but was significantly decreased after 8 weeks of IH. Compared with the wild-type mice, MT knock-out mice exhibited earlier and more severe pathogenic changes of oxidative damages, inflammatory responses, and cellular apoptosis, as indicated by the significant accumulation of collagen, increased levels of connective tissue growth factor, transforming growth factor β1, tumor necrosis factor-alpha, vascular cell adhesion molecule 1,3-nitrotyrosine, and 4-hydroxy-2-nonenal in the aorta. These findings suggested that chronic IH may lead to aortic damages characterized by oxidative stress and inflammation, and MT may play a pivotal role in the above pathogenesis process.

  18. Sleep state dependence of ventilatory long-term facilitation following acute intermittent hypoxia in Lewis rats.

    Science.gov (United States)

    Nakamura, A; Olson, E B; Terada, J; Wenninger, J M; Bisgard, G E; Mitchell, G S

    2010-08-01

    Ventilatory long-term facilitation (vLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia (AIH). Although vLTF has been reported in unanesthetized animals, little is known concerning the effects of vigilance state on vLTF expression. We hypothesized that AIH-induced vLTF is preferentially expressed in sleeping vs. awake male Lewis rats. Vigilance state was assessed in unanesthetized rats with chronically implanted EEG and nuchal EMG electrodes, while tidal volume, frequency, minute ventilation (Ve), and CO(2) production were measured via plethysmography, before, during, and after AIH (five 5-min episodes of 10.5% O(2) separated by 5-min normoxic intervals), acute sustained hypoxia (25 min of 10.5% O(2)), or a sham protocol without hypoxia. Vigilance state was classified as quiet wakefulness (QW), light and deep non-rapid eye movement (NREM) sleep (l-NREM and d-NREM sleep, respectively), or rapid eye movement sleep. Ventilatory variables were normalized to pretreatment baseline values in the same vigilance state. During d-NREM sleep, vLTF was observed as a progressive increase in Ve post-AIH (27 + or - 5% average, 30-60 min post-AIH). In association, Ve/Vco(2) (36 + or - 2%), tidal volume (14 + or - 2%), and frequency (7 + or - 2%) were increased 30-60 min post-AIH during d-NREM sleep. vLTF was significant but less robust during l-NREM sleep, was minimal during QW, and was not observed following acute sustained hypoxia or sham protocols in any vigilance state. Thus, vLTF is state-dependent and pattern-sensitive in unanesthetized Lewis rats, with the greatest effects during d-NREM sleep. Although the physiological significance of vLTF is not clear, its greatest significance to ventilatory control is most likely during sleep. PMID:20360430

  19. Intermittent enhancement in chronic nodular calcified neurocysticercosis

    Directory of Open Access Journals (Sweden)

    Martin Oselkin, MD

    2015-01-01

    Full Text Available Neurocysticercosis (NCC is the most common cause of new onset seizures and epilepsy in the developing and tropical world. There has been a marked increase in domestic cases of diseases traditionally associated with developing countries, and now NCC should be high on a radiologist's differential diagnosis list for a patient with seizures. Radiologic findings of NCC correlate with the parasite's life cycle within the host. The calcified granulomas signify the final stage (nodular calcified as nonenhancing punctate calcifications on imaging and are traditionally known to remain without enhancement. Here we describe a unique case of intermittent enhancement of a cortical calcified nodule secondary to NCC that was followed for over 10 years. Radiologists must challenge the traditionally accepted progression of imaging findings and accept that calcified nodules of chronic NCC may intermittently enhance.

  20. Hypoxia in a neonate caused by intermittent positive pressure ventilation.

    OpenAIRE

    Beddis, I R; Silverman, M

    1980-01-01

    A newborn baby receiving mechanical ventilation was noted to have an extremely variable degree of hypoxia, despite the administration of 100% oxygen. The hypoxia was relieved rapidly when mechanical ventilation was withdrawn.

  1. Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease.

    Science.gov (United States)

    Manukhina, Eugenia B; Downey, H Fred; Shi, Xiangrong; Mallet, Robert T

    2016-06-01

    Alzheimer's disease (AD) is a leading cause of death and disability among older adults. Modifiable vascular risk factors for AD (VRF) include obesity, hypertension, type 2 diabetes mellitus, sleep apnea, and metabolic syndrome. Here, interactions between cerebrovascular function and development of AD are reviewed, as are interventions to improve cerebral blood flow and reduce VRF. Atherosclerosis and small vessel cerebral disease impair metabolic regulation of cerebral blood flow and, along with microvascular rarefaction and altered trans-capillary exchange, create conditions favoring AD development. Although currently there are no definitive therapies for treatment or prevention of AD, reduction of VRFs lowers the risk for cognitive decline. There is increasing evidence that brief repeated exposures to moderate hypoxia, i.e. intermittent hypoxic training (IHT), improve cerebral vascular function and reduce VRFs including systemic hypertension, cardiac arrhythmias, and mental stress. In experimental AD, IHT nearly prevented endothelial dysfunction of both cerebral and extra-cerebral blood vessels, rarefaction of the brain vascular network, and the loss of neurons in the brain cortex. Associated with these vasoprotective effects, IHT improved memory and lessened AD pathology. IHT increases endothelial production of nitric oxide (NO), thereby increasing regional cerebral blood flow and augmenting the vaso- and neuroprotective effects of endothelial NO. On the other hand, in AD excessive production of NO in microglia, astrocytes, and cortical neurons generates neurotoxic peroxynitrite. IHT enhances storage of excessive NO in the form of S-nitrosothiols and dinitrosyl iron complexes. Oxidative stress plays a pivotal role in the pathogenesis of AD, and IHT reduces oxidative stress in a number of experimental pathologies. Beneficial effects of IHT in experimental neuropathologies other than AD, including dyscirculatory encephalopathy, ischemic stroke injury, audiogenic

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  3. Role of endoplasmic reticular stress in aortic endothelial apoptosis induced by intermittent/persistent hypoxia

    Institute of Scientific and Technical Information of China (English)

    YANG Yuan-yuan; SHANG Jin; LIU Hui-guo

    2013-01-01

    Background Accumulated evidence shows that hypoxia can induce endothelial apoptosis,however the mechanism is still unknown.We hypothesized whether intermittent or persistent hypoxia could induce endoplasmic reticular stress,leading to endothelial apoptosis.Methods Twenty-four 8-week male Sprague Dawley (SD) rats were divided into three groups:normoxia (NC) group,intermittent hypoxia (IH) group and persistent hypoxia (PH) group.TUNEL staining was performed to detect aortic arch endotheliar apoptosis,and immunohistochemistry for BIP,CHOP and caspase12 to test protein expression;human umbilical vein endothelial cells (HUVECs) of the line ECV304 were cultured (with or without taurodeoxycholic acid (TUDCA) 10 mmol/L,100 mmol/L) and divided into four groups:NC group (20.8% O2 for 4 hours),PH1 group (5% O2 for 4 hours),PH2 group (5% O2 for 12 hours) and IH group (20.8% O2 and 5% O2 alternatively for 8 hours).Annexin V-fluorescein-isothiocyanate/propidium iodide flow cytometry was used to assess apoptosis in each group.The expressions of GRP78,CHOP and caspase12 were detected by real-time quantitative reverse-transcription PCR.Result Intermittent and persistent hypoxia could increase the rate of endothelium apoptosis and the expressions of GRP78,CHOP and caspase12 compared with the control,induction by intermittent hypoxia was slightly higher than persistent hypoxia.In the HUVEC experiment,TUDCA significantly reduced apoptosis and the expressions of GRP78,CHOP and caspase12.Conclusion Hypoxia,especially intermittent,can induce endothelial cell apoptosis possibly through endoplasmic reticulum stress pathway,which can be attenuated by taurodeoxycholic acid.

  4. Uncoupling protein-2 mRNA expression in mice subjected to intermittent hypoxia

    Directory of Open Access Journals (Sweden)

    Luciana Rodrigues Vieira

    2015-04-01

    Full Text Available Objective: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA-on pancreatic expression of uncoupling protein-2 (UCP2, as well as on glycemic and lipid profiles, in C57BL mice. Methods: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group or to a sham procedure (normoxia group. The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period. Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. Results: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11. Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01. The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09 and 21% higher pancreatic β-cell function (p = 0.01. Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and β-cell staining for insulin and glucagon. Conclusions: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted.

  5. Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat.

    Science.gov (United States)

    Darnall, R A; McWilliams, S; Schneider, R W; Tobia, C M

    2010-12-01

    Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups were exposed to either eight trials of hypoxia (3 min 5% O(2) alternating with room air) (group A), or three hypoxia trials as in group A, followed by five trials in which hypoxia was terminated at arousal (group B). In both groups A and B, latency increased over the first four trials of hypoxia, but reversed in group B animals during trials 5-8. Progressive arousal blunting was more pronounced in the older pups. The effects of intermittent hypoxia on heart rate also depended on age. In the older pups, heart rate increased with each hypoxia exposure. In the P5 pups, however, heart rate decreased during hypoxia and did not return to baseline between exposures, resulting in a progressive fall of baseline values over successive hypoxia exposures. In the group B animals, heart rate changes during trials 1-4 also reversed during trials 5-8. We conclude that exposure to repeated episodes of hypoxia can cause progressive blunting of arousal, which is reversible by altering the exposure times to hypoxia and the period of recovery between hypoxia exposures. PMID:20930126

  6. Evidence for intermittent radiobiological hypoxia in experimental tumour systems

    International Nuclear Information System (INIS)

    This paper describes flow and static fluorescence cytometry techniques to visualize and quantitate acute radiobiological hypoxia resulting from transient fluctuation in tumour blood flow in experimental tumour systems. The application of these techniques in two murine tumour systems provides evidence that such hypoxia exists and reduces the effectiveness of single doses of radiation. Possible mechanisms for and implications of these findings are discussed. (author)

  7. 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

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

    Institute of Scientific and Technical Information of China (English)

    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

  9. Pathophysiology and clinical effects of chronic hypoxia.

    Science.gov (United States)

    Pierson, D J

    2000-01-01

    Hypoxia exists when there is a reduced amount of oxygen in the tissues of the body. Hypoxemia refers to a reduction in PO2 below the normal range, regardless of whether gas exchange is impaired in the lung, CaO2 is adequate, or tissue hypoxia exists. There are several potential physiologic mechanisms for hypoxemia, but in patients with COPD the predominant one is V/Q mismatching, with or without alveolar hypoventilation, as indicated by PaCO2. Hypoxemia caused by V/Q mismatching as seen in COPD is relatively easy to correct, so that only comparatively small amounts of supplemental oxygen (less than 3 L/min for the majority of patients) are required for LTOT. Although hypoxemia normally stimulates ventilation and produces dyspnea, these phenomena and the other symptoms and signs of hypoxia are sufficiently variable in patients with COPD as to be of limited value in patient assessment. Chronic alveolar hypoxia is the main factor leading to development of cor pulmonale--right ventricular hypertrophy with or without overt right ventricular failure--in patients with COPD. Pulmonary hypertension adversely affects survival in COPD, to an extent that parallels the degree to which resting mean pulmonary artery pressure is elevated. Although the severity of airflow obstruction as measured by FEV1 is the best correlate with overall prognosis in patients with COPD, chronic hypoxemia increases mortality and morbidity for any severity of disease. Large-scale studies of LTOT in patients with COPD have demonstrated a dose-response relationship between daily hours of oxygen use and survival. There is reason to believe that continuous, 24-hours-per-day oxygen use in appropriately selected patients would produce a survival benefit even greater than that shown in the NOTT and MRC studies. PMID:10771781

  10. 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

  11. Diaphragm long-term facilitation following acute intermittent hypoxia during wakefulness and sleep

    OpenAIRE

    Terada, J.; Mitchell, G.S.

    2011-01-01

    Acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). Here, we tested four hypotheses in unanesthetized, spontaneously breathing rats using radiotelemetry for EEG and diaphragm electromyography (Dia EMG) activity: 1) AIH induces LTF in Dia EMG activity; 2) diaphragm LTF (Dia LTF) is more robust during sleep vs. wakefulness; 3) AIH (or repetitive AIH) disrupts natural sleep-wake architecture; and 4) preconditioning with daily AIH (dAIH...

  12. LIPOPOLYSACCHARIDE ATTENUATES PHRENIC LONG-TERM FACILITATION FOLLOWING ACUTE INTERMITTENT HYPOXIA

    OpenAIRE

    Vinit, Stéphane; Windelborn, James A; Mitchell, Gordon S.

    2011-01-01

    Lipopolysaccharide (LPS) induces inflammatory responses, including microglial activation in the central nervous system. Since LPS impairs certain forms of hippocampal and spinal neuroplasticity, we hypothesized that LPS would impair phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) in outbred Sprague-Dawley (SD) and inbred Lewis (L) rats.. Approximately three hours following a single LPS injection (i.p.), the phrenic response during hypoxic episodes is reduced i...

  13. One Week of Exposure to Intermittent Hypoxia Impairs Attentional Set-shifting in Rats

    OpenAIRE

    McCoy, John G.; McKenna, James T.; Connolly, Nina P.; Poeta, Devon L.; Ling, Liming; McCARLEY, ROBERT W.; Strecker, Robert E.

    2010-01-01

    Intermittent hypoxia (IH), a characteristic of sleep apnea, was modeled in Fischer Brown Norway rats (10 h/day for 7 days) followed by cognitive testing in an attentional set-shifting task. The ability to shift attention from one sensory modality (e.g., odor) to another (e.g., digging medium) was impaired, a finding that could not be attributed to deficits in attention, discrimination, learning, or motor performance. Instead, the deficit is likely to reflect impaired allocation of attentional...

  14. Influence of gonadal hormones on the behavioral effects of intermittent hypoxia in mice

    OpenAIRE

    Aubrecht, Taryn G.; Jenkins, Richelle; Magalang, Ulysses J.; Nelson, Randy J.

    2014-01-01

    Obstructive sleep apnea (OSA) is characterized by repetitive upper airway obstruction resulting in cyclic intermittent hypoxia (IH) during sleep in affected individuals. OSA occurs more frequently in postmenopausal than premenopausal women and the severity of OSA increases after menopause. Gonadal hormones can influence brain and behavior; testosterone and estrogens in particular can enhance spatial learning and memory. We hypothesized that estrogens may protect mice from IH-induced hippocamp...

  15. Influence of chronic hypoxia and radiation quality on cell survival

    International Nuclear Information System (INIS)

    The purpose of this study was to investigate the influence of chronic hypoxia and anoxia on cell survival after low- and high-linear energy transfer (LET) radiation, Chinese hamster ovary K1 (CHO-K1) cells were kept for 24 h under chronic hypoxia (94.5% N2; 5% CO2; 0.5% O2) or chronic anoxia (95% N2; 5% CO2). Irradiation was performed using 250 kVp X-rays or carbon ions with a dose average LET of 100 keV/μm either directly under the chronic oxygenation states, or at different time points after reoxygenation. Moreover, the cell cycle distribution for cells irradiated under different chronic oxic states was measured over 24 h during reoxygenation. The measurements showed a fairly uniform cell cycle distribution under chronic hypoxia, similar to normoxic conditions. Chronic anoxia induced a block in G1 and a strong reduction of S-phase cells. A distribution similar to normoxic conditions was reached after 12 h of reoxygenation. CHO cells had a similar survival under both acute and chronic hypoxia. In contrast, survival after irradiation under chronic anoxia was slightly reduced compared to that under acute anoxia. We conclude that, in hamster cells, chronic anoxia is less effective than acute anoxia in inducing radioresistance for both X-rays and carbon ions, whereas in hypoxia, acute and chronic exposures have a similar impact on cell killing. (author)

  16. Chronic Salmonella eimsbuettel septicaemia presenting with intermittent sweats and haematuria.

    OpenAIRE

    Lowes, J A; Clark, A J; Britten, K. E.

    1980-01-01

    An unusual presentation is reported of salmonellosis, frank haematuria and chronic septicaemia arising during an outbreak of food poisoning caused by Salmonella eimsbuettel. The patient whose gut was colonized gave a history of chronic pyrexia and weight loss and suffered an intermittent urinary infection but had no gastroenteritis.

  17. Ghrelin Increases Lymphocytes in Chronic Normobaric Hypoxia

    OpenAIRE

    Mirzaie Bavil, Fariba; Mohaddes, Gisou; Ebrahimi, Hadi; Keyhanmanesh, Rana; Ghiyasi, Rafigheh; Alipour, Mohammad Reza

    2014-01-01

    Purpose: Hypoxia is a condition of decreased availability of oxygen. To adapt hypoxia, some changes in blood cells occur in the body. The aim of this study was to evaluate the effect of ghrelin on different types of blood cell in normobaric hypoxia situation.

  18. Beta-Adrenergic signaling in rat heart is similarly affected by continuous and intermittent normobaric hypoxia

    Czech Academy of Sciences Publication Activity Database

    Hahnová, K.; Kašparová, D.; Žurmanová, J.; Neckář, Jan; Kolář, František; Novotný, J.

    2016-01-01

    Roč. 35, č. 2 (2016), s. 165-173. ISSN 0231-5882 R&D Projects: GA ČR(CZ) GAP303/12/1162 Institutional support: RVO:67985823 Keywords : rat myocardium * chronic hypoxia * beta-adrenergic receptors * adenylyl cyclase Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.173, year: 2014

  19. The influence of chronic intermittent hypoxia on insulin function in OSAHS patients%慢性间歇低氧对阻塞性睡眠呼吸暂停低通气综合征患者胰岛素功能的影响

    Institute of Scientific and Technical Information of China (English)

    徐春明; 朱晔涵; 王姝; 黄建安

    2010-01-01

    目的 探讨慢性间歇低氧及继发的氧化应激对OSAHS患者胰岛素抵抗(IR)、胰腺β细胞功能的影响.方法 研究纳入15例单纯性鼾症患者、31例轻中度OSAHS患者及34例重度OSAHS患者.其中单纯性鼾症患者15例,男14例,女1例;轻中度OSAHS患者31例,男29例,女2例;重度OSAHS患者34人,男31例,女3例.所有患者收集一般临床资料,采用多导睡眠仪整晚监测取得夜间睡眠资料.用ELISA法检测8异前列腺素(8-isoprostane)、空腹血胰岛素(FINS),分光光度计法检测谷胱甘肽过氧化物酶(GSH-Px).采用稳态模型胰岛素抵抗指数(HOMA-IR)、FINS评价IR,稳态模型胰腺β细胞功能指数(HOMA-β)评价胰腺β细胞功能.三组数据间的比较采用多个独立样本非参数检验(Kruskal-Wallis H 检验),两两比较采用Nemenyi检验.数据间的相关性采用spearman秩相关分析,采用多元线性回归分析排除数据间的干扰.计数资料采用χ2检验.结果 随着OSAHS病情的加重,3组患者血清8-异前列腺素、GSH-Px、空腹血糖(FBG)、FINS及HOMA-IR整体比较均存在统计学差异(P=0.0034,P0.05).血清氧减指数(ODI)、血氧饱和度0.05).结论 OSAHS特征性的慢性间歇低氧与IR独立相关,与低氧严重程度相比,IR与氧减次数的联系更密切.OSAHS增强的氧化应激与IR独立相关,未发现胰腺β细胞功能和慢性间歇低氧及继发的氧化应激之间存在相关性.%Objective To discuss the influence of chronic intermittent hypoxia and secondum oxidative stress on insulin resistance and the function of Pancreatic β cells in OSAHS patients. Methods 15 patients with primary snoring, 31 patients with light to moderate OSAHS and 34 patients with severe OSAHS were investigated. General clinical data of every patient were collected, while nocturnal data were gained by using PSG with entire night monitor. 8-isoprostane and fasting insulin (FINS) were detected through ELISA; GSH-Px through Spectrophotometer

  20. 慢性间歇低氧对大鼠肝细胞IRS-2、 FoxO1表达的影响%Effects of chronic intermittent hypoxia on IRS-2 and FoxO1 expression in rat heptocytes

    Institute of Scientific and Technical Information of China (English)

    李娜娜; 任寿安

    2015-01-01

    .Methods Twenty-four healthy male Sprauge-Dawley rats at 6-week age were divided into normal control group (NC group),chronic intermittent hypoxia for 4 weeks group (CIH4 group) and chronic intermittent hypoxia for 8 weeks group (CIH8 group) according to random number table,with 8 rats in each group.CIH4 group and CIH8 group were placed in intermittent low oxygen cabin for 8 hours per day,the minimum oxygen concentration was 6%-8%.NC group was placed in normal air cabin.Fasting blood glucose and fasting insulin level were measured on 4th week,8th week and after an overnight fast of 12 hours on 8th week in CIH4,CIH8 and NC group,respectively.Homeostatic model assessment of insulin resistance index (HOMA-IR) and insulin sensitive index (ISI) were used to evaluate insulin resistance.HE staining was used for morphologic study of liver.IRS-2 and FoxO1 expression in heptocytes were analyzed by immunohistochemistry.Average gray value was used to represent the protein expression,and which was inversely proportional to average gray value.Results Compared with NC group,CIH4 and CIH8 group had elevated fasting blood glucose,fasting insulin,HOMA-IR,and reduced ISI,especially in CIH8 group (F =50.23-90.26,all P < 0.05).Compared with NC group,the expression of IRS-2 decreased in CIH4 and CIH8 group;the expression of FoxO1 increased in CIH4 and CIH8 group with the re-distribution in the nucleus,especially in CIH8 group (F =69.46,618.94,all P < 0.05).Pearson correlation analysis showed that HOMA-IR was positively correlated with the average gray value of IRS-2 (r =0.857,P < 0.05),but was negatively correlated with the average gray value of FoxO1 (r =-0.926,P < 0.05).ISI was negatively correlated with the average gray value of IRS-2 (r =-0.823,P < 0.05) and was positively correlated with the average gray value of FoxO1 (r=0.848,P<0.05).Conclusions In intermittent hypoxia,the liver is damaged along with the occurrence of insulin resistance and the abnormal expression of IRS-2 and

  1. 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.

  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. Brain Development after Neonatal Intermittent Hyperoxia-Hypoxia in the Rat Studied by Longitudinal MRI and Immunohistochemistry

    OpenAIRE

    Morken, Tora Sund; Nyman, Axel Karl Gottfrid; Sandvig, Ioanna; Torp, Sverre Helge; Skranes, Jon Sverre; Goa, Pål Erik; Brubakk, Ann-Mari; Widerøe, Marius

    2013-01-01

    Background: Neonatal intermittent hyperoxia-hypoxia (IHH) is involved in the pathogenesis of retinopathy of prematurity. Whether similar oxygen fluctuations will create pathological changes in the grey and white matter of the brain is unknown. Methods: From birth until postnatal day 14 (P14), two litters (total n = 22) were reared in IHH: hyperoxia (50% O2) interrupted by three consecutive two-minute episodes of hypoxia (12% O2) every sixth hour. Controls (n = 8) were rea...

  4. 慢性间歇低氧对大鼠肝脏的损伤及4-羟基-2,2,6,6-四甲基哌啶的干预作用%Hepatic injury in rats exposed to chronic intermittent hypoxia and the effect of tempol

    Institute of Scientific and Technical Information of China (English)

    姜秋芳; 陈宝元; 董丽霞; 林慧; 孔铖英; 张静; 郑立文

    2012-01-01

    Objective To investigate the mechanism of liver injury in rats exposed to chronic intermittent hypoxia (CIH) and to investigate the effect of tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl or 4-hydroxy-TEMPO).Methods A CIH animal model of rats was established to mimic the intermittent hypoxia/re-oxygenation(IH/ROX) of obstructive sleep apnea syndrome in humans.Thirty-two healthy male Wistar rats were randomly assigned to 4 groups:conventional intermittent hypoxia group( CIH group),intermittent hypoxia Tempol treatment group ( CIH + T group),intermittent hypoxia normal saline matched group( CIH + NS group),and normoxic control group( NC group),with 8 rats in each group.The frequency of every CIH group was 30 times/h,and the minimum oxygen concentration was 5%.After the experiment,sections of liver were stained with hematoxylin-eosin ( HE ) and the levels of nuclear factor-kappaB (NF-tcB),glutathione peroxidase (GSH-PX) and malondialdehyde (MDA) in rat liver homogenate were measured.Results Liver histology revealed that the C1H group and the CIH + NS group showed hepatocellular swelling with rarefaction of the cytoplasm,hyperchromatosis and hepatocellular membrane disruption,but the liver histology of the CIH + T group and the NC group was normal.Compared with the NC group,the levels of NF-κB and MDA in the CIH group [ (12.4 ±2.0) ng/g,(101 +22) μ,mol/g]and the CIH + NS group [ ( 12.2 ± 1.9 ) ng/g,( 99 ± 18 ) μmol/g] were increased( all P < 0.05 ),but the activities of GSH-PX [ ( 88 ± 17 ) U/mg,(90 + 15 ) U/mg ] were decreased ( all P < 0.05 ).Compared with the CIH + NS group and the CIH group,the activity of GSH-PX in the CIH + T group [ ( 181 + 29 ) U/mg ]was increased(P <0.05),but the levels of NF-κB [ (7.8 ± 1.3) ng/g] and MDA [ (59 ± 10) μmol/g]were decreased(all P < 0.05 ).The levels of GSH-PX and MDA in the CIH + T group were not significantly different compared to the NC group ( P were 0.242,0.177 respectively),but the level of NF

  5. Dietary Polyunsaturated Fatty Acids Alter Myocardial Protein Kinase C Expression and Affect Cardioprotection Induced by Chronic Hypoxia

    Czech Academy of Sciences Publication Activity Database

    Hlaváčková, M.; Neckář, Jan; Ježková, J.; Balková, P.; Staňková, B.; Nováková, O.; Kolář, František; Novák, F.

    2007-01-01

    Roč. 232, č. 6 (2007), s. 823-832. ISSN 1535-3702 R&D Projects: GA ČR(CZ) GA305/04/0465; GA MŠk(CZ) 1M0510 Grant ostatní: GA UK(CZ) 110/2005/C/PrF Institutional research plan: CEZ:AV0Z50110509 Keywords : chronic intermittent hypoxia * cardioprotection * PKC Subject RIV: ED - Physiology Impact factor: 1.979, year: 2007

  6. Effect of intermittent hypoxia and exercise on blood rheology and oxygen transport in trained rats.

    Science.gov (United States)

    Núñez-Espinosa, Cristian; Douziech, Anne; Ríos-Kristjánsson, Juan Gabriel; Rizo, David; Torrella, Joan Ramon; Pagès, Teresa; Viscor, Ginés

    2014-02-01

    Intermittent hypobaric hypoxia (IHH) exposure, accompanied or not with active recovery, can help to skeletal muscle repair. However, the erythropoietic response elicited can disturb blood rheology and thus alter the oxygen delivery to tissues. Male Sprague-Dawley rats were studied in two basal states: untrained and trained and compared with early (1-3 days) and late (7-14 days) stages of damage recovery in three groups of trained rats that had suffered skeletal muscle injury: Control, passive recovery rats; HYP, rats exposed to IHH after muscle damage; and EHYP, trained rats that performed light aerobic exercise sessions in addition to IHH. Hematocrit, RBC count and hemoglobin were only elevated in the late stage of recovery in HYP (13%; 14% and 8%) and EHYP (18%; 13% and 15%) groups. Blood viscosity increased about double for EHYP rats. It is concluded that intermittent exposure to hypobaric hypoxia in combination with light aerobic exercise in normoxia has an erythropoietic effect, but also provides advantageous hemorheological conditions for the perfusion of damaged muscle. PMID:24373840

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

    Science.gov (United States)

    Serebrovskaya, Tatiana V; Xi, Lei

    2015-01-01

    Intermittent hypoxia (IH) often occurs in early infancy in both preterm and term infants and especially at 36-44 weeks postmenstrual age. These episodes of IH could result from sleep-disordered breathing or may be temporally unrelated to apnea or bradycardia events. There are numerous reports indicating adverse effects of IH on development, behavior, academic achievement, and cognition in children with sleep apnea syndrome. It remains uncertain about the exact causative relationship between the neurocognitive and behavioral morbidities and IH and/or its associated sleep fragmentation. On the other hand, well-controlled and moderate IH 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 maximizing its potential utility as an effective therapeutic tool in pediatric patients. PMID:26042211

  8. The radiation response of cells recovering after chronic hypoxia

    International Nuclear Information System (INIS)

    Experiments were performed to study the influence of hypoxic pretreatment on the radiation response of A431 human squamous carcinoma cells. Reaeration for 10 min after chronic hypoxia (greater than 2 h) was found to enhance the radiosensitivity of A431 cells, and the maximal effect was seen for those cells reaerated after 12 h of hypoxia. The radiosensitivity enhancement for reaerated cells after 12 h of hypoxia was maximized by 5 min after the return to aerobic conditions and reached the control level by 12 h of reaeration. This enhanced radiosensitive state was characterized by a reduced shoulder region and increased slope of the radiation dose-response curve for cells in both the exponential and plateau phases of growth. There was a slight increase in the number of G1 and decrease in the number of S and G2 + M cells for both exponential- and plateau-phase cultures following 12 h hypoxic treatment. Although growth inhibition induced by 12 h of hypoxia was seen for cells in the exponential phase, there was no cell number change in the plateau-phase culture after hypoxia. Plating efficiency (PE) of cells in both growth phases was reduced by 30% after hypoxia. Furthermore, in the exponential-phase culture, the extent of reduction in PE after hypoxia was similar among cells in different phases of the cell cycle. Although S-phase cells in exponentially growing cultures were relatively more resistant to radiation than G1 and G2 + M cells, the cell age-response pattern was the same whether the cells had been aerobic or hypoxic before reaeration and irradiation. Furthermore, the enhancement ratio associated with reaeration after 12 h of hypoxia for these three subpopulations of cells was 1.3. Our results indicate that the increase in radiosensitivity due to reaeration after chronic hypoxia is unlikely to be related to the changes of cell cycle stage and growth phase during hypoxic treatment

  9. Influences of chronic intermittent hypoxia on morphology and ultra-structure of renal tissue in the rats%慢性间歇低氧对大鼠肾脏组织细胞形态和超微结构的影响

    Institute of Scientific and Technical Information of China (English)

    邵川; 鲁沈源; 励雯静; 隆玄; 李善群; 白春学

    2011-01-01

    目的 探讨慢性间歇低氧( CIH)对肾脏组织细胞形态和超微结构的影响及其意义.方法 采用自制的CIH动物舱,通过控制程序调节舱内氧气、氮气的输入流量,使得每1次缺氧循环时间为1 min,氧气浓度循环于7%~21%之间.将18只大鼠随机分成2组,每组9只,分别为对照组和CIH组.将CIH组置于动物舱给予间歇缺氧,每天8h,持续35 d.对照组动物舱内输入空气,其余条件同CIH组.HE染色观察肾脏组织细胞形态,透射电镜观察肾近曲小管上皮细胞超微结构.结果 HE染色示对照组肾脏组织形态基本正常,CIH组肾小球高度肿胀,肾球囊狭窄,近曲小管上皮细胞高度肿胀,管腔狭窄.透射电镜观察发现对照组肾脏超微结构基本正常,CIH组肾近曲小管上皮细胞出现空泡变性、核膜肿胀和线粒体肿胀.结论 CIH导致肾脏组织细胞水肿变性和超微结构异常,可能与OSAHS引起肾脏损害有关.%Objective To discuss the influence of chronic intermittent hypoxia (CIH) on morphology and ultra-structure of renal tissue and its significance. Methods The oxygen and nitrogen input flow of the self-made CIH animal cabin could be adjusted through control procedures, so as to make sure the every hypoxic cycle lasted for 1 minute and the oxygen concentration within the cabin fluctuated between 7% - 21 %. 18 rats were randomly divided into control and CIH groups respectively with each of nine. Rats of CIH group were exposed to intermittent hypoxia in the cabin 8 hours per day for successive 35 days. Oxygen and nitrogen were replaced by air for rats of control group with other conditions being the same as CIH group. Tissue morphology of kidney was examined through HE dyeing and ultra-structures of proximal tubular cells were observed by transmission electron microscopy. Results HE staining showed the renal tissue morphology of control group was normal While in CIH group, high degree of swelling of glomerulus and

  10. 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

  11. Circulating endothelin-1 concentrations in patients with chronic hypoxia.

    OpenAIRE

    Ferri, C; C. Bellini; Angelis, C; De Siati, L; A. Perrone; Properzi, G; Santucci, A.

    1995-01-01

    AIMS--To evaluate the behavior of plasma endothelin-1 in patients with chronic hypoxia. METHODS--Fifteen male patients (mean age 52.1 +/- 3.1 years) with mild chronic obstructive pulmonary disease (COPD) were studied. Twelve healthy men (mean age 48.3 +/- 5.4 years) served as controls. Both patients and controls underwent standard pulmonary function tests, echocardiographic evaluation, and arterial blood gas evaluation. Blood samples for endothelin-1 assay were taken from a previously incannu...

  12. Long-Term Intermittent Hypoxia Elevates Cobalt Levels in the Brain and Injures White Matter in Adult Mice

    Science.gov (United States)

    Veasey, Sigrid C.; Lear, Jessica; Zhu, Yan; Grinspan, Judith B.; Hare, Dominic J.; Wang, SiHe; Bunch, Dustin; Doble, Philip A.; Robinson, Stephen R.

    2013-01-01

    Study Objectives: Exposure to the variable oxygenation patterns in obstructive sleep apnea (OSA) causes oxidative stress within the brain. We hypothesized that this stress is associated with increased levels of redox-active metals and white matter injury. Design: Participants were randomly allocated to a control or experimental group (single independent variable). Setting: University animal house. Participants: Adult male C57BL/6J mice. Interventions: To model OSA, mice were exposed to long-term intermittent hypoxia (LTIH) for 10 hours/day for 8 weeks or sham intermittent hypoxia (SIH). Measurements and Results: Laser ablation-inductively coupled plasma-mass spectrometry was used to quantitatively map the distribution of the trace elements cobalt, copper, iron, and zinc in forebrain sections. Control mice contained 62 ± 7 ng cobalt/g wet weight, whereas LTIH mice contained 5600 ± 600 ng cobalt/g wet weight (P < 0.0001). Other elements were unchanged between conditions. Cobalt was concentrated within white matter regions of the brain, including the corpus callosum. Compared to that of control mice, the corpus callosum of LTIH mice had significantly more endoplasmic reticulum stress, fewer myelin-associated proteins, disorganized myelin sheaths, and more degenerated axon profiles. Because cobalt is an essential component of vitamin B12, serum methylmalonic acid (MMA) levels were measured. LTIH mice had low MMA levels (P < 0.0001), indicative of increased B12 activity. Conclusions: Long-term intermittent hypoxia increases brain cobalt, predominantly in the white matter. The increased cobalt is associated with endoplasmic reticulum stress, myelin loss, and axonal injury. Low plasma methylmalonic acid levels are associated with white matter injury in long-term intermittent hypoxia and possibly in obstructive sleep apnea. Citation: Veasey SC; Lear J; Zhu Y; Grinspan JB; Hare DJ; Wang S; Bunch D; Doble PA; Robinson SR. Long-term intermittent hypoxia elevates cobalt

  13. The Role of Intermittent Hypoxia on the Proliferative Inhibition of Rat Cerebellar Astrocytes.

    Directory of Open Access Journals (Sweden)

    Sheng-Chun Chiu

    Full Text Available Sleep apnea syndrome, characterized by intermittent hypoxia (IH, is linked with increased oxidative stress. This study investigates the mechanisms underlying IH and the effects of IH-induced oxidative stress on cerebellar astrocytes. Rat primary cerebellar astrocytes were kept in an incubator with an oscillating O2 concentration between 20% and 5% every 30 min for 1-4 days. Although the cell loss increased with the duration, the IH incubation didn't induce apoptosis or necrosis, but rather a G0/G1 cell cycle arrest of cerebellar astrocytes was noted. ROS accumulation was associated with cell loss during IH. PARP activation, resulting in p21 activation and cyclin D1 degradation was associated with cell cycle G0/G1 arrest of IH-treated cerebellar astrocytes. Our results suggest that IH induces cell loss by enhancing oxidative stress, PARP activation and cell cycle G0/G1 arrest in rat primary cerebellar astrocytes.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Role of mitochondrial hydrogen peroxide induced by intermittent hypoxia in airway epithelial wound repair in vitro.

    Science.gov (United States)

    Hamada, Satoshi; Sato, Atsuyasu; Hara-Chikuma, Mariko; Satooka, Hiroki; Hasegawa, Koichi; Tanimura, Kazuya; Tanizawa, Kiminobu; Inouchi, Morito; Handa, Tomohiro; Oga, Toru; Muro, Shigeo; Mishima, Michiaki; Chin, Kazuo

    2016-05-15

    The airway epithelium acts as a frontline barrier against various environmental insults and its repair process after airway injury is critical for the lung homeostasis restoration. Recently, the role of intracellular reactive oxygen species (ROS) as transcription-independent damage signaling has been highlighted in the wound repair process. Both conditions of continuous hypoxia and intermittent hypoxia (IH) induce ROS. Although IH is important in clinical settings, the roles of IH-induced ROS in the airway repair process have not been investigated. In this study, we firstly showed that IH induced mitochondrial hydrogen peroxide (H2O2) production and significantly decreased bronchial epithelial cell migration, prevented by catalase treatment in a wound scratch assay. RhoA activity was higher during repair process in the IH condition compared to in the normoxic condition, resulting in the cellular morphological changes shown by immunofluorescence staining: round cells, reduced central stress fiber numbers, pronounced cortical actin filament distributions, and punctate focal adhesions. These phenotypes were replicated by exogenous H2O2 treatment under the normoxic condition. Our findings confirmed the transcription-independent role of IH-induced intracellular ROS in the bronchial epithelial cell repair process and might have significant implications for impaired bronchial epithelial cell regeneration. PMID:27093911

  16. Pulmonary arterial hypertension in rats due to age-related arginase activation in intermittent hypoxia.

    Science.gov (United States)

    Nara, Akina; Nagai, Hisashi; Shintani-Ishida, Kaori; Ogura, Sayoko; Shimosawa, Tatsuo; Kuwahira, Ichiro; Shirai, Mikiyasu; Yoshida, Ken-ichi

    2015-08-01

    Pulmonary arterial hypertension (PAH) is prevalent in patients with obstructive sleep apnea syndrome (OSAS). Aging induces arginase activation and reduces nitric oxide (NO) production in the arteries. Intermittent hypoxia (IH), conferred by cycles of brief hypoxia and normoxia, contributes to OSAS pathogenesis. Here, we studied the role of arginase and aging in the pathogenesis of PAH in adult (9-mo-old) and young (2-mo-old) male Sprague-Dawley rats subjected to IH or normoxia for 4 weeks and analyzed them with a pressure-volume catheter inserted into the right ventricle (RV) and by pulsed Doppler echocardiography. Western blot analysis was conducted on arginase, NO synthase isoforms, and nitrotyrosine. IH induced PAH, as shown by increased RV systolic pressure and RV hypertrophy, in adult rats but not in young rats. IH increased expression levels of arginase I and II proteins in the adult rats. IH also increased arginase I expression in the pulmonary artery endothelium and arginase II in the pulmonary artery adventitia. Furthermore, IH reduced pulmonary levels of nitrate and nitrite but increased nitrotyrosine levels in adult rats. An arginase inhibitor (N(ω)-hydroxy-nor-1-arginine) prevented IH-induced PAH and normalized nitrite and nitrate levels in adult rats. IH induced arginase up-regulation and PAH in adult rats, but not in young rats, through reduced NO production. Our findings suggest that arginase inhibition prevents or reverses PAH. PMID:25490411

  17. Role of hippocampal neuronal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia%海马神经元细胞内钙超载对慢性间歇低氧小鼠认知功能的损伤及盐酸美金刚的保护作用

    Institute of Scientific and Technical Information of China (English)

    明红; 陈锐; 王婧; 琚静美; 孙丽; 张国兴

    2014-01-01

    Objective To investigate the role of hippocampal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia.Methods 45 ICR male mice were randomly divided into 3 groups:the unhandled control group (UC group,n =15),the chronic intermittent hypoxia (CIH group,n =15) and the pretreatment memantine group (MEM group,n =15).CIH and MEM mice were subjected to intermittent hypoxia while UC mice to room air for 8 h per day during 4 weeks.Mice in the MEM group were pretreated with memantine (5 mg/kg) by intraperitoneal injection before the cycle started,and those in the UC group and the CIH group were treated with same volume of physiological saline.Neurobehavioral assessments were performed by Open filed and Morris water maze,[Ca2+] i in hippocampal neurons was evaluate by flow cytometry,and the expression of cleaved caspase-3,phospho-ERK1/2 in hippocampus were detected by Western blotting.Results Compared with the UC group,CIH mice displayed markedly more locomotor activity (P < 0.05) in Open filed test,longer mean escape latency (P < 0.05),less number of times of crossing the platform (P <0.01) and less percentage of time in target quadrant (P <0.01).Furthermore,exposure to CIH enhanced [Ca2+]i (vs.UC mice,155 ±12 vs.92 ±8,P<0.01),and up-regulated the expression of cleaved caspase-3 (P < 0.01),but down-regulated the level of phospho-ERK1/2 (P < 0.05) in the hippocampus.Pre-treatment with memantine significantly decreased hyperlocomotion (P < 0.05),attenuated memory deficit (P < 0.05),mitigated [Ca2 +] i (vs.CIH mice,90 ± 8 vs.155 ± 12,P < 0.01),decrease the expression of cleaved caspase-3 (P < 0.01),but increased the level of phosphoERK1/2(P < 0.05) comparing to the CIH group.Conclusion The neurobehavioral impairments induced by CIH are mediated,at least in part,by intracellular calcium concentration overload,neuron apoptosis

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

    Directory of Open Access Journals (Sweden)

    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

  19. Brain Development after Neonatal Intermittent Hyperoxia-Hypoxia in the Rat Studied by Longitudinal MRI and Immunohistochemistry

    OpenAIRE

    Morken, Tora Sund; Nyman, Axel Karl Gottfrid; Sandvig, Ioanna; Torp, Sverre Helge; Skranes, Jon; Goa, Pål Erik; Brubakk, Ann-Mari; Widerøe, Marius

    2013-01-01

    Background Neonatal intermittent hyperoxia-hypoxia (IHH) is involved in the pathogenesis of retinopathy of prematurity. Whether similar oxygen fluctuations will create pathological changes in the grey and white matter of the brain is unknown. Methods From birth until postnatal day 14 (P14), two litters (total n = 22) were reared in IHH: hyperoxia (50% O2) interrupted by three consecutive two-minute episodes of hypoxia (12% O2) every sixth hour. Controls (n = 8) were reared in room-air (20.9% ...

  20. Ontogenetic Aspects of Cardiac Adaptation to Chronic Hypoxia

    Czech Academy of Sciences Publication Activity Database

    Ošťádal, Bohuslav; Ošťádalová, Ivana; Charvátová, Z.; Kolář, František

    New York : Springer, 2013 - (Ošťádal, B.; Dhalla, N.), s. 99-110 ISBN 978-1-4614-5202-7. - (Advances in Biochemistry in Health and Disease) R&D Projects: GA ČR(CZ) GAP303/12/1162 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : cardiac adaptation * ontogeny * chronic hypoxia Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  1. Repetitive acute intermittent hypoxia increases growth/neurotrophic factor expression in non-respiratory motor neurons.

    Science.gov (United States)

    Satriotomo, I; Nichols, N L; Dale, E A; Emery, A T; Dahlberg, J M; Mitchell, G S

    2016-05-13

    Repetitive acute intermittent hypoxia (rAIH) increases growth/trophic factor expression in respiratory motor neurons, thereby eliciting spinal respiratory motor plasticity and/or neuroprotection. Here we demonstrate that rAIH effects are not unique to respiratory motor neurons, but are also expressed in non-respiratory, spinal alpha motor neurons and upper motor neurons of the motor cortex. In specific, we used immunohistochemistry and immunofluorescence to assess growth/trophic factor protein expression in spinal sections from rats exposed to AIH three times per week for 10weeks (3×wAIH). 3×wAIH increased brain-derived neurotrophic factor (BDNF), its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and phosphorylated TrkB (pTrkB) immunoreactivity in putative alpha motor neurons of spinal cervical 7 (C7) and lumbar 3 (L3) segments, as well as in upper motor neurons of the primary motor cortex (M1). 3×wAIH also increased immunoreactivity of vascular endothelial growth factor A (VEGFA), the high-affinity VEGFA receptor (VEGFR-2) and an important VEGF gene regulator, hypoxia-inducible factor-1α (HIF-1α). Thus, rAIH effects on growth/trophic factors are characteristic of non-respiratory as well as respiratory motor neurons. rAIH may be a useful tool in the treatment of disorders causing paralysis, such as spinal injury and motor neuron disease, as a pretreatment to enhance motor neuron survival during disease, or as preconditioning for cell-transplant therapies. PMID:26944605

  2. Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia

    OpenAIRE

    Kaushal, Navita; Ramesh, Vijay; Gozal, David

    2012-01-01

    Intermittent hypoxia (IH) and sleep fragmentation (SF) are major manifestations of sleep apnea, a frequent condition in aging humans. Sleep perturbations are frequent in Alzheimer's disease (AD) and may underlie the progression of disease. We hypothesized that acute short-term IH, SF, and their combination (IH+SF) may reveal unique susceptibility in sleep integrity in a murine model of AD. The effects of acute IH, SF, and IH+SF on sleep architecture, delta power, sleep latency, and core body ...

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

    OpenAIRE

    Azqueta Carmen; Martin-Henao Gregorio; Ricart Antoni; Ventura Josep-Lluis; Pagès Teresa; Javierre Casimiro; Viscor Ginés; Segura Ramon

    2009-01-01

    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...

  4. Combined intermittent hypobaric hypoxia and muscle electro-stimulation: a method to increase circulating progenitor cell concentration?

    OpenAIRE

    Corral, Luisa; Javierre, Casimiro; Blasi, Juan; Viscor, Ginés; Ricart, Antoni; Ventura, Josep Lluis

    2014-01-01

    Background Our goal was to test whether short-term intermittent hypobaric hypoxia (IHH) at a level well tolerated by healthy humans could, in combination with muscle electro-stimulation (ME), mobilize circulating progenitor cells (CPC) and increase their concentration in peripheral circulation. Methods Nine healthy male subjects were subjected, as the active group (HME), to a protocol involving IHH plus ME. IHH exposure consisted of four, three-hour sessions at a barometric pressure of 540 hP...

  5. Repair of potentially lethal radiation damage in human squamous carcinoma cells after chronic hypoxia

    International Nuclear Information System (INIS)

    The purpose of this study was to examine the repair of radiation-induced potentially lethal damage in A431 and CaSki cells after chronic hypoxia. Cells in exponential phase are subjected to hypoxia (4 h of hypoxia. The repair returned to aerobic control level by 3 h of reoxygenation. PLDR of A431 cells reached maximum at about 9 h after irradiation in cells reoxygenated for 10 min after hypoxia. However, the repair is maximum at 6 h in cells reoxygenated for 3 h after hypoxia and in aerobic cells not previously exposed to hypoxia. Reoxygenation after chronic hypoxia did not affect the PLDR capacity and repair kinetics of CaSki cells. The results suggest that radiosensitization by reoxygenation after chronic hypoxia is not related to inhibition of PLDR. 14 refs., 3 figs

  6. Effect of intermittent hypoxia on arcuate nucleus in the leptin-deficient rat.

    Science.gov (United States)

    Ciriello, John; Moreau, Jason M; McCoy, Aaron; Jones, Douglas L

    2016-07-28

    Intermittent hypoxia (IH) is a major pathophysiological consequence of obstructive sleep apnea. Recently, it has been shown that IH results in changes in body energy balance, leptin secretion and concomitant alterations in arcuate nucleus (ARC). In this study, the role of leptin on these changes was investigated in leptin-deficient rats exposed to IH or normoxic control conditions. Body weights, consumatory and locomotor behaviours, and protein signaling in ARC were assessed immediately after IH exposure. Compared to normoxia, IH altered body weight, food intake, locomotor pattern, and the plasma concentration of leptin and angiotensin II in the wild-type rat. However, these changes were not observed in the leptin-deficient rat. Within ARC of wild-type animals, IH increased phosphorylated signal transducer and activator of transcription 3 and pro-opiomelanocortin protein expression, but not in the leptin-deficient rat. The long-form leptin receptor protein expression was not altered following IH in either rat strain. These data suggest that leptin is involved in mediating the alterations to body energy balance and ARC activity following IH. PMID:27222924

  7. Intermittent Hypoxia Does not Elicit Memory Impairment in Spinal Cord Injury Patients.

    Science.gov (United States)

    Navarrete-Opazo, Angela; Alcayaga, Julio; Testa, Denisse; Quinteros, Ana Luisa

    2016-06-01

    There is a critical need for new therapeutic strategies to restore motor function in patients with spinal cord injuries (SCIs), without unwanted effects. Intermittent hypoxia (IH) induces plasticity in spared synaptic pathways to motor neurons below the level of injury, which can be harnessed to elicit motor recovery in incomplete SCI patients. However, there is conflicting evidence regarding the effects of IH on memory function. The aim of this study was to assess episodic verbal and visual memory function with the Complutense verbal learning test (TAVEC) and the Rey-Osterrieth Complex Figure Test (ROCF), respectively, before and after a 4-week protocol of repetitive IH combined with body weight-supported treadmill training (BWSTT) in incomplete ASIA C and D SCI subjects. Subjects received either IH (cycling 9%/21% FiO2 every 1.5 min, 15 cycles per day) or continued normoxia (Nx, 21% FiO2) combined with 45 min of BWSTT for 5 consecutive days, followed by 3 times per week IH and BWSTT for 3 additional weeks. ROCF Z scores between IH plus BWSTT and Nx plus BWSTT were not significantly different (p = .43). Compared with baseline, IH and BWSTT group showed a significantly greater (p .05). Our results suggest that a 4-week protocol of moderate IH does not elicit visual or verbal memory impairment. Thus, repetitive IH may be a safe therapeutic approach to incomplete spinal cord injury patients, without deleterious cognitive effects. PMID:27084733

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

    Science.gov (United States)

    Kesavan, Kalpashri; Frank, Paul; Cordero, Daniella M.; Benharash, Peyman; Harper, Ronald M.

    2016-01-01

    Background Apnea of Prematurity (AOP) is common, affecting the majority of infants born at 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. Objective 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. Methods 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. Results Fewer respiratory pauses occurred during vibration periods, relative to baseline (ppremature 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 intermittent hypoxia in premature neonates. Trial Registration ClinicalTrials.gov NCT02641249 PMID:27304988

  9. Resveratrol attenuates intermittent hypoxia-induced macrophage migration to visceral white adipose tissue and insulin resistance in male mice.

    Science.gov (United States)

    Carreras, Alba; Zhang, Shelley X L; Almendros, Isaac; Wang, Yang; Peris, Eduard; Qiao, Zhuanhong; Gozal, David

    2015-02-01

    Chronic intermittent hypoxia during sleep (IH), as occurs in sleep apnea, promotes systemic insulin resistance. Resveratrol (Resv) has been reported to ameliorate high-fat diet-induced obesity, inflammation, and insulin resistance. To examine the effect of Resv on IH-induced metabolic dysfunction, male mice were subjected to IH or room air conditions for 8 weeks and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin, and leptin were obtained, homeostatic model assessment of insulin resistance index levels were calculated, and insulin sensitivity tests (phosphorylated AKT [also known as protein kinase B]/total AKT) were performed in 2 visceral white adipose tissue (VWAT) depots (epididymal [Epi] and mesenteric [Mes]) along with flow cytometry assessments for VWAT macrophages and phenotypes (M1 and M2). IH-Veh and IH-Resv mice showed initial reductions in food intake with later recovery, with resultant lower body weights after 8 weeks but with IH-Resv showing better increases in body weight vs IH-Veh. IH-Veh and IH-Resv mice exhibited lower fasting glucose levels, but only IH-Veh had increased homeostatic model assessment of insulin resistance index vs all 3 other groups. Leptin levels were preserved in IH-Veh but were significantly lower in IH-Resv. Reduced VWAT phosphorylated-AKT/AKT responses to insulin emerged in both Mes and Epi in IH-Veh but normalized in IH-Resv. Increases total macrophage counts and in M1 to M2 ratios occurred in IH-Veh Mes and Epi compared all other 3 groups. Thus, Resv ameliorates food intake and weight gain during IH exposures and markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy for metabolic morbidity in the context of sleep apnea. PMID:25406018

  10. Reversible blunting of arousal from sleep in response to intermittent hypoxia in the developing rat

    OpenAIRE

    Darnall, R.A.; McWilliams, S.; Schneider, R. W.; Tobia, C. M.

    2010-01-01

    Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups wer...

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Intermittent hypoxia reduces microglia proliferation and induces DNA damage in vitro

    Science.gov (United States)

    Liu, Song; Wang, Zhonghua; Xu, Bo; Chen, Kui; Sun, Jinyuan; Ren, Lianping

    2016-01-01

    Objective(s): Intermittent hypoxia (IH), caused by obstructive sleep apnea (OSA), could cause hippocampus or neuron damage through multiple signaling pathways, while the underlying mechanisms are still unclear. Thus, the present study aimed to explore the effect of IH on the biological functions of microglia cells. Materials and Methods: Cell proliferation of BV2 cells after exposure to IH were observed by MTT assay and then DNA damage was detected by comet assay. RNA-sequencing assay was performed in cells under IH condition and normal conditions to find out the differentially expressed genes, which were further confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot assay. Results: As results, IH inhibited the proliferation of BV2 cells, as well as caused DNA damage. RNA-sequencing assay revealed 4 differentially expressed genes (p21, Cyclin D1, Cyclin E2, and Gadd45α) which were associated with the network of P53 signaling pathways in BV2 cells, among which, p21 and Gadd45α were dramatically increased while Cyclin D1 and Cyclin E2 were both decreased significantly. Moreover, inflammatory factors including IL-6, TNF-α and iNOS were significantly up-regulated in microglia cells under IH conditions for 8 hr. Conclusion: Our results indicated that IH could inhibit cyclin D1 and cyclin E2 expression via initiating multiple P53 pathways, which further blocked cell cycle transition and attenuated proliferative capability of BV2 cells. Meanwhile, IH activated inflammation reactions in BV2 cells. Present study elaborate the effects of IH on biological functions of microglia and provide theoretical foundation for further study on new therapy methods for OSA.

  13. Diaphragm long-term facilitation following acute intermittent hypoxia during wakefulness and sleep.

    Science.gov (United States)

    Terada, J; Mitchell, G S

    2011-05-01

    Acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). Here, we tested four hypotheses in unanesthetized, spontaneously breathing rats using radiotelemetry for EEG and diaphragm electromyography (Dia EMG) activity: 1) AIH induces LTF in Dia EMG activity; 2) diaphragm LTF (Dia LTF) is more robust during sleep vs. wakefulness; 3) AIH (or repetitive AIH) disrupts natural sleep-wake architecture; and 4) preconditioning with daily AIH (dAIH) for 7 days enhances Dia LTF. Sleep-wake states and Dia EMG were monitored before (60 min), during, and after (60 min) AIH (10, 5-min hypoxic episodes, 5-min normoxic intervals; n = 9), time control (continuous normoxia, n = 8), and AIH following dAIH preconditioning for 7 days (n = 7). Dia EMG activities during quiet wakefulness (QW), rapid eye movement (REM), and non-REM (NREM) sleep were analyzed and normalized to pre-AIH values in the same state. During NREM sleep, diaphragm amplitude (25.1 ± 4.6%), frequency (16.4 ± 4.7%), and minute diaphragm activity (amplitude × frequency; 45.2 ± 6.6%) increased above baseline 0-60 min post-AIH (all P 0.05). We conclude that 1) AIH induces Dia LTF during NREM sleep and wakefulness; 2) Dia LTF is greater in NREM sleep vs. QW and is abolished during REM sleep; 3) AIH and repetitive AIH disrupt natural sleep patterns; and 4) Dia LTF is unaffected by dAIH. The capacity for plasticity in spinal pump muscles during sleep and wakefulness suggests an important role in the neural control of breathing. PMID:21372099

  14. Cardioprotective adaptation of rats to intermittent hypobaric hypoxia is accompanied by the increased association of hexokinase with mitochondria

    Czech Academy of Sciences Publication Activity Database

    Wasková-Arnoštová, P.; Elsnicová, B.; Kašparová, D.; Horníková, D.; Kolář, František; Novotný, J.; Žurmanová, J.

    2015-01-01

    Roč. 119, č. 12 (2015), s. 1487-1493. ISSN 8750-7587 Institutional support: RVO:67985823 Keywords : hexokinase * mitochondrial colocalization * cardioprotection * chronic hypoxia * rat heart Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 3.056, year: 2014

  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. 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.

  17. 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

  18. 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

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

    International Nuclear Information System (INIS)

    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

  20. The autophagy associated gene, ULK1, promotes tolerance to chronic and acute hypoxia

    International Nuclear Information System (INIS)

    Background and purpose: Tumor hypoxia is associated with therapy resistance and malignancy. Previously we demonstrated that activation of autophagy and the unfolded protein response (UPR) promote hypoxia tolerance. Here we explored the importance of ULK1 in hypoxia tolerance, autophagy induction and its prognostic value for recurrence after treatment. Material and methods: Hypoxic regulation of ULK1 mRNA and protein was assessed in vitro and in primary human head and neck squamous cell carcinoma (HNSCC) xenografts. Its importance in autophagy induction, mitochondrial homeostasis and tolerance to chronic and acute hypoxia was evaluated in ULK1 knockdown cells. The prognostic value of ULK1 mRNA expression was assessed in 82 HNSCC patients. Results: ULK1 enrichment was observed in hypoxic tumor regions. High enrichment was associated with a high hypoxic fraction. In line with these findings, high ULK1 expression in HNSCC patients appeared associated with poor local control. Exposure of cells to hypoxia induced ULK1 mRNA in a UPR and HIF1α dependent manner. ULK1 knockdown decreased autophagy activation, increased mitochondrial mass and ROS exposure and sensitized cells to acute and chronic hypoxia. Conclusions: We demonstrate that ULK1 is a hypoxia regulated gene and is associated with hypoxia tolerance and a worse clinical outcome

  1. 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 recovery, combined with the ability to suppress ATP-demanding cellular functions during hypoxia, may contribute to high resilience of clams to H/R stress and help maintain energy homeostasis during frequent H/R cycles in the intertidal zone. PMID:27252455

  2. Effect of intermittent high altitude hypoxia on gene expression in rat heart and lung

    Czech Academy of Sciences Publication Activity Database

    Deindl, E.; Kolář, František; Neubauer, E.; Vogel, S.; Schaper, W.; Ošťádal, Bohuslav

    2003-01-01

    Roč. 52, č. 2 (2003), s. 147-157. ISSN 0862-8408 R&D Projects: GA ČR GA305/01/0279; GA ČR GA305/00/1659; GA MŠk LN00A069 Institutional research plan: CEZ:AV0Z5011922 Keywords : hypoxia regulated genes * transforming growth factor-Beta * vascular endothelial growth factor Subject RIV: ED - Physiology Impact factor: 0.939, year: 2003

  3. 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.

  4. Dormancy of Cancer Cells with Suppression of AKT Activity Contributes to Survival in Chronic Hypoxia

    OpenAIRE

    Hiroko Endo; Hiroaki Okuyama; Masayuki Ohue; Masahiro Inoue

    2014-01-01

    A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these c...

  5. 55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

    OpenAIRE

    Shimoda, Larissa A.

    2012-01-01

    When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in ...

  6. A cognitive deficit induced in rats by chronic intermittent cold stress is reversed by chronic antidepressant treatment

    OpenAIRE

    Danet, M.; Lapiz-Bluhm, S.; Morilak, David A

    2010-01-01

    We have previously reported that 14-days of chronic intermittent cold (CIC) stress induced a cognitive deficit in reversal learning on the rat attentional set-shifting test. This effect may be related to dysregulation of 5-HT function in orbitofrontal cortex, as a model of cognitive dysfunction in depression. To test the ability of chronic antidepressant drug treatment to reverse the cognitive deficit induced by CIC, it was first necessary to assess the temporal characteristics of the CIC-ind...

  7. Chronic intermittent diarrhea in a 14-month-old Abyssinian cat

    OpenAIRE

    Pham, Dorothy

    2009-01-01

    A 14-month-old intact, female Abyssinian cat was presented for chronic intermittent diarrhea and bilateral enlargement of the mammary glands. Gastrointestinal coccidiosis was diagnosed; therapy with sulfadi-methoxine was unsuccessful in the elimination of Isospora felis and clinical signs. Infection with Tritrichomonas foetus was diagnosed by fecal polymerase chain reaction (PCR) and successfully treated with ronidazole and dietary modification.

  8. Effects of intermittent normobaric hypoxia on the state of the CNS and cerebral circulation in children with cerebral palsy.

    Science.gov (United States)

    Yatsenko, K V; Berezovskii, V A; Deyeva, J V

    2012-01-01

    We studied the effects of intermittent normobaric hypoxia (INH) on the processes of CNS functions and cerebral circulation recovery in children with cerebral palsy (CP). Altogether, 87 patients (from 8.5 months to 12 years) with CP were examined and received the course of treatment. Clinico-neurophysiological examination was performed before the treatment and immediately after termination of the therapeutic course. Patients were divided into two groups; age and sex distributions and clinical manifestations of CP were randomized. The comparison group was formed from 34 children who received the course of the generally accepted complex therapy (medicamental treatment, massage, Bobat-therapy, Vojta-therapy at al).. The main group included 53 patients who, in addition to the same therapy, were exposed to INH using an individual apparatus for artificial mountain air, Borey-M, made in the Scientific Medico-Engineering Center NORT (Ukrainian National Academy of Sciences, Kyiv). Children of the main group were exposed to the dosed normobaric sanogenetic level hypoxia intermittently once per day. For this purpose, we used a normobaric gas hypoxic mixture (12% O2 + 88% N2). Each cycle included a 15-min-long episode of breathing with the gas mixture alternated by a 5-min-long episode of breathing an ambient atmospheric air. The number of hypoxic cycles was gradually increased (from one to three). The entire course of treatment included, on average, 10 sessions. After complex therapy the stable positive effects on the motor status were observed in 94% of patients of the main group (exposed to INH) and in 74% of patients of the comparison group (unexposed to INH). EEG examination showed that positive dynamics of spectral EEG components were in 70% of patients of the main group and in 56% of children of the comparison group. Doppler examination showed that brain hemodynamics was normalized in 85% of patients of the main group and in 59% of children of the comparison group. In

  9. Circulating progenitor cells during exercise, muscle electro-stimulation and intermittent hypobaric hypoxia in patients with traumatic brain injury. A pilot study

    OpenAIRE

    Corral Ansa, Luisa; Conde, L; Guillamó Casanoves, Elisabet; Blasi Cabús, Joan; Juncadella i Puig, Montserrat; Javierre Garcés, Casimiro F.; Viscor Carrasco, Ginés; Ventura i Farré, Josep Lluís

    2014-01-01

    BACKGROUND: Circulating progenitor cells (CPC) treatments may have great potential for the recovery of neurons and brain function. OBJECTIVE: To increase and maintain CPC with a program of exercise, muscle electro-stimulation (ME) and/or intermittent-hypobaric-hypoxia (IHH), and also to study the possible improvement in physical or psychological functioning of participants with Traumatic Brain Injury (TBI). METHODS: Twenty-one participants. Four groups: exercise and ME group (EEG), cycling gr...

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

    Directory of Open Access Journals (Sweden)

    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

  11. In Vivo Neurochemical Characterization of Developing Guinea Pigs and the Effect of Chronic Fetal Hypoxia.

    Science.gov (United States)

    Wang, Wen-Tung; Lee, Phil; Dong, Yafeng; Yeh, Hung-Wen; Kim, Jieun; Weiner, Carl P; Brooks, William M; Choi, In-Young

    2016-07-01

    The guinea pig is a frequently used animal model for human pregnancy complications, such as oxygen deprivation or hypoxia, which result in altered brain development. To investigate the impact of in utero chronic hypoxia on brain development, pregnant guinea pigs underwent either normoxic or hypoxic conditions at about 70 % of 65-day term gestation. After delivery, neurochemical profiles consisting of 19 metabolites and macromolecules were obtained from the neonatal cortex, hippocampus, and striatum from birth to 12 weeks postpartum using in vivo (1)H MR spectroscopy at 9.4 T. The effects of chronic fetal hypoxia on the neurochemical profiles were particularly significant at birth. However, the overall developmental trends of neurochemical concentration changes were similar between normoxic and hypoxic animals. Alterations of neurochemicals including N-acetylaspartate (NAA), phosphorylethanolamine, creatine, phosphocreatine, and myo-inositol indicate neuronal loss, delayed myelination, and altered brain energetics due to chronic fetal hypoxia. These observed neurochemical alterations in the developing brain may provide insights into hypoxia-induced brain pathology, neurodevelopmental compromise, and potential neuroprotective measures. PMID:27233245

  12. Dormancy of cancer cells with suppression of AKT activity contributes to survival in chronic hypoxia.

    Directory of Open Access Journals (Sweden)

    Hiroko Endo

    Full Text Available A hypoxic microenvironment in tumors has been recognized as a cause of malignancy or resistance to various cancer therapies. In contrast to recent progress in understanding the acute response of cancer cells to hypoxia, the characteristics of tumor cells in chronic hypoxia remain elusive. We have identified a pancreatic cancer cell line, AsPC-1, that is exceptionally able to survive for weeks under 1% oxygen conditions while most tested cancer cell lines die after only some days under these conditions. In chronic hypoxia, AsPC-1 cells entered a state of dormancy characterized by no proliferation, no death, and metabolic suppression. They reversibly switched to active status after being placed again in optimal culture conditions. ATP turnover, an indicator of energy demand, was markedly decreased and accompanied by reduced AKT phosphorylation. Forced activation of AKT resulted in increased ATP turnover and massive cell death in vitro and a decreased number of dormant cells in vivo. In contrast to most cancer cell lines, primary-cultured colorectal cancer cells easily entered the dormant status with AKT suppression under hypoxia combined with growth factor-depleted conditions. Primary colorectal cancer cells in dormancy were resistant to chemotherapy. Thus, the ability to survive in a deteriorated microenvironment by entering into dormancy under chronic hypoxia might be a common property among cancer cells. Targeting the regulatory mechanism inducing this dormant status could provide a new strategy for treating cancer.

  13. Response of channel x blue hybrid catfish to chronic diurnal hypoxia

    Science.gov (United States)

    Performance traits and metabolic responses of the channel x blue hybrid catfish (Ictalurus punctatus female x I. furcatus male) in response to chronic diurnal hypoxia were evaluated in this 197-d study. Sixteen 0.1-ha earthen ponds were stocked with 15,169 hybrid catfish/ha (47 g/fish) and managed t...

  14. Antioxidative enzymes and PKC in cardioprotection induced by chronic hypoxia: influence of lipid diets

    Czech Academy of Sciences Publication Activity Database

    Hlaváčková, M.; Ježková, J.; Neckář, Jan; Balková, P.; Nováková, O.; Kolář, František; Novák, F.

    Elsevier. Roč. 38, č. 6 (2005), s. 1028-1029. ISSN 0022-2828. [Annual ISHR European Section Meeting /25./. 21.06.2005-25.06.2005, Tromso] R&D Projects: GA ČR(CZ) GA305/04/0465 Institutional research plan: CEZ:AV0Z50110509 Keywords : chronic hypoxia * lipid diet * oxidative stress Subject RIV: ED - Physiology

  15. Impact of perinatal chronic hypoxia on cardiac tolerance to acute ischemia

    Czech Academy of Sciences Publication Activity Database

    Ošťádal, Bohuslav; Ošťádalová, Ivana; Kolář, František; Netuka, I.; Szárszoi, O.

    New York : Springer, 2011 - (Dhalla, N.; Nagano, M.; Ošťádal, B.), s. 55-67 ISBN 978-1-4419-7129-6 R&D Projects: GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : perinatal period * cardiac development * chronic hypoxia Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  16. 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

    2008-05-30

    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 a decreased ATP level and significantly compromised survival in hypoxia. Dose-dependent prosurvival effects of rapamycin were consistent with mTOR inhibition being a critical downstream mediator of AMPK in persistent low oxygen. PMID:18359290

  17. 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.

  18. ZFP580, a Novel Zinc-Finger Transcription Factor, Is Involved in Cardioprotection of Intermittent High-Altitude Hypoxia against Myocardial Ischemia-Reperfusion Injury

    OpenAIRE

    Meng, Xiang-yan; Yu, Hai-long; Zhang, Wen-Cheng; Wang, Tian-hui; Mai, Xia; Liu, Hong-Tao; Xu, Rui-cheng

    2014-01-01

    Background ZFP580 is a novel C2H2 type zinc-finger transcription factor recently identified by our laboratory. We previously showed that ZFP580 may be involved in cell survival and growth. The aim of this study was to elucidate whether ZFP580 is involved in the cardioprotective effects of intermittent high-altitude (IHA) hypoxia against myocardial ischemia-reperfusion (I/R) injury. Methods and Results After rats were subjected to myocardial ischemia for 30 min followed by reperfusion, ZFP580 ...

  19. 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.

  20. The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia.

    Science.gov (United States)

    Zhao, Lan; Oliver, Eduardo; Maratou, Klio; Atanur, Santosh S; Dubois, Olivier D; Cotroneo, Emanuele; Chen, Chien-Nien; Wang, Lei; Arce, Cristina; Chabosseau, Pauline L; Ponsa-Cobas, Joan; Frid, Maria G; Moyon, Benjamin; Webster, Zoe; Aldashev, Almaz; Ferrer, Jorge; Rutter, Guy A; Stenmark, Kurt R; Aitman, Timothy J; Wilkins, Martin R

    2015-08-20

    The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension. PMID:26258299

  1. Biventricular function at high altitude: implications for regulation of stroke volume in chronic hypoxia.

    Science.gov (United States)

    Gibbs, J Simon R

    2007-01-01

    The myocardium is well protected against chronic hypoxia. In chronic hypoxia stroke volume falls both at rest and on exercise. The fall in stroke volume is associated with reduction in left ventricular dimensions and filling pressure. An obvious explanation for this is the reduction in plasma volume observed at high altitude, but this does not appear to be the whole story. Neither is left ventricular systolic function abnormal even at the summit of Mount Everest. Hypoxia itself may have a direct effect on impairing myocardial relaxation. Increased pulmonary vascular resistance leads to right ventricular pressure overload. This may impair right ventricular function, and reduce stroke volume and venous return to the left atrium. Interaction between the right and left ventricles, which share a common septum and are potentially constrained in volume by the pericardium, may impair diastolic left ventricular filling as a consequence of right ventricular pressure overload, and hence reduce stroke volume. It is questionable how clinically significant is this left ventricular diastolic dysfunction. The relative importance of different mechanisms which reduce stroke volume probably depends whether hemodynamics are measured at rest or on exercise. Intervention with sildenafil to ameliorate hypoxic pulmonary vasoconstriction is associated with both an increase in exercise capacity and stroke volume in hypoxia. Whether these have a causal association remains to be demonstrated. PMID:18269185

  2. Effect of closed v. intermittent-flow respirometry on hypoxia tolerance in the shiner perch Cymatogaster aggregata

    DEFF Research Database (Denmark)

    Snyder, S; Nadler, L E; Bayley, J S;

    2016-01-01

    hypoxia tolerance in closed respirometry is consistent with additional stress, caused by a build-up of ammonia and carbon dioxide and a faster rate in dissolved oxygen decline. The results indicate that these two methods of determining hypoxia tolerance in aquatic organisms are not comparable, and that...

  3. Chronic hypoxia downregulates ZO-2 expression in children with cyanotic congenital heart defect

    OpenAIRE

    Jenkins, Emma L.; Caputo, Massimo; Angelini, Gianni D; Ghorbel, Mohamed

    2016-01-01

    AimsTight junction protein zonula occludens protein 2 (ZO-2) is a member of the membrane-associated guanylate kinases protein family known to be expressed at tight junctions of epithelial and endothelial cells and at adherens junctions (AJs) in cardiomyocytes. Little is known about ZO-2 expression and function in the human heart. Here, we examined the hypothesis that chronic hypoxia down-regulates ZO-2 expression in human myocardium and cultured rat cardiomyocytes.Methods and resultsPatients ...

  4. Chronic hypoxia inhibits MMP-2 activation and cellular invasion in human cardiac myofibroblasts

    OpenAIRE

    Riches, Kirsten; Morley, Michael E.; Turner, Neil A; O'Regan, David J; Ball, Stephen G; Peers, Chris; Porter, Karen E

    2009-01-01

    Cardiac myofibroblasts are pivotal to adaptive remodelling after myocardial infarction (MI). These normally quiescent cells invade and proliferate as a wound healing response, facilitated by activation of matrix metalloproteinases, particularly MMP-2. Following MI these reparative events occur under chronically hypoxic conditions yet the mechanisms by which hypoxia might modulate MMP-2 activation and cardiac myofibroblast invasion have not been investigated. Human cardiac myofibroblasts cultu...

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

    OpenAIRE

    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 ...

  6. Involvement of PKC epsilon in Cardioprotection Induced by Adaptation to Chronic Continuous Hypoxia

    Czech Academy of Sciences Publication Activity Database

    Holzerová, K.; Hlaváčková, Markéta; Žurmanová, J.; Borchert, Gudrun H.; Neckář, Jan; Kolář, František; Novák, F.; Nováková, O.

    2015-01-01

    Roč. 64, č. 2 (2015), s. 191-201. ISSN 0862-8408 R&D Projects: GA ČR(CZ) GAP303/12/1162; GA ČR(CZ) GA13-10267S Institutional support: RVO:67985823 Keywords : chronic hypoxia * cardioprotection * ventricular myocytes * protein kinase C * PKC epsilon inhibitory peptide KP-1633 Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.293, year: 2014

  7. Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice.

    Science.gov (United States)

    Silvennoinen, Reija; Quesada, Helena; Kareinen, Ilona; Julve, Josep; Kaipiainen, Leena; Gylling, Helena; Blanco-Vaca, Francisco; Escola-Gil, Joan Carles; Kovanen, Petri T; Lee-Rueckert, Miriam

    2015-05-11

    Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress. PMID:25969465

  8. Effects of intermittent hypoxia and light aerobic exercise on circulating stem cells and side population, after strenuous eccentric exercise in trained rats.

    Science.gov (United States)

    Núñez-Espinosa, Cristian; Ferreira, Inês; Ríos-Kristjánsson, Juan Gabriel; Rizo-Roca, David; García Godoy, Maria Dolors; Rico, Laura G; Rubi-Sans, Gerard; Torrella, Joan Ramon; Pagès, Teresa; Petriz, Jordi; Viscor, Ginés

    2015-01-01

    Our goal was to address if intermittent hypobaric hypoxia (IHH) exposure can help to increase the number of peripheral blood circulating progenitor cells and side population (SP) stem cells, in order to establish the usefulness of this intervention for skeletal muscle repair, because these cells play a role in tissue regeneration. Male Sprague-Dawley rats were studied in two basal states: untrained and trained and compared with 1, 3, 7 and 14 days stages of damage recovery of trained rats that had suffered skeletal muscle injury. Three experimental groups were studied: rats with passive recovery (CTRL); rats exposed to IHH after muscle damage (HYP); and, trained rats that, in addition to IHH, performed light aerobic exercise sessions (EHYP). We observed an increase in hematopoietic stem cells (HSCs) (mean = 0.153% of cells) and endothelial progenitor cells (EPCs) (mean = 0.0020% of cells) in EHYP on day 7. Also these cells showed characteristics of more primitive progenitors in comparison to the other experimental groups (mean = 0.107% of cells), as deduced by retention of the promising fluorescent probe Vybrant Dye Cycle Violet. We concluded that intermittent exposure to hypobaric hypoxia in combination with light aerobic exercise increased the number of HSCs and EPCs on the 7th day in EHYP group, although the exercise-induced stimulus showed a reverse effect on SP kinetics. PMID:25266982

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

    Science.gov (United States)

    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.

  10. The effect of hypoxia on cognitive performance in patients with chronic obstructive pulmonary disease.

    Science.gov (United States)

    Martin, Susan E; Bradley, Judy M; Buick, Joseph B; Crossan, Amanda; Elborn, J Stuart

    2011-06-30

    Air travel may cause significant hypoxia in passengers with chronic obstructive pulmonary disease (COPD). It is not known whether this level of hypoxia will cause impairment in cognitive function. The aim of this study was to determine the effect of hypoxia on cognitive performance in patients with COPD when Pa(O2) was decreased <6.6 kPa. In ten patients with moderate to severe COPD trail making tasks and complex figure tasks were used to assess cognitive performance when the patients breathed 21% O(2), and when Pa(O2) was decreased to <6.6 kPa. During administration of 21% O(2), Pa(O2) was 9.5 (8.9-10.2) kPa. When Sp(O2) was decreased to 85% via manipulation of the FI(O2) (inspired fraction of oxygen) Pa(O2), decreased to 6.1 (5.9-6.2) kPa. No short term deterioration in visual search, mental flexibility or visuospatial constructional ability was detected when Pa(O2) was decreased to <6.6 kPa. The results show that short term exposure to hypoxia had no adverse effect on cognitive function. PMID:21397736

  11. 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. PMID:25830761

  12. 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. PMID:17679848

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

    Directory of Open Access Journals (Sweden)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  15. Chronic hypoxia enhances adenosine release in rat PC12 cells by altering adenosine metabolism and membrane transport.

    Science.gov (United States)

    Kobayashi, S; Zimmermann, H; Millhorn, D E

    2000-02-01

    Acute exposure to hypoxia causes a release of adenosine (ADO) that is inversely related to the O2 levels in oxygen-sensitive pheochromocytoma (PC12) cells. In the current study, chronic exposure (48 h) of PC12 cells to moderate hypoxia (5% O2) significantly enhanced the release of ADO during severe, acute hypoxia (1% O2). Investigation into the intra- and extracellular mechanisms underpinning the secretion of ADO in PC12 cells chronically exposed to hypoxia revealed changes in gene expression and activities of several key enzymes associated with ADO production and metabolism, as well as the down-regulation of a nucleoside transporter. Decreases in the enzymatic activities of ADO kinase and ADO deaminase accompanied by an increase in those of cytoplasmic and ecto-5'-nucleotidases bring about an increased capacity to produce intra- and extracellular ADO. This increased potential to generate ADO and decreased capacity to metabolize ADO indicate that PC12 cells shift toward an ADO producer phenotype during hypoxia. The reduced function of the rat equilibrative nucleoside transporter rENT1 also plays a role in controlling extracellular ADO levels. The hypoxia-induced alterations in the ADO metabolic enzymes and the rENT1 transporter seem to increase the extracellular concentration of ADO. The biological significance of this regulation is unclear but is likely to be associated with modulating cellular activity during hypoxia. PMID:10646513

  16. Role of the D2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells.

    Science.gov (United States)

    Kobayashi, S; Conforti, L; Zhu, W H; Beitner-Johnson, D; Millhorn, D E

    1999-11-01

    We have previously shown that pheochromocytoma (PC12) cells rapidly depolarize and undergo Ca2+ influx through voltage-dependent Ca2+ channels in response to moderate hypoxia and that intracellular free Ca2+ is modulated by activation of dopamine D2 receptors in this cell type. The present study shows that D2 (quinpirole-mediated) inhibition of a voltage-dependent Ca2+ current (ICa) in PC12 cells is dramatically attenuated after chronic exposure to moderate hypoxia (24 h at 10% O2). Pretreatment of cells with pertussis toxin abolished D2-mediated inhibition of ICa. The D2-induced inhibition of ICa did not depend on protein kinase A (PKA), as it persisted both in the presence of a specific PKA inhibitor (PKI) and in PKA-deficient PC12 cells. Prolonged exposure to hypoxia (24 h) significantly reduced the level of Gi/o alpha immunoreactivity, but did not alter G beta levels. Furthermore, dialysis of recombinant G(o) alpha protein through the patch pipette restored the inhibitory effect of quinpirole in cells chronically exposed to hypoxia. We conclude that the attenuation of the D2-mediated inhibition of ICa by chronic hypoxia is caused by impaired receptor-G protein coupling, due to reduced levels of G(o) alpha protein. This attenuated feedback modulation of ICa by dopamine may allow for a more sustained Ca2+ influx and enhanced cellular excitation during prolonged hypoxia. PMID:10591061

  17. Acute intermittent hypoxia-induced expression of Brain-Derived Neurotrophic Factor is disrupted in the brainstem of mecp2 null mice

    Science.gov (United States)

    Vermehren-Schmaedick, Anke; Jenkins, Victoria K.; Knopp, Sharon J.; Balkowiec, Agnieszka; Bissonnette, John M.

    2012-01-01

    Rett syndrome is a neurodevelopmental disorder caused by loss of function mutations in the gene encoding the transcription factor methyl-CpG-binding protein 2 (MeCP2). One of its targets is the gene encoding brain-derived neurotrophic factor (bdnf). In vitro studies using cultured neurons have produced conflicting results with respect to the role of MeCP2 in BDNF expression. Acute intermittent hypoxia (AIH) induces plasticity in the respiratory system characterized by long-term facilitation of phrenic nerve amplitude. This paradigm induces an increase in BDNF protein. We hypothesized that AIH leads to augmentation of BDNF transcription in respiratory-related areas of the brainstem and that MeCP2 is necessary for this process. Wild-type and mecp2 null (mecp2−/y) mice were subjected to three 5-min episodes of exposure to 8% O2/4% CO2/88% N2, delivered at 5-min intervals. Normoxia control wild-type and mecp2 null mice were exposed to room air for the total length of time, i.e. 30 min. Following a recovery in room air, the pons and medulla were rapidly removed. Expression of BDNF protein and transcripts were determined by ELISA and quantitative PCR, respectively. AIH induced a significant increase in BDNF protein in the pons and medulla, and in mRNA transcript levels in the pons of wild-type animals. In contrast, there were no significant changes in either BDNF protein or transcripts in the pons or medulla of mice lacking Mecp2. The results indicate that Mecp2 is required for regulation of BDNF expression by acute intermittent hypoxia in vivo. PMID:22297041

  18. Acute intermittent hypoxia-induced expression of brain-derived neurotrophic factor is disrupted in the brainstem of methyl-CpG-binding protein 2 null mice.

    Science.gov (United States)

    Vermehren-Schmaedick, A; Jenkins, V K; Knopp, S J; Balkowiec, A; Bissonnette, J M

    2012-03-29

    Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding the transcription factor methyl-CpG-binding protein 2 (MeCP2). One of its targets is the gene encoding brain-derived neurotrophic factor (bdnf). In vitro studies using cultured neurons have produced conflicting results with respect to the role of MeCP2 in BDNF expression. Acute intermittent hypoxia (AIH) induces plasticity in the respiratory system characterized by long-term facilitation of phrenic nerve amplitude. This paradigm induces an increase in BDNF protein. We hypothesized that AIH leads to augmentation of BDNF transcription in respiratory-related areas of the brainstem and that MeCP2 is necessary for this process. Wild-type and mecp2 null (mecp2(-/y)) mice were subjected to three 5-min episodes of exposure to 8% O(2)/4% CO(2)/88% N(2), delivered at 5-min intervals. Normoxia control wild-type and mecp2 null mice were exposed to room air for the total length of time, that is, 30 min. Following a recovery in room air, the pons and medulla were rapidly removed. Expression of BDNF protein and transcripts were determined by ELISA and quantitative PCR, respectively. AIH induced a significant increase in BDNF protein in the pons and medulla, and in mRNA transcript levels in the pons of wild-type animals. In contrast, there were no significant changes in either BDNF protein or transcripts in the pons or medulla of mice lacking MeCP2. The results indicate that MeCP2 is required for regulation of BDNF expression by acute intermittent hypoxia in vivo. PMID:22297041

  19. Changes of hypoxia-inducible factor-1 signaling and the effect of cilostazol in chronic cerebral ischemia*

    Institute of Scientific and Technical Information of China (English)

    Han Chen; Aixuan Wei; Jinting He; Ming Yu; Jing Mang; Zhongxin Xu

    2013-01-01

    Hypoxia-inducible factor-1 and its specific target gene heme oxygenase-1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hypox-ia-inducible factor-1/heme oxygenase-1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol (30 mg/kg) for 9 weeks. Morris water maze results showed that cognitive impairment gradual y worsened as the cerebral ischemia proceeded. Immunohistochemistry, semi-quantitative PCR and western blot analysis showed that hypoxia-inducible factor-1α and heme oxygenase-1 expression levels in-creased after chronic cerebral ischemia, with hypoxia-inducible factor-1α expression peaking at 3 weeks and heme oxygenase-1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxia-inducible factor-1α may upregulate heme oxygenase-1 expression fol-lowing chronic cerebral ischemia and that the hypoxia-inducible factor-1/heme oxygenase-1 sig-naling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment al eviated the cognitive impairment in rats with chronic cerebral is-chemia, decreased hypoxia-inducible factor-1α and heme oxygenase-1 expression levels, and re-duced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an anti-apoptotic mecha-nism.

  20. Antioxidative enzymes and PKC in cardioprotection induced by chronic hypoxia: Influence of lipid diets

    Czech Academy of Sciences Publication Activity Database

    Hlaváčková, M.; Balková, P.; Nováková, O.; Neckář, Jan; Kolář, František; Novák, F.

    Praha : IV.interní klinika 1.LF UK, 2005, s. 37-41. ISBN 80-239-5545-4. [Atherosklerosa 2005. Diagnostika, léčba, prevence v dětském i dospělém věku. Praha (CZ), 14.09.2005-16.09.2005] R&D Projects: GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : chronic hypoxia * proteinkinase C * heart Subject RIV: ED - Physiology

  1. Hypoxia selects bortezomib-resistant stem cells of chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Michele Tanturli

    Full Text Available We previously demonstrated that severe hypoxia inhibits growth of Chronic Myeloid Leukemia (CML cells and selects stem cells where BCR/Abl(protein is suppressed, although mRNA is not, so that hypoxia-selected stem cells, while remaining leukemic, are independent of BCR/Abl signaling and thereby refractory to Imatinib-mesylate. The main target of this study was to address the effects of the proteasome inhibitor Bortezomib (BZ on the maintenance of stem or progenitor cells in hypoxic primary cultures (LC1, by determining the capacity of LC1 cells to repopulate normoxic secondary cultures (LC2 and the kinetics of this repopulation. Unselected K562 cells from day-2 hypoxic LC1 repopulated LC2 with rapid, progenitor-type kinetics; this repopulation was suppressed by BZ addition to LC1 at time 0, but completely resistant to day-1 BZ, indicating that progenitors require some time to adapt to stand hypoxia. K562 cells selected in hypoxic day-7 LC1 repopulated LC2 with stem-type kinetics, which was largely resistant to BZ added at either time 0 or day 1, indicating that hypoxia-selectable stem cells are BZ-resistant per se, i.e. before their selection. Furthermore, these cells were completely resistant to day-6 BZ, i.e. after selection. On the other hand, hypoxia-selected stem cells from CD34-positive cells of blast-crisis CML patients appeared completely resistant to either time-0 or day-1 BZ. To exploit in vitro the capacity of CML cells to adapt to hypoxia enabled to detect a subset of BZ-resistant leukemia stem cells, a finding of particular relevance in light of the fact that our experimental system mimics the physiologically hypoxic environment of bone marrow niches where leukemia stem cells most likely home and sustain minimal residual disease in vivo. This suggests the use of BZ as an enhanced strategy to control CML. in particular to prevent relapse of disease, to be considered with caution and to need further deepening.

  2. Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic hypoxia in mice.

    Science.gov (United States)

    Sunderram, Jagadeeshan; Semmlow, John; Thakker-Varia, Smita; Bhaumik, Mantu; Hoang-Le, Oanh; Neubauer, Judith A

    2009-08-01

    Adaptations to chronic hypoxia (CH) could reflect cellular changes within the cardiorespiratory regions of the rostral ventrolateral medulla (RVLM), the C1 region, and the pre-Bötzinger complex (pre-BötC). Previous studies have shown that the hypoxic chemosensitivity of these regions are heme oxygenase (HO) dependent and that CH induces HO-1. To determine the time course of HO-1 induction within these regions and explore its relevance to the respiratory and sympathetic responses during CH, the expression of HO-1 mRNA and protein in the RVLM and measures of respiration, sigh frequency, and sympathetic activity (spectral analysis of heart rate) were examined during 10 days of CH. Respiratory and sympathetic responses to acute hypoxia were obtained in chronically instrumented awake wild-type (WT) and HO-1 null mice. After 4 days of CH, there was a significant induction of HO-1 within the C1 region and pre-BötC. WT mice acclimated to CH by increasing peak diaphragm EMG after 10 days of CH but had no change in the respiratory response to acute hypoxia. There were no significant differences between WT and HO-1 null mice. In WT mice, hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity initially declined before returning toward baseline after 5 days of CH, correlating with the induction of HO-1. In contrast, HO-1 null mice had a persistent decline in hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity. We conclude that induction of HO-1 in these RVLM cardiorespiratory regions may be important for the hypoxic sensitivity of sighs and sympathetic activity during CH. PMID:19458275

  3. Ultrastructural and tissue restructuring of the rat atrial myocardium under the influence of acute and chronic prenatal hypoxia

    Directory of Open Access Journals (Sweden)

    Shevchenko K. M.

    2015-09-01

    Full Text Available Background. There are relatively few researches that focused on the study of the influence of hypoxia on atrial myocardium. However the results of previous researches are contradictory and fragmentary, that leades to the further study of this item. Objective. Purpose of the work was to determine the tissue, cellular and ultrastructural changes of the rat atrial myocardium during the stages of cardiogenesis under the conditions of acute and chronic prenatal hypoxia. Methods. Embryo hearts were investigated on 14th, 16th and 18th day of prenatal ontogenesis, newborn rat hearts and the hearts of rats on the 3rd, 14th and 30th day of postnatal ontogenesis. Animals were subdivided into three groups: first experimental group animals were exposed to acute prenatal hypoxia, second experimental group animals were exposed to chronic prenatal hypoxia and control group animals. Hypoxia modeling was conducted on pregnant females by injection of 1% sodium nitrite intraperitonealy in doses that lead to moderate hypoxia. During the work complex of histological, immunohistochemical and morphometric methods was used. Results and conclusion. Effect of acute hypoxia leads to stimulation of proliferative activity of fibroblasts and endothelial cells on the right atrium, which causes to increasing of the relative volume of connective tissue and blood vessels of microvasculature of myocardium. Relative volume of connective tissue of the atrial myocardium exceeds significantly the control level of newborn rats. Ultrastructural changes of the atrial cardiomyocytes in 3 days after the influence of acute prenatal hypoxia reveals on violation of mitochondrial structure, significant inhibition of myofibrils accumulation. Until the birth of most of morphometric parameters renewal and reach control levels, however changes of the degree of myofibrils orientation on the left atrium proves stability of hypoxic damages. Chronic prenatal hypoxia causes a significant increase of

  4. Interhemispheric Plasticity following Intermittent Theta Burst Stimulation in Chronic Poststroke Aphasia

    Directory of Open Access Journals (Sweden)

    Joseph C. Griffis

    2016-01-01

    Full Text Available The effects of noninvasive neurostimulation on brain structure and function in chronic poststroke aphasia are poorly understood. We investigated the effects of intermittent theta burst stimulation (iTBS applied to residual language-responsive cortex in chronic patients using functional and anatomical MRI data acquired before and after iTBS. Lateralization index (LI analyses, along with comparisons of inferior frontal gyrus (IFG activation and connectivity during covert verb generation, were used to assess changes in cortical language function. Voxel-based morphometry (VBM was used to assess effects on regional grey matter (GM. LI analyses revealed a leftward shift in IFG activity after treatment. While left IFG activation increased, right IFG activation decreased. Changes in right to left IFG connectivity during covert verb generation also decreased after iTBS. Behavioral correlations revealed a negative relationship between changes in right IFG activation and improvements in fluency. While anatomical analyses did not reveal statistically significant changes in grey matter volume, the fMRI results provide evidence for changes in right and left IFG function after iTBS. The negative relationship between post-iTBS changes in right IFG activity during covert verb generation and improvements in fluency suggests that iTBS applied to residual left-hemispheric language areas may reduce contralateral responses related to language production and facilitate recruitment of residual language areas after stroke.

  5. 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

  6. Effect of chronic hypoxia on 45Ca and 86Rb uptake in aortic smooth muscle from spontaneously hypertensive rats (SHR)

    International Nuclear Information System (INIS)

    The effect of chronic hypobaric hypoxia equivalent to a simulated high altitude of 4000 m was investigated on the Ca2+ and Rb+ uptake in vascular smooth muscle. The decline in systolic blood pressure in SHR due to hypoxia was associated with a significant decrease in 45Ca uptake and ouabain-insensitive 86Rb uptake as well as the tissue Ca2+ and K+ content. It seems likely that the reduction of the higher vascular tone in SHR by chronic hypoxia is due to the alteration of the transmembrane ion fluxes in the vascular smooth muscle cells. However, the meaning and the nature of the active and passive ion fluxes involved in this problem remains to be clarified. (author)

  7. Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium.

    Directory of Open Access Journals (Sweden)

    Giuseppina Milano

    Full Text Available UNLABELLED: Although chronic hypoxia is a claimed myocardial risk factor reducing tolerance to ischemia/reperfusion (I/R, intermittent reoxygenation has beneficial effects and enhances heart tolerance to I/R. AIM OF THE STUDY: To test the hypothesis that, by mimicking intermittent reoxygenation, selective inhibition of phosphodiesterase-5 activity improves ischemia tolerance during hypoxia. Adult male Sprague-Dawley rats were exposed to hypoxia for 15 days (10% O₂ and treated with placebo, sildenafil (1.4 mg/kg/day, i. p., intermittent reoxygenation (1 h/day exposure to room air or both. Controls were normoxic hearts. To assess tolerance to I/R all hearts were subjected to 30-min regional ischemia by left anterior descending coronary artery ligation followed by 3 h-reperfusion. Whereas hypoxia depressed tolerance to I/R, both sildenafil and intermittent reoxygenation reduced the infarct size without exhibiting cumulative effects. The changes in myocardial cGMP, apoptosis (DNA fragmentation, caspase-3 activity (alternative marker for cardiomyocyte apoptosis, eNOS phosphorylation and Akt activity paralleled the changes in cardioprotection. However, the level of plasma nitrates and nitrites was higher in the sildenafil+intermittent reoxygenation than sildenafil and intermittent reoxygenation groups, whereas total eNOS and Akt proteins were unchanged throughout. CONCLUSIONS: Sildenafil administration has the potential to mimic the cardioprotective effects led by intermittent reoxygenation, thereby opening the possibility to treat patients unable to be reoxygenated through a pharmacological modulation of NO-dependent mechanisms.

  8. Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

    Czech Academy of Sciences Publication Activity Database

    Maslov, L. N.; Naryzhnaya, N. V.; Tsibulnikov, S.Yu.; Kolář, František; Zhang, Y.; Wang, H.; Gusakova, A. M.; Lishmanov, Yu. B.

    2013-01-01

    Roč. 93, 9-11 (2013), s. 373-379. ISSN 0024-3205 R&D Projects: GA ČR(CZ) GAP303/12/1162 Institutional support: RVO:67985823 Keywords : chronic hypoxia * myocardial infarction * cardioprotection * opioid peptides * opioid receptors Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.296, year: 2013

  9. Preserved cardiac mitochondrial function and reduced ischaemia/reperfusion injury afforded by chronic continuous hypoxia: Role of opioid receptors

    Czech Academy of Sciences Publication Activity Database

    Maslov, L. N.; Naryzhnaya, N. V.; Prokudina, E. S.; Kolář, František; Gorbunov, A. S.; Zhang, Y.; Wang, H.; Tsibulnikov, S.Yu.; Portnichenko, A. G.; Lasukova, T. V.; Lishmanov, Yu. B.

    2015-01-01

    Roč. 42, č. 5 (2015), s. 496-501. ISSN 1440-1681 R&D Projects: GA ČR(CZ) GAP303/12/1162 Institutional support: RVO:67985823 Keywords : cardioprotection * chronic hypoxia * ischaemia/reperfusion * mitochondrial function * opioid receptors Subject RIV: ED - Physiology Impact factor: 2.372, year: 2014

  10. Dietary polyunsaturated fatty acids and adaptation to chronic hypoxia alter acyl composition of serum and heart lipids

    Czech Academy of Sciences Publication Activity Database

    Balková, P.; Ježková, J.; Hlaváčková, M.; Neckář, Jan; Staňková, B.; Kolář, František; Novák, F.; Nováková, O.

    2009-01-01

    Roč. 102, č. 9 (2009), s. 1297-1307. ISSN 0007-1145 R&D Projects: GA ČR(CZ) GA305/07/0875 Institutional research plan: CEZ:AV0Z50110509 Keywords : chronic hypoxia * dietary n-3 and n-6 PUFA * heart Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 3.446, year: 2009

  11. Role of Sodium-Hydrogen Exchanger-1 (NHE-1) in the Effect of Exercise on Intermittent Hypoxia-Induced Left Ventricular Dysfunction.

    Science.gov (United States)

    Chen M, Yu-Chih; Yang, Kun-Ta; Shen, Yan-Jhih; Cheng, Ching-Feng; Tu, Wei-Chia; Chen, Tsung-I

    2015-08-31

    Intermittent hypoxia (IH) occurs frequently in patients with obstructive sleep apnoea and can cause ventricular dysfunction. However, whether myocardial inflammation and sodium-hydrogen exchanger-1 (NHE-1) expression play an important role in IH-induced ventricular dysfunction remains unclear. This study aimed to investigate whether short-term exercise provides a protective effect on IH-induced left ventricular (LV) function impairment. Male Sprague-Dawley rats were randomly assigned to 4 groups: control (CON), IH, exercise (EXE) or IH interspersed with EXE (IHEXE). IH rats were exposed to repetitive hypoxia/reoxygenation cycles (2%-6% O₂ for 2-5 s per 75 s, followed by 21% O₂ for 6 h/day) during the light phase for 12 consecutive days. EXE rats were habituated to treadmill running for 5 days, permitted 2 days of rest, and followed by 5 exercise bouts (30 m/min for 60 min on a 2% grade) on consecutive days during the dark phase. IHEXE rats were exposed to IH during the light phase interspersed with exercise programs during the dark phase on the same day. Cardiac function was quantified by echocardiographic evaluation. Myocardial levels of tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and NHE-1 were determined. IH rats showed LV dysfunction characterized by lower LV fractional shortening (LVFS%) and LV ejection fraction (LVEF%). LV dysfunction was associated with higher myocardial levels of TNF-α, IL-6 and NHE-1 mRNA and protein. These changes were not observed in IHEXE rats (P > 0.05 for all). EXE rats showed lower levels of NHE-1 protein than CON rats (P 0.05 for all). These data indicated that exercise may provide a protective effect on IH-induced LV dysfunction by attenuating IH-induced myocardial NHE-1 hyperactivity. PMID:26211649

  12. Spatial learning and memory deficits following exposure to 24 h of sleep fragmentation or intermittent hypoxia in a rat model of obstructive sleep apnea.

    Science.gov (United States)

    Ward, Christopher P; McCoy, John G; McKenna, James T; Connolly, Nina P; McCarley, Robert W; Strecker, Robert E

    2009-10-19

    Obstructive sleep apnea is primarily characterized by hypoxemia due to frequent apneic episodes and fragmentation of sleep due to the brief arousals that terminate the apneic episodes. Though neurobehavioral deficits frequently accompany sleep apnea, the relative roles of hypoxia versus sleep fragmentation are difficult to separate in apneic patients. Here, we assessed cognitive function as measured by water maze in the Fischer/Brown Norway (FBN) rat, comparing 24 h of sleep interruption (SI) to 24 h of intermittent hypoxia (IH), in order to dissociate their relative contributions to cognitive impairment. For SI, automated treadmills were used to induce brief ambulation in rats every 2 min, either prior to, or after, initial water maze acquisition training. IH was simulated by cycling environmental oxygen levels between 6% and 19% every 2 min, again either prior to, or after, acquisition. Twenty-four hours of IH exposure had no significant effect on either acquisition or retention, irrespective of whether IH occurred prior to, or after, acquisition. To replicate previous work, another group of rats, exposed to 3 days of IH (10 h/day) prior to acquisition, had impaired performance during acquisition. A comparison of the 24 h IH and 3 day IH findings suggests that a minimum amount of IH exposure is necessary to produce detectable spatial memory impairments. Although SI before acquisition had no effect on acquisition or later retention of the hidden platform location, SI after acquisition robustly impaired retention, indicating that spatial memory consolidation is more susceptible to the effects of sleep disruption than is the acquisition (learning) of spatial information. PMID:19643093

  13. Intermittent hypoxia-induced respiratory long-term facilitation is dominated by enhanced burst frequency, not amplitude, in spontaneously breathing urethane-anesthetized neonatal rats.

    Science.gov (United States)

    Reid, Inefta M; Solomon, Irene C

    2014-01-01

    Acute intermittent hypoxia (AIH) triggers a form of respiratory plasticity known as long-term facilitation (LTF), which is manifested as a progressive increase in respiratory motor activity that lasts for minutes to hours after the hypoxic stimulus is removed. Respiratory LTF has been reported in numerous animal models, but it appears to be influenced by a variety of factors (e.g., species, age, and gender). While most studies focusing on respiratory LTF have been conducted in adult (including young adult) rat preparations, little is known about the influence of postnatal maturation on AIH-induced respiratory LTF. To begin to address this issue, we examined diaphragm EMG activity in response to and at 5-min intervals for 60 min following three 5-min episodes of hypoxia (8% O2) in urethane-anesthetized spontaneously breathing P14-P15 neonatal rats (n=15). For these experiments, the hypoxic episodes were separated by hyperoxia (40% O2), and all rats were continuously supplied with ~4% CO2. During the AIH trials, burst frequency was increased by ~20-90% above baseline in each of the rats examined while changes in burst amplitude were highly variable. Following the AIH episodes, respiratory LTF was characterized by predominantly an increase in burst frequency (fLTF) ranging from ~10% to 55%, with most rats exhibiting a 20-40% increase. In seven rats, however, an increase in amplitude (ampLTF) (~10%, n=3; ~20%, n=3; ~30%, n=1) was also noted. These data suggest that in contrast to observations in anesthetized ventilated adult rats, in anesthetized spontaneously breathing P14-P15 neonatal rats, respiratory LTF is dominated by fLTF, not ampLTF. PMID:25194200

  14. Astrocytic adaptation during cerebral angiogenesis follows the new vessel formation induced through chronic hypoxia in adult mouse cortex

    Science.gov (United States)

    Masamoto, Kazuto; Kanno, Iwao

    2014-03-01

    We examined longitudinal changes of the neuro-glia-vascular unit during cerebral angiogenesis induced through chronic hypoxia in the adult mouse cortex. Tie2-GFP mice in which the vascular endothelial cells expressed green fluorescent proteins (GFP) were exposed to chronic hypoxia, while the spatiotemporal developments of the cortical capillary sprouts and the neighboring astrocytic remodeling were characterized with repeated two-photon microscopy. The capillary sprouts appeared at early phases of the hypoxia adaptation (1-2 weeks), while the morphological changes of the astrocytic soma and processes were not detected in this phase. In the later phases of the hypoxia adaptation (> 2 weeks), the capillary sprouts created a new connection with existing capillaries, and its neighboring astrocytes extended their processes to the newly-formed vessels. The findings show that morphological adaptation of the astrocytes follow the capillary development during the hypoxia adaptation, which indicate that the newly-formed vessels provoke cellular interactions with the neighboring astrocytes to strengthen the functional blood-brain barrier.

  15. 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.

    2014-01-01

    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. PMID:25266936

  16. Theoretical simulation of tumour oxygenation and results from acute and chronic hypoxia

    International Nuclear Information System (INIS)

    The tumour microenvironment is considered to be responsible for the outcome of cancer treatment and therefore it is extremely important to characterize and quantify it. Unfortunately, most of the experimental techniques available now are invasive and generally it is not known how this influences the results. Non-invasive methods on the other hand have a geometrical resolution that is not always suited for the modelling of the tumour response. Theoretical simulation of the microenvironment may be an alternative method that can provide quantitative data for accurately describing tumour tissues. This paper presents a computerized model that allows the simulation of the tumour oxygenation. The model simulates numerically the fundamental physical processes of oxygen diffusion and consumption in a two-dimensional geometry in order to study the influence of the different parameters describing the tissue geometry. The paper also presents a novel method to simulate the effects of diffusion-limited (chronic) hypoxia and perfusion-limited (acute) hypoxia. The results show that all the parameters describing tissue vasculature are important for describing tissue oxygenation. Assuming that vascular structure is described by a distribution of inter-vessel distances, both the average and the width of the distribution are needed in order to fully characterize the tissue oxygenation. Incomplete data, such as distributions measured in a non-representative region of the tissue, may not give relevant tissue oxygenation. Theoretical modelling of tumour oxygenation also allows the separation between acutely and chronically hypoxic cells, a distinction that cannot always be seen with other methods. It was observed that the fraction of acutely hypoxic cells depends not only on the fraction of collapsed blood vessels at any particular moment, but also on the distribution of vessels in space as well. All these suggest that theoretical modelling of tissue oxygenation starting from the basic

  17. Comparison of salbutamol given by intermittent positive-pressure breathing and pressure-packed aerosol in chronic asthma.

    OpenAIRE

    Anderson, P. B.; Goude, A; Peake, M D

    1982-01-01

    A double-blind crossover study was performed to compare 4 . 8 mg salbutamol given by pressure-packed aerosol and intermittent positive-pressure breathing nebulization in chronic asthmatic patients. The two delivery techniques produced similar changes in respiratory function and pulse rates. Given equal effect, a high-dose pressure-packed aerosol would have advantages in cost and convenience over nebulization techniques.

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

    OpenAIRE

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

    2012-01-01

    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 ...

  19. Role of the D2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells

    OpenAIRE

    Kobayashi, Shuichi; Conforti, Laura; Zhu Dana Beitner-Johnson, Wylie H.; Millhorn, David E.

    1999-01-01

    We have previously shown that pheochromocytoma (PC12) cells rapidly depolarize and undergo Ca2+ influx through voltage-dependent Ca2+ channels in response to moderate hypoxia and that intracellular free Ca2+ is modulated by activation of dopamine D2 receptors in this cell type. The present study shows that D2 (quinpirole-mediated) inhibition of a voltage-dependent Ca2+ current (ICa) in PC12 cells is dramatically attenuated after chronic exposure to moderate hypoxia (24 h at 10% O2). Pretreatm...

  20. 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...

  1. Chronic in ovo hypoxia decreases pulmonary arterial contractile reactivity and induces biventricular cardiac enlargement in the chicken embryo.

    Science.gov (United States)

    Villamor, Eduardo; Kessels, Carolina G A; Ruijtenbeek, Karin; van Suylen, Robert J; Belik, Jaques; de Mey, Jo G R; Blanco, Carlos E

    2004-09-01

    Although chronic prenatal hypoxia is considered a major cause of persistent pulmonary hypertension of the newborn, experimental studies have failed to consistently find pulmonary hypertensive changes after chronic intrauterine hypoxia. We hypothesized that chronic prenatal hypoxia induces changes in the pulmonary vasculature of the chicken embryo. We analyzed pulmonary arterial reactivity and structure and heart morphology of chicken embryos maintained from days 6 to 19 of the 21-day incubation period under normoxic (21% O(2)) or hypoxic (15% O(2)) conditions. Hypoxia increased mortality (0.46 vs. 0.14; P < 0.01) and reduced the body mass of the surviving 19-day embryos (22.4 +/- 0.5 vs. 26.6 +/- 0.7 g; P < 0.01). A decrease in the response of the pulmonary artery to KCl was observed in the 19-day hypoxic embryos. The contractile responses to endothelin-1, the thromboxane A(2) mimetic U-46619, norepinephrine, and electrical-field stimulation were also reduced in a proportion similar to that observed for KCl-induced contractions. In contrast, no hypoxia-induced decrease of response to vasoconstrictors was observed in externally pipped 21-day embryos (incubated under normoxia for the last 2 days). Relaxations induced by ACh, sodium nitroprusside, or forskolin were unaffected by chronic hypoxia in the pulmonary artery, but femoral artery segments of 19-day hypoxic embryos were significantly less sensitive to ACh than arteries of control embryos [pD(2) (= -log EC(50)): 6.51 +/- 0.1 vs. 7.05 +/- 0.1, P < 0.01]. Pulmonary vessel density, percent wall area, and periarterial sympathetic nerve density were not different between control and hypoxic embryos. In contrast, hypoxic hearts showed an increase in right and left ventricular wall area and thickness. We conclude that, in the chicken embryo, chronic moderate hypoxia during incubation transiently reduced pulmonary arterial contractile reactivity, impaired endothelium-dependent relaxation of femoral but not pulmonary

  2. Chronic Hypoxia Promotes Pulmonary Artery Endothelial Cell Proliferation through H2O2-Induced 5-Lipoxygenase

    OpenAIRE

    Porter, Kristi M.; Bum-Yong Kang; Adesina, Sherry E.; Murphy, Tamara C.; C Michael Hart; Sutliff, Roy L.

    2014-01-01

    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 stimula...

  3. miR-210 as a marker of chronic hypoxia, but not a therapeutic target in prostate cancer

    International Nuclear Information System (INIS)

    Introduction: Radiotherapy in combination with medical castration is the standard treatment for high-risk prostate cancer. Some relapses may be explained by the presence of radioresistant clones arising from hypoxic microenvironment. Since microRNAs (miR) are increased upon hypoxia, the aim of this study was to see whether miR-210 is a potential marker for hypoxia and/or a therapeutic target in prostate cancer. Methods: Human LNCaP, DU145 or PC3 prostate cancer cells were exposed to normoxia or hypoxia for several hours. Gene expression of miR-210, miR-373 and several hypoxia markers were analyzed by Taqman and SYBR green qRT-PCR, respectively. Clonogenic survival after LNA miR-210 inhibitor (78 nM) and concomitant irradiation were evaluated. Results: During anoxia, CAIX and VEGF expressions were dramatically increased. miR-210 expression increased during anoxia exposure, while basal miR-373 expression was low and remained stable upon anoxia. LNA miR-210 inhibitor decreased anoxic miR-210 expression by 90% and clonogenic survival under anoxia (p = 0.01). However, no enhanced effect was observed when miR-210 inhibitor was combined with irradiation. Conclusion: miR-210 could be an interesting marker of chronic hypoxia irrespective of the androgen dependency and should, therefore, be tested as a prognostic marker in high risk prostate cancer patients.

  4. Prenatal exposure to maternal voluntary exercise during pregnancy provides protection against mild chronic postnatal hypoxia in rat offspring.

    Science.gov (United States)

    Akhavan, Maziar Mohammad; Foroutan, Tahereh; Safari, Manouchehr; Sadighi-Moghaddam, Bizhan; Emami-Abarghoie, Mitra; Rashidy-Pour, Ali

    2012-01-01

    Postnatal hypoxia is a main cause of neuronal damage in newborn. However, our understanding of the possible preventive or therapeutic methods to reduce the harmful effects of hypoxia is still primary. Pregnant rats were provided with running wheels during their pregnancy. On PND4 (postnatal day 4)to PND8, the rat pups were exposed to postnatal chronic hypoxia (11% O(2), 89% N(2)) in an air-tight plastic chamber for a period of six hours per day. The number of neurons and also angiogenesis in hippocampus were studied. Postnatal exposure to mild hypoxia decreased the number of the neurons in all studied regions of the hippocampus CA1, CA3 (cornu ammonis), DG(dentate gyrus) and SUB(cubiculum) in rat pups. In other words the number of the neurons in rat pups born from voluntary exercise group was not significantly less than control group in CA1, CA3 and DG regions. So maternal Voluntary exercise during pregnancy increases the blood vessel density in the DG region of the hippocampus of the rat pups. In this study for the first time we provide evidences that show the protective effect of maternal voluntary exercise during pregnancy on rat offspring against postnatal hypoxia. We revealed that maternal exercise during pregnancy increases the hippocampal neuron number and angiogenesis in offspring. PMID:22186335

  5. Long-term reversal of chronic anemia using a hypoxia-regulated erythropoietin gene therapy.

    Science.gov (United States)

    Binley, Katie; Askham, Zoe; Iqball, Sharifah; Spearman, Hayley; Martin, Leigh; de Alwis, Mahesh; Thrasher, Adrian J; Ali, Robin R; Maxwell, Patrick H; Kingsman, Susan; Naylor, Stuart

    2002-10-01

    Anemia is a common clinical problem, and there is much interest in its role in promoting left ventricular hypertrophy through increasing cardiac workload. Normally, red blood cell production is adjusted through the regulation of erythropoietin (Epo) production by the kidney. One important cause of anemia is relative deficiency of Epo, which occurs in most types of renal disease. Clinically, this can be corrected by supplementation with recombinant Epo. Here we describe an oxygen-regulated gene therapy approach to treating homozygous erythropoietin-SV40 T antigen (Epo-TAg(h)) mice with relative erythropoietin deficiency. We used vectors in which murine Epo expression was directed by an Oxford Biomedica hypoxia response element (OBHRE) or a constitutive cytomegalovirus (CMV) promoter. Both corrected anemia, but CMV-Epo-treated mice acquired fatal polycythemia. In contrast, OBHRE-Epo corrected the hematocrit level in anemic mice to a normal physiologic level that stabilized without resulting in polycythemia. Importantly, the OBHRE-Epo vector had no significant effect on the hematocrit of control mice. Homozygous Epo-TAg(h) mice display cardiac hypertrophy, a common adaptive response in patients with chronic anemia. In the OBHRE-Epo-treated Epo-TAg(h) mice, we observed a significant reversal of cardiac hypertrophy. We conclude that the OBHRE promoter gives rise to physiologically regulated Epo secretion such that the hematocrit level is corrected to healthy in anemic Epo-TAg(h) mice. This establishes that a hypoxia regulatory mechanism similar to the natural mechanism can be achieved, and it makes EPO gene therapy more attractive and safer in clinical settings. We envisage that this control system will allow regulated delivery of therapeutic gene products in other ischemic settings. PMID:12239150

  6. Characterization of carbonic anhydrase IX (CA IX) as an endogenous marker of chronic hypoxia in live human tumor cells

    International Nuclear Information System (INIS)

    Purpose: Published clinical studies provide conflicting data regarding the prognostic significance of carbonic anhydrase IX (CA IX) overexpression as an endogenous marker of tumor hypoxia and its comparability with other methods of hypoxia detection. We performed a systematic analysis of CA IX protein levels under various in vitro conditions of tumor hypoxia in HT 1080 human fibrosarcoma and FaDu human pharyngeal carcinoma cells. Because sorting of live CA IX positive cells from tumors provides a tool to study the radiosensitivity of chronically hypoxic cells, we modified and tested a CA IX flow cytometry protocol on mixed hypoxic/aerobic suspensions of HT 1080 and FaDu cells. Methods and materials: HT 1080 and FaDu cells were treated with up to 24 h of in vitro hypoxia and up to 96 h of reoxygenation. To test the effect of nonhypoxic stimuli, glucose and serum availability, pH and cell density were modified. CA IX protein was quantified in Western blots of whole-cell lysates. Mixed suspensions with known percentages of hypoxic cells were prepared for CA IX flow cytometry. The same mixtures were assayed for clonogenic survival after 10 Gy. Results: Hypoxia-induced CA IX protein expression was seen after >6 h at ≤5% O2, and protein was stable over 96 h of reoxygenation in both cell lines. Glucose deprivation abolished the hypoxic CA IX response, and high cell density caused CA IX induction under aerobic conditions. Measured percentages of CA IX-positive cells in mixtures closely reflected known percentages of hypoxic cells in HT 1080 and were associated with radioresistance of mixtures after 10 Gy. Conclusion: CA IX is a stable marker of current or previous chronic hypoxia but influenced by nonhypoxic stimuli. Except the time course of accumulation, all properties of this marker resembled our previous findings for hypoxia-inducible factor-1α. A modified flow cytometry protocol provided good separability of CA IX-negative and -positive cells in vitro and can be

  7. Tumour necrosis factor-alpha contributes to improved cardiac ischaemic tolerance in rats adapted to chronic continuous hypoxia

    Czech Academy of Sciences Publication Activity Database

    Chytilová, Anna; Borchert, Gudrun H.; Mandíková-Alánová, Petra; Hlaváčková, Markéta; Kopkan, L.; Khan, M. A. H.; Imig, J. D.; Kolář, František; Neckář, Jan

    2015-01-01

    Roč. 241, č. 1 (2015), s. 97-108. ISSN 1748-1708 R&D Projects: GA ČR(CZ) GA13-10267S; GA ČR(CZ) GAP303/12/1162 Institutional support: RVO:67985823 Keywords : chronic hypoxia * ischaemia/reperfusion injury * reactive oxygen species * tumor necrosis factor - alpha Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 4.382, year: 2014

  8. Poly (ADP-ribose polymerase plays an important role in intermittent hypoxia-induced cell death in rat cerebellar granule cells

    Directory of Open Access Journals (Sweden)

    Chiu Sheng-Chun

    2012-03-01

    Full Text Available Abstract Background Episodic cessation of airflow during sleep in patients with sleep apnea syndrome results in intermittent hypoxia (IH. Our aim was to investigate the effects of IH on cerebellar granule cells and to identify the mechanism of IH-induced cell death. Methods Cerebellar granule cells were freshly prepared from neonatal Sprague-Dawley rats. IH was created by culturing the cerebellar granule cells in the incubators with oscillating O2 concentration at 20% and 5% every 30 min for 1-4 days. The results of this study are based on image analysis using a confocal microscope and associated software. Cellular oxidative stress increased with increase in IH. In addition, the occurrence of cell death (apoptosis and necrosis increased as the duration of IH increased, but decreased in the presence of an iron chelator (phenanthroline or poly (ADP-ribose polymerase (PARP inhibitors [3-aminobenzamide (3-AB and DPQ]. The fluorescence of caspase-3 remained the same regardless of the duration of IH, and Western blots did not detect activation of caspase-3. However, IH increased the ratio of apoptosis-inducing factor (AIF translocation to the nucleus, while PARP inhibitors (3-AB reduced this ratio. Results According to our findings, IH increased oxidative stress and subsequently leading to cell death. This effect was at least partially mediated by PARP activation, resulting in ATP depletion, calpain activation leading to AIF translocation to the nucleus. Conclusions We suggest that IH induces cell death in rat primary cerebellar granule cells by stimulating oxidative stress PARP-mediated calpain and AIF activation.

  9. 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. PMID:27021659

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Reversibility of electrophysiological changes induced by chronic high-altitude hypoxia in adult rat heart.

    Science.gov (United States)

    Chouabe, C; Amsellem, J; Espinosa, L; Ribaux, P; Blaineau, S; Mégas, P; Bonvallet, R

    2002-04-01

    Recent studies indicate that regression of left ventricular hypertrophy normalizes membrane ionic current abnormalities. This work was designed to determine whether regression of right ventricular hypertrophy induced by permanent high-altitude exposure (4,500 m, 20 days) in adult rats also normalizes changes of ventricular myocyte electrophysiology. According to the current data, prolonged action potential, decreased transient outward current density, and increased inward sodium/calcium exchange current density normalized 20 days after the end of altitude exposure, whereas right ventricular hypertrophy evidenced by both the right ventricular weight-to-heart weight ratio and the right ventricular free wall thickness measurement normalized 40 days after the end of altitude exposure. This morphological normalization occurred at both the level of muscular tissue, as shown by the decrease toward control values of some myocyte parameters (perimeter, capacitance, and width), and the level of the interstitial collagenous connective tissue. In the chronic high-altitude hypoxia model, the regression of right ventricular hypertrophy would not be a prerequisite for normalization of ventricular electrophysiological abnormalities. PMID:11893582

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. 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. PMID:25265561

  15. Contribution of elevated intracellular calcium to pulmonary arterial myocyte alkalinization during chronic hypoxia.

    Science.gov (United States)

    Undem, Clark; Luke, Trevor; Shimoda, Larissa A

    2016-03-01

    In the lung, exposure to chronic hypoxia (CH) causes pulmonary hypertension, a debilitating disease. Development of this condition arises from increased muscularity and contraction of pulmonary vessels, associated with increases in pulmonary arterial smooth muscle cell (PASMC) intracellular pH (pHi) and Ca(2+) concentration ([Ca(2+)]i). In this study, we explored the interaction between pHi and [Ca(2+)]i in PASMCs from rats exposed to normoxia or CH (3 weeks, 10% O2). PASMC pHi and [Ca(2+)]i were measured with fluorescent microscopy and the dyes BCECF and Fura-2. Both pHi and [Ca(2+)]i levels were elevated in PASMCs from hypoxic rats. Exposure to KCl increased [Ca(2+)]i and pHi to a similar extent in normoxic and hypoxic PASMCs. Conversely, removal of extracellular Ca(2+) or blockade of Ca(2+) entry with NiCl2 or SKF 96365 decreased [Ca(2+)]i and pHi only in hypoxic cells. Neither increasing pHi with NH4Cl nor decreasing pHi by removal of bicarbonate impacted PASMC [Ca(2+)]i. We also examined the roles of Na(+)/Ca(2+) exchange (NCX) and Na(+)/H(+) exchange (NHE) in mediating the elevated basal [Ca(2+)]i and Ca(2+)-dependent changes in PASMC pHi. Bepridil, dichlorobenzamil, and KB-R7943, which are NCX inhibitors, decreased resting [Ca(2+)]i and pHi only in hypoxic PASMCs and blocked the changes in pHi induced by altering [Ca(2+)]i. Exposure to ethyl isopropyl amiloride, an NHE inhibitor, decreased resting pHi and prevented changes in pHi due to changing [Ca(2+)]i. Our findings indicate that, during CH, the elevation in basal [Ca(2+)]i may contribute to the alkaline shift in pHi in PASMCs, likely via mechanisms involving reverse-mode NCX and NHE. PMID:27076907

  16. Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth.

    Science.gov (United States)

    Blum-Johnston, Carla; Thorpe, Richard B; Wee, Chelsea; Romero, Monica; Brunelle, Alexander; Blood, Quintin; Wilson, Rachael; Blood, Arlin B; Francis, Michael; Taylor, Mark S; Longo, Lawrence D; Pearce, William J; Wilson, Sean M

    2016-02-01

    Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of large-conductance Ca(2+)-activated K(+) (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca(2+). Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca(2+) signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (∼ 140 days gestation) and newborn, 10- to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for >100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca(2+) responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 μM nitro-L-arginine methyl ester or 10 μM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel α1-subunit expression but increased β1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. PMID:26637638

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

    Directory of Open Access Journals (Sweden)

    Dincer UD

    2014-12-01

    Full Text Available U Deniz Dincer Department of Basic and Clinical Pharmacology, School of Medicine, Bezmialem Vakif University (BAVU, Fatih/Istanbul, Turkey Abstract: 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. Keywords: endothelial progenitor cells, gestational diabetes mellitus, chronic hypoxia, human cord blood

  18. 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...

  19. Impact of chronic intermittent external compressions on forearm blood flow capacity in humans

    OpenAIRE

    Roseguini, Bruno T.; Sheldon, Ryan; Stroup, Abigail; Bell, Jeffrey W.; Maurer, David; Crist, Brett D.; Laughlin, M. H.; Newcomer, Sean C.

    2010-01-01

    During dynamic exercise, the vasculature embedded within skeletal muscle intermittently collapses due to increased intramuscular pressure (IMP). The aim of this study was to ascertain whether oscillations in IMP during muscle contractions independently contribute to exercise training-induced increases in blood flow capacity (BFC). Based on IMP measurements during handgrip exercise, we attempted to mimic the action of repeated vascular compressions by using external inflatable cuffs. Thus, 24 ...

  20. Chronic effects of metoprolol and methyldopa on calf blood flow in intermittent claudication.

    OpenAIRE

    Lepäntalo, M

    1984-01-01

    In a placebo-controlled double-blind study 14 hypertensive patients with intermittent claudication were treated with metoprolol (100-200 mg daily) and methyldopa (500-1000 mg daily) for 3 weeks and their effects on heart rate, blood pressure as well as on resting and hyperaemic calf blood flow and vascular resistance were compared. In their antihypertensive effect metoprolol and methyldopa did not differ significantly. In 23 diseased limbs the calf blood flow and vascular resistance remained ...

  1. Gene expression profiling of sex differences in HIF1-dependent adaptive cardiac responses to chronic hypoxia

    Czech Academy of Sciences Publication Activity Database

    Bohuslavová, Romana; Kolář, František; Kuthanová, Lada; Neckář, Jan; Tichopád, Aleš; Pavlínková, Gabriela

    2010-01-01

    Roč. 109, č. 4 (2010), s. 1195-1202. ISSN 8750-7587 R&D Projects: GA ČR GA301/09/0117 Institutional research plan: CEZ:AV0Z50520701; CEZ:AV0Z50110509 Keywords : Hypoxia inducible factor 1 alpha * hypoxia * gene expression profiling Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.232, year: 2010

  2. Brief Daily Episode of Normoxia Inhibits Cardioprotection Conferred by Chronic Continuous Hypoxia. Role of Oxidative Stress and BKCa Channels

    Czech Academy of Sciences Publication Activity Database

    Neckář, Jan; Borchert, Gudrun H.; Hloušková, P.; Míčová, P.; Nováková, O.; Novák, F.; Hroch, M.; Papoušek, František; Ošťádal, Bohuslav; Kolář, František

    2013-01-01

    Roč. 19, č. 39 (2013), s. 6880-6889. ISSN 1381-6128 R&D Projects: GA AV ČR(CZ) IAAX01110901; GA ČR(CZ) GA305/07/0875; GA ČR(CZ) GAP303/12/1162 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : chronic continuous hypoxia * reoxygenation * ischemia/reperfusion * myocardial infarction * potassium channels * oxidative stress Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 3.288, year: 2013

  3. HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology.

    Science.gov (United States)

    Favier, F B; Britto, F A; Freyssenet, D G; Bigard, X A; Benoit, H

    2015-12-01

    Skeletal muscle is a metabolically active tissue and the major body protein reservoir. Drop in ambient oxygen pressure likely results in a decrease in muscle cells oxygenation, reactive oxygen species (ROS) overproduction and stabilization of the oxygen-sensitive hypoxia-inducible factor (HIF)-1α. However, skeletal muscle seems to be quite resistant to hypoxia compared to other organs, probably because it is accustomed to hypoxic episodes during physical exercise. Few studies have observed HIF-1α accumulation in skeletal muscle during ambient hypoxia probably because of its transient stabilization. Nevertheless, skeletal muscle presents adaptations to hypoxia that fit with HIF-1 activation, although the exact contribution of HIF-2, I kappa B kinase and activating transcription factors, all potentially activated by hypoxia, needs to be determined. Metabolic alterations result in the inhibition of fatty acid oxidation, while activation of anaerobic glycolysis is less evident. Hypoxia causes mitochondrial remodeling and enhanced mitophagy that ultimately lead to a decrease in ROS production, and this acclimatization in turn contributes to HIF-1α destabilization. Likewise, hypoxia has structural consequences with muscle fiber atrophy due to mTOR-dependent inhibition of protein synthesis and transient activation of proteolysis. The decrease in muscle fiber area improves oxygen diffusion into muscle cells, while inhibition of protein synthesis, an ATP-consuming process, and reduction in muscle mass decreases energy demand. Amino acids released from muscle cells may also have protective and metabolic effects. Collectively, these results demonstrate that skeletal muscle copes with the energetic challenge imposed by O2 rarefaction via metabolic optimization. PMID:26298291

  4. The express of PTP-1 B and IRS-1 in liver cells of rats during chronic intermittent hypoxic%PTP-1B 及 IRS-1在慢性间歇低氧大鼠肝细胞中的表达

    Institute of Scientific and Technical Information of China (English)

    赵勇; 任寿安; 蔡月伟

    2015-01-01

    目的:探讨慢性间歇低氧(CIH)对大鼠肝细胞蛋白酪氨酸磷酸酶-1B(protein tyrosine phosphatase-1B,PTP-1B)及胰岛素受体底物-1(insulin receptor substrate-1,IRS-1)蛋白表达量的影响及其导致胰岛素抵抗发生的可能机制。方法选取健康雄性 SD 大鼠24只,按随机数字表法分为正常对照组(NC 组)、慢性间歇低氧4周组(CIH4组)、慢性间歇低氧8周组(CIH8组),每组8只。NC 组无间歇低氧暴露正常饲养,CIH4组及 CIH8组于上午9时至下午5时放入间歇低氧仓暴露于间歇低氧环境中,舱内最低氧浓度为6%~7%。分别于第4周及第8周检测大鼠空腹血糖及空腹胰岛素水平,用稳态模型胰岛素抵抗指数(HOMA-IR)以及胰岛素敏感指数(insulin sensitive index,ISI)评价胰岛素抵抗, SABC 法免疫组织化学试剂盒检测 CIH 大鼠肝细胞 PTP-1B 及 IRS-1蛋白表达,以平均灰度值表示PTP-1B 及 IRS-1的蛋白表达量,并做统计学分析。结果与 NC 组比较,CIH4组及 CIH8组空腹血糖、空腹胰岛素及 HOMA-IR 升高,ISI 降低,差异有统计学意义(P <0.05),且 CIH8组更为显著;与 NC 组相比较,CIH4组及 CIH8组 PTP-1B 蛋白表达增加,IRS-1蛋白表达减少,差异有统计学意义(P <0.05),Pearson 相关分析显示,HOMA-IR 与 PTP-1B 平均灰度值呈负相关、与 IRS-1平均灰度值呈正相关;ISI 与 PTP-1B 平均灰度值呈正相关、与 IRS-1平均灰度值呈负相关。结论①CIH 暴露使大鼠空腹血糖及胰岛素水平升高且发生胰岛素抵抗,随着 CIH 暴露时间的延长,胰岛素抵抗程度加重。②CIH 导致大鼠肝细胞 PTP-1B 蛋白表达增加,IRS-1蛋白表达减少,PTP-1B 及 IRS-1可能共同参与了 CIH 大鼠胰岛素抵抗的发生发展。%Objective To investigate the effects of chronic intermittent hypoxia on the expression of PTP-1B and IRS-1 and the possible mechanism of insulin resistance caused by chronic intermittent hypoxia.Methods According to the

  5. Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines.

    Science.gov (United States)

    Uys, Joachim D; McGuier, Natalie S; Gass, Justin T; Griffin, William C; Ball, Lauren E; Mulholland, Patrick J

    2016-05-01

    Alcohol use disorder is a chronic relapsing brain disease characterized by the loss of ability to control alcohol (ethanol) intake despite knowledge of detrimental health or personal consequences. Clinical and pre-clinical models provide strong evidence for chronic ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the nucleus accumbens (NAc). However, the neural mechanisms that contribute to aberrant glutamatergic signaling in ethanol-dependent individuals in this critical brain structure remain unknown. Using an unbiased proteomic approach, we investigated the effects of chronic intermittent ethanol (CIE) exposure on neuroadaptations in postsynaptic density (PSD)-enriched proteins in the NAc of ethanol-dependent mice. Compared with controls, CIE exposure significantly changed expression levels of 50 proteins in the PSD-enriched fraction. Systems biology and functional annotation analyses demonstrated that the dysregulated proteins are expressed at tetrapartite synapses and critically regulate cellular morphology. To confirm this latter finding, the density and morphology of dendritic spines were examined in the NAc core of ethanol-dependent mice. We found that CIE exposure and withdrawal differentially altered dendrite diameter and dendritic spine density and morphology. Through the use of quantitative proteomics and functional annotation, these series of experiments demonstrate that ethanol dependence produces neuroadaptations in proteins that modify dendritic spine morphology. In addition, these studies identified novel PSD-related proteins that contribute to the neurobiological mechanisms of ethanol dependence that drive maladaptive structural plasticity of NAc neurons. PMID:25787124

  6. Imaging Tumor Hypoxia to Advance Radiation Oncology

    OpenAIRE

    Lee, Chen-Ting; Boss, Mary-Keara; Dewhirst, Mark W.

    2014-01-01

    Significance: Most solid tumors contain regions of low oxygenation or hypoxia. Tumor hypoxia has been associated with a poor clinical outcome and plays a critical role in tumor radioresistance. Recent Advances: Two main types of hypoxia exist in the tumor microenvironment: chronic and cycling hypoxia. Chronic hypoxia results from the limited diffusion distance of oxygen, and cycling hypoxia primarily results from the variation in microvessel red blood cell flux and temporary disturbances in p...

  7. Chronic hypoxia up-regulates alpha1H T-type channels and low-threshold catecholamine secretion in rat chromaffin cells.

    Science.gov (United States)

    Carabelli, V; Marcantoni, A; Comunanza, V; de Luca, A; Díaz, J; Borges, R; Carbone, E

    2007-10-01

    alpha(1H) T-type channels recruited by beta(1)-adrenergic stimulation in rat chromaffin cells (RCCs) are coupled to fast exocytosis with the same Ca(2+) dependence of high-threshold Ca(2+) channels. Here we show that RCCs exposed to chronic hypoxia (CH) for 12-18 h in 3% O(2) express comparable densities of functional T-type channels that depolarize the resting cells and contribute to low-voltage exocytosis. Following chronic hypoxia, most RCCs exhibited T-type Ca(2+) channels already available at -50 mV with the same gating, pharmacological and molecular features as the alpha(1H) isoform. Chronic hypoxia had no effects on cell size and high-threshold Ca(2+) current density and was mimicked by overnight incubation with the iron-chelating agent desferrioxamine (DFX), suggesting the involvement of hypoxia-inducible factors (HIFs). T-type channel recruitment occurred independently of PKA activation and the presence of extracellular Ca(2+). Hypoxia-recruited T-type channels were partially open at rest (T-type 'window-current') and contributed to raising the resting potential to more positive values. Their block by 50 microm Ni(2+) caused a 5-8 mV hyperpolarization. The secretory response associated with T-type channels could be detected following mild cell depolarizations, either by capacitance increases induced by step depolarizations or by amperometric current spikes induced by increased [KCl]. In the latter case, exocytotic bursts could be evoked even with 2-4 mm KCl and spike frequency was drastically reduced by 50 microm Ni(2+). Chronic hypoxia did not alter the shape of spikes, suggesting that hypoxia-recruited T-type channels increase the number of secreted vesicles at low voltages, without altering the mechanism of catecholamine release and the quantal content of released molecules. PMID:17690152

  8. Chronic hypoxia up-regulates α1H T-type channels and low-threshold catecholamine secretion in rat chromaffin cells

    Science.gov (United States)

    Carabelli, V; Marcantoni, A; Comunanza, V; de Luca, A; Díaz, J; Borges, R; Carbone, E

    2007-01-01

    α1H T-type channels recruited by β1-adrenergic stimulation in rat chromaffin cells (RCCs) are coupled to fast exocytosis with the same Ca2+ dependence of high-threshold Ca2+ channels. Here we show that RCCs exposed to chronic hypoxia (CH) for 12–18 h in 3% O2 express comparable densities of functional T-type channels that depolarize the resting cells and contribute to low-voltage exocytosis. Following chronic hypoxia, most RCCs exhibited T-type Ca2+ channels already available at −50 mV with the same gating, pharmacological and molecular features as the α1H isoform. Chronic hypoxia had no effects on cell size and high-threshold Ca2+ current density and was mimicked by overnight incubation with the iron-chelating agent desferrioxamine (DFX), suggesting the involvement of hypoxia-inducible factors (HIFs). T-type channel recruitment occurred independently of PKA activation and the presence of extracellular Ca2+. Hypoxia-recruited T-type channels were partially open at rest (T-type ‘window-current’) and contributed to raising the resting potential to more positive values. Their block by 50 μm Ni2+ caused a 5–8 mV hyperpolarization. The secretory response associated with T-type channels could be detected following mild cell depolarizations, either by capacitance increases induced by step depolarizations or by amperometric current spikes induced by increased [KCl]. In the latter case, exocytotic bursts could be evoked even with 2–4 mm KCl and spike frequency was drastically reduced by 50 μm Ni2+. Chronic hypoxia did not alter the shape of spikes, suggesting that hypoxia-recruited T-type channels increase the number of secreted vesicles at low voltages, without altering the mechanism of catecholamine release and the quantal content of released molecules. PMID:17690152

  9. Carotid body AT4 receptor expression and its upregulation in chronic hypoxia

    OpenAIRE

    Fung, Man-Lung; Lam, Siu-Yin; Wong, Tung-Po; Tjong, Yung-Wui; Leung, Po-Sing

    2007-01-01

    Hypoxia regulates the local expression of angiotensin-generating system in the rat carotid body and the me-tabolite angiotensin IV (Ang IV) may be involved in the modulation of carotid body function. We tested the hypothesis that Ang IV-binding angiotensin AT(4) receptors play a role in the adaptive change of the carotid body in hypoxia. The expression and localization of Ang IV-binding sites and AT(4) receptors in the rat carotid bodies were studied with histochemistry. Specific fluorescein-...

  10. Chronic hypoxia reduces adenosine A2A receptor-mediated inhibition of calcium current in rat PC12 cells via downregulation of protein kinase A.

    Science.gov (United States)

    Kobayashi, S; Beitner-Johnson, D; Conforti, L; Millhorn, D E

    1998-10-15

    1. Adenosine has been shown to decrease Ca2+ current (ICa) and attenuate the hypoxia-induced enhancement of intracellular free Ca2+ ([Ca2+]i) in oxygen-sensitive rat phaeochromocytoma (PC12) cells. These effects are mediated via the adenosine A2A receptor and protein kinase A (PKA). The current study was undertaken to determine the effects of adenosine on Ca2+ current and hypoxia-induced change in [Ca2+]i during chronic hypoxia. 2. Whole cell patch-clamp studies revealed that the effect of adenosine on ICa was significantly reduced when PC12 cells were exposed to hypoxia (10 % O2) for 24 and 48 h. 3. Ca2+ imaging studies using fura-2 revealed that the anoxia-induced increase in [Ca2+]i was significantly enhanced when PC12 cells were exposed to 10 % O2 for up to 48 h. In contrast, the inhibitory effects of adenosine on anoxia-induced elevation of [Ca2+]i was significantly blunted in PC12 cells exposed to hypoxia for 48 h. 4. Northern blot analysis revealed that mRNA for the A2A receptor, which is the only adenosine receptor subtype expressed in PC12 cells, was significantly upregulated by hypoxia. Radioligand binding analysis with [3H]CGS21680, a selective A2A receptor ligand, showed that the number of adenosine A2A receptor binding sites was similarly increased during exposure to 10% O2 for 48 h. 5. PKA enzyme activity was significantly inhibited when PC12 cells were exposed to 10% O2 for 24 and 48 h. However, we found that hypoxia failed to induce change in adenosine- and forskolin-stimulated adenylate cyclase enzyme activity. Chronic hypoxia also did not alter the immunoreactivity level of the G protein Gsalpha, an effector of the A2 signalling pathway. 6. Whole cell patch-clamp analysis showed that the effect of 8-bromo-cAMP, an activator of PKA, on ICa was significantly attenuated during 48 h exposure to 10% O2.7. We conclude therefore that the reduced effect of adenosine on ICa and [Ca2+]i in PC12 cells exposed to chronic hypoxia is due to hypoxia

  11. 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

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

    International Nuclear Information System (INIS)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Chronic Cervicogenic Tinnitus Rapidly Resolved by Intermittent Use of Cervical Collar

    OpenAIRE

    Bechter, Karl; Wieland, Martin; Hamann, Gerhard F

    2016-01-01

    Introduction Cervicogenic tinnitus is not a 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 (CPS) and successful add-on treatment with cervical collar (CC), the idea was pursued in several individual treatments in patients. Patients and methods Reporting one particular case with chronic tinnitus, considered untreatable, t...

  15. Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems

    Czech Academy of Sciences Publication Activity Database

    Kašparová, D.; Neckář, Jan; Dabrowská, L.; Novotný, J.; Mráz, J.; Kolář, František; Žurmanová, J.

    2015-01-01

    Roč. 47, č. 12 (2015), s. 612-620. ISSN 1094-8341 R&D Projects: GA ČR(CZ) GAP303/12/1162; GA ČR(CZ) GA13-10267S Institutional support: RVO:67985823 Keywords : adaptation to hypoxia * cardioprotection * ischemia -reperfusion injury * oxidative stress * antioxidant defense Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.374, year: 2014

  16. Effects of mitochondrial KATP modulators on cardioprotection induced by chronic high altitude hypoxia in rats

    Czech Academy of Sciences Publication Activity Database

    Neckář, Jan; Szárszoi, Ondrej; Koten, L.; Papoušek, František; Ošťádal, Bohuslav; Grover, G. J.; Kolář, František

    2002-01-01

    Roč. 55, č. 3 (2002), s. 567-575. ISSN 0008-6363 R&D Projects: GA ČR GA306/98/0470; GA ČR GA305/01/0279; GA MŠk LN00A069 Institutional research plan: CEZ:AV0Z5011922 Keywords : contractile function * hypoxia/anoxia * K-ATP channel Subject RIV: ED - Physiology Impact factor: 4.692, year: 2002

  17. 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.

  18. ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats

    Czech Academy of Sciences Publication Activity Database

    Rakusan, K.; Chvojková, Zuzana; Oliviero, P.; Ošťádalová, Ivana; Kolář, František; Chassagne, C.; Samuel, J. L.; Ošťádal, Bohuslav

    2007-01-01

    Roč. 292, č. 3 (2007), H1237-H1244. ISSN 0363-6135 R&D Projects: GA MŠk 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : angiogenesis neonatal rat * ANG II type 1 receptor antagonist heart * ischemic tolerance Subject RIV: ED - Physiology Impact factor: 3.973, year: 2007

  19. 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

  20. Effects of intermittent hypoxia on the expression of GSK-3 and mTOR in rat liver%间歇低氧对大鼠肝脏GSK-3及mTOR表达的影响

    Institute of Scientific and Technical Information of China (English)

    任国梅; 任寿安

    2015-01-01

    目的 测定间歇低氧大鼠肝脏糖原合成酶激酶-3(GSK-3)及哺乳动物雷帕霉素靶蛋白(mTOR)的表达,观察间歇低氧对胰岛素信号转导通路的影响.方法 将24只健康雄性Sprague-Dawley大鼠按照随机数字表法分成间歇空气组(NC组)、间歇低氧4周组(IH4组)、间歇低氧8周组(IH8组),每组8只.于上午9:00至下午5:00将IH4组及IH8组暴露于间歇低氧舱内,NC组则给予间歇压缩空气.检测各组大鼠空腹血糖、空腹胰岛素(FINS),并以稳态模型评估-胰岛素敏感指数(HOMA-IS)及稳态模型评估-胰岛素抵抗指数(HOMA-IR)评价胰岛素抵抗;免疫组化法测定大鼠肝脏GSK-3及mTOR的表达,以平均灰度值评价二者的蛋白表达量.结果 与NC组相比,IH4组、IH8组HOMA-IS降低,空腹血糖、FINS、HOMA-IR升高,以IH8组更为显著(F值分别为62.52,100.37,68.90,8549,P均<0.01);与NC组相比,IH4组、IH8组GSK-3及mTOR蛋白表达均升高,以IH8组更明显(F值分别为72.25,148.01,P均<0.01).Pearson相关分析显示GSK-3、mTOR平均灰度值与HOMA-IS呈正相关(r =0.786,0.811,P均<0.01),与HOMA-IR呈负相关(r=-0.882,-0.889,P均<0.01).结论 间歇低氧暴露使大鼠肝脏GSK-3、mTOR表达增加,从而引起胰岛素抵抗.%Objective To determine the expression of glycogen synthase kinase-3 (GSK-3) and mammalian target of rapamycin (mTOR) in the liver of rats exposed to intermittent hypoxic,and to observe the effects of intermittent hypoxia on the insulin signaling pathway.Methods Twenty four healthy male Sprague-Dawley rats were randomly divided into 3 groups according to the random number table:intermittent air group (NC group),4 weeks of intermittent hypoxia group (IH4 group) and 8 weeks of intermittent hypoxia group (IH8 group),with 8 rats in each group.Each day from 9:00 am to 5:00 pm,rats in NC group were housed in intermittent air cabin,while rats in IH4 group and IH8 group were housed in intermittent low oxygen cabin.Fasting blood

  1. Vascular endothelial growth factor and hypoxia-inducible factor-1α gene polymorphisms and coronary collateral formation in patients with coronary chronic total occlusions

    Science.gov (United States)

    Amoah, Vincent; Wrigley, Benjamin; Holroyd, Eric; Smallwood, Andrew; Armesilla, Angel L; Nevill, Alan; Cotton, James

    2016-01-01

    Introduction: We evaluated the association between two single nucleotide polymorphisms of the vascular endothelial growth factor gene and one of the hypoxia-inducible factor-1α gene and the degree of coronary collateral formation in patients with a coronary chronic total occlusion. Methods: Totally, 98 patients with symptomatic coronary artery disease and a chronic total occlusion observed during coronary angiography were recruited. Genotyping of two vascular endothelial growth factor promoter single nucleotide polymorphisms (−152G>A and −165C>T) and the C1772T single nucleotide polymorphism of hypoxia-inducible factor-1α were performed using polymerase chain reaction and restriction fragment length polymorphism analysis. The presence and extent of collateral vessel filling was scored by blinded observers using the Rentrop grade. Results: We found no association between the vascular endothelial growth factor −152G>A, −165C>T and hypoxia-inducible factor-1α −1772C>T with the presence and filling of coronary collateral vessels. A history of percutaneous coronary intervention and transient ischaemic attack/cerebrovascular accident were associated with the presence of enhanced collateral vessel formation following binary logistic regression analysis. Conclusion: The study findings suggest that coronary collateral formation is not associated with the tested polymorphic variants of vascular endothelial growth factor and hypoxia-inducible factor-1α in patients with symptomatic coronary artery disease and the presence of a chronic total occlusion.

  2. The effects of intermittent fasting during the month of Ramadan in chronic haemodialysis patients in a tropical climate country.

    Directory of Open Access Journals (Sweden)

    Wan Ahmad Hafiz Wan Md Adnan

    Full Text Available BACKGROUND: Chronic kidney disease is an emerging problem in the majority Muslim countries. Despite the uncertainties of the risks involved, some Muslim patients undergoing chronic haemodialysis choose to observe intermittent fasting during the month of Ramadan. This study aims to investigate the effect of Ramadan fasting in haemodialysis patients residing in a tropical climate country. METHODS: This prospective cross sectional study recruited Muslim patients on regular haemodialysis from three haemodialysis centres in Kuala Lumpur from 15th July 2011 to 29th August 2011. Patients who fasted for any number of days were included (n = 35, 54% female, age 54±11 years. 89% of patients fasted for more than 15 days and 49% were diabetics. Dialysis parameters and blood samples were obtained one week prior to Ramadan and during the last week of Ramadan. The differences in dialysis parameters and biochemical values pre- and end-Ramadan were examined using paired t-test. RESULTS: Both pre- and post-dialysis weight were significantly decreased during Ramadan fasting compared to the month prior (p = <0.001. There was a significant decrease in the amount of ultrafiltration (p = 0.002. There were no significant differences in dry weight, inter-dialytic weight gain, mean urea reduction ratio or blood pressure measurements comparing pre- and end of Ramadan fasting. There was a significant increase in serum albumin level (p = 0.006 and decrease in serum phosphate level (p = 0.02 at the end of Ramadan. CONCLUSION: Ramadan fasting is associated with reduced weight, improved serum albumin and phosphate level in our population of haemodialysis patients. A larger multi-centre study will allow us to understand more about the effects of fasting in this population.

  3. In vivo chronic intermittent ethanol exposure reverses the polarity of synaptic plasticity in the nucleus accumbens shell.

    Science.gov (United States)

    Jeanes, Zachary M; Buske, Tavanna R; Morrisett, Richard A

    2011-01-01

    Glutamatergic synaptic plasticity in the nucleus accumbens (NAc) is implicated in response to sensitization to psychomotor-stimulating agents, yet ethanol effects here are undefined. We studied the acute in vitro and in vivo effects of ethanol in medium spiny neurons from the shell NAc subregion of slices of C57BL/6 mice by using whole-cell voltage-clamp recordings of α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) excitatory postsynaptic current (EPSCs). Synaptic conditioning (low-frequency stimulation with concurrent postsynaptic depolarization) reliably depressed AMPA EPSCs by nearly 30%; this accumbal long-term depression (LTD) was blocked by a nonselective N-methyl-D-aspartate (NMDA) receptor antagonist (DL-2-amino-5-phosphonovaleric acid) and a selective NMDA receptor 2B antagonist [R-(R*,S*)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol]. Acute ethanol exposure inhibited the depression of AMPA EPSCs differentially with increasing concentrations, but this inhibitory action of ethanol was occluded by a D1-selective dopamine receptor agonist. Ethanol dependence was elicited in C57BL/6 mice by two separate 4-day bouts of chronic intermittent ethanol (CIE) vapor exposure. When assessed 24 h after a single bout of in vivo CIE vapor exposure, NAc LTD was absent, and instead NMDA receptor-dependent synaptic potentiation [long-term potentiation (LTP)] was reliably observed. It is noteworthy that both LTP and LTD were completely absent after an extended withdrawal (72 h) after a single 3-day CIE vapor bout. These observations demonstrate that 1) accumbal synaptic depression is mediated by NR2B receptors, 2) accumbal synaptic depression is highly sensitive to both acute and chronic ethanol exposure, and 3) alterations in this synaptic process may constitute a neural adaptation that contributes to the induction and/or expression of ethanol dependence. PMID:20947635

  4. 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

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

    OpenAIRE

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

  6. Spatial learning and memory deficits following exposure to 24 hours of sleep fragmentation or intermittent hypoxia in a rat model of obstructive sleep apnea

    OpenAIRE

    Ward, Christopher P; McCoy, John G; McKenna, James T.; Connolly, Nina P.; McCarley, Robert W.; Strecker, Robert E.

    2009-01-01

    Obstructive sleep apnea is primarily characterized by hypoxemia due to frequent apneic episodes and fragmentation of sleep due to the brief arousals that terminate the apneic episodes. Though neurobehavioral deficits frequently accompany sleep apnea, the relative roles of hypoxia versus sleep fragmentation are difficult to separate in apneic patients. Here, we assessed cognitive function as measured by water maze in the Fischer/Brown Norway (FBN) rat, comparing 24 h of sleep interruption (SI)...

  7. Cerebral Hypoxia

    Science.gov (United States)

    ... Enhancing Diversity Find People About NINDS NINDS Cerebral Hypoxia Information Page Synonym(s): Hypoxia, Anoxia Table of Contents ( ... Trials Organizations Publicaciones en Español What is Cerebral Hypoxia? Cerebral hypoxia refers to a condition in which ...

  8. Comparison of (immuno-)fluorescence data with serial [18F]Fmiso PET/CT imaging for assessment of chronic and acute hypoxia in head and neck cancers

    International Nuclear Information System (INIS)

    Purpose: Both, acute and chronic hypoxia can have unfavorable impacts on tumor progression and therapy response. The aim of this study was to optimize a macroscopic technique for the quantification of acute and chronic hypoxia (Wang model assessment of serial [18F]Fmiso PET/CT imaging) by comparing with a microscopic technique [(immuno-)fluorescence staining in tumor cryosections]. Materials and methods: Tumor pieces from the human squamous cell carcinoma lines from the head and neck FaDu and CAL33 were xenografted into the hind leg of NMRI nu/nu mice. Tumor-bearing mice were placed on an in-house developed multi-point fixation system and subjected to two consecutive dynamic [18F]Fmiso PET/CTs within a 24 h interval. The Wang model was applied to SUV (standard uptake values) to quantify the fractions of acute and chronic hypoxia. Hypoxia subtypes were also assessed in vital tumor tissue of cryosections from the same tumors for (immuno-)fluorescence distributions of Hoechst 33342 (perfusion), pimonidazole (hypoxia), and CD31 (endothelium) using pattern recognition in microcirculatory supply units (defined as vital tumor tissue area supplied by a single microvessel). Results: Using our multi-point fixation system, acceptable co-registration (registration errors ε ranged from 0.34 to 1.37) between serial PET/CT images within individual voxels was achieved. The Wang model consistently yielded higher fractions of acute hypoxia than the MCSU method. Through specific modification of the Wang model (Wangmod), it was possible to reduce the fraction of acute hypoxia. However, there was no significant correlation between the fractions of acute hypoxia in individual tumors assessed by the Wangmod model and the MCSU method for either tumor line (FaDu: r = 0.68, p = 0.21 and CAL33: r = 0.71, p = 0.18). This lack of correlation is most-likely due to the difference between the non-linear uptake of [18F]Fmiso and the spatial assessment of MCSUs. Conclusions: Whether the Wang model

  9. Molecular characterization and in vivo expression of hypoxia inducible factor (HIF-1α in sea bass (Dicentrarchus labrax exposed to acute and chronic hypoxi

    Directory of Open Access Journals (Sweden)

    Marco Saroglia

    2010-01-01

    Full Text Available Aquatic hypoxia is a frequent event and in fish a complex set of physiological and bi- ochemical alterations are employed to cope with this environmental stress. Many of these adjustments depend to a large extent on changes in the expression of genes that encode for physiologically relevant proteins. Genes that are induced by hypoxia appear to share a common mode of transcriptional regula- tion. This induction depends upon activation of a transcription factor, the hypoxia inducible factor-1 (HIF-1, which is a heterodimer composed of two subunits: α ‧ and β. In this study we report first on the molecular cloning and characterization of HIF-1α ‧ in sea bass (Dicentrarchus labrax. The full-length sea bass cDNA for HIF-1α was isolated and deposited in the GenBank with accession no. DQ171936. It consists of 3317 base pairs (bp carrying a single open-read- ing frame that encompasses 2265 bp of the coding region and 1052 bp of the 3’ UTR. We then utilized the real-time PCR technology to monitor dynamic changes in levels of HIF-1α ‧ tran- scripts, in response to acute and chronic hypoxic stress. The number of HIF-1α ‧ mRNA copies were signifi- cantly increased in response to both acute (1.9 mg/L, dissolved oxygen for 4 hours and chronic (4.3 mg/L, DO for 15 days hypoxia in sea bass, whereas it remained unchanged in fish exposed to hyperoxic (DO 13.5±1.2 mg/L, 155 % saturation conditions. This is the first study carried out to investigate the behaviour of HIF-1α gene transcripts during hypoxia in representative of marine hypoxia-sensitive fish species.

  10. 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

  11. Regulation of N-methyl-D-aspartate receptor expression and N-methyl-D-aspartate-induced cellular response during chronic hypoxia in differentiated rat PC12 cells.

    Science.gov (United States)

    Kobayashi, S; Millhorn, D E

    2000-01-01

    The purpose of the present study was to examine the effect of chronic hypoxia on N-methyl-D-aspartate-mediated cellular responses in differentiated PC12 cells. PC12 cells were differentiated by treatment with nerve growth factor. Patch-clamp analysis in differentiated PC12 cells showed that extracellularly applied N-methyl-D-aspartate induced an inward current that was abolished by the presence of the N-methyl-D-aspartate receptor antagonist MK-801. Results from Ca(2+) imaging experiments showed that N-methyl-D-aspartate induced an elevation in intracellular free Ca(2+) which was also abolished by MK-801. We also examined the effect of hypoxia on the N-methyl-D-aspartate-induced current in nerve growth factor-treated cells. We found that the N-methyl-D-aspartate-induced inward current and the N-methyl-D-aspartate-induced elevation in intracellular free Ca(2+) were markedly attenuated by chronic hypoxia. We next examined the possibility that the reduced N-methyl-D-aspartate responsiveness was due to down-regulation of N-methyl-D-aspartate receptor levels. Northern blot and immunoblot analyses showed that both messenger RNA and protein levels for N-methyl-D-aspartate receptor subunit 1 were markedly decreased during hypoxia. However, the messenger RNA for N-methyl-D-aspartate receptor subunit 2C was increased, whereas the protein level for subunit 2C did not change. Our results indicate that differentiated PC12 cells express functional N-methyl-D-aspartate receptors and that chronic exposure to hypoxia attenuates the N-methyl-D-aspartate-induced Ca(2+) accumulation in these cells via down-regulation of N-methyl-D-aspartate receptor subunit 1. This mechanism may play an important role in protecting PC12 cells against hypoxic stress. PMID:11113364

  12. 间断性缺氧对小鼠海马tau蛋白异常过度磷酸化的影响%Effects on hyperphosphorylation of tau protein in hippocampus of mouse with intermittent hypoxia

    Institute of Scientific and Technical Information of China (English)

    刘静; 杨遥; 徐江涛

    2013-01-01

    Objective To observe the expression of tau phosphorylation in hippocampus of mouse after intermittent hypoxia ( IH). Methods 30 male Kun Ming mice were divided into the control group (n = 5) and IH group (n = 25). The mice of IH group suffered 8 hours intermittent hypoxia. Morphological changes of nerve cells were observed with HE. The expression of tau phosphorylation (P-tau) and the total of tau protein (T-tau) were examined by immunohistochemistry at 1 h,6h, 12h,24 h,48 h after IH in hippocampus of mouse. Results HE staining results showed that there were dilated intercellular spaces, reduced number of cells and part of hippocampal neurons presented morphological changes after IH. The expressions of P-tau in 6 h, 12 h, 24 h and 48 h in IH group were higher than those in control group( all P <0.05) , in 24 h higher than in 6 h, 12 h and 48 h(all P<0.05) . The lever of P-tau began enhanced at 6 h after IH, up to peak at 24 h. T-tau had no significant differences in all groups (P >0.05). Conclusion Intermittent hypoxia could increase hyperphosphorylation of tau protein.%目的 观察间断性缺氧(IH)对小鼠海马tau蛋白磷酸化的影响.方法 选取雄性昆明小鼠30只,随机分为对照组5只和IH组25只.对照组置于IH箱内不行IH处理,8h后取脑组织待测;IH组置于IH箱内给予IH处理8h,分别于IH后1、6、12、24、48 h取脑组织待测.HE染色观察海马神经细胞形态变化,免疫组化法检测海马区磷酸化tau蛋白(P-tau)及总tau蛋白(T-tau)的表达.结果 HE染色结果显示,IH后细胞间隙增宽,细胞数目减少,部分细胞出现形态学改变.免疫组化结果显示,IH后1、6、12、24、48 h P-tau的平均光密度值除IH后1h组外,其余各组均高于对照组(P均<0.05);24 h组高于其他各组(P均<0.05).不同时间点的T-tau表达差异无统计学意义(P均>0.05).结论 IH可导致小鼠海马tau蛋白过度磷酸化.

  13. The Effects of Chronic Hypoxia on Thermoregulation and Metabolism in Phrynocephalus vlangalii

    Institute of Scientific and Technical Information of China (English)

    Qiang CHEN

    2016-01-01

    Phrynocephalus vlangalii are widely distributed on Tibetan plateau spanning diverse altitudes and habitats. In the present study, P. vlangalii were exposed to 8% oxygen concentration in a hypoxic chamber for 6 weeks. Then the body temperature (Tb), standard metabolic rate (SMR), heart rate and metabolic enzyme activities of the lizards were measured at 20°C and 30°C. The results indicated that hypoxia exposure decreased Tb, SMR and heart rate. Lactate dehydrogenase (LDH) activity of 8% O2 group became significant elevated in liver and skeletal muscle compared with control group at 20°C, but descended significantly in heart. Using electrophoresis we found that LDH contains five isozymes (LDH1, LDH2, LDH3, LDH4 and LDH5) and are expressed specifically in liver, skeletal muscle and heart. Citrate synthase (CS) activity in the liver also decreased at 20°C and 30°C. No significant difference of CS activity was found between the two groups in skeletal muscle and heart.

  14. 重度间歇低氧大鼠学习记忆功能与氧化应激的关系%The relation of learning deficits with oxidative stress in rats exposed to severe intermittent hypoxia

    Institute of Scientific and Technical Information of China (English)

    王红阳; 韩晓庆; 赵雅宁; 张盼盼; 杨林; 雷军旗; 陈宝元

    2012-01-01

    Objective To observe the relations between learning memory function and oxidative stress in rats exposed to severe intermittent hypoxia (IH).Methods Adult male Wistar rats (n =48)were randomly assigned to 2 groups: untreated control group (UC) and 5% intermittent hypoxia group (5% IH).At 2,4,6 and 8 weeks,the learning and memory ability of the rats in each group were assessed with the Morris water maze (MWM) test.The ultrastructural changes in the hippocampus of the rats were observed with transmission electron microscopy (TEM).The levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by colorimetric method.Results The water maze test showed that the rats in the 5% IH group had prolonged latency in escaping,reduced target quadrant time in crossing and reduced frequency of crossing the platform,as compared to the UC group (P < 0.05).With longer time of hypoxia,the damage became more significant.It was observed that the structure of neuron cell was complete and organelles were abundant in UC groups.With the extention of exposure time,the number of hippocampus neurons and synaptic were decreased in 5% IH groups,nucleus shrank,synaptic frame became indefinite and synaptic cleft widen.Comparing with control group,the level of MDA in the hippocampal region group was significantly higher (P <0.05) and the activity of SOD significantly was lower (P <0.05) in 5% IH,along with the time expand,which aggravated.Conclusion Severe intermittent hypoxia that results in learning and memory dysfunction.It is possible that oxidative stress change the quantity and structure of hippocampal neurons and synaptic,which aggravates along with the intermittent low oxygen time expand.%目的 通过建立重度间歇低氧动物模型,探讨OSAHS大鼠学习记忆功能与氧化应激的关系.方法 成年雄性Wistar大鼠48只,体重(170±10)g,采用随机数字法分为5%间歇性低氧组和对照组,每组又分为2、4、6和8周时间组,每组6

  15. 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

  16. 间歇低氧对大鼠胰岛素抵抗及骨骼肌细胞GLUT4、Akt2的影响%Effects of intermittent hypoxia on insulin resistance and expression of GLUT4 and Akt2 in skeletal muscle cells of rats

    Institute of Scientific and Technical Information of China (English)

    汤玮娜; 任寿安

    2016-01-01

    目的 检测不同间歇低氧暴露时间对骨骼肌葡萄糖转运蛋白(GLUT)4与蛋白激酶B(PKB/Akt)2表达的影响,探讨二者在间歇低氧导致胰岛素抵抗中的作用.方法 选取健康雄性Sprague-Dawley大鼠40只,按照随机数字表法分为5组:常氧对照组(NC组),间歇低氧2周组(IH2组),间歇低氧4周组(IH4组),间歇低氧6周组(IH6组),间歇低氧8周组(IH8组),每组8只.IH2组、IH4组、IH6组、IH8组每天给予8h间歇低氧暴露(9:00~17:00),NC组室内环境正常饲养.检测各组空腹血糖和空腹胰岛素水平,计算稳态模型评估-胰岛素抵抗指数(HOMA-IR).采用免疫组织化学法检测大鼠骨骼肌GLUT4及Akt2蛋白的表达,蛋白表达量用平均灰度值表示,并分析GLUT4与Akt2的相关性.结果 与NC组相比,IH2组、IH4组、IH6组、IH8组空腹血糖、HOMA-IR升高,骨骼肌GLUT4与Akt2灰度值升高,并且随间歇低氧暴露时间的延长而升高明显(F =87.67~288.63,P均<0.05);与NC组相比,IH2组、IH4组、IH6组、IH8组空腹胰岛素升高,其中IH2组、IH4组、IH6组,随间歇低氧暴露时间的延长而升高明显,IH8组较IH6组下降(F=86.04,P<0.01).Pearson相关分析显示GLUT4与Akt2的表达呈正相关(r=0.895,P <0.05).结论 随着间歇低氧暴露时间的延长胰岛素抵抗程度增加,GLUT4与Akt2蛋白表达水平下降,二者在间歇低氧导致胰岛素抵抗的过程中起协同作用.%Objective To investigate the effects of different time of exposure to intermittent hypoxia on the expression of glucose transporter (GLUT) 4 and protein kinase B(PKB/Akt)2,and their roles in insulin resistance induced by intermittent hypoxia.Methods Forty male Sprauge-Dawley rats were divided into 5 groups by random number table method:normal control group (NC group),group of intermittent hypoxia for 2 weeks (IH2 group),group of intermittent hypoxia for 4 weeks (IH4 group),group of intermittent hypoxia for 6 weeks (IH6 group) and group of

  17. 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

  18. 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

  19. Effect of Intermittent Hypercapnia on Respiratory Control in Rat Pups

    OpenAIRE

    Steggerda, Justin A.; Mayer, Catherine A; Martin, Richard J.; Wilson, Christopher G.

    2009-01-01

    Preterm infants are subject to fluctuations in blood gas status associated with immature respiratory control. Intermittent hypoxia during early postnatal life has been shown to increase chemoreceptor sensitivity and destabilize the breathing pattern; however, intermittent hypercapnia remains poorly studied. Therefore, to test the hypothesis that intermittent hypercapnia results in altered respiratory control, we examined the effects of daily exposure to intermittent hypercapnia on the ventila...

  20. 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

  1. Reduction of Oxidative Stress Attenuates Lipoapoptosis Exacerbated by Hypoxia in Human Hepatocytes

    Directory of Open Access Journals (Sweden)

    Sang Youn Hwang

    2015-02-01

    Full Text Available Chronic intermittent hypoxia, a characteristic of obstructive sleep apnea (OSA, is associated with the progression of simple hepatic steatosis to necroinflammatory hepatitis. We determined whether inhibition of a hypoxia-induced signaling pathway could attenuate hypoxia-exacerbated lipoapoptosis in human hepatocytes. The human hepatocellular carcinoma cell line (HepG2 was used in this study. Palmitic acid (PA-treated groups were used for two environmental conditions: Hypoxia (1% O2 and normoxia (20% O2. Following the treatment, the cell viability was determined by the 3,4-(5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H-tetrazolium salt (MTS assay, and the mechanism of lipoapoptosis was evaluated by Western blotting. Hypoxia exacerbated the suppression of hepatocyte growth induced by palmitic acid via activation of mitochondrial apoptotic pathways as a result of endoplasmic reticulum (ER and oxidative stresses. Ammonium pyrrolidine dithiocarbamate, a scavenger of reactive oxygen species, attenuated the hypoxia-exacerbated lipoapoptosis in hepatocytes, whereas glycerol, which reduces ER stress, did not. This may have been because inhibition of oxidative stress decreases the expression of pro-apoptotic proteins, such as caspase 9 and cytochrome c. These results suggested that modulation of apoptotic signaling pathways activated by oxidative stress can aid in identifying novel therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH with OSA. Further in vivo studies are necessary to understand the pathophysiologic mechanism of NASH with OSA and to prove the therapeutic effect of the modulation of the signaling pathways.

  2. Efficacy of agents counteracting hypoxia in fractionated radiation regimes

    International Nuclear Information System (INIS)

    Background and purpose: Solid tumours contain hypoxic cells which are resistant to radiotherapy. This study compares the efficacy of several strategies to counteract diffusion-limited hypoxia, or intermittent hypoxia in a fractionated regimen of 1 to 6 x 2 Gy. Materials and methods: Nicotinamide (250 mg/kg), perflubron emulsion (OxygentTM) (4 ml/kg), tirapazamine (SR4233) (0.10 mmol/kg) and carbogen breathing, administered alone or in combination, were investigated on two tumour cell lines: EMT6 (a rodent mammary carcinoma) and HRT18 (a human rectal adenocarcinoma) using a clonogenic assay. The radiosensitizing effect of the agents was assessed after 1 and 6 x 2 Gy for drugs used alone, and 1, 2, 4, 6 x 2 Gy for drugs used in combination. Results: At the end of the fractionated radiation regimen, the combination of nicotinamide + carbogen induced the greatest radiosensitization for EMT6 tumours, while greatest radiosensitization of HRT18 was obtained with nicotinamide + carbogen + tirapazamine. Conclusion: The efficacy of the strategies for overcoming hypoxia using a fractionated regimen depends on the tumour cell line. These differences could be linked to differences in the initial percentages of acute and chronic hypoxic cells, and to changes in the two types of hypoxia during treatment

  3. 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

    -legged knee extension exercise: Knee)muscle mass in normoxia, acute hypoxia (AH) (FIO2 = 0.105) and after 9 weeks of residence at 5260 m (CH). Reducing the size of the active muscle mass blunted by 62% the effect of hypoxia on VO2,peak in AH and abolished completely the effect of hypoxia on VO2,peak after...... altitude acclimatization. Acclimatization improved Bike peak exercise Pa,O2 from 34 +/- 1 in AH to 45 +/- 1 mmHg in CH(P <0.05) and Knee Pa,O2 from 38 +/- 1 to 55 +/- 2 mmHg(P <0.05). Peak cardiac output and leg blood flow were reduced in hypoxia only during Bike. Acute hypoxia resulted in reduction of...... during hypoxic exercise, attenuates the Bohr effect on oxygen uploading at the lungs and preserves sea level convective O2 transport to the active muscles. Thus, the altitude-acclimatized human has potentially a similar exercising capacity as at sea level when the exercise model allows for an adequate...

  4. A study of rat liver oxidative stress injury with different frequencies intermittent hypoxia and the effect of Tempol%不同频率间歇低氧下大鼠肝脏氧化应激损伤及Tempol的干预作用

    Institute of Scientific and Technical Information of China (English)

    姜秋芳; 陈宝元; 董丽霞; 林慧; 孔铖英; 张静; 郑立文

    2011-01-01

    Objective To study the effect of different frequencies intermittent hypoxia on malondialdehyde (MDA),superoxide dismutase (SOD) and total antioxidant capacity (T-AOC)of rat liver and to investigate the effect of Tempol.Methods To establish a chronic intermittent hypoxia (CIH)animal model in rats,in order to mimic the intermittent hypoxia/reoxygenation (IH/ROX) of obstructive sleep apnea syndrome in humans.56 healthy male Wistar rats were randomly assigned to seven groups:4different IH frequencies groups (IH1:10 times/h,IH2:20 times/h,IH3:30 times/h,IH4:40 times/h with 5 % O2 ),the I H3+Tempol group (30T group),the IH3 +normal saline control group (30N group)and normoxia control group (NC group),each group of eight rats.After the experiment,we measured the levels of MDA,SOD and T-AOC in rat liver homogenate.Results The level of MDA in 4 different IH frequencies groups was higher than in NC group (all P <0.05),the activity of SOD,T-AOC were lower than in NC group (all P <0.05).And there was a trend as the IH frequency increased,the level of MDA was gradually increased,the activity of SOD and T-AOC were gradually decreased.The differences of MDA,SOD,T-AOC level were statistical significant between each two different IH frequencies groups (all P <0.05),except the differences between IH3 group and IH4 group (all P >0.05).Compared with IH3 group,30N group,the level of MDA in 30T group was decreased ( P <0.05),the activity of SOD,T-AOC were increased (all P <0.05),an> the levels of MDA,SOD,T-AOC in 30T group were not significant with in NC group (all P >0.05).The level of MDA in 4 different IH frequencies groups was negative correlation with the activity of SOD,T-AOC ( r were -0.721,-0.653 respectively,all P =0.000).Conclusions Different CIH frequencies had different degrees of injury of oxidative stress on rat liver,but the relationship between the degree of injury on liver and the CIH frequencies was not entirely a linear.Tempol could prevent the

  5. 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, Jennifer N; Sharrett-Field, Lynda; Prendergast, Mark A

    2015-05-01

    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 chronic intermittent ethanol (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 h 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 cycles of CIE 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

  6. 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...

  7. A new animal model of (chronic) depression induced by repeated and intermittent lipopolysaccharide administration for 4 months

    Czech Academy of Sciences Publication Activity Database

    Kubera, M.; Curzytek, K.; Duda, W.; Leskiewicz, M.; Basta-Kaim, A.; Budziszewska, B.; Roman, A.; Zajícová, Alena; Holáň, Vladimír; Szczesny, E.; Lason, W.; Maes, M.

    2013-01-01

    Roč. 31, July (2013), s. 96-104. ISSN 0889-1591 Institutional support: RVO:68378041 Keywords : chronic depression * inflammation * cytokines Subject RIV: EC - Immunology Impact factor: 6.128, year: 2013

  8. Treatment fractionation for stereotactic radiotherapy of lung tumours: a modelling study of the influence of chronic and acute hypoxia on tumour control probability

    International Nuclear Information System (INIS)

    Stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC) has led to promising local control and overall survival for fractionation schemes with increasingly high fractional doses. A point has however been reached where the number of fractions used might be too low to allow efficient local inter-fraction reoxygenation of the hypoxic cells residing in the tumour. It was therefore the purpose of this study to investigate the impact of hypoxia and extreme hypofractionation on the tumour control probability (TCP) from SBRT. A three-dimensional model of tumour oxygenation able to simulate oxygenation changes on the microscale was used. The TCP was determined for clinically relevant SBRT fractionation schedules of 1, 3 and 5 fractions assuming either static tumour oxygenation or that the oxygenation changes locally between fractions due to fast reoxygenation of acute hypoxia without an overall reduction in chronic hypoxia. For the schedules applying three or five fractions the doses required to achieve satisfying levels of TCP were considerably lower when local oxygenation changes were assumed compared to the case of static oxygenation; a decrease in D50 of 17.7 Gy was observed for a five-fractions schedule applied to a 20% hypoxic tumour when fast reoxygenation was modelled. Assuming local oxygenation changes, the total doses required for a tumor control probability of 50% were of similar size for one, three and five fractions. Although attractive from a practical point of view, extreme hypofractionation using just one single fraction may result in impaired local control of hypoxic tumours, as it eliminates the possibility for any kind of reoxygenation

  9. Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol.

    Science.gov (United States)

    Nimitvilai, Sudarat; Lopez, Marcelo F; Mulholland, Patrick J; Woodward, John J

    2016-03-01

    Alcoholism is associated with changes in brain reward and control systems, including the prefrontal cortex. In prefrontal areas, the orbitofrontal cortex (OFC) has been suggested to have an important role in the development of alcohol-abuse disorders and studies from this laboratory demonstrate that OFC-mediated behaviors are impaired in alcohol-dependent animals. However, it is not known whether chronic alcohol (ethanol) exposure alters the fundamental properties of OFC neurons. In this study, mice were exposed to repeated cycles of chronic intermittent ethanol (CIE) exposure to induce dependence and whole-cell patch-clamp electrophysiology was used to examine the effects of CIE treatment on lateral OFC (lOFC) neuron excitability, synaptic transmission, and plasticity. Repeated cycles of CIE exposure and withdrawal enhanced current-evoked action potential (AP) spiking and this was accompanied by a reduction in the after-hyperpolarization and a decrease in the functional activity of SK channels. CIE mice also showed an increase in the AMPA/NMDA ratio, and this was associated with an increase in GluA1/GluA2 AMPA receptor expression and a decrease in GluN2B NMDA receptor subunits. Following CIE treatment, lOFC neurons displayed a persistent long-term potentiation of glutamatergic synaptic transmission following a spike-timing-dependent protocol. Lastly, CIE treatment diminished the inhibitory effect of acute ethanol on AP spiking of lOFC neurons and reduced expression of the GlyT1 transporter. Taken together, these results suggest that chronic exposure to ethanol leads to enhanced intrinsic excitability and glutamatergic synaptic signaling of lOFC neurons. These alterations may contribute to the impairment of OFC-dependent behaviors in alcohol-dependent individuals. PMID:26286839

  10. 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

  11. 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

  12. Chronic Hypoxia Enhances Expression and Activity of Mitochondrial Creatine Kinase and Hexokinase in the Rat Ventricular Myocardium

    Czech Academy of Sciences Publication Activity Database

    Wasková-Arnoštová, P.; Kašparová, D.; Elsnicová, B.; Novotný, J.; Neckář, Jan; Kolář, František; Žurmanová, J.

    2014-01-01

    Roč. 33, č. 2 (2014), s. 310-320. ISSN 1015-8987 R&D Projects: GA AV ČR(CZ) IAAX01110901; GA ČR(CZ) GAP303/12/1162 Grant ostatní: Univerzita Karlova(CZ) 349211; GA AV ČR(CZ) IAA601110908 Institutional support: RVO:67985823 Keywords : creatine kinase * hexokinase * normobaric hypoxia * left ventricle * right ventricle * mitochondria co-localization Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 2.875, year: 2014

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

    Science.gov (United States)

    Rose, Jamie H.; Karkhanis, Anushree N.; Steiniger-Brach, Björn; Jones, Sara R.

    2016-01-01

    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. PMID:27472317

  14. 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.

  15. 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

  16. 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

  17. Up-regulation and redistribution of protein kinase C-delta in chronically hypoxic heart

    Czech Academy of Sciences Publication Activity Database

    Hlaváčková, M.; Kožichová, K.; Neckář, Jan; Kolář, František; Musters, R.J.P.; Novák, O.; Nováková, O.

    2010-01-01

    Roč. 345, 1-2 (2010), s. 271-282. ISSN 0300-8177 R&D Projects: GA ČR(CZ) GA305/07/0875; GA MŠk(CZ) 1M0510 Grant ostatní: Univerzita Karlova(CZ) 97908 Institutional research plan: CEZ:AV0Z50110509 Keywords : protein kinase C * chronic intermittent hypoxia * heart Subject RIV: ED - Physiology Impact factor: 2.168, year: 2010

  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. 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.

  20. HIF and pulmonary vascular responses to hypoxia

    OpenAIRE

    Shimoda, Larissa A.; Steven S Laurie

    2013-01-01

    In the lung, acute reductions in oxygen lead to hypoxic pulmonary vasoconstriction, whereas prolonged exposures to hypoxia result in sustained vasoconstriction, pulmonary vascular remodeling, and the development of pulmonary hypertension. Data from both human subjects and animal models implicate a role for hypoxia-inducible factors (HIFs), oxygen-sensitive transcription factors, in pulmonary vascular responses to both acute and chronic hypoxia. In this review, we discuss work from our laborat...

  1. Cerebral hypoxia

    Science.gov (United States)

    ... the veins ( deep vein thrombosis ) Lung infections (pneumonia) Malnutrition When to Contact a Medical Professional Cerebral hypoxia ... References Bernat JL. Coma, vegetative state, and brain death. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...

  2. Intermittent hyperthyreosis

    International Nuclear Information System (INIS)

    Intermittent hyperthyreosis occurs under various forms of stress, especially heat stress. The clinician may diagnose such cases as masked or apathetic hyperthyroidism or 'forme fruste' hyperthyreosis or thyroid autonomy. As most routine and standard tests may here yield inconsistent results, it is the patients' anamnesis which may provide the clue. Our Bioclimatology Unit has now seen over 100 cases in which thyroid hypersensitivity towards heat was the most prominent syndrome: 10-15% of weather-sensitive patients are affected. The patients complain before or during heat spells of such contradictory symptoms as insomnia, irritability, tension, tachycardia, palpitations, precordial pain, dyspnoe, flushes with sweating or chills, tremor, abdominal pain or diarrhea, polyuria or pollakisuria, weight loss in spite of ravenous appetite, fatigue, exhaustion, depression, adynamia, lack of concentration and confusion. Determination of urinary neurohormones allows a differential diagnosis, intermittent hyperthyreosis being characterized by three cardinal symptoms: tachycardia - every case with more than 80 pulse beats being suspect (not specific); urinary histamine - every case excreting more than 90 μg/day being suspect. Again the drawback of this test is its lack of specificity, as histamine may also be increased in cases of allergy and spondylitis; urinary thyroxine - every case excreting more than 20 μg/day T-4 being suspect. This is the only specific test. Therapy should make use of lithium carbonate and betablockers. Propyl thiouracil is rarely required. (orig.)

  3. N-acetylcysteine treatment prevents the up-regulation of MnSOD in chronically hypoxic rat hearts

    Czech Academy of Sciences Publication Activity Database

    Balková, P.; Hlaváčková, M.; Milerová, Marie; Neckář, Jan; Kolář, František; Novák, F.; Nováková, O.

    2011-01-01

    Roč. 60, č. 3 (2011), s. 467-474. ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA305/07/0875; GA ČR(CZ) GA305/07/1008 Institutional research plan: CEZ:AV0Z50110509 Keywords : heart * chronic intermittent hypoxia * superoxide dismutase Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.555, year: 2011

  4. 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

  5. Hypoxia, Oxidative Stress and Fat

    Directory of Open Access Journals (Sweden)

    Nikolaus Netzer

    2015-06-01

    Full Text Available Metabolic disturbances in white adipose tissue in obese individuals contribute to the pathogenesis of insulin resistance and the development of type 2 diabetes mellitus. Impaired insulin action in adipocytes is associated with elevated lipolysis and increased free fatty acids leading to ectopic fat deposition in liver and skeletal muscle. Chronic adipose tissue hypoxia has been suggested to be part of pathomechanisms causing dysfunction of adipocytes. Hypoxia can provoke oxidative stress in human and animal adipocytes and reduce the production of beneficial adipokines, such as adiponectin. However, time-dose responses to hypoxia relativize the effects of hypoxic stress. Long-term exposure of fat cells to hypoxia can lead to the production of beneficial substances such as leptin. Knowledge of time-dose responses of hypoxia on white adipose tissue and the time course of generation of oxidative stress in adipocytes is still scarce. This paper reviews the potential links between adipose tissue hypoxia, oxidative stress, mitochondrial dysfunction, and low-grade inflammation caused by adipocyte hypertrophy, macrophage infiltration and production of inflammatory mediators.

  6. 不同模式间歇低氧对大鼠血糖、血清胰岛素及胰腺组织Caspase-3活性及其表达的影响%Effects of Different Patterns of Intermittent Hypoxia on Glucose, Insulin and Activity and Expression of Pancre-as Caspase-3 in Rats

    Institute of Scientific and Technical Information of China (English)

    王东亮; 卢巍; 刘练达; 林雪娇; 康健

    2014-01-01

    目的:探讨两种模式间歇低氧对大鼠血糖、胰岛素及胰腺组织Caspase-3活性及其表达的影响。方法将63只SD大鼠随机分为常氧对照组、间歇低氧1组(高频轻度)、间歇低氧2组(低频重度),3组又各自随机分为暴露1、2、4周组,每组7只。3个暴露4周组分别于0周及暴露1、2、4周检测空腹血糖;3组大鼠分别于暴露1、2、4周检测胰岛素水平,胰腺组织Caspase-3活性及其mRNA和蛋白表达水平。结果间歇低氧1组暴露4周组血糖从暴露2周开始升高,暴露4周与暴露2周比较差异无统计学意义( P>0.05);间歇低氧2组暴露4周组血糖从暴露1周即出现升高,随着暴露时间的延长进行性增高,暴露4周较间歇低氧1组暴露4周增高( P0. 05);group B was exposured for 4 weeks, and glucose level was increased after exposure for 1 week, and glucose level was progressively increased with prolonging exposure time, and the level after exposure for 4 weeks was significantly higher than that in group A (P0. 05). The levels of Caspase-3 activity and mRNA in group B were progressively increased with prolonging time (P<0. 05, P<0. 01). Conclusion Low frequence and severe degree of intermittent hypoxia can cause severe damage on pancreas tis- sues than that by high frequence and mild degree of intermittent hypoxia, and the damage is progressive aggravation.

  7. 不同间歇低氧方式对内皮细胞c-fos mRNA表达水平的影响%Changes of c-fos mRNA in Endothelial Cells Exposed to Various Intermittent Hypoxia

    Institute of Scientific and Technical Information of China (English)

    高梦丽; 刘春霞; 冯靖; 曹洁; 陈宝元

    2013-01-01

    目的测定不同程度、频率间歇低氧(IH)条件下,人脐静脉内皮细胞即刻早期基因c-fos mRNA的表达水平。方法在自制细胞培养舱中程控产生预制的IH/ROX(再氧和)暴露环境,将内皮细胞暴露于该环境共60次循环,分为A、B、C组,每组包括5个小组。A组分正常氧组、标准孵箱对照组、持续低氧(CH)组、1.5%O2 IH组、10%O2 IH组。B、C组分别为1.5%O2,10%O2的不同IH频率组,低氧时间均为15 s,循环次数均为60次,ROX时间不同,总循环时间不同,分别为1.5 h组、3 h组、5 h组、6.5 h组、9.5 h共5个小组。采用Real-time PCR方法测定c-fos mRNA的表达水平。结果正常氧组与CH组的c-fos mRNA表达水平差异无统计学意义。1.5%O2 IH组、10%O2 IH组c-fos mRNA表达水平均高于正常氧组,且1.5%O2 IH组高于10%O2 IH组(P<0.01)。在IH程度相同时,随着ROX时间延长,c-fos mRNA表达水平均呈现先逐渐增加,后逐渐下降的规律,5 h组c-fos mRNA表达水平明显高于其余各组(P<0.01)。结论 IH/ROX暴露可诱导内皮细胞即刻早期基因c-fos mRNA表达,这一过程与IH程度及频率密切相关。%Objective To measure the mRNA expression of immediate-early gene c-fos in endothelial cells by the use of different intermittent hypoxia (IH) protocols. Methods A gas control delivery system was homemade, which pro-duced IH/re-oxygenation(ROX) environmental exposure. The endothelial cells were exposed to IH/ROX cycles, and were di-vided into three groups (A, B and C). There were five sub-groups in each group. Group A included intermittent normoxia group, standard incubator control group, continuous hypoxia group (CH), 1.5%O2 IH group and 10%O2 IH group. There were different frequency IH of 1.5%O2 and 10%O2 sub-groups in group B and group C. Hypoxia time was 15 s. The intermittent hypoxia cycle was 60 and the ROX time was different. The total cycle time was different, including 1

  8. 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.

  9. Hypoxia and oxidative stress in breast cancer: Tumour hypoxia – therapeutic considerations

    International Nuclear Information System (INIS)

    Conclusive research has shown that regions of acute/chronic hypoxia, which exist within the majority of solid tumours, have a profound influence on the therapeutic outcome of cancer chemotherapy and radiotherapy and are a strong prognostic factor of disease progression and survival. A strong argument therefore exists for assessing the hypoxic fraction of tumours, prior to patient treatment, and to tailor this treatment accordingly. Tumour hypoxia also provides a powerful physiological stimulus that can be exploited as a tumour-specific condition, allowing for the rationale design of hypoxia-activated anticancer drugs or novel hypoxia-regulated gene therapy strategies

  10. Mitochondrial physiology and reactive oxygen species production are altered by hypoxia acclimation in killifish (Fundulus heteroclitus).

    Science.gov (United States)

    Du, Sherry N N; Mahalingam, Sajeni; Borowiec, Brittney G; Scott, Graham R

    2016-04-15

    Many fish encounter hypoxia in their native environment, but the role of mitochondrial physiology in hypoxia acclimation and hypoxia tolerance is poorly understood. We investigated the effects of hypoxia acclimation on mitochondrial respiration, O2kinetics, emission of reactive oxygen species (ROS), and antioxidant capacity in the estuarine killifish ( ITALIC! Fundulus heteroclitus). Killifish were acclimated to normoxia, constant hypoxia (5 kPa O2) or intermittent diel cycles of nocturnal hypoxia (12 h:12 h normoxia:hypoxia) for 28-33 days and mitochondria were isolated from liver. Neither pattern of hypoxia acclimation affected the respiratory capacities for oxidative phosphorylation or electron transport, leak respiration, coupling control or phosphorylation efficiency. Hypoxia acclimation also had no effect on mitochondrial O2kinetics, but ITALIC! P50(the O2tension at which hypoxia inhibits respiration by 50%) was lower in the leak state than during maximal respiration, and killifish mitochondria endured anoxia-reoxygenation without any impact on mitochondrial respiration. However, both patterns of hypoxia acclimation reduced the rate of ROS emission from mitochondria when compared at a common O2tension. Hypoxia acclimation also increased the levels of protein carbonyls and the activities of superoxide dismutase and catalase in liver tissue (the latter only occurred in constant hypoxia). Our results suggest that hypoxia acclimation is associated with changes in mitochondrial physiology that decrease ROS production and may help improve hypoxia tolerance. PMID:26896545

  11. Growth Inhibition and Compensation in Response to Neonatal Hypoxia in Rats

    OpenAIRE

    Radom-Aizik, Shlomit; Zaldivar, Frank P.; Nance, Dwight M.; Haddad, Fadia; COOPER, DAN M.; Adams, Gregory R

    2013-01-01

    Background Hypoxia is an important disease mechanism in prematurity, childhood asthma and obesity. In children, hypoxia results in chronic inflammation. Methods We investigated the effects of hypoxia (Hx) (12% O2) during postnatal day 2 to 20 in rats. Control groups were normoxic (Nc), and normoxic growth restricted (14 pup liters) (Gr). Results Hypoxia decreased growth similar Gr. Hx increased plasma TNFα and IL-6 and decreased IGF-I and VEGF. Hypoxia resulted in right ventricular (RV) hyper...

  12. Growth Inhibition and Compensation in Response to Neonatal Hypoxia in Rats

    OpenAIRE

    Radom-Aizik, Shlomit; Zaldivar, Frank P.; Nance, Dwight M.; Haddad, Fadia; COOPER, DAN M.; Adams, Gregory R

    2013-01-01

    BackgroundHypoxia is an important disease mechanism in prematurity, childhood asthma and obesity. In children, hypoxia results in chronic inflammation.MethodsWe investigated the effects of hypoxia (Hx) (12% O2) during postnatal day 2 to 20 in rats. Control groups were normoxic (Nc), and normoxic growth restricted (14 pup liters) (Gr).ResultsHypoxia decreased growth similar Gr. Hx increased plasma TNFα and IL-6 and decreased IGF-I and VEGF. Hypoxia resulted in right ventricular (RV) hypertroph...

  13. Hypoxia. 2. Hypoxia regulates cellular metabolism

    OpenAIRE

    Wheaton, William W.; Chandel, Navdeep S.

    2010-01-01

    Adaptation to lowering oxygen levels (hypoxia) requires coordinated downregulation of metabolic demand and supply to prevent a mismatch in ATP utilization and production that might culminate in a bioenergetic collapse. Hypoxia diminishes ATP utilization by downregulating protein translation and the activity of the Na-K-ATPase. Hypoxia diminishes ATP production in part by lowering the activity of the electron transport chain through activation of the transcription factor hypoxia-inducible fact...

  14. 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

  15. Hypoxia: a Review

    OpenAIRE

    Kambiz Gilany; Mohtaram Vafakhah

    2010-01-01

    Tissue hypoxia occurs where there is an imbalance between oxygen supply and consumption. Growing evidence from experimental and clinical studies points to the fundamental and patho-physiologic role of hypoxia in cancer, ischemic tolerance, and stroke. Hypoxia-induced changes in ion homeostasis, erythropoiesis, angiogenesis, proliferation and differentiation. This review outlines hypoxia effect at molecular level and describes briefly hypoxia role in the physiological and pathological conditions.

  16. Game performance and intermittent hypoxic training.

    Science.gov (United States)

    Hinckson, E A; Hamlin, M J; Wood, M R; Hopkins, W G

    2007-08-01

    Live high-train low altitude exposure simulated by hypoxic devices may improve athletic performance. In this study, intermittent normobaric hypoxia was achieved with the GO2altitude hypoxicator to determine its effects on sea level performance in rugby players. Ten players were randomly assigned to two groups. Players in each group received 14 sessions of either hypoxic (10-15% O(2)) or normoxic (21% O(2)) exposure at rest over 14 consecutive days in a single blind fashion. Various performance measures were obtained consecutively in a single testing session pre- and post-exposure. Effects of hypoxic exposure on maximum speed and sprint times were trivial (rugby simulation, hypoxic exposure produced impairments of peak power in two scrums (15%, +/-8%; 9%, +/-7%) and impairments of time in offensive sprints (7%, +/-8%) and tackle sprints (11%, +/-9%). Pending further research, rugby players would be unwise to use normobaric intermittent hypoxic exposure to prepare for games at sea level. PMID:17311807

  17. Rat Spermatogenesis Damage in Intermittent Hypobaric Hypoxia and the Protective Role of Melatonin. II: Testicular Parameters Daño de la Espermatogénesis en Rata en la Hipoxia Hipobárica Intermitente y Rol Protector de la Melatonina. II: Parámetros Testiculares

    Directory of Open Access Journals (Sweden)

    Eduardo Bustos-Obregón

    2010-06-01

    Full Text Available At present it is not clear if male fertility is affected by intermittent hypobaric hypoxia (IHH. This is an important issue since a large human population works over 3000 masl. This study analyzes testicular changes in adult Sprague Dawley rats after five cycles of IHH (7 day exposure to 4200 masl in a hypobaric chamber / 7 day at 500 masl. The animals were separated into groups of 8, one group was exposed to hypoxia (7 days, and the others to IHH for one to five cycles. Controls (500 masl were examined at the beginning and at the end of the 70 experimental days. A duplicate set of rats treated with melatonin (supposedly protecting from hypoxia was also examined, as were their controls, injected with 0,03% ethanol (melatonin solvent.Immunohistochemical and histometric analysis of testicular tissue were performed. Damage caused by IHH increases with time. Morphometry reveals an increase in tubular and luminal diameters and a reduction in epithelial height. Inmunohistochemistry for HIF-1alpha shows an increase with time, however the opposite happens with HSP-70. Spermatogenic cells submitted to comet assay present an increase of (+ cells. Melatonin counteracts all this damage, possibly due to its high efficiency as a reactive oxygen species scavenger. In conclusion, IHH exposure damages male reproductive function.Actualmente no se conoce claramente si la fertilidad masculina se afecta por la hipoxia hipobarica intermitente (IHH. Esto es de importancia porque una gran población humana trabaja sobre 3000 metros sobre el nivel del mar (sml. Este trabajo analiza los cambios testiculares en ratas adultas Sprague Dawley luego de cinco ciclos de IHH (7 días a 4.200 sml en una camara hipobarica/7días a 500 metros: Normoxia. Los animales de dividieron en grupos de 8; un grupo expuesto a hipoxia (7 días y los otros a IHH por uno y hasta cinco ciclos. Los controles ( 500 sml se analizaron al inicio y al final de los 70 días experimentales. Un set

  18. Rat Spermatogenesis Damage in Intermittent Hypobaric Hypoxia and the Protective Role of Melatonin: I Cauda Epididymal Spermatozoa Daño en la Espermatogénesis de Rata en Hipoxia Hipobárica Intermitente y el Papel Protector de la Melatonina: I Espermatozoides de la Cauda Epididimaria

    Directory of Open Access Journals (Sweden)

    Ricardo Hartley

    2009-12-01

    Full Text Available At present it is not clear if male fertility is affected by intermittent hypobaric hypoxia (IHH. This is an important issue since a large human population works over 3000 masl. This study analyzes epididymal sperm, in adult Sprague Dawley rats after five cycles of IHH (7 days exposure to 4200 masl in a hypobaric chamber / 7 days at 500 masl. The animals were separated into groups of 8, one group was exposed to hypoxia (7 days, and the others to IHH for one to five cycles. Controls (500 masl were examined at the beginning and at the end of the 70 experimental days. A duplicate set of rats treated with melatonin (supposedly protecting from hypoxia was also examined, as were their controls, injected with 0,03% ethanol (melatonin solvent. Epididymal sperm parameters, were evaluated. Damage caused by IHH increases with time. Sperm counts drop, while sperm chromatin swelling, DNA instability (metachromasia with acridine orange epifluorescence and comet (+ tests increase. Melatonin counteracts all this damage, possibly due to its high efficiency as a reactive oxygen species scavenger. In conclusion, IHH exposure damages sperm quality and therefore male reproductive function.En la actualidad no está claro si la fertilidad masculina se ve afectada por la hipoxia hipobárica intermitente (HHI. Esta es una cuestión importante, ya que una gran población humana trabaja a más de 3000 metros sobre el nivel del mar (msnm. Este estudio analiza los espermatozoides del epidídimo, en ratas Sprague Dawley adultas, después de cinco ciclos de HHI (7 días de exposición a 4200 msnm en una cámara hipobárica / 7 días a 500 msnm. Los animales fueron separados en grupos de 8, un grupo fue expuesto a la hipoxia (7 días, y los otros a HHI de uno a cinco ciclos. Los controles (500 msnm se examinaron al comienzo y al final de los 70 días de experimentación. Un grupo duplicado de ratas tratadas con melatonina (supuestamente protegiendo de la hipoxia también fue

  19. 不同程度间歇低氧对3T3-L1脂肪细胞炎性细胞因子和脂肪因子的影响%Effects of Different Degrees of Intermittent Hypoxia on Inflammatory Cytokines and Adipokines in 3T3-L1 Adipocytes

    Institute of Scientific and Technical Information of China (English)

    杨庆婵; 周芹; 王彦; 何庆; 冯靖; 陈宝元

    2013-01-01

    目的:测定不同程度间歇低氧(IH)处理的3T3-L1脂肪细胞中炎性细胞因子和脂肪因子水平的变化。方法建立阻塞性睡眠呼吸暂停(OSA)模式间歇低氧/再氧合(IH/ROX)细胞模型,将分化成熟的3T3-L1脂肪细胞分为5组,即3个不同程度IH组(5%O2,7.5%O2,10%O2,编号为IH-1,IH-2,IH-3)、持续低氧(10%O2,CH)组和正常氧对照(21%O2,IN)组。采用ELISA法测定脂肪细胞上清液中肿瘤坏死因子(TNF)-α、白细胞介素(IL)-6、瘦素和脂联素的水平,Western blot测定脂肪细胞中低氧诱导因子(HIF)-1α、葡萄糖转运蛋白(Glut)-1水平,Real-time-PCR测定脂肪细胞中HIF-1α、Glut-1、TNF-α、IL-6、瘦素、脂联素的mRNA表达水平。结果 IH组和CH组TNF-α、IL-6和瘦素蛋白及其mRNA水平均高于IN组,IH-1组TNF-α、IL-6和瘦素蛋白及瘦素mRNA水平高于IH-2、IH-3组(均P<0.05);IH组和CH组脂联素蛋白及其mRNA水平均低于IN组,IH-1组低于IH-2、IH-3组(均P<0.05)。结论OSA模式IH与脂肪细胞炎性细胞因子和脂肪因子的表达和释放有关,IH可能是脂肪细胞炎症反应的基础,参与OSA患者胰岛素抵抗的发生。%Objective To study the effect of different degrees of intermittent hypoxia (IH) on inflammatory cytokines and adipokines in 3T3-L1 adipocytes. Methods An intermittent hypoxia/reoxygenation (IH/ROX) from obstructive sleep apnea (OSA) adipocyte model was established. 3T3-L1 adipocytes were divided into five groups, three IH groups (5% O2, 7.5%O2 and 10%O2, referred to as IH-1, IH-2 and IH-3), sustained hypoxia group (10%O2, CH) and the normal oxygen control group (21%O2, IN). ELISA method was used to detect values of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), leptin and adiponectin in cell supernatant. Western blot analysis was used to detect levels of hypoxia-inducible fac-tor-1α(HIF-1α) and glucose transporter-1 (Glut

  20. 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.

  1. 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.

    Science.gov (United States)

    Xuan, Meiyan; Okazaki, Mari; Iwata, Naohiro; Asano, Satoshi; Kamiuchi, Shinya; Matsuzaki, Hirokazu; Sakamoto, Takeshi; Miyano, Yoshiyuki; Iizuka, Hiroshi; Hibino, Yasuhide

    2015-01-01

    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. PMID:25945116

  2. Intermittent Explosive Disorder

    OpenAIRE

    Lut Tamam; Meliha Zengin Eroglu; Ozlem Paltaci

    2011-01-01

    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. Etio...

  3. INTERMITTENT DEGRADATION AND SCHIZOTYPY

    OpenAIRE

    Roché, Matthew W.; Silverstein, Steven M.; Lenzenweger, Mark F.

    2015-01-01

    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-repo...

  4. The two aspects of tumour hypoxia

    International Nuclear Information System (INIS)

    Hypoxia is a therapeutic problem as it renders solid tumours resistant to sparsely ionizing radiation and some forms of chemotherapy. At present it is postulated that tumour hypoxia induces two types of reactions. On the one hand tissue O2 concentration 2 2 0.5-20 mm Hg), not severely, hypoxic cells may be of the greatest importance in determining biological resistance. The methods of assessing hypoxia currently applied in clinical practice are not satisfactory. However, recent advances in imaging technologies suggest that in the near future it might be possible to track temporal changes in O2 level and acute and chronic hypoxic tumour sub fractions. The ultimate goal is understanding tumour biology basing on the clinical bio markers that reflect hypoxia-associated genetic or proteomic signatures in tumour cells, in order to individualize therapy. (authors)

  5. Effect of intermittent hypercapnia on respiratory control in rat pups.

    Science.gov (United States)

    Steggerda, Justin A; Mayer, Catherine A; Martin, Richard J; Wilson, Christopher G

    2010-01-01

    Preterm infants are subject to fluctuations in blood gas status associated with immature respiratory control. Intermittent hypoxia during early postnatal life has been shown to increase chemoreceptor sensitivity and destabilize the breathing pattern; however, intermittent hypercapnia remains poorly studied. Therefore, to test the hypothesis that intermittent hypercapnia results in altered respiratory control, we examined the effects of daily exposure to intermittent hypercapnia on the ventilatory response to subsequent hypercapnic and hypoxic exposure in neonatal rat pups. Exposure cycles consisted of 5 min of intermittent hypercapnia (5% CO(2), 21% O(2), balance N(2)) followed by 10 min of normoxia. Rat pups were exposed to 18 exposure cycles each day for 1 week, from postnatal day 7 to 14. We analyzed diaphragm electromyograms (EMGs) from pups exposed to subsequent acute hypercapnic (5% CO(2)) and hypoxic (12% O(2)) challenges. In response to a subsequent hypercapnia challenge, there was no significant difference in the ventilatory response between control and intermittent hypercapnia-exposed groups. In contrast, intermittent hypercapnia-exposed rat pups showed an enhanced ventilatory response to hypoxic challenge with an increase in minute EMG to 118 +/- 14% of baseline versus 107 +/- 13% for control pups (p < 0.05). We speculate that prior hypercapnic exposure may increase peripheral chemoreceptor response to subsequent hypoxic exposures and result in perturbed neonatal respiratory control. PMID:19752577

  6. Hypoxia, MTOR and autophagy

    OpenAIRE

    Blagosklonny, Mikhail V.

    2013-01-01

    Although hypoxia can cause cell cycle arrest, it may simultaneously suppress a conversion from this arrest to senescence. Furthermore, hypoxia can suppress senescence caused by diverse stimuli, maintaining reversible quiescence instead. Hypoxia activates autophagy and inhibits MTOR, thus also activating autophagy. What is the relationship between autophagy and cellular senescence? Also, can inhibition of MTOR and stimulation of autophagy explain the gerosuppressive effects of hypoxia?

  7. 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.

  8. Forecasting intermittent demand

    OpenAIRE

    Teunter, R.H.; Duncan, L

    2006-01-01

    Methods for forecasting intermittent demand are compared using a large data-set from the UK Royal Air Force (RAF). Several important results are found. First, we show that the traditional per period forecast error measures are not appropriate for intermittent demand, even though they are consistently used in the literature. Second, by comparing target service levels to achieved service levels when inventory decisions are based on demand forecasts, we show that Croston's method (and a variant)...

  9. 间歇低氧合并肺气肿大鼠系统与内皮炎症状态及外周血内皮祖细胞水平研究%Systematic and Endothelial Inflammation Status and Endothelial Progenitor Cell Levels in Peripheral Blood in Intermittent Hypoxia and Emphysema Rat Model

    Institute of Scientific and Technical Information of China (English)

    王彦; 曹洁; 杨庆婵; 冯靖; 陈宝元

    2014-01-01

    目的:建立间歇低氧(IH)合并肺气肿重叠综合征(OS)大鼠模型,探讨OS大鼠系统及血管内皮炎症状态,并观察外周血内皮祖细胞(EPC)水平的变化。方法自制熏箱对大鼠进行16周的熏烟暴露造成大鼠肺气肿,从13周开始,在熏烟暴露同时,通过程控产生预制的间歇低氧/再氧合(IH/ROX)环境对大鼠进行IH暴露4周。60只雄性Wistar大鼠随机分为正常组(A组)、IH组(B组)、肺气肿组(C组)和OS组(D组),暴露结束后分别以ELISA法测定血浆及右颈总动脉内皮细胞中肿瘤坏死因子(TNF)-α、白介素(IL)-6水平,Real-time PCR法检测血管内皮细胞中RhoA mRNA含量,病理标本中测定颈动脉内中膜厚度(IMT)占全层厚度比值(C-IMT%),流式细胞仪测定循环血中EPC数量。结果 D组血浆和血管内皮细胞中TNF-α、IL-6水平以及血管内皮细胞中RhoA mRNA水平、C-IMT%均高于A、B、C组,而EPC数量均低于其他3组(均P<0.05)。结论 OS大鼠较单纯IH或单纯肺气肿大鼠系统及内皮损伤更加严重,且内皮修复能力更差,增加了心血管疾病风险。%Objective To establish the rat overlap syndrome (OS) model of intermittent hypoxia (IH) and emphyse-ma, explore the systematic and endothelial inflammation status, and observe the changes of endothelial progenitor cell (EPC) level in peripheral blood. Methods Sixty male Wistar rats were randomly divided into four groups:normal oxygen control group (A), IH group (B), emphysema group (C) and OS group (D). The rat model of emphysema was established by smoke ex-posure for 16 weeks. From the 13-week, pre-programmed intermittent hypoxia/re-oxygenation (IH/ROX) exposure was giv-en in the meantime of smoke exposure. After exposure, ELISA method was used to detect values of tumor necrosis factor al-pha (TNF-α) and interleukin (IL)-6 in plasma and in the endothelium of right common carotid artery

  10. Intermittency in particle physics

    International Nuclear Information System (INIS)

    This thesis presents an analysis of intermittency as it appears in high energy multiparticle production. Momentum space particle distributions are scale invariant and fluctuate from events to events. This phenomenon originates from Hydrodynamics. Some results about hydrodynamics intermittency are by the way deduced using random diffusion processes and the Landau-Ginzburg equation. A phenomenological approach utilizing random cascading models is used to describe the morphology and intermittent features of particle distributions. Along these lines, a thorough study of random cascades is performed. The origin of intermittent fluctuation is to be found within the Framework of Quantum Field Theory. Indeed intermittency is intimately linked to the perturbative cascade of Quantum Chromodynamics. The long distance behaviour of perturbative QCD is intermittent at the leading collinear logarithm approximation. Moreover fluctuations of matter density along the rapidity axis suggest that the gluon cascade undergoes a phase transition towards a valley landscape where gluons are prone to get clumped within small regions. This is compatible with the so-called preconfinement

  11. EPO对慢性缺氧心肌细胞线粒体生物合成的影响%Effect of erythropoietin on mitochondrial biogenesis in cardiomyocytes during chronic hypoxia in vitro

    Institute of Scientific and Technical Information of China (English)

    周胜凯; 秦川; 陈林; 肖颖彬

    2013-01-01

    Objective To determine the effect of erythropoietin (EPO) on the mitochondrial biogenesis in rat cardiomyocytes under the condition of chronic hypoxia.Methods Rat cardiomyocyte-derived H9c2 cells were deprived of oxygen for 7 d to establish the chronic hypoxia model (94% N2,5%CO2and 1% O2).Then the obtained H9c2 cells were treated by recombinant human EPO (rhEPO,5,10 and 20 U/ml) for 3 or 7 d.Fluorescent probe was used to mark mitochondria in the cells for the amount of mitochondria.The protein levds of Akt,phospho-Akt (serine473),endothelial nitric oxide synthase (eNOS),and phospho-eNOS (serine1177) were determined with Western blotting.RT-PCR was used to detect the relative copy number of mitochondrial DNA.Results rhEPO treatment for 7 d resulted in a significant increase in the amount and copy number of mitochondria (P < 0.05).The phosphorylation levels of Akt and eNOS were also enhanced,but those of akt and eNOS had no change (P > 0.05).Conclusion EPO improves mitochondrial biogenesis in the cardiomyocytes exposure to chronic hypoxia,probably through Akt and eNOS signal transduction.%目的 观察促红细胞生成素(erythropoietin,EPO)在慢性缺氧条件下对心肌线粒体生物合成的影响及其可能的机制.方法 将H9c2心肌细胞株置入缺氧培养箱7 d(94%N2,5% CO2,1%O2),建立H9c2心肌细胞株慢性缺氧模型;采用5、10、20 U/mL不同浓度的rhEPO(recombinant human erythropoietin;重组人促红细胞生成素)干预处理后,用荧光探针标记线粒体,观察线粒体数目的变化;RT-PCR技术检测线粒体DNA的相对拷贝数变化;Western blot技术检测Akt、eNOS及其磷酸化蛋白水平的变化.结果 rhEPO干预7d后线粒体数目及拷贝数增加(P<0.05);Akt、eNOS蛋白磷酸化水平增强(P<0.05),Akt、eNOS总蛋白无明显变化(P>0.05).结论 EPO增强了慢性缺氧心肌细胞的线粒体生物合成,Akt、eNOS可能是EPO增强线粒体生物合成的重要信号通路.

  12. 不同频率间歇低氧暴露后兔颈动脉体的炎症状态和窦神经传入活性%Carotid body inflammation and carotid sinus nerve afferent activity after intermittent hypoxia exposure of various frequencies in rabbits

    Institute of Scientific and Technical Information of China (English)

    冯靖; 陈宝元; 崔林阳; 王宝利; 刘春霞; 陈攀峰; 郭美南; 董丽霞; 李硕

    2008-01-01

    Objective To explore the inflammatory reactions,endothelin level and carotid sinus nerve(CSN)afferent activity of carotid body(CB)after intermittent hypoxia/reoxygenation(IH/ROX)exposure of various frequencies in rabbits.Methods Forty-nine male adult New Zealand white rabbits (2.5~3.0 kg)were separated into 7 groups(n=7 each).After anesthetization,the fight carotid artery and CSN were cleared of surrounding tissues without touching the right CB and the left carotid region.The CSN was unenveloped to pareally expose the myelin sheath.and electrodes were placed to the"single"chemoreceptor bundle of the CSN.with CSN afferent activity carefully monitored and recorded.Then the right 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 perfusate bubbled with normoxia or hypoxia gas mixtures formed IH/ROX cycles in right carotid common artery,simulating the pattern of hypoxic episodes seen in obstructive sleep apnea,or with continuously perfusing hypoxia perfusate to form continuous hypoxia (CH)modes.Groups were defined with different frequencies,and groups were: intermittent normnxia group (IN group) (21% O2,15 s;21% O2,1 min 45 s),10/hr group (5% O2,15 s ;21% O2,5 rain 45 s),30/hrgroup (5%O2,15 s;21%O2,1 min45 s),50/hr group (5%O2,15 s;21%O2,57 s),60/hr group (5%O2 ,15 s;21%O2,45 s) and 90/hr group (5%O2,15 s;21%O2,25 s).All the above groups were exposed to 60 treatment cycles;continuous hypoxia group (CH group),IN for 1 h 45min and then 5% O2 for 15 min.After exposure and 30 min of static placing,CSN afferent frequencies (Charge F) were recorded from chemoreceptor bundles,and the right CB was cleared of surrounding tissues and harvested.Interleukin-6 (IL-6),endothelin-1 (ET-1),hypoxla-indacible factor-1 (HIF-I),and vascular endothelial growth factor (VEGF) concentrations of the CB

  13. Posterior mediastinal extramedullary hematopoiesis secondary to hypoxia

    Science.gov (United States)

    Solazzo, A; D’Auria, V; Moccia, LG; Vatrella, A; Bocchino, M; Rea, G

    2016-01-01

    Two mediastinal masses were incidentally detected at high resolution computed tomography (HRCT) of a 72 year-old male patient, former smoker, affected by chronic obstructive pulmonary disease with worsening dyspnea and 2-year medical history of polycythemia secondary to hypoxia. Integration with a multidetector computed tomography (MDCT) scan after administration of intravenous injection contrast medium showed slightly inhomogeneous increase of enhancement of masses, suggesting in the first case potential malignancy. Diagnosis of extramedullary hematopoiesis was achieved by fine needle aspiration citology (FNAC). Extramedullary hematopoiesis must be considered in differential diagnosis in patients with medical history of polycythemia and severe hypoxia. PMID:27326388

  14. 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 and...

  15. 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...

  16. Clinical relevance of intermittent tumour blood flow

    International Nuclear Information System (INIS)

    One of the goals of translational cancer research is to understand basic 'phenomena' so that tumour response to therapy can be improved. One such phenomenon is intermittent tumour blood flow. The impact of the transient hypoxia that results from decreased tumour blood flow is now beginning to be appreciated in preclinical systems, and also receiving some attention in clinical practise. Thus in this article we review the nature and frequency of microregional blood flow changes in preclinical and clinical tumours and examine the impact of those changes on response to both radiotherapy and chemotherapy. Additionally, the implications of non-constant blood flow for both the growth of the unperturbed tumour and the regrowth of surviving tumour clonogens during and after therapy are examined

  17. Are renewable energies intermittent?

    International Nuclear Information System (INIS)

    This article outlines that renewable energies, notably photovoltaic and wind energy, are not that intermittent. Besides the fact that their operation is progressive (they do not pass from nothing to one), the fact they are distributed among the territory means that, when considering them all, the production is smoothed at the territory scale. They are in fact more varying than intermittent and they are smoothed and predictable. On the other side, thermal plants are regularly stopped, for maintenance for example. It states that in absence of wind or sun, fossil energies can be replaced by hydraulic energy and nuclear energy

  18. Intermittency and random matrices

    Science.gov (United States)

    Sokoloff, Dmitry; Illarionov, E. A.

    2015-08-01

    A spectacular phenomenon of intermittency, i.e. a progressive growth of higher statistical moments of a physical field excited by an instability in a random medium, attracted the attention of Zeldovich in the last years of his life. At that time, the mathematical aspects underlying the physical description of this phenomenon were still under development and relations between various findings in the field remained obscure. Contemporary results from the theory of the product of independent random matrices (the Furstenberg theory) allowed the elaboration of the phenomenon of intermittency in a systematic way. We consider applications of the Furstenberg theory to some problems in cosmology and dynamo theory.

  19. Hypoxia regulates glutamate metabolism and membrane transport in rat PC12 cells.

    Science.gov (United States)

    Kobayashi, S; Millhorn, D E

    2001-03-01

    We investigated the effect of hypoxia on glutamate metabolism and uptake in rat pheochromocytoma (PC12) cells. Various key enzymes relevant to glutamate production, metabolism and transport were coordinately regulated by hypoxia. PC12 cells express two glutamate-metabolizing enzymes, glutamine synthetase (GS) and glutamate decarboxylase (GAD), as well as the glutamate-producing enzyme, phosphate-activated glutaminase (PAG). Exposure to hypoxia (1% O(2)) for 6 h or longer increased expression of GS mRNA and protein and enhanced GS enzymatic activity. In contrast, hypoxia caused a significant decrease in expression of PAG mRNA and protein, and also decreased PAG activity. In addition, hypoxia led to an increase in GAD65 and GAD67 protein levels and GAD enzymatic activity. PC12 cells express three Na(+)-dependent glutamate transporters; EAAC1, GLT-1 and GLAST. Hypoxia increased EAAC1 and GLT-1 protein levels, but had no effect on GLAST. Chronic hypoxia significantly enhanced the Na(+)-dependent component of glutamate transport. Furthermore, chronic hypoxia decreased cellular content of glutamate, but increased that of glutamine. Taken together, the hypoxia-induced changes in enzymes related to glutamate metabolism and transport are consistent with a decrease in the extracellular concentration of glutamate. This may have a role in protecting PC12 cells from the cytotoxic effects of glutamate during chronic hypoxia. PMID:11259512

  20. Ventilatory adaptation to hypoxia occurs in serotonin-depleted rats.

    Science.gov (United States)

    Olson, E B

    1987-08-01

    To test the hypothesis that serotonin mediated respiratory activity is involved in ventilatory adaptation to hypoxia, rats were treated with parachlorophenylalanine (PCPA), a potent, long-acting inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin. In normoxia, a single, intraperitoneal injection of 300 mg PCPA/kg body weight decreased the Paco2 from a control level at 39.1 +/- 0.6 Torr (mean +/- 95% confidence limits) to 34.0 +/- 0.6 Torr measured during a period from 1 to 48 h following PCPA treatment. This PCPA-produced hyperventilation corresponds to an increase of 3.7 +/- 0.5 in the VA (BTPS)/Vco2 (STPD) ratio. Hyperventilation during ventilatory adaptation to hypoxia (PIO2 approximately equal to 90 Torr) was superimposed in an additive fashion on the underlying hyperventilation due to PCPA pretreatment. Specifically, PCPA pretreatment caused an average 3.5 +/- 1.2 increase in the VA/VCO2 ratio determined in acute (1 h) hypoxia, chronic (24 h) hypoxia and acute return to normoxia following chronic hypoxia. Since ventilatory adaptation to hypoxia occurred in rats treated with PCPA, the prolonged, serotonin mediated respiratory activity described by Millhorn et al. (1980b) is probably not important in ventilatory acclimatization to - or deacclimatization from - hypoxia. PMID:2957766

  1. Zooplankton intermittency and turbulence

    Science.gov (United States)

    Schmitt, François G.

    2010-05-01

    Planktonic organisms usually live in a turbulent world. Since marine turbulence is characterized by very high Reynolds numbers, it possesses very intermittent fluctuations which in turn affect marine life. We consider here such influence on zooplankton on 2 aspects. First we consider zooplankton motion in the lab. Many copepods display swimming abilities. More and more species have been recently recorded using normal or high speed cameras, and many trajectories have been extracted from these movies and are now available for analysis. These trajectories can be complex, stochastic, with random switching from low velocity to high velocity events and even jumps. These complex trajectories show that an adequate modeling is necessary to understand and characterize them. Here we review the results published in the literature on copepod trajectories. We discuss the random walk, Levy walk modeling and introduce also multifractal random walks. We discuss the way to discriminate between these different walks using experimental data. Stochastic simulations will be performed to illustrate the different families. Second, we consider zooplankton contact rates in the framework of intermittent turbulence. Intermittency may have influence on plankton contact rates. We consider the Particle Stokes number of copepods, in a intermediate dissipation range affected by intermittent fluctuations. We show that they may display preferential concentration effects, and we consider the influence on contact rates of this effect in the intermediate dissipation range.

  2. Chronic cannulation for intermittent intravenous fluid administration.

    Science.gov (United States)

    Mostardi, R A; Worsencroft, D; Stern, J; Vanessen, F

    1975-04-01

    A system is described for rapid and effective venous cannulation for long-term administration of fluids in rabbits. This method is completely free of any harness or sling-type apparatus and in no way interferes with the normal mobility of the animal. The animals maintained in this way have participated in programs of tri-weekly administration (2-3 ml/dose) of fluid for as long as 5 mo. PMID:1141108

  3. PET imaging of hypoxia

    International Nuclear Information System (INIS)

    Hypoxia in tumors has been related to poor response to conventional therapies. This paper will discuss the methods, both invasive and non-invasive, used to determine hypoxia levels within tumors. PET imaging with two lead compounds 18F-fluoro misonidazole (18FMISO) and Cu-(II)-diacetyl-bis(N4-methylthiosemicarbazone (Cu-ATSM) and their relative effectiveness in delineating hypoxic regions will be discussed. The advantages of Cu-ATSM-PET over existing imaging agents will be discussed along with its potential application as a direct-and/or surrogate marker for the determination of oncological hypoxia in vivo

  4. Cardiac responses to hypoxia and reoxygenation in Drosophila.

    Science.gov (United States)

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

    2015-12-01

    An adequate supply of oxygen is important for the survival of all tissues, but it is especially critical for tissues with high-energy demands, such as the heart. Insufficient tissue oxygenation occurs under a variety of conditions, including high altitude, embryonic and fetal development, inflammation, and thrombotic diseases, often affecting multiple organ systems. Responses and adaptations of the heart to hypoxia are of particular relevance in human cardiovascular and pulmonary diseases, in which the effects of hypoxic exposure can range in severity from transient to long-lasting. This study uses the genetic model system Drosophila to investigate cardiac responses to acute (30 min), sustained (18 h), and chronic (3 wk) hypoxia with reoxygenation. Whereas hearts from wild-type flies recovered quickly after acute hypoxia, exposure to sustained or chronic hypoxia significantly compromised heart function upon reoxygenation. Hearts from flies with mutations in sima, the Drosophila homolog of the hypoxia-inducible factor alpha subunit (HIF-α), exhibited exaggerated reductions in cardiac output in response to hypoxia. Heart function in hypoxia-selected flies, selected over many generations for survival in a low-oxygen environment, revealed reduced cardiac output in terms of decreased heart rate and fractional shortening compared with their normoxia controls. Hypoxia-selected flies also had smaller hearts, myofibrillar disorganization, and increased extracellular collagen deposition, consistent with the observed reductions in contractility. This study indicates that longer-duration hypoxic insults exert deleterious effects on heart function that are mediated, in part, by sima and advances Drosophila models for the genetic analysis of cardiac-specific responses to hypoxia and reoxygenation. PMID:26377557

  5. Feigning Acute Intermittent Porphyria

    OpenAIRE

    Rania Elkhatib; Modupe Idowu; Gregory S. Brown; Jaber, Yasmeen M.; Reid, Matthew B.; Cheryl Person

    2014-01-01

    Acute intermittent porphyria (AIP) is an autosomal dominant genetic defect in heme synthesis. Patients with this illness can have episodic life-threatening attacks characterized by abdominal pain, neurological deficits, and psychiatric symptoms. Feigning this illness has not been reported in the English language literature to date. Here, we report on a patient who presented to the hospital with an acute attack of porphyria requesting opiates. Diligent assessment of extensive prior treatment r...

  6. Children with chronic lung diseases have cognitive dysfunction as assessed by event-related potential (auditory P300) and Stanford-Binet IQ (SB-IV) test.

    Science.gov (United States)

    Kamel, Terez Boshra; Abd Elmonaem, Mahmoud Tarek; Khalil, Lobna Hamed; Goda, Mona Hamdy; Sanyelbhaa, Hossam; Ramzy, Mourad Alfy

    2016-10-01

    Chronic lung disease (CLD) in children represents a heterogeneous group of many clinico-pathological entities with risk of adverse impact of chronic or intermittent hypoxia. So far, few researchers have investigated the cognitive function in these children, and the role of auditory P300 in the assessment of their cognitive function has not been investigated yet. This study was designed to assess the cognitive functions among schoolchildren with different chronic pulmonary diseases using both auditory P300 and Stanford-Binet test. This cross-sectional study included 40 school-aged children who were suffering from chronic chest troubles other than asthma and 30 healthy children of similar age, gender and socioeconomic state as a control group. All subjects were evaluated through clinical examination, radiological evaluation and spirometry. Audiological evaluation included (basic otological examination, pure-tone, speech audiometry and immittancemetry). Cognitive function was assessed by auditory P300 and psychological evaluation using Stanford-Binet test (4th edition). Children with chronic lung diseases had significantly lower anthropometric measures compared to healthy controls. They had statistically significant lower IQ scores and delayed P300 latencies denoting lower cognitive abilities. Cognitive dysfunction correlated to severity of disease. P300 latencies were prolonged among hypoxic patients. Cognitive deficits in children with different chronic lung diseases were best detected using both Stanford-Binet test and auditory P300. P300 is an easy objective tool. P300 is affected early with hypoxia and could alarm subtle cognitive dysfunction. PMID:27075686

  7. Impact of Hypoxia on the Metastatic Potential of Human Prostate Cancer Cells

    International Nuclear Information System (INIS)

    Purpose: Intratumoral hypoxia is known to be associated with radioresistance and metastasis. The present study examined the effect of acute and chronic hypoxia on the metastatic potential of prostate cancer PC-3, DU145, and LNCaP cells. Methods and Materials: Cell proliferation and clonogenicity were tested by MTT assay and colony formation assay, respectively. 'Wound-healing' and Matrigel-based chamber assays were used to monitor cell motility and invasion. Hypoxia-inducible factor 1 alpha (HIF-1α) expression was tested by Western blot, and HIF-1-target gene expression was detected by real-time polymerase chain reaction. Secretion of matrix metalloproteinases (MMPs) was determined by gelatin zymography. Results: When PC-3 cells were exposed to 1% oxygen (hypoxia) for various periods of time, chronic hypoxia (≥24 h) decreased cell proliferation and induced cell death. In contrast, prostate cancer cells exposed to acute hypoxia (≤6 h) displayed increased motility, clonogenic survival, and invasive capacity. At the molecular level, both hypoxia and anoxia transiently stabilized HIF-1α. Exposure to hypoxia also induced the early expression of MMP-2, an invasiveness-related gene. Treatment with the HIF-1 inhibitor YC-1 attenuated the acute hypoxia-induced migration, invasion, and MMP-2 activity. Conclusions: The length of oxygen deprivation strongly affected the functional behavior of all three prostate cancer cell lines. Acute hypoxia in particular was found to promote a more aggressive metastatic phenotype.

  8. 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.

  9. The molecular basis of O2-sensing and hypoxia tolerance in pheochromocytoma cells.

    Science.gov (United States)

    Conrad, P W; Conforti, L; Kobayashi, S; Beitner-Johnson, D; Rust, R T; Yuan, Y; Kim, H W; Kim, R H; Seta, K; Millhorn, D E

    2001-02-01

    Hypoxia is a common environmental stimulus. However, very little is known about the mechanisms by which cells sense and respond to changes in oxygen. Our laboratory has utilized the PC12 cell line in order to study the biophysical and molecular response to hypoxia. The current review summarizes our results. We demonstrate that the O2-sensitive K(+) channel, Kv1.2, is present in PC12 cells and plays a critical role in the hypoxia-induced depolarization of PC12 cells. Previous studies have shown that PC12 cells secrete a variety of autocrine/paracrine factors, including dopamine, norepinephrine, and adenosine during hypoxia. We investigated the mechanisms by which adenosine modulates cell function and the effect of chronic hypoxia on this modulation. Finally, we present results identifying the mitogen- and stress-activated protein kinases (MAPKs and SAPKs) as hypoxia-regulated protein kinases. Specifically, we show that p38 and an isoform, p38gamma, are activated by hypoxia. In addition, our results demonstrate that the p42/p44 MAPK protein kinases are activated by hypoxia. We further show that p42/p44 MAPK is critical for the hypoxia-induced transactivation of endothelial PAS-domain protein 1 (EPAS1), a hypoxia-inducible transcription factor. Together, these results provide greater insight into the mechanisms by which cells sense and adapt to hypoxia. PMID:11207433

  10. Anaerobic training in hypoxia: A new approach to stimulate the rating of effort perception.

    Science.gov (United States)

    Álvarez-Herms, J; Julià-Sánchez, S; Gatterer, H; Blank, C; Corbi, F; Pagès, T; Burtscher, M; Viscor, G

    2016-09-01

    This study compared subjective effort perception with objective physiological measures during high-intensive intermittent exercise performed in normoxia, moderate hypoxia (FiO2: 16.5%) and severe hypoxia (FiO2: 13.5%). Sixteen physically active subjects performed an equal training session on three different days. Training consisted of 6 "all-out" series of continuous jumps lasting for 15s each. Average power output during the jumps was similar in all three conditions (~3200W). Greater hypoxemia was observed in hypoxia as compared to normoxia. Likewise, a significantly higher value in perceived effort was observed after hypoxia training as compared to normoxia training (pcreatine kinase increased in moderate (p=0.02) and severe (p<0.01) hypoxia compared to normoxia 24h after the training. Perceived fatigue was also significantly elevated 24h after hypoxic exercise only. Heart rate variability pre and 24h after exercise showed a tendency to sympathetic predominance in severe hypoxia as compared to moderate hypoxia and normoxia. In conclusion, a single session of anaerobic exercise can be executed at the same intensity in moderate/severe hypoxia as in normoxia. This type of hypoxic training may be considered as a method potentially to improve the ability tolerating discomfort and consequently also exercise performance. PMID:27126970

  11. Forecast combinations for intermittent demand

    OpenAIRE

    Fotios PETROPOULOS; Kourentzes, Nikos

    2015-01-01

    Intermittent demand is characterised by infrequent demand arrivals, where many periods have zero demand, coupled with varied demand sizes. The dual source of variation renders forecasting for intermittent demand a very challenging task. Many researchers have focused on the development of specialised methods for intermittent demand. However, apart from a case study on hierarchical forecasting, the effects of combining, which is a standard practice for regular demand, have not been investigated...

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

    OpenAIRE

    Nilsson, Göran E.; Ostlund-Nilsson, Sara

    2004-01-01

    Using respirometry, we examined the hypoxia tolerance of 31 teleost fish species (seven families) inhabiting coral reefs at a 2-5 m depth in the lagoon at Lizard Island (Great Barrier Reef, Australia). All fishes studied maintained their rate of oxygen consumption down to relatively severe hypoxia (20-30% air saturation). Indeed, most fishes appeared unaffected by hypoxia until the oxygen level fell below 10% of air saturation. This, hitherto unrecognized, hypoxia tolerance among coral reef f...

  13. 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...... 113 of the patients (44%) had died. Causes of death were no different from those in the general population. Mortality was twice that of the general population matched for age and sex. Mortality among the men was twice that among the women. In men under 60 mortality was four times that expected. The...

  14. Hypoxia targeting copper complexes

    International Nuclear Information System (INIS)

    The importance and incidence of tumour hypoxia, its measurement and current treatments available, including pharmacological and radiopharmacological methods of targeting hypoxia, are discussed. A variety of in vitro and in vivo methods for imposing hypoxia have been developed and are reviewed. Copper, its chemistry, biochemistry and radiochemistry, the potential for use of copper radionuclides and its use to date in this field is considered with particular reference to the thiosemicarbazones. Their biological activity, metal chelation, in vitro and in vivo studies of their radiocopper complexes and the potential for their use as hypoxia targeting radiopharmaceuticals is described. The reduction of the copper(II) complex to copper(l), its pivotal importance in their biological behaviour, and the potential for manipulation of this to effect hypoxia selectivity are described. An in vitro method for assessing the hypoxia selectivity of radiopharmaceuticals is reported. The rapid deoxygenation and high viability of a mammalian cell culture in this system is discussed and factors which may affect the cellular uptake of a radiopharmaceutical are described. The design, synthesis and complexation with copper and radiocopper of a range of bis(thiosemicarbazones) is reported. Synthesis of these compounds is simple giving high yields of pure products. The characteristics of the radiocopper complexes (64Cu) including lipophilicity and redox activity are reported (reduction potentials in the range -0.314 - -0.590 V). High cellular uptakes of the radiocopper complexes of the ligands, in hypoxic and normoxic EMT6 and CHO320 cells, were observed. Extremes of selectivity are shown ranging from the hypoxia selective 64Cu(II)ATSM to normoxic cell selective 64Cu(II)GTS. The selectivities observed are compared with the physico chemical characteristics of the complexes. A good correlation exists between selectivity of the complex and its Cu(II)/Cu(I) reduction potential, with hypoxia

  15. Hypoxia targeting copper complexes

    Energy Technology Data Exchange (ETDEWEB)

    Dearling, J.L

    1998-11-01

    The importance and incidence of tumour hypoxia, its measurement and current treatments available, including pharmacological and radiopharmacological methods of targeting hypoxia, are discussed. A variety of in vitro and in vivo methods for imposing hypoxia have been developed and are reviewed. Copper, its chemistry, biochemistry and radiochemistry, the potential for use of copper radionuclides and its use to date in this field is considered with particular reference to the thiosemicarbazones. Their biological activity, metal chelation, in vitro and in vivo studies of their radiocopper complexes and the potential for their use as hypoxia targeting radiopharmaceuticals is described. The reduction of the copper(II) complex to copper(l), its pivotal importance in their biological behaviour, and the potential for manipulation of this to effect hypoxia selectivity are described. An in vitro method for assessing the hypoxia selectivity of radiopharmaceuticals is reported. The rapid deoxygenation and high viability of a mammalian cell culture in this system is discussed and factors which may affect the cellular uptake of a radiopharmaceutical are described. The design, synthesis and complexation with copper and radiocopper of a range of bis(thiosemicarbazones) is reported. Synthesis of these compounds is simple giving high yields of pure products. The characteristics of the radiocopper complexes ({sup 64}Cu) including lipophilicity and redox activity are reported (reduction potentials in the range -0.314 - -0.590 V). High cellular uptakes of the radiocopper complexes of the ligands, in hypoxic and normoxic EMT6 and CHO320 cells, were observed. Extremes of selectivity are shown ranging from the hypoxia selective {sup 64}Cu(II)ATSM to normoxic cell selective {sup 64}Cu(II)GTS. The selectivities observed are compared with the physico chemical characteristics of the complexes. A good correlation exists between selectivity of the complex and its Cu(II)/Cu(I) reduction potential

  16. The role of hypoxia in intestinal inflammation.

    Science.gov (United States)

    Shah, Yatrik M

    2016-12-01

    Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestine. IBD is a multifactorial disorder, and IBD-associated genes are critical in innate immune response, inflammatory response, autophagy, and epithelial barrier integrity. Moreover, epithelial oxygen tension plays a critical role in intestinal inflammation and resolution in IBD. The intestines have a dynamic and rapid fluctuation in cellular oxygen tension, which is dysregulated in IBD. Intestinal epithelial cells have a steep oxygen gradient where the tips of the villi are hypoxic and the oxygenation increases at the base of the villi. IBD results in heightened hypoxia throughout the mucosa. Hypoxia signals through a well-conserved family of transcription factors, where hypoxia-inducible factor (HIF)-1α and HIF-2α are essential in maintaining intestinal homeostasis. In inflamed mucosa, HIF-1α increases barrier protective genes, elicits protective innate immune responses, and activates an antimicrobial response through the increase in β-defensins. HIF-2α is essential in maintaining an epithelial-elicited inflammatory response and the regenerative and proliferative capacity of the intestine following an acute injury. HIF-1α activation in colitis leads to a protective response, whereas chronic activation of HIF-2α increases the pro-inflammatory response, intestinal injury, and cancer. In this mini-review, we detail the role of HIF-1α and HIF-2α in intestinal inflammation and injury and therapeutic implications of targeting HIF signaling in IBD. PMID:26812949

  17. Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

    OpenAIRE

    Leonard, Martin O.; Howell, Katherine; Madden, Stephen F; Costello, Christine M; Higgins, Desmond G.; Taylor, Cormac T; McLoughlin, Paul

    2008-01-01

    Rationale: Pulmonary hypertension is a common complication of chronic hypoxic lung diseases and is associated with increased morbidity and reduced survival. The pulmonary vascular changes in response to hypoxia, both structural and functional, are unique to this circulation.

  18. Interventions for intermittent exotropia

    Science.gov (United States)

    Hatt, Sarah R; Gnanaraj, Lawrence

    2014-01-01

    Background The clinical management of intermittent exotropia has been discussed extensively in the literature, yet there remains a lack of clarity regarding indications for intervention, the most effective form of treatment and whether or not there is an optimal time in the evolution of the disease at which any treatment should be carried out. Objectives The objective of this review was to analyse the effects of various surgical and non-surgical treatments in randomised trials of participants with intermittent exotropia, and to report intervention criteria and determine the significance of factors such as age with respect to outcome. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library, Issue 4, 2012), MEDLINE (January 1966 to May 2012), EMBASE (January 1980 to May 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to May 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 4 May 2012. We are no longer searching the UK Clinical Trials Gateway (UKCTG) for this review. We manually searched the British Orthoptic Journal up to 2002, and the proceedings of the European Strabismological Association (ESA), International Strabismological Association (ISA) and American Academy of Paediatric Ophthalmology and Strabismus meeting (AAPOS) up to 2001. We contacted researchers who are active in the field for information about further published or unpublished studies. Selection criteria We included randomised controlled trials of any surgical or non-surgical treatment for intermittent exotropia. Data collection and

  19. The critical role of ERK in death resistance and invasiveness of hypoxia-selected glioblastoma cells

    OpenAIRE

    Lee Sun; Kim Yong-Jun; Kim Jee-Youn; Park Jae-Hoon

    2009-01-01

    Abstract Background The rapid growth of tumor parenchyma leads to chronic hypoxia that can result in the selection of cancer cells with a more aggressive behavior and death-resistant potential to survive and proliferate. Thus, identifying the key molecules and molecular mechanisms responsible for the phenotypic changes associated with chronic hypoxia has valuable implications for the development of a therapeutic modality. The aim of this study was to identify the molecular basis of the phenot...

  20. Hypoxia, Nitrogen, and Fisheries: Integrating Effects Across Local and Global Landscapes

    Science.gov (United States)

    Breitburg, Denise L.; Hondorp, Darryl W.; Davias, Lori A.; Diaz, Robert J.

    2009-01-01

    Anthropogenic nutrient enrichment and physical characteristics result in low dissolved oxygen concentrations (hypoxia) in estuaries and semienclosed seas throughout the world. Published research indicates that within and near oxygen-depleted waters, finfish and mobile macroinvertebrates experience negative effects that range from mortality to altered trophic interactions. Chronic exposure to hypoxia and fluctuating oxygen concentrations impair reproduction, immune responses, and growth. We present an analysis of hypoxia, nitrogen loadings, and fisheries landings in 30 estuaries and semienclosed seas worldwide. Our results suggest that hypoxia does not typically reduce systemwide fisheries landings below what would be predicted from nitrogen loadings, except where raw sewage is released or particularly sensitive species lose critical habitat. A number of compensatory mechanisms limit the translation of local-scale effects of hypoxia to the scale of the whole system. Hypoxia is, however, a serious environmental challenge that should be considered in fisheries management strategies and be a direct target of environmental restoration.

  1. Hypoxia/oxidative stress alters the pharmacokinetics of CPU86017-RS through mitochondrial dysfunction and NADPH oxidase activation

    OpenAIRE

    Gao, Jie; Ding, Xuan-Sheng; Zhang, Yu-mao; Dai, De-zai; Liu, Mei; Zhang, Can; Dai, Yin

    2013-01-01

    Aim: Hypoxia/oxidative stress can alter the pharmacokinetics (PK) of CPU86017-RS, a novel antiarrhythmic agent. The aim of this study was to investigate the mechanisms underlying the alteration of PK of CPU86017-RS by hypoxia/oxidative stress. Methods: Male SD rats exposed to normal or intermittent hypoxia (10% O2) were administered CPU86017-RS (20, 40 or 80 mg/kg, ig) for 8 consecutive days. The PK parameters of CPU86017-RS were examined on d 8. In a separate set of experiments, female SD ra...

  2. 慢性间歇低氧对大鼠肝细胞SOCS3表达的影响%The effect of SOCS3 expression on rat liver cells by chronic intermittent hypoxic

    Institute of Scientific and Technical Information of China (English)

    任寿安; 康耀文; 蔡月伟

    2014-01-01

    Objective To established chronic intermittent hypoxic (CIH) animal model for investigate the mechanism of insulin resistance caused by CIH.Methods Twenty-four healthy male SD rats were randomly divided into four groups:normal control group (NC group),CIH 2 weeks group (CIH2 group),and CIH 5 weeks group (CIH5 group),with 8 rats in each group.The minimum oxygen concentration was 6%-7% in animal chamber.About 8 hours per day (from 9AM to 5 PM),the experimental lasted for 35 days.The rats in control group were placed in the same animal box without CIH.After the experiment,to measure fasting blood glucose and insulin levels by radioimmunoassay and then according to the homeostasis model of insulin resistance index (HOMA) was calculated.The expressions of SOCS3 protein were detected with immunohistochemical method in rat liver cells.To detect the SOCS3-mRNA gene expression by reverse transcription and polymerase chain reaction (RT-PCR).Results Compared with the NC group,fasting blood glucose(F =33.582,P <0.05),insulin level (F =35.633,P <0.05) and HOMA-IR (F =49.045,P <0.05) of the CIH2.CIH5 group was higher than other groups (P <0.05).Compared with the NC group,the expression of SOCS3 protein was increased in CIH2 and CHI5 group (F =9.472,P <0.05),but in CIH2 and CIH5 group were no significantly differences (P >0.05).And then the expression of SOCS3-mRNA in CIH5 was higher than CIH2 and CIH5 group (F =8.665,P < 0.05).Pearson correlation analysis showed that HOMA-IR and the expression of SOCS3 protein was negatively correlated (r =-0.759,P <0.001) and was positively correlated with SOCS3-mRNA (r =0.603,P =0.01).Conclusions ①CIH exposure caused fasting blood glucose level and increase insulin level and insulin resistance in rats with CIH.With the intermittent hypoxic exposure time prolonged,the degree of insulin resistance was increased.②CIH leads to increased expression of SOCS3 protein and SOCS3-mRNA gene in rat liver cells with CIH exposure

  3. Instantons and intermittency

    CERN Document Server

    Falkovich, G; Lebedev, V; Migdal, A

    1995-01-01

    We propose the new method for finding the non-Gaussian tails of probability distribution function (PDF) for solutions of a stochastic differential equation, such as convection equation for a passive scalar, random driven Navier-Stokes equation etc. Existence of such tails is generally regarded as a manifestation of intermittency phenomenon. Our formalism is based on the WKB approximation in the functional integral for the conditional probability of large fluctuation. We argue that the main contribution to the functional integral is given by a coupled field-force configuration -- {\\em instanton}. As an example, we examine the correlation functions of the passive scalar u advected by a large-scale velocity field \\delta-correlated in time. We find the instanton determining the tails of the generating functional and show that it is different from the instanton that determines the probability distribution function of high powers of u. We discuss the simplest instantons for the Navier-Stokes equation.

  4. 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. PMID:27399821

  5. Chronic penile strangulation

    OpenAIRE

    Lopes, Roberto I.; Silvia I Lopes; Roberto N. Lopes

    2003-01-01

    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 examin...

  6. Increased hemoglobin O2 affinity protects during acute hypoxia.

    Science.gov (United States)

    Yalcin, Ozlem; Cabrales, Pedro

    2012-08-01

    Acclimatization to hypoxia requires time to complete the adaptation mechanisms that influence oxygen (O(2)) transport and O(2) utilization. Although decreasing hemoglobin (Hb) O(2) affinity would favor the release of O(2) to the tissues, increasing Hb O(2) affinity would augment arterial O(2) saturation during hypoxia. This study was designed to test the hypothesis that pharmacologically increasing the Hb O(2) affinity will augment O(2) transport during severe hypoxia (10 and 5% inspired O(2)) compared with normal Hb O(2) affinity. RBC Hb O(2) affinity was increased by infusion of 20 mg/kg of 5-hydroxymethyl-2-furfural (5HMF). Control animals received only the vehicle. The effects of increasing Hb O(2) affinity were studied in the hamster window chamber model, in terms of systemic and microvascular hemodynamics and partial pressures of O(2) (Po(2)). Pimonidazole binding to hypoxic areas of mice heart and brain was also studied. 5HMF decreased the Po(2) at which the Hb is 50% saturated with O(2) by 12.6 mmHg. During 10 and 5% O(2) hypoxia, 5HMF increased arterial blood O(2) saturation by 35 and 48% from the vehicle group, respectively. During 5% O(2) hypoxia, blood pressure and heart rate were 58 and 30% higher for 5HMF compared with the vehicle. In addition, 5HMF preserved microvascular blood flow, whereas blood flow decreased to 40% of baseline in the vehicle group. Consequently, perivascular Po(2) was three times higher in the 5HMF group compared with the control group at 5% O(2) hypoxia. 5HMF also reduced heart and brain hypoxic areas in mice. Therefore, increased Hb O(2) affinity resulted in hemodynamics and oxygenation benefits during severe hypoxia. This acute acclimatization process may have implications in survival during severe environmental hypoxia when logistic constraints prevent chronic acclimatization. PMID:22636677

  7. The role of mRNA translation in the adaptation to hypoxia

    International Nuclear Information System (INIS)

    Hypoxia commonly occurs in human tumours and is associated with a poor prognosis. We and others have shown that global mRNA translation is rapidly inhibited during hypoxia. However, some mRNAs, such as those coding for HIF-1 α and VEGF, remain efficiently translated. We therefore hypothesize that the inhibition of mRNA translation serves to promote hypoxia tolerance in two ways: i) through conservation of energy and ii) through differential gene expression involved in hypoxia adaptation. We are investigating the mechanisms responsible for the down regulation of protein synthesis during hypoxia, and how specific mRNAs maintain their ability to be translated under such conditions. Our goal is to understand the significance of these regulatory mechanisms for hypoxia tolerance in vitro and tumor growth in vivo. We have previously shown that one mechanism responsible for inhibiting protein synthesis during hypoxia is the activation of PERK, which inhibits the essential translation factor eIF2 α . Here we show that PERK-/- MEFs are not able to inhibit protein synthesis efficiently during hypoxia and are significantly less tolerant to hypoxia than wt cells. We also show that other mechanisms are important for sustained low protein synthesis during chronic hypoxia. We demonstrate that the eIF4F complex is disrupted during prolonged hypoxia, and that this is mediated by 4E-BP1 and 4E-T. eIF4F is essential for translation which is dependent upon the 5'mRNA cap-structure. These studies therefore indicate a switch from the inhibition of all translation through eIF2 α during acute hypoxia, to the inhibition of only cap-dependent translation during chronic hypoxia. This model predicts the differential induction of genes that can be translated cap-independently during chronic hypoxia, which is consistent with the observed differential translation of HIF-1 α and VEGF. The functional significance of the disruption of the eIF4F complex during hypoxia is currently being addressed

  8. The impact of obesity and hypoxia on left ventricular function and glycolytic metabolism

    OpenAIRE

    Rodriguez, Rosa H.; Bickta, Janelle L.; Murawski, Patrick; O'Donnell, Christopher P.

    2014-01-01

    Abstract We have previously reported that 4 weeks of intermittent hypoxia (IH) exposure, mimicking the hypoxic stress of obstructive sleep apnea, produces compensatory increases in left ventricular (LV) contractility in lean C57BL/6J mice. In this study we compared the effects of 4 weeks IH to 4 weeks of sustained hypoxia (SH) on LV function and cardiac glycolysis in lean C57BL/6J mice and obese ob/ob mice at 10–12 weeks of age. The four exposure conditions were IH (nadir O2 [5–6%] at 60 cycl...

  9. 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.

  10. Intermittency Growth in Fluid Turbulence

    Institute of Scientific and Technical Information of China (English)

    ZHU Jian-Zhou

    2006-01-01

    @@ Measurement and phenomenological analyses of intermittency growth in an experimental turbulent pipe flow and numerical turbulence are performed, for which working definitions such as degree, increment, and growth rate of intermittency are introduced with the help of quasiscaling theory. The logarithmic-normal inertial scaling model is extended to quasiscaling as the second-order truncation of the Taylor expansion and is used for studying the intermittency growth problem. The extended self-similarity properties are shown to be not consistent with the monotonicity of the third order local quasiscaling exponent and the nonmonotonic behaviour of the intermittency growth rate as a result of bottleneck. Digestions of the results with scale-dependent multifractals are provided.

  11. Intermittency in spiral Poiseuille flow

    International Nuclear Information System (INIS)

    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

  12. Hypoxia regulates the cAMP- and Ca2+/calmodulin signaling systems in PC12 cells.

    Science.gov (United States)

    Beitner-Johnson, D; Leibold, J; Millhorn, D E

    1998-01-01

    Hypoxic/ischemic trauma is a primary factor in the pathology of various disease states. Yet, very little is known about the molecular mechanisms involved in cellular responses and adaptations to hypoxia. As a means of identifying intracellular signaling systems that are regulated in response to hypoxia, the effects of acute and chronic hypoxia on the activity of protein kinase A (PKA) and Ca2+/CaM-dependent protein kinase II (CaMK-II) were evaluated in rat pheochromocytoma (PC12) cells. Chronic (> 6 hr), but not acute exposure to hypoxia (5% O2) significantly decreased both PKA enzyme activity and immunoreactivity compared to control levels. This effect was not due to hypoxia-induced alterations in cell number or viability. Similarly, chronic hypoxia significantly decreased CaMK-II enzyme activity and protein levels in PC12 cells. These data demonstrate that down-regulation of the cAMP and Ca2+/CaM-signaling systems is a mechanism by which PC12 cells adapt to long-term hypoxia. PMID:9439610

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

    International Nuclear Information System (INIS)

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

  14. The critical role of ERK in death resistance and invasiveness of hypoxia-selected glioblastoma cells

    Directory of Open Access Journals (Sweden)

    Lee Sun

    2009-01-01

    Full Text Available Abstract Background The rapid growth of tumor parenchyma leads to chronic hypoxia that can result in the selection of cancer cells with a more aggressive behavior and death-resistant potential to survive and proliferate. Thus, identifying the key molecules and molecular mechanisms responsible for the phenotypic changes associated with chronic hypoxia has valuable implications for the development of a therapeutic modality. The aim of this study was to identify the molecular basis of the phenotypic changes triggered by chronic repeated hypoxia. Methods Hypoxia-resistant T98G (HRT98G cells were selected by repeated exposure to hypoxia and reoxygenation. Cell death rate was determined by the trypan blue exclusion method and protein expression levels were examined by western blot analysis. The invasive phenotype of the tumor cells was determined by the Matrigel invasion assay. Immunohistochemistry was performed to analyze the expression of proteins in the brain tumor samples. The Student T-test and Pearson Chi-Square test was used for statistical analyses. Results We demonstrate that chronic repeated hypoxic exposures cause T98G cells to survive low oxygen tension. As compared with parent cells, hypoxia-selected T98G cells not only express higher levels of anti-apoptotic proteins such as Bcl-2, Bcl-XL, and phosphorylated ERK, but they also have a more invasive potential in Matrigel invasion chambers. Activation or suppression of ERK pathways with a specific activator or inhibitor, respectively, indicates that ERK is a key molecule responsible for death resistance under hypoxic conditions and a more invasive phenotype. Finally, we show that the activation of ERK is more prominent in malignant glioblastomas exposed to hypoxia than in low grade astrocytic glial tumors. Conclusion Our study suggests that activation of ERK plays a pivotal role in death resistance under chronic hypoxia and phenotypic changes related to the invasive phenotype of HRT98G

  15. The critical role of ERK in death resistance and invasiveness of hypoxia-selected glioblastoma cells

    International Nuclear Information System (INIS)

    The rapid growth of tumor parenchyma leads to chronic hypoxia that can result in the selection of cancer cells with a more aggressive behavior and death-resistant potential to survive and proliferate. Thus, identifying the key molecules and molecular mechanisms responsible for the phenotypic changes associated with chronic hypoxia has valuable implications for the development of a therapeutic modality. The aim of this study was to identify the molecular basis of the phenotypic changes triggered by chronic repeated hypoxia. Hypoxia-resistant T98G (HRT98G) cells were selected by repeated exposure to hypoxia and reoxygenation. Cell death rate was determined by the trypan blue exclusion method and protein expression levels were examined by western blot analysis. The invasive phenotype of the tumor cells was determined by the Matrigel invasion assay. Immunohistochemistry was performed to analyze the expression of proteins in the brain tumor samples. The Student T-test and Pearson Chi-Square test was used for statistical analyses. We demonstrate that chronic repeated hypoxic exposures cause T98G cells to survive low oxygen tension. As compared with parent cells, hypoxia-selected T98G cells not only express higher levels of anti-apoptotic proteins such as Bcl-2, Bcl-XL, and phosphorylated ERK, but they also have a more invasive potential in Matrigel invasion chambers. Activation or suppression of ERK pathways with a specific activator or inhibitor, respectively, indicates that ERK is a key molecule responsible for death resistance under hypoxic conditions and a more invasive phenotype. Finally, we show that the activation of ERK is more prominent in malignant glioblastomas exposed to hypoxia than in low grade astrocytic glial tumors. Our study suggests that activation of ERK plays a pivotal role in death resistance under chronic hypoxia and phenotypic changes related to the invasive phenotype of HRT98G cells compared to parent cells

  16. Hypoxia-inducible factors as molecular targets for liver diseases.

    Science.gov (United States)

    Ju, Cynthia; Colgan, Sean P; Eltzschig, Holger K

    2016-06-01

    Liver disease is a growing global health problem, as deaths from end-stage liver cirrhosis and cancer are rising across the world. At present, pharmacologic approaches to effectively treat or prevent liver disease are extremely limited. Hypoxia-inducible factor (HIF) is a transcription factor that regulates diverse signaling pathways enabling adaptive cellular responses to perturbations of the tissue microenvironment. HIF activation through hypoxia-dependent and hypoxia-independent signals have been reported in liver disease of diverse etiologies, from ischemia-reperfusion-induced acute liver injury to chronic liver diseases caused by viral infection, excessive alcohol consumption, or metabolic disorders. This review summarizes the evidence for HIF stabilization in liver disease, discusses the mechanistic involvement of HIFs in disease development, and explores the potential of pharmacological HIF modifiers in the treatment of liver disease. PMID:27094811

  17. Contribution of transient blood flow to tumour hypoxia in mice

    International Nuclear Information System (INIS)

    Tumours grown in mice typically exhibit regions of hypoxia believed to result from two different processes: chronic oxygen deprivation due to consumption/diffusion limitations, and periodic deprivation resulting from transient reductions in tumour blood flow. The relative contribution of each is, however, not generally known. We have addressed this issue in transplanted SCCVII squamous cell carcinomas in C3H mice, using a quantitative extension of the fluorescence 'mismatch' technique coupled with cell sorting from irradiated tumours. At least half of the vessels in these tumours exhibit transient perfusion changes. Additionally, a majority of the 15-20% of cells that are sufficiently hypoxic to be resistant to radiation in the SCCVII tumours appear to result from cyclic, not continuous (diffusion-limited) hypoxia. Since different strategies may be necessary to counteract cyclic hypoxia in tumours, the possibility of transient blood flow changes should not be ignored when planning cancer therapy for humans. (orig.)

  18. Intermittency in 197Au fragmentation

    International Nuclear Information System (INIS)

    The concept of factorial moments was applied to an analysis of the dynamical fluctuations in the charge distributions of the fragments emitted from gold nuclei with energies 10.6 and < 1.0 GeV/n interacting with emulsion nuclei. Clear evidence for intermittent fluctuations has been found in an analysis using all the particles released from the gold projectile, with a stronger effect observed below 1 GeV/n than at 10.6 GeV/n. For the full data sets, however, the intermittency effect was found to be very sensitive to the singly charged particles, and neglecting these particles strongly reduces the intermittency signal. When the analysis is restricted to the multiply charged fragments, an intermittency effect is revealed only for multifragmentation events, although one that is enhanced as compared to the analysis of all, singly and multiply charged, particles. The properties of the anomalous fractal dimensions suggest a sequential decay mechanism, rather than the existence of possible critical behaviour in the process of nuclear fragmentation. The likely influence of the charge conservation effects and the finite size of decaying systems on the observed intermittency signals was pointed out. (author). 37 refs, 9 figs, 5 tabs

  19. Elastic wave turbulence and intermittency

    Science.gov (United States)

    Chibbaro, Sergio; Josserand, Christophe

    2016-07-01

    We investigate the onset of intermittency for vibrating elastic plate turbulence in the framework of the weak wave turbulence theory using a numerical approach. The spectrum of the displacement field and the structure functions of the fluctuations are computed for different forcing amplitudes. At low forcing, the spectrum predicted by the theory is observed, while the fluctuations are consistent with Gaussian statistics. When the forcing is increased, the spectrum varies at large scales, corresponding to the oscillations of nonlinear structures made of ridges delimited by d cones. In this regime, the fluctuations exhibit small-scale intermittency that can be fitted via a multifractal model. The analysis of the nonlinear frequency shows that the intermittency is linked to the breakdown of the weak turbulence at large scales only.

  20. 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.

  1. Recent advances in renal hypoxia: insights from bench experiments and computer simulations.

    Science.gov (United States)

    Layton, Anita T

    2016-07-01

    The availability of oxygen in renal tissue is determined by the complex interactions among a host of processes, including renal blood flow, glomerular filtration, arterial-to-venous oxygen shunting, medullary architecture, Na(+) transport, and oxygen consumption. When this delicate balance is disrupted, the kidney may become susceptible to hypoxic injury. Indeed, renal hypoxia has been implicated as one of the major causes of acute kidney injury and chronic kidney diseases. This review highlights recent advances in our understanding of renal hypoxia; some of these studies were published in response to a recent Call for Papers of this journal: Renal Hypoxia. PMID:27147670

  2. Selective induction of integrin β1 by hypoxia-inducible factor: implications for wound healing

    OpenAIRE

    Keely, Simon; Glover, Louise E; MacManus, Christopher F.; Campbell, Eric L.; Scully, Melanie M.; Furuta, Glenn T.; Colgan, Sean P.

    2009-01-01

    Because of localized vascular damage and increased tissue oxygen demand, wound healing occurs in a relatively hypoxic microenvironment. These features are particularly relevant to wound healing and fibrosis in chronic inflammatory conditions, such as Crohn’s disease and ulcerative colitis. In these studies, we sought to identify the contribution of hypoxia to mechanisms of wound repair in a model of the intestinal submucosa. Initial studies revealed that hypoxia promotes wound healing, as mod...

  3. Hypoxia and oxidative stress in breast cancer: Hypoxia and tumourigenesis

    International Nuclear Information System (INIS)

    The microenvironmental hypoxia that arises as a consequence of the development of a solid tumour also acts to promote tumour growth. Hypoxia induces the expression of key components of the angiogenic and apoptotic signalling cascades, the glycolytic pathway and various cell-cycle control proteins. At the cellular level it mediates the infiltration and accumulation of tumour-associated macrophages within avascular tumour regions. Complex interactions between tumour cell and macrophage hypoxia-regulated gene products and their associated pathways form the basis for the hypoxic promotion of tumourigenesis and malignant progression

  4. Intermittent control of coexisting attractors.

    Science.gov (United States)

    Liu, Yang; Wiercigroch, Marian; Ing, James; Pavlovskaia, Ekaterina

    2013-06-28

    This paper proposes a new control method applicable for a class of non-autonomous dynamical systems that naturally exhibit coexisting attractors. The central idea is based on knowledge of a system's basins of attraction, with control actions being applied intermittently in the time domain when the actual trajectory satisfies a proximity constraint with regards to the desired trajectory. This intermittent control uses an impulsive force to perturb one of the system attractors in order to switch the system response onto another attractor. This is carried out by bringing the perturbed state into the desired basin of attraction. The method has been applied to control both smooth and non-smooth systems, with the Duffing and impact oscillators used as examples. The strength of the intermittent control force is also considered, and a constrained intermittent control law is introduced to investigate the effect of limited control force on the efficiency of the controller. It is shown that increasing the duration of the control action and/or the number of control actuations allows one to successfully switch between the stable attractors using a lower control force. Numerical and experimental results are presented to demonstrate the effectiveness of the proposed method. PMID:23690639

  5. Intermittency patterns in hadron multiproduction

    International Nuclear Information System (INIS)

    Short-range fluctuations in rapidity are observed in high energy multiproduction of hadrons. Using a factorial moment method, we show how to isolate non-statistical fluctuations and discuss some model predictions. Models including a space-time cascade of cluster decays are expected to lead to fluctuation patterns typical of intermittency whereas the dual parton model gives a very different steady behaviour

  6. Hypoxia. Hypoxia in the pathogenesis of systemic sclerosis

    OpenAIRE

    Beyer, C.; Schett, G; Gay, S; Distler, O.; Distler, J.H. W.

    2009-01-01

    Autoimmunity, microangiopathy and tissue fibrosis are hallmarks of systemic sclerosis (SSc). Vascular alterations and reduced capillary density decrease blood flow and impair tissue oxygenation in SSc. Oxygen supply is further reduced by accumulation of extracellular matrix (ECM), which increases diffusion distances from blood vessels to cells. Therefore, severe hypoxia is a characteristic feature of SSc and might contribute directly to the progression of the disease. Hypoxia stimulates the p...

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

    International Nuclear Information System (INIS)

    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)-α, 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.

  8. 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.

  9. Chronic stress in adulthood followed by intermittent stress impairs spatial memory and the survival of newborn hippocampal cells in aging animals: prevention by FGL, a peptide mimetic of neural cell adhesion molecule

    DEFF Research Database (Denmark)

    Borcel, Erika; Pérez-Alvarez, Laura; Herrero, Ana Isabel;

    2008-01-01

    . Administration of FGL, a peptide mimetic of neural cell adhesion molecule, during the 4 weeks of continuous stress not only prevented the deleterious effects of chronic stress on spatial memory, but also reduced the survival of the newly generated hippocampal cells in aging animals. FGL treatment did not......, however, prevent the decrease in the total number of granular neurons that resulted from prolonged exposure to stress. These findings suggest that the development of new drugs that mimic neural cell adhesion molecule activity might be of therapeutic relevance to treat stress-induced cognitive impairment....

  10. Clinical Biomarkers for Hypoxia Targeting

    OpenAIRE

    Le, Quynh-Thu; Courter, Don

    2008-01-01

    Tumor hypoxia or a reduction of the tissue oxygen tension is a key microenvironmental factor for tumor progression and treatment resistance in solid tumors. Because hypoxic tumor cells have been demonstrated to be more resistant to ionizing radiation, hypoxia has been a focus of laboratory and clinical research in radiation therapy for many decades. It is believed that proper detection of hypoxic regions would guide treatment options and ultimately improve tumor response. To date, most clinic...

  11. Molecular imaging of tumour hypoxia

    International Nuclear Information System (INIS)

    By allowing an earlier diagnosis and a more exhaustive assessment of extension of the disease, the tomography by emission of positrons (PET) transforms the care of numerous cancers. At present, 18F-fluorodeoxyglucose ([18F]-F.D.G.) imaging appears as the only one available but new molecular markers are being developed. In the next future they would modify the approach of cancers. In this context, the molecular imaging of the hypoxia and especially the 18Fluoromisonidazole PET ([18F]-MISO PET) can give supplementary information allowing the mapping of hypoxic regions within the tumour. Because of the links, which exist between tumour hypoxia and treatment resistance of very numerous cancers, this information can have an interest, for determination of prognosis as well as for the delineation, volumes to be irradiated. Head and neck tumours are doubtless those for which the literature gives the most elements on the therapeutic impact of tumour hypoxia. Targeted therapies, based on hypoxia, already exist and the contribution of the molecular imaging could be decisive in the evaluation of the impact of such treatment. Molecular imaging of brain tumours remains to be developed. The potential contributions of the [18F]-MISO PET for the care of these patients need to be confirmed. In this context, we propose a review of hypoxia molecular imaging taking as examples head and neck tumours and glioblastomas (GB), two tumours for which hypoxia is one of the key factors to overcome in order to increase therapeutics results

  12. 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

  13. 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.

  14. Power-constrained intermittent control

    OpenAIRE

    Gawthrop, Peter J.; Wagg, David J; Neild, Simon A; Wang, Liuping

    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...

  15. Lattice splitting under intermittent flows

    OpenAIRE

    Schläpfer, Markus; Trantopoulos, Konstantinos

    2010-01-01

    We study the splitting of regular square lattices subject to stochastic intermittent flows. Various flow patterns are produced by different groupings of the nodes, based on their random alternation between two possible states. The resulting flows on the lattices decrease with the number of groups according to a power law. By Monte Carlo simulations we reveal how the time span until the occurrence of a splitting depends on the flow patterns. Increasing the flow fluctuation frequency shortens t...

  16. Hypoxia and Hypoxia-Inducible Factors in Leukemias.

    Science.gov (United States)

    Deynoux, Margaux; Sunter, Nicola; Hérault, Olivier; Mazurier, Frédéric

    2016-01-01

    Despite huge improvements in the treatment of leukemia, the percentage of patients suffering relapse still remains significant. Relapse most often results from a small number of leukemic stem cells (LSCs) within the bone marrow, which are able to self-renew, and therefore reestablish the full tumor. The marrow microenvironment contributes considerably in supporting the protection and development of leukemic cells. LSCs share specific niches with normal hematopoietic 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 hematopoietic niche is low oxygen partial pressure, indeed this hypoxia is necessary for the long-term maintenance of hematopoietic stem/progenitor cells. Hypoxia is a strong signal, principally maintained by members of the hypoxia-inducible factor (HIF) family. In solid tumors, 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 leukemia is not considered a "solid" tumor, 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 leukemic cell proliferation, differentiation, and resistance to chemotherapy. However, the role of HIF proteins remains controversial with HIFs being considered as either oncogenes or tumor suppressor genes, depending on the study and model. The purpose of this review is to highlight our knowledge of hypoxia and HIFs in leukemic development and therapeutic resistance and to discuss the recent hypoxia-based strategies proposed to eradicate leukemias. PMID:26955619

  17. 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.

  18. Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia

    Science.gov (United States)

    Minamino, Tohru; Christou, Helen; Hsieh, Chung-Ming; Liu, Yuxiang; Dhawan, Vijender; Abraham, Nader G.; Perrella, Mark A.; Mitsialis, S. Alex; Kourembanas, Stella

    2001-07-01

    Chronic hypoxia causes pulmonary hypertension with smooth muscle cell proliferation and matrix deposition in the wall of the pulmonary arterioles. We demonstrate here that hypoxia also induces a pronounced inflammation in the lung before the structural changes of the vessel wall. The proinflammatory action of hypoxia is mediated by the induction of distinct cytokines and chemokines and is independent of tumor necrosis factor- signaling. We have previously proposed a crucial role for heme oxygenase-1 (HO-1) in protecting cardiomyocytes from hypoxic stress, and potent anti-inflammatory properties of HO-1 have been reported in models of tissue injury. We thus established transgenic mice that constitutively express HO-1 in the lung and exposed them to chronic hypoxia. HO-1 transgenic mice were protected from the development of both pulmonary inflammation as well as hypertension and vessel wall hypertrophy induced by hypoxia. Significantly, the hypoxic induction of proinflammatory cytokines and chemokines was suppressed in HO-1 transgenic mice. Our findings suggest an important protective function of enzymatic products of HO-1 activity as inhibitors of hypoxia-induced vasoconstrictive and proinflammatory pathways.

  19. Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia.

    Science.gov (United States)

    Selfridge, Andrew C; Cavadas, Miguel A S; Scholz, Carsten C; Campbell, Eric L; Welch, Lynn C; Lecuona, Emilia; Colgan, Sean P; Barrett, Kim E; Sporn, Peter H S; Sznajder, Jacob I; Cummins, Eoin P; Taylor, Cormac T

    2016-05-27

    Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2 Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated. PMID:27044749

  20. 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.

  1. 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...... to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise....... 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...

  2. Hypoxia-mediated tumour targeting.

    Science.gov (United States)

    Binley, K; Askham, Z; Martin, L; Spearman, H; Day, D; Kingsman, S; Naylor, S

    2003-04-01

    Hypoxia is a common physiological feature of tumours. It activates a signalling cascade that culminates in the stabilization of the HIF-1 transcription factor and activation of genes that possess a hypoxia response element (HRE). We have used an optimized hypoxia responsive promoter (OBHRE) to investigate hypoxia-targeted gene expression in vivo in the context of an adenovirus vector. The OBHRE promoter showed limited activity in the liver or spleen such that expression was 1000-fold lower than that driven by the strong CMV/IE promoter. However, in the context of the tumour microenvironment, the OBHRE promoter achieved expression levels comparable to that of the CMV/IE promoter. Next, we showed that an adenovirus expressing the human cytochrome P450 (CYP2B6) regulated by the OBHRE promoter delays tumour growth in response to the prodrug cyclophosphamide (CPA). Finally, we exploited the hepatotropism of adenovirus to investigate whether the OBHRE promoter could mitigate the hepatotoxicity of a recombinant adenovirus expressing thymidine kinase (TK) in the context of the prodrug ganciclovir (GCV). High-dose Ad.CMVTK/GCV treatment caused significant liver necrosis whereas the same dose of Ad.HRETK was well tolerated. These in vivo data demonstrate that hypoxia-targeted gene expression via the OBHRE promoter can be used to increase the therapeutic window of cytotoxic cancer gene therapy. PMID:12646859

  3. Hypoxia and oxidative stress in breast cancer: Hypoxia signalling pathways

    International Nuclear Information System (INIS)

    Hypoxia-inducible factor-1 (HIF), which is centrally involved in physiological oxygen homeostasis, is also activated in the majority of tumours. Activation of HIF can occur through genetic mechanisms or as a result of hypoxia within the tumour microenvironment. In some cases HIF activation appears to be intimately linked to the proliferative stimulus itself. HIF affects patterns of gene expression and tumour growth, although precise effects vary between tumour types. Modulation of HIF activity, if correctly applied, may be therapeutically beneficial in tumour therapy

  4. Bifurcations and intermittent magnetic activity

    International Nuclear Information System (INIS)

    The sequence of equilibria of two-dimensional reduced magnetohydrodynamics has been studied as a function of the tearing mode stability parameter Δ'. After a symmetry-breaking bifurcation occurring at Δ' ∼ 0, which originates a state with a small magnetic island, the system undergoes a second bifurcation, of tangent type, at Δ' ∼ 1. Above this value, no stationary solutions with small islands exist. The system rapidly develops an island of macroscopic size. This general property is proposed as a basic ingredient of the intermittent events observed in magnetically confined plasmas. (author)

  5. Bifurcations and intermittent magnetic activity

    Energy Technology Data Exchange (ETDEWEB)

    Tebaldi, C.; Ottaviani, M.; Porcelli, F. [Commission of the European Communities, Abingdon (United Kingdom). JET Joint Undertaking

    1996-04-01

    The sequence of equilibria of two-dimensional reduced magnetohydrodynamics has been studied as a function of the tearing mode stability parameter {Delta}`. After a symmetry-breaking bifurcation occurring at {Delta}` {approx} 0, which originates a state with a small magnetic island, the system undergoes a second bifurcation, of tangent type, at {Delta}` {approx} 1. Above this value, no stationary solutions with small islands exist. The system rapidly develops an island of macroscopic size. This general property is proposed as a basic ingredient of the intermittent events observed in magnetically confined plasmas. (author).

  6. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis

    OpenAIRE

    Greijer, A.E.; Wall

    2004-01-01

    Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory proteins are delicately balanced. In solid tumours, hypoxia is a common phenomenon. Cells adapt to this environmental stress, so that after repeated periods of hypoxia, selection for resistance to hypoxi...

  7. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis

    OpenAIRE

    2004-01-01

    Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory proteins are delicately balanced. In solid tumours, hypoxia is a common phenomenon. Cells adapt to this environmental stress, so that after repeated periods of hypoxia, selection for resistance to hypoxi...

  8. 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

  9. Effects of a 12-day maximal shuttle-run shock microcycle in hypoxia on soccer specific performance and oxidative stress.

    Science.gov (United States)

    Gatterer, Hannes; Klarod, Kultida; Heinrich, Dieter; Schlemmer, Philipp; Dilitz, Stefan; Burtscher, Martin

    2015-08-01

    The purpose of this study was to investigate the effect of a maximal shuttle-run shock microcycle in hypoxia on repeated sprint ability (RSA, 6 × 40-m (6 × 20 m back and forth, 20" rest in between)), Yo-Yo-intermittent-recovery (YYIR) test performance, and redox-status. Fourteen soccer players (age: 23.9 ± 2.1 years), randomly assigned to hypoxia (∼ 3300 m) or normoxia training, performed 8 maximal shuttle-run training sessions within 12 days. YYIR test performance and RSA fatigue-slope improved independently of the hypoxia stimulus (p < 0.05). Training reduced the oxidative stress level (-7.9%, p < 0.05), and the reduction was associated with performance improvements (r = 0.761, ΔRSA; r = -0.575, ΔYYIR, p < 0.05). PMID:26212372

  10. 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

  11. Approximate Simulation of Acute Hypobaric Hypoxia with Normobaric Hypoxia

    Science.gov (United States)

    Conkin, J.; Wessel, J. H., III

    2011-01-01

    INTRODUCTION. Some manufacturers of reduced oxygen (O2) breathing devices claim a comparable hypobaric hypoxia (HH) training experience by providing F(sub I) O2 hypoxia (NH) as for HH exposures the devices ignore P(sub A)O2 and P(sub A)CO2 as more direct agents to induce signs and symptoms of hypoxia during acute training exposures. RESULTS. There is not a sufficient integrated physiological understanding of the determinants of P(sub A)O2 and P(sub A)CO2 under acute NH and HH given the same hypoxic pO2 to claim a device that provides isohypoxia. Isohypoxia is defined as the same distribution of hypoxia signs and symptoms under any circumstances of equivalent hypoxic dose, and hypoxic pO2 is an incomplete hypoxic dose. Some devices that claim an equivalent HH experience under NH conditions significantly overestimate the HH condition, especially when simulating altitudes above 10,000 feet (3,048 m). CONCLUSIONS. At best, the claim should be that the devices provide an approximate HH experience since they only duplicate the ambient pO2 at sea level as at altitude (iso-pO2 machines). An approach to reduce the overestimation is to at least provide machines that create the same P(sub I)O2 (iso-P(sub I)O2 machines) conditions at sea level as at the target altitude, a simple software upgrade.

  12. 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

  13. Improved Intermittency Analysis of Individual Events

    OpenAIRE

    Janik, R. A.; Ziaja, B.

    1998-01-01

    Recent progress on the event-by-event analysis of intermittent data by R. A. Janik and myself is reported. 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.}

  14. 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 ...

  15. Autonomic neuropathy in acute intermittent porphyria.

    OpenAIRE

    Laiwah, A C; Macphee, G. J.; P Boyle; Moore, M R; Goldberg, A

    1985-01-01

    Autonomic function was assessed in subjects with acute intermittent porphyria and age- and sex-matched controls using five different bedside tests of cardiovascular reflexes. During the acute attack both parasympathetic and sympathetic tests were impaired, but subsequently improved during remission. Early parasympathetic dysfunction was also detected during remission and in latent asymptomatic acute intermittent porphyria.

  16. 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.

  17. Preeclampsia, Hypoxia, Thrombosis, and Inflammation

    OpenAIRE

    Shamshirsaz, Amir A.; Michael Paidas; Graciela Krikun

    2011-01-01

    Reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes. In this review, we detail these effects and their relationship to preeclampsia (PE) and intrauterine growth restriction (IUGR).

  18. Experimental hypoxia and embryonic angiogenesis

    Czech Academy of Sciences Publication Activity Database

    Nanka, O.; Valášek, P.; Dvořáková, Marta; Grim, M.

    2006-01-01

    Roč. 235, č. 3 (2006), s. 723-733. ISSN 1058-8388 Institutional research plan: CEZ:AV0Z50520514 Keywords : Experimental hypoxia * Embryonic angiogenesis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.169, year: 2006

  19. 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). PMID:22106819

  20. 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. PMID:26915308

  1. 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.

  2. Moderate Hypoxia Exposure: A Novel Strategy to Improve Glucose Metabolism in Humans?

    Directory of Open Access Journals (Sweden)

    Max Vogel

    2015-11-01

    Full Text Available The obesity epidemic calls for novel strategies to prevent and treat obesity and its comorbidities. Several studies have indicated that the amount of oxygen to which tissues are exposed may substantially impact cardiometabolic health. Interestingly, living at high altitude (hypobaric hypoxia seems to be associated with improved glucose homeostasis and a decreased prevalence of Type 2 diabetes. Furthermore, normobaric hypoxia exposure has been shown to exert beneficial effects on glucose homeostasis and insulin sensitivity in rodents and humans. This may, at least in part, be explained by altered adipose tissue and skeletal muscle oxygen tension. In contrast, patients with obstructive sleep apnoea syndrome, which is characterised by episodes of severe intermittent hypoxia due to periodic collapse of the upper airway during sleep, show impairments in glucose homeostasis and are at increased cardiovascular risk. These discrepancies may be explained by the severity, duration, and pattern (number of cycles of hypoxic episodes, but underlying mechanisms have not yet been studied in detail. The purpose of this review is to provide an overview of available studies on the link between oxygen tension, inflammation, and glucose homeostasis. Detailed studies to elucidate the effects of moderate hypoxia exposure on wholebody and tissue-specific insulin sensitivity in humans are clearly warranted.

  3. Intermittent dystonia in Hartnup disease.

    Science.gov (United States)

    Darras, B T; Ampola, M G; Dietz, W H; Gilmore, H E

    1989-01-01

    A 6-month-old girl developed intermittent dystonic posture of the legs and eczematous dermatitis without ataxia. Qualitative and quantitative urine amino acid testing confirmed the diagnosis of Hartnup disease. Cranial computed tomography, electroencephalogram, electromyogram/nerve conduction study, posterior tibial somatosensory evoked potentials, 24-hour electroencephalographic telemetry, and metrizamide myelogram were normal. Spinal fluid hydroxy-indoleacetic acid concentration was less than or equal to 2 S.D. of normal; oral tryptophan loading (70 mg/kg) resulted in a two-fold rise in cerebrospinal fluid 5-hydroxy-indoleacetic acid concentration. Tryptophan administered alone or with nicotinic acid failed to improve the dystonia; however, trihexyphenidyl (1-2 mg/kg/day) dramatically improved it. Hartnup disease should be considered in children with unexplained dystonia. PMID:2712944

  4. Anisotropic Intermittency of Magnetohydrodynamic Turbulence

    CERN Document Server

    Osman, K T; Chapman, S C; Hnat, B

    2013-01-01

    A higher-order multiscale analysis of spatial anisotropy in inertial range magnetohydrodynamic turbulence is presented using measurements from the STEREO spacecraft in fast ambient solar wind. We show for the first time that, when measuring parallel to the local magnetic field direction, the full statistical signature of the magnetic and Els\\"asser field fluctuations is that of a non-Gaussian globally scale-invariant process. This is distinct from the classic multi-exponent statistics observed when the local magnetic field is perpendicular to the flow direction. These observations are interpreted as evidence for the weakness, or absence, of a parallel magnetofluid turbulence energy cascade. As such, these results present strong observational constraints on the statistical nature of intermittency in turbulent plasmas.

  5. Optical diagnostics of intermittent flows

    DEFF Research Database (Denmark)

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

    2007-01-01

    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......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...... 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...

  6. Analytical approach to continuous and intermittent bottleneck flows

    DEFF Research Database (Denmark)

    Helbing, D.; Johansson, A.; Mathiesen, Joachim Kaj; Jensen, M.H.; Hansen, A.

    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...

  7. Guanfacine ameliorates hypobaric hypoxia induced spatial working memory deficits.

    Science.gov (United States)

    Kauser, H; Sahu, S; Kumar, S; Panjwani, U

    2014-01-17

    Hypobaric hypoxia (HH) observed at high altitude causes mild cognitive impairment specifically affecting attention and working memory. Adrenergic dysregulation and neuronal damage in prefrontal cortex (PFC) has been implicated in hypoxia induced memory deficits. Optimal stimulation of alpha 2A adrenergic receptor in PFC facilitates the spatial working memory (SWM) under the conditions of adrenergic dysregulation. Therefore the present study was designed to test the efficacy of alpha 2A adrenergic agonist, Guanfacine (GFC), to restore HH induced SWM deficits and PFC neuronal damage. The rats were exposed to chronic HH equivalent to 25,000ft for 7days in an animal decompression chamber and received daily treatment of GFC at a dose of 1mg/kg body weight via the intramuscular route during the period of exposure. The cognitive performance was assessed by Delayed Alternation Task (DAT) using T-Maze and PFC neuronal damage was studied by apoptotic and neurodegenerative markers. Percentage of correct choice decreased significantly while perseverative errors showed a significant increase after 7days HH exposure, GFC significantly ameliorated the SWM deficits and perseveration. There was a marked and significant increase in chromatin condensation, DNA fragmentation, neuronal pyknosis and fluoro Jade positive cells in layer II of the medial PFC in hypoxia exposed group, administration of GFC significantly reduced the magnitude of these changes. Modulation of adrenergic mechanisms by GFC may serve as an effective countermeasure in amelioration of prefrontal deficits and neurodegenerative changes during HH. PMID:24184415

  8. Vascular abnormalities associated with acute hypoxia in human melanoma xenografts

    International Nuclear Information System (INIS)

    Background and purpose: The fraction of hypoxic cells has been shown to differ substantially among human tumors of the same histological type. In this study, a window chamber model was used to identify possible mechanisms leading to the development of highly different hypoxic fractions in A-07 and R-18 human melanoma xenografts. Materials and methods: Chronic and acute hypoxia was assessed in intradermal tumors using an immunohistochemical and a radiobiological assay. Functional and morphological parameters of the vascular networks of tumors growing in dorsal window chambers were assessed with intravital microscopy. Results: R-18 tumors showed significantly higher hypoxic fractions than A-07 tumors, and the difference was mostly due to acute hypoxia. Compared to A-07 tumors, R-18 tumors showed low vascular densities, low vessel diameters, long vessel segments, low blood flow velocities, frequent fluctuations in blood flow, and a high fraction of narrow vessels with absent or very low and varying flux of red blood cells. Conclusion: The high fraction of acute hypoxia in R-18 tumors was a consequence of frequent fluctuations in blood flow and red blood cell flux combined with low vascular density. The fluctuations were most likely caused by high geometric resistance to blood flow in the tumor microvasculature.

  9. CYP2E1 Potentiates Ethanol-induction of Hypoxia and HIF-1α in vivo

    OpenAIRE

    Wang, Xiaodong; Wu, Defeng; Yang, Lili; Gan, Lixia; Cederbaum, Arthur I.

    2013-01-01

    Ethanol induces hypoxia and elevates HIF-1α in the liver. CYP2E1 plays a role in the mechanisms by which ethanol generates oxidative stress, fatty liver and liver injury. The current study evaluated whether CYP2E1 contributes to ethanol-induced hypoxia and activation of HIF-1α in vivo and whether HIF-1α protects against or promotes CYP2E1-dependent toxicity in vitro. Wild type (WT), CYP2E1-knockin (KI) and CYP2E1 knockout (KO) mice were fed ethanol chronically; pair fed controls received isoc...

  10. 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.

  11. Assessing Relative Volatility/Intermittency/Energy Dissipation

    DEFF Research Database (Denmark)

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

    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......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...... processes and Ito semimartingales and discuss how it can be used for inference on relative volatility/intermittency....

  12. Fluctuations and intermittency in fragment size distributions

    International Nuclear Information System (INIS)

    The intermittency signal on the size frequency of fragments found in various fragmenting systems is reconsidered. This signal extracted from a factorial moment analysis was interpreted as a genuine intermittency. The conclusion is that the signal found in earlier works and interpreted as an intermittency behaviour results from both the power law of the mean size fragment distribution and from the finite width of the multiplicity distribution. Any partition of integers exhibiting these two features will provide a similar signal. (author). 38 refs., 9 figs

  13. Hypobaric Hypoxia Induces Depression-like Behavior in Female Sprague-Dawley Rats, but not in Males

    OpenAIRE

    Kanekar, Shami; Bogdanova, Olena V.; Olson, Paul R.; Sung, Young-Hoon; D'Anci, Kristen E.; Renshaw, Perry F.

    2015-01-01

    Kanekar, Shami, Olena V. Bogdanova, Paul R. Olson, Young-Hoon Sung, Kristen E. D'Anci, and Perry F. Renshaw. Hypobaric hypoxia induces depression-like behavior in female Sprague-Dawley rats, but not males. High Alt Med Biol 16:52–60, 2015—Rates of depression and suicide are higher in people living at altitude, and in those with chronic hypoxic disorders like asthma, chronic obstructive pulmonary disorder (COPD), and smoking. Living at altitude exposes people to hypobaric hypoxia, which can lo...

  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 and......(Evans') and PV(CO) increased from 1.04 (0.99-1.09) at sea level to 1.15 (1.06-1.24) at high altitude (P <0.05). In conclusion, the two methods were not interchangeable as measures of hypoxia-induced changes in PV. The mechanism responsible for the bias remains unknown, but it is suggested that the results may...

  15. The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

    OpenAIRE

    Walsh, Joseph C.; Lebedev, Artem; Aten, Edward; Madsen, Kathleen; Marciano, Liane; Kolb, Hartmuth C.

    2014-01-01

    Tumor hypoxia is a well-established biological phenomenon that affects the curability of solid tumors, regardless of treatment modality. Especially for head and neck cancer patients, tumor hypoxia is linked to poor patient outcomes. Given the biological problems associated with tumor hypoxia, the goal for clinicians has been to identify moderately to severely hypoxic tumors for differential treatment strategies. The “gold standard” for detecting and characterizing of tumor hypoxia are the inv...

  16. Detecting and responding to hypoxia

    OpenAIRE

    Zhu, Hao; Jackson, Tim; Bunn, H. Franklin

    2002-01-01

    Adaptation to hypoxia is a topic of considerable clinical relevance, as it influences the pathophysiology of anaemia, polycythaemia, tissue ischaemia and cancer. A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. These include genes encoding erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase. Studies on the regulation of the erythropoietin gene have provided insights into the common mechanism of oxy...

  17. Obstructive Sleep Apnoea, Intermittent Hypoxia and Respiratory Muscle Structure and Function

    OpenAIRE

    Bradford, Aidan; O'Halloran, Ken D.

    2013-01-01

    Obstructive sleep apnoea is a common condition associated with significant morbidity and increased mortality. During sleep, the sub atmospheric pressure developed in the extra thoracic airway by the contraction of the thoracic pump muscles during inspiration causes collapse of the compliant upper airway, resulting in an episode of apnoea. Normally, upper airway collapse is prevented by contraction of upper airway muscles and if the airway does collapse, it is re-opened by a reflex augmented n...

  18. PPARα Protein Expression Was Increased by Four Weeks of Intermittent Hypoxic Training via AMPKα2-Dependent Manner in Mouse Skeletal Muscle.

    Directory of Open Access Journals (Sweden)

    Ge Li

    Full Text Available Peroxisome proliferator-activated receptor α (PPARα is critical for muscle endurance due to its role in the regulation of fatty acid oxidation. The 5'-AMP-activated protein kinase (AMPK is an energy sensor in cells, but its role in PPARα regulation in vivo remains unknown. In this study, we examined PPARα expression in the skeletal muscle of AMPKα2 overexpression (OE, knockout (KO and wild-type (WT mice after four weeks of exercise under intermittent hypoxia. WT, OE and KO mice were used at 40 mice/strain and randomly subdivided into four subgroups: control (C, running (R, hypoxia (H, and running plus hypoxia (R+H at 10 mice/group. The treadmill running was performed at the speed of 12 m/min, 60 min/day with a slope of 0 degree for four weeks. The hypoxia treatment was performed in daytime with normobaric hypoxia (11.20% oxygen, 8 hours/day. In the R+H group, the treadmill running was conducted in the hypoxic condition. AMPKα2, phosphor-AMPKα (p-AMPKα (Thr172, nuclear PPARα proteins were measured by Western blot and the medium chain acyl coenzyme A dehydrogenase (MCAD mRNA, the key enzyme for fatty acid oxidation and one of the PPARα target genes, was also measured in skeletal muscles after the interventions. The results showed that nuclear PPARα protein was significantly increased by R+H in WT muscles, the increase was enhanced by 41% (p<0.01 in OE mice, but was reduced by 33% (p<0.01 in KO mice. The MCAD mRNA expression was increased after four weeks of R+H intervention. The change in MCAD mRNA followed a similar trend as that of PPARα protein in OE and KO mice. Our data suggest that the increase in nuclear PPARα protein by four-week exercise training under the intermittent hypoxia was dependent on AMPK activation.

  19. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis

    NARCIS (Netherlands)

    Greijer, A.E.; Wall, E. van der

    2004-01-01

    Apoptosis can be induced in response to hypoxia. The severity of hypoxia determines whether cells become apoptotic or adapt to hypoxia and survive. A hypoxic environment devoid of nutrients prevents the cell undergoing energy dependent apoptosis and cells become necrotic. Apoptosis regulatory protei

  20. Intermittent sea-level acceleration

    Science.gov (United States)

    Olivieri, M.; Spada, G.

    2013-10-01

    Using instrumental observations from the Permanent Service for Mean Sea Level (PSMSL), we provide a new assessment of the global sea-level acceleration for the last ~ 2 centuries (1820-2010). Our results, obtained by a stack of tide gauge time series, confirm the existence of a global sea-level acceleration (GSLA) and, coherently with independent assessments so far, they point to a value close to 0.01 mm/yr2. However, differently from previous studies, we discuss how change points or abrupt inflections in individual sea-level time series have contributed to the GSLA. Our analysis, based on methods borrowed from econometrics, suggests the existence of two distinct driving mechanisms for the GSLA, both involving a minority of tide gauges globally. The first effectively implies a gradual increase in the rate of sea-level rise at individual tide gauges, while the second is manifest through a sequence of catastrophic variations of the sea-level trend. These occurred intermittently since the end of the 19th century and became more frequent during the last four decades.

  1. Intermittency in Human Heart Rate Variability

    International Nuclear Information System (INIS)

    Intermittency in time series of the time intervals between heart beats (RR intervals) extracted from 24 hour (portable) ECG is found for some cases of humans with arrhythmia. Laminar phases are found by sweeping a short (5 intervals) time window through the time series and calculating the standard deviation of the series in each window. 8 of the 18 arrhythmia cases studied had a bimodal distribution of the standard deviation values indicating some kind of intermittency. The distribution of lengths of the laminar phases identifies the intermittency obtained in human heart rate variability as Type 1 in the Pomeau and Manneville classification. Although the arrhythmia cases studied were medically very different - in those instances that intermittency did occur the probability distributions of laminar phase lengths were strikingly similar. (author)

  2. 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.

  3. Scalings of intermittent structures in magnetohydrodynamic turbulence

    CERN Document Server

    Zhdankin, Vladimir; Uzdensky, Dmitri A

    2016-01-01

    Turbulence is ubiquitous in plasmas, leading to rich dynamics characterized by irregularity, irreversibility, energy fluctuations across many scales, and energy transfer across many scales. Another fundamental and generic feature of turbulence, although sometimes overlooked, is the inhomogeneous dissipation of energy in space and in time. This is a consequence of intermittency, the scale-dependent inhomogeneity of dynamics caused by fluctuations in the turbulent cascade. Intermittency causes turbulent plasmas to self-organize into coherent dissipative structures, which may govern heating, diffusion, particle acceleration, and radiation emissions. In this paper, we present recent progress on understanding intermittency in incompressible magnetohydrodynamic turbulence with a strong guide field. We focus on the statistical analysis of intermittent dissipative structures, which occupy a small fraction of the volume but arguably account for the majority of energy dissipation. We show that, in our numerical simulat...

  4. Intermittent cyclophosphamide in refractory rheumatoid arthritis

    OpenAIRE

    Hørslev-Petersen, Kim; Beyer, Jannie M; Helin, Pekka

    1983-01-01

    Three patients with refractory rheumatoid arthritis were treated with oral cyclophosphamide; in two cases this was supplemented with pulse treatment with methylprednisolone. Long term remission was induced in all three patients and was sustained until follow up at least nine months after the methylprednisolone was stopped. Leucopenia occurred but resolved when cyclophosphamide was reduced from daily to intermittent dosing. Intermittent treatment with cyclophosphamide, possibly in conjunction ...

  5. Insights from Intermittent Binocular Rivalry and EEG

    OpenAIRE

    Pitts, Michael A.; Juliane eBritz

    2011-01-01

    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...

  6. Origin of intermittency in the fragmentation models

    International Nuclear Information System (INIS)

    Intermittency has been much discussed for momentum distribution of produced particles in ultrarelativistic collisions of leptons, hadrons and nuclei. More recently, scale invariant fluctuations has been found in the fragment-charge distribution following the decay of hot nuclear residuum. In this review the origin of intermittent fluctuations is discussed in cluster fragmentation models such as the percolation model and the fragmentation-inactivation binary cascading model. (author) 21 refs., 4 figs

  7. Scalings of intermittent structures in magnetohydrodynamic turbulence

    Science.gov (United States)

    Zhdankin, Vladimir; Boldyrev, Stanislav; Uzdensky, Dmitri A.

    2016-05-01

    Turbulence is ubiquitous in plasmas, leading to rich dynamics characterized by irregularity, irreversibility, energy fluctuations across many scales, and energy transfer across many scales. Another fundamental and generic feature of turbulence, although sometimes overlooked, is the inhomogeneous dissipation of energy in space and in time. This is a consequence of intermittency, the scale-dependent inhomogeneity of dynamics caused by fluctuations in the turbulent cascade. Intermittency causes turbulent plasmas to self-organize into coherent dissipative structures, which may govern heating, diffusion, particle acceleration, and radiation emissions. In this paper, we present recent progress on understanding intermittency in incompressible magnetohydrodynamic turbulence with a strong guide field. We focus on the statistical analysis of intermittent dissipative structures, which occupy a small fraction of the volume but arguably account for the majority of energy dissipation. We show that, in our numerical simulations, intermittent structures in the current density, vorticity, and Elsässer vorticities all have nearly identical statistical properties. We propose phenomenological explanations for the scalings based on general considerations of Elsässer vorticity structures. Finally, we examine the broader implications of intermittency for astrophysical systems.

  8. Effect of hypoxia on the dynamic response of hyperaemia in the contracting human calf muscle.

    Science.gov (United States)

    Donnelly, J; Green, S

    2013-01-01

    Although systemic hypoxia increases the muscle hyperaemic response during 'steady-state' exercise, its effect on the dynamic characteristics of this response is not clear. In the present study, we first established that hypoxia increases the steady-state hyperaemic response at low workloads during calf exercise. To study dynamic aspects of this response, eight subjects performed eight exercise trials while breathing a normoxic (fractional inspired O(2) = 0.2094) or hypoxic gas mixture (fractional inspired O(2) = 0.105). Subjects performed intermittent contractions (1 s) of the calf muscle at 20% maximal voluntary contraction, and the leg blood flow (LBF), leg vascular conductance (LVC) and EMG activities of the triceps surae muscles were measured during each contraction-relaxation period (3 s). The LBF and LVC responses were averaged for each subject and fitted using a four-phase, exponential growth and decay function. Hypoxia evoked significant increases in the change in LBF (15%) and LVC (23%) from the start to the end of exercise, as well as the amplitude of the rapid growth phase of LBF and LVC (21%). Similar, but non-significant, effects on the amplitude of the slow growth phase of LBF (P = 0.08) and LVC (P = 0.10) were observed. By contrast, hypoxia had no effect on temporal parameters of these growth phases, parameters defining the decay phases or EMG activities. These results suggest that the effect of hypoxia on exercise hyperaemia is targeted at the rapid and perhaps the slow growth phase of the response, and is not mediated by a change in the level of muscle activation. PMID:22689444

  9. Relationship between human respiratory reactivity and neutrophil metabolism under intermittent hypoxic influences in humans exposed to low-level radiation

    International Nuclear Information System (INIS)

    The group of 18 men exposed to radiation during amelioration work in the Chernobyl NPP was examined in the course of adaptation to intermittent hypoxia (rebreathing technique during 10 days of three dayly 5-7 min sessions with 15 min break). The starting level of ventilatory response to hypoxic stimulus (HVR) did not differ from the one in persons living in non-contaminated areas. This hypoxic training (HT) caused the increase of HVR, activity of NADPH-oxidase and cationic protein content in neutrophyls as well as various changes in mieloperoxidase activity. The correlation between respiration reactivity and deviations in neutrophil metabolism under HT was found. 14 refs., 2 figs

  10. [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. PMID:8059397

  11. Betaine reduces the expression of inflammatory adipokines caused by hypoxia in human adipocytes.

    Science.gov (United States)

    Olli, K; Lahtinen, S; Rautonen, N; Tiihonen, K

    2013-01-14

    Obesity is characterised by a state of chronic low-grade inflammation and the elevated circulating and tissue levels of inflammatory markers, including inflammation-related adipokines, released from white adipose tissue. The expression and release of these adipokines generally rises as the adipose tissue expands and hypoxic conditions start to develop within the tissue. Here, the effect of betaine, a trimethylglycine having a biological role as an osmolyte and a methyl donor, on the expression of inflammation-related markers was tested in human adipocytes under hypoxia. Differentiated adipocytes were cultivated under low (1 %) oxygen tension for 8-20 h. The expression of different adipokines, including IL-6, leptin, PPARγ, TNF-α and adiponectin, was measured by quantitative PCR by determining the relative mRNA level from the adipocytes. Hypoxia, in general, led to a decrease in the expression of PPARγ mRNA in human adipocytes, whereas the expression levels of leptin and IL-6 mRNA were substantially increased by hypoxia. The cultivation of adipocytes under hypoxia also led to a reduction in the expression of TNF-α mRNA. The results showed that hypoxia increased the relative quantification of leptin gene transcription, and that betaine (250 μmol/l) reduced this effect, caused by low oxygen conditions. Under hypoxia, betaine also reduced the mRNA level of the pro-inflammatory markers IL-6 and TNF-α. These results demonstrate that the extensive changes in the expression of inflammation-related adipokines in human adipocytes caused by hypoxia can be diminished by the presence of physiologically relevant concentrations of betaine. PMID:22424556

  12. VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

    International Nuclear Information System (INIS)

    Research highlights: → Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. → CoCl2-induced VEGF secretion in mast cells occurs by a Ca2+-insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. → Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits FcεRI-dependent anaphylactic degranulation in mast cells. → 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 (CoCl2) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl2 promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl2-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 CoCl2-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl2 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-dependent Fyn kinase activation.

  13. 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

  14. Assessment of intermittent trace element pollution by moss bags

    International Nuclear Information System (INIS)

    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

  15. 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.

  16. Changes in the fraction of total hypoxia and hypoxia subtypes in human squamous cell carcinomas upon fractionated irradiation: Evaluation using pattern recognition in microcirculatory supply units

    International Nuclear Information System (INIS)

    Background and purpose: Evaluate changes in total hypoxia and hypoxia subtypes in vital tumor tissue of human head and neck squamous cell carcinomas (hHNSCC) upon fractionated irradiation. Materials and methods: Xenograft tumors were generated from 5 hHNSCC cell lines (UT-SCC-15, FaDu, SAS, UT-SCC-5 and UT-SCC-14). Hypoxia subtypes were quantified in cryosections based on (immuno-)fluorescent marker distribution patterns of Hoechst 33342 (perfusion), pimonidazole (hypoxia) and CD31 (endothelium) in microcirculatory supply units (MCSUs). Tumors were irradiated with 5 or 10 fractions of 2 Gy, 5×/week. Results: Upon irradiation with 10 fractions, the overall fraction of hypoxic MCSUs decreased in UT-SCC-15, FaDu and SAS, remained the same in UT-SCC-5 and increased in UT-SCC-14. Decreases were observed in the proportion of chronically hypoxic MCSUs in UT-SCC-15, in the fraction of acutely hypoxic MCSUs in UT-SCC-15 and SAS, and in the percentage of hypoxemically hypoxic MCSUs in SAS tumors. After irradiation with 5 fractions, there were no significant changes in hypoxia subtypes. Changes in the overall fraction of hypoxic MCSUs were comparable to corresponding alterations in the proportions of acutely hypoxic MCSUs. There was no correlation between radiation resistance (TCD50) and any of the investigated hypoxic fractions upon fractionated irradiation. Conclusions: This study shows that there are large alterations in the fractions of hypoxia subtypes upon irradiation that can differ from changes in the overall fraction of hypoxic MCSUs.

  17. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

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

    Science.gov (United States)

    Newby, Elizabeth A; Myers, Dean A; Ducsay, Charles A

    2015-09-01

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

  19. 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.

  20. [Exercise training in hypoxia prevents hypoxia induced mitochondrial DNA oxidative damage in skeletal muscle].

    Science.gov (United States)

    Bo, Hai; Li, Ling; Duan, Fu-Qiang; Zhu, Jiang

    2014-10-25

    This study was undertaken to investigate the effect of exercise training on mitochondrial DNA (mtDNA) oxidative damage and 8-oxoguanine DNA glycosylase-1 (OGG1) expression in skeletal muscle of rats under continuous exposure to hypoxia. Male Sprague-Dawley rats were randomly divided into 4 groups (n = 8): normoxia control group (NC), normoxia training group (NT), hypoxia control group (HC), and hypoxia training group (HT). The hypoxia-treated animals were housed in normobaric hypoxic tent containing 11.3% oxygen for consecutive 4 weeks. The exercise-trained animals were exercised on a motor-driven rodent treadmill at a speed of 15 m/min, 5% grade for 60 min/day, 5 days per week for 4 weeks. The results showed that, compared with NC group, hypoxia attenuated complex I, II, IV and ATP synthase activities of the electron transport chain, and the level of mitochondrial membrane potential in HC group (P hypoxia decreased mitochondrial OGG1, MnSOD, and GPx activities (P hypoxia attenuated muscle and mitochondrial [NAD⁺]/ [NADH] ratio, and SIRT3 protein expression (P exercise training in hypoxia elevated complex I, II, IV and ATP synthase activities, and the level of mitochondrial membrane potential in HT group (P exercise training in hypoxia increased MnSOD and GPx activities and mitochondrial OGG1 level (P exercise training in hypoxia increased muscle and mitochondrial [NAD⁺]/[NADH] ratio, as well as SIRT3 protein expression (P exercise training in hypoxia can decrease hypoxia-induced mtDNA oxidative damage in the skeletal muscle through up-regulating exercise-induced mitochondrial OGG1 and antioxidant enzymes. Exercise training in hypoxia may improve hypoxia tolerance in skeletal muscle mitochondria via elevating [NAD⁺]/[NADH] ratio and SIRT3 expression. PMID:25332006

  1. Targeting hypoxia in head and neck cancer

    International Nuclear Information System (INIS)

    The idea of 'targeting' hypoxia stems from recognition of the fact that oxygen (or its lack) is central to the practice of radiation oncology. Targeting embraces the alternative goals of trying to overcome hypoxia on the one hand and trying to exploit it on the other. This presentation briefly reviews these two approaches with major emphasis on the latter

  2. Impact of Ramadan Intermittent Fasting on Oxidative Stress Measured by Urinary 15--Isoprostane

    OpenAIRE

    Mo'ez Al-Islam Ezzat Faris; Rand Nidal Hussein; Ref'at Ahmad Al-Kurd; Mohammed Ahmed Al-Fararjeh; Yasser Khalil Bustanji; Mohammad Khalil Mohammad

    2012-01-01

    Fasting and caloric restriction have been associated with reduced incidence of chronic diseases and cancers. These effects have been attributed to reduced oxidative stress. Since Ramadan intermittent fasting (RIF) has been associated with reduced caloric intake, it was hypothesized that RIF would alleviate oxidative stress in healthy volunteers. The study was designed to elucidate the impact of RIF on oxidative stress measured by 15-F2t-Isoprostane (15FIP). Fifty healthy subjects (23 men and ...

  3. Advances of Hypoxia and Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xuebing LI

    2013-04-01

    Full Text Available Lung cancer is one of the malignant tumors with fastest growing rates in incidence and mortality in our country, also with largest threat to human health and life. However, the exact mechanisms underlying lung cancer development remain unclear. The microenvironment of tumor hypoxia was discovered in 1955, but hypoxia in lung cancer tissues had not been successfully detected till 2006. Further studies show that hypoxia not only functions through the resistance to radiotherapy, but also regulates lung cancer development, invasion, metastasis, chemotherapy resistance and prognosis through an important oncogene HIF (hypoxia inducible factor, with its regulators PHD (prolyl hydroxylase domain and pVHL (product of von Hippel-Lindau gene. Therefore, hypoxia, HIF, PHD and pVHL should be considered as potential therapeutic targets for lung cancer pathogenesis and progression.

  4. Functional alterations in macrophages after hypoxia selection.

    Science.gov (United States)

    Degrossoli, Adriana; Giorgio, Selma

    2007-01-01

    Regions of low oxygen tension are common features of inflamed and infected tissues and provide physiologic selective pressure for the expansion of cells with enhanced hypoxia tolerance. The aim of this study was to investigate whether macrophages resistant to death induced by hypoxia were accompanied by functional alterations. A mouse macrophage cell line (J774 cells) was used to obtain subpopulations of death-resistant macrophages induced by long-term exposure to severe hypoxia (J774 macrophages to periods of severe hypoxia results in the selection of cells with phenotypes associated with the modulation of heat-shock protein 70 kDa (HSP70) expression, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production and reduced susceptibility to parasite Leishmania infection. Thus, we suggest that hypoxia-selected macrophages may influence the outcome of inflammation and infection. PMID:17202589

  5. pO2 Fluctuation Pattern and Cycling Hypoxia in Human Cervical Carcinoma and Melanoma Xenografts

    International Nuclear Information System (INIS)

    Purpose: Blood perfusion in tumors is spatially and temporally heterogeneous, resulting in local fluctuations in tissue oxygen tension (pO2) and tissue regions showing cycling hypoxia. In this study, we investigated whether the pO2 fluctuation pattern and the extent of cycling hypoxia differ between tumor types showing high (e.g., cervical carcinoma xenograft) and low (e.g., melanoma xenograft) fractions of connective tissue-associated blood vessels. Methods and Materials: Two cervical carcinoma lines (CK-160 and TS-415) and two melanoma lines (A-07 and R-18) transplanted into BALB/c nu/nu mice were included in the study. Tissue pO2 was measured simultaneously in two positions in each tumor by using a two-channel OxyLite fiber-optic oxygen-sensing device. The extent of acute and chronic hypoxia was assessed by combining a radiobiological and a pimonidazole-based immunohistochemical assay of tumor hypoxia. Results: The proportion of tumor regions showing pO2 fluctuations, the pO2 fluctuation frequency in these regions, and the relative amplitude of the pO2 fluctuations were significantly higher in the melanoma xenografts than in the cervical carcinoma xenografts. Cervical carcinoma and melanoma xenografts did not differ significantly in the fraction of acutely hypoxic cells or the fraction of chronically hypoxic cells. However, the ratio between fraction of acutely hypoxic cells and fraction of chronically hypoxic cells was significantly higher in melanoma than in cervical carcinoma xenografts. Conclusions: Temporal heterogeneity in blood flow and tissue pO2 in tumors may depend on tumor histology. Connective tissue surrounding microvessels may stabilize blood flow and pO2 and, thus, protect tumor tissue from cycling hypoxia.

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

    Science.gov (United States)

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

    2014-04-01

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

  7. Adipose Tissue-specific Inhibition of Hypoxia-inducible Factor 1α Induces Obesity and Glucose Intolerance by Impeding Energy Expenditure in Mice*

    OpenAIRE

    Zhang, Xinmei; Lam, Karen S.L.; Ye, Hongying; Chung, Sookja K.; Zhou, Mingyan; Wang, Yu; Xu, Aimin

    2010-01-01

    Hypoxia in adipose tissue has been postulated as a possible contributor to obesity-related chronic inflammation, insulin resistance, and metabolic dysfunction. HIF1α (hypoxia-inducible factor 1α), a master signal mediator of hypoxia response, is elevated in obese adipose tissue. However, the role of HIF1α in obesity-related pathologies remains to be determined. Here we show that transgenic mice with adipose tissue-selective expression of a dominant negative version of HIF1α developed more sev...

  8. 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.

  9. No effect of dietary nitrate supplementation on endurance training in hypoxia.

    Science.gov (United States)

    Puype, J; Ramaekers, M; Van Thienen, R; Deldicque, L; Hespel, P

    2015-04-01

    We investigated whether dietary nitrate (NO(3)(-)) supplementation enhances the effect of training in hypoxia on endurance performance at sea level. Twenty-two healthy male volunteers performed high-intensity endurance training on a cycle ergometer (6 weeks, 5×30 min/week at 4-6 mmol/L blood lactate) in normobaric hypoxia (12.5% FiO(2)), while ingesting either beetroot juice [0.07 mmol NO(3)(-) /kg body weight (bw)/day; BR, n = 11] or a control drink (CON, n = 11). During the pretest and the posttest, the subjects performed a 30-min simulated time trial (TT) and an incremental VO(2max) test. Furthermore, a biopsy was taken from m. vastus lateralis before and after the TT. Power output during the training sessions in both groups increased by ∼6% from week 1 to week 6 (P hypoxia inducible factor-1α mRNA content, and glycogen breakdown during the TT were similar between the groups in both the pretest and the posttest. In conclusion, low-dose dietary NO(3)(-) supplementation does not enhance the effects of intermittent hypoxic training on endurance exercise performance at sea level. PMID:24646076

  10. Differential effect of metabolic alkalosis and hypoxia on high-intensity cycling performance.

    Science.gov (United States)

    Flinn, Samantha; Herbert, Kathryn; Graham, Kenneth; Siegler, Jason C

    2014-10-01

    The purpose of this study was to investigate the effects of sodium bicarbonate (NaHCO3) ingestion and acute hypoxic exposure on repeated bouts of high-intensity cycling to task failure. Twelve subjects completed 4 separate intermittent cycling bouts cycling bouts to task failure (120% peak power output for 30-second interspersed with 30-second active recovery) under the following conditions: normoxia (FIO2% at 20.93%) alkalosis (NA), normoxia placebo (NP), hypoxia (FIO2% at 14.7%) alkalosis (HA), and hypoxia placebo (HP). For the NA and HA trials, the buffer solution (0.3 g·kg of NaHCO3) was dispensed into gelatin capsules and consumed over 90 minutes with 1 L of water. Whole-blood acid-base findings demonstrated metabolic alkalosis in both NA and HA before exercise (HCO3: 32.8 ± 1.8 mmol·L). Time to task failure was significantly impaired in the hypoxic conditions (NA: 199.1 ± 62.3 seconds, NP: 183.8 ± 45.0 seconds, HA: 127.8 ± 27.9 seconds, HP: 133.3 ± 28.7 seconds; p hypoxia and NaHCO3 concurrently to improve performance under these conditions does not seem warranted. PMID:24983849

  11. Ecosystem impacts of hypoxia: thresholds of hypoxia and pathways to recovery

    International Nuclear Information System (INIS)

    Coastal hypoxia is increasing in the global coastal zone, where it is recognized as a major threat to biota. Managerial efforts to prevent hypoxia and achieve recovery of ecosystems already affected by hypoxia are largely based on nutrient reduction plans. However, these managerial efforts need to be informed by predictions on the thresholds of hypoxia (i.e. the oxygen levels required to conserve biodiversity) as well as the timescales for the recovery of ecosystems already affected by hypoxia. The thresholds for hypoxia in coastal ecosystems are higher than previously thought and are not static, but regulated by local and global processes, being particularly sensitive to warming. The examination of recovery processes in a number of coastal areas managed for reducing nutrient inputs and, thus, hypoxia (Northern Adriatic; Black Sea; Baltic Sea; Delaware Bay; and Danish Coastal Areas) reveals that recovery timescales following the return to normal oxygen conditions are much longer than those of loss following the onset of hypoxia, and typically involve decadal timescales. The extended lag time for ecosystem recovery from hypoxia results in non-linear pathways of recovery due to hysteresis and the shift in baselines, affecting the oxygen thresholds for hypoxia through time.

  12. Intermittent hypoendorphinaemia in migraine attack.

    Science.gov (United States)

    Baldi, E; Salmon, S; Anselmi, B; Spillantini, M G; Cappelli, G; Brocchi, A; Sicuteri, F

    1982-06-01

    Beta-endorphin (RIA method, previous chromatographic extraction) was evaluated in plasma of migraine sufferers in free periods and during attacks. Decreased levels of the endogenous opioid peptide were found in plasma sampled during the attacks but not in free periods. Even chronic headache sufferers exhibited significantly lowered levels of beta-endorphin, when compared with control subjects with a negative personal and family history of head pains. The mechanism of the hypoendorphinaemia is unknown: lowered levels of the neuropeptide, which controls nociception, vegetative functions and hedonia, could be important in a syndrome such as migraine, characterized by pain, dysautonomia and anhedonia. The impairment of monoaminergic synapses ("empty neuron" condition) constantly present in sufferers from serious headaches, could be due to the fact that opioid neuropeptides, because of a receptoral or metabolic impairment, poorly modulate the respective monoaminergic neurons, resulting in imbalance of synaptic neurotransmission. PMID:6290072

  13. Dynamics of desynchronized episodes in intermittent synchronization

    Directory of Open Access Journals (Sweden)

    Leonid L Rubchinsky

    2014-06-01

    Full Text Available Intermittent synchronization is observed in a variety of different experimental settings in physics and beyond and is an established research topic in nonlinear dynamics. When coupled oscillators exhibit relatively weak, intermittent synchrony, the trajectory in the phase space spends a substantial fraction of time away from a vicinity of a synchronized state. Thus to describe and understand the observed dynamics one may consider both synchronized episodes and desynchronized episodes (the episodes when oscillators are not synchronous. This mini-review discusses recent developments in this area. We explain how one can consider variation in synchrony on the very short time-scales, provided that there is some degree of overall synchrony. We show how to implement this approach in the case of intermittent phase locking, review several recent examples of the application of these ideas to experimental data and modeling systems, and discuss when and why these methods may be useful.

  14. Assessing relative volatility/intermittency/energy dissipation

    DEFF Research Database (Denmark)

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

    2014-01-01

    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.......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...

  15. 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.

  16. The breathing pattern and the ventilatory response to aquatic and aerial hypoxia and hypercarbia in the frog Pipa carvalhoi.

    Science.gov (United States)

    Fonseca, Elisa M; da Silva, Glauber S F; Fernandes, Marcelo; Giusti, Humberto; Noronha-de-Souza, Carolina R; Glass, Mogens L; Bícego, Kênia C; Gargaglioni, Luciane H

    2012-07-01

    Anuran amphibians are known to exhibit an intermittent pattern of pulmonary ventilation and to exhibit an increased ventilatory response to hypoxia and hypercarbia. However, only a few species have been studied to date. The aquatic frog Pipa carvalhoi inhabits lakes, ponds and marshes that are rich in nutrients but low in O(2). There are no studies of the respiratory pattern of this species and its ventilation during hypoxia or hypercarbia. Accordingly, the aim of the present study was to characterize the breathing pattern and the ventilatory response to aquatic and aerial hypoxia and hypercarbia in this species. With this purpose, pulmonary ventilation (V(I)) was directly measured by the pneumotachograph method during normocapnic normoxia to determine the basal respiratory pattern and during aerial and aquatic hypercarbia (5% CO(2)) and hypoxia (5% O(2)). Our data demonstrate that P. carvalhoi exhibits a periodic breathing pattern composed of single events (single breaths) of pulmonary ventilation separated by periods of apnea. The animals had an enhanced V(I) during aerial hypoxia, but not during aquatic hypoxia. This increase was strictly the result of an increase in the breathing frequency. A pronounced increase in V(I) was observed if the animals were simultaneously exposed to aerial and aquatic hypercarbia, whereas small or no ventilatory responses were observed during separately administered aerial or aquatic hypercarbia. P. carvalhoi primarily inhabits an aquatic environment. Nevertheless, it does not respond to low O(2) levels in water, although it does so in air. The observed ventilatory responses to hypercarbia may indicate that this species is similar to other anurans in possessing central chemoreceptors. PMID:22503869

  17. Intermittent versus continuous androgen deprivation therapy.

    Science.gov (United States)

    Higano, Celestia S

    2014-05-01

    Androgen deprivation therapy (ADT) has been the standard of care for metastatic prostate cancer for decades; however, the choice of continuous or intermittent administration is a matter of debate. Two large phase III trials have reported results comparing these 2 forms of ADT administration. The National Cancer Institute of Canada (NCIC) PR-7 trial studied men with an increasing prostate-specific antigen (PSA) level and no evidence of metastatic disease after definitive or salvage radiation therapy and radical prostatectomy. The Southwest Oncology Group 9346 trial studied men with newly diagnosed hormone-sensitive metastatic disease. The primary end point in both trials was overall survival with a noninferiority design. The NCIC trial showed that the overall survival in men treated with intermittent ADT was not inferior to that of men treated with continuous ADT, but the SWOG trial was inconclusive regarding noninferiority. Certain domains of quality of life were better in the intermittent arms of both trials. If using ADT in the setting of biochemical relapse, intermittent ADT should be strongly considered over continuous ADT, except perhaps in patients with Gleason score of 8 or higher. In men with metastatic disease, continuous ADT remains the standard of care, because the SWOG trial did not establish noninferiority of intermittent ADT with respect to survival. However, for those with significant side effects from ADT, establishing the risk group, as determined by PSA value after 7 months of ADT or the presence of pain at diagnosis, may help guide the choice of intermittent versus continuous ADT in men with metastatic disease. PMID:24812139

  18. Intermittent heat exposure and thirst in rats

    OpenAIRE

    Barney, Christopher C.; Kuhrt, David M.

    2016-01-01

    Abstract Adequate water intake, supporting both cardiovascular function and evaporative cooling, is a critical factor in mitigating the effects of heat waves, which are expected to increase with global warming. However, the regulation of water intake during periods of intermittent heat exposure is not well understood. In this study, the effects of access to water or no access during intermittent heat exposure were assessed using male Sprague‐Dawley rats exposed to 37.5°C for 4 h/day. After 7 ...

  19. Effects of Intermittent Pneumatic Compression on Reduction of Postoperative Lower Extremity Edema and Normalization of Foot Microcirculation Flow in Patients Undergoing Arterial Revascularization

    OpenAIRE

    Pawlaczyk, Katarzyna; Gabriel, Marcin; Urbanek, Tomasz; Dzieciuchowicz, Łukasz; Krasiński, Zbigniew; Gabriel, Zofia; Olejniczak-Nowakowska, Małgorzata; Stanisić, Michał

    2015-01-01

    Background In patients with chronic leg ischemia, the beneficial effect of arterial revascularization can be significantly decreased due to postoperative leg swelling. The aim of this study was to assess the effects of intermittent pneumatic compression (IPC) on skin flow normalization in patients undergoing revascularization procedures due to chronic leg ischemia. Material/Methods We evaluated 116 patients with chronic leg ischemia. The patients were divided into groups according to the perf...

  20. A 26-Gene Hypoxia Signature Predicts Benefit from Hypoxia-Modifying Therapy in Laryngeal Cancer but Not Bladder Cancer

    NARCIS (Netherlands)

    Eustace, A.; Mani, N.; Span, P.N.; Irlam, J.J.; Taylor, J.; Betts, G.N.; Denley, H.; Miller, C.J.; Homer, J.J.; Rojas, A.M.; Hoskin, P.J.; Buffa, F.M.; Harris, A.L.; Kaanders, J.H.A.M.; West, C.M.

    2013-01-01

    PURPOSE: Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefi

  1. Assessing temporal and spatial variability of hypoxia over the inner Louisiana-upper Texas shelf: Application of an unstructured-grid three-dimensional coupled hydrodynamic-water quality model

    Science.gov (United States)

    Justić, Dubravko; Wang, Lixia

    2014-01-01

    Patterns of temporal and spatial variability in hypoxia (Volume Coastal Ocean Model (FVCOM). The coupled model was driven by surface wind forcing, tidal forcing, offshore remote forcing, heat fluxes, oxygen exchanges at the air-sea interface, solar radiation, and freshwater and nutrient (nitrogen and phosphorus) fluxes from the Mississippi and Atchafalaya Rivers. The model simulations were carried out over a 9-month period, from January 1 to October 4, 2002, and the model skill was assessed using multiple sets of observational data that included time series of dissolved oxygen concentrations from a station within the core of the Gulf hypoxic zone (C6), dissolved oxygen measurements collected during the mid-summer shelfwide cruise, and vertical dissolved oxygen profiles through the year. The model results indicate that hypoxia originates in bottom waters on the mid-continental shelf, where isolated pockets of hypoxic water develop during early spring and later join into a larger continuous hypoxic zone. The model accurately described the seasonal cycle of hypoxia at station C6, including the episodes of intermittent hypoxia during May and June, persistent hypoxia during July and August, and dissipation of hypoxia during September. The onset of hypoxia coincided with high stability of the water column (i.e., Richardson number values>1) and the initial transition from normoxia (i.e., 6 mg O2 l-1) to hypoxia lasted about three weeks. The model results point to a significant short-term variability in the extent of hypoxic bottom waters, indicating that the size of the mid-summer hypoxic zone cannot be adequately captured by a single shelfwide cruise. The dynamics of bottom-water hypoxia is clearly influenced by the bathymetric features of the LaTex shelf, namely the presence of three shallow shoals (respiration in the lower water column, and in this manner promote redevelopment of hypoxia.

  2. Regulation of Hypoxia-Induced Cell Death in Human Tenocytes

    OpenAIRE

    Min Liang; Cornell, Hannah R.; Nasim Zargar Baboldashti; Thompson, Mark S.; Carr, Andrew J.; Hulley, Philippa A

    2012-01-01

    Degenerate shoulder tendons display evidence of hypoxia. However tendons are relatively avascular and not considered to have high oxygen requirements and the vulnerability of tendon cells to hypoxia is unclear. Cultured human tenocytes were exposed to hypoxia and the cellular response detected using QPCR, Western blotting, viability, and ELISA assays. We find that tenocytes respond to hypoxia in vitro by activating classical HIF-1 α -driven pathways. Total hypoxia caused significant tenocyte ...

  3. Oxidative Stress in Hypobaric Hypoxia and Influence on Vessel-Tone Modifying Mediators

    OpenAIRE

    Pichler Hefti, Jacqueline Renée; Sonntag, Denise; Hefti, Urs; Risch, Lorenz; Schoch, Otto D; Turk, Alexander J; Hess, Thomas; Bloch, Konrad E; Maggiorini,Marco; Merz, Tobias Michael; Weinberger, Klaus M.; Huber, Andreas R

    2013-01-01

    Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an ...

  4. Oxidative stress in hypobaric hypoxia and influence on vessel-tone modifying mediators

    OpenAIRE

    Pichler Hefti, Jacqueline; Sonntag, Denise; Hefti, Urs; Risch, Lorenz; Schoch, Otto D; Turk, Alexander J; Hess, Thomas; Bloch, Konrad E; Maggiorini,Marco; Merz, Tobias M; Weinberger, Klaus M.; Huber, Andreas R

    2013-01-01

    Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an incr...

  5. Chronic Diarrhea

    Science.gov (United States)

    ... infections that cause chronic diarrhea be prevented? Chronic Diarrhea What is chronic diarrhea? Diarrhea that lasts for more than 2-4 ... represent a life-threatening illness. What causes chronic diarrhea? Chronic diarrhea has many different causes; these causes ...

  6. Hypoxia inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

    OpenAIRE

    Fang, Hsin-Yu; Hughes, Russell; Murdoch, Craig; Coffelt, Seth; Biswas, Subhra K.; Harris, Adrian L.; Johnson, Randall S; Imityaz, Hongxia Z.; Simon, M. Celeste; Fredlund, Erik; Greten, Florian; Rius, Jordi; Lewis, Claire E.

    2009-01-01

    Ischemia exists in many diseased tissues including arthritic joints, atherosclerotic plaques and malignant tumors. Macrophages accumulate in these sites and upregulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18h. For example, they were seen to upregulate the cell surface receptors, CXCR4 and GLUT1, and th...

  7. Interstitial pressure and lung oedema in chronic hypoxia

    Czech Academy of Sciences Publication Activity Database

    Rivolta, I.; Lucchini, G.; Rocchetti, M.; Kolář, František; Palazzo, F.; Zaza, A.; Miserocchi, G.

    2011-01-01

    Roč. 37, č. 4 (2011), s. 943-949. ISSN 0903-1936 Institutional research plan: CEZ:AV0Z50110509 Keywords : capillary patency * lung morphometry * microvascular permeability * pulmonary hypertension * pulmonary interstitial pressure Subject RIV: FC - Pulmology Impact factor: 5.895, year: 2011

  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. Clean Intermittent Catheterization in the School Setting

    Science.gov (United States)

    Katrancha, Elizabeth D.

    2008-01-01

    Spina bifida (SB) is a neural tube defect that causes many physical and mental disabilities. Bowel and bladder incontinence is the disability seen most often in these students that requires the school nurse's attention. Clean intermittent catheterization (CIC) provides the student with SB a vehicle to reach a satisfactory level of continence,…

  10. UNSTEADY DISPERSION IN RANDOM INTERMITTENT FLOW

    Science.gov (United States)

    The longitudinal dispersion coefficient of a conservative tracer was calculated from flow tests in a dead-end pipe loop system. Flow conditions for these tests ranged from laminar to transitional flow, and from steady to intermittent and random. Two static mixers linked in series...

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

    International Nuclear Information System (INIS)

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Ruggieri, Ruggero, E-mail: ruggieri.ruggero@gmail.com [Department of Radiation Oncology, S. Cuore-don Calabria Hospital, Negrar (VR) (Italy); Stavreva, Nadejda [Medical Physics Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (FC) (Italy); Naccarato, Stefania [Department of Radiation Oncology, S. Cuore-don Calabria Hospital, Negrar (VR) (Italy); Stavrev, Pavel [Medical Physics Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (FC) (Italy)

    2012-08-01

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

  13. Bus Lanes with Intermittent Priority: Screening Formulae and an Evaluation

    OpenAIRE

    Eichler, Michael; Daganzo, Carlos F.

    2005-01-01

    This paper evaluates strategies for operating buses on signal-controlled arterials using special lanes that are made intermittently available to general traffic. The advantage of special bus lanes, intermittent or dedicated, is that they free buses from traffic interference; the disadvantage is that they disrupt traffic. We find that intermittent lanes, unlike dedicated ones, do not significantly reduce street capacity. Intermittence, however, increases the average traffic density at which th...

  14. The fetal brain sparing response to hypoxia: physiological mechanisms.

    Science.gov (United States)

    Giussani, Dino A

    2016-03-01

    How the fetus withstands an environment of reduced oxygenation during life in the womb has been a vibrant area of research since this field was introduced by Joseph Barcroft, a century ago. Studies spanning five decades have since used the chronically instrumented fetal sheep preparation to investigate the fetal compensatory responses to hypoxia. This defence is contingent on the fetal cardiovascular system, which in late gestation adopts strategies to decrease oxygen consumption and redistribute the cardiac output away from peripheral vascular beds and towards essential circulations, such as those perfusing the brain. The introduction of simultaneous measurement of blood flow in the fetal carotid and femoral circulations by ultrasonic transducers has permitted investigation of the dynamics of the fetal brain sparing response for the first time. Now we know that major components of fetal brain sparing during acute hypoxia are triggered exclusively by a carotid chemoreflex and that they are modified by endocrine agents and the recently discovered vascular oxidant tone. The latter is determined by the interaction between nitric oxide and reactive oxygen species. The fetal brain sparing response matures as the fetus approaches term, in association with the prepartum increase in fetal plasma cortisol, and treatment of the preterm fetus with clinically relevant doses of synthetic steroids mimics this maturation. Despite intense interest into how the fetal brain sparing response may be affected by adverse intrauterine conditions, this area of research has been comparatively scant, but it is likely to take centre stage in the near future. PMID:26496004

  15. 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.

  16. 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...

  17. 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...

  18. 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...

  19. Hypoxia and the heart of poikilotherms

    Czech Academy of Sciences Publication Activity Database

    Ošťádal, Bohuslav

    2014-01-01

    Roč. 1, č. 1 (2014), s. 28-32 Institutional support: RVO:67985823 Keywords : blood supply heart * poikilotherms * tolerance to hypoxia Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  20. 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...

  1. 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...

  2. 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...

  3. 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...

  4. 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.

  5. 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

  6. Intermittent heat exposure and thirst in rats.

    Science.gov (United States)

    Barney, Christopher C; Kuhrt, David M

    2016-04-01

    Adequate water intake, supporting both cardiovascular function and evaporative cooling, is a critical factor in mitigating the effects of heat waves, which are expected to increase with global warming. However, the regulation of water intake during periods of intermittent heat exposure is not well understood. In this study, the effects of access to water or no access during intermittent heat exposure were assessed using male Sprague-Dawley rats exposed to 37.5°C for 4 h/day. After 7 days of intermittent heat exposure, reductions in evaporative water loss were observed in all animals and reductions in water intake following heat exposure occurred as the days of heat exposure increased. Rats that were not allowed water during the 7 days of exposure had decreased rehydration levels, however, rats allowed access to water increased water intake during exposure and exhibited higher overall rehydration levels over the same time period. Peripheral administration of angiotensinII, mimicking activation of volemic thirst, or hypertonic saline solution, activating intracellular thirst, did not result in alteration of water intake in rats exposed to heat with access to water compared to control rats. In contrast, rats exposed to heat without access to water had reduced water intake after administration of hypertonic saline and increased water intake after administration of angiotensinIIcompared to control rats. These experiments demonstrate that thirst responses to intermittent heat exposure are altered by providing water during heat exposure and that intermittent heat exposure without access to water alters drinking responses to both intracellular and extracellular thirst challenges. PMID:27095836

  7. 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

  8. Editorial: an introduction and welcome to Hypoxia

    OpenAIRE

    Katschinski DM

    2013-01-01

    Dörthe M Katschinski Institute of Cardiovascular Physiology, University Medical Center Göttingen, Georg-August University Göttingen, Göttingen, GermanyHypoxia can influence many aspects of physiology and pathophysiology, including high altitude, embryonic development, wound healing, anemia, inflammation, cancer, and ischemic diseases, such as infarction and stroke. Researchers involved in hypoxia-related science are from a variety of different fields, and include cell biol...

  9. Editorial: an introduction and welcome to Hypoxia

    OpenAIRE

    Katschinski, Doerthe

    2013-01-01

    Dörthe M Katschinski Institute of Cardiovascular Physiology, University Medical Center Göttingen, Georg-August University Göttingen, Göttingen, GermanyHypoxia can influence many aspects of physiology and pathophysiology, including high altitude, embryonic development, wound healing, anemia, inflammation, cancer, and ischemic diseases, such as infarction and stroke. Researchers involved in hypoxia-related science are from a variety of different fields, and i...

  10. Steroids for Chronic Inflammatory Demyelinating Polyneuropathy

    OpenAIRE

    J Gordon Millichap

    2005-01-01

    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.

  11. 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.

  12. [The dynamic detection of cytokins under aplastic anemia and idiopathic thrombocytopenic purpura in the process of impact of hypoxic hypoxia].

    Science.gov (United States)

    Éralieva, M O

    2012-05-01

    The natural hypoxic hypoxia enhances the synthesis processes and decrease the concentration balance in cytokine rets in patients with depression of hematopoiesis. It is established that the patients with aplastic anemia and idiopathic thrombocytopenic purpura, in contrast with patients with acute leucosis, chronic myelolecosis and erythroid myeloma, have quite high values of IL-2, which can be involved in the organization of full-fledgee response to antigen stimuli. The application of hypoxic hypoxia as an additional method in treatment of aplastic anemia and idiopathic thrombocytopenic purpura has no side effects and contraindications. PMID:22834158

  13. 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. PMID:25959851

  14. Immunohistochemical Detection of Changes in Tumor Hypoxia

    International Nuclear Information System (INIS)

    Purpose: Although hypoxia is a known prognostic factor, its effect will be modified by the rate of reoxygenation and the extent to which the cells are acutely hypoxic. We tested the ability of exogenous and endogenous markers to detect reoxygenation in a xenograft model. Our technique might be applicable to stored patient samples. Methods and Materials: The human colorectal carcinoma line, HT29, was grown in nude mice. Changes in tumor hypoxia were examined by injection of pimonidazole, followed 24 hours later by EF5. Cryosections were stained for these markers and for carbonic anhydrase IX (CAIX) and hypoxia-inducible factor 1α (HIF1α). Tumor hypoxia was artificially manipulated by carbogen exposure. Results: In unstressed tumors, all four markers showed very similar spatial distributions. After carbogen treatment, pimonidazole and EF5 could detect decreased hypoxia. HIF1α staining was also decreased relative to CAIX, although the effect was less pronounced than for EF5. Control tumors displayed small regions that had undergone spontaneous changes in tumor hypoxia, as judged by pimonidazole relative to EF5; most of these changes were reflected by CAIX and HIF1α. Conclusion: HIF1α can be compared with either CAIX or a previously administered nitroimidazole to provide an estimate of reoxygenation

  15. Molecular imaging of hypoxia with radiolabelled agents

    International Nuclear Information System (INIS)

    Tissue hypoxia results from an inadequate supply of oxygen (O2) that compromises biological functions. Structural and functional abnormalities of the tumour vasculature together with altered diffusion conditions inside the tumour seem to be the main causes of tumour hypoxia. Evidence from experimental and clinical studies points to a role for tumour hypoxia in tumour propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and non-invasive approaches have been developed to measure tumour oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), autoradiography and immunohistochemistry. This review aims to give a detailed overview of non-invasive molecular imaging modalities with radiolabelled PET and SPECT tracers that are available to measure tumour hypoxia. (orig.)

  16. Tribute to R. G. Boutilier: the role for skeletal muscle in the hypoxia-induced hypometabolic responses of submerged frogs.

    Science.gov (United States)

    West, T G; Donohoe, P H; Staples, J F; Askew, G N

    2006-04-01

    Much of Bob Boutilier's research characterised the subcellular, organ-level and in vivo behavioural responses of frogs to environmental hypoxia. His entirely integrative approach helped to reveal the diversity of tissue-level responses to O(2) lack and to advance our understanding of the ecological relevance of hypoxia tolerance in frogs. Work from Bob's lab mainly focused on the role for skeletal muscle in the hypoxic energetics of overwintering frogs. Muscle energy demand affects whole-body metabolism, not only because of its capacity for rapid increases in ATP usage, but also because hypometabolism of the large skeletal muscle mass in inactive animals impacts so greatly on in vivo energetics. The oxyconformance and typical hypoxia-tolerance characteristics (e.g. suppressed heat flux and preserved membrane ion gradients during O(2) lack) of skeletal muscle in vitro suggest that muscle hypoperfusion in vivo is possibly a key mechanism for (i) downregulating muscle and whole-body metabolic rates and (ii) redistributing O(2) supply to hypoxia-sensitive tissues. The gradual onset of a low-level aerobic metabolic state in the muscle of hypoxic, cold-submerged frogs is indeed important for slowing depletion of on-board fuels and extending overwintering survival time. However, it has long been known that overwintering frogs cannot survive anoxia or even severe hypoxia. Recent work shows that they remain sensitive to ambient O(2) and that they emerge rapidly from quiescence in order to actively avoid environmental hypoxia. Hence, overwintering frogs experience periods of hypometabolic quiescence interspersed with episodes of costly hypoxia avoidance behaviour and exercise recovery. In keeping with this flexible physiology and behaviour, muscle mechanical properties in frogs do not deteriorate during periods of overwintering quiescence. On-going studies inspired by Bob Boutilier's integrative mindset continue to illuminate the cost-benefit(s) of intermittent locomotion in

  17. THE EFFECTS OF INTERMITTENT HYPOXIC TRAINING ON AEROBIC CAPACITY AND ENDURANCE PERFORMANCE IN CYCLISTS

    Directory of Open Access Journals (Sweden)

    Milosz Czuba

    2011-03-01

    Full Text Available The aim of the present study was to evaluate the efficacy of intermittent hypoxic training (IHT with 95 % of lactate threshold workload (WRLT on aerobic capacity and endurance performance in well-trained cyclists. Twenty male elite cyclists, randomly divided into a hypoxia (H group (n=10; age 22 ± 2.7years; VO2max 67.8 ± 2.5 ml·kg-1·min-1; body height (BH 1.78 ± 0.05 m; body mass (BM 66.7 ± 5.4kg; fat free mass (FFM 59.3 ± 5.1kg; fat content (FAT% 11.3 ± 2.1%, and a control (C group (n = 10; age 23.5 ± 3. 5years; VO2max 67.7 ± 2.0 ml·kg-1·min-1; BH 1.79 ± 3.2 m; BM 69.2 ± 5.5 kg; FFM 63.6 ± 4.8 kg; FAT% 7.9 ± 1.94 % took part in the research project. The training program used during the experiment was the same for the both groups. For three weeks, the subjects in H group performed 3 training sessions per week in normobaric hypoxia environment (IHT - O2 = 15. 2%. During the elemental core of the IHT session, the intensity was set at 95% WRLT for 30-min in 1st microcycle, 35-min in 2nd microcycle and 40-min in 3rd microcycle. The same training procedure was provided in C group, yet the intensity of the main sessions were set at 100% WRLT in the normoxia environment. The results indicate a significant (p < 0.05 increase in VO2max,VO2LT, WRmax, WRLT and change in lactate concentration (∆LA during incremental test in H group. Also a significant (p < 0.05 decrease in time of the time trial was seen, associated with a significant increase (p < 0.05 in average generated power (Pavg and average speed (Vavg during the time trial. The intermittent hypoxic training (IHT applied in this research did not significantly affect the hematological variables considered: number of erythrocytes (RBC, hemoglobin concentration (HGB and haematocrit value (HCT. Significant blood value increases (p < 0.05 were only observed in MCV in H group. This data suggests that intermittent hypoxic training at lactate threshold intensity and medium duration (30

  18. Metabolism as means for hypoxia adaptation: metabolic profiling and flux balance analysis

    Directory of Open Access Journals (Sweden)

    Paternostro Giovanni

    2009-09-01

    Full Text Available Abstract Background Cellular hypoxia is a component of many diseases, but mechanisms of global hypoxic adaptation and resistance are not completely understood. Previously, a population of Drosophila flies was experimentally selected over several generations to survive a chronically hypoxic environment. NMR-based metabolomics, combined with flux-balance simulations of genome-scale metabolic networks, can generate specific hypotheses for global reaction fluxes within the cell. We applied these techniques to compare metabolic activity during acute hypoxia in muscle tissue of adapted versus "naïve" control flies. Results Metabolic profiles were gathered for adapted and control flies after exposure to acute hypoxia using 1H NMR spectroscopy. Principal Component Analysis suggested that the adapted flies are tuned to survive a specific oxygen level. Adapted flies better tolerate acute hypoxic stress, and we explored the mechanisms of this tolerance using a flux-balance model of central metabolism. In the model, adapted flies produced more ATP per glucose and created fewer protons than control flies, had lower pyruvate carboxylase flux, and had greater usage of Complex I over Complex II. Conclusion We suggest a network-level hypothesis of metabolic regulation in hypoxia-adapted flies, in which lower baseline rates of biosynthesis in adapted flies draws less anaplerotic flux, resulting in lower rates of glycolysis, less acidosis, and more efficient use of substrate during acute hypoxic stress. In addition we suggest new specific hypothesis, which were found to be consistent with existing data.

  19. MIBG scintigraphic assessment of cardiac adrenergic activity in response to altitude hypoxia

    International Nuclear Information System (INIS)

    High altitude hypoxia induces a decrease in the cardiac chronotropic function at maximal exercise or in response to isoproterenol infusion, suggesting an alteration in the cardiac sympathetic activation. Iodine-123 metaiodobenzylguanidine [(123I]MIBG) was used to map scintigraphically the cardiac sympathetic neuronal function in six male subjects (aged 32 ± 7 yr) after an exposure to high altitude that created hypoxic conditions. Results obtained just after return to sea level (RSL) were compared with the normal values obtained after 2 or 3 mo of normoxia (N). A static image was created as the sum of the 16-EKG gated images recorded for 10 min in the anterior view of the chest at 20, 60, 120, and 240 min after injection. Regions of interest were located over the heart (H), lungs (L), and mediastinum (M) regions. There was a significant decrease in the H/M and the L/M ratios in RSL compared to N condition. Plasma norepinephrine concentration was elevated during the stay at altitude but not significantly different in RSL compared to N. In conclusion, cardiac [123I]MIBG uptake is reduced after an exposure to altitude hypoxia, supporting the hypothesis of an hypoxia-induced reduction of adrenergic neurotransmitter reserve in the myocardium. Furthermore, the observed significant decrease in pulmonary MIBG uptake suggests an alteration of endothelial cell function after exposure to chronic hypoxia

  20. Gastrointestinal bleeding due to large bowel infiltration by chronic lymphocytic leukaemia.

    OpenAIRE

    Tucker, J.; Cachia, P. G.

    1986-01-01

    A 66 year old woman with a 9 year history of chronic lymphocytic leukaemia developed intermittent rectal bleeding for 9 months; sigmoidoscopic biopsy proved that this was due to large bowel infiltration by leukaemia. This is a very rare occurrence.

  1. Detection of hypoxic cells with the 2-nitroimidazole, EF5, correlates with early redox changes in rat brain after perinatal hypoxia-ischemia.

    Science.gov (United States)

    Bergeron, M; Evans, S M; Sharp, F R; Koch, C J; Lord, E M; Ferriero, D M

    1999-01-01

    The hypoxia-dependent activation of nitroheterocyclic drugs by cellular nitroreductases leads to the formation of intracellular adducts between the drugs and cellular macromolecules. Because this covalent binding is maximal in the absence of oxygen, detection of bound adducts provides an assay for estimating the degree of cellular hypoxia in vivo. Using a pentafluorintated derivative of etanidazole called EF5, we studied the distribution of EF5 adducts in seven-day-old rats subjected to different treatments which decrease the level of oxygen in the brain. EF5 solution was administered intraperitoneally 30 min prior to each treatment. The effect of acute and chronic hypoxia on EF5 adduct formation (binding) was studied in the brain of newborn rats exposed to global hypoxia (8% O2 for 30, 90 or 150 min) and in the brain of chronically hypoxic rat pups with congenital cardiac defects (Wistar Kyoto). The effect of combined hypoxia-ischemia was investigated in rat pups subjected to right carotid coagulation and concurrent exposure to 8% O2 for 30, 90 or 150 min. Brains were frozen immediately at the end of each treatment. Using a Cy3-conjugated monoclonal mouse antibody (ELK3-51) raised against EF5 adducts, hypoxic cells within brain regions were visualized by fluorescence immunocytochemistry. Brains from controls or vehicle-injected animals showed no EF5 binding. Notably, brains from animals which were chronically hypoxemic as a result of congenital cardiac defects also showed no EF5 binding. A short exposure (30 min) to hypoxia or to combined hypoxia-ischemia resulted in increased background stain and few scattered cells with low-intensity immunostaining. Acute hypoxia exposure of at least 90-150 min, which in this age animal does not result in frank cellular damage, produced patchy areas of low- to moderate-intensity fluorescence scattered throughout the brain. In contrast, 90-150 min of hypoxia-ischemia was associated with intense immunofluorescence in the

  2. Radial evolution of solar wind intermittency in the inner heliosphere

    CERN Document Server

    Bruno, R; Sorriso-Valvo, L; Bavassano, B

    2003-01-01

    We analyzed intermittency in the solar wind, as observed on the ecliptic plane, looking at magnetic field and velocity fluctuations between 0.3 and 1 AU, for both fast and slow wind and for compressive and directional fluctuations. Our analysis focused on the property that probability distribution functions of a fluctuating field affected by intermittency become more and more peaked at smaller and smaller scales. Since the peakedness of a distribution is measured by its flatness factor we studied the behavior of this parameter for different scales to estimate the degree of intermittency of our time series. We confirmed that both magnetic field and velocity fluctuations are rather intermittent and that compressive magnetic fluctuations are generally more intermittent than the corresponding velocity fluctuations. In addition, we observed that compressive fluctuations are always more intermittent than directional fluctuations and that while slow wind intermittency does not depend on the radial distance from the ...

  3. Hypoxia and hypoxia-regulated proteins in gastric cancer: prognostic significance for clinical outcome

    International Nuclear Information System (INIS)

    Full text: To examine the relationship between hypoxia level, hypoxia-inducible factor-1α (HIF-1α) expression, tumor vascularity, and clinicopathologic parameters in gastric cancer; to assess the impact of hypoxia-associated events on the prognosis of clinical outcome. High hypoxia levels were found in 29 % of pts., and low - in 71 % of pts. Strong nuclear expressions of HIF-1α were found in 7 % of pts., moderate - in 80 % of pts., and weak - in 13 % of pts. Strong microvessel densities were observed in 54 % of pts. and moderate - in 46 % of pts. It was revealed a close association between the hypoxia level in tumor assessed by 31P NMR spectroscopy and expression of HIF-1α in tumor cells (P0.05). Hypoxia level and microvessel density in tumor tissue correlated with clinical stage (P<0.05). High hypoxia levels positively correlated with decreased overall survival (P=0.044). For overall survival, hypoxia level and HIF-1α expression (hazard ratio, 2.10; 95 % CI, 0.67-4.67; P=0.035 and 3.45; 0.89-3.01, 0.047, respectively) were independently predictive in multivariate analysis for lymph-node negative patients; and hypoxia level (hazard ratio, 4.50; 95 % CI, 0.42-2.57; P=0.027) for lymph-node positive patients. Statistical analysis has indicated that PME/Pi ratio in tumor tissue may be used as an parameter of hypoxia level as well as independent prognostic factor of clinical outcome in patients with gastric cancer. Methodological approaches are started now to be used in the analysis of head and neck tumors treated with hyperthermia combined with radiation/chemotherapy. (author)

  4. Insights from intermittent binocular rivalry and EEG

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    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. Stochastic resonance in on-off intermittency

    International Nuclear Information System (INIS)

    Stochastic resonance (SR) is studied in chaotic systems exhibiting on-off intermittency (OOI). They include a discrete-time system - the logistic map with the control parameter varying randomly in time and a continuous time system - chaotic oscillators just below the synchronisation threshold. As a weak additive or multiplicative periodic forcing is added to such systems, the signal-to-noise ratio (SNR) exhibits a maximum as a function of the intermittency control parameter. In all cases SNR shows dependence on the forcing frequency. In the case of additive periodic forcing in continuous-time systems a distinct minimum of SNR is observed when the periodic forcing frequency is close to the characteristic frequency of chaotic oscillations of the system. In the case of multiplicative periodic forcing this dependence retains even for very small frequencies; this is a result of a very long characteristic time scale, typical of systems with OOI. (author)

  6. Intermittent tracking of flat plate collectors

    International Nuclear Information System (INIS)

    A theoretical analysis of different intervals of intermittent two-axis tracking of the sun, on the amount of annual energy received by flat-plate collectors, has been carried out. The analysis was done for Ipoh, a city near the university at a latitude of 40 34 North in Malaysia. For the analysis, a computer program was developed to calculate the solar insulation according to the interval settings, considering ASHRAE Standard Sky assumption. Both direct and diffused components of solar radiation have been considered. The tracking system was targeted for flat plate collectors where the degree of tracking accuracy would be much lower Hence, the tracking mechanism will be much simpler and lower in costs. Results showed that by a 3-hour intermittent tracking, a flat-plate collector could get as much as 35% more annual energy than a fixed one. The 3-hour interval tracking greatly simplifies the gear mechanism from the motor to the solar collector. (Author)

  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. Intermittency exponent of the turbulent energy cascade

    International Nuclear Information System (INIS)

    We consider the turbulent energy dissipation from one-dimensional records in experiments using air and gaseous helium at cryogenic temperatures, and obtain the intermittency exponent via the two-point correlation function of the energy dissipation. The air data are obtained in a number of flows in a wind tunnel and the atmospheric boundary layer at a height of about 35 m above the ground. The helium data correspond to the centerline of a jet exhausting into a container. The air data on the intermittency exponent are consistent with each other and with a trend that increases with the Taylor microscale Reynolds number, Rλ, of up to about 1000 and saturates thereafter. On the other hand, the helium data cluster around a constant value at nearly all Rλ, this being about half of the asymptotic value for the air data. Some possible explanation is offered for this anomaly. (author)

  9. Correcting intermittent central suppression improves binocular marksmanship.

    Science.gov (United States)

    Hussey, Eric S

    2007-04-01

    Intermittent central suppression (ICS) is a defect in normal binocular (two-eyed) vision that causes confusion in visual detail. ICS is a repetitive intermittent loss of visual sensation in the central area of vision. As the central vision of either eye "turns on and off", aiming errors in sight can occur that must be corrected when both eyes are seeing again. Any aiming errors in sight might be expected to interfere with marksmanship during two-eyed seeing. We compared monocular (one-eyed, patched) and binocular (two-eyed) marksmanship with pistol shooting with an Army ROTC cadet before and after successful therapy for diagnosed ICS. Pretreatment, monocular marksmanship was significantly better than binocular marksmanship, suggesting defective binocularity reduced accuracy. After treatment for ICS, binocular and monocular marksmanship were essentially the same. Results confirmed predictions that with increased visual stability from correcting the suppression, binocular and monocular marksmanship accuracies should merge. PMID:17484315

  10. 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.

  11. Intermittence and roughening of periodic elastic media

    International Nuclear Information System (INIS)

    We analyze intermittence and roughening of an elastic interface or domain wall pinned in a periodic potential, in the presence of random-bond disorder in 1+1 and 2+1 dimensions. Though the ensemble average behavior is smooth, the typical behavior of a large sample is intermittent, and does not self-average to a smooth behavior. Instead, large fluctuations occur in the mean location of the interface and the onset of interface roughening is via an extensive fluctuation which leads to a jump in the roughness of order λ, the period of the potential. Analytical arguments based on extreme statistics are given for the number of the minima of the periodicity visited by the interface and for the roughening crossover, which is confirmed by extensive exact ground state calculations

  12. Functional genomics approach to hypoxia signaling.

    Science.gov (United States)

    Seta, Karen A; Millhorn, David E

    2004-02-01

    Mammalian cells require a constant supply of oxygen to maintain energy balance, and sustained hypoxia can result in cell death. It is therefore not surprising that sophisticated adaptive mechanisms have evolved that enhance cell survival during hypoxia. During the past few years, there have been a growing number of reports on hypoxia-induced transcription of specific genes. In this review, we describe a unique experimental approach that utilizes focused cDNA libraries coupled to microarray analyses to identify hypoxia-responsive signal transduction pathways and genes that confer the hypoxia-tolerant phenotype. We have used the subtractive suppression hybridization (SSH) method to create a cDNA library enriched in hypoxia-regulated genes in oxygen-sensing pheochromocytoma cells and have used this library to create microarrays that allow us to examine hundreds of genes at a time. This library contains over 300 genes and expressed sequence tags upregulated by hypoxia, including tyrosine hydroxylase, vascular endothelial growth factor, and junB. Hypoxic regulation of these and other genes in the library has been confirmed by microarray, Northern blot, and real-time PCR analyses. Coupling focused SSH libraries with microarray analyses allows one to specifically study genes relevant to a phenotype of interest while reducing much of the biological noise associated with these types of studies. When used in conjunction with high-throughput, dye-based assays for cell survival and apoptosis, this approach offers a rapid method for discovering validated therapeutic targets for the treatment of cardiovascular disease, stroke, and tumors. PMID:14715686

  13. Hypoxia and Hypoxia Mimetics Decrease Aquaporin 5 (AQP5) Expression through Both Hypoxia Inducible Factor-1α and Proteasome-Mediated Pathways

    OpenAIRE

    Kawedia, Jitesh D.; Fan Yang; Sartor, Maureen A.; David Gozal; Maria Czyzyk-Krzeska; Menon, Anil G.

    2013-01-01

    The alveolar epithelium plays a central role in gas exchange and fluid transport, and is therefore critical for normal lung function. Since the bulk of water flux across this epithelium depends on the membrane water channel Aquaporin 5 (AQP5), we asked whether hypoxia had any effect on AQP5 expression. We show that hypoxia causes a significant (70%) decrease in AQP5 expression in the lungs of mice exposed to hypoxia. Hypoxia and the hypoxia mimetic, cobalt, also caused similar decreases in AQ...

  14. Noopept reduces the postischemic functional and metabolic disorders in the brain of rats with different sensitivity to hypoxia.

    Science.gov (United States)

    Zarubina, I V; Shabanov, P D

    2009-03-01

    Chronic cerebral ischemia was induced by ligation of both common carotid arteries in Wistar rats, divided by sensitivity to hypoxia into highly sensitive and low-sensitive. Noopept (peptide preparation), injected (0.5 mg/kg) during 7 days after occlusion of the carotid arteries, reduced the neurological disorders in rats with high and low sensitivity to hypoxia and improved their survival during the postischemic period. Noopept normalized behavior disordered by cerebral ischemia (according to the open field and elevated plus maze tests), prevented accumulation of LPO products and inhibition of antioxidant systems in the brain of rats with high and low sensitivity to hypoxia. Hence, noopept exhibited a neuroprotective effect in cerebral ischemia. PMID:19529857

  15. Intermittent permeation of cylindrical nanopores by water

    OpenAIRE

    Allen, Rosalind; Melchionna, Simone; Hansen, Jean-Pierre

    2002-01-01

    Molecular Dynamics simulations of water molecules in nanometre sized cylindrical channels connecting two reservoirs show that the permeation of water is very sensitive to the channel radius and to electric polarization of the embedding material. At threshold, the permeation is {\\emph{intermittent}} on a nanosecond timescale, and strongly enhanced by the presence of an ion inside the channel, providing a possible mechanism for gating. Confined water remains surprisingly fluid and bulk-like. It...

  16. Intermittent chaotic chimeras for coupled rotators

    DEFF Research Database (Denmark)

    Olmi, Simona; Martens, Erik Andreas; Thutupalli, Shashi; Torcini, Alessandro

    2015-01-01

    wo 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 othe...... 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....

  17. Intermittency Studies in Directed Bond Percolation

    OpenAIRE

    Henkel, Malte; Peschanski, Robert

    1992-01-01

    The self-similar cluster fluctuations of directed bond percolation at the percolation threshold are studied using techniques borrowed from inter\\-mit\\-ten\\-cy-related analysis in multi-particle production. Numerical simulations based on the factorial moments for large $1+1$-dimensional lattices allow to handle statistical and boundary effects and show the existence of weak but definite intermittency patterns. The extracted fractal dimensions are in agreement with scaling arguments leading to ...

  18. Intermittent Aeration in Biological Treatment of Wastewater

    OpenAIRE

    Doan, H.; Lohi, A.

    2009-01-01

    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 ...

  19. Cardiac calcification in acute intermittent porphyria

    Directory of Open Access Journals (Sweden)

    Tanmoy Ghatak

    2011-01-01

    Full Text Available Aetiology of pericardial calcifications can be multifactorial. Tuberculosis has been reported as the most common cause. Other known causes include uraemia, asbestosis, post-traumatic or postoperative. We report a rare case of pericardial calcification seen in a patient with established acute intermittent porphyria. A direct causal relationship cannot be established between porphyria and pericardial calcification, but it may be due to deposition of the porphyrin in the pericardium.

  20. Cardiac calcification in acute intermittent porphyria

    OpenAIRE

    Tanmoy Ghatak; Afzal Azim; Arvind K Baronia; Banani Poddar

    2011-01-01

    Aetiology of pericardial calcifications can be multifactorial. Tuberculosis has been reported as the most common cause. Other known causes include uraemia, asbestosis, post-traumatic or postoperative. We report a rare case of pericardial calcification seen in a patient with established acute intermittent porphyria. A direct causal relationship cannot be established between porphyria and pericardial calcification, but it may be due to deposition of the porphyrin in the pericardium.