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Sample records for hypoxia augments chemoreflex

  1. Carotid Body Chemoreflex Mediates Intermittent Hypoxia-Induced Oxidative Stress in the Adrenal Medulla

    PubMed Central

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

    2016-01-01

    Intermittent hypoxia (IH) increases reactive oxygen species generation resulting in oxidative stress in the adrenal medulla (AM), a major end-organ of the sympathetic nervous system which facilitates catecholamine secretion by hypoxia. Here, we show that carotid body chemoreflex contributes to IH-induced oxidative stress in the AM. Carotid bodies were ablated by cryocoagulation of glomus cells, the putative O2 sensing cells. Carotid body ablated (CBA) and control rats were exposed to IH and the redox state of the AM was assessed biochemically. We found that IH raised reactive oxygen species levels along with an increase in NADPH oxidase (Nox), a pro-oxidant enzyme and a decrease in superoxide dismutase-2 (SOD2), an anti-oxidant enzyme. Further, IH increased hypoxia-inducible factor (HIF)-1α, whereas decreased HIF-2α, the transcriptional regulator of Nox and SOD-2, respectively. These IH-induced changes in the AM were absent in CBA rats. Moreover, IH increased splanchnic nerve activity and facilitated hypoxia-evoked catecholamine efflux from the AM and CBA prevented these effects. These findings suggest that IH-induced oxidative stress and catecholamine efflux in the AM occurs via carotid body chemoreflex involving HIF α isoform mediated imbalance in pro-, and anti-oxidant enzymes. PMID:26303481

  2. Volatile Anaesthetic Depression of the Carotid Body Chemoreflex-Mediated Ventilatory Response to Hypoxia: Directions for Future Research

    PubMed Central

    Pandit, J. J.

    2014-01-01

    In assessing whether volatile anaesthetics directly depress the carotid body response to hypoxia it is necessary to combine in meta-analysis studies of when it is “functionally isolated” (e.g., recordings are made from its afferent nerve). Key articles were retrieved (full papers in English) and subjected to quantitative analysis to yield an aggregate estimate of effect. Results from articles that did not use such methodology were assessed separately from this quantitative approach, to see what could be learned also from a nonquantitative overview. Just 7 articles met the inclusion criteria for hypoxia and just 6 articles for hypercapnia. Within these articles, the anaesthetic (mean dose 0.75, standard deviation (SD) 0.40 minimum alveolar concentration, MAC) statistically significantly depressed carotid body hypoxic response by 24% (P = 0.041), but a similar dose (mean 0.81 (0.42) MAC) did not affect the hypercapnic response. The articles not included in the quantitative analysis (31 articles), assessed qualitatively, also indicated that anaesthetics depress carotid body function. This conclusion helps direct future research on the anaesthetic effects on putative cellular/molecular processes that underlie the transduction of hypoxia in the carotid body. PMID:24808974

  3. Carotid body chemoreflex: a driver of autonomic abnormalities in sleep apnoea.

    PubMed

    Prabhakar, Nanduri R

    2016-08-01

    What is the topic of this review? This article presents emerging evidence for heightened carotid body chemoreflex activity as a major driver of sympathetic activation and hypertension in sleep apnoea patients. What advances does it heighlight? This article discusses the recent advances on cellular, molecular and epigenetic mechanisms underlying the exaggerated chemoreflex in experimental models of sleep apnoea. The carotid bodies are the principal peripheral chemoreceptors for detecting changes in arterial blood oxygen concentration, and the resulting chemoreflex is a potent regulator of the sympathetic tone, blood pressure and breathing. Sleep apnoea is a disease of the respiratory system that affects several million adult humans. Apnoeas occur during sleep, often as a result of obstruction of the upper airway (obstructive sleep apnoea) or because of defective respiratory rhythm generation by the CNS (central sleep apnoea). Patients with sleep apnoea exhibit several co-morbidities, with the most notable among them being heightened sympathetic nerve activity and hypertension. Emerging evidence suggests that intermittent hypoxia resulting from periodic apnoea stimulates the carotid body, and the ensuing chemoreflex mediates the increased sympathetic tone and hypertension in sleep apnoea patients. Rodent models of intermittent hypoxia that simulate the O2 saturation profiles encountered during sleep apnoea have provided important insights into the cellular and molecular mechanisms underlying the heightened carotid body chemoreflex. This article describes how intermittent hypoxia affects the carotid body function and discusses the cellular, molecular and epigenetic mechanisms underlying the exaggerated chemoreflex. PMID:27474260

  4. Peripheral chemoreflex sensitivity and sympathetic nerve activity are normal in apnea divers during training season.

    PubMed

    Breskovic, Toni; Ivancev, Vladimir; Banic, Ivana; Jordan, Jens; Dujic, Zeljko

    2010-04-19

    Apnea divers are exposed to repeated massive arterial oxygen desaturation, which could perturb chemoreflexes. An earlier study suggested that peripheral chemoreflex regulation of sympathetic vasomotor tone and ventilation may have recovered 4 or more weeks into the off season. Therefore, we tested the hypothesis that peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone is present during the training season. We determined ventilation, heart rate, blood pressure, cardiac stroke volume, and muscle sympathetic nerve activity (MSNA) during isocapnic hypoxia in 10 breath hold divers and 11 matched control subjects. The study was carried out at the end of the season of intense apnea trainings. Baseline MSNA frequency was 30+/-4bursts/min in control subjects and 25+/-4bursts/min in breath hold divers (P=0.053). During hypoxia burst frequency and total sympathetic activity increased similarly in both groups. Sympathetic activity normalized during the 30-minute recovery. Hypoxia-induced stimulation of minute ventilation was similar in both groups, although in divers it was maintained by higher tidal volumes and lower breathing frequency compared with control subjects. In both groups, hypoxia increased heart rate and cardiac output whereas total peripheral resistance decreased. Blood pressure remained unchanged. We conclude that peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone is paradoxically preserved in apnea divers, both, during the off and during the training season. The observation suggests that repeated arterial oxygen desaturation may not be sufficient explaining sympathetic reflex abnormalities similar to those in obstructive sleep apnea patients. PMID:19926535

  5. Augmentation of aerobic respiration and mitochondrial biogenesis in skeletal muscle by hypoxia preconditioning with cobalt chloride

    SciTech Connect

    Saxena, Saurabh; Shukla, Dhananjay; Bansal, Anju

    2012-11-01

    High altitude/hypoxia training is known to improve physical performance in athletes. Hypoxia induces hypoxia inducible factor-1 (HIF-1) and its downstream genes that facilitate hypoxia adaptation in muscle to increase physical performance. Cobalt chloride (CoCl{sub 2}), a hypoxia mimetic, stabilizes HIF-1, which otherwise is degraded in normoxic conditions. We studied the effects of hypoxia preconditioning by CoCl{sub 2} supplementation on physical performance, glucose metabolism, and mitochondrial biogenesis using rodent model. The results showed significant increase in physical performance in cobalt supplemented rats without (two times) or with training (3.3 times) as compared to control animals. CoCl{sub 2} supplementation in rats augmented the biological activities of enzymes of TCA cycle, glycolysis and cytochrome c oxidase (COX); and increased the expression of glucose transporter-1 (Glut-1) in muscle showing increased glucose metabolism by aerobic respiration. There was also an increase in mitochondrial biogenesis in skeletal muscle observed by increased mRNA expressions of mitochondrial biogenesis markers which was further confirmed by electron microscopy. Moreover, nitric oxide production increased in skeletal muscle in cobalt supplemented rats, which seems to be the major reason for peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) induction and mitochondrial biogenesis. Thus, in conclusion, we state that hypoxia preconditioning by CoCl{sub 2} supplementation in rats increases mitochondrial biogenesis, glucose uptake and metabolism by aerobic respiration in skeletal muscle, which leads to increased physical performance. The significance of this study lies in understanding the molecular mechanism of hypoxia adaptation and improvement of work performance in normal as well as extreme conditions like hypoxia via hypoxia preconditioning. -- Highlights: ► We supplemented rats with CoCl{sub 2} for 15 days along with training. ► Co

  6. Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity.

    PubMed

    Matsuura, Yunosuke; Yamashita, Atsushi; Iwakiri, Takashi; Sugita, Chihiro; Okuyama, Nozomi; Kitamura, Kazuo; Asada, Yujiro

    2015-07-01

    Atherosclerotic lesions represent a hypoxic milieu. However, the significance of this milieu in atherothrombosis has not been established. We aimed to assess the hypothesis that vascular wall hypoxia promotes arterial thrombus formation. We examined the relation between vascular wall hypoxia and arterial thrombus formation using a rabbit model in which arterial thrombosis was induced by 0.5 %-cholesterol diet and repeated balloon injury of femoral arteries. Vascular wall hypoxia was immunohistochemically detected by pimonidazole hydrochloride, a hypoxia marker. Rabbit neointima and THP-1 macrophages were cultured to analyse prothrombotic factor expression under hypoxic conditions (1 % O2). Prothrombotic factor expression and nuclear localisation of hypoxia-inducible factor (HIF)-1α and nuclear factor-kappa B (NF-κB) p65 were immunohistochemically assessed using human coronary atherectomy plaques. Hypoxic areas were localised in the macrophage-rich deep portion of rabbit neointima and positively correlated with the number of nuclei immunopositive for HIF-1α and NF-κB p65, and tissue factor (TF) expression. Immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly correlated with hypoxic areas in arteries. TF and plasminogen activator inhibitor-1 (PAI-1) expression was increased in neointimal tissues and/or macrophages cultured under hypoxia, and both were suppressed by inhibitors of either HIF-1 or NF-κB. In human coronary plaques, the number of HIF-1α-immunopositive nuclei was positively correlated with that of NF-κB-immunopositive nuclei and TF-immunopositive and PAI-1-immunopositive area, and it was significantly higher in thrombotic plaques. Vascular wall hypoxia augments the thrombogenic potential of atherosclerotic plaque and thrombus formation on plaques via prothrombotic factor upregulation. PMID:25833755

  7. Peripheral chemoreflex inhibition with low-dose dopamine: new insight into mechanisms of extreme apnea.

    PubMed

    Bain, Anthony R; Dujic, Zeljko; Hoiland, Ryan L; Barak, Otto F; Madden, Dennis; Drvis, Ivan; Stembridge, Mike; MacLeod, David B; MacLeod, Douglas M; Ainslie, Philip N

    2015-11-01

    The purpose of this study was to determine the impact of peripheral chemoreflex inhibition with low-dose dopamine on maximal apnea time, and the related hemodynamic and cerebrovascular responses in elite apnea divers. In a randomized order, participants performed a maximal apnea while receiving either intravenous 2 μg·kg(-1)·min(-1) dopamine or volume-matched saline (placebo). The chemoreflex and hemodynamic response to dopamine was also assessed during hypoxia [arterial O2 tension, (PaO2 ) ∼35 mmHg] and mild hypercapnia [arterial CO2 tension (PaCO2 ) ∼46 mmHg] that mimicked the latter parts of apnea. Outcome measures included apnea duration, arterial blood gases (radial), heart rate (HR, ECG), mean arterial pressure (MAP, intra-arterial), middle (MCAv) and posterior (PCAv) cerebral artery blood velocity (transcranial ultrasound), internal carotid (ICA) and vertebral (VA) artery blood flow (ultrasound), and the chemoreflex responses. Although dopamine depressed the ventilatory response by 27 ± 41% (vs. placebo; P = 0.01), the maximal apnea duration was increased by only 5 ± 8% (P = 0.02). The PaCO2 and PaO2 at apnea breakpoint were similar (P > 0.05). When compared with placebo, dopamine increased HR and decreased MAP during both apnea and chemoreflex test (P all <0.05). At rest, dopamine compared with placebo dilated the ICA (3.0 ± 4.1%, P = 0.05) and VA (6.6 ± 5.0%, P < 0.01). During apnea and chemoreflex test, conductance of the cerebral vessels (ICA, VA, MCAv, PCAv) was increased with dopamine; however, flow (ICA and VA) was similar. At least in elite apnea divers, the small increase in apnea time and similar PaO2 at breakpoint (∼31 mmHg) suggest the apnea breakpoint is more related to PaO2 , rather than peripheral chemoreflex drive to breathe. PMID:26290106

  8. Prediction of the Chemoreflex Gain by Common Clinical Variables in Heart Failure

    PubMed Central

    Mirizzi, Gianluca; Giannoni, Alberto; Ripoli, Andrea; Iudice, Giovanni; Bramanti, Francesca; Emdin, Michele; Passino, Claudio

    2016-01-01

    Background Peripheral and central chemoreflex sensitivity, assessed by the hypoxic or hypercapnic ventilatory response (HVR and HCVR, respectively), is enhanced in heart failure (HF) patients, is involved in the pathophysiology of the disease, and is under investigation as a potential therapeutic target. Chemoreflex sensitivity assessment is however demanding and, therefore, not easily applicable in the clinical setting. We aimed at evaluating whether common clinical variables, broadly obtained by routine clinical and instrumental evaluation, could predict increased HVR and HCVR. Methods and results 191 patients with systolic HF (left ventricular ejection fraction—LVEF—<50%) underwent chemoreflex assessment by rebreathing technique to assess HVR and HCVR. All patients underwent clinical and neurohormonal evaluation, comprising: echocardiogram, cardiopulmonary exercise test (CPET), daytime cardiorespiratory monitoring for breathing pattern evaluation. Regarding HVR, multivariate penalized logistic regression, Bayesian Model Averaging (BMA) logistic regression and random forest analysis identified, as predictors, the presence of periodic breathing and increased slope of the relation between ventilation and carbon dioxide production (VE/VCO2) during exercise. Again, the above-mentioned statistical tools identified as HCVR predictors plasma levels of N-terminal fragment of proBNP and VE/VCO2 slope. Conclusions In HF patients, the simple assessment of breathing pattern, alongside with ventilatory efficiency during exercise and natriuretic peptides levels identifies a subset of patients presenting with increased chemoreflex sensitivity to either hypoxia or hypercapnia. PMID:27099934

  9. Chemoreflexes, Sleep Apnea, and Sympathetic Dysregulation

    PubMed Central

    Mansukhani, Meghna P.; Kara, Tomas; Caples, Sean; Somers, Virend K.

    2014-01-01

    Obstructive sleep apnea (OSA) and hypertension are closely linked conditions. Disordered breathing events in OSA are characterized by increasing efforts against an occluded airway whilst asleep, resulting in a marked sympathetic response. This is predominantly due to hypoxemia activating the chemoreflexes, resulting in reflex increases in sympathetic neural outflow. In addition, apnea, and the consequent lack of inhibition of the sympathetic system that occurs with lung inflation during normal breathing, potentiates central sympathetic outflow. Sympathetic activation persists into the daytime, and is thought to contribute to hypertension and other adverse cardiovascular outcomes. This review discusses chemoreflex physiology and sympathetic modulation during normal sleep, as well as the sympathetic dysregulation seen in OSA, its extension into wakefulness, and changes after treatment. Evidence supporting the role of the peripheral chemoreflex in the sympathetic dysregulation seen in OSA, including in the context of co-morbid obesity, metabolic syndrome and systemic hypertension is reviewed. Finally, alterations in cardiovascular variability and other potential mechanisms that might play a role in the autonomic imbalance seen in OSA are also discussed. PMID:25097113

  10. Superoxide scavengers augment contractile but not energetic responses to hypoxia in rat diaphragm.

    PubMed

    Wright, V P; Klawitter, P F; Iscru, D F; Merola, A J; Clanton, T L

    2005-05-01

    Acute exposure to severe hypoxia depresses contractile function and induces adaptations in skeletal muscle that are only partially understood. Previous studies have demonstrated that antioxidants (AOXs) given during hypoxia partially protect contractile function, but this has not been a universal finding. This study confirms that specific AOXs, known to act primarily as superoxide scavengers, protect contractile function in severe hypoxia. Furthermore, the hypothesis is tested that the mechanism of protection involves preservation of high-energy phosphates (ATP, creatine phosphate) and reductions of P(i). Rat diaphragm muscle strips were treated with AOXs and subjected to 30 min of hypoxia. Contractile function was examined by using twitch and tetanic stimulations and the degree of elevation in passive force occurring during hypoxia (contracture). High-energy phosphates were measured at the end of 30-min hypoxia exposure. Treatment with the superoxide scavengers 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron, 10 mM) or Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (50 microM) suppressed contracture during hypoxia and protected maximum tetanic force. N-acetylcysteine (10 or 18 mM) had no influence on tetanic force production. Contracture during hypoxia without AOXs was also shown to be dependent on the extracellular Ca(2+) concentration. Although hypoxia resulted in only small reductions in ATP concentration, creatine phosphate concentration was decreased to approximately 10% of control. There were no consistent influences of the AOX treatments on high-energy phosphates during hypoxia. The results demonstrate that superoxide scavengers can protect contractile function and reduce contracture in hypoxia through a mechanism that does not involve preservation of high-energy phosphates. PMID:15640388

  11. Sympatho-adrenal activation by chronic intermittent hypoxia

    PubMed Central

    Kumar, Ganesh K.; Peng, Ying-Jie

    2012-01-01

    Recurrent apnea with chronic intermittent hypoxia (CIH) is a major clinical problem in adult humans and infants born preterm. Patients with recurrent apnea exhibit heightened sympathetic activity as well as elevated plasma catecholamine levels, and these phenotypes are effectively recapitulated in rodent models of CIH. This article summarizes findings from studies addressing sympathetic activation in recurrent apnea patients and rodent models of CIH and the underlying cellular and molecular mechanisms. Available evidence suggests that augmented chemoreflex and attenuated baroreflex contribute to sympathetic activation by CIH. Studies on rodents showed that CIH augments the carotid body response to hypoxia and attenuates the carotid baroreceptor response to increased sinus pressures. Processing of afferent information from chemoreceptors at the central nervous system is also facilitated by CIH. Adult and neonatal rats exposed to CIH exhibit augmented catecholamine secretion from the adrenal medulla. Adrenal demedullation prevents the elevation of circulating catecholamines in CIH-exposed rodents. Reactive oxygen species (ROS)-mediated signaling is emerging as the major cellular mechanism triggering sympatho-adrenal activation by CIH. Molecular mechanisms underlying increased ROS generation by CIH seem to involve transcriptional dysregulation of genes encoding pro-and antioxidant enzymes by hypoxia-inducible factor-1 and -2, respectively. PMID:22723632

  12. Influence of CO2 on cardiovascular response to hypoxia in conscious dogs.

    PubMed

    Koehler, R C; McDonald, B W; Krasney, J A

    1980-10-01

    The modulating effect of CO2 on the circulatory response to hypoxia in chronically instrumented conscious dogs was examined over a wide range of arterial partial pressure of O2 [PaO2 (from 80 to 25 Torr)] during a 41-min rebreathing period at three CO2 levels: hypocapnia (from PaCO2 of 32 to 18 Torr), eucapnia (32 Torr), and mild hypercapnia (40 Torr). Eucapnic and hypercapnic hypoxic responses were also measured after sinoaortic denervation (SAD) to assess the arterial chemoreceptor and baroreceptor reflex contributions. Elevating PaCO2 attenuated the tachycardia during hypoxia and produced progressively greater systemic, renal, and splanchnic vasoconstriction before but not after SAD. Vagal block converted the rises in renal and splanchnic flows observed during hypocapnic hypoxia to declines. The increase in left ventricular dP/dtmax was not affected by varying PaCO2 either before or after SAD. Coronary flow increased an additional onefold during hypoxia when PaCO2 was elevated both before and after SAD, but the tension-time indices did not differ significantly. These results indicate that: a) cardiopulmonary vagal afferents effectively counteract chemoreflex-induced vasoconstriction during hypocapnic hypoxia; b) chemoreflex vasoconstriction predominates in the renal and splanchnic beds when PaCO2 is elevated; c) the sinoaortic reflexes restrain the heart rate, but not the contractility response to hypoxia when PaCO2 is increased; and d) the augmented coronary vasodilation produced by CO2 is probably mediated by local CO2-hypoxic interactions. PMID:6775543

  13. Pulmonary chemoreflex and phrenic sympathetic efferents.

    PubMed

    Bałkowiec, A; Szulczyk, P

    1993-11-01

    The pulmonary chemoreflex components such as reactions of phrenic sympathetic neuron (PhSN) activity, phrenic nerve activity, heart rate and blood pressure were tested in chloralose-anesthetized, paralyzed cats. 10 micrograms to 160 micrograms phenylbiguanide (PBG) in 0.9% NaCl was injected into the pulmonary circulation. PBG injected into the right atrium (in 11 of 19 experiments) and into the pulmonary artery (in 5 of 8 experiments), evoked short-latency (1-1.4 sec) dose-dependent increase in PhSN activity accompanied by increase in blood pressure, and followed by decrease in these two variables. In all experiments, activity of the phrenic nerve was depressed, and bradycardia occurred after PBG injection. All responses to PBG injections into the pulmonary artery were abolished following bilateral vagotomy. In the same procedure related to the right atrium after vagotomy, the increases in PhSN activity and blood pressure were also abolished, although a decrease in heart rate, PhSN activity and in the amplitude of phrenic nerve discharges together with an increase in their frequency persisted. Our results suggest that short-latency increase in PhSN activity is a component of pulmonary chemoreflex. PMID:8272587

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

    PubMed Central

    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 brainstem termination site of chemoreceptor afferents, expresses a form of synaptic plasticity that increases overall nTS activity following intermittent hypoxia. Following CIH, an increase in presynaptic spontaneous neurotransmitter release occurs under baseline conditions. Furthermore, during and following afferent stimulation there is an augmentation of spontaneous transmitter release that occurs out of synchrony with sensory stimulation. On the other hand, afferent evoked synchronous transmitter release is attenuated. Overall, this shift from synchronous to asynchronous transmitter release enhances nTS cellular discharge. The role of the neurotransmitter dopamine in CIH-induced plasticity is also discussed. Dopamine attenuates synaptic transmission in nTS cells by blockade of N-type calcium channels, and this mechanism occurs tonically following normoxia and CIH. This dopaminergic pathway, however, is not altered in CIH. Taken together, alterations in nTS synaptic activity may play a role in the changes of chemoreflex function and cardiorespiratory activity in the CIH apnea model. PMID:20416405

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

    PubMed

    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

  16. Prolonged (9 h) poikilocapnic hypoxia (12% O2) augments cutaneous thermal hyperaemia in healthy humans.

    PubMed

    Lawley, Justin S; Oliver, Samuel J; Mullins, Paul G; Macdonald, Jamie H; Moore, Jonathan P

    2014-06-01

    The primary aim of this study was to investigate the effect of systemic poikilocapnic hypoxia on forearm cutaneous thermal hyperaemia. A secondary aim was to examine the relationship between the individual susceptibility to oxygen desaturation and cutaneous vasodilator capacity. Twelve healthy participants (seven male) were exposed to 9 h of normoxia and 12% poikilocapnic hypoxia in a temperature- and humidity-controlled environmental chamber. Skin blood flow was assessed at the ventral forearm using laser Doppler flowmetry combined with rapid local heating. After 6 min at baseline (skin temperature clamped at 33°C), local skin temperature was elevated at a rate of 0.5°C every 5 s up to 42°C to elicit a sensory axon response and then held constant for 30 min to cause a plateau. Skin blood flow was calculated as cutaneous vascular conductance [CVC; in perfusion units/mean arterial blood pressure (APU mmHg(-1))] and expressed in raw format and relative to heating at 44°C in normoxia (%CVC44). During hypoxaemia, vasodilatation was greater during the initial peak (raw, Δ0.35 APU mmHg(-1), P = 0.09; %CVC44, Δ18%, P = 0.05) and the plateau phase (raw, Δ0.55 APU mmHg(-1), P = 0.03; %CVC44, Δ26%, P = 0.02). The rate of rise in cutaneous blood flow during the initial peak was significantly greater during poikilocapnic hypoxia (P < 0.01). We observed a negative relationship between oxygen saturation in poikilocapnic hypoxia and the change in baseline (P = 0.06), initial peak (P = 0.01) and plateau phase of thermal hyperaemia (P = 0.01). Prolonged poikilocapnic hypoxia causes robust increases in CVC during both phases of thermal hyperaemia that are dependent on the oxygen saturation of the individual. PMID:24706191

  17. Hypoxia Precondition Promotes Adipose-Derived Mesenchymal Stem Cells Based Repair of Diabetic Erectile Dysfunction via Augmenting Angiogenesis and Neuroprotection

    PubMed Central

    Li, ShaoDan; Xu, Yong; Chen, Ping; Liu, Yi; Ding, Qiang; Wahafu, Wasilijiang; Hong, BaoFa; Yang, MingHui

    2015-01-01

    The aim of the present study was to examine whether hypoxia preconditioning could improve therapeutic effects of adipose derived mesenchymal stem cells (AMSCs) for diabetes induced erectile dysfunction (DED). AMSCs were pretreated with normoxia (20% O2, N-AMSCs) or sub-lethal hypoxia (1% O2, H-AMSCs). The hypoxia exposure up-regulated the expression of several angiogenesis and neuroprotection related cytokines in AMSCs, including vascular endothelial growth factor (VEGF) and its receptor FIK-1, angiotensin (Ang-1), basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), stromal derived factor-1 (SDF-1) and its CXC chemokine receptor 4 (CXCR4). DED rats were induced via intraperitoneal injection of streptozotocin (60 mg/kg) and were randomly divided into three groups—Saline group: intracavernous injection with phosphate buffer saline; N-AMSCs group: N-AMSCs injection; H-AMSCs group: H-AMSCs injection. Ten rats without any treatment were used as normal control. Four weeks after injection, the mean arterial pressure (MAP) and intracavernosal pressure (ICP) were measured. The contents of endothelial, smooth muscle, dorsal nerve in cavernoursal tissue were assessed. Compared with N-AMSCs and saline, intracavernosum injection of H-AMSCs significantly raised ICP and ICP/MAP (p<0.05). Immunofluorescent staining analysis demonstrated that improved erectile function by MSCs was significantly associated with increased expression of endothelial markers (CD31 and vWF) (p<0.01) and smooth muscle markers (α-SMA) (p<0.01). Meanwhile, the expression of nNOS was also significantly higher in rats receiving H-AMSCs injection than those receiving N-AMSCs or saline injection. The results suggested that hypoxic preconditioning of MSCs was an effective approach to enhance their therapeutic effect for DED, which may be due to their augmented angiogenesis and neuroprotection. PMID:25790284

  18. Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure.

    PubMed

    Zychowski, Katherine E; Lucas, Selita N; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J

    2016-08-15

    Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability. PMID:27286659

  19. Exercise training attenuates chemoreflex-mediated reductions of renal blood flow in heart failure.

    PubMed

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

    2015-07-15

    In chronic heart failure (CHF), carotid body chemoreceptor (CBC) activity is increased and contributes to increased tonic and hypoxia-evoked elevation in renal sympathetic nerve activity (RSNA). Elevated RSNA and reduced renal perfusion may contribute to development of the cardio-renal syndrome in CHF. Exercise training (EXT) has been shown to abrogate CBC-mediated increases in RSNA in experimental heart failure; however, the effect of EXT on CBC control of renal blood flow (RBF) is undetermined. We hypothesized that CBCs contribute to tonic reductions in RBF in CHF, that stimulation of the CBC with hypoxia would result in exaggerated reductions in RBF, and that these responses would be attenuated with EXT. RBF was measured in CHF-sedentary (SED), CHF-EXT, CHF-carotid body denervation (CBD), and CHF-renal denervation (RDNX) groups. We measured RBF at rest and in response to hypoxia (FiO2 10%). All animals exhibited similar reductions in ejection fraction and fractional shortening as well as increases in ventricular systolic and diastolic volumes. Resting RBF was lower in CHF-SED (29 ± 2 ml/min) than in CHF-EXT animals (46 ± 2 ml/min, P < 0.05) or in CHF-CBD animals (42 ± 6 ml/min, P < 0.05). In CHF-SED, RBF decreased during hypoxia, and this was prevented in CHF-EXT animals. Both CBD and RDNX abolished the RBF response to hypoxia in CHF. Mean arterial pressure increased in response to hypoxia in CHF-SED, but was prevented by EXT, CBD, and RDNX. EXT is effective in attenuating chemoreflex-mediated tonic and hypoxia-evoked reductions in RBF in CHF. PMID:26001414

  20. Peripheral Chemoreception and Arterial Pressure Responses to Intermittent Hypoxia

    PubMed Central

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

    2015-01-01

    Carotid bodies are the principal peripheral chemoreceptors for detecting changes in arterial blood oxygen levels, and the resulting chemoreflex is a potent regulator of blood pressure. Recurrent apnea with intermittent hypoxia (IH) is a major clinical problem in adult humans and infants born preterm. Adult patients with recurrent apnea exhibit heightened sympathetic nerve activity and hypertension. Adults born preterm are predisposed to early onset of hypertension. Available evidence suggests that carotid body chemoreflex contributes to hypertension caused by IH in both adults and neonates. Experimental models of IH provided important insights into cellular and molecular mechanisms underlying carotid body chemoreflex-mediated hypertension. This article provides a comprehensive appraisal of how IH affects carotid body function, underlying cellular, molecular, and epigenetic mechanisms, and the contribution of chemoreflex to the hypertension. PMID:25880505

  1. Daily intermittent hypoxia augments spinal BDNF levels, ERK phosphorylation and respiratory long-term facilitation

    PubMed Central

    Wilkerson, Julia E.R.; Mitchell, Gordon S.

    2009-01-01

    Acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). We hypothesized that: 1) daily AIH (dAIH) preconditioning enhances phrenic and hypoglossal (XII) LTF in a rat strain with low constitutive LTF expression; 2) dAIH induces brain-derived neurotrophic factor (BDNF), a critical protein for phrenic LTF (pLTF) in the cervical spinal cord; and 3) dAIH increases post-AIH extracellular regulated kinase (ERK) activation. Phrenic and XII motor output were monitored in anesthetized dAIH- or sham-treated Brown Norway rats with and without acute AIH. pLTF was observed in both sham (18 ± 9% baseline; 60 min post-hypoxia; p < 0.05; n = 18) and dAIH treated rats (37 ± 8%; p < 0.05; n = 14), but these values were not significantly different (p = 0.13). XII LTF was not observed in sham-treated rats (4 ± 5%), but was revealed in dAIH pretreated rats (48 ± 18%; p < 0.05). dAIH preconditioning increased basal ventral cervical BDNF protein levels (24 ± 8%; p < 0.05), but had no significant effect on ERK phosphorylation. AIH increased BDNF in sham (25 ± 8%; p < 0.05), but not dAIH-pretreated rats (−7 ± 4%), and had complex effects on ERK phosphorylation (ERK2 increased in shams whereas ERK1 increased in dAIH-treated rats). Thus, dAIH elicits metaplasticity in LTF, revealing XII LTF in a rat strain with no constitutive XII LTF expression. Increased BDNF synthesis may no longer be necessary for phrenic LTF following dAIH preconditioning since BDNF concentration is already elevated. PMID:19416672

  2. Molecular Mechanisms of Chronic Intermittent Hypoxia and Hypertension

    PubMed Central

    Sunderram, J.; Androulakis, I.P.

    2013-01-01

    Obstructive sleep apnea (OSA) is characterized by episodes of repeated airway obstruction resulting in cessation (apnea) or reduction (hypopnea) in airflow during sleep. These events lead to intermittent hypoxia and hypercapnia, sleep fragmentation, and changes in intrathoracic pressure, and are associated with a marked surge in sympathetic activity and an abrupt increase in blood pressure. Blood pressure remains elevated during wakefulness despite the absence of obstructive events resulting in a high prevalence of hypertension in patients with OSA. There is substantial evidence that suggests that chronic intermittent hypoxia (CIH) leads to sustained sympathoexcitation during the day and changes in vasculature resulting in hypertension in patients with OSA. Mechanisms of sympathoexcitation include augmentation of peripheral chemoreflex sensitivity and a direct effect on central sites of sympathetic regulation. Interestingly, the vascular changes that occur with CIH have been ascribed to the same molecules that have been implicated in the augmented sympathetic tone in CIH. This review will discuss the hypothesized molecular mechanisms involved in the development of hypertension with CIH, will build a conceptual model for the development of hypertension following CIH, and will propose a systems biology approach in further elucidating the relationship between CIH and the development of hypertension. PMID:23140119

  3. HDAC inhibitor sodium butyrate augments the MEF2C enhancement of Nampt expression under hypoxia.

    PubMed

    Yan, Shao-Fei; You, Hong-Jie; Xing, Tian-Yu; Zhang, Chen-Guang; Ding, Wei

    2014-01-01

    Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme for the salvage biosynthesis of nicotinamide adenine dinucleotide (NAD). Although elevated level of Nampt expression has been observed in various cancers, the involvement of Nampt promoter regulation was not well understood. We have identified a cluster of MEF2 recognition sites upstream of the functional hypoxia response elements (HREs) within the human Nampt promoter, and demonstrated that the two MEF2 sites at -1272 and -1200 were functional to upregulate the promoter activity by luciferase reporter assays. The Nampt promoter was able to be activated cooperatively following hypoxic stimulation by CoCl₂ treatment with associated MEF2C overexpression. During the investigation on MEF2C regulation of endogenous Nampt expression in HeLa cells, the most significant enhancement of Nampt expression observed was by overexpression of MEF2C in combination with sodium butyrate exposure. By chromatin immunoprecipitation with a MEF2C anti-body, we found that MEF2C indeed interacted with endogenous Nampt promoter. The requirement of HDAC inhibition for the MEF2C enhancement of Nampt transcription was verified by RNAi of HDAC. Our results were in support of reports indicating that MEF2 family transcription factors interacted with HDACs and regulated downstream gene expression at the epigenetic levels. Our study provided important evidence to demonstrate the sophisticated mechanism of endogenous Nampt promoter regulation, and therefore, will help to better understand the Nampt overexpression in cancer progression, especially in the context of MEF2C upregulation which frequently occurred in cancer development and drug resistance. PMID:23888946

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

    PubMed

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

    2016-01-01

    Chronic intermittent hypoxia (CIH) is a hallmark manifestation of sleep apnea. A heightened carotid body activity and the resulting chemosensory reflex mediate increased sympathetic nerve activity by CIH. However, the mechanisms underlying heightened carotid body activity by CIH are not known. An elevation of intracellular calcium ion concentration ([Ca(2+)]i) in glomus cells, the primary oxygen-sensing cells, is an essential step for carotid body activation by hypoxia. In the present study, we examined the effects of CIH on the glomus cell [Ca(2+)]i response to hypoxia and assessed the underlying mechanisms. Glomus cells were harvested from adult rats or wild-type mice treated with 10 days of either room air (control) or CIH (alternating cycles of 15 s of hypoxia and 5 min of room air; 9 episodes/h; 8 h/day). CIH-treated glomus cells exhibited an enhanced [Ca(2+)]i response to hypoxia, and this effect was absent in the presence of 2-(4-cyclopropylphenyl)-N-((1R)-1-[5-[(2,2,2-trifluoroethyl)oxo]-pyridin-2-yl]ethyl)acetamide (TTA-A2), a specific inhibitor of T-type Ca(2+) channels, and in voltage-gated calcium channel, type 3.2 (CaV3.2), null glomus cells. CaV3.2 knockout mice exhibited an absence of CIH-induced hypersensitivity of the carotid body. CIH increased reactive oxygen species (ROS) levels in glomus cells. A ROS scavenger prevented the exaggerated TTA-A2-sensitive [Ca(2+)]i response to hypoxia. CIH had no effect on CaV3.2 mRNA levels. CIH augmented Ca(2+) currents and increased CaV3.2 protein in plasma membrane fractions of human embryonic kidney-293 cells stably expressing CaV3.2, and either a ROS scavenger or brefeldin-A, an inhibitor of protein trafficking, prevented these effects. These findings suggest that CIH leads to an augmented Ca(2+) influx via ROS-dependent facilitation of CaV3.2 protein trafficking to the plasma membrane. PMID:26561606

  5. NK1 receptor activation in rat rostral ventrolateral medulla selectively attenuates somato-sympathetic reflex while antagonism attenuates sympathetic chemoreflex.

    PubMed

    Makeham, John M; Goodchild, Ann K; Pilowsky, Paul M

    2005-06-01

    The effects of activation and blockade of the neurokinin 1 (NK1) receptor in the rostral ventrolateral medulla (RVLM) on arterial blood pressure (ABP), splanchnic sympathetic nerve activity (sSNA), phrenic nerve activity, the somato-sympathetic reflex, baroreflex, and chemoreflex were studied in urethane-anesthetized and artificially ventilated Sprague-Dawley rats. Bilateral microinjection of either the stable substance P analog (pGlu5, MePhe8, Sar9)SP(5-11) (DiMe-SP) or the highly selective NK1 agonist [Sar9, Met (O(2))11]SP into the RVLM resulted in an increase in ABP, sSNA, and heart rate and an abolition of phrenic nerve activity. The effects of [Sar9, Met (O(2))11]SP were blocked by the selective nonpeptide NK1 receptor antagonist WIN 51708. NK1 receptor activation also dramatically attenuated the somato-sympathetic reflex elicited by tibial nerve stimulation, while leaving the baroreflex and chemoreflex unaffected. This effect was again blocked by WIN 51708. NK1 receptor antagonism in the RVLM, with WIN 51708 significantly attenuated the sympathoexcitatory response to hypoxia but had no effect on baseline respiratory function. Our findings suggest that substance P and the NK1 receptor play a significant role in the cardiorespiratory reflexes integrated within the RVLM. PMID:15731401

  6. Cardiovascular responses to peripheral chemoreflex activation and comparison of different methods to evaluate baroreflex gain in conscious mice using telemetry.

    PubMed

    Braga, Valdir A; Burmeister, Melissa A; Sharma, Ram V; Davisson, Robin L

    2008-10-01

    Peripheral chemoreceptors located in the carotid bodies are the primary sensors of systemic hypoxia. Although the pattern of responses elicited by peripheral chemoreceptor activation is well established in rats, lambs, and rabbits, the cardiovascular responses to peripheral chemoreflex activation in conscious mice have not been delineated. Here we report that stimulation of peripheral chemoreceptors by potassium cyanide (KCN) in conscious mice elicits a unique biphasic response in blood pressure that is characterized by an initial and robust rise followed by a decrease in blood pressure, which is accompanied by a marked reduction in heart rate. The depressor and bradycardic responses to KCN were abolished by muscarinic receptor blockade with atropine, and the pressor response was abolished by alpha-adrenergic receptor blockade with prazosin, suggesting that vagal and sympathetic drive to the heart and sympathetic drive to the vasculature mediate these cardiovascular responses. These studies characterized the chemoreflex in conscious mice and established the reliability of using them for studying hypoxia-related diseases such as obstructive sleep apnea. In another series of experiments, two methods for analyzing baroreflex sensitivity were compared: the classical pharmacological approach using phenylephrine and sodium nitroprusside (i.e., the Oxford technique) or the sequence method for analyzing spontaneous baroreflex activity. Our findings indicate that both methods are reliable, and the sequence method certainly has its benefits as a predictive tool in the context of long-term noninvasive studies using telemetry. However, for absolute determination of baroreflex function, analysis of spontaneous baroreflex activity should be complemented by the classical pharmacological method. PMID:18667715

  7. Chemoreflex and baroreflex alterations in Parkinsonism induced by 6-OHDA in unanesthetized rats.

    PubMed

    Ariza, Deborah; Lopes, Fernanda Novi Cortegoso; Crestani, Carlos Cesar; Martins-Pinge, Marli Cardoso

    2015-10-21

    Parkinson's disease (PD) is mainly characterized by motor signals. However, non-motor signals also affect and decrease the quality of life of PD patients. Among these non-motor signs are cardiovascular disorders as orthostatic hypotension, postprandial hypotension and cardiac arrhythmias, which may be due to the involvement of both central nervous system and peripheral autonomic nervous system. In the present study we investigated the cardiovascular function, evaluating cardiovascular reflexes (chemoreflex and baroreflex), in an animal model of Parkinsonism induced by bilateral infusion of the toxin 6-hydroxydopamine (6-OHDA), in the substantia nigra pars compacta (SNpc). The results showed that the animals induced to Parkinsonism had lower arterial pressure (AP) and heart rate HR) compared to control animals. We showed that after activation of the baroreceptors by phenylephrine (Phe) and sodium nitroprusside (SNP), the baroreflex sensitivity index was not changed between the groups. However, there was a greater increase in the AP when stimulated with Phe and greater tachycardia when stimulated with SNP in 6-OHDA animals. After activation of the peripheral chemoreceptors through KCN injection (cytotoxic hypoxia), there was a higher increase in pressor and bradycardic response in injured animals with bilateral 6-OHDA. These changes in the cardiovascular reflexes may be important adjustments mechanisms to maintain the cerebral blood flow in those animals, and may be a result of denervation supersensitivity to catecholamines in autonomic targets. PMID:26409036

  8. Fetal acidosis and hypotension during repeated umbilical cord occlusions are associated with enhanced chemoreflex responses in near-term fetal sheep.

    PubMed

    Bennet, Laura; Westgate, Jenny A; Liu, Yung-Chi Jack; Wassink, Guido; Gunn, Alistair J

    2005-10-01

    This study examined the hypothesis that repeated episodes of brief but severe hypoxia would not attenuate the chemoreflex-mediated rapid initial fall in fetal heart rate (FHR) and, further, that greater hypoxic stress, as shown by hypotension and metabolic acidosis, would be associated with an enhanced chemoreflex response. Chronically instrumented, near-term fetal sheep received 1 min total umbilical cord occlusion either every 5 min for 4 h (1:5 group; n = 8) or every 2.5 min (1:2.5 group; n = 8) until mean arterial blood pressure fell to <20 mmHg on two successive occlusions. Umbilical cord occlusion caused variable decelerations, with sustained hypertension in the 1:5 group and little change in acid-base status (pH 7.34 +/- 0.03 after 4 h). In contrast, the 1:2.5 group showed progressive hypotension and metabolic acidemia (pH 6.92 +/- 0.04 after the last occlusion). The 1:2.5 group showed a significant increase in the rate of initial fall in FHR during the occlusion series, which was greater than the 1:5 group in the last 30 min of the occlusion series (9.4 +/- 1.4 vs. 3.5 +/- 0.3 beats.min(-1).s(-1); P < 0.01), with a greater fall in FHR (71.9 +/- 6.5 vs. 47.0 +/- 8.7 beats/min; P < 0.05). In summary, this study demonstrated that repetitive laborlike cord occlusions, which led to severe fetal compromise, were associated with an increase in the slope and magnitude of the initial FHR deceleration. These findings support the concept of the chemoreflex as a central, robust component of fetal adaptation to severe hypoxia. PMID:15976361

  9. Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1α

    PubMed Central

    Patel, Nitin; Gonsalves, Caryn S.

    2008-01-01

    Pulmonary hypertension (PHT) develops in sickle cell disease (SCD) and is associated with high mortality. We previously showed that erythroid cells produce placenta growth factor (PlGF), which activates monocytes to induce proinflammatory cytochemokines, contributing to the baseline inflammation and severity in SCD. In this study, we observed that PlGF increased expression of endothelin-1 (ET-1) and endothelin-B receptor (ET-BR) from human pulmonary microvascular endothelial cells (HPMVECs) and monocytes, respectively. PlGF-mediated ET-1 and ET-BR expression occurred via activation of PI-3 kinase, reactive oxygen species and hypoxia inducible factor-1α (HIF-1α). PlGF increased binding of HIF-1α to the ET-1 and ET-BR promoters; this effect was abrogated with mutation of hypoxia response elements in the promoter regions and HIF-1α siRNA and confirmed by chromatin immunoprecipitation analysis. Furthermore, PlGF-mediated ET-1 release from HPMVECs and ET-BR expression in monocytes creates a PlGF–ET-1–ET-BR loop, leading to increased expression of MCP-1 and IL-8. Our studies show that PlGF-induced expression of the potent vasoconstrictor ET-1 and its cognate ET-BR receptor occur via activation of HIF-1α, independent of hypoxia. PlGF levels are intrinsically elevated from the increased red cell turnover in SCD and in other chronic anemia (eg, thalassemia) and may contribute to inflammation and PHT seen in these diseases. PMID:18411415

  10. Menstrual cycle and sex effects on sympathetic responses to acute chemoreflex stress.

    PubMed

    Usselman, Charlotte W; Gimon, Tamara I; Nielson, Chantelle A; Luchyshyn, Torri A; Coverdale, Nicole S; Van Uum, Stan H M; Shoemaker, J Kevin

    2015-03-15

    This study aimed to examine the effects of sex (males vs. females) and sex hormones (menstrual cycle phases in women) on sympathetic responsiveness to severe chemoreflex activation in young, healthy individuals. Muscle sympathetic nerve activity (MSNA) was measured at baseline and during rebreathing followed by a maximal end-inspiratory apnea. In women, baseline MSNA was greater in the midluteal (ML) than early-follicular (EF) phase of the menstrual cycle. Baseline MSNA burst incidence was greater in men than women, while burst frequency and total MSNA were similar between men and women only in the ML phase. Chemoreflex activation evoked graded increases in MSNA burst frequency, amplitude, and total activity in all participants. In women, this sympathoexcitation was greater in the EF than ML phase. The sympathoexcitatory response to chemoreflex stimulation of the EF phase in women was also greater than in men. Nonetheless, changes in total peripheral resistance were similar between sexes and menstrual cycle phases. This indicates that neurovascular transduction was attenuated during the EF phase during chemoreflex activation, thereby offsetting the exaggerated sympathoexcitation. Chemoreflex-induced increases in mean arterial pressure were similar across sexes and menstrual cycle phases. During acute chemoreflex stimulation, reduced neurovascular transduction could provide a mechanism by which apnea-associated morbidity might be attenuated in women relative to men. PMID:25527774

  11. Interactions between CO2 chemoreflexes and arterial baroreflexes.

    PubMed

    Henry, R A; Lu, I L; Beightol, L A; Eckberg, D L

    1998-06-01

    We studied interactions between CO2 chemoreflexes and arterial baroreflexes in 10 supine healthy young men and women. We measured vagal carotid baroreceptor-cardiac reflexes and steady-state fast Fourier transform R-R interval and photoplethysmographic arterial pressure power spectra at three arterial pressure levels (nitroprusside, saline, and phenylephrine infusions) and three end-tidal CO2 levels (3, 4, and 5%, fixed-frequency, large-tidal-volume breathing, CO2 plus O2). Our study supports three principal conclusions. First, although low levels of CO2 chemoreceptor stimulation reduce R-R intervals and R-R interval variability, statistical modeling suggests that this effect is indirect rather than direct and is mediated by reductions of arterial pressure. Second, reductions of R-R intervals during hypocapnia reflect simple shifting of vagally mediated carotid baroreflex responses on the R-R interval axis rather than changes of baroreflex gain, range, or operational point. Third, the influence of CO2 chemoreceptor stimulation on arterial pressure (and, derivatively, on R-R intervals and R-R interval variability) depends critically on baseline arterial pressure levels: chemoreceptor effects are smaller when pressure is low and larger when arterial pressure is high. PMID:9841543

  12. Chemoreflex Physiology and Implications for Sleep Apnea – Insights from Studies in Humans

    PubMed Central

    Mansukhani, Meghna P.; Wang, Shihan; Somers, Virend K.

    2015-01-01

    Activation of the chemoreflex in response to hypoxemia results in an increase in sympathetic neural outflow. This process is predominantly mediated by the peripheral chemoreceptors in the carotid bodies and is potentiated by the absence of the sympatho-inhibitory influence of ventilation during apnea, as is seen in patients with sleep apnea. In these patients, repetitive nocturnal hyoxemia and apnea elicit sympathetic activation, which may persist into wakefulness, and is thought to contribute to the development of systemic hypertension, and cardiac and vascular dysfunction. Chemoreflex activation could possibly lead to adverse cardiovascular outcomes such as nocturnal myocardial infarction, systolic and/or diastolic heart failure, cardiac arrhythmias and sudden death in patients with sleep apnea. This review summarizes chemoreflex physiology in health and disease, with specific focus on chemoreflex-mediated pathophysiology in obstructive and central sleep apnea. Measurement of the chemoreflex response may serve as a potential avenue for individualized screening for cardiovascular disease. Whether modulation of this response in sleep apnea may aid in the prevention and treatment of adverse cardiovascular consequences will require further study. PMID:25398715

  13. Interactive effect of hypoxia and otolith organ engagement on cardiovascular regulation in humans

    NASA Technical Reports Server (NTRS)

    Monahan, Kevin D.; Ray, Chester A.

    2002-01-01

    We determined the interaction between the vestibulosympathetic reflex and the arterial chemoreflex in 12 healthy subjects. Subjects performed three trials in which continuous recordings of muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP), heart rate (HR), and arterial oxygen saturation were obtained. First, in prone subjects the otolith organs were engaged by use of head-down rotation (HDR). Second, the arterial chemoreflex was activated by inspiration of hypoxic gas (10% O2 and 90% N2) for 7 min with HDR being performed during minute 6. Third, hypoxia was repeated (15 min) with HDR being performed during minute 14. HDR [means +/- SE; increase (Delta)7 +/- 1 bursts/min and Delta50 +/- 11% for burst frequency and total MSNA, respectively; P < 0.05] and hypoxia (Delta6 +/- 2 bursts/min and Delta62 +/- 29%; P < 0.05) increased MSNA. Additionally, MSNA increased when HDR was performed during hypoxia (Delta11 +/- 2 bursts/min and Delta127 +/- 57% change from normoxia; P < 0.05). These increases in MSNA were similar to the algebraic sum of the individual increase in MSNA elicited by HDR and hypoxia (Delta13 +/- 1 bursts/min and Delta115 +/- 36%). Increases in MAP (Delta3 +/- 1 mmHg) and HR (Delta19 +/- 1 beats/min) during combined HDR and hypoxia generally were smaller (P < 0.05) than the algebraic sum of the individual responses (Delta5 +/- 1 mmHg and Delta24 +/- 2 beats/min for MAP and HR, respectively; P < 0.05). These findings indicate an additive interaction between the vestibulosympathetic reflex and arterial chemoreflex for MSNA. Therefore, it appears that MSNA outputs between the vestibulosympathetic reflex and arterial chemoreflex are independent of one another in humans.

  14. Cerebral Hypoxia

    MedlinePlus

    ... 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 ...

  15. Spinal cord injury is associated with enhanced peripheral chemoreflex sensitivity.

    PubMed

    Bascom, Amy T; Sankari, Abdulghani; Badr, M Safwan

    2016-09-01

    Sleep-disordered breathing (SDB) is prevalent in individuals with chronic spinal cord injury (SCI), but the exact mechanism is unknown. The aim of this study was to investigate whether peripheral chemoreceptors activity is enhanced in individuals with chronic SCI compared to abled-bodied control subjects using CO2 and O2 chemical tests. In protocol (1) 30 subjects (8 cervical [cSCI], 7 thoracic [tSCI] and 15 able-bodied [AB]) were studied to determine the ventilatory response to hyperoxia during wakefulness in the supine position. In protocol (2) 24 subjects (6 cSCI, 6 tSCI, and 12 AB subjects) were studied to determine the ventilatory response to a single breath of CO2 (SBCO2). The chemoreflex response to SBCO2 was calculated as ∆VE/∆CO2 (L/min/mmHg). The ventilatory response to hyperoxia was defined as the % change in VT following acute hyperoxia compared to preceding baseline. During hyperoxia SCI subjects had a significant decrease in VT and VE (63.4 ± 21.7% and 63.1 ± 23.0% baseline, respectively, P < 0.05) compared to AB (VT: 87.1 ± 14.3% and VE: 91.38 ± 15.1% baseline, respectively, P < 0.05). There was no significant difference between cSCI and tSCI in the VT or VE during hyperoxia (P = NS). There was no significant correlation between AHI and VE% baseline (r = -0.28) in SCI and AB (n = 30). SCI participants had a greater ventilatory response to an SBCO2 than AB (0.78 ± 0.42 L/min/mmHg vs. 0.26 ± 0.10 L/min/mmHg, respectively, P < 0.05). Peripheral ventilatory chemoresponsiveness is elevated in individuals with chronic SCI compared to able-bodied individuals. PMID:27597767

  16. Relevance of the Carotid Body Chemoreflex in the Progression of Heart Failure

    PubMed Central

    Andrade, David C.; Lucero, Claudia; Toledo, Camilo; Madrid, Carlos; Marcus, Noah J.; Schultz, Harold D.; Del Rio, Rodrigo

    2015-01-01

    Chronic heart failure (CHF) is a global health problem affecting millions of people. Autonomic dysfunction and disordered breathing patterns are commonly observed in patients with CHF, and both are strongly related to poor prognosis and high mortality risk. Tonic activation of carotid body (CB) chemoreceptors contributes to sympathoexcitation and disordered breathing patterns in experimental models of CHF. Recent studies show that ablation of the CB chemoreceptors improves autonomic function and breathing control in CHF and improves survival. These exciting findings indicate that alterations in CB function are critical to the progression of CHF. Therefore, better understanding of the physiology of the CB chemoreflex in CHF could lead to improvements in current treatments and clinical management of patients with CHF characterized by high chemosensitivity. Accordingly, the main focus of this brief review is to summarize current knowledge of CB chemoreflex function in different experimental models of CHF and to comment on their potential translation to treatment of human CHF. PMID:26779536

  17. Autonomic and cardiovascular responses to chemoreflex stress in apnoea divers.

    PubMed

    Steinback, Craig D; Breskovic, Toni; Banic, Ivana; Dujic, Zeljko; Shoemaker, J Kevin

    2010-08-25

    Sleep apnoea, with repeated periods of hypoxia, results in cardiovascular morbidity and concomitant autonomic dysregulation. Trained apnoea divers also perform prolonged apnoeas accompanied by large lung volumes, large reductions in cardiac output and severe hypoxia and hypercapnia. We tested the hypothesis that apnoea training would be associated with decreased cardiovagal and sympathetic baroreflex gains and reduced respiratory modulation of muscle sympathetic nerve activity (MSNA; microneurography). Six trained divers and six controls were studied at rest and during asphyxic rebreathing. Despite an elevated resting heart rate (70+/-14 vs. 56+/-10 bpm; p=0.038), divers had a similar cardiovagal baroreflex gain (-1.22+/-0.47 beats/mmHg) as controls (-1.29+/-0.61; NS). Similarly, though MSNA burst frequency was slightly higher in divers at rest (16+/-4 bursts/min vs. 10+/-5 bursts/min, p=0.03) there was no difference in baseline burst incidence, sympathetic baroreflex gain (-3.8+/-2.1%/mmHg vs. -4.7+/-1.7%/mmHg) or respiratory modulation of MSNA between groups. Resting total peripheral resistance (11.9+/-2.6 vs. 12.3+/-2.2 mmHg/L/min) and pulse wave velocity (5.82+/-0.55 vs. 6.10+/-0.51 m/s) also were similar between divers and controls, respectively. Further, the sympathetic response to asphyxic rebreathing was not different between controls and divers (-1.70+/-1.07 vs. -1.74+/-0.84 a.u./% desaturation). Thus, these data suggest that, unlike patients with sleep apnoea, apnoea training in otherwise healthy individuals does not produce detectable autonomic dysregulation or maladaption. PMID:20627720

  18. Hypoxia in Diabetic Kidneys

    PubMed Central

    Takiyama, Yumi; Haneda, Masakazu

    2014-01-01

    Diabetic nephropathy (DN) is now a leading cause of end-stage renal disease. In addition, DN accounts for the increased mortality in type 1 and type 2 diabetes, and then patients without DN achieve long-term survival compatible with general population. Hypoxia represents an early event in the development and progression of DN, and hypoxia-inducible factor- (HIF-) 1 mediates the metabolic responses to renal hypoxia. Diabetes induces the “fraternal twins” of hypoxia, that is, pseudohypoxia and hypoxia. The kidneys are susceptible to hyperoxia because they accept 20% of the cardiac output. Therefore, the kidneys have specific vasculature to avoid hyperoxia, that is, AV oxygen shunting. The NAD-dependent histone deacetylases (HDACs) sirtuins are seven mammalian proteins, SIRTs 1–7, which are known to modulate longevity and metabolism. Recent studies demonstrated that some isoforms of sirtuins inhibit the activation of HIF by deacetylation or noncatalyzing effects. The kidneys, which have a vascular system that protects them against hyperoxia, unfortunately experience extraordinary hypernutrition today. Then, an unexpected overload of glucose augments the oxygen consumption, which ironically results in hypoxia. This review highlights the primary role of HIF in diabetic kidneys for the metabolic adaptation to diabetes-induced hypoxia. PMID:25054148

  19. Effect of carotid denervation on plasma vasopressin levels during acute hypoxia in the late-gestation sheep fetus.

    PubMed Central

    Giussani, D A; McGarrigle, H H; Spencer, J A; Moore, P J; Bennet, L; Hanson, M A

    1994-01-01

    1. We measured plasma concentrations of arginine vasopressin (AVP), arterial, venous and amniotic pressures, and carotid and femoral blood flows in fifteen chronically instrumented fetal sheep at 119-125 days of gestation. In eight of the fetuses the carotid sinus nerves were cut (denervated fetuses); the other seven remained intact and served as controls (intact fetuses). 2. In the intact fetuses during hypoxia there was an increase in plasma [AVP] and in perfusion (arterial-venous) pressure, a transient bradycardia, and an increase in carotid and a decrease in femoral blood flow. Whilst femoral vascular resistance (perfusion pressure/femoral blood flow) increased, there were no changes in carotid vascular resistance during hypoxia. 3. In the denervated fetuses no significant bradycardia, fall in femoral blood flow or increase in femoral vascular resistance was present soon after the onset of hypoxia but plasma AVP increased to similar concentrations to those observed in intact fetuses during hypoxia. 4. We conclude that carotid denervation does not affect plasma [AVP] during hypoxia in fetal sheep. This suggests that (1) AVP release during hypoxia is not mediated by a carotid chemoreflex and (2) AVP does not play an important role in these initial fetal cardiovascular responses. Furthermore, we previously reported that intact fetuses survive acute hypoxia better than denervated fetuses following phentolamine treatment, and we believe this to be due to the action of a non-alpha-adrenergic vasoconstrictor released in part via a carotid chemoreflex. The present results suggest that this vasoconstrictor is not AVP. PMID:8071890

  20. The myths and physiology surrounding intrapartum decelerations: the critical role of the peripheral chemoreflex.

    PubMed

    Lear, Christopher A; Galinsky, Robert; Wassink, Guido; Yamaguchi, Kyohei; Davidson, Joanne O; Westgate, Jenny A; Bennet, Laura; Gunn, Alistair J

    2016-09-01

    A distinctive pattern of recurrent rapid falls in fetal heart rate, called decelerations, are commonly associated with uterine contractions during labour. These brief decelerations are mediated by vagal activation. The reflex triggering this vagal response has been variably attributed to a mechanoreceptor response to fetal head compression, to baroreflex activation following increased blood pressure during umbilical cord compression, and/or a Bezold-Jarisch reflex response to reduced venous return from the placenta. Although these complex explanations are still widespread today, there is no consistent evidence that they are common during labour. Instead, the only mechanism that has been systematically investigated, proven to be reliably active during labour and, crucially, capable of producing rapid decelerations is the peripheral chemoreflex. The peripheral chemoreflex is triggered by transient periods of asphyxia that are a normal phenomenon associated with all uterine contractions. This should not cause concern as the healthy fetus has a remarkable ability to adapt to these repeated but short periods of asphyxia. This means that the healthy fetus is typically not at risk of hypotension and injury during uncomplicated labour even during repeated brief decelerations. The physiologically incorrect theories surrounding decelerations that ignore the natural occurrence of repeated asphyxia probably gained widespread support to help explain why many babies are born healthy despite repeated decelerations during labour. We propose that a unified and physiological understanding of intrapartum decelerations that accepts the true nature of labour is critical to improve interpretation of intrapartum fetal heart rate patterns. PMID:27328617

  1. Acrolein Causes TRPA1-Mediated Sensory Irritation and Indirect Potentiation of TRPV1-Mediated Pulmonary Chemoreflex Response

    EPA Science Inventory

    We previously demonstrated that acute exposure to acrolein causes immediate sensory irritation, with rapid decrease in heart rate (HR) and increase in inspiratory time (Ti), and potentiation of pulmonary chemoreflex response 24hrs later; of these effects only the latter is mediat...

  2. Sympathetic neural recruitment strategies: responses to severe chemoreflex and baroreflex stress.

    PubMed

    Badrov, Mark B; Usselman, Charlotte W; Shoemaker, J Kevin

    2015-07-15

    This study tested the hypothesis that neural coding patterns exist within the autonomic nervous system. We investigated sympathetic axonal recruitment strategies in humans during chemoreflex- and baroreflex-mediated sympathoexcitation using a novel action potential (AP) analysis technique. Muscle sympathetic nerve activity (microneurography) was collected in 11 young individuals (6 females) during baseline and two subsequent protocols: 1) severe chemoreflex stimulation (maximal end-inspiratory apnea following rebreathe), and 2) severe baroreceptor unloading (-80 mmHg lower body negative pressure; LBNP). When compared with each respective baseline, apnea and LBNP increased AP frequency and mean AP content per sympathetic burst (all P < 0.01). When APs were binned according to peak-to-peak amplitude (i.e., into "clusters"), total clusters detected increased during both apnea (Δ7 ± 5; P = 0.0009) and LBNP (Δ11 ± 8; P = 0.0012) compared with baseline. This was concomitant to an increased number of active clusters per burst during apnea (Δ3 ± 1; P < 0.0001) and LBNP (Δ3 ± 3; P = 0.0076). At baseline and during apnea (R(2) = 0.98; P < 0.0001) and LBNP (R(2) = 0.95; P < 0.0001), a pattern emerged whereby AP cluster latency decreased as cluster size increased. Furthermore, the AP cluster latency profile was shifted downward during apnea (∼53 ms) and upward during LBNP (∼31 ms). The data indicate that variations in synaptic delays and latent subpopulations of larger axons exist as recruitment strategies for sympathetic outflow. The synaptic delay component appears to express reflex specificity, whereas latent subpopulation recruitment demonstrates sensitivity to stress severity. PMID:25947171

  3. Sympathetic neural recruitment strategies: responses to severe chemoreflex and baroreflex stress

    PubMed Central

    Badrov, Mark B.; Usselman, Charlotte W.

    2015-01-01

    This study tested the hypothesis that neural coding patterns exist within the autonomic nervous system. We investigated sympathetic axonal recruitment strategies in humans during chemoreflex- and baroreflex-mediated sympathoexcitation using a novel action potential (AP) analysis technique. Muscle sympathetic nerve activity (microneurography) was collected in 11 young individuals (6 females) during baseline and two subsequent protocols: 1) severe chemoreflex stimulation (maximal end-inspiratory apnea following rebreathe), and 2) severe baroreceptor unloading (−80 mmHg lower body negative pressure; LBNP). When compared with each respective baseline, apnea and LBNP increased AP frequency and mean AP content per sympathetic burst (all P < 0.01). When APs were binned according to peak-to-peak amplitude (i.e., into “clusters”), total clusters detected increased during both apnea (Δ7 ± 5; P = 0.0009) and LBNP (Δ11 ± 8; P = 0.0012) compared with baseline. This was concomitant to an increased number of active clusters per burst during apnea (Δ3 ± 1; P < 0.0001) and LBNP (Δ3 ± 3; P = 0.0076). At baseline and during apnea (R2 = 0.98; P < 0.0001) and LBNP (R2 = 0.95; P < 0.0001), a pattern emerged whereby AP cluster latency decreased as cluster size increased. Furthermore, the AP cluster latency profile was shifted downward during apnea (∼53 ms) and upward during LBNP (∼31 ms). The data indicate that variations in synaptic delays and latent subpopulations of larger axons exist as recruitment strategies for sympathetic outflow. The synaptic delay component appears to express reflex specificity, whereas latent subpopulation recruitment demonstrates sensitivity to stress severity. PMID:25947171

  4. Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep.

    PubMed Central

    Giussani, D A; Spencer, J A; Moore, P J; Bennet, L; Hanson, M A

    1993-01-01

    afferent limb of this reflex. The bradycardia is mediated through a muscarinic pathway, as it is blocked by atropine. The femoral vasoconstriction is mediated through an alpha-adrenergic mechanism, mediated both neurally by a carotid chemoreflex and via catecholamines released directly from the adrenal medulla. Both these components are blocked by phentolamine. 7. The differences in survival between intact and denervated fetuses during hypoxia after phentolamine suggest that the carotid chemoreflex response to hypoxia involves mechanisms in addition to vagal efferents to the heart and alpha-adrenergic actions at peripheral blood vessels.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8350271

  5. Serotonin in the solitary tract nucleus shortens the laryngeal chemoreflex in anaesthetized neonatal rats.

    PubMed

    Donnelly, William T; Bartlett, Donald; Leiter, J C

    2016-07-01

    What is the central question of this study? Failure to terminate apnoea and arouse is likely to contribute to sudden infant death syndrome (SIDS). Serotonin is deficient in the brainstems of babies who died of SIDS. Therefore, we tested the hypothesis that serotonin in the nucleus of the solitary tract (NTS) would shorten reflex apnoea. What is the main finding and its importance? Serotonin microinjected into the NTS shortened the apnoea and respiratory inhibition associated with the laryngeal chemoreflex. Moreover, this effect was achieved through a 5-HT3 receptor. This is a new insight that is likely to be relevant to the pathogenesis of SIDS. The laryngeal chemoreflex (LCR), an airway-protective reflex that causes apnoea and bradycardia, has long been suspected as an initiating event in the sudden infant death syndrome. Serotonin (5-HT) and 5-HT receptors may be deficient in the brainstems of babies who die of sudden infant death syndrome, and 5-HT seems to be important in terminating apnoeas directly or in causing arousals or as part of the process of autoresuscitation. We hypothesized that 5-HT in the brainstem would limit the duration of the LCR. We studied anaesthetized rat pups between 7 and 21 days of age and made microinjections into the cisterna magna or into the nucleus of the solitary tract (NTS). Focal, bilateral microinjections of 5-HT into the caudal NTS significantly shortened the LCR. The 5-HT1a receptor antagonist, WAY 100635, did not affect the LCR consistently, nor did a 5-HT2 receptor antagonist, ketanserin, alter the duration of the LCR. The 5-HT3 specific agonist, 1-(3-chlorophenyl)-biguanide, microinjected bilaterally into the caudal NTS significantly shortened the LCR. Thus, endogenous 5-HT released within the NTS may curtail the respiratory depression that is part of the LCR, and serotonergic shortening of the LCR may be attributed to activation of 5-HT3 receptors within the NTS. 5-HT3 receptors are expressed presynaptically on C

  6. Effect of acute hypoxia on blood flow in vertebral and internal carotid arteries.

    PubMed

    Ogoh, Shigehiko; Sato, Kohei; Nakahara, Hidehiro; Okazaki, Kazunobu; Subudhi, Andrew W; Miyamoto, Tadayoshi

    2013-03-01

    Hypoxia changes the regional distribution of cerebral blood flow and stimulates the ventilatory chemoreflex, thereby reducing CO2 tension. We examined the effects of both hypoxia and isocapnic hypoxia on acute changes in internal carotid (ICA) and vertebral artery (VA) blood flow. Ten healthy male subjects underwent the following two randomly assigned respiratory interventions after a resting baseline period with room air: (i) hypoxia; and (ii) isocapnic hypoxia with a controlled gas mixture (12% O2; inspiratory mmHg). In the isocapnic hypoxia intervention, subjects were instructed to maintain the rate and depth of breathing to maintain the level of end-tidal partial pressure of CO2 ( ) during the resting baseline period. The ICA and VA blood flow (velocity × cross-sectional area) were measured using Doppler ultrasonography. The was decreased (-6.3 ± 0.9%, P < 0.001) during hypoxia by hyperventilation (minute ventilation +12.9 ± 2.2%, P < 0.001), while was unchanged during isocapnic hypoxia. The ICA blood flow was unchanged (P = 0.429), while VA blood flow increased (+10.3 ± 3.1%, P = 0.010) during hypoxia. In contrast, isocapnic hypoxia increased both ICA (+14.5 ± 1.4%, P < 0.001) and VA blood flows (+10.9 ± 2.4%, P < 0.001). Thus, hypoxic vasodilatation outweighed hypocapnic vasoconstriction in the VA, but not in the ICA. These findings suggest that acute hypoxia elicits an increase in posterior cerebral blood flow, possibly to maintain essential homeostatic functions of the brainstem. PMID:23143991

  7. Hypoxia Silences Retrotrapezoid Nucleus Respiratory Chemoreceptors via Alkalosis

    PubMed Central

    Basting, Tyler M.; Burke, Peter G.R.; Kanbar, Roy; Viar, Kenneth E.; Stornetta, Daniel S.; Stornetta, Ruth L.

    2015-01-01

    In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (ΔfR) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔVT) followed the same trend. The effect of hypoxia on ΔfR was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). ΔfR was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN. PMID:25589748

  8. Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis.

    PubMed

    Basting, Tyler M; Burke, Peter G R; Kanbar, Roy; Viar, Kenneth E; Stornetta, Daniel S; Stornetta, Ruth L; Guyenet, Patrice G

    2015-01-14

    In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (Δf(R)) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔV(T)) followed the same trend. The effect of hypoxia on Δf(R) was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). Δf(R) was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN. PMID:25589748

  9. Nucleus tractus solitarii A(2a) adenosine receptors inhibit cardiopulmonary chemoreflex control of sympathetic outputs.

    PubMed

    Minic, Zeljka; O'Leary, Donal S; Scislo, Tadeusz J

    2014-02-01

    Previously we have shown that stimulation of inhibitory A1 adenosine receptors located in the nucleus tractus solitarii (NTS) attenuates cardiopulmonary chemoreflex (CCR) evoked inhibition of renal, adrenal and lumbar sympathetic nerve activity and reflex decreases in arterial pressure and heart rate. Activation of facilitatory A2a adenosine receptors, which dominate over A1 receptors in the NTS, contrastingly alters baseline activity of regional sympathetic outputs: it decreases renal, increases adrenal and does not change lumbar nerve activity. Considering that NTS A2a receptors may facilitate release of inhibitory transmitters we hypothesized that A2a receptors will act in concert with A1 receptors differentially inhibiting regional sympathetic CCR responses (adrenal>lumbar>renal). In urethane/chloralose anesthetized rats (n=38) we compared regional sympathetic responses evoked by stimulation of the CCR with right atrial injections of serotonin 5HT3 receptor agonist, phenylbiguanide, (1-8μg/kg) before and after selective stimulation, blockade or combined blockade and stimulation of NTS A2a adenosine receptors (microinjections into the NTS of CGS-21680 0.2-20pmol/50nl, ZM-241385 40pmol/100nl or ZM-241385+CGS-21680, respectively). We found that stimulation of A2a adenosine receptors uniformly inhibited the regional sympathetic and hemodynamic reflex responses and this effect was abolished by the selective blockade of NTS A2a receptors. This indicates that A2a receptor triggered inhibition of CCR responses and the contrasting shifts in baseline sympathetic activity are mediated via different mechanisms. These data implicate that stimulation of NTS A2a receptors triggers unknown inhibitory mechanism(s) which in turn inhibit transmission in the CCR pathway when adenosine is released into the NTS during severe hypotension. PMID:24216055

  10. Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors.

    PubMed

    Minic, Zeljka; Li, Cailian; O'Leary, Donal S; Scislo, Tadeusz J

    2014-09-15

    Selective stimulation of inhibitory A1 and facilitatory A2a adenosine receptor subtypes located in the nucleus of the solitary tract (NTS) powerfully inhibits cardiopulmonary chemoreflex (CCR) control of regional sympathetic outputs via different mechanisms: direct inhibition of glutamate release and facilitation of an inhibitory neurotransmitter release, respectively. However, it remains unknown whether adenosine naturally released into the NTS has similar inhibitory effects on the CCR as the exogenous agonists do. Our previous study showed that adenosine is released into the NTS during severe hemorrhage and contributes to reciprocal changes of renal (decreases) and adrenal (increases) sympathetic nerve activity observed in this setting. Both A1 and A2a adenosine receptors are involved. Therefore, we tested the hypothesis that, during severe hemorrhage, CCR control of the two sympathetic outputs is attenuated by adenosine naturally released into the NTS. We compared renal and adrenal sympathoinhibitory responses evoked by right atrial injections of 5HT3 receptor agonist phenylbiguanide (2-8 μg/kg) under control conditions, during hemorrhage, and during hemorrhage preceded by blockade of NTS adenosine receptors with bilateral microinjections of 8-(p-sulfophenyl) theophylline (1 nmol/100 nl) in urethane/chloralose anesthetized rats. CCR-mediated inhibition of renal and adrenal sympathetic activity was significantly attenuated during severe hemorrhage despite reciprocal changes in the baseline activity levels, and this attenuation was removed by bilateral blockade of adenosine receptors in the caudal NTS. This confirmed that adenosine endogenously released into the NTS has a similar modulatory effect on integration of cardiovascular reflexes as stimulation of NTS adenosine receptors with exogenous agonists. PMID:25063794

  11. Distinct physiological strategies are used to cope with constant hypoxia and intermittent hypoxia in killifish (Fundulus heteroclitus).

    PubMed

    Borowiec, Brittney G; Darcy, Kimberly L; Gillette, Danielle M; Scott, Graham R

    2015-04-15

    Many fish encounter hypoxia on a daily cycle, but the physiological effects of intermittent hypoxia are poorly understood. We investigated whether acclimation to constant (sustained) hypoxia or to intermittent diel cycles of nocturnal hypoxia (12 h normoxia:12 h hypoxia) had distinct effects on hypoxia tolerance or on several determinants of O2 transport and O2 utilization in estuarine killifish. Adult killifish were acclimated to normoxia, constant hypoxia, or intermittent hypoxia for 7 or 28 days in brackish water (4 ppt). Acclimation to both hypoxia patterns led to comparable reductions in critical O2 tension and resting O2 consumption rate, but only constant hypoxia reduced the O2 tension at loss of equilibrium. Constant (but not intermittent) hypoxia decreased filament length and the proportion of seawater-type mitochondrion-rich cells in the gills (which may reduce ion loss and the associated costs of active ion uptake), increased blood haemoglobin content, and reduced the abundance of oxidative fibres in the swimming muscle. In contrast, only intermittent hypoxia augmented the oxidative and gluconeogenic enzyme activities in the liver and increased the capillarity of glycolytic muscle, each of which should facilitate recovery between hypoxia bouts. Neither exposure pattern affected muscle myoglobin content or the activities of metabolic enzymes in the brain or heart, but intermittent hypoxia increased brain mass. We conclude that the pattern of hypoxia exposure has an important influence on the mechanisms of acclimation, and that the optimal strategies used to cope with intermittent hypoxia may be distinct from those for coping with constant hypoxia. PMID:25722002

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

    PubMed Central

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

    2014-01-01

    Previous studies reported that chronic intermittent hypoxia (CIH) results in an imbalanced expression of hypoxia-inducible factor-α (HIF-α) isoforms and oxidative stress in rodents, which may be due either to the direct effect of CIH or indirectly via hitherto uncharacterized mechanism(s). As neural activity is a potent regulator of gene transcription, we hypothesized that carotid body (CB) neural activity contributes to CIH-induced HIF-α isoform expression and oxidative stress in the chemoreflex pathway. Experiments were performed on adult rats exposed to CIH for 10 days. Rats exposed to CIH exhibited: increased HIF-1α and decreased HIF-2α expression; increased NADPH oxidase 2 and decreased superoxide dismutase 2 expression; and oxidative stress in the nucleus tractus solitarius and rostral ventrolateral medulla as well as in the adrenal medulla (AM), a major end organ of the sympathetic nervous system. Selective ablation of the CB abolished these effects. In the AM, sympathetic activation by the CB chemoreflex mediates CIH-induced HIF-α isoform imbalance via muscarinic acetylcholine receptor-mediated Ca2+ influx, and the resultant activation of mammalian target of rapamycin pathway and calpain proteases. Rats exposed to CIH presented with hypertension, elevated sympathetic activity and increased circulating catecholamines. Selective ablation of either the CB (afferent pathway) or sympathetic innervation to the AM (efferent pathway) abolished these effects. These observations uncover CB neural activity-dependent regulation of HIF-α isoforms and the redox state by CIH in the central and peripheral nervous systems associated with the chemoreflex. PMID:24973414

  13. Consequences of peripheral chemoreflex inhibition with low-dose dopamine in humans

    PubMed Central

    Niewinski, Piotr; Tubek, Stanislaw; Banasiak, Waldemar; Paton, Julian F R; Ponikowski, Piotr

    2014-01-01

    Low-dose dopamine inhibits peripheral chemoreceptors and attenuates the hypoxic ventilatory response (HVR) in humans. However, it is unknown: (1) whether it also modulates the haemodynamic reactions to acute hypoxia, (2) whether it also modulates cardiac baroreflex sensitivity (BRS) and (3) if there is any effect of dopamine withdrawal. We performed a double-blind, placebo-controlled study on 11 healthy male volunteers. At sea level over 2 days every subject was administered low-dose dopamine (2 μg kg–1 min–1) or saline infusion, during which we assessed both ventilatory and haemodynamic responses to acute hypoxia. Separately, we evaluated effects of initiation and withdrawal of each infusion and BRS. The initiation of dopamine infusion did not affect minute ventilation (MV) or mean blood pressure (MAP), but increased both heart rate (HR) and cardiac output. Concomitantly, it decreased systemic vascular resistance. Dopamine blunted the ventilatory, MAP and HR reactions (hypertension, tachycardia) to acute hypoxia. Dopamine attenuated cardiac BRS to falling blood pressure. Dopamine withdrawal evoked an increase in MV. The magnitude of the increment in MV due to dopamine withdrawal correlated with the size of the HVR and depended on the duration of dopamine administration. The ventilatory reaction to dopamine withdrawal constitutes a novel index of peripheral chemoreceptor function. PMID:24396060

  14. Carotid body potentiation during chronic intermittent hypoxia: implication for hypertension.

    PubMed

    Del Rio, Rodrigo; Moya, Esteban A; Iturriaga, Rodrigo

    2014-01-01

    Autonomic dysfunction is involved in the development of hypertension in humans with obstructive sleep apnea, and animals exposed to chronic intermittent hypoxia (CIH). It has been proposed that a crucial step in the development of the hypertension is the potentiation of the carotid body (CB) chemosensory responses to hypoxia, but the temporal progression of the CB chemosensory, autonomic and hypertensive changes induced by CIH are not known. We tested the hypothesis that CB potentiation precedes the autonomic imbalance and the hypertension in rats exposed to CIH. Thus, we studied the changes in CB chemosensory and ventilatory responsiveness to hypoxia, the spontaneous baroreflex sensitivity (BRS), heart rate variability (HRV) and arterial blood pressure in pentobarbital anesthetized rats exposed to CIH for 7, 14, and 21 days. After 7 days of CIH, CB chemosensory and ventilatory responses to hypoxia were enhanced, while BRS was significantly reduced by 2-fold in CIH-rats compared to sham-rats. These alterations persisted until 21 days of CIH. After 14 days, CIH shifted the HRV power spectra suggesting a predominance of sympathetic over parasympathetic tone. In contrast, hypertension was found after 21 days of CIH. Concomitant changes between the gain of spectral HRV, BRS, and ventilatory hypoxic chemoreflex showed that the CIH-induced BRS attenuation preceded the HRV changes. CIH induced a simultaneous decrease of the BRS gain along with an increase of the hypoxic ventilatory gain. Present results show that CIH-induced persistent hypertension was preceded by early changes in CB chemosensory control of cardiorespiratory and autonomic function. PMID:25429271

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

    PubMed

    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

  16. The fetal brain sparing response to hypoxia: physiological mechanisms.

    PubMed

    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

  17. Tetraplegia is associated with enhanced peripheral chemoreflex sensitivity and ventilatory long-term facilitation

    PubMed Central

    Sankari, Abdulghani; Bascom, Amy T.; Riehani, Anas; Badr, M. Safwan

    2016-01-01

    Cardiorespiratory plasticity induced by acute intermittent hypoxia (AIH) may contribute to recovery following spinal cord injury (SCI). We hypothesized that patients with cervical SCI would demonstrate higher minute ventilation (V̇e) following AIH compared with subjects with thoracic SCI and able-bodied subjects who served as controls. Twenty-four volunteers (8 with cervical SCI, 8 with thoracic SCI, and 8 able-bodied) underwent an AIH protocol during wakefulness. Each subject experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2), 8% O2, and 40% CO2 to achieve oxygen saturation ≤90% followed by room air (RA). Measurements were obtained before, during, and 40 min after AIH to obtain ventilation and heart rate variability data [R-R interval (RRI) and low-frequency/ high-frequency power (LF/HF)]. AIH results were compared with those of sham studies conducted in RA during the same time period. Individuals with cervical SCI had higher V̇e after AIH compared with able-bodied controls (117.9 ± 23.2% vs. 97.9 ± 11.2%, P < 0.05). RRI decreased during hypoxia in all individuals (those with cervical SCI, from 1,009.3 ± 65.0 ms to 750.2 ± 65.0 ms; those with thoracic SCI, from 945.2 ± 65.0 ms to 674.9 ± 65.0 ms; and those who were able-bodied, from 949 ± 75.0 to 682.2 ± 69.5 ms; P < 0.05). LH/HF increased during recovery in individuals with thoracic SCI and those who were able-bodied (0.54 ± 0.22 vs. 1.34 ± 0.22 and 0.67 ± 0.23 vs. 1.82 ± 0.23, respectively; P < 0.05) but remained unchanged in the group with cervical SCI. Our conclusion is that patients with cervical SCI demonstrate ventilatory long-term facilitation following AIH compared with able-bodied controls. Heart rate responses to hypoxia are acutely present in patients with cervical SCI but are absent during posthypoxic recovery. PMID:26272316

  18. [Refractory hypoxia].

    PubMed

    Cuchard, P; Guillemin, P

    2011-04-27

    We report a case of refractory hypoxia in an 85 years old smoker patient, who is known for cardiac and pulmonary comorbidities. The whole clinical picture at the time of his admission to hospital was pointing to a cardiac failure or a pneumonia that were causing the respiratory insufficiency. Despite an optimal treatment which stabilised these conditions, the patient remained severely hypoxic, but with relatively few symptoms. The non response to the oxygen and the worsening of the oxygen saturation when changing from the lying to the sitting (or supine) position finally evoke the syndrome of platypnea-orthodeoxia caused by a cardiac right to left shunt; that diagnosis was confirmed by a cardiac ultrasound with contrast which revealed an important inter-auricular shunt. The patient didn't wish to undertake the curative treatment (shunt closure). PMID:21526473

  19. Lip augmentation.

    PubMed

    Byrne, Patrick J; Hilger, Peter A

    2004-02-01

    Lip augmentation has become increasingly popular in recent years as a reflection of cultural trends emphasizing youth and beauty. Techniques to enhance the appearance of the lips have evolved with advances in biotechnology. An understanding of lip anatomy and aesthetics forms the basis for successful results. We outline the pertinent anatomy and aesthetics of the preoperative evaluation. A summary of various filler materials available is provided. Augmentation options include both injectable and open surgical techniques. The procedures and materials currently favored by the authors are described in greater detail. PMID:15034811

  20. Hypoxia-induced autophagy mediates cisplatin resistance in lung cancer cells

    PubMed Central

    Wu, Hui-Mei; Jiang, Zi-Feng; Ding, Pei-Shan; Shao, Li-Jie; Liu, Rong-Yu

    2015-01-01

    Hypoxia which commonly exists in solid tumors, leads to cancer cells chemoresistance via provoking adaptive responses including autophagy. Therefore, we sought to evaluate the role of autophagy and hypoxia as well as the underlying mechanism in the cisplatin resistance of lung cancer cells. Our study demonstrated that hypoxia significantly protected A549 and SPC-A1 cells from cisplatin-induced cell death in a Hif-1α- and Hif-2α- dependent manner. Moreover, compared with normoxia, cisplatin-induced apoptosis under hypoxia was markedly reduced. However, when autophagy was inhibited by 3-MA or siRNA targeted ATG5, this reduction was effectively attenuated, which means autophagy mediates cisplatin resisitance under hypoxia. In parallel, we showed that hypoxia robustly augmented cisplatin-induced autophagy activation, accompanying by suppressing cisplatin-induced BNIP3 death pathways, which was due to the more efficient autophagic process under hypoxia. Consequently, we proposed that autophagy was a protective mechanism after cisplatin incubation under both normoxia and hypoxia. However, under normoxia, autophagy activation ‘was unable to counteract the stress induced by cisplatin, therefore resulting in cell death, whereas under hypoxia, autophagy induction was augmented that solved the cisplatin-induced stress, allowing the cells to survival. In conclusion, augmented induction of autophagy by hypoxia decreased lung cancer cells susceptibility to cisplatin-induced apoptosis. PMID:26201611

  1. Chin augmentation.

    PubMed

    Choe, K S; Stucki-McCormick, S U

    2000-01-01

    The primary goal of facial aesthetic surgery is to restore, enhance, and rejuvenate the aging face to a more youthful appearance, achieving balance and harmony. The mental area must be addressed in order to have a complete synthesis of the face. The concept of augmenting the mental area with implants has evolved so significantly that it now stands by itself as an important procedure. Various autogenous implants for chin augmentation have been in use for over 100 years but have complications. The advent of synthetic materials has given rise to various types of alloplastic implants: Gore-Tex, Medpor, Supramid, Silastic, and Mersilene. No one implant is perfect for every face. This article overviews several alloplastic implants--their advantages, disadvantages, and complications, in addition to the different techniques of preparing and delivering the implants. PMID:11802346

  2. Time of day affects chemoreflex sensitivity and the carbon dioxide reserve during NREM sleep in participants with sleep apnea.

    PubMed

    El-Chami, Mohamad; Shaheen, David; Ivers, Blake; Syed, Ziauddin; Badr, M Safwan; Lin, Ho-Sheng; Mateika, Jason H

    2014-11-15

    Our investigation was designed to determine whether the time of day affects the carbon dioxide reserve and chemoreflex sensitivity during non-rapid eye movement (NREM) sleep. Ten healthy men with obstructive sleep apnea completed a constant routine protocol that consisted of sleep sessions in the evening (10 PM to 1 AM), morning (6 AM to 9 AM), and afternoon (2 PM to 5 PM). Between sleep sessions, the participants were awake. During each sleep session, core body temperature, baseline levels of carbon dioxide (PET(CO2)) and minute ventilation, as well as the PET(CO2) that demarcated the apneic threshold and hypocapnic ventilatory response, were measured. The nadir of core body temperature during sleep occurred in the morning and was accompanied by reductions in minute ventilation and PetCO2 compared with the evening and afternoon (minute ventilation: 5.3 ± 0.3 vs. 6.2 ± 0.2 vs. 6.1 ± 0.2 l/min, P < 0.02; PET(CO2): 39.7 ± 0.4 vs. 41.4 ± 0.6 vs. 40.4 ± 0.6 Torr, P < 0.02). The carbon dioxide reserve was reduced, and the hypocapnic ventilatory response increased in the morning compared with the evening and afternoon (carbon dioxide reserve: 2.1 ± 0.3 vs. 3.6 ± 0.5 vs. 3.5 ± 0.3 Torr, P < 0.002; hypocapnic ventilatory response: 2.3 ± 0.3 vs. 1.6 ± 0.2 vs. 1.8 ± 0.2 l·min(-1)·mmHg(-1), P < 0.001). We conclude that time of day affects chemoreflex properties during sleep, which may contribute to increases in breathing instability in the morning compared with other periods throughout the day/night cycle in individuals with sleep apnea. PMID:25213638

  3. Hypoxia. 3. Hypoxia and neurotransmitter synthesis

    PubMed Central

    2011-01-01

    Central and peripheral neurons as well as neuroendocrine cells express a variety of neurotransmitters/modulators that play critical roles in regulation of physiological systems. The synthesis of several neurotransmitters/modulators is regulated by O2-requiring rate-limiting enzymes. Consequently, hypoxia resulting from perturbations in O2 homeostasis can affect neuronal functions by altering neurotransmitter synthesis. Two broad categories of hypoxia are frequently encountered: continuous hypoxia (CH) and intermittent hypoxia (IH). CH is often seen during high altitude sojourns, whereas IH is experienced in sleep-disordered breathing with recurrent apneas (i.e., brief, repetitive cessations of breathing). This article presents what is currently known on the effects of both forms of hypoxia on neurotransmitter levels and neurotransmitter synthesizing enzymes in the central and peripheral nervous systems. PMID:21270298

  4. NTS adenosine A2a receptors inhibit the cardiopulmonary chemoreflex control of regional sympathetic outputs via a GABAergic mechanism.

    PubMed

    Minic, Zeljka; O'Leary, Donal S; Scislo, Tadeusz J

    2015-07-01

    Adenosine is a powerful central neuromodulator acting via opposing A1 (inhibitor) and A2a (activator) receptors. However, in the nucleus of the solitary tract (NTS), both adenosine receptor subtypes attenuate cardiopulmonary chemoreflex (CCR) sympathoinhibition of renal, adrenal, and lumbar sympathetic nerve activity and attenuate reflex decreases in arterial pressure and heart rate. Adenosine A1 receptors inhibit glutamatergic transmission in the CCR pathway, whereas adenosine A2a receptors most likely facilitate release of an unknown inhibitory neurotransmitter, which, in turn, inhibits the CCR. We hypothesized that adenosine A2a receptors inhibit the CCR via facilitation of GABA release in the NTS. In urethane-chloralose-anesthetized rats (n = 51), we compared regional sympathetic responses evoked by stimulation of the CCR with right atrial injections of the 5-HT3 receptor agonist phenylbiguanide (1-8 μg/kg) before and after selective stimulation of NTS adenosine A2a receptors [microinjections into the NTS of CGS-21680 (20 pmol/50 nl)] preceded by blockade of GABAA or GABAB receptors in the NTS [bicuculline (10 pmol/100 nl) or SCH-50911 (1 nmol/100 nl)]. Blockade of GABAA receptors virtually abolished adenosine A2a receptor-mediated inhibition of the CCR. GABAB receptors had much weaker but significant effects. These effects were similar for the different sympathetic outputs. We conclude that stimulation of NTS adenosine A2a receptors inhibits CCR-evoked hemodynamic and regional sympathetic reflex responses via a GABA-ergic mechanism. PMID:25910812

  5. Carotid Body Ablation Abrogates Hypertension and Autonomic Alterations Induced by Intermittent Hypoxia in Rats.

    PubMed

    Del Rio, Rodrigo; Andrade, David C; Lucero, Claudia; Arias, Paulina; Iturriaga, Rodrigo

    2016-08-01

    Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea, enhances carotid body (CB) chemosensory responses to hypoxia and produces autonomic dysfunction, cardiac arrhythmias, and hypertension. We tested whether autonomic alterations, arrhythmogenesis, and the progression of hypertension induced by CIH depend on the enhanced CB chemosensory drive, by ablation of the CB chemoreceptors. Male Sprague-Dawley rats were exposed to control (Sham) conditions for 7 days and then to CIH (5% O2, 12/h 8 h/d) for a total of 28 days. At 21 days of CIH exposure, rats underwent bilateral CB ablation and then exposed to CIH for 7 additional days. Arterial blood pressure and ventilatory chemoreflex response to hypoxia were measured in conscious rats. In addition, cardiac autonomic imbalance, cardiac baroreflex gain, and arrhythmia score were assessed during the length of the experiments. In separate experimental series, we measured extracellular matrix remodeling content in cardiac atrial tissue and systemic oxidative stress. CIH induced hypertension, enhanced ventilatory response to hypoxia, induced autonomic imbalance toward sympathetic preponderance, reduced baroreflex gain, and increased arrhythmias and atrial fibrosis. CB ablation normalized blood pressure, reduced ventilatory response to hypoxia, and restored cardiac autonomic and baroreflex function. In addition, CB ablation reduced the number of arrhythmias, but not extracellular matrix remodeling or systemic oxidative stress, suggesting that reductions in arrhythmia incidence during CIH were related to normalization of cardiac autonomic balance. Present results show that autonomic alterations induced by CIH are critically dependent on the CB and support a main role for the CB in the CIH-induced hypertension. PMID:27381902

  6. Augmented RIGS

    NASA Technical Reports Server (NTRS)

    Kaminskas, R. A.; Mcguire, D.

    1974-01-01

    The results of the Phase 2 Resonant Infrasonic Gauging System (RIGS) development program are presented. The program consisted of design, fabrication, and testing of an "augmented" RIGS concept. The RIGS is a gauging system capable of measuring propellant quantities in zero-g as well as under accelerated conditions. Except for hydrogen, it can be used to gauge virtually any propellant in liquid form, including cryogenics. The gage consists of a sensor unit which is attached to the propellant tank and an electronic control unit which may be positioned separately from the sensor. The control unit receives signals from the sensor as well as the propellant temperature measurement and the ullage gas pressure, and computes the propellant quantity in the tank.

  7. Hypoxia in Microscopic Tumors

    PubMed Central

    Li, Xiao-Feng; O’Donoghue, Joseph A

    2008-01-01

    Tumor hypoxia has been commonly observed in a broad spectrum of primary solid malignancies. Hypoxia is associated with tumor progression, increased aggressiveness, enhanced metastatic potential and poor prognosis. Hypoxic tumor cells are resistant to radiotherapy and some forms of chemotherapy. Using an animal model, we recently showed that microscopic tumors less than 1 mm diameter were severely hypoxic. In this review, models and techniques for the study of hypoxia in microscopic tumors are discussed. PMID:18384940

  8. Increased hemoglobin O2 affinity protects during acute hypoxia.

    PubMed

    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

  9. Increased hemoglobin O2 affinity protects during acute hypoxia

    PubMed Central

    Yalcin, Ozlem

    2012-01-01

    Acclimatization to hypoxia requires time to complete the adaptation mechanisms that influence oxygen (O2) transport and O2 utilization. Although decreasing hemoglobin (Hb) O2 affinity would favor the release of O2 to the tissues, increasing Hb O2 affinity would augment arterial O2 saturation during hypoxia. This study was designed to test the hypothesis that pharmacologically increasing the Hb O2 affinity will augment O2 transport during severe hypoxia (10 and 5% inspired O2) compared with normal Hb O2 affinity. RBC Hb O2 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 O2 affinity were studied in the hamster window chamber model, in terms of systemic and microvascular hemodynamics and partial pressures of O2 (Po2). Pimonidazole binding to hypoxic areas of mice heart and brain was also studied. 5HMF decreased the Po2 at which the Hb is 50% saturated with O2 by 12.6 mmHg. During 10 and 5% O2 hypoxia, 5HMF increased arterial blood O2 saturation by 35 and 48% from the vehicle group, respectively. During 5% O2 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 Po2 was three times higher in the 5HMF group compared with the control group at 5% O2 hypoxia. 5HMF also reduced heart and brain hypoxic areas in mice. Therefore, increased Hb O2 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

  10. Mechanisms of Sympathetic Activation and Blood Pressure Elevation by Intermittent Hypoxia

    PubMed Central

    Prabhakar, Nanduri R.; Kumar, Ganesh K.

    2010-01-01

    Sleep disordered breathing with recurrent apneas is one of the most frequently encountered breathing disorder in adult humans and preterm infants. Recurrent apnea patients exhibit several co-morbidities including hypertension and persistent sympathetic activation. Intermittent hypoxia (IH) resulting from apneas appears to be the primary stimulus for evoking autonomic changes. The purpose of this article is to briefly review the effects of IH on chemo-and baro-reflexes and circulating vasoactive hormones and their contribution to sympathetic activation and blood pressures. Sleep apnea patients and IH-treated rodents exhibit exaggerated arterial chemo-reflex. Studies on rodent models demonstrated that IH leads to hyperactive carotid body response to hypoxia. On the other hand, baro-reflex function is attenuated in patients with sleep apnea and in IH-treated rodents. Circulating vasoactive hormone levels are elevated in sleep apnea patients and in rodent models of IH. Thus, persistent sympathetic activation and hypertension associated with sleep apneas seems to be due to a combination of altered chemo-and baro-reflexes resulting in sympathetic activation and action of elevated circulating levels of vasoactive hormones on vasculature. PMID:20804865

  11. Intermittent hypoxia and respiratory plasticity in humans and other animals: does exposure to intermittent hypoxia promote or mitigate sleep apnoea?

    PubMed Central

    Mateika, Jason H.; Narwani, Gunjan

    2009-01-01

    This review focuses on two phenomena that are initiated during and after exposure to intermittent hypoxia. The two phenomena are referred to as long-term facilitation and progressive augmentation of respiratory motor output. Both phenomena are forms of respiratory plasticity. Long-term facilitation is characterized by a sustained elevation in respiratory activity after exposure to intermittent hypoxia. Progressive augmentation is characterized by a gradual increase in respiratory activity from the initial to the final hypoxic exposure. There is much speculation that long-term facilitation may have a significant role in individuals with sleep apnoea because this disorder is characterized by periods of upper airway collapse accompanied by intermittent hypoxia, one stimulus known to induce long-term facilitation. It has been suggested that activation of long-term facilitation may serve to mitigate apnoea by facilitating ventilation and, more importantly, upper airway muscle activity. We examine the less discussed but equally plausible situation that exposure to intermittent hypoxia might ultimately lead to the promotion of apnoea. There are at least two scenarios in which apnoea might be promoted following exposure to intermittent hypoxia. In both scenarios, long-term facilitation of upper airway muscle activity is initiated but ultimately rendered ineffective because of other physiological conditions. Thus, one of the primary goals of this review is to discuss, with support from basic and clinical studies, whether various forms of respiratory motor neuronal plasticity have a beneficial and/or a detrimental impact on breathing stability in individuals with sleep apnoea. PMID:19060117

  12. Hypoxia-Inducible Hydrogels

    PubMed Central

    Park, Kyung Min; Gerecht, Sharon

    2014-01-01

    Oxygen is vital for the existence of all multicellular organisms, acting as a signaling molecule regulating cellular activities. Specifically, hypoxia, which occurs when the partial pressure of oxygen falls below 5%, plays a pivotal role during development, regeneration, and cancer. Here we report a novel hypoxia-inducible (HI) hydrogel composed of gelatin and ferulic acid that can form hydrogel networks via oxygen consumption in a laccase-mediated reaction. Oxygen levels and gradients within the hydrogels can be accurately controlled and precisely predicted. We demonstrate that HI hydrogels guide vascular morphogenesis in vitro via hypoxia-inducible factors activation of matrix metalloproteinases and promote rapid neovascularization from the host tissue during subcutaneous wound healing. The HI hydrogel is a new class of biomaterials that may prove useful in many applications, ranging from fundamental studies of developmental, regenerative and disease processes through the engineering of healthy and diseased tissue models towards the treatment of hypoxia-regulated disorders. PMID:24909742

  13. Hypoxia. 4. Hypoxia and ion channel function

    PubMed Central

    Polak, Jan

    2011-01-01

    The ability to sense and respond to oxygen deprivation is required for survival; thus, understanding the mechanisms by which changes in oxygen are linked to cell viability and function is of great importance. Ion channels play a critical role in regulating cell function in a wide variety of biological processes, including neuronal transmission, control of ventilation, cardiac contractility, and control of vasomotor tone. Since the 1988 discovery of oxygen-sensitive potassium channels in chemoreceptors, the effect of hypoxia on an assortment of ion channels has been studied in an array of cell types. In this review, we describe the effects of both acute and sustained hypoxia (continuous and intermittent) on mammalian ion channels in several tissues, the mode of action, and their contribution to diverse cellular processes. PMID:21178108

  14. Breast augmentation surgery

    MedlinePlus

    Breast augmentation; Breast implants; Implants - breast; Mammaplasty ... Breast augmentation is done by placing implants behind breast tissue or under the chest muscle. An implant is a sac filled with either sterile salt water (saline) or a ...

  15. The efficacy of antihypertensive drugs in chronic intermittent hypoxia conditions

    PubMed Central

    Diogo, Lucilia N.; Monteiro, Emília C.

    2014-01-01

    Sleep apnea/hypopnea disorders include centrally originated diseases and obstructive sleep apnea (OSA). This last condition is renowned as a frequent secondary cause of hypertension (HT). The mechanisms involved in the pathogenesis of HT can be summarized in relation to two main pathways: sympathetic nervous system stimulation mediated mainly by activation of carotid body (CB) chemoreflexes and/or asphyxia, and, by no means the least important, the systemic effects of chronic intermittent hypoxia (CIH). The use of animal models has revealed that CIH is the critical stimulus underlying sympathetic activity and hypertension, and that this effect requires the presence of functional arterial chemoreceptors, which are hyperactive in CIH. These models of CIH mimic the HT observed in humans and allow the study of CIH independently without the mechanical obstruction component. The effect of continuous positive airway pressure (CPAP), the gold standard treatment for OSA patients, to reduce blood pressure seems to be modest and concomitant antihypertensive therapy is still required. We focus this review on the efficacy of pharmacological interventions to revert HT associated with CIH conditions in both animal models and humans. First, we explore the experimental animal models, developed to mimic HT related to CIH, which have been used to investigate the effect of antihypertensive drugs (AHDs). Second, we review what is known about drug efficacy to reverse HT induced by CIH in animals. Moreover, findings in humans with OSA are cited to demonstrate the lack of strong evidence for the establishment of a first-line antihypertensive regimen for these patients. Indeed, specific therapeutic guidelines for the pharmacological treatment of HT in these patients are still lacking. Finally, we discuss the future perspectives concerning the non-pharmacological and pharmacological management of this particular type of HT. PMID:25295010

  16. Skeletal muscle vasodilation during systemic hypoxia in humans.

    PubMed

    Dinenno, Frank A

    2016-01-15

    In humans, the net effect of acute systemic hypoxia in quiescent skeletal muscle is vasodilation despite significant reflex increases in muscle sympathetic vasoconstrictor nerve activity. This vasodilation increases tissue perfusion and oxygen delivery to maintain tissue oxygen consumption. Although several mechanisms may be involved, we recently tested the roles of two endothelial-derived substances during conditions of sympathoadrenal blockade to isolate local vascular control mechanisms: nitric oxide (NO) and prostaglandins (PGs). Our findings indicate that 1) NO normally plays a role in regulating vascular tone during hypoxia independent of the PG pathway; 2) PGs do not normally contribute to vascular tone during hypoxia, however, they do affect vascular tone when NO is inhibited; 3) NO and PGs are not independently obligatory to observe hypoxic vasodilation when assessed as a response from rest to steady-state hypoxia; and 4) combined NO and PG inhibition abolishes hypoxic vasodilation in human skeletal muscle. When the stimulus is exacerbated via combined submaximal rhythmic exercise and systemic hypoxia to cause further red blood cell (RBC) deoxygenation, skeletal muscle blood flow is augmented compared with normoxic exercise via local dilator mechanisms to maintain oxygen delivery to active tissue. Data obtained in a follow-up study indicate that combined NO and PG inhibition during hypoxic exercise blunts augmented vasodilation and hyperemia compared with control (normoxic) conditions by ∼50%; however, in contrast to hypoxia alone, the response is not abolished, suggesting that other local substances are involved. Factors associated with greater RBC deoxygenation such as ATP release, or nitrite reduction to NO, or both likely play a role in regulating this response. PMID:26023228

  17. Imaging hypoxia in gliomas

    PubMed Central

    Mendichovszky, I; Jackson, A

    2011-01-01

    Hypoxia plays a central role in tumour development, angiogenesis, growth and resistance to treatment. Owing to constant developments in medical imaging technology, significant advances have been made towards in vitro and in vivo imaging of hypoxia in a variety of tumours, including gliomas of the central nervous system. The aim of this article is to review the literature on imaging approaches currently available for measuring hypoxia in human gliomas and provide an insight into recent advances and future directions in this field. After a brief overview of hypoxia and its importance in gliomas, several methods of measuring hypoxia will be presented. These range from invasive monitoring by Eppendorf polarographic O2 microelectrodes, positron electron tomography (PET) tracers based on 2-nitroimidazole compounds [18F-labelled fluoro-misonidazole (18F-MISO) or 1-(2-[(18)F]fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole (FRP-170)], 64Cu-ATSM Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) or 99mTc- and 68Ga-labelled metronidazole (MN) agents to advanced MRI methods, such as blood oxygenation level dependent (BOLD) MRI, oxygen-enhanced MRI, diffusion-weighted MRI (DWI-MRI), dynamic contrast-enhanced MRI (DCE-MRI) and 1H-magnetic resonance spectroscopy. PMID:22433825

  18. Catecholaminergic neurons projecting to the paraventricular nucleus of the hypothalamus are essential for cardiorespiratory adjustments to hypoxia.

    PubMed

    King, T Luise; Ruyle, Brian C; Kline, David D; Heesch, Cheryl M; Hasser, Eileen M

    2015-10-01

    Brainstem catecholamine neurons modulate sensory information and participate in control of cardiorespiratory function. These neurons have multiple projections, including to the paraventricular nucleus (PVN), which contributes to cardiorespiratory and neuroendocrine responses to hypoxia. We have shown that PVN-projecting catecholaminergic neurons are activated by hypoxia, but the function of these neurons is not known. To test the hypothesis that PVN-projecting catecholamine neurons participate in responses to respiratory challenges, we injected IgG saporin (control; n = 6) or anti-dopamine β-hydroxylase saporin (DSAP; n = 6) into the PVN to retrogradely lesion catecholamine neurons projecting to the PVN. After 2 wk, respiratory measurements (plethysmography) were made in awake rats during normoxia, increasing intensities of hypoxia (12, 10, and 8% O2) and hypercapnia (5% CO2-95% O2). DSAP decreased the number of tyrosine hydroxylase-immunoreactive terminals in PVN and cells counted in ventrolateral medulla (VLM; -37%) and nucleus tractus solitarii (nTS; -36%). DSAP produced a small but significant decrease in respiratory rate at baseline (during normoxia) and at all intensities of hypoxia. Tidal volume and minute ventilation (VE) index also were impaired at higher hypoxic intensities (10-8% O2; e.g., VE at 8% O2: IgG = 181 ± 22, DSAP = 91 ± 4 arbitrary units). Depressed ventilation in DSAP rats was associated with significantly lower arterial O2 saturation at all hypoxic intensities. PVN DSAP also reduced ventilatory responses to 5% CO2 (VE: IgG = 176 ± 21 and DSAP = 84 ± 5 arbitrary units). Data indicate that catecholamine neurons projecting to the PVN are important for peripheral and central chemoreflex respiratory responses and for maintenance of arterial oxygen levels during hypoxic stimuli. PMID:26157062

  19. Apelin/APJ signaling in hypoxia-related diseases.

    PubMed

    He, Lu; Xu, Jin; Chen, Linxi; Li, Lanfang

    2015-12-01

    The regulatory peptide apelin is the endogenous ligand for the orphan G protein-coupled receptor APJ. Apelin and APJ exist in a variety of tissues, with special status in the heart, lung and tumors. Consequently, the apelin/APJ system exerts a broad range of activities that affect multiple organ systems. Accumulating evidence indicates that the expressions of apelin and APJ are significantly augmented by hypoxia through the hypoxia-inducible factor-1 alpha (HIF-1α) signaling pathway. Increased apelin promotes cellular proliferation, migration and survival, therefore regulating angiogenesis. In addition, the pre-administration of exogenous apelin is involved in the occurrence and development of hypoxia-induced pathological diseases. The purpose of this article is to review the properties of the apelin/APJ system, which is affected by hypoxic conditions, and the regulation of apelin/APJ signaling in hypoxia-associated disorders. Thus, the apelin/APJ system may be a potential therapeutic target in hypoxia-related diseases. PMID:26436483

  20. Augmented Reality in astrophysics

    NASA Astrophysics Data System (ADS)

    Vogt, Frédéric P. A.; Shingles, Luke J.

    2013-09-01

    Augmented Reality consists of merging live images with virtual layers of information. The rapid growth in the popularity of smartphones and tablets over recent years has provided a large base of potential users of Augmented Reality technology, and virtual layers of information can now be attached to a wide variety of physical objects. In this article, we explore the potential of Augmented Reality for astrophysical research with two distinct experiments: (1) Augmented Posters and (2) Augmented Articles. We demonstrate that the emerging technology of Augmented Reality can already be used and implemented without expert knowledge using currently available apps. Our experiments highlight the potential of Augmented Reality to improve the communication of scientific results in the field of astrophysics. We also present feedback gathered from the Australian astrophysics community that reveals evidence of some interest in this technology by astronomers who experimented with Augmented Posters. In addition, we discuss possible future trends for Augmented Reality applications in astrophysics, and explore the current limitations associated with the technology. This Augmented Article, the first of its kind, is designed to allow the reader to directly experiment with this technology.

  1. Concepts in hypoxia reborn.

    PubMed

    Martin, Daniel S; Khosravi, Maryam; Grocott, Mike Pw; Mythen, Michael G

    2010-01-01

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

  2. Concepts in hypoxia reborn

    PubMed Central

    2010-01-01

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

  3. Confronting an Augmented Reality

    ERIC Educational Resources Information Center

    Munnerley, Danny; Bacon, Matt; Wilson, Anna; Steele, James; Hedberg, John; Fitzgerald, Robert

    2012-01-01

    How can educators make use of augmented reality technologies and practices to enhance learning and why would we want to embrace such technologies anyway? How can an augmented reality help a learner confront, interpret and ultimately comprehend reality itself ? In this article, we seek to initiate a discussion that focuses on these questions, and…

  4. Equating of Augmented Subscores

    ERIC Educational Resources Information Center

    Sinharay, Sandip; Haberman, Shelby J.

    2011-01-01

    Recently, there has been an increasing level of interest in subscores for their potential diagnostic value. Haberman (2008b) suggested reporting an augmented subscore that is a linear combination of a subscore and the total score. Sinharay and Haberman (2008) and Sinharay (2010) showed that augmented subscores often lead to more accurate…

  5. Subfascial gluteal augmentation.

    PubMed

    de la Peña, J Abel; Rubio, Omar V; Cano, Jacobo P; Cedillo, Mariana C; Garcés, Miriam T

    2006-07-01

    Developing the concept of gluteal augmentation through the past 17 years has been an academic adventure. During these years my coworkers and I have progressively improved surgical technique and devised an anatomical system for gluteal augmentation that includes an ideal implant design and templates to assist in evaluating patients in the preoperative period and to identify the most appropriate implant size. PMID:16818097

  6. Hypoxia and spermatogenesis.

    PubMed

    Jankovic Velickovic, Ljubinka; Stefanovic, Vladisav

    2014-05-01

    This review mainly focuses on our understanding of spermatogenesis in physiological and pathological hypoxic condition. Real hypoxia is closely related to vascular changes and an increase in testicular temperature. Both induce a reduction in sperm count and can be related to the increase in germ cell apoptosis. On the other hand, change in the temperature, and oxygen levels in the microenvironment have influence on spermatogonial stem cell function and differentiation. The initial connection between hypoxia and a factor critical for stem cell maintenance is alteration in Oct-4 expression, and these data may be a useful strategy for modulating stem cell function. Unilateral testicular ischemia-induced cell death can be accompanied by an increase in germ cell apoptosis in the contralateral testis. The injury of contralateral testis following unilateral testicular damage is controversial, and it can contribute to the reduction in fertility. PMID:24265038

  7. Inhalation of the nerve gas sarin impairs ventilatory responses to hypercapnia and hypoxia in rats

    SciTech Connect

    Zhuang Jianguo; Xu Fadi Campen, Matthew J.; Zhang Cancan; Pena-Philippides, Juan C.; Sopori, Mohan L.

    2008-11-01

    Sarin, a highly toxic nerve gas, is believed to cause bronchoconstriction and even death primarily through respiratory failure; however, the mechanism underlying the respiratory failure is not fully understood. The goals of this study were to ascertain whether sarin affects baseline ventilation (V{sub E}) and V{sub E} chemoreflexes as well as airway resistance and, if so, whether these changes are reversible. Four groups of F344 rats were exposed to vehicle (VEH) or sarin at 2.5, 3.5, and 4.0 mg h m{sup -3} (SL, SM, and SH, respectively). V{sub E} and V{sub E} responses to hypercapnia (7% CO{sub 2}) or hypoxia (10% O{sub 2}) were measured by plethysmography at 2 h and 1, 2, and 5 days after VEH or sarin exposure. Total pulmonary resistance (R{sub L}) also was measured in anesthetized VEH- and SH-exposed animals 2 h after exposure. Our results showed that within 2 h after exposure 11% of the SM- and 52% of the SH- exposed groups died. Although the SM and SH significantly decreased hypercapnic and hypoxic V{sub E} to similar levels (64 and 69%), SH induced greater respiratory impairment, characterized by lower baseline V{sub E} (30%; P < 0.05), and total loss of the respiratory frequency response to hypercapnia and hypoxia. V{sub E} impairment recovered within 1-2 days after sarin exposure; interestingly, SH did not significantly affect baseline R{sub L}. Moreover, sarin induced body tremors that were unrelated to the changes in the V{sub E} responses. Thus, LC{sub 50} sarin causes a reversible impairment of V{sub E} that is not dependent on the sarin-induced body tremors and not associated with changes in R{sub L}.

  8. Intermittent hypoxia and neurorehabilitation.

    PubMed

    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

  9. Hypoxia and fetal heart development.

    PubMed

    Patterson, A J; Zhang, L

    2010-10-01

    Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not the only gene involved in adaptation to hypoxia, its role places it as a central figure in orchestrating events needed for adaptation to hypoxic stress. Although "normal" hypoxia (lower oxygen tension in the fetus as compared with the adult) is essential in heart formation, further abnormal hypoxia in utero adversely affects cardiogenesis. Prenatal hypoxia alters myocardial structure and causes a decline in cardiac performance. Not only are the effects of hypoxia apparent during the perinatal period, but prolonged hypoxia in utero also causes fetal programming of abnormality in the heart's development. The altered expression pattern of cardioprotective genes such as protein kinase c epsilon, heat shock protein 70, and endothelial nitric oxide synthase, likely predispose the developing heart to increased vulnerability to ischemia and reperfusion injury later in life. The events underlying the long-term changes in gene expression are not clear, but likely involve variation in epigenetic regulation. PMID:20712587

  10. Augmented reality: a review.

    PubMed

    Berryman, Donna R

    2012-01-01

    Augmented reality is a technology that overlays digital information on objects or places in the real world for the purpose of enhancing the user experience. It is not virtual reality, that is, the technology that creates a totally digital or computer created environment. Augmented reality, with its ability to combine reality and digital information, is being studied and implemented in medicine, marketing, museums, fashion, and numerous other areas. This article presents an overview of augmented reality, discussing what it is, how it works, its current implementations, and its potential impact on libraries. PMID:22559183

  11. Effects of specific carotid body and brain hypoxia on respiratory muscle control in the awake goat.

    PubMed Central

    Smith, C A; Engwall, M J; Dempsey, J A; Bisgard, G E

    1993-01-01

    1. We assessed the effects of specific brain hypoxia on the control of inspiratory and expiratory muscle electromyographic (EMG) activities in response to specific carotid body hypoxia in seven awake goats. We used an isolated carotid body perfusion technique that permitted specific, physiological, steady-state stimulation of the carotid bodies or maintenance of normoxia and normocapnia at the carotid bodies while varying the level of systemic, and therefore, brain oxygenation. 2. Isolated brain normocapnic hypoxia of up to 1.5 h duration increased inspired minute ventilation (VI) by means of increases in both tidal volume (VT) and respiratory frequency (fR). Electromyographic activities of both inspiratory and expiratory muscles were augmented as well. These responses were similar to those produced by low levels of whole-body normoxic hypercapnia. We conclude that moderate levels of brain hypoxia (Pa,O2 approximately 40 mmHg) in awake goats caused a net stimulation of ventilatory motor output. 3. Hypoxic stimulation of the carotid bodies alone caused comparable increases in VT and fR, and EMG augmentation of both inspiratory and expiratory muscles whether the brain was hypoxic or normoxic. These responses were quite similar to those obtained over a wide range of whole-body normoxic hypercapnia. We conclude that the integration of carotid body afferent information is not affected by moderate brain hypoxia in awake goats. 4. We found no evidence for an asymmetrical recruitment pattern of inspiratory vs. expiratory muscles in response to carotid body hypoxia or in response to brain hypoxia alone. 5. Our data support the concept that moderate brain hypoxia results in a net stimulation of respiratory motor output. These findings question the significance of 'central hypoxic depression' to the regulation of breathing under physiological levels of hypoxaemia in the awake animal. PMID:8487210

  12. Breast augmentation surgery

    MedlinePlus

    ... the shape of your breasts. Talk with a plastic surgeon if you are considering breast augmentation. Discuss ... mammograms or breast x-rays before surgery. The plastic surgeon will do a routine breast exam. Several ...

  13. RMS active damping augmentation

    NASA Technical Reports Server (NTRS)

    Gilbert, Michael G.; Scott, Michael A.; Demeo, Martha E.

    1992-01-01

    The topics are presented in viewgraph form and include: RMS active damping augmentation; potential space station assembly benefits to CSI; LaRC/JSC bridge program; control law design process; draper RMS simulator; MIMO acceleration control laws improve damping; potential load reduction benefit; DRS modified to model distributed accelerations; accelerometer location; Space Shuttle aft cockpit simulator; simulated shuttle video displays; SES test goals and objectives; and SES modifications to support RMS active damping augmentation.

  14. Hypoxia Inducible Factors and Hypertension: Lessons from Sleep Apnea Syndrome

    PubMed Central

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

    2015-01-01

    Systemic hypertension is one of the most prevalent cardiovascular diseases. Sleep disordered breathing (SDB) with recurrent apnea is a major risk factor for developing essential hypertension. Chronic intermittent hypoxia (CIH) is a hallmark manifestation of recurrent apnea. Rodent models patterned after the O2 profiles seen with SDB patients showed that CIH is the major stimulus for causing systemic hypertension. This article reviews the physiological and molecular basis of CIH-induced hypertension. Physiological studies have identified that augmented carotid body chemosensory reflex and the resulting increase in sympathetic nerve activity is a major contributor to CIH-induced hypertension. Analysis of molecular mechanisms revealed that CIH activates hypoxia-inducible factor (HIF)-1 and suppresses HIF-2- mediated transcription. Dysregulation of HIF-1- and HIF-2- mediated transcription leads to imbalance of pro-oxidant and anti-oxidant enzyme gene expression resulting in increased reactive species (ROS) generation in the chemosensory reflex which is central for developing hypertension. PMID:25772710

  15. Ureteral bladder augmentation.

    PubMed

    Churchill, B M; Aliabadi, H; Landau, E H; McLorie, G A; Steckler, R E; McKenna, P H; Khoury, A E

    1993-08-01

    Virtually all segments of the gastrointestinal tract have been used successfully in augmentation cystoplasty. The complications inherent in enterocystoplasty are well described. Megaureters subtending effete kidneys (poorly or nonfunctioning) provide a novel and excellent source of augmentation material with urothelium and muscular backing, free of the electrolyte and acid base disturbances, and mucus production that plague enterocystoplasty. Augmentation cystoplasty using detubularized, reconfigured, otherwise disposable megaureter, with or without ipsilateral total or partial nephrectomy, was performed in 16 patients (mean age 8.8 years, range 1 to 25) with inadequate and dysfunctional bladders. Postoperative followup varied between 8 and 38 months (mean 22). The overall renal function and radiographic appearance of the remaining upper tracts have remained stable or improved in all patients. Of the 16 patients 15 require intermittent catheterization and 1 voids spontaneously. Ten patients are continent day and night, 5 have improved continence (4 damp at night and 1 stress incontinence) and 1 has failed to gain continence despite good capacity and compliance. Complete postoperative urodynamic evaluations in 12 of 13 patients show good capacity, low pressure bladders with no instability. Complications occurred in 5 patients, including transient urine extravasation in 2, contralateral ureterovesical obstruction in 2 and Mitrofanoff stomal stenosis in 1. Augmentation ureterocystoplasty combines the benefits common to all enterocystoplasties without adding any of the untoward complications or risks associated with nonurothelial augmentations. PMID:8326632

  16. Augmenting computer networks

    NASA Technical Reports Server (NTRS)

    Bokhari, S. H.; Raza, A. D.

    1984-01-01

    Three methods of augmenting computer networks by adding at most one link per processor are discussed: (1) A tree of N nodes may be augmented such that the resulting graph has diameter no greater than 4log sub 2((N+2)/3)-2. Thi O(N(3)) algorithm can be applied to any spanning tree of a connected graph to reduce the diameter of that graph to O(log N); (2) Given a binary tree T and a chain C of N nodes each, C may be augmented to produce C so that T is a subgraph of C. This algorithm is O(N) and may be used to produce augmented chains or rings that have diameter no greater than 2log sub 2((N+2)/3) and are planar; (3) Any rectangular two-dimensional 4 (8) nearest neighbor array of size N = 2(k) may be augmented so that it can emulate a single step shuffle-exchange network of size N/2 in 3(t) time steps.

  17. Hypoxia signaling pathways: modulators of oxygen-related organelles

    PubMed Central

    Schönenberger, Miriam J.; Kovacs, Werner J.

    2015-01-01

    Oxygen (O2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1α and EPAS1/HIF-2α) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-α signaling regulates the abundance and function of major O2-consuming organelles. Abundant evidence suggests key roles for HIF-1α in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1α activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2α as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O2 availability. HIF-2α activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2α might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2α-mediated pexophagy for human health. PMID:26258123

  18. Inflammation and hypoxia linked to renal injury by CCAAT/enhancer-binding protein δ.

    PubMed

    Yamaguchi, Junna; Tanaka, Tetsuhiro; Eto, Nobuaki; Nangaku, Masaomi

    2015-08-01

    Tubulointerstitial hypoxia plays a critical role in the pathogenesis of kidney injury, and hypoxia-inducible factor (HIF)-1 is a master regulator of cellular adaptation to hypoxia. Aside from oxygen molecules, factors that modify HIF-1 expression and functional operation remain obscure. Therefore, we sought to identify novel HIF-1-regulating genes in kidney. A short-hairpin RNA library consisting of 150 hypoxia-inducible genes was derived from a microarray analysis of the rat renal artery stenosis model screened for the effect on HIF-1 response. We report that CCAAT/enhancer-binding protein δ (CEBPD), a transcription factor and inflammatory response gene, is a novel HIF-1 regulator in kidney. CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys. In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1β in a nuclear factor-κB-dependent manner, which not only increased HIF-1α expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1α. Thus our study provides novel insight into HIF-1 regulation in tubular epithelial cells and offers a potential hypoxia and inflammation link relevant in both acute and chronic kidney diseases. PMID:25692954

  19. Augmented Thermal Bus

    NASA Technical Reports Server (NTRS)

    Schrage, Dean S. (Inventor)

    1996-01-01

    The present invention is directed to an augmented thermal bus. In the present design a plurality of thermo-electric heat pumps are used to couple a source plate to a sink plate. Each heat pump is individually controlled by a model based controller. The controller coordinates the heat pumps to maintain isothermality in the source.

  20. Augmented thermal bus

    NASA Technical Reports Server (NTRS)

    Schrage, Dean S. (Inventor)

    1993-01-01

    The present invention is directed to an augmented thermal bus. In the present design a plurity of thermo-electric heat pumps are used to couple a source plate to a sink plate. Each heat pump is individually controlled by a model based controller. The controller coordinates the heat pump to maintain isothermality in the source.

  1. Computer Augmented Lectures

    ERIC Educational Resources Information Center

    Seitz, W. A.; Matsen, F. A.

    1974-01-01

    Discusses the use of a central computer linked to a CRT console, with display projected onto a large screen, to operate computer augmentation of lectures in large group instruction. Indicates that both introductory tutorial and computer modes are feasible in subject matter presentation. (CC)

  2. Augmentative & Alternative Communication

    ERIC Educational Resources Information Center

    Murphy, Patti

    2007-01-01

    There is no definitive recipe for augmentative and alternative communication (AAC) success, but its universal ingredients can be found at home. The main ones are: (1) Understanding that all children need to express themselves, however outgoing or shy they may be; (2) Willingness to embrace the technology that may help your child regardless of your…

  3. Augmented Reality Binoculars.

    PubMed

    Oskiper, Taragay; Sizintsev, Mikhail; Branzoi, Vlad; Samarasekera, Supun; Kumar, Rakesh

    2015-05-01

    In this paper we present an augmented reality binocular system to allow long range high precision augmentation of live telescopic imagery with aerial and terrain based synthetic objects, vehicles, people and effects. The inserted objects must appear stable in the display and must not jitter and drift as the user pans around and examines the scene with the binoculars. The design of the system is based on using two different cameras with wide field of view and narrow field of view lenses enclosed in a binocular shaped shell. Using the wide field of view gives us context and enables us to recover the 3D location and orientation of the binoculars much more robustly, whereas the narrow field of view is used for the actual augmentation as well as to increase precision in tracking. We present our navigation algorithm that uses the two cameras in combination with an inertial measurement unit and global positioning system in an extended Kalman filter and provides jitter free, robust and real-time pose estimation for precise augmentation. We have demonstrated successful use of our system as part of information sharing example as well as a live simulated training system for observer training, in which fixed and rotary wing aircrafts, ground vehicles, and weapon effects are combined with real world scenes. PMID:26357208

  4. Hypoxia, Oxidative Stress and Fat.

    PubMed

    Netzer, Nikolaus; Gatterer, Hannes; Faulhaber, Martin; Burtscher, Martin; Pramsohler, Stephan; Pesta, Dominik

    2015-01-01

    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. PMID:26061760

  5. Hypoxia and Hypoxia-Inducible Factors in Leukemias.

    PubMed

    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

  6. Hypoxia and Hypoxia-Inducible Factors in Leukemias

    PubMed Central

    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

  7. [Classification of hypoxia, hypo-, and hypercapnia].

    PubMed

    Agadzhanian, N A; Chizhov, A Ia

    2003-01-01

    The new classifications of hypoxical, hypo- and hypercapnical conditions are elaborated. They take into account the ecological factors in the development of various kinds of exogenic hypoxia, hypercapnia. For the first time the positive sides of physiological hypoxia and hypercapnia are brought in. In all classification til the last days hypoxia was considered as pathological process only. However hypoxia can be met in different physiologic conditions of organism: internal period of fetus development, hard physical work, increased sportsmen activity, hypoxia after hearty meal, hypoxia of aged organism. The same it is possible to say about the hypo- and hypercapnical conditions. PMID:12918246

  8. Batten augmented triangular beam

    NASA Technical Reports Server (NTRS)

    Adams, Louis R.; Hedgepeth, John M.

    1986-01-01

    The BAT (Batten-Augmented Triangular) BEAM is characterized by battens which are buckled in the deployed state, thus preloading the truss. The preload distribution is determined, and the effects of various external loading conditions are investigated. The conceptual design of a deployer is described and loads are predicted. The influence of joint imperfections on effective member stiffness is investigated. The beam is assessed structurally.

  9. Postreduction Breast Augmentation

    PubMed Central

    Doft, Melissa A.

    2015-01-01

    Background: Most breast reduction patients are highly satisfied after surgery. However, there is a subset of women who seek breast augmentation years later to restore lost volume chiefly associated with weight loss and postpartum changes. Breast shape and overall aesthetics are often revised at the same time. Methods: A retrospective review was performed of 2 surgeons’ experiences with post-reduction breast augmentation. Twenty patients were identified between 2002 and 2014. An in-depth chart review was conducted to determine patient motivation and to examine the operative techniques employed. Implant variables, a reduction specimen weight to implant volume comparison (where available), and complications are reported. Results: The average age was 37.1 years and average body mass index was 21.8 kg/m2. Most patients waited over a decade to have their breasts revised. Weight loss was the motivating factor in 8 patients and pregnancy changes in 11. Nineteen patients wished to stay with the same bra size or 1 cup size larger. Although all patients elected to have an implant placed, 19 patients wished to have an improved breast shape, not specifically a larger volume. The average breast implant was 203.5 cm3 (range, 120–340 cm3). Complications from implant placement included a seroma treated by aspiration and a Baker class III capsular contracture that required surgical correction. Conclusions: A small subset of reduction mammaplasty patients seek breast augmentation many years later primarily to improve breast contour, not to restore their prereduction breast volumes. Conservative augmentation combined with revision of breast shape and areolar aesthetics yields good results with minimal complications. PMID:26579333

  10. Imaging Tumor Hypoxia to Advance Radiation Oncology

    PubMed Central

    Lee, Chen-Ting; Boss, Mary-Keara

    2014-01-01

    Abstract 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 perfusion. Chronic hypoxia may cause either tumor progression or regressive effects depending on the tumor model. However, there is a general trend toward the development of a more aggressive phenotype after cycling hypoxia. With advanced hypoxia imaging techniques, spatiotemporal characteristics of tumor hypoxia and the changes to the tumor microenvironment can be analyzed. Critical Issues: In this review, we focus on the biological and clinical consequences of chronic and cycling hypoxia on radiation treatment. We also discuss the advanced non-invasive imaging techniques that have been developed to detect and monitor tumor hypoxia in preclinical and clinical studies. Future Directions: A better understanding of the mechanisms of tumor hypoxia with non-invasive imaging will provide a basis for improved radiation therapeutic practices. Antioxid. Redox Signal. 21, 313–337. PMID:24329000

  11. Hypoxia-mediated tumour targeting.

    PubMed

    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

  12. Lung Oxidative Damage by Hypoxia

    PubMed Central

    Araneda, O. F.; Tuesta, M.

    2012-01-01

    One of the most important functions of lungs is to maintain an adequate oxygenation in the organism. This organ can be affected by hypoxia facing both physiological and pathological situations. Exposure to this condition favors the increase of reactive oxygen species from mitochondria, as from NADPH oxidase, xanthine oxidase/reductase, and nitric oxide synthase enzymes, as well as establishing an inflammatory process. In lungs, hypoxia also modifies the levels of antioxidant substances causing pulmonary oxidative damage. Imbalance of redox state in lungs induced by hypoxia has been suggested as a participant in the changes observed in lung function in the hypoxic context, such as hypoxic vasoconstriction and pulmonary edema, in addition to vascular remodeling and chronic pulmonary hypertension. In this work, experimental evidence that shows the implied mechanisms in pulmonary redox state by hypoxia is reviewed. Herein, studies of cultures of different lung cells and complete isolated lung and tests conducted in vivo in the different forms of hypoxia, conducted in both animal models and humans, are described. PMID:22966417

  13. Neurally augmented sexual function.

    PubMed

    Meloy, S

    2007-01-01

    Neurally Augmented Sexual Function (NASF) is a technique utilizing epidural electrodes to restore and improve sexual function. Orgasmic dysfunction is common in adult women, affecting roughly one quarter of populations studied. Many male patients suffering from erectile dysfunction are not candidates for phosphdiesterase therapy due to concomitant nitrate therapy. Positioning the electrodes at roughly the level of the cauda equina allows for stimulation of somatic efferents and afferents as well as modifying sympathetic and parasympathetic activity. Our series of women treated by NASF is described. Our experience shows that the evaluation of potential candidates for both correctable causes and psychological screening are important considerations. PMID:17691397

  14. Mutually Augmented Cognition

    NASA Astrophysics Data System (ADS)

    Friesdorf, Florian; Pangercic, Dejan; Bubb, Heiner; Beetz, Michael

    In mac, an ergonomic dialog-system and algorithms will be developed that enable human experts and companions to be integrated into knowledge gathering and decision making processes of highly complex cognitive systems (e.g. Assistive Household as manifested further in the paper). In this event we propose to join algorithms and methodologies coming from Ergonomics and Artificial Intelligence that: a) make cognitive systems more congenial for non-expert humans, b) facilitate their comprehension by utilizing a high-level expandable control code for human experts and c) augment representation of such cognitive system into “deep representation” obtained through an interaction with human companions.

  15. History of gluteal augmentation.

    PubMed

    de la Peña, J Abel; Rubio, Omar V; Cano, Jacobo P; Cedillo, Mariana C; Garcés, Miriam T

    2006-07-01

    The concept of female beauty has changed throughout time, but the form and size of the breasts and gluteal region have remained constant as symbols of maximum femininity. Sculptures and prints show us feminine figures that are voluminous and reflect human history's interest in fertility. The early years of gluteal augmentation saw few published reports that described the procedure technique, follow-up, or possible complications. But developments continued as surgeons began experimenting with different anatomical planes for implant placement. The most important goal in plastic surgery is meeting a patient's expectations. It is important for the surgeon to thoroughly explain to patients what can realistically be achieved with a procedure. PMID:16818090

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

    PubMed

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

    2016-07-01

    Despite its extraordinary antioxidant capacity, the clinical usage of silymarin has remained restricted to amelioration of hepatic pathology. Perhaps its low bioavailability and uneven bio-distribution, owing to its poor aqueous solubility, are two main causes that have dampened the clinical applicability and scope of this preparation. We took these two challenges and suggested an unexplored application of silymarin. Apart from liver, two of the most susceptible vital organs at the highest risk of oxidative stress are brain and lung, especially during reduced oxygen saturation (hypoxia) at anatomical level. Hypoxia causes excess generation of radicals primarily in the lungs as it is the first organ at the interphase of atmosphere and organism making it the most prone and vulnerable to oxidative stress and the first responder against hypobaric hypoxia. As our first objective, we improved the silymarin formulation by restricting its size to the lower threshold and then successfully tested the prophylactic and therapeutic action in rat lung challenged with simulated hypobaric hypoxia. After dose optimization, we observed that 50mg/kg BW silymarin as size restricted and homogenous aqueous suspension successfully minimized the reactive oxygen species and augmented the antioxidant defense by significant upregulation of catalase and superoxide dismutase and reduced glutathione. Moreover, the well-established hypoxia markers and proteins related to hypoxia adaptability, hif1a and VEGF were differentially regulated conferring significant reduction in the inflammation caused by hypobaric hypoxia. We therefore report,the unexplored potential benefits of silymarin for preventing high altitude associated pathophysiology further paving its road to clinical trials. PMID:27105952

  17. Pilot-optimal augmentation synthesis

    NASA Technical Reports Server (NTRS)

    Schmidt, D. K.

    1978-01-01

    An augmentation synthesis method usable in the absence of quantitative handling qualities specifications, and yet explicitly including design objectives based on pilot-rating concepts, is presented. The algorithm involves the unique approach of simultaneously solving for the stability augmentation system (SAS) gains, pilot equalization and pilot rating prediction via optimal control techniques. Simultaneous solution is required in this case since the pilot model (gains, etc.) depends upon the augmented plant dynamics, and the augmentation is obviously not a priori known. Another special feature is the use of the pilot's objective function (from which the pilot model evolves) to design the SAS.

  18. NASA Communications Augmentation network

    NASA Astrophysics Data System (ADS)

    Omidyar, Guy C.; Butler, Thomas E.; Laios, Straton C.

    1990-09-01

    The NASA Communications (Nascom) Division of the Mission Operations and Data Systems Directorate (MO&DSD) is to undertake a major initiative to develop the Nascom Augmentation (NAUG) network to achieve its long-range service objectives for operational data transport to support the Space Station Freedom Program, the Earth Observing System (EOS), and other projects. The NAUG is the Nascom ground communications network being developed to accommodate the operational traffic of the mid-1990s and beyond. The NAUG network development will be based on the Open Systems Interconnection Reference Model (OSI-RM). This paper describes the NAUG network architecture, subsystems, topology, and services; addresses issues of internetworking the Nascom network with other elements of the Space Station Information System (SSIS); discusses the operations environment. This paper also notes the areas of related research and presents the current conception of how the network will provide broadband services in 1998.

  19. Augmented Virtual Reality Laboratory

    NASA Technical Reports Server (NTRS)

    Tully-Hanson, Benjamin

    2015-01-01

    Real time motion tracking hardware has for the most part been cost prohibitive for research to regularly take place until recently. With the release of the Microsoft Kinect in November 2010, researchers now have access to a device that for a few hundred dollars is capable of providing redgreenblue (RGB), depth, and skeleton data. It is also capable of tracking multiple people in real time. For its original intended purposes, i.e. gaming, being used with the Xbox 360 and eventually Xbox One, it performs quite well. However, researchers soon found that although the sensor is versatile, it has limitations in real world applications. I was brought aboard this summer by William Little in the Augmented Virtual Reality (AVR) Lab at Kennedy Space Center to find solutions to these limitations.

  20. NASA Communications Augmentation network

    NASA Technical Reports Server (NTRS)

    Omidyar, Guy C.; Butler, Thomas E.; Laios, Straton C.

    1990-01-01

    The NASA Communications (Nascom) Division of the Mission Operations and Data Systems Directorate (MO&DSD) is to undertake a major initiative to develop the Nascom Augmentation (NAUG) network to achieve its long-range service objectives for operational data transport to support the Space Station Freedom Program, the Earth Observing System (EOS), and other projects. The NAUG is the Nascom ground communications network being developed to accommodate the operational traffic of the mid-1990s and beyond. The NAUG network development will be based on the Open Systems Interconnection Reference Model (OSI-RM). This paper describes the NAUG network architecture, subsystems, topology, and services; addresses issues of internetworking the Nascom network with other elements of the Space Station Information System (SSIS); discusses the operations environment. This paper also notes the areas of related research and presents the current conception of how the network will provide broadband services in 1998.

  1. NAESA Augmentation Pilot Project

    NASA Technical Reports Server (NTRS)

    Hoover, John J.

    1998-01-01

    This project was one project within the Native American Earth and Space Academy (NAESA). NAESA is a national initiative comprised of several organizations that support programs which focus on 1) enhancing the technological, scientific and pedagogical skills of K-14 teachers who instruct Native Americans, 2) enhancing the understanding and applications of science, technology, and engineering of college-bound Native Americans and teaching them general college "survival skills" (e.g., test taking, time management, study habits), 3) enhancing the scientific and pedagogical skills of the faculty of tribally-controllcd colleges and community colleges with large Native American enrollments, and 4) strengthening the critical relationships between students, their parents, tribal elders, and their communities. This Augmentation Pilot Project focused on the areas of community-school alliances and intemet technology use in teaching and learning and daily living addressing five major objectives.

  2. Augmented reality system

    NASA Astrophysics Data System (ADS)

    Lin, Chien-Liang; Su, Yu-Zheng; Hung, Min-Wei; Huang, Kuo-Cheng

    2010-08-01

    In recent years, Augmented Reality (AR)[1][2][3] is very popular in universities and research organizations. The AR technology has been widely used in Virtual Reality (VR) fields, such as sophisticated weapons, flight vehicle development, data model visualization, virtual training, entertainment and arts. AR has characteristics to enhance the display output as a real environment with specific user interactive functions or specific object recognitions. It can be use in medical treatment, anatomy training, precision instrument casting, warplane guidance, engineering and distance robot control. AR has a lot of vantages than VR. This system developed combines sensors, software and imaging algorithms to make users feel real, actual and existing. Imaging algorithms include gray level method, image binarization method, and white balance method in order to make accurate image recognition and overcome the effects of light.

  3. Magnetohydrodynamic Augmented Propulsion Experiment

    NASA Technical Reports Server (NTRS)

    Litchford, Ron J.

    2008-01-01

    Over the past several years, efforts have been under way to design and develop an operationally flexible research facility for investigating the use of cross-field MHD accelerators as a potential thrust augmentation device for thermal propulsion systems. The baseline configuration for this high-power experimental facility utilizes a 1.5-MWe multi-gas arc-heater as a thermal driver for a 2-MWe MHD accelerator, which resides in a large-bore 2-tesla electromagnet. A preliminary design study using NaK seeded nitrogen as the working fluid led to an externally diagonalized segmented MHD channel configuration based on an expendable heat-sink design concept. The current status report includes a review of engineering/design work and performance optimization analyses and summarizes component hardware fabrication and development efforts, preliminary testing results, and recent progress toward full-up assembly and testing

  4. Orexin in the toad Rhinella schneideri: The location of orexinergic neurons and the role of orexin in ventilatory responses to hypercarbia and hypoxia.

    PubMed

    Fonseca, Elisa M; Dias, Mirela B; Bícego, Kênia C; Gargaglioni, Luciane H

    2016-04-01

    Recent reports have suggested that orexins, also known as hypocretins, play an important role in the modulation of respiratory control in mammals, but there are no data available describing the role of the orexinergic system in the peripheral and central chemoreception of non-mammalian vertebrates. Therefore, the present study was designed to examine the localization of orexin-immunoreactive neurons in the brain of toads (Rhinella schneideri) and to investigate the contribution of orexin receptor-1 (OX1R) to the hypoxic and hypercarbic ventilatory responses of these animals during light and dark phases. Our results demonstrated that the orexinergic neurons of R. schneideri are located in the suprachiasmatic nucleus of the diencephalon. Additionally, the intracerebroventricular injection of SB-334867 (OX1R selective antagonist) attenuated the ventilatory response to hypercarbia during the dark phase by acting on tidal volume and breathing frequency, while during the light phase, SB-334867 attenuated the ventilatory response to hypoxia by acting on tidal volume only. We conclude that in the toad R. schneideri, orexinergic neurons are located in the suprachiasmatic nucleus and that OX1R contributes to hypercarbic and hypoxic chemoreflexes. PMID:25434286

  5. Inhaled 45-50% argon augments hypothermic brain protection in a piglet model of perinatal asphyxia.

    PubMed

    Broad, Kevin D; Fierens, Igor; Fleiss, Bobbi; Rocha-Ferreira, Eridan; Ezzati, Mojgan; Hassell, Jane; Alonso-Alconada, Daniel; Bainbridge, Alan; Kawano, Go; Ma, Daqing; Tachtsidis, Ilias; Gressens, Pierre; Golay, Xavier; Sanders, Robert D; Robertson, Nicola J

    2016-03-01

    Cooling to 33.5°C in babies with neonatal encephalopathy significantly reduces death and disability, however additional therapies are needed to maximize brain protection. Following hypoxia-ischemia we assessed whether inhaled 45-50% Argon from 2-26h augmented hypothermia neuroprotection in a neonatal piglet model, using MRS and aEEG, which predict outcome in babies with neonatal encephalopathy, and immunohistochemistry. Following cerebral hypoxia-ischemia, 20 Newborn male Large White piglets<40h were randomized to: (i) Cooling (33°C) from 2-26h (n=10); or (ii) Cooling and inhaled 45-50% Argon (Cooling+Argon) from 2-26h (n=8). Whole-brain phosphorus-31 and regional proton MRS were acquired at baseline, 24 and 48h after hypoxia-ischemia. EEG was monitored. At 48h after hypoxia-ischemia, cell death (TUNEL) was evaluated over 7 brain regions. There were no differences in body weight, duration of hypoxia-ischemia or insult severity; throughout the study there were no differences in heart rate, arterial blood pressure, blood biochemistry and inotrope support. Two piglets in the Cooling+Argon group were excluded. Comparing Cooling+Argon with Cooling there was preservation of whole-brain MRS ATP and PCr/Pi at 48h after hypoxia-ischemia (p<0.001 for both) and lower (1)H MRS lactate/N acetyl aspartate in white (p=0.03 and 0.04) but not gray matter at 24 and 48h. EEG background recovery was faster (p<0.01) with Cooling+Argon. An overall difference between average cell-death of Cooling versus Cooling+Argon was observed (p<0.01); estimated cells per mm(2) were 23.9 points lower (95% C.I. 7.3-40.5) for the Cooling+Argon versus Cooling. Inhaled 45-50% Argon from 2-26h augmented hypothermic protection at 48h after hypoxia-ischemia shown by improved brain energy metabolism on MRS, faster EEG recovery and reduced cell death on TUNEL. Argon may provide a cheap and practical therapy to augment cooling for neonatal encephalopathy. PMID:26687546

  6. Insulin- and warts-dependent regulation of tracheal plasticity modulates systemic larval growth during hypoxia in Drosophila melanogaster.

    PubMed

    Wong, Daniel M; Shen, Zhouyang; Owyang, Kristin E; Martinez-Agosto, Julian A

    2014-01-01

    Adaptation to dynamic environmental cues during organismal development requires coordination of tissue growth with available resources. More specifically, the effects of oxygen availability on body size have been well-documented, but the mechanisms through which hypoxia restricts systemic growth have not been fully elucidated. Here, we characterize the larval growth and metabolic defects in Drosophila that result from hypoxia. Hypoxic conditions reduced fat body opacity and increased lipid droplet accumulation in this tissue, without eliciting lipid aggregation in hepatocyte-like cells called oenocytes. Additionally, hypoxia increased the retention of Dilp2 in the insulin-producing cells of the larval brain, associated with a reduction of insulin signaling in peripheral tissues. Overexpression of the wildtype form of the insulin receptor ubiquitously and in the larval trachea rendered larvae resistant to hypoxia-induced growth restriction. Furthermore, Warts downregulation in the trachea was similar to increased insulin receptor signaling during oxygen deprivation, which both rescued hypoxia-induced growth restriction, inhibition of tracheal molting, and developmental delay. Insulin signaling and loss of Warts function increased tracheal growth and augmented tracheal plasticity under hypoxic conditions, enhancing oxygen delivery during periods of oxygen deprivation. Our findings demonstrate a mechanism that coordinates oxygen availability with systemic growth in which hypoxia-induced reduction of insulin receptor signaling decreases plasticity of the larval trachea that is required for the maintenance of systemic growth during times of limiting oxygen availability. PMID:25541690

  7. Hypoxia drives apoptosis independently of p53 and metallothionein transcript levels in hemocytes of the whiteleg shrimp Litopenaeus vannamei.

    PubMed

    Felix-Portillo, Monserrath; Martínez-Quintana, José A; Arenas-Padilla, Marina; Mata-Haro, Verónica; Gómez-Jiménez, Silvia; Yepiz-Plascencia, Gloria

    2016-10-01

    The cellular mechanisms used by the shrimp Litopenaeus vannamei to respond to hypoxia have been studied from the energetic metabolism and antioxidant angles. We herein investigated the participation of p53 and metallothionein (MT) in the apoptotic process in response to hypoxia in shrimp hemocytes. The Lvp53 or LvMT genes were efficiently silenced by injection of double stranded RNA for p53 or MT. The effects of silencing on apoptosis were measured as caspase-3 activity and flow cytometry in hemocytes after 24 and 48 h of hypoxia (1.5 mg DO L(-1)). Hemocytes from unsilenced animals had significantly higher apoptosis levels upon both times of hypoxia. The apoptotic levels were diminished but not suppressed in dsp53-silenced but not dsMT-silenced hemocytes after 24 h of hypoxia, indicating a contribution of Lvp53 to apoptosis. Apoptosis in normoxia was significantly higher in dsp53-and dsMT-silenced animals compared to the unsilenced controls, pointing to a possible cytoprotective role of LvMT and Lvp53 during the basal apoptotic program in normoxia. Overall, these results indicate that hypoxia augments apoptosis in shrimp hemocytes and high mRNA levels of Lvp53 and LvMT are not necessary for this response. PMID:27459156

  8. Insulin- and Warts-Dependent Regulation of Tracheal Plasticity Modulates Systemic Larval Growth during Hypoxia in Drosophila melanogaster

    PubMed Central

    Wong, Daniel M.; Shen, Zhouyang; Owyang, Kristin E.; Martinez-Agosto, Julian A.

    2014-01-01

    Adaptation to dynamic environmental cues during organismal development requires coordination of tissue growth with available resources. More specifically, the effects of oxygen availability on body size have been well-documented, but the mechanisms through which hypoxia restricts systemic growth have not been fully elucidated. Here, we characterize the larval growth and metabolic defects in Drosophila that result from hypoxia. Hypoxic conditions reduced fat body opacity and increased lipid droplet accumulation in this tissue, without eliciting lipid aggregation in hepatocyte-like cells called oenocytes. Additionally, hypoxia increased the retention of Dilp2 in the insulin-producing cells of the larval brain, associated with a reduction of insulin signaling in peripheral tissues. Overexpression of the wildtype form of the insulin receptor ubiquitously and in the larval trachea rendered larvae resistant to hypoxia-induced growth restriction. Furthermore, Warts downregulation in the trachea was similar to increased insulin receptor signaling during oxygen deprivation, which both rescued hypoxia-induced growth restriction, inhibition of tracheal molting, and developmental delay. Insulin signaling and loss of Warts function increased tracheal growth and augmented tracheal plasticity under hypoxic conditions, enhancing oxygen delivery during periods of oxygen deprivation. Our findings demonstrate a mechanism that coordinates oxygen availability with systemic growth in which hypoxia-induced reduction of insulin receptor signaling decreases plasticity of the larval trachea that is required for the maintenance of systemic growth during times of limiting oxygen availability. PMID:25541690

  9. Augmented Reality Comes to Physics

    ERIC Educational Resources Information Center

    Buesing, Mark; Cook, Michael

    2013-01-01

    Augmented reality (AR) is a technology used on computing devices where processor-generated graphics are rendered over real objects to enhance the sensory experience in real time. In other words, what you are really seeing is augmented by the computer. Many AR games already exist for systems such as Kinect and Nintendo 3DS and mobile apps, such as…

  10. FDG uptake, a surrogate of tumour hypoxia?

    PubMed Central

    Van de Wiele, Christophe

    2008-01-01

    Introduction Tumour hyperglycolysis is driven by activation of hypoxia-inducible factor-1 (HIF-1) through tumour hypoxia. Accordingly, the degree of 2-fluro-2-deoxy-d-glucose (FDG) uptake by tumours might indirectly reflect the level of hypoxia, obviating the need for more specific radiopharmaceuticals for hypoxia imaging. Discussion In this paper, available data on the relationship between hypoxia and FDG uptake by tumour tissue in vitro and in vivo are reviewed. In pre-clinical in vitro studies, acute hypoxia was consistently shown to increase FDG uptake by normal and tumour cells within a couple of hours after onset with mobilisation or modification of glucose transporters optimising glucose uptake, followed by a delayed response with increased rates of transcription of GLUT mRNA. In pre-clinical imaging studies on chronic hypoxia that compared FDG uptake by tumours grown in rat or mice to uptake by FMISO, the pattern of normoxic and hypoxic regions within the human tumour xenografts, as imaged by FMISO, largely correlated with glucose metabolism although minor locoregional differences could not be excluded. In the clinical setting, data are limited and discordant. Conclusion Further evaluation of FDG uptake by various tumour types in relation to intrinsic and bioreductive markers of hypoxia and response to radiotherapy or hypoxia-dependent drugs is needed to fully assess its application as a marker of hypoxia in the clinical setting. PMID:18509637

  11. Bayesian Inference of Tumor Hypoxia

    NASA Astrophysics Data System (ADS)

    Gunawan, R.; Tenti, G.; Sivaloganathan, S.

    2009-12-01

    Tumor hypoxia is a state of oxygen deprivation in tumors. It has been associated with aggressive tumor phenotypes and with increased resistance to conventional cancer therapies. In this study, we report on the application of Bayesian sequential analysis in estimating the most probable value of tumor hypoxia quantification based on immunohistochemical assays of a biomarker. The `gold standard' of tumor hypoxia assessment is a direct measurement of pO2 in vivo by the Eppendorf polarographic electrode, which is an invasive technique restricted to accessible sites and living tissues. An attractive alternative is immunohistochemical staining to detect proteins expressed by cells during hypoxia. Carbonic anhydrase IX (CAIX) is an enzyme expressed on the cell membrane during hypoxia to balance the immediate extracellular microenvironment. CAIX is widely regarded as a surrogate marker of chronic hypoxia in various cancers. The study was conducted with two different experimental procedures. The first data set was a group of three patients with invasive cervical carcinomas, from which five biopsies were obtained. Each of the biopsies was fully sectioned and from each section, the proportion of CAIX-positive cells was estimated. Measurements were made by image analysis of multiple deep sections cut through these biopsies, labeled for CAIX using both immunofluorescence and immunohistochemical techniques [1]. The second data set was a group of 24 patients, also with invasive cervical carcinomas, from which two biopsies were obtained. Bayesian parameter estimation was applied to obtain a reliable inference about the proportion of CAIX-positive cells within the carcinomas, based on the available biopsies. From the first data set, two to three biopsies were found to be sufficient to infer the overall CAIX percentage in the simple form: best estimate±uncertainty. The second data-set led to a similar result in 70% of the cases. In the remaining cases Bayes' theorem warned us

  12. Magnetohydrodynamic Augmented Propulsion Experiment

    NASA Technical Reports Server (NTRS)

    Litchford, Ron J.; Cole, John; Lineberry, John; Chapman, Jim; Schmidt, Harold; Cook, Stephen (Technical Monitor)

    2002-01-01

    A fundamental obstacle to routine space access is the specific energy limitations associated with chemical fuels. In the case of vertical take-off, the high thrust needed for vertical liftoff and acceleration to orbit translates into power levels in the 10 GW range. Furthermore, useful payload mass fractions are possible only if the exhaust particle energy (i.e., exhaust velocity) is much greater than that available with traditional chemical propulsion. The electronic binding energy released by the best chemical reactions (e.g., LOX/LH2 for example, is less than 2 eV per product molecule (approx. 1.8 eV per H2O molecule), which translates into particle velocities less than 5 km/s. Useful payload fractions, however, will require exhaust velocities exceeding 15 km/s (i.e., particle energies greater than 20 eV). As an added challenge, the envisioned hypothetical RLV (reusable launch vehicle) should accomplish these amazing performance feats while providing relatively low acceleration levels to orbit (2-3g maximum). From such fundamental considerations, it is painfully obvious that planned and current RLV solutions based on chemical fuels alone represent only a temporary solution and can only result in minor gains, at best. What is truly needed is a revolutionary approach that will dramatically reduce the amount of fuel and size of the launch vehicle. This implies the need for new compact high-power energy sources as well as advanced accelerator technologies for increasing engine exhaust velocity. Electromagnetic acceleration techniques are of immense interest since they can be used to circumvent the thermal limits associated with conventional propulsion systems. This paper describes the Magnetohydrodynamic Augmented Propulsion Experiment (MAPX) being undertaken at NASA Marshall Space Flight Center (MSFC). In this experiment, a 1-MW arc heater is being used as a feeder for a 1-MW magnetohydrodynamic (MHD) accelerator. The purpose of the experiment is to demonstrate

  13. Role of hypoxia during nephrogenesis.

    PubMed

    Hemker, Shelby L; Sims-Lucas, Sunder; Ho, Jacqueline

    2016-10-01

    Mammals develop in a physiologically hypoxic state, and the oxygen tension of different tissues in the embryo is precisely controlled. Deviation from normal oxygenation, such as what occurs in placental insufficiency, can disrupt fetal development. Several studies demonstrate that intrauterine hypoxia has a negative effect on kidney development. As nascent nephrons are forming from nephron progenitors in the nephrogenic zone, they are exposed to varying oxygen tension by virtue of the development of the renal vasculature. Thus, nephrogenesis may be linked to oxygen tension. However, the mechanism(s) by which this occurs remains unclear. This review focuses on what is known about molecular mechanisms active in physiological and pathological hypoxia and their effects on kidney development. PMID:26872484

  14. Imaging tumour hypoxia with positron emission tomography

    PubMed Central

    Fleming, I N; Manavaki, R; Blower, P J; West, C; Williams, K J; Harris, A L; Domarkas, J; Lord, S; Baldry, C; Gilbert, F J

    2015-01-01

    Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers. PMID:25514380

  15. Effect of Hypoxia and Bedrest on Peripheral Vasoconstriction

    NASA Astrophysics Data System (ADS)

    McDonnell, Adam C.; Mekjavic, Igor B.; Dolenc-Groselj, Leja; Jaki Mekjavic, Polona; Eiken, Ola

    2013-02-01

    Future planetary habitats may expose astronauts to both microgravity and hypobaric hypoxia, both inducing a reduction in peripheral perfusion. Peripheral temperature changes have been linked to sleep onset and quality [5]. However, it is still unknown what effect combining hypoxia and bedrest has on this relationship. Eleven male participants underwent three 10-day campaigns in a randomized manner: 1) normobaric hypoxic ambulatory confinement (HAmb); 2) normobaric hypoxic bed rest (HBR); 3) normobaric normoxic bed rest (NBR). There was no change in skin temperature gradient between the calf and toes, an index of peripheral perfusion (Δ Tc-t), over the 10-d period in the HAmb trial. However, there was a significant increase (p< 0.001) in daytime (9am-9pm) Δ Tc-t on day 10 of the inactivity/unloading periods (HBR and NBR trials). This reduction in the perfusion of the toes during the daytime was augmented during the HBR trial compared to NBR (p< 0.001). Before and on day 10 of the interventions we conducted polysomnographic assessment, which revealed no changes in sleep onset and/or architecture. These data support the theory that circadian changes in temperature are functionally linked to sleepiness [1].

  16. Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension

    PubMed Central

    Woods, Crystal; Taylor, Joann M.; Benninger, Richard K. P.; Johnson, Richard D.; Villegas, Leah R.; Stenmark, Kurt R.; Harrison, David G.; Majka, Susan M.; Irwin, David; Farrow, Kathryn N.

    2014-01-01

    Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC-SODloxp/loxp × Tgcre/SMMHC mice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH-1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC-SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inactivation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function. PMID:25326578

  17. Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension.

    PubMed

    Nozik-Grayck, Eva; Woods, Crystal; Taylor, Joann M; Benninger, Richard K P; Johnson, Richard D; Villegas, Leah R; Stenmark, Kurt R; Harrison, David G; Majka, Susan M; Irwin, David; Farrow, Kathryn N

    2014-12-01

    Excess superoxide has been implicated in pulmonary hypertension (PH). We previously found lung overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) attenuates PH and pulmonary artery (PA) remodeling. Although comprising a small fraction of total SOD activity in most tissues, EC-SOD is abundant in arteries. We hypothesize that the selective loss of vascular EC-SOD promotes hypoxia-induced PH through redox-sensitive signaling pathways. EC-SOD(loxp/loxp) × Tg(cre/SMMHC) mice (SMC EC-SOD KO) received tamoxifen to conditionally deplete smooth muscle cell (SMC)-derived EC-SOD. Mice were exposed to hypobaric hypoxia for 35 days, and PH was assessed by right ventricular systolic pressure measurements and right ventricle hypertrophy. Vascular remodeling was evaluated by morphometric analysis and two-photon microscopy for collagen. We examined cGMP content and soluble guanylate cyclase expression and activity in lung, lung phosphodiesterase 5 (PDE5) expression and activity, and expression of endothelial nitric oxide synthase and GTP cyclohydrolase-1 (GTPCH-1), the rate-limiting enzyme in tetrahydrobiopterin synthesis. Knockout of SMC EC-SOD selectively decreased PA EC-SOD without altering total lung EC-SOD. PH and vascular remodeling induced by chronic hypoxia was augmented in SMC EC-SOD KO. Depletion of SMC EC-SOD did not impact content or activity of lung soluble guanylate cyclase or PDE5, yet it blunted the hypoxia-induced increase in cGMP. Although total eNOS was not altered, active eNOS and GTPCH-1 decreased with hypoxia only in SMC EC-SOD KO. We conclude that the localized loss of PA EC-SOD augments chronic hypoxic PH. In addition to oxidative inactivation of NO, deletion of EC-SOD seems to reduce eNOS activity, further compromising pulmonary vascular function. PMID:25326578

  18. Control Augmented Structural Synthesis

    NASA Technical Reports Server (NTRS)

    Lust, Robert V.; Schmit, Lucien A.

    1988-01-01

    A methodology for control augmented structural synthesis is proposed for a class of structures which can be modeled as an assemblage of frame and/or truss elements. It is assumed that both the plant (structure) and the active control system dynamics can be adequately represented with a linear model. The structural sizing variables, active control system feedback gains and nonstructural lumped masses are treated simultaneously as independent design variables. Design constraints are imposed on static and dynamic displacements, static stresses, actuator forces and natural frequencies to ensure acceptable system behavior. Multiple static and dynamic loading conditions are considered. Side constraints imposed on the design variables protect against the generation of unrealizable designs. While the proposed approach is fundamentally more general, here the methodology is developed and demonstrated for the case where: (1) the dynamic loading is harmonic and thus the steady state response is of primary interest; (2) direct output feedback is used for the control system model; and (3) the actuators and sensors are collocated.

  19. Augmented Likelihood Image Reconstruction.

    PubMed

    Stille, Maik; Kleine, Matthias; Hägele, Julian; Barkhausen, Jörg; Buzug, Thorsten M

    2016-01-01

    The presence of high-density objects remains an open problem in medical CT imaging. Data of projections passing through objects of high density, such as metal implants, are dominated by noise and are highly affected by beam hardening and scatter. Reconstructed images become less diagnostically conclusive because of pronounced artifacts that manifest as dark and bright streaks. A new reconstruction algorithm is proposed with the aim to reduce these artifacts by incorporating information about shape and known attenuation coefficients of a metal implant. Image reconstruction is considered as a variational optimization problem. The afore-mentioned prior knowledge is introduced in terms of equality constraints. An augmented Lagrangian approach is adapted in order to minimize the associated log-likelihood function for transmission CT. During iterations, temporally appearing artifacts are reduced with a bilateral filter and new projection values are calculated, which are used later on for the reconstruction. A detailed evaluation in cooperation with radiologists is performed on software and hardware phantoms, as well as on clinically relevant patient data of subjects with various metal implants. Results show that the proposed reconstruction algorithm is able to outperform contemporary metal artifact reduction methods such as normalized metal artifact reduction. PMID:26208310

  20. Perceptually Augmented Simulator Design.

    PubMed

    Edmunds, T; Pai, D K

    2012-01-01

    Training simulators have proven their worth in a variety of fields, from piloting to air-traffic control to nuclear power station monitoring. Designing surgical simulators, however, poses the challenge of creating trainers that effectively instill not only high-level understanding of the steps to be taken in a given situation, but also the low-level "muscle-memory" needed to perform delicate surgical procedures. It is often impossible to build an ideal simulator that perfectly mimics the haptic experience of a surgical procedure, but by focussing on the aspects of the experience that are perceptually salient we can build simulators that effectively instill learning. We propose a general method for the design of surgical simulators that augment the perceptually salient aspects of an interaction. Using this method, we can increase skill-transfer rates without requiring expensive improvements in the capability of the rendering hardware or the computational complexity of the simulation. In this paper, we present our decomposition-based method for surgical simulator design, and describe a user-study comparing the training effectiveness of a haptic-search-task simulator designed using our method versus an unaugmented simulator. The results show that perception-based task decomposition can be used to improve the design of surgical simulators that effectively impart skill by targeting perceptually significant aspects of the interaction. PMID:26963831

  1. Structural consequences of railgun augmentation

    SciTech Connect

    Wellman, G.W.; Schuler, K.W. . Applied Mechanics Div. III)

    1989-01-01

    An augmented railgun can provide the same driving force on a projectile at a lower plasma arc current and thus less potential erosion and barrel damage as an unaugmented railgun. However, there are structural consequences to railgun augmentation which must be overcome before the advantages of lower plasma arc currents can be realized. To investigate these consequences, a bolted V-block supporting structure is considered with two cores; unaugmented (a single pair of conducting rails), and augmented (conducting rails augmented by a second tandem set of conductors). The mechanical load on the cores consist of the static bolt preload, the plasma pressure behind the projectile, and the magnetic pressure induced by currents flowing in the rails or augmenting conductors. Assuming no current diffusion into the conductors, the magnetic pressure distribution on the conductors is determined by solving the two dimensional magnetostatic field equations using an analogy with heat transfer. These loads are then used in a dynamic finite element structural model. The maximum rail current is found at which the unaugmented railgun can be repetitively fired without detrimental gaps forming at the bore. For the augmented railgun, at the same projectile acceleration, large permanent deformations can occur. Thus successful implementation of rail gun augmentation will require improvement of the supporting structure.

  2. Structural consequences of railgun augmentation

    SciTech Connect

    Wellman, G.W.; Schuler, K.W.

    1988-01-01

    An augmented railgun can provide the same driving force on a projectile at a lower plasma arc current and thus less potential erosion and barrel damage as an unaugmented railgun. However, there are structural consequences to railgun augmentation which must be overcome before the advantages of lower plasma arc currents can be realized. To investigate these consequences, a bolted V-block supporting structure is considered with two cores; unaugmented (a single pair of conducting rails), and augmented (conducting rails augmented by a second tandem set of conductors). The mechanical load on the cores consist of the static bolt preload, the plasma pressure behind the projectile, and the magnetic pressure induced by currents flowing in the rails or augmenting conductors. Assuming no current diffusion into the conductors, the magnetic pressure distribution on the conductors is determined by solving the two-dimensional magnetostatic field equations using an analogy with heat transfer. These loads are then used in a dynamic finite element structural model. The maximum rail current is found at which the unaugmented railgun can be repetitively fired without detrimental gaps forming at the bore. For the augmented railgun, at the same projectile acceleration, large permanent deformations can occur. Thus successful implementation of rail gun augmentation will require improvement of the supporting structure.

  3. Role of HIF-1 on phosphofructokinase and fructose 1, 6-bisphosphatase expression during hypoxia in the white shrimp Litopenaeus vannamei.

    PubMed

    Cota-Ruiz, Keni; Leyva-Carrillo, Lilia; Peregrino-Uriarte, Alma B; Valenzuela-Soto, Elisa M; Gollas-Galván, Teresa; Gómez-Jiménez, Silvia; Hernández, Jesús; Yepiz-Plascencia, Gloria

    2016-08-01

    HIF-1 is a transcription factor that controls a widespread range of genes in metazoan organisms in response to hypoxia and is composed of α and β subunits. In shrimp, phosphofructokinase (PFK) and fructose bisphosphatase (FBP) are up-regulated in hypoxia. We hypothesized that HIF-1 is involved in the regulation of PFK and FBP genes in shrimp hepatopancreas under hypoxia. Long double stranded RNA (dsRNA) intramuscular injection was utilized to silence simultaneously both HIF-1 subunits, and then, we measured the relative expression of PFK and FBP, as well as their corresponding enzymatic activities in hypoxic shrimp hepatopancreas. The results indicated that HIF-1 participates in the up-regulation of PFK transcripts under short-term hypoxia since the induction caused by hypoxia (~1.6 and ~4.2-fold after 3 and 48h, respectively) is significantly reduced in the dsRNA animals treated. Moreover, PFK activity was significantly ~2.8-fold augmented after 3h in hypoxia alongside to an ~1.9-fold increment in lactate. However, when animals were dsRNA treated, both were significantly reduced. On the other hand, FBP transcripts were ~5.3-fold up-regulated in long-term hypoxic conditions (48h). HIF-1 is involved in this process since FBP transcripts were not induced by hypoxia when HIF-1 was silenced. Conversely, the FBP activity was not affected by hypoxia, which suggests its possible regulation at post-translational level. Taken together, these results position HIF-1 as a prime transcription factor in coordinating glucose metabolism through the PFK and FBP genes among others, in shrimp under low oxygen environments. PMID:27032338

  4. Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes

    SciTech Connect

    Chen Baoying; Lam, Karen S.L.; Wang Yu; Wu Donghai; Lam, Michael C.; Shen Jiangang; Wong Laiching; Hoo, Ruby L.C.; Zhang Jialiang; Xu Aimin . E-mail: amxu@hkucc.hku.hk

    2006-03-10

    Low plasma levels of adiponectin (hypoadiponectinemia) and elevated circulating concentrations of plasminogen activator inhibitor (PAI)-1 are causally associated with obesity-related insulin resistance and cardiovascular disease. However, the mechanism that mediates the aberrant production of these two adipokines in obesity remains poorly understood. In this study, we investigated the effects of hypoxia and reactive oxygen species (ROS) on production of adiponectin and PAI-1 in 3T3-L1 adipocytes. Quantitative PCR and immunoassays showed that ambient hypoxia markedly suppressed adiponectin mRNA expression and its protein secretion, and increased PAI-1 production in mature adipocytes. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1{alpha} (HIF-1{alpha}), mimicked the hypoxia-mediated modulations of these two adipokines. Hypoxia caused a modest elevation of ROS in adipocytes. However, ablation of intracellular ROS by antioxidants failed to alleviate hypoxia-induced aberrant production of adiponectin and PAI-1. On the other hand, the antioxidants could reverse hydrogen peroxide (H{sub 2}O{sub 2})-induced dysregulation of adiponectin and PAI-1 production. H{sub 2}O{sub 2} treatment decreased the expression levels of peroxisome proliferator-activated receptor gamma (PPAR{gamma}) and CCAAT/enhancer binding protein (C/EBP{alpha}), but had no effect on HIF-1{alpha}, whereas hypoxia stabilized HIF-1{alpha} and decreased expression of C/EBP{alpha}, but not PPAR{gamma}. Taken together, these data suggest that hypoxia and ROS decrease adiponectin production and augment PAI-1 expression in adipocytes via distinct signaling pathways. These effects may contribute to hypoadiponectinemia and elevated PAI-1 levels in obesity, type 2 diabetes, and cardiovascular diseases.

  5. Hypoxia induces hypersensitivity and hyperreactivity to thromboxane receptor agonist in neonatal pulmonary arterial myocytes.

    PubMed

    Hinton, M; Mellow, L; Halayko, A J; Gutsol, A; Dakshinamurti, S

    2006-02-01

    PPHN, caused by perinatal hypoxia or inflammation, is characterized by an increased thromboxane-prostacyclin ratio and pulmonary vasoconstriction. We examined effects of hypoxia on myocyte thromboxane responsiveness. Myocytes from 3rd-6th generation pulmonary arteries of newborn piglets were grown to confluence and synchronized in contractile phenotype by serum deprivation. On the final 3 days of culture, myocytes were exposed to 10% O2 for 3 days; control myocytes from normoxic piglets were cultured in 21% O2. PPHN was induced in newborn piglets by 3-day hypoxic exposure (Fi(O2) 0.10); pulmonary arterial myocytes from these animals were maintained in normoxia. Ca2+ mobilization to thromboxane mimetic U-46619 and ATP was quantified using fura-2 AM. Three-day hypoxic exposure in vitro results in increased basal [Ca2+]i, faster and heightened peak Ca2+ response, and decreased U-46619 EC50. These functional changes persist in myocytes exposed to hypoxia in vivo but cultured in 21% O2. Blockade of Ca2+ entry and store refilling do not alter peak U-46619 Ca2+ responses in hypoxic or normoxic myocytes. Blockade of ryanodine-sensitive or IP3-gated intracellular Ca2+ channels inhibits hypoxic augmentation of peak U-46619 response. Ca2+ response to ryanodine alone is undetectable; ATP-induced Ca2+ mobilization is unaltered by hypoxia, suggesting no independent increase in ryanodine-sensitive or IP3-linked intracellular Ca2+ pool mobilization. We conclude hypoxia has a priming effect on neonatal pulmonary arterial myocytes, resulting in increased resting Ca2+, thromboxane hypersensitivity, and hyperreactivity. We postulate that hypoxia increases agonist-induced TP-R-linked IP3 pathway activation. Myocyte thromboxane hyperresponsiveness persists in culture after removal from the initiating hypoxic stimulus, suggesting altered gene expression. PMID:16214814

  6. Dietary nitrate reduces muscle metabolic perturbation and improves exercise tolerance in hypoxia.

    PubMed

    Vanhatalo, Anni; Fulford, Jonathan; Bailey, Stephen J; Blackwell, James R; Winyard, Paul G; Jones, Andrew M

    2011-11-15

    Exercise in hypoxia is associated with reduced muscle oxidative function and impaired exercise tolerance. We hypothesised that dietary nitrate supplementation (which increases plasma [nitrite] and thus NO bioavailability) would ameliorate the adverse effects of hypoxia on muscle metabolism and oxidative function. In a double-blind, randomised crossover study, nine healthy subjects completed knee-extension exercise to the limit of tolerance (T(lim)), once in normoxia (20.9% O(2); CON) and twice in hypoxia (14.5% O(2)). During 24 h prior to the hypoxia trials, subjects consumed 0.75 L of nitrate-rich beetroot juice (9.3 mmol nitrate; H-BR) or 0.75 L of nitrate-depleted beetroot juice as a placebo (0.006 mmol nitrate; H-PL). Muscle metabolism was assessed using calibrated (31)P-MRS. Plasma [nitrite] was elevated (P < 0.01) following BR (194 ± 51 nm) compared to PL (129 ± 23 nm) and CON (142 ± 37 nM). T(lim) was reduced in H-PL compared to CON (393 ± 169 vs. 471 ± 200 s; P < 0.05) but was not different between CON and H-BR (477 ± 200 s). The muscle [PCr], [P(i)] and pH changed at a faster rate in H-PL compared to CON and H-BR. The [PCr] recovery time constant was greater (P < 0.01) in H-PL (29 ± 5 s) compared to CON (23 ± 5 s) and H-BR (24 ± 5 s). Nitrate supplementation reduced muscle metabolic perturbation during exercise in hypoxia and restored exercise tolerance and oxidative function to values observed in normoxia. The results suggest that augmenting the nitrate-nitrite-NO pathway may have important therapeutic applications for improving muscle energetics and functional capacity in hypoxia. PMID:21911616

  7. Dietary nitrate reduces muscle metabolic perturbation and improves exercise tolerance in hypoxia

    PubMed Central

    Vanhatalo, Anni; Fulford, Jonathan; Bailey, Stephen J; Blackwell, James R; Winyard, Paul G; Jones, Andrew M

    2011-01-01

    Abstract Exercise in hypoxia is associated with reduced muscle oxidative function and impaired exercise tolerance. We hypothesised that dietary nitrate supplementation (which increases plasma [nitrite] and thus NO bioavailability) would ameliorate the adverse effects of hypoxia on muscle metabolism and oxidative function. In a double-blind, randomised crossover study, nine healthy subjects completed knee-extension exercise to the limit of tolerance (Tlim), once in normoxia (20.9% O2; CON) and twice in hypoxia (14.5% O2). During 24 h prior to the hypoxia trials, subjects consumed 0.75 L of nitrate-rich beetroot juice (9.3 mmol nitrate; H-BR) or 0.75 L of nitrate-depleted beetroot juice as a placebo (0.006 mmol nitrate; H-PL). Muscle metabolism was assessed using calibrated 31P-MRS. Plasma [nitrite] was elevated (P < 0.01) following BR (194 ± 51 nm) compared to PL (129 ± 23 nm) and CON (142 ± 37 nM). Tlim was reduced in H-PL compared to CON (393 ± 169 vs. 471 ± 200 s; P < 0.05) but was not different between CON and H-BR (477 ± 200 s). The muscle [PCr], [Pi] and pH changed at a faster rate in H-PL compared to CON and H-BR. The [PCr] recovery time constant was greater (P < 0.01) in H-PL (29 ± 5 s) compared to CON (23 ± 5 s) and H-BR (24 ± 5 s). Nitrate supplementation reduced muscle metabolic perturbation during exercise in hypoxia and restored exercise tolerance and oxidative function to values observed in normoxia. The results suggest that augmenting the nitrate–nitrite–NO pathway may have important therapeutic applications for improving muscle energetics and functional capacity in hypoxia. PMID:21911616

  8. Augmented Reality Comes to Physics

    NASA Astrophysics Data System (ADS)

    Buesing, Mark; Cook, Michael

    2013-04-01

    Augmented reality (AR) is a technology used on computing devices where processor-generated graphics are rendered over real objects to enhance the sensory experience in real time. In other words, what you are really seeing is augmented by the computer. Many AR games already exist for systems such as Kinect and Nintendo 3DS and mobile apps, such as Tagwhat and Star Chart (a must for astronomy class). The yellow line marking first downs in a televised football game2 and the enhanced puck that makes televised hockey easier to follow3 both use augmented reality to do the job.

  9. Hypoxia-Sensitive Materials for Biomedical Applications.

    PubMed

    Yu, Jicheng; Zhang, Yuqi; Hu, Xiuli; Wright, Grace; Gu, Zhen

    2016-06-01

    Hypoxia is a typical hallmark of various diseases, including cancer, ischemic diseases, and stroke. It is also associated with the disease progression. Therefore, it is critical to develop an effective strategy to target the hypoxic region for diagnosis and treatment. In this review, we summarize recent progress in the development of hypoxia-responsive systems for imaging, sensing and therapy. Two types of hypoxia-sensitive systems, the hypoxia inducible factor-1 based systems and bioreductive molecule based systems, were reviewed with comments on their advantages and limitations. Future opportunities and challenges are also discussed in the end. PMID:26926694

  10. An oxidative DNA "damage" and repair mechanism localized in the VEGF promoter is important for hypoxia-induced VEGF mRNA expression.

    PubMed

    Pastukh, Viktor; Roberts, Justin T; Clark, David W; Bardwell, Gina C; Patel, Mita; Al-Mehdi, Abu-Bakr; Borchert, Glen M; Gillespie, Mark N

    2015-12-01

    In hypoxia, mitochondria-generated reactive oxygen species not only stimulate accumulation of the transcriptional regulator of hypoxic gene expression, hypoxia inducible factor-1 (Hif-1), but also cause oxidative base modifications in hypoxic response elements (HREs) of hypoxia-inducible genes. When the hypoxia-induced base modifications are suppressed, Hif-1 fails to associate with the HRE of the VEGF promoter, and VEGF mRNA accumulation is blunted. The mechanism linking base modifications to transcription is unknown. Here we determined whether recruitment of base excision DNA repair (BER) enzymes in response to hypoxia-induced promoter modifications was required for transcription complex assembly and VEGF mRNA expression. Using chromatin immunoprecipitation analyses in pulmonary artery endothelial cells, we found that hypoxia-mediated formation of the base oxidation product 8-oxoguanine (8-oxoG) in VEGF HREs was temporally associated with binding of Hif-1α and the BER enzymes 8-oxoguanine glycosylase 1 (Ogg1) and redox effector factor-1 (Ref-1)/apurinic/apyrimidinic endonuclease 1 (Ape1) and introduction of DNA strand breaks. Hif-1α colocalized with HRE sequences harboring Ref-1/Ape1, but not Ogg1. Inhibition of BER by small interfering RNA-mediated reduction in Ogg1 augmented hypoxia-induced 8-oxoG accumulation and attenuated Hif-1α and Ref-1/Ape1 binding to VEGF HRE sequences and blunted VEGF mRNA expression. Chromatin immunoprecipitation-sequence analysis of 8-oxoG distribution in hypoxic pulmonary artery endothelial cells showed that most of the oxidized base was localized to promoters with virtually no overlap between normoxic and hypoxic data sets. Transcription of genes whose promoters lost 8-oxoG during hypoxia was reduced, while those gaining 8-oxoG was elevated. Collectively, these findings suggest that the BER pathway links hypoxia-induced introduction of oxidative DNA modifications in promoters of hypoxia-inducible genes to transcriptional

  11. Regulation of carotid body oxygen sensing by hypoxia-inducible factors.

    PubMed

    Prabhakar, Nanduri R; Semenza, Gregg L

    2016-01-01

    Oxygen (O2) sensing by the carotid body and its chemosensory reflex is critical for homeostatic regulation of breathing and blood pressure. Carotid body responses to hypoxia are not uniform but instead exhibit remarkable inter-individual variations. The molecular mechanisms underlying variations in carotid body O2 sensing are not known. Hypoxia-inducible factor-1 (HIF-1) and HIF-2 mediate transcriptional responses to hypoxia. This article reviews the emerging evidence that proper expression of the HIF-α isoforms is a key molecular determinant for carotid body O2 sensing. HIF-1α deficiency leads to a blunted carotid body hypoxic response, which is due to increased abundance of HIF-2α, elevated anti-oxidant enzyme activity, and a reduced intracellular redox state. Conversely, HIF-2α deficiency results in augmented carotid body sensitivity to hypoxia, which is due to increased abundance of HIF-1α, elevated pro-oxidant enzyme activity, and an oxidized intracellular redox state. Double heterozygous mice with equally reduced HIF-1α and HIF-2α showed no abnormality in redox state or carotid body O2 sensing. Thus, mutual antagonism between HIF-α isoforms determines the redox state and thereby establishes the set point for hypoxic sensing by the carotid body. PMID:26265380

  12. Effective Augmentation of Complex Networks.

    PubMed

    Wang, Jinjian; Yu, Xinghuo; Stone, Lewi

    2016-01-01

    Networks science plays an enormous role in many aspects of modern society from distributing electrical power across nations to spreading information and social networking amongst global populations. While modern networks constantly change in size, few studies have sought methods for the difficult task of optimising this growth. Here we study theoretical requirements for augmenting networks by adding source or sink nodes, without requiring additional driver-nodes to accommodate the change i.e., conserving structural controllability. Our "effective augmentation" algorithm takes advantage of clusters intrinsic to the network topology, and permits rapidly and efficient augmentation of a large number of nodes in one time-step. "Effective augmentation" is shown to work successfully on a wide range of model and real networks. The method has numerous applications (e.g. study of biological, social, power and technological networks) and potentially of significant practical and economic value. PMID:27165120

  13. Mersiline mesh in premaxillary augmentation.

    PubMed

    Foda, Hossam M T

    2005-01-01

    Premaxillary retrusion may distort the aesthetic appearance of the columella, lip, and nasal tip. This defect is characteristically seen in, but not limited to, patients with cleft lip nasal deformity. This study investigated 60 patients presenting with premaxillary deficiencies in which Mersiline mesh was used to augment the premaxilla. All the cases had surgery using the external rhinoplasty technique. Two methods of augmentation with Mersiline mesh were used: the Mersiline roll technique, for the cases with central symmetric deficiencies, and the Mersiline packing technique, for the cases with asymmetric deficiencies. Premaxillary augmentation with Mersiline mesh proved to be simple technically, easy to perform, and not associated with any complications. Periodic follow-up evaluation for a mean period of 32 months (range, 12-98 months) showed that an adequate degree of premaxillary augmentation was maintained with no clinically detectable resorption of the mesh implant. PMID:15959688

  14. Approximate Simulation of Acute Hypobaric Hypoxia with Normobaric Hypoxia

    NASA Technical Reports Server (NTRS)

    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 < 0.209 at or near sea level pressure to match the ambient O2 partial pressure (iso-pO2) of the target altitude. METHODS. Literature from investigators and manufacturers indicate that these devices may not properly account for the 47 mmHg of water vapor partial pressure that reduces the inspired partial pressure of O2 (P(sub I) O2). Nor do they account for the complex reality of alveolar gas composition as defined by the Alveolar Gas Equation. In essence, by providing iso-pO2 conditions for normobaric 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.

  15. Hypoxia affects in vitro proliferation and differentiation of mouse corneal epithelial progenitor cell.

    PubMed

    Dong, Nuo; Qin, Wenjuan; Xue, Yuhua; Li, Cheng; Liu, Zuguo

    2013-08-01

    This study was to investigate the proliferation and differentiation of mouse corneal epithelial progenitor cell in hypoxic airlift culture. Mouse corneal epithelial progenitor cell line progenitor cells were cultured under airlift with normoxic and hypoxic conditions for various durations up to 2 wk. Under normoxic conditions when exposed to air, the hyperproliferation and abnormal epidermal-like differentiation of mouse corneal epithelium was induced, whereas when exposed to air under hypoxic conditions, although we observed augmented proliferation, the abnormal differentiation was inhibited. The mechanism by which hypoxia prevents abnormal differentiation may involve downregulation of Wnt signaling pathways, which were inhibited in cells cultured with hypoxic airlift technique. In conclusion, hypoxia can prevent abnormal differentiation while enhancing the proliferation of corneal epithelial cells by blocking Wnt/β-catenin signaling pathway. PMID:23739874

  16. Thresholds of hypoxia for marine biodiversity.

    PubMed

    Vaquer-Sunyer, Raquel; Duarte, Carlos M

    2008-10-01

    Hypoxia is a mounting problem affecting the world's coastal waters, with severe consequences for marine life, including death and catastrophic changes. Hypoxia is forecast to increase owing to the combined effects of the continued spread of coastal eutrophication and global warming. A broad comparative analysis across a range of contrasting marine benthic organisms showed that hypoxia thresholds vary greatly across marine benthic organisms and that the conventional definition of 2 mg O(2)/liter to designate waters as hypoxic is below the empirical sublethal and lethal O(2) thresholds for half of the species tested. These results imply that the number and area of coastal ecosystems affected by hypoxia and the future extent of hypoxia impacts on marine life have been generally underestimated. PMID:18824689

  17. Tissue hypoxia: implications for the respiratory clinician.

    PubMed

    MacIntyre, Neil R

    2014-10-01

    Oxygen is essential for normal aerobic metabolism in mammals. Hypoxia is the presence of lower than normal oxygen content and pressure in the cell. Causes of hypoxia include hypoxemia (low blood oxygen content and pressure), impaired oxygen delivery, and impaired cellular oxygen uptake/utilization. Many compensatory mechanisms exist at the global, regional, and cellular levels to allow cells to function in a hypoxic environment. Clinical management of tissue hypoxia usually focuses on global hypoxemia and oxygen delivery. As we move into the future, the clinical focus needs to change to assessing and managing mission-critical regional hypoxia to avoid unnecessary and potential toxic global strategies. We also need to focus on understanding and better harnessing the body's own adaptive mechanisms to hypoxia. PMID:25161296

  18. Functional alterations in macrophages after hypoxia selection.

    PubMed

    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 (<1% O(2)). The results indicated that exposing 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

  19. Low-dose radiation augments vasculogenesis signaling through HIF-1-dependent and -independent SDF-1 induction.

    PubMed

    Lerman, Oren Z; Greives, Matthew R; Singh, Sunil P; Thanik, Vishal D; Chang, Christopher C; Seiser, Natalie; Brown, Daniel J; Knobel, Denis; Schneider, Robert J; Formenti, Silvia C; Saadeh, Pierre B; Levine, Jamie P

    2010-11-01

    The inflammatory response to ionizing radiation (IR) includes a proangiogenic effect that could be counterproductive in cancer but can be exploited for treating impaired wound healing. We demonstrate for the first time that IR stimulates hypoxia-inducible factor-1α (HIF-1α) up-regulation in endothelial cells (ECs), a HIF-1α-independent up-regulation of stromal cell-derived factor-1 (SDF-1), as well as endothelial migration, all of which are essential for angiogenesis. 5 Gray IR-induced EC HIF-1α and SDF-1 expression was greater when combined with hypoxia suggesting an additive effect. While small interfering RNA silencing of HIF-1α mRNA and abolition of HIF-1α protein induction down-regulated SDF-1 induction by hypoxia alone, it had little effect on SDF-1 induction by IR, demonstrating an independent pathway. SDF-1-mediated EC migration in hypoxic and/or radiation-treated media showed IR induced strong SDF-1-dependent migration of ECs, augmented by hypoxia. IR activates a novel pathway stimulating EC migration directly through the expression of SDF-1 independent of HIF-1α induction. These observations might be exploited for stimulation of wound healing or controlling tumor angiogenesis. PMID:20631377

  20. Cerium oxide nanoparticles promote neurogenesis and abrogate hypoxia-induced memory impairment through AMPK–PKC–CBP signaling cascade

    PubMed Central

    Arya, Aditya; Gangwar, Anamika; Singh, Sushil Kumar; Roy, Manas; Das, Mainak; Sethy, Niroj Kumar; Bhargava, Kalpana

    2016-01-01

    Structural and functional integrity of the brain is adversely affected by reduced oxygen saturation, especially during chronic hypoxia exposure and often encountered by altitude travelers or dwellers. Hypoxia-induced generation of reactive nitrogen and oxygen species reportedly affects the cortex and hippocampus regions of the brain, promoting memory impairment and cognitive dysfunction. Cerium oxide nanoparticles (CNPs), also known as nanoceria, switch between +3 and +4 oxidation states and reportedly scavenge superoxide anions, hydrogen peroxide, and peroxynitrite in vivo. In the present study, we evaluated the neuroprotective as well as the cognition-enhancing activities of nanoceria during hypobaric hypoxia. Using polyethylene glycol-coated 3 nm nanoceria (PEG-CNPs), we have demonstrated efficient localization of PEG-CNPs in rodent brain. This resulted in significant reduction of oxidative stress and associated damage during hypoxia exposure. Morris water maze-based memory function tests revealed that PEG-CNPs ameliorated hypoxia-induced memory impairment. Using microscopic, flow cytometric, and histological studies, we also provide evidences that PEG-CNPs augmented hippocampus neuronal survival and promoted neurogenesis. Molecular studies revealed that PEG-CNPs promoted neurogenesis through the 5′-adenine monophosphate-activated protein kinase–protein kinase C–cyclic adenosine monophosphate response element-binding protein binding (AMPK-PKC-CBP) protein pathway. Our present study results suggest that nanoceria can be translated as promising therapeutic molecules for neurodegenerative diseases. PMID:27069362

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

    PubMed Central

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

    2014-01-01

    I. Introduction II. The Clinical Importance of Tumor Hypoxia A. Pathophysiology of hypoxia B. Hypoxia's negative impact on the effectiveness of curative treatment 1. Hypoxic tumors accumulate and propagate cancer stem cells 2. Hypoxia reduces the effectiveness of radiotherapy 3. Hypoxia increases metastasis risk and reduces the effectiveness of surgery 4. Hypoxic tumors are resistant to the effects of chemotherapy and chemoradiation C. Hypoxia is prognostic for poor patient outcomes III. Diagnosis of Tumor Hypoxia A. Direct methods 1. Oxygen electrode—direct pO2 measurement most used in cancer research 2. Phosphorescence quenching—alternative direct pO2 measurement 3. Electron paramagnetic resonance 4. 19F-magnetic resonance spectroscopy 5. Overhauser-enhanced MRI B. Endogenous markers of hypoxia 1. Hypoxia-inducible factor-1α 2. Carbonic anhydrase IX 3. Glucose transporter 1 4. Osteopontin 5. A combined IHC panel of protein markers for hypoxia 6. Comet assay C. Physiologic methods 1. Near-infrared spectroscopy/tomography—widely used for pulse oximetry 2. Photoacoustic tomography 3. Contrast-enhanced color duplex sonography 4. MRI-based measurements 5. Blood oxygen level-dependent MRI 6. Pimonidazole 7. EF5 (pentafluorinated etanidazole) 8. Hypoxia PET imaging—physiologic hypoxia measurement providing tomographic information a. 18F-fluoromisonidazole b. 18F-fluoroazomycinarabinofuranoside c. 18F-EF5 (pentafluorinated etanidazole) d. 18F-flortanidazole e. Copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) f. 18F-FDG imaging of hypoxia IV. Modifying Hypoxia to Improve Therapeutic Outcomes A. Use of hypoxia information in radiation therapy planning B. Use of hypoxia assessment for selection of patients responsive to nimorazole C. Use of hypoxia assessment for selection of patients responsive to tirapazamine D. Use of hypoxia assessment for selection of patients

  2. SUSCEPTIBILITY OF A NORTHEASTERN GULF OF MEXICO ESTUARY TO HYPOXIA

    EPA Science Inventory

    Bottom water hypoxia is a common adverse consequence of nutrient enrichment in estuaries and coastal waters. To protect against hypoxia, it is helpful to know which waters are most susceptible to hypoxia. Hypoxia has been observed regularly in Pensacola Bay, a northeastern Gulf o...

  3. Augmentation cystoplasty in neurogenic bladder

    PubMed Central

    Kocjancic, Ervin; Demirdağ, Çetin

    2016-01-01

    The aim of this review is to update the indications, contraindications, technique, complications, and the tissue engineering approaches of augmentation cystoplasty (AC) in patients with neurogenic bladder. PubMed/MEDLINE was searched for the keywords "augmentation cystoplasty," "neurogenic bladder," and "bladder augmentation." Additional relevant literature was determined by examining the reference lists of articles identified through the search. The update review of of the indications, contraindications, technique, outcome, complications, and tissue engineering approaches of AC in patients with neurogenic bladder is presented. Although some important progress has been made in tissue engineering AC, conventional AC still has an important role in the surgical treatment of refractory neurogenic lower urinary tract dysfunction. PMID:27617312

  4. Augmented Reality Tower Technology Assessment

    NASA Technical Reports Server (NTRS)

    Reisman, Ronald J.; Brown, David M.

    2009-01-01

    Augmented Reality technology may help improve Air Traffic Control Tower efficiency and safety during low-visibility conditions. This paper presents the assessments of five off-duty controllers who shadow-controlled' with an augmented reality prototype in their own facility. Initial studies indicated unanimous agreement that this technology is potentially beneficial, though the prototype used in the study was not adequate for operational use. Some controllers agreed that augmented reality technology improved situational awareness, had potential to benefit clearance, control, and coordination tasks and duties and could be very useful for acquiring aircraft and weather information, particularly aircraft location, heading, and identification. The strongest objections to the prototype used in this study were directed at aircraft registration errors, unacceptable optical transparency, insufficient display performance in sunlight, inadequate representation of the static environment and insufficient symbology.

  5. Augmentation cystoplasty in neurogenic bladder.

    PubMed

    Çetinel, Bülent; Kocjancic, Ervin; Demirdağ, Çetin

    2016-09-01

    The aim of this review is to update the indications, contraindications, technique, complications, and the tissue engineering approaches of augmentation cystoplasty (AC) in patients with neurogenic bladder. PubMed/MEDLINE was searched for the keywords "augmentation cystoplasty," "neurogenic bladder," and "bladder augmentation." Additional relevant literature was determined by examining the reference lists of articles identified through the search. The update review of of the indications, contraindications, technique, outcome, complications, and tissue engineering approaches of AC in patients with neurogenic bladder is presented. Although some important progress has been made in tissue engineering AC, conventional AC still has an important role in the surgical treatment of refractory neurogenic lower urinary tract dysfunction. PMID:27617312

  6. Augmentation mentoplasty using Mersilene mesh.

    PubMed

    McCollough, E G; Hom, D B; Weigel, M T; Anderson, J R

    1990-10-01

    Many different materials are available for augmentation mentoplasty. However, the optimal implant material for chin implantation has yet to be found. During the past several years, a number of experienced surgeons have turned to the use of Mersilene mesh. Mersilene mesh is a non-absorbable Dacron polyester fiber that can be conformed easily into layers to achieve tailored dimensions and shape. At the McCollough Plastic Surgery Clinic PA, Birmingham, Ala, 277 patients over a 10-year period underwent chin augmentation with Mersilene mesh implants. The material provides excellent tensile strength, durability, and surgical adaptability. The overall complication rate was 3.2% (nine patients); infection rate, 2.5% (seven patients); and removal secondary to infection, 1.7% (five patients). Based on this 10-year experience, Mersilene mesh remains our material of choice for chin augmentation. PMID:2206500

  7. Augmentation-related brain plasticity.

    PubMed

    Di Pino, Giovanni; Maravita, Angelo; Zollo, Loredana; Guglielmelli, Eugenio; Di Lazzaro, Vincenzo

    2014-01-01

    Today, the anthropomorphism of the tools and the development of neural interfaces require reconsidering the concept of human-tools interaction in the framework of human augmentation. This review analyses the plastic process that the brain undergoes when it comes into contact with augmenting artificial sensors and effectors and, on the other hand, the changes that the use of external augmenting devices produces in the brain. Hitherto, few studies investigated the neural correlates of augmentation, but clues on it can be borrowed from logically-related paradigms: sensorimotor training, cognitive enhancement, cross-modal plasticity, sensorimotor functional substitution, use and embodiment of tools. Augmentation modifies function and structure of a number of areas, i.e., primary sensory cortices shape their receptive fields to become sensitive to novel inputs. Motor areas adapt the neuroprosthesis representation firing-rate to refine kinematics. As for normal motor outputs, the learning process recruits motor and premotor cortices and the acquisition of proficiency decreases attentional recruitment, focuses the activity on sensorimotor areas and increases the basal ganglia drive on the cortex. Augmentation deeply relies on the frontoparietal network. In particular, premotor cortex is involved in learning the control of an external effector and owns the tool motor representation, while the intraparietal sulcus extracts its visual features. In these areas, multisensory integration neurons enlarge their receptive fields to embody supernumerary limbs. For operating an anthropomorphic neuroprosthesis, the mirror system is required to understand the meaning of the action, the cerebellum for the formation of its internal model and the insula for its interoception. In conclusion, anthropomorphic sensorized devices can provide the critical sensory afferences to evolve the exploitation of tools through their embodiment, reshaping the body representation and the sense of the self

  8. Augmentation-related brain plasticity

    PubMed Central

    Di Pino, Giovanni; Maravita, Angelo; Zollo, Loredana; Guglielmelli, Eugenio; Di Lazzaro, Vincenzo

    2014-01-01

    Today, the anthropomorphism of the tools and the development of neural interfaces require reconsidering the concept of human-tools interaction in the framework of human augmentation. This review analyses the plastic process that the brain undergoes when it comes into contact with augmenting artificial sensors and effectors and, on the other hand, the changes that the use of external augmenting devices produces in the brain. Hitherto, few studies investigated the neural correlates of augmentation, but clues on it can be borrowed from logically-related paradigms: sensorimotor training, cognitive enhancement, cross-modal plasticity, sensorimotor functional substitution, use and embodiment of tools. Augmentation modifies function and structure of a number of areas, i.e., primary sensory cortices shape their receptive fields to become sensitive to novel inputs. Motor areas adapt the neuroprosthesis representation firing-rate to refine kinematics. As for normal motor outputs, the learning process recruits motor and premotor cortices and the acquisition of proficiency decreases attentional recruitment, focuses the activity on sensorimotor areas and increases the basal ganglia drive on the cortex. Augmentation deeply relies on the frontoparietal network. In particular, premotor cortex is involved in learning the control of an external effector and owns the tool motor representation, while the intraparietal sulcus extracts its visual features. In these areas, multisensory integration neurons enlarge their receptive fields to embody supernumerary limbs. For operating an anthropomorphic neuroprosthesis, the mirror system is required to understand the meaning of the action, the cerebellum for the formation of its internal model and the insula for its interoception. In conclusion, anthropomorphic sensorized devices can provide the critical sensory afferences to evolve the exploitation of tools through their embodiment, reshaping the body representation and the sense of the self

  9. Effects of chronic intermittent hypoxia on allergen-induced airway inflammation in rats.

    PubMed

    Broytman, Oleg; Braun, Rudolf K; Morgan, Barbara J; Pegelow, David F; Hsu, Pei-Ning; Mei, Linda S; Koya, Ajay K; Eldridge, Marlowe; Teodorescu, Mihaela

    2015-02-01

    Obstructive sleep apnea aggravates asthma, but its mechanisms are unknown. Chronic intermittent hypoxia is one hallmark feature of sleep apnea. In this study, we tested the effects of chronic intermittent hypoxia on allergen-induced inflammation in rats. Four groups (n = 9-11/group) of ovalbumin (OVA)-sensitized Brown-Norway rats underwent intermittent hypoxia (10% oxygen, 30 cycles/h, 10 h/d) or normoxia for 30 days concurrent with weekly OVA or vehicle challenges. Lung physiology, differential leukocyte counts from bronchoalveolar lavage, and histology (Picro Sirius Red staining for collagen content) were compared between groups 2 days after the last challenge. Gene expression in bronchoalveolar lavage cells was quantified by quantitative PCR. Compared with normoxia, chronic intermittent hypoxia reduced the FEV0.1/FVC ratio (P = 0.005), peak expiratory flow (P = 0.002), and mean midexpiratory flow (P = 0.004), predominantly in medium and large airways; decreased the baseline eosinophil number (P = 0.01) and amplified the effect of OVA on monocyte number (P = 0.02 for the interaction); in proximal airways, increased (P = 0.008), whereas in distal airways it decreased (P = 0.004), collagen density; induced qualitative emphysematous changes in lung periphery; and increased expression of the M2 macrophage marker YM-1 and augmented OVA-induced expression of plasminogen activator inhibitor-1. Chronic intermittent hypoxia alters immune response to allergen toward a more TH-1-predominant cellular phenotype with collagen deposition and matrix degradation, leading to airflow limitation. These findings highlight the potential of sleep apnea to aggravate airway dysfunction in patients with preexistent asthma. PMID:25004109

  10. Cerebral perturbations during exercise in hypoxia.

    PubMed

    Verges, Samuel; Rupp, Thomas; Jubeau, Marc; Wuyam, Bernard; Esteve, François; Levy, Patrick; Perrey, Stéphane; Millet, Guillaume Y

    2012-04-15

    Reduction of aerobic exercise performance observed under hypoxic conditions is mainly attributed to altered muscle metabolism due to impaired O(2) delivery. It has been recently proposed that hypoxia-induced cerebral perturbations may also contribute to exercise performance limitation. A significant reduction in cerebral oxygenation during whole body exercise has been reported in hypoxia compared with normoxia, while changes in cerebral perfusion may depend on the brain region, the level of arterial oxygenation and hyperventilation induced alterations in arterial CO(2). With the use of transcranial magnetic stimulation, inconsistent changes in cortical excitability have been reported in hypoxia, whereas a greater impairment in maximal voluntary activation following a fatiguing exercise has been suggested when arterial O(2) content is reduced. Electromyographic recordings during exercise showed an accelerated rise in central motor drive in hypoxia, probably to compensate for greater muscle contractile fatigue. This accelerated development of muscle fatigue in moderate hypoxia may be responsible for increased inhibitory afferent signals to the central nervous system leading to impaired central drive. In severe hypoxia (arterial O(2) saturation <70-75%), cerebral hypoxia per se may become an important contributor to impaired performance and reduced motor drive during prolonged exercise. This review examines the effects of acute and chronic reduction in arterial O(2) (and CO(2)) on cerebral blood flow and cerebral oxygenation, neuronal function, and central drive to the muscles. Direct and indirect influences of arterial deoxygenation on central command are separated. Methodological concerns as well as future research avenues are also considered. PMID:22319046

  11. Hypoxia and metabolic adaptation of cancer cells

    PubMed Central

    Eales, K L; Hollinshead, K E R; Tennant, D A

    2016-01-01

    Low oxygen tension (hypoxia) is a pervasive physiological and pathophysiological stimulus that metazoan organisms have contended with since they evolved from their single-celled ancestors. The effect of hypoxia on a tissue can be either positive or negative, depending on the severity, duration and context. Over the long-term, hypoxia is not usually consistent with normal function and so multicellular organisms have had to evolve both systemic and cellular responses to hypoxia. Our reliance on oxygen for efficient adenosine triphosphate (ATP) generation has meant that the cellular metabolic network is particularly sensitive to alterations in oxygen tension. Metabolic changes in response to hypoxia are elicited through both direct mechanisms, such as the reduction in ATP generation by oxidative phosphorylation or inhibition of fatty-acid desaturation, and indirect mechanisms including changes in isozyme expression through hypoxia-responsive transcription factor activity. Significant regions of cancers often grow in hypoxic conditions owing to the lack of a functional vasculature. As hypoxic tumour areas contain some of the most malignant cells, it is important that we understand the role metabolism has in keeping these cells alive. This review will outline our current understanding of many of the hypoxia-induced changes in cancer cell metabolism, how they are affected by other genetic defects often present in cancers, and how these metabolic alterations support the malignant hypoxic phenotype. PMID:26807645

  12. Gluteal augmentation with cryopreserved fat.

    PubMed

    Moscatiello, Fabrizio; Aznar-Benitah, Salvador; Grella, Roberto; Jover, Javier Herrero

    2010-03-01

    Gluteal augmentation with autologous fat is becoming a standard ancillary procedure for sculpting the buttock area. The high rate of resorption due to aggressive harvesting techniques or inadequate injection procedures often leads to repeated treatments. Currently, several techniques for storing fat by controlled freezing and thawing procedures can guarantee a high rate of cell viability, similar to that obtained with fresh tissue. This allows surgeons to compile fat tissue available for future repeat injections, decreasing additional costs and morbidity for patients. The authors describe a case of gluteal augmentation with cryopreserved fat in a 42-year-old man. PMID:20442098

  13. Acetyl-l-carnitine (ALCAR) prevents hypobaric hypoxia-induced spatial memory impairment through extracellular related kinase-mediated nuclear factor erythroid 2-related factor 2 phosphorylation.

    PubMed

    Barhwal, K; Hota, S K; Jain, V; Prasad, D; Singh, S B; Ilavazhagan, G

    2009-06-30

    Exposure to hypobaric hypoxia, a condition involving decreased availability of oxygen is known to be associated with oxidative stress, neurodegeneration and memory impairment. The multifactorial response of the brain and the complex signaling pathways involved therewith limits the therapeutic efficacy of several antioxidants in ameliorating hypobaric hypoxia-induced memory impairment. The present study was therefore aimed at investigating the potential of acetyl-l-carnitine (ALCAR), a known antioxidant that has been reported to augment neurotrophin-mediated survival mechanisms, in ameliorating hypoxia-induced neurodegeneration and memory impairment. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor involved in the cellular defense mechanism against oxidative stress related to brain injury and neurological disorders. The study was designed to understand the mechanisms involving Nrf2 stabilization following exposure to hypobaric hypoxia. The results displayed reference memory impairment in Sprague-Dawley rats exposed to hypobaric hypoxia (7620 m) for 14 consecutive days which however improved on administration of ALCAR during hypoxic exposure. The study also revealed Nrf2 regulated augmented antioxidant response on administration of ALCAR which was through a novel tyrosine kinase A (TrkA) receptor-mediated mechanism. A decrease in free radical generation, lipid peroxidation and protein oxidation was also observed along with a concomitant increase in thioredoxin and reduced glutathione levels on administration of ALCAR during exposure to hypobaric hypoxia. The present study therefore reveals the therapeutic potential of ALCAR under conditions of hypobaric hypoxia and elucidates a novel mechanism of action of the drug. PMID:19318118

  14. Targeting hypoxia in the leukemia microenvironment

    PubMed Central

    Benito, Juliana; Zeng, Zhihong; Konopleva, Marina; Wilson, William R

    2013-01-01

    SUMMARY The bone marrow (BM) microenvironment regulates survival and maintenance of normal hematopoietic stem cells. Within the endosteal niche, hypoxia has an essential role in maintenance of the primitive quiescent hematopoietic stem cell. We and others have demonstrated that in the context of hematologic malignancies the BM is highly hypoxic, and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic HIF-1α. This review will provide an overview of the normal and leukemic BM microenvironment with a special emphasis on pathological hypoxia including the development of hypoxia-activated prodrugs and their applicability in hematological malignancies. PMID:24490034

  15. Hypoxia Promotes Glycogen Accumulation through Hypoxia Inducible Factor (HIF)-Mediated Induction of Glycogen Synthase 1

    PubMed Central

    Pescador, Nuria; Garcia-Rocha, Mar; Ortiz-Barahona, Amaya; Vazquez, Silvia; Ordoñez, Angel; Cuevas, Yolanda; Saez-Morales, David; Garcia-Bermejo, Maria Laura; Landazuri, Manuel O.; Guinovart, Joan; del Peso, Luis

    2010-01-01

    When oxygen becomes limiting, cells reduce mitochondrial respiration and increase ATP production through anaerobic fermentation of glucose. The Hypoxia Inducible Factors (HIFs) play a key role in this metabolic shift by regulating the transcription of key enzymes of glucose metabolism. Here we show that oxygen regulates the expression of the muscle glycogen synthase (GYS1). Hypoxic GYS1 induction requires HIF activity and a Hypoxia Response Element within its promoter. GYS1 gene induction correlated with a significant increase in glycogen synthase activity and glycogen accumulation in cells exposed to hypoxia. Significantly, knockdown of either HIF1α or GYS1 attenuated hypoxia-induced glycogen accumulation, while GYS1 overexpression was sufficient to mimic this effect. Altogether, these results indicate that GYS1 regulation by HIF plays a central role in the hypoxic accumulation of glycogen. Importantly, we found that hypoxia also upregulates the expression of UTP:glucose-1-phosphate urydylyltransferase (UGP2) and 1,4-α glucan branching enzyme (GBE1), two enzymes involved in the biosynthesis of glycogen. Therefore, hypoxia regulates almost all the enzymes involved in glycogen metabolism in a coordinated fashion, leading to its accumulation. Finally, we demonstrated that abrogation of glycogen synthesis, by knock-down of GYS1 expression, impairs hypoxic preconditioning, suggesting a physiological role for the glycogen accumulated during chronic hypoxia. In summary, our results uncover a novel effect of hypoxia on glucose metabolism, further supporting the central importance of metabolic reprogramming in the cellular adaptation to hypoxia. PMID:20300197

  16. Computer Augmented Learning; A Survey.

    ERIC Educational Resources Information Center

    Kindred, J.

    The report contains a description and summary of computer augmented learning devices and systems. The devices are of two general types programed instruction systems based on the teaching machines pioneered by Pressey and developed by Skinner, and the so-called "docile" systems that permit greater user-direction with the computer under student…

  17. Augmenting a Classical Electrochemical Demonstration.

    ERIC Educational Resources Information Center

    Yochum, Susan M.; Luoma, John R.

    1995-01-01

    Presents an augmentation of a classical electrochemical demonstration that addresses the learning styles of the students and teaches electrochemistry in a concrete manner. Enables each student to see each event clearly, repeatedly, or in stop-action mode and enables students to improve their own mental models by providing them with a visually…

  18. Gluteus augmentation with fat grafting.

    PubMed

    Perén, P A; Gómez, J B; Guerrerosantos, J; Salazar, C A

    2000-01-01

    This study presents the authors' experience with gluteus augmentation with autologus fat grafts and liposuction methods, having recorded the evolution of gluteus reshaping with autologus intramuscular fat graft injections for the past 5 years. Preoperative shape is discussed and patient evaluations, operative techniques, postoperative management, and longterm results are emphasized. PMID:11246428

  19. [Neonatal intermittent hypoxia and hypertension].

    PubMed

    Sukhova, G K; Nozdrachev, A D; Gozal, D

    2009-01-01

    Obstructive apnea during sleep is accompanied by intermittent hypoxia (IH) leading to hypertension and other cardiovascular disturbances. A comparative evaluation of long-term effects of the neonatal IH on the cardiovascular function was performed in normotensive Sprague-Dawley and spontaneously hypertensive rats (SHR). The newborn rats were placed for 30 days to conditions of IH (8 and 21% O2, alternating every 90 s for 12 h/day). Control groups of rats were constantly kept in normoxia. By 6 months, in the spontaneously hypertensive rats submitted to IH at the period of wakefulness there was a statistically significant increase (as compared with control) of the systolic (correspondingly 185.8 +/- 1.7 and 169.9 +/- 1.4 mm Hg, p < 0.01) and diastolic pressure (correspondingly 96.2 +/- 4.9 and 86.0 +/- 2.6 mm Hg, p < 0.01). During sleep, the systolic and diastolic pressure in these rats was higher than in control animals by 10 mm Hg (p < 0.01) and 12 mm Hg (p < 0.01), its decrease during sleep being absent. SHR submitted to IH had an increase in low- to the high-frequency power ratio of the heart rate variability from 0.9 +/- 0.15 to 1.5 +/- 0.17, which indicates a shift of the sympatho-parasympathetic balance in this group towards predominance of the sympathetic component. In the Sprague-Dawley rats submitted to neonatal hypoxia, the above changes were not pronounced. These peculiarities of the hypertensive rats allow establishing connection of the genetic factor with the sympathetic mechanism providing long-term consequences of the neonatal IH for the cardiovascular control in these rats. PMID:19435263

  20. Carotid body denervation prevents fasting hyperglycemia during chronic intermittent hypoxia

    PubMed Central

    Shin, Mi-Kyung; Yao, Qiaoling; Jun, Jonathan C.; Bevans-Fonti, Shannon; Yoo, Doo-Young; Han, Woobum; Mesarwi, Omar; Richardson, Ria; Fu, Ya-Yuan; Pasricha, Pankaj J.; Schwartz, Alan R.; Shirahata, Machiko

    2014-01-01

    Obstructive sleep apnea causes chronic intermittent hypoxia (IH) and is associated with impaired glucose metabolism, but mechanisms are unknown. Carotid bodies orchestrate physiological responses to hypoxemia by activating the sympathetic nervous system. Therefore, we hypothesized that carotid body denervation would abolish glucose intolerance and insulin resistance induced by chronic IH. Male C57BL/6J mice underwent carotid sinus nerve dissection (CSND) or sham surgery and then were exposed to IH or intermittent air (IA) for 4 or 6 wk. Hypoxia was administered by decreasing a fraction of inspired oxygen from 20.9% to 6.5% once per minute, during the 12-h light phase (9 a.m.–9 p.m.). As expected, denervated mice exhibited blunted hypoxic ventilatory responses. In sham-operated mice, IH increased fasting blood glucose, baseline hepatic glucose output (HGO), and expression of a rate-liming hepatic enzyme of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK), whereas the whole body glucose flux during hyperinsulinemic euglycemic clamp was not changed. IH did not affect glucose tolerance after adjustment for fasting hyperglycemia in the intraperitoneal glucose tolerance test. CSND prevented IH-induced fasting hyperglycemia and increases in baseline HGO and liver PEPCK expression. CSND trended to augment the insulin-stimulated glucose flux and enhanced liver Akt phosphorylation at both hypoxic and normoxic conditions. IH increased serum epinephrine levels and liver sympathetic innervation, and both increases were abolished by CSND. We conclude that chronic IH induces fasting hyperglycemia increasing baseline HGO via the CSN sympathetic output from carotid body chemoreceptors, but does not significantly impair whole body insulin sensitivity. PMID:25103977

  1. Carotid body denervation prevents fasting hyperglycemia during chronic intermittent hypoxia.

    PubMed

    Shin, Mi-Kyung; Yao, Qiaoling; Jun, Jonathan C; Bevans-Fonti, Shannon; Yoo, Doo-Young; Han, Woobum; Mesarwi, Omar; Richardson, Ria; Fu, Ya-Yuan; Pasricha, Pankaj J; Schwartz, Alan R; Shirahata, Machiko; Polotsky, Vsevolod Y

    2014-10-01

    Obstructive sleep apnea causes chronic intermittent hypoxia (IH) and is associated with impaired glucose metabolism, but mechanisms are unknown. Carotid bodies orchestrate physiological responses to hypoxemia by activating the sympathetic nervous system. Therefore, we hypothesized that carotid body denervation would abolish glucose intolerance and insulin resistance induced by chronic IH. Male C57BL/6J mice underwent carotid sinus nerve dissection (CSND) or sham surgery and then were exposed to IH or intermittent air (IA) for 4 or 6 wk. Hypoxia was administered by decreasing a fraction of inspired oxygen from 20.9% to 6.5% once per minute, during the 12-h light phase (9 a.m.-9 p.m.). As expected, denervated mice exhibited blunted hypoxic ventilatory responses. In sham-operated mice, IH increased fasting blood glucose, baseline hepatic glucose output (HGO), and expression of a rate-liming hepatic enzyme of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK), whereas the whole body glucose flux during hyperinsulinemic euglycemic clamp was not changed. IH did not affect glucose tolerance after adjustment for fasting hyperglycemia in the intraperitoneal glucose tolerance test. CSND prevented IH-induced fasting hyperglycemia and increases in baseline HGO and liver PEPCK expression. CSND trended to augment the insulin-stimulated glucose flux and enhanced liver Akt phosphorylation at both hypoxic and normoxic conditions. IH increased serum epinephrine levels and liver sympathetic innervation, and both increases were abolished by CSND. We conclude that chronic IH induces fasting hyperglycemia increasing baseline HGO via the CSN sympathetic output from carotid body chemoreceptors, but does not significantly impair whole body insulin sensitivity. PMID:25103977

  2. [Assessment of fetus' hypoxia treatment with actovegin].

    PubMed

    Lominadze, A A; Sharvashidze, N K

    2006-09-01

    The condition of fetus dramatically impairs in the case of pregnancy pathologies, when uterine-placental blood circulation impairment reveals, as it happens during placental presentation followed by bleeding, chronic anemia, heart and lung diseases of mother and pneumonia. Fetus' hypoxia develops when blood circulation in the vessels of cord is impaired, placental blood circulation disorders reveal. Preventive measures of fetus intra-natal hypoxia lay in elimination of obstetric and extra-genital causes. For the treatment of fetus hypoxia the solution Actovegin 4.0+5% glucose 400.0+vitamin "C" 4.0 in dosage of 15-20 drops per minute was applied. Out of 36 pregnant patients treatment was effective in 24 cases. In 12 cases a Caesarean section was performed. In cases of fetus hypoxia Actovegin allows to transfer metabolic processes in the form of anaerobic glycolysis, thus protecting vital centers from oxygen deprivation. PMID:17057302

  3. Evaluation of Hypoxia with Cu-ATSM

    PubMed Central

    Lapi, Suzanne E.; Lewis, Jason S.; Dehdashti, Farrokh

    2015-01-01

    Imaging of hypoxia is important in many diseases states in oncology, cardiology and neurology. The radiopharmaceutical, copper labelled diacetyl-bis(N-methylthiosemicarbazone) (Cu-ATSM), has been used to assess hypoxia in many studies. In particular, Cu-ATSM has been used in oncologic settings to investigate tumor hypoxia and the role of this parameter in response to therapy and outcome. Other groups have conducted imaging studies assessing the role of hypoxia in cardiovascular disease and neurological disorders. Additionally, several groups have made significant progress into understanding the mechanism by which this compound accumulates in cells. Multiple preclinical and clinical studies have been conducted, shedding light on the important of careful image analysis when using this tracer. This review article focusses on the recent preclinical and clinical studies with this tracer. PMID:25704389

  4. Reduced TIMP-2 in hypoxia enhances angiogenesis.

    PubMed

    Lahat, Nitza; Bitterman, Haim; Engelmayer-Goren, Miri; Rosenzweig, Doron; Weiss-Cerem, Lea; Rahat, Michal A

    2011-03-01

    Hypoxia, which characterizes ischemia, trauma, inflammation, and solid tumors, recruits monocytes, immobilizes them, and alters their function, leading to an anti-inflammatory and proangiogenic phenotype. Monocyte extravasation from the circulation and their migration in tissues are partially mediated by the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). The mechanisms evoked by hypoxia that regulate monocyte migration and activation are not entirely clear. Specifically, the effect of hypoxia on TIMPs in these cells has hardly been investigated. We show that hypoxia reduces TIMP-2 secretion from human primary monocytes and from the monocyte-like cell lines U937 and THP-1 by three- to fourfold (P < 0.01), by inhibiting TIMP-2 transcription through mechanisms that involve the transcription factor SP-1. Hypoxia also lowers TIMP-2 protein secretion from human endothelial cells (by 2-fold, P < 0.05). TIMP-2 levels do not influence the reduced migration of THP-1 cells in hypoxia; however, low TIMP-2 levels enhance endothelial cell migration/proliferation, their ability to form tubelike structures in vitro, and the appearance of mature blood vessels in a Matrigel plug assay in vivo. Thus we conclude that reduced TIMP-2 levels secreted from both hypoxic monocytes and endothelial cells are proangiogenic. PMID:21148412

  5. Immunohistochemical Detection of Changes in Tumor Hypoxia

    SciTech Connect

    Russell, James Carlin, Sean; Burke, Sean A.; Wen Bixiu; Yang, Kwang Mo; Ling, C. Clifton

    2009-03-15

    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 1{alpha} (HIF1{alpha}). 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. HIF1{alpha} 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 HIF1{alpha}. Conclusion: HIF1{alpha} can be compared with either CAIX or a previously administered nitroimidazole to provide an estimate of reoxygenation.

  6. Sensing and surviving hypoxia in vertebrates.

    PubMed

    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

  7. Acid-sensing ion channels under hypoxia

    PubMed Central

    Yingjun, Guo; Xun, Qu

    2013-01-01

    Hypoxia represents the lack of oxygen below the basic level, and the range of known channels related to hypoxia is continually increasing. Since abnormal hypoxia initiates pathological processes in numerous diseases via, to a great degree, producing acidic microenvironment, the significance of these channels in this environment has, until now, remained completely unknown. However, recent discovery of acid-sensing ion channels (ASICs) have enhanced our understanding of the hypoxic channelome. They belong to the degenerin/epithelial Na+ channel family and function once extracellular pH decreases to a certain level. So does the ratiocination emerge that ASICs participate in many hypoxia-induced pathological processes, including pain, apoptosis, malignancy, which all appear to involve them. Since evidence suggests that activity of ASICs is altered under pathological hypoxia, future studies are needed to deeply explore the relationship between ASICs and hypoxia, which may provide a progressive understanding of hypoxic effects in cancer, arthritis, intervertebral disc degeneration, ischemic brain injury and so on. PMID:23764948

  8. Potassium Channels and Uterine Vascular Adaptation to Pregnancy and Chronic Hypoxia

    PubMed Central

    Zhu, Ronghui; Xiao, DaLiao; Zhang, Lubo

    2014-01-01

    During a normal course of pregnancy, uterine vascular tone is significantly decreased resulting in a striking increase in uterine blood flow, which is essential for fetal development and fetal growth. Chronic hypoxia during gestation may adversely affect the normal adaptation of uterine vascular tone and increase the risk of preeclampsia and fetal intrauterine growth restriction. In this review, we present evidence that the regulation of K+ channels is an important mechanism in the adaptation of uterine vascular tone to pregnancy and hypoxia. There are four types of K+ channels identified in arterial smooth muscle cells: 1) voltage-dependent K+ (Kv) channels, 2) Ca2+-activated K+ (KCa) channels, 3) inward rectifier K+ (KIR) channels, and 4) ATP-sensitive K+ (KATP) channels. Pregnancy differentially augments the expression and activity of K+ channels via downregulation of protein kinase C signaling in uterine and other vascular beds, leading to decreased uterine vascular tone and increased uterine blood flow. Sex steroid hormones play an important role in the pregnancy-mediated alteration of K+ channels in the uterine vasculature. In addition, chronic hypoxia alters uterine vascular K+ channels expression and activities via modulation of steroid hormones/receptors-mediated signaling, resulting in increased uterine vascular tone during pregnancy. PMID:24063385

  9. Increased SCF/c-kit by hypoxia promotes autophagy of human placental chorionic plate-derived mesenchymal stem cells via regulating the phosphorylation of mTOR.

    PubMed

    Lee, Youjin; Jung, Jieun; Cho, Kyung Jin; Lee, Seoung-Kwan; Park, Jong-Wan; Oh, Il-Hoan; Kim, Gi Jin

    2013-01-01

    Hypoxia triggers physiological and pathological cellular processes, including proliferation, differentiation, and death, in several cell types. Mesenchymal stem cells (MSCs) derived from various tissues have self-renewal activity and can differentiate towards multiple lineages. Recently, it has been reported that hypoxic conditions tip the balance between survival and death by hypoxia-induced autophagy, although the underlying mechanism is not clear. The objectives of this study are to compare the effect of hypoxia on the self-renewal of bone marrow-derived mesenchymal stem cells (BM-MSCs) and placental chorionic plate-derived mesenchymal stem cells (CP-MSCs) and to investigate the regulatory mechanisms of self-renewal in each MSC type during hypoxia. The expression of self-renewal markers (e.g., Oct4, Nanog, Sox2) was assessed in both cell lines. PI3K and stem cell factor (SCF) expression gradually increased in CP-MSCs but were markedly downregulated in BM-MSCs by hypoxia. The phosphorylation of ERK and mTOR was augmented by hypoxia in CP-MSCs compared to control. Also, the expression of LC3 II, a component of the autophagosome and the hoof-shaped autophagosome was detected more rapidly in CP-MSCs than in BM-MSCs under hypoxia. Hypoxia induced the expression of SCF in CP-MSCs and increased SCF/c-kit pathway promotes the self-renewal activities of CP-MSCs via an autocrine/paracrine mechanism that balances cell survival and cell death events by autophagy. These activities occur to a greater extent in CP-MSCs than in BM-MSCs through regulating the phosphorylation of mTOR. These findings will provide useful guidelines for better understanding the function of SCF/c-kit in the self-renewal and autophagy-regulated mechanisms that promote of MSC survival. PMID:22833529

  10. The ternary complex factor net is downregulated by hypoxia and regulates hypoxia-responsive genes.

    PubMed

    Gross, Christian; Buchwalter, Gilles; Dubois-Pot, Hélène; Cler, Emilie; Zheng, Hong; Wasylyk, Bohdan

    2007-06-01

    Hypoxia and the Net ternary complex factor (TCF) regulate similar processes (angiogenesis, wound healing, and cellular migration) and genes (PAI-1, c-fos, erg-1, NOS-2, HO-1, and vascular endothelial growth factor genes), suggesting that they are involved in related pathways. We show here that hypoxia regulates Net differently from the other TCFs and that Net plays a role in the hypoxic response in vivo in mice and in cells. Hypoxia induces Net depletion from target promoters, nuclear export, ubiquitylation, and proteasomal degradation. Key mediators of the hypoxic response, the prolyl-4-hydroxylases containing domain proteins (PHDs), regulate Net. PHD downregulation in normoxia leads to Net degradation, and PHD overexpression delays Net downregulation by hypoxia. Net inhibition by RNA interference or mutation leads to altered regulation by hypoxia of the Net targets PAI-1, c-fos, and egr-1. We propose that hypoxia stimulates transcription of target promoters through removal of the repressor function of Net. Interestingly, the hematocrit response to a chemical inducer of hypoxia-like responses (cobalt chloride) is strongly altered in Net mutant mice. Our results show that the Net TCF is part of the biological response to hypoxia, adding a new component to an important pathological and physiological process. PMID:17403894

  11. Augmented reality building operations tool

    DOEpatents

    Brackney, Larry J.

    2014-09-09

    A method (700) for providing an augmented reality operations tool to a mobile client (642) positioned in a building (604). The method (700) includes, with a server (660), receiving (720) from the client (642) an augmented reality request for building system equipment (612) managed by an energy management system (EMS) (620). The method (700) includes transmitting (740) a data request for the equipment (612) to the EMS (620) and receiving (750) building management data (634) for the equipment (612). The method (700) includes generating (760) an overlay (656) with an object created based on the building management data (634), which may be sensor data, diagnostic procedures, or the like. The overlay (656) is configured for concurrent display on a display screen (652) of the client (642) with a real-time image of the building equipment (612). The method (700) includes transmitting (770) the overlay (656) to the client (642).

  12. Effective Augmentation of Complex Networks

    NASA Astrophysics Data System (ADS)

    Wang, Jinjian; Yu, Xinghuo; Stone, Lewi

    2016-05-01

    Networks science plays an enormous role in many aspects of modern society from distributing electrical power across nations to spreading information and social networking amongst global populations. While modern networks constantly change in size, few studies have sought methods for the difficult task of optimising this growth. Here we study theoretical requirements for augmenting networks by adding source or sink nodes, without requiring additional driver-nodes to accommodate the change i.e., conserving structural controllability. Our “effective augmentation” algorithm takes advantage of clusters intrinsic to the network topology, and permits rapidly and efficient augmentation of a large number of nodes in one time-step. “Effective augmentation” is shown to work successfully on a wide range of model and real networks. The method has numerous applications (e.g. study of biological, social, power and technological networks) and potentially of significant practical and economic value.

  13. Effective Augmentation of Complex Networks

    PubMed Central

    Wang, Jinjian; Yu, Xinghuo; Stone, Lewi

    2016-01-01

    Networks science plays an enormous role in many aspects of modern society from distributing electrical power across nations to spreading information and social networking amongst global populations. While modern networks constantly change in size, few studies have sought methods for the difficult task of optimising this growth. Here we study theoretical requirements for augmenting networks by adding source or sink nodes, without requiring additional driver-nodes to accommodate the change i.e., conserving structural controllability. Our “effective augmentation” algorithm takes advantage of clusters intrinsic to the network topology, and permits rapidly and efficient augmentation of a large number of nodes in one time-step. “Effective augmentation” is shown to work successfully on a wide range of model and real networks. The method has numerous applications (e.g. study of biological, social, power and technological networks) and potentially of significant practical and economic value. PMID:27165120

  14. Optimizing Hypoxia Detection and Treatment Strategies

    PubMed Central

    Koch, Cameron J.; Evans, Sydney M.

    2015-01-01

    Clinical studies using Eppendorf® needle sensors have invariably documented the resistance of hypoxic human tumors to therapy. These studies first documented the need for individual patient measurement of hypoxia, since hypoxia varied from tumor-to-tumor. Furthermore, hypoxia in sarcomas & cervical cancer leads to distant metastasis or local/regional spread, respectively. For various reasons, the field has moved away from direct needle-sensor oxygen measurements to indirect assays (HIF-related changes; bioreductive metabolism) and the latter can be imaged non-invasively. Many of hypoxia’s detrimental therapeutic effects are reversible in mice but little treatment-improvement in hypoxic human tumors has been seen. The question is why? What factors cause human tumors to be refractory to anti-hypoxia strategies? We suggest the primary cause to be the complexity of hypoxia formation and its characteristics. Three basic types of hypoxia exist, encompassing various diffusional (distance from perfused vessel), temporal (on/off cycling) and perfusional (blood-flow efficiency) limitations. Surprisingly, there is no current information on their relative prevalence in human tumors and even animal models. This is important because different hypoxia sub-types are predicted to require different diagnostic and therapeutic approaches, but the implications of this remain unknown. Even more challenging, no agreement exists for the best way to measure hypoxia. Some results even suggest that hypoxia is unlikely to be targetable therapeutically. In this review, the authors will revisit various critical aspects of this field that are sometimes forgotten or misrepresented in the recent literature. Since most current non-invasive imaging studies involve PET-isotope-labelled 2-nitroimidazoles, we will emphasize key findings made in our studies using EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide] and F18-labelled EF5. These will show the importance of

  15. Hypoxia in the Northern Gulf of Mexico

    SciTech Connect

    Dale, Virginia H

    2010-01-01

    Since 1985, scientists have been documenting a hypoxic zone in the Gulf of Mexico each year. The hypoxic zone, an area of low dissolved oxygen that cannot support marine life, generally manifests itself in the spring. Since marine species either die or flee the hypoxic zone, the spread of hypoxia reduces the available habitat for marine species, which are important for the ecosystem as well as commercial and recreational fishing in the Gulf. Since 2001, the hypoxic zone has averaged 16,500 km{sup 2} during its peak summer months, an area slightly larger than the state of Connecticut, and ranged from a low of 8,500 km{sup 2} to a high of 22,000 km{sup 2}. To address the hypoxia problem, the Mississippi River/Gulf of Mexico Watershed Nutrient Task Force (or Task Force) was formed to bring together representatives from federal agencies, states, and tribes to consider options for responding to hypoxia. The Task Force asked the White House Office of Science and Technology Policy to conduct a scientific assessment of the causes and consequences of Gulf hypoxia through its Committee on Environment and Natural Resources (CENR). In 2000 the CENR completed An Integrated Assessment: Hypoxia in the Northern Gulf of Mexico (or Integrated Assessment), which formed the scientific basis for the Task Force's Action Plan for Reducing, Mitigating, and Controlling Hypoxia in the Northern Gulf of Mexico (Action Plan, 2001). In its Action Plan, the Task Force pledged to implement ten management actions and to assess progress every 5 years. This reassessment would address the nutrient load reductions achieved, the responses of the hypoxic zone and associated water quality and habitat conditions, and economic and social effects. The Task Force began its reassessment in 2005. In 2006 as part of the reassessment, USEPA's Office of Water, on behalf of the Task Force, requested that the U.S. Environmental Protection Agency (USEPA) Science Advisory Board (SAB) convene an independent panel to

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

    PubMed

    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 < 0.05 or P < 0.01). Moreover, hypoxia decreased mitochondrial OGG1, MnSOD, and GPx activities (P < 0.05 or P < 0.01), whereas elevated reactive oxygen species (ROS) generation and the level of 8-oxo-deoxyguanosine (8-oxodG) in mtDNA (P < 0.01). Furthermore, hypoxia attenuated muscle and mitochondrial [NAD⁺]/ [NADH] ratio, and SIRT3 protein expression (P < 0.05 or P < 0.01). Compared with HC group, exercise training in hypoxia elevated complex I, II, IV and ATP synthase activities, and the level of mitochondrial membrane potential in HT group (P < 0.05 or P < 0.01). Moreover, exercise training in hypoxia increased MnSOD and GPx activities and mitochondrial OGG1 level (P < 0.01), whereas decreased ROS generation and the level of 8-oxodG in mtDNA (P < 0.01). Furthermore, exercise training in hypoxia increased muscle and mitochondrial [NAD⁺]/[NADH] ratio, as well as SIRT3 protein expression (P < 0.05 or P < 0.01). These findings suggest that exercise training in hypoxia can decrease hypoxia-induced mtDNA oxidative damage in the skeletal muscle through up

  17. Media-Augmented Exercise Machines

    NASA Astrophysics Data System (ADS)

    Krueger, T.

    2002-01-01

    Cardio-vascular exercise has been used to mitigate the muscle and cardiac atrophy associated with adaptation to micro-gravity environments. Several hours per day may be required. In confined spaces and long duration missions this kind of exercise is inevitably repetitive and rapidly becomes uninteresting. At the same time, there are pressures to accomplish as much as possible given the cost- per-hour for humans occupying orbiting or interplanetary. Media augmentation provides a the means to overlap activities in time by supplementing the exercise with social, recreational, training or collaborative activities and thereby reducing time pressures. In addition, the machine functions as an interface to a wide range of digital environments allowing for spatial variety in an otherwise confined environment. We hypothesize that the adoption of media augmented exercise machines will have a positive effect on psycho-social well-being on long duration missions. By organizing and supplementing exercise machines, data acquisition hardware, computers and displays into an interacting system this proposal increases functionality with limited additional mass. This paper reviews preliminary work on a project to augment exercise equipment in a manner that addresses these issues and at the same time opens possibilities for additional benefits. A testbed augmented exercise machine uses a specialty built cycle trainer as both input to a virtual environment and as an output device from it using spatialized sound, and visual displays, vibration transducers and variable resistance. The resulting interactivity increases a sense of engagement in the exercise, provides a rich experience of the digital environments. Activities in the virtual environment and accompanying physiological and psychological indicators may be correlated to track and evaluate the health of the crew.

  18. TDRSS Augmentation System for Satellites

    NASA Technical Reports Server (NTRS)

    Heckler, Gregory W.; Gramling, Cheryl; Valdez, Jennifer; Baldwin, Philip

    2016-01-01

    In 2015, NASA Goddard Space Flight Center (GSFC) reinvigorated the development of the TDRSS Augmentation Service for Satellites (TASS). TASS is a global, space-based, communications and navigation service for users of Global Navigation Satellite Systems(GNSS) and the Tracking and Data Relay Satellite System (TDRSS). TASS leverages the existing TDRSS to provide an S-band beacon radio navigation and messaging source to users at orbital altitudes 1400 km and below.

  19. Aesthetic occiput augmentation using methylmethacrylate.

    PubMed

    Song, Yong Tai

    2015-01-01

    Cranioplasty for only aesthetic reasons has not been commonly performed to date. However, recently there has been a new focus by the public on a more aesthetically pleasing head shape with frequent patient requests for purely aesthetic contouring of the occiput, an important definer of cosmetic head shape. For example, in Asia, where the normal cranial shape is mesocephalic or brachycephalic and often with a planar occiput, requests for its aesthetic correction are increasingly common. Accordingly, the author developed a minimally invasive occiput augmentation using methylmethacrylate. In this study, the indications for aesthetic occiput contouring were planar occiput, left-right asymmetric occiput, and grooved occiput. Under local anesthesia, soft methylmethacrylate is subperiosteally inserted through a small incision (about 5-cm length), manually and precisely contoured in situ through the scalp to the desired occipital shape. All is performed as an outpatient procedure, and a quick recovery is the case. Between March 2007 and October 2013, 959 patients received such aesthetic occiput augmentation. The mean follow-up period was 49 months (range, 3-84 months). Nearly all patients were satisfied with the outcome, and complications were very rare. Only 5 patients (0.5%) needed additional corrective procedures. The author has concluded that aesthetic occiput augmentation using methylmethacrylate yields consistent, predictable, and satisfactory results. Additional long-term follow-up is required for a final conclusion, however. PMID:25569386

  20. Energy Flux, Lactate Shuttling, Mitochondrial Dynamics, and Hypoxia.

    PubMed

    Brooks, George A

    2016-01-01

    Our understanding of what happens in working muscle and at the whole-body level at sea level and at high altitude is different from that a few years ago. If dietary CHO and nutrition are adequate, at sea level metabolism shifts from a mix of lipid and CHO-derived fuels toward carbohydrate (glycogen, glucose, and lactate) oxidation at moderate and greater exercise intensities. As given by the Crossover Concept, a percentage to total energy expenditure, lipid oxidation is greatest at exercise power outputs eliciting 45-50 % of VO2max with greater intensities requiring relatively more CHO and lesser lipid oxidation. At altitude, a given exercise power output is achieved at a greater relative intensity expressed as % VO2max. Hence, exercise under conditions of hypoxia requires greater glycolytic flux, and lactate production than does the same effort at sea level, normoxic conditions. Glycolytic flux is further augmented at altitude by the effect of hypoxemia on sympathetic nervous system activity. Hence, augmented lactate production during exercise is adaptive. Over the short term, accelerated lactate flux provides ATP supporting muscle contraction and balances cytosolic redox. As well, lactate provides and energy substrate and gluconeogenic precursor. Over a longer term, via redox and ROS-generating mechanisms, lactate may affect adaptations in mitochondrial biogenesis and solute (glucose and lactate) transport. While important, the energy substrate, gluconeogenic, and signaling qualities of lactate production and disposal at altitude need to be considered within the context of overall dietary energy intake and expenditure during exercise at sea level and high altitude. PMID:27343113

  1. Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling.

    PubMed

    Souma, Tomokazu; Nezu, Masahiro; Nakano, Daisuke; Yamazaki, Shun; Hirano, Ikuo; Sekine, Hiroki; Dan, Takashi; Takeda, Kotaro; Fong, Guo-Hua; Nishiyama, Akira; Ito, Sadayoshi; Miyata, Toshio; Yamamoto, Masayuki; Suzuki, Norio

    2016-02-01

    Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia-inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein from a modified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition to myofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF-REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs. PMID:26054543

  2. Functional genomics approach to hypoxia signaling.

    PubMed

    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

  3. Oxygen Deprivation and the Cellular Response to Hypoxia in Adipocytes – Perspectives on White and Brown Adipose Tissues in Obesity

    PubMed Central

    Trayhurn, Paul; Alomar, Suliman Yousef

    2015-01-01

    Relative hypoxia has been shown to develop in white adipose tissue depots of different types of obese mouse (genetic, dietary), and this leads to substantial changes in white adipocyte function. These changes include increased production of inflammation-related adipokines (such as IL-6, leptin, Angptl4, and VEGF), an increase in glucose utilization and lactate production, and the induction of fibrosis and insulin resistance. Whether hypoxia also occurs in brown adipose tissue depots in obesity has been little considered. However, a recent study has reported low pO2 in brown fat of obese mice, this involving mitochondrial loss and dysfunction. We suggest that obesity-linked hypoxia may lead to similar alterations in brown adipocytes as in white fat cells – particularly changes in adipokine production, increased glucose uptake and lactate release, and insulin resistance. This would be expected to compromise thermogenic activity and the role of brown fat in glucose homeostasis and triglyceride clearance, underpinning the development of the metabolic syndrome. Hypoxia-induced augmentation of lactate production may also stimulate the “browning” of white fat depots through recruitment of UCP1 and the development of brite adipocytes. PMID:25745415

  4. Withanolide A prevents neurodegeneration by modulating hippocampal glutathione biosynthesis during hypoxia.

    PubMed

    Baitharu, Iswar; Jain, Vishal; Deep, Satya Narayan; Shroff, Sabita; Sahu, Jayanta Kumar; Naik, Pradeep Kumar; Ilavazhagan, Govindasamy

    2014-01-01

    Withania somnifera root extract has been used traditionally in ayurvedic system of medicine as a memory enhancer. Present study explores the ameliorative effect of withanolide A, a major component of withania root extract and its molecular mechanism against hypoxia induced memory impairment. Withanolide A was administered to male Sprague Dawley rats before a period of 21 days pre-exposure and during 07 days of exposure to a simulated altitude of 25,000 ft. Glutathione level and glutathione dependent free radicals scavenging enzyme system, ATP, NADPH level, γ-glutamylcysteinyl ligase (GCLC) activity and oxidative stress markers were assessed in the hippocampus. Expression of apoptotic marker caspase 3 in hippocampus was investigated by immunohistochemistry. Transcriptional alteration and expression of GCLC and Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) were investigated by real time PCR and immunoblotting respectively. Exposure to hypobaric hypoxia decreased reduced glutathione (GSH) level and impaired reduced gluatathione dependent free radical scavenging system in hippocampus resulting in elevated oxidative stress. Supplementation of withanolide A during hypoxic exposure increased GSH level, augmented GSH dependent free radicals scavenging system and decreased the number of caspase and hoescht positive cells in hippocampus. While withanolide A reversed hypoxia mediated neurodegeneration, administration of buthionine sulfoximine along with withanolide A blunted its neuroprotective effects. Exogenous administration of corticosterone suppressed Nrf2 and GCLC expression whereas inhibition of corticosterone synthesis upregulated Nrf2 as well as GCLC. Thus present study infers that withanolide A reduces neurodegeneration by restoring hypoxia induced glutathione depletion in hippocampus. Further, Withanolide A increases glutathione biosynthesis in neuronal cells by upregulating GCLC level through Nrf2 pathway in a corticosterone dependenet manner. PMID

  5. Withanolide A Prevents Neurodegeneration by Modulating Hippocampal Glutathione Biosynthesis during Hypoxia

    PubMed Central

    Baitharu, Iswar; Jain, Vishal; Deep, Satya Narayan; Shroff, Sabita; Sahu, Jayanta Kumar; Naik, Pradeep Kumar; Ilavazhagan, Govindasamy

    2014-01-01

    Withania somnifera root extract has been used traditionally in ayurvedic system of medicine as a memory enhancer. Present study explores the ameliorative effect of withanolide A, a major component of withania root extract and its molecular mechanism against hypoxia induced memory impairment. Withanolide A was administered to male Sprague Dawley rats before a period of 21 days pre-exposure and during 07 days of exposure to a simulated altitude of 25,000 ft. Glutathione level and glutathione dependent free radicals scavenging enzyme system, ATP, NADPH level, γ-glutamylcysteinyl ligase (GCLC) activity and oxidative stress markers were assessed in the hippocampus. Expression of apoptotic marker caspase 3 in hippocampus was investigated by immunohistochemistry. Transcriptional alteration and expression of GCLC and Nuclear factor (erythroid-derived 2)–related factor 2 (Nrf2) were investigated by real time PCR and immunoblotting respectively. Exposure to hypobaric hypoxia decreased reduced glutathione (GSH) level and impaired reduced gluatathione dependent free radical scavenging system in hippocampus resulting in elevated oxidative stress. Supplementation of withanolide A during hypoxic exposure increased GSH level, augmented GSH dependent free radicals scavenging system and decreased the number of caspase and hoescht positive cells in hippocampus. While withanolide A reversed hypoxia mediated neurodegeneration, administration of buthionine sulfoximine along with withanolide A blunted its neuroprotective effects. Exogenous administration of corticosterone suppressed Nrf2 and GCLC expression whereas inhibition of corticosterone synthesis upregulated Nrf2 as well as GCLC. Thus present study infers that withanolide A reduces neurodegeneration by restoring hypoxia induced glutathione depletion in hippocampus. Further, Withanolide A increases glutathione biosynthesis in neuronal cells by upregulating GCLC level through Nrf2 pathway in a corticosterone dependenet manner

  6. Regulation of cardiac output in hypoxia.

    PubMed

    Siebenmann, Christoph; Lundby, Carsten

    2015-12-01

    This brief review addresses the regulation of cardiac output (Q) at rest and during submaximal exercise in acute and chronic hypoxia. To preserve systemic O2 delivery in acute hypoxia Q is increased by an acceleration of heart rate, whereas stroke volume (SV) remains unchanged. Tachycardia is governed by activation of carotid and aortic chemoreceptors and a concomitant reduction in arterial baroreflex activation, all balancing sympathovagal activity toward sympathetic dominance. As hypoxia extends over several days a combination of different adaptive processes restores arterial O2 content to or beyond sea level values and hence Q normalizes. The latter however occurs as a consequence of a decrease in SV whereas tachycardia persists. The diminished SV reflects a lower left ventricular end-diastolic volume which is primarily related to hypoxia-generated reduction in plasma volume. Hypoxic pulmonary vasoconstriction may contribute by increasing right ventricular afterload and thus decreasing its ejection fraction. In summary, the Q response to hypoxia is the result of a complex interplay between several physiological mechanisms. Future studies are encouraged to establish the individual contributions of the different components from an integrative perspective. PMID:26589118

  7. Immunohistochemical Detection of Changes in Tumor Hypoxia

    PubMed Central

    Russell, James; Carlin, Sean; Burke, Sean A.; Wen, Bixiu; Yang, Kwang Mo; Ling, C Clifton

    2009-01-01

    Purpose Although hypoxia is a known prognostic factor, its impact will be modified by the rate of reoxygenation and the extent to which cells are acutely hypoxic. We tested the ability of exogenous and endogenous markers to detect reoxygenation in a xenograft model. Our technique may 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 CAIX and 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, though 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 Conclusions HIF1α can be compared to either CAIX or a previously administered nitroimidazole to provide an estimate of reoxygenation. PMID:19251089

  8. Hypoxia-Inducible Factor in Thyroid Carcinoma

    PubMed Central

    Burrows, Natalie; Babur, Muhammad; Resch, Julia; Williams, Kaye J.; Brabant, Georg

    2011-01-01

    Intratumoural hypoxia (low oxygen tension) is associated with aggressive disease and poor prognosis. Hypoxia-inducible factor-1 is a transcription factor activated by hypoxia that regulates the expression of genes that promote tumour cell survival, progression, metastasis, and resistance to chemo/radiotherapy. In addition to hypoxia, HIF-1 can be activated by growth factor-signalling pathways such as the mitogen-activated protein kinases- (MAPK-) and phosphatidylinositol-3-OH kinases- (PI3K-) signalling cascades. Mutations in these pathways are common in thyroid carcinoma and lead to enhanced HIF-1 expression and activity. Here, we summarise current data that highlights the potential role of both hypoxia and MAPK/PI3K-induced HIF-1 signalling in thyroid carcinoma progression, metastatic characteristics, and the potential role of HIF-1 in thyroid carcinoma response to radiotherapy. Direct or indirect targeting of HIF-1 using an MAPK or PI3K inhibitor in combination with radiotherapy may be a new potential therapeutic target to improve the therapeutic response of thyroid carcinoma to radiotherapy and reduce metastatic burden. PMID:21765994

  9. Effects of hypoxia on vertebrate blood vessels.

    PubMed

    Russell, Michael J; Dombkowski, Ryan A; Olson, Kenneth R

    2008-03-01

    Hypoxia contracts mammalian respiratory vessels and increases vascular resistance in respiratory tissues of many vertebrates. In systemic vessels these responses vary, hypoxia relaxes mammalian vessels and contracts systemic arteries from cyclostomes. It has been proposed that hypoxic vasoconstriction in cyclostome systemic arteries is the antecedent to mammalian hypoxic pulmonary vasoconstriction, however, phylogenetic characterization of hypoxic responses is lacking. In this study, we characterized the hypoxic response of isolated systemic and respiratory vessels from a variety of vertebrates using standard myography. Pre-gill/respiratory (ventral aorta, afferent branchial artery, pulmonary artery) and post-gill/systemic (dorsal and thoracic aortas, efferent branchial artery) from lamprey (Petromyzon marinus), sandbar shark (Carcharhinus plumbeus), yellowfin tuna (Thunnus albacares), American bullfrog (Rana catesbeiana), American alligator (Alligator mississippiensis), Pekin duck (Anas platyrhynchos domesticus), chicken (Gallus domesticus) and rat (Rattus norvegicus) were exposed to hypoxia at rest or during pre-stimulation (elevated extracellular potassium, epinephrine or norepinephrine). Hypoxia produced a relaxation or transient contraction followed by relaxation in all pre-gill vessels, except for contraction in lamprey, and vasoconstriction or tri-phasic constriction-dilation-constriction in all pulmonary vessels. Hypoxia contracted systemic vessels from all animals except shark and rat and in pre-contracted rat aortas it produced a transient contraction followed by relaxation. These results show that while the classic "systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction" may occur in the microcirculation, the hypoxic response of the vertebrate macrocirculation is quite variable. These findings also suggest that hypoxic vasoconstriction is a phylogenetically ancient response. PMID:18214862

  10. Rat reaction to hypokinesia after prior adaptation to hypoxia

    NASA Technical Reports Server (NTRS)

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

    1980-01-01

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

  11. Hypoxia Reduces Arylsulfatase B Activity and Silencing Arylsulfatase B Replicates and Mediates the Effects of Hypoxia

    PubMed Central

    Bhattacharyya, Sumit; Tobacman, Joanne K.

    2012-01-01

    This report presents evidence of 1) a role for arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) in mediating intracellular oxygen signaling; 2) replication between the effects of ARSB silencing and hypoxia on sulfated glycosaminoglycan content, cellular redox status, and expression of hypoxia-associated genes; and 3) a mechanism whereby changes in chondroitin-4-sulfation that follow either hypoxia or ARSB silencing can induce transcriptional changes through galectin-3. ARSB removes 4-sulfate groups from the non-reducing end of chondroitin-4-sulfate and dermatan sulfate and is required for their degradation. For activity, ARSB requires modification of a critical cysteine residue by the formylglycine generating enzyme and by molecular oxygen. When primary human bronchial and human colonic epithelial cells were exposed to 10% O2×1 h, ARSB activity declined by ∼41% and ∼30% from baseline, as nuclear hypoxia inducible factor (HIF)-1α increased by ∼53% and ∼37%. When ARSB was silenced, nuclear HIF-1α increased by ∼81% and ∼61% from baseline, and mRNA expression increased to 3.73 (±0.34) times baseline. Inversely, ARSB overexpression reduced nuclear HIF-1α by ∼37% and ∼54% from baseline in the epithelial cells. Hypoxia, like ARSB silencing, significantly increased the total cellular sulfated glycosaminoglycans and chondroitin-4-sulfate (C4S) content. Both hypoxia and ARSB silencing had similar effects on the cellular redox status and on mRNA expression of hypoxia-associated genes. Transcriptional effects of both ARSB silencing and hypoxia may be mediated by reduction in galectin-3 binding to more highly sulfated C4S, since the galectin-3 that co-immunoprecipitated with C4S declined and the nuclear galectin-3 increased following ARSB knockdown and hypoxia. PMID:22428001

  12. Individual variation in whole-animal hypoxia tolerance is associated with cardiac hypoxia tolerance in a marine teleost

    PubMed Central

    Joyce, William; Ozolina, Karlina; Mauduit, Florian; Ollivier, Hélène; Claireaux, Guy

    2016-01-01

    Hypoxia is a pervasive problem in coastal environments and is predicted to have enduring impacts on aquatic ecosystems. Intraspecific variation in hypoxia tolerance is well documented in fish; however, the factors underlying this variation remain unknown. Here, we investigate the role of the heart in individual hypoxia tolerance of the European sea bass (Dicentrarchus labrax). We found individual whole-animal hypoxia tolerance is a stable trait in sea bass for more than 18 months (duration of study). We next examined in vitro cardiac performance and found myocardial muscle from hypoxia-tolerant individuals generated greater force, with higher rates of contraction and relaxation, than hypoxic-sensitive individuals during hypoxic exposure. Thus, whole-animal hypoxia tolerance is associated with cardiac hypoxia tolerance. As the occurrence of aquatic hypoxia is expected to increase in marine ecosystems, our experimental data suggest that cardiac performance may influence fish survival and distribution. PMID:26740561

  13. Webizing mobile augmented reality content

    NASA Astrophysics Data System (ADS)

    Ahn, Sangchul; Ko, Heedong; Yoo, Byounghyun

    2014-01-01

    This paper presents a content structure for building mobile augmented reality (AR) applications in HTML5 to achieve a clean separation of the mobile AR content and the application logic for scaling as on the Web. We propose that the content structure contains the physical world as well as virtual assets for mobile AR applications as document object model (DOM) elements and that their behaviour and user interactions are controlled through DOM events by representing objects and places with a uniform resource identifier. Our content structure enables mobile AR applications to be seamlessly developed as normal HTML documents under the current Web eco-system.

  14. Hypoxia as a therapy for mitochondrial disease.

    PubMed

    Jain, Isha H; Zazzeron, Luca; Goli, Rahul; Alexa, Kristen; Schatzman-Bone, Stephanie; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Shalem, Ophir; Sanjana, Neville E; Zhang, Feng; Goessling, Wolfram; Zapol, Warren M; Mootha, Vamsi K

    2016-04-01

    Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction. PMID:26917594

  15. Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise.

    PubMed

    Casey, Darren P; Madery, Brandon D; Pike, Tasha L; Eisenach, John H; Dietz, Niki M; Joyner, Michael J; Wilkins, Brad W

    2009-10-01

    We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2 saturation). In protocol 1 (n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 (n = 10), subjects received intra-arterial phentolamine (alpha-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml x min(-1).100 mmHg(-1)) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (DeltaFVC; change from normoxic baseline) during hypoxic exercise with saline was 172 +/- 29 and 314 +/- 34 ml x min(-1) x 100 mmHg(-1) (10% and 20%, respectively). Aminophylline administration did not affect DeltaFVC during hypoxic exercise at 10% (190 +/- 29 ml x min(-1)x100 mmHg(-1), P = 0.4) or 20% (287 +/- 48 ml x min(-1) x 100 mmHg(-1), P = 0.3). In protocol 2, DeltaFVC due to hypoxic exercise with phentolamine infusion was 313 +/- 30 and 453 +/- 41 ml x min(-1) x 100 mmHg(-1) (10% and 20% respectively). DeltaFVC was similar at 10% (352 +/- 39 ml min(-1) x 100 mmHg(-1), P = 0.8) and 20% (528 +/- 45 ml x min(-1) x 100 mmHg(-1), P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, DeltaFVC to exogenous adenosine was reduced by aminophylline administration in both protocols (P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans. PMID:19661449

  16. Posterior mediastinal extramedullary hematopoiesis secondary to hypoxia

    PubMed Central

    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

  17. Posterior mediastinal extramedullary hematopoiesis secondary to hypoxia.

    PubMed

    Solazzo, A; D'Auria, V; Moccia, L G; Vatrella, A; Bocchino, M; Rea, G

    2016-05-01

    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

  18. PRP Augmentation for ACL Reconstruction

    PubMed Central

    Di Matteo, Berardo; Kon, Elizaveta; Marcacci, Maurilio

    2015-01-01

    Current research is investigating new methods to enhance tissue healing to speed up recovery time and decrease the risk of failure in Anterior Cruciate Ligament (ACL) reconstructive surgery. Biological augmentation is one of the most exploited strategies, in particular the application of Platelet Rich Plasma (PRP). Aim of the present paper is to systematically review all the preclinical and clinical papers dealing with the application of PRP as a biological enhancer during ACL reconstructive surgery. Thirty-two studies were included in the present review. The analysis of the preclinical evidence revealed that PRP was able to improve the healing potential of the tendinous graft both in terms of histological and biomechanical performance. Looking at the available clinical evidence, results were not univocal. PRP administration proved to be a safe procedure and there were some evidences that it could favor the donor site healing in case of ACL reconstruction with patellar tendon graft and positively contribute to graft maturation over time, whereas the majority of the papers did not show beneficial effects in terms of bony tunnels/graft area integration. Furthermore, PRP augmentation did not provide superior functional results at short term evaluation. PMID:26064903

  19. Augmented reality in medical education?

    PubMed

    Kamphuis, Carolien; Barsom, Esther; Schijven, Marlies; Christoph, Noor

    2014-09-01

    Learning in the medical domain is to a large extent workplace learning and involves mastery of complex skills that require performance up to professional standards in the work environment. Since training in this real-life context is not always possible for reasons of safety, costs, or didactics, alternative ways are needed to achieve clinical excellence. Educational technology and more specifically augmented reality (AR) has the potential to offer a highly realistic situated learning experience supportive of complex medical learning and transfer. AR is a technology that adds virtual content to the physical real world, thereby augmenting the perception of reality. Three examples of dedicated AR learning environments for the medical domain are described. Five types of research questions are identified that may guide empirical research into the effects of these learning environments. Up to now, empirical research mainly appears to focus on the development, usability and initial implementation of AR for learning. Limited review results reflect the motivational value of AR, its potential for training psychomotor skills and the capacity to visualize the invisible, possibly leading to enhanced conceptual understanding of complex causality. PMID:24464832

  20. PRP Augmentation for ACL Reconstruction.

    PubMed

    Andriolo, Luca; Di Matteo, Berardo; Kon, Elizaveta; Filardo, Giuseppe; Venieri, Giulia; Marcacci, Maurilio

    2015-01-01

    Current research is investigating new methods to enhance tissue healing to speed up recovery time and decrease the risk of failure in Anterior Cruciate Ligament (ACL) reconstructive surgery. Biological augmentation is one of the most exploited strategies, in particular the application of Platelet Rich Plasma (PRP). Aim of the present paper is to systematically review all the preclinical and clinical papers dealing with the application of PRP as a biological enhancer during ACL reconstructive surgery. Thirty-two studies were included in the present review. The analysis of the preclinical evidence revealed that PRP was able to improve the healing potential of the tendinous graft both in terms of histological and biomechanical performance. Looking at the available clinical evidence, results were not univocal. PRP administration proved to be a safe procedure and there were some evidences that it could favor the donor site healing in case of ACL reconstruction with patellar tendon graft and positively contribute to graft maturation over time, whereas the majority of the papers did not show beneficial effects in terms of bony tunnels/graft area integration. Furthermore, PRP augmentation did not provide superior functional results at short term evaluation. PMID:26064903

  1. Striae distensae after subfascial breast augmentation.

    PubMed

    Keramidas, Evangelos; Rodopoulou, Stavroula

    2008-03-01

    Striae distensae or stretch marks after breast augmentation are a rare complication. To date, 10 cases have been published. In seven of these cases, the implant was placed in a subglandular position and in the other three cases, placement was submuscular. Two cases of stretch marks in two young nulliparous women who underwent subfacial breast augmentation are presented. To the best of the authors' knowledge, this is the first report of striae distensae after subfascial breast augmentation. PMID:18043962

  2. Transcriptomic Changes Triggered by Hypoxia: Evidence for HIF-1α -Independent, [Na+]i/[K+]i-Mediated, Excitation-Transcription Coupling

    PubMed Central

    Koltsova, Svetlana V.; Shilov, Boris; Birulina, Julia G.; Akimova, Olga A.; Haloui, Mounsif; Kapilevich, Leonid V.; Gusakova, Svetlana V.; Tremblay, Johanne; Hamet, Pavel; Orlov, Sergei N.

    2014-01-01

    This study examines the relative impact of canonical hypoxia-inducible factor-1alpha- (HIF-1α and Na+i/K+i-mediated signaling on transcriptomic changes evoked by hypoxia and glucose deprivation. Incubation of RASMC in ischemic conditions resulted in ∼3-fold elevation of [Na+]i and 2-fold reduction of [K+]i. Using global gene expression profiling we found that Na+,K+-ATPase inhibition by ouabain or K+-free medium in rat aortic vascular smooth muscle cells (RASMC) led to the differential expression of dozens of genes whose altered expression was previously detected in cells subjected to hypoxia and ischemia/reperfusion. For further investigations, we selected Cyp1a1, Fos, Atf3, Klf10, Ptgs2, Nr4a1, Per2 and Hes1, i.e. genes possessing the highest increments of expression under sustained Na+,K+-ATPase inhibition and whose implication in the pathogenesis of hypoxia was proved in previous studies. In ouabain-treated RASMC, low-Na+, high-K+ medium abolished amplification of the [Na+]i/[K+]i ratio as well as the increased expression of all tested genes. In cells subjected to hypoxia and glucose deprivation, dissipation of the transmembrane gradient of Na+ and K+ completely eliminated increment of Fos, Atf3, Ptgs2 and Per2 mRNAs and sharply diminished augmentation expression of Klf10, Edn1, Nr4a1 and Hes1. In contrast to low-Na+, high-K+ medium, RASMC transfection with Hif-1a siRNA attenuated increments of Vegfa, Edn1, Klf10 and Nr4a1 mRNAs triggered by hypoxia but did not impact Fos, Atf3, Ptgs2 and Per2 expression. Thus, our investigation demonstrates, for the first time, that Na+i/K+i-mediated, Hif-1α- -independent excitation-transcription coupling contributes to transcriptomic changes evoked in RASMC by hypoxia and glucose deprivation. PMID:25375852

  3. Hypoxia inducible factor pathway inhibitors as anticancer therapeutics

    PubMed Central

    Burroughs, Sarah K; Kaluz, Stefan; Wang, Danzhu; Wang, Ke

    2013-01-01

    Hypoxia is a significant feature of solid tumor cancers. Hypoxia leads to a more malignant phenotype that is resistant to chemotherapy and radiation, is more invasive and has greater metastatic potential. Hypoxia activates the hypoxia inducible factor (HIF) pathway, which mediates the biological effects of hypoxia in tissues. The HIF complex acts as a transcription factor for many genes that increase tumor survival and proliferation. To date, many HIF pathway inhibitors indirectly affect HIF but there have been no clinically approved direct HIF inhibitors. This can be attributed to the complexity of the HIF pathway, as well as to the challenges of inhibiting protein–protein interactions. PMID:23573973

  4. Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1

    PubMed Central

    Zhou, Guofei; Dada, Laura A.; Wu, Minghua; Kelly, Aileen; Trejo, Humberto; Zhou, Qiyuan; Varga, John

    2009-01-01

    Patients with acute lung injury develop hypoxia, which may lead to lung dysfunction and aberrant tissue repair. Recent studies have suggested that epithelial-mesenchymal transition (EMT) contributes to pulmonary fibrosis. We sought to determine whether hypoxia induces EMT in alveolar epithelial cells (AEC). We found that hypoxia induced the expression of α-smooth muscle actin (α-SMA) and vimentin and decreased the expression of E-cadherin in transformed and primary human, rat, and mouse AEC, suggesting that hypoxia induces EMT in AEC. Both severe hypoxia and moderate hypoxia induced EMT. The reactive oxygen species (ROS) scavenger Euk-134 prevented hypoxia-induced EMT. Moreover, hypoxia-induced expression of α-SMA and vimentin was prevented in mitochondria-deficient ρ0 cells, which are incapable of ROS production during hypoxia. CoCl2 and dimethyloxaloylglycine, two compounds that stabilize hypoxia-inducible factor (HIF)-α under normoxia, failed to induce α-SMA expression in AEC. Furthermore, overexpression of constitutively active HIF-1α did not induce α-SMA. However, loss of HIF-1α or HIF-2α abolished induction of α-SMA mRNA during hypoxia. Hypoxia increased the levels of transforming growth factor (TGF)-β1, and preincubation of AEC with SB431542, an inhibitor of the TGF-β1 type I receptor kinase, prevented the hypoxia-induced EMT, suggesting that the process was TGF-β1 dependent. Furthermore, both ROS and HIF-α were necessary for hypoxia-induced TGF-β1 upregulation. Accordingly, we have provided evidence that hypoxia induces EMT of AEC through mitochondrial ROS, HIF, and endogenous TGF-β1 signaling. PMID:19801454

  5. Hypoxia Inducible Factor-1α Regulates the Migration of Bone Marrow Mesenchymal Stem Cells via Integrin α4

    PubMed Central

    Choi, Jong Ho; Lee, Yun Bin; Jung, Jieun; Hwang, Seong Gyu; Oh, IL-Hoan; Kim, Gi Jin

    2016-01-01

    Although hypoxic environments have been known to regulate the migratory ability of bone marrow-derived mesenchymal stem cells (BM-MSCs), which is a critical factor for maximizing the therapeutic effect, the underlying mechanisms remain unclear. Therefore, we aimed to confirm the effect of hypoxia-inducible factor-1α (HIF-1α) on the migration of BM-MSCs and to analyze the interaction between HIF-1α and integrin-mediated signals. Hypoxia-activated HIF-1α significantly increased BM-MSC migration. The expression of integrin α4 was decreased in BM-MSCs by increased HIF-1α under hypoxia, whereas the expression of Rho-associated kinase 1 (ROCK1) and Rac1/2/3 was increased. After downregulation of HIF-1α by YC-1, which is an inhibitor of HIF-1α, BM-MSC migration was decreased via upregulation of integrin α4 and downregulation of ROCK1 and Rac1/2/3. Knockdown of integrin α4 by integrin α4 siRNA (siITGA4) treatment increased BM-MSC migration by upregulation of ROCK1, Rac1/2/3, and matrix metalloproteinase-2 regardless of oxygen tension. Moreover, siITGA4 treatment increased HIF-1α expression and augmented the translocation of HIF-1α into the nucleus under hypoxia. Taken together, the alternative expression of HIF-1α induced by microenvironment factors, such as hypoxia and integrin α4, may regulate the migration of BM-MSCs. These findings may provide insights to the underlying mechanisms of BM-MSC migration for successful stem cell-based therapy. PMID:26880989

  6. Pre- and Perinatal Ischemia-Hypoxia, the Ischemia-Hypoxia Response Pathway, and ADHD Risk.

    PubMed

    Smith, Taylor F; Schmidt-Kastner, Rainald; McGeary, John E; Kaczorowski, Jessica A; Knopik, Valerie S

    2016-05-01

    This review focuses on how measured pre- and perinatal environmental and (epi)genetic risk factors are interrelated and potentially influence one, of many, common developmental pathway towards ADHD. Consistent with the Developmental Origins of Health and Disease hypothesis, lower birth weight is associated with increased ADHD risk. Prenatal ischemia-hypoxia (insufficient blood and oxygen supply in utero) is a primary pathway to lower birth weight and produces neurodevelopmental risk for ADHD. To promote tissue survival in the context of ischemia-hypoxia, ischemia-hypoxia response (IHR) pathway gene expression is altered in the developing brain and peripheral tissues. Although altered IHR gene expression is adaptive in the context of ischemia-hypoxia, lasting IHR epigenetic modifications may lead to increased ADHD risk. Taken together, IHR genetic vulnerability to ischemia-hypoxia and IHR epigenetic alterations following prenatal ischemia-hypoxia may result in neurodevelopmental vulnerability for ADHD. Limitations of the extant literature and future directions for genetically-informed research are discussed. PMID:26920003

  7. Cardiovascular and cerebrovascular responses to acute hypoxia following exposure to intermittent hypoxia in healthy humans

    PubMed Central

    Foster, Glen E; Brugniaux, Julien V; Pialoux, Vincent; Duggan, Cailean T C; Hanly, Patrick J; Ahmed, Sofia B; Poulin, Marc J

    2009-01-01

    Intermittent hypoxia (IH) is thought to be responsible for many of the long-term cardiovascular consequences associated with obstructive sleep apnoea (OSA). Experimental human models of IH can aid in investigating the pathophysiology of these cardiovascular complications. The purpose of this study was to determine the effects of IH on the cardiovascular and cerebrovascular response to acute hypoxia and hypercapnia in an experimental human model that simulates the hypoxaemia experienced by OSA patients. We exposed 10 healthy, male subjects to IH for 4 consecutive days. The IH profile involved 2 min of hypoxia (nadir = 45.0 mmHg) alternating with 2 min of normoxia (peak = 88.0 mmHg) for 6 h. The cerebral blood flow response and the pressor responses to hypoxia and hypercapnia were assessed after 2 days of sham exposure, after each day of IH, and 4 days following the discontinuation of IH. Nitric oxide derivatives were measured at baseline and following the last exposure to IH. After 4 days of IH, mean arterial pressure increased by 4 mmHg (P < 0.01), nitric oxide derivatives were reduced by 55% (P < 0.05), the pressor response to acute hypoxia increased (P < 0.01), and the cerebral vascular resistance response to hypoxia increased (P < 0.01). IH alters blood pressure and cerebrovascular regulation, which is likely to contribute to the pathogenesis of cardiovascular and cerebrovascular disease in patients with OSA. PMID:19417094

  8. Multimodality imaging of hypoxia in preclinical settings

    PubMed Central

    Mason, Ralph P.; Zhao, Dawen; Pacheco-Torres, Jesús; Cui, Weina; Kodibagkar, Vikram D.; Gulaka, Praveen K.; Hao, Guiyang; Thorpe, Philip; Hahn, Eric W.; Peschke, Peter

    2011-01-01

    Hypoxia has long been recognized to influence solid tumor response to therapy. Increasingly, hypoxia has also been implicated in tumor aggressiveness, including growth, development and metastatic potential. Thus, there is a fundamental, as well as a clinical interest, in assessing in situ tumor hypoxia. This review will examine diverse approaches focusing on the pre-clinical setting, particularly, in rodents. The strategies are inevitably a compromise in terms of sensitivity, precision, temporal and spatial resolution, as well as cost, feasibility, ease and robustness of implementation. We will review capabilities of multiple modalities and examine what makes them particularly suitable for investigating specific aspects of tumor pathophysiology. Current approaches range from nuclear imaging to magnetic resonance and optical, with varying degrees of invasiveness and ability to examine spatial heterogeneity, as well as dynamic response to interventions. Ideally, measurements would be non-invasive, exploiting endogenous reporters to reveal quantitatively local oxygen tension dynamics. A primary focus of this review is magnetic resonance imaging (MRI) based techniques, such as 19F MRI oximetry, which reveals not only hypoxia in vivo, but more significantly, spatial distribution of pO2 quantitatively, with a precision relevant to radiobiology. It should be noted that pre-clinical methods may have very different criteria for acceptance, as compared with potential investigations for prognostic radiology or predictive biomarkers suitable for use in patients. PMID:20639813

  9. GULF OF MEXICO HYPOXIA MONITORING AND MODELING

    EPA Science Inventory

    Greene, Richard M. and Russell G. Kreis. In press. Gulf of Mexico Hypoxia Monitoring and Modeling (Abstract). To be presented at the EPA Science Forum: Healthy Communities and Ecosystems, 1-3 June 2004, Washington, DC. 1 p. (ERL,GB R990).

    Oxygen-depleted or hypoxic bottom...

  10. Molecular mechanisms regulating macrophage response to hypoxia.

    PubMed

    Rahat, Michal A; Bitterman, Haim; Lahat, Nitza

    2011-01-01

    Monocytes and Macrophages (Mo/Mɸ) exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mɸ), combating invading pathogens and tumor cells (classically activated or M1 Mo/Mɸ), orchestrating wound healing (alternatively activated or M2 Mo/Mɸ), and restoring homeostasis after an inflammatory response (resolution Mɸ). Hypoxia is an important factor in the Mɸ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mɸ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mɸ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators hypoxia-induced factor-1 and NF-κB, as well as other transcription factors (e.g., AP-1, Erg-1), but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mɸ pro-angiogenic mediators, suppress M1 Mɸ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mɸ into an activation state which approximate the alternatively activated or resolution Mɸ. PMID:22566835

  11. Acridine-intercalator based hypoxia selective cytotoxins

    DOEpatents

    Papadopoulou-Rosenzweig, Maria; Bloomer, William D.; Bloomer, William D.

    1994-01-01

    Hypoxia selective cytotoxins of the general formula ##STR1## wherein n is from 1 to 5, and NO.sub.2 is in at least one of the 2, 4 or 5-positions of the imidazole. Such compounds have utility as radiosensitizers and chemosensitizers.

  12. Molecular Mechanisms Regulating Macrophage Response to Hypoxia

    PubMed Central

    Rahat, Michal A.; Bitterman, Haim; Lahat, Nitza

    2011-01-01

    Monocytes and Macrophages (Mo/Mɸ) exhibit great plasticity, as they can shift between different modes of activation and, driven by their immediate microenvironment, perform divergent functions. These include, among others, patrolling their surroundings and maintaining homeostasis (resident Mo/Mɸ), combating invading pathogens and tumor cells (classically activated or M1 Mo/Mɸ), orchestrating wound healing (alternatively activated or M2 Mo/Mɸ), and restoring homeostasis after an inflammatory response (resolution Mɸ). Hypoxia is an important factor in the Mɸ microenvironment, is prevalent in many physiological and pathological conditions, and is interdependent with the inflammatory response. Although Mo/Mɸ have been studied in hypoxia, the mechanisms by which hypoxia influences the different modes of their activation, and how it regulates the shift between them, remain unclear. Here we review the current knowledge about the molecular mechanisms that mediate this hypoxic regulation of Mɸ activation. Much is known about the hypoxic transcriptional regulatory network, which includes the master regulators hypoxia-induced factor-1 and NF-κB, as well as other transcription factors (e.g., AP-1, Erg-1), but we also highlight the role of post-transcriptional and post-translational mechanisms. These mechanisms mediate hypoxic induction of Mɸ pro-angiogenic mediators, suppress M1 Mɸ by post-transcriptionally inhibiting pro-inflammatory mediators, and help shift the classically activated Mɸ into an activation state which approximate the alternatively activated or resolution Mɸ. PMID:22566835

  13. Acridine-intercalator based hypoxia selective cytotoxins

    DOEpatents

    Papadopoulou-Rosenzweig, M.; Bloomer, W.D.

    1994-03-15

    Hypoxia selective cytotoxins of the general formula STR1 wherein n is from 1 to 5, and NO[sub 2] is in at least one of the 2, 4 or 5-positions of the imidazole are developed. Such compounds have utility as radiosensitizers and chemosensitizers. 9 figs.

  14. New Approaches to the Gulf Hypoxia Problem

    NASA Astrophysics Data System (ADS)

    Bianchi, Thomas S.; Allison, Mead A.; Chapman, Piers; Cowan, James H.; Dagg, Michael J.; Day, John W.; DiMarco, Steve F.; Hetland, Robert D.; Powell, Rodney

    2010-05-01

    Coastal water hypoxia, where dissolved oxygen is less than 2 milligrams per liter, is a global environmental problem [e.g., Diaz and Rosenberg, 2008]. It is largely associated with eutrophication, whereby nutrient inputs (nitrogen and phosphorous) to coastal waters lead to elevated primary production and accelerated rates of microbial respiration, which results in oxygen depletion. Despite more than 25 years of monitoring [Rabalais et al., 2007] (see also Figure S1 in the online supplement to this Eos issue (http://www.agu.org/eos_elec/)), the relative importance of the various processes that control hypoxia in bottom waters of the northern Gulf of Mexico (GOM)—in particular, those beyond the direct influence of river plumes [Dagg et al., 2007; Bianchi et al., 2008, 2010, and references therein]—remains uncertain. For example, a prediction last June pronounced that the 2009 hypoxic area would be the largest on record (˜23,000 square kilometers; see http://www.gulfhypoxia.net/Research/Shelfwide%20Cruises/2009/Files/2009_Hypoxia_Forecast.pdf). However, the most recent annual surveys estimated its size at 8000 square kilometers, only 35% of that predicted. This occurred in the absence of a significant hurricane impact on this margin in 2009—hurricanes tend to dissipate hypoxia.

  15. LOFT Augmented Operator Capability Program

    SciTech Connect

    Hollenbeck, D.A.; Krantz, E.A.; Hunt, G.L.; Meyer, O.R.

    1980-01-01

    The outline of the LOFT Augmented Operator Capability Program is presented. This program utilizes the LOFT (Loss-of-Fluid Test) reactor facility which is located at the Idaho National Engineering Laboratory and the LOFT operational transient experiment series as a test bed for methods of enhancing the reactor operator's capability for safer operation. The design of an Operational Diagnotics and Display System is presented which was backfit to the existing data acquisition computers. Basic color-graphic displays of the process schematic and trend type are presented. In addition, displays were developed and are presented which represent safety state vector information. A task analysis method was applied to LOFT reactor operating procedures to test its usefulness in defining the operator's information needs and workload.

  16. Folate augmentation of antidepressant response.

    PubMed

    Owen, R T

    2013-12-01

    The use of two antidepressants from the initiation of treatment in major depressive disorder has been investigated in several recent studies and forms a paradigm shift in the pharmacotherapy of the condition. Several, but not all, trials have claimed improved response and remission rates with the combinations as opposed to monotherapy. The use of folate preparations (folic and folinic acid and l-meth-ylfolate) have shown effective augmentation of antidepressant response in a variety of controlled and open-label settings in patients with normo- and hypofolatemic status. Several recent trials using L-methylfolate, the active and more bioavailable form of folic acid, have shown promising adjunctive use with a well-tolerated adverse event profile. PMID:24524097

  17. Augmented Reality and Mobile Art

    NASA Astrophysics Data System (ADS)

    Gwilt, Ian

    The combined notions of augmented-reality (AR) and mobile art are based on the amalgamation of a number of enabling technologies including computer imaging, emergent display and tracking systems and the increased computing-power in hand-held devices such as Tablet PCs, smart phones, or personal digital assistants (PDAs) which have been utilized in the making of works of art. There is much published research on the technical aspects of AR and the ongoing work being undertaken in the development of faster more efficient AR systems [1] [2]. In this text I intend to concentrate on how AR and its associated typologies can be applied in the context of new media art practices, with particular reference to its application on hand-held or mobile devices.

  18. Sensory Augmentation for the Blind

    PubMed Central

    Kärcher, Silke M.; Fenzlaff, Sandra; Hartmann, Daniela; Nagel, Saskia K.; König, Peter

    2012-01-01

    Common navigational aids used by blind travelers during large-scale navigation divert attention away from important cues of the immediate environment (i.e., approaching vehicles). Sensory augmentation devices, relying on principles similar to those at work in sensory substitution, can potentially bypass the bottleneck of attention through sub-cognitive implementation of a set of rules coupling motor actions with sensory stimulation. We provide a late blind subject with a vibrotactile belt that continually signals the direction of magnetic north. The subject completed a set of behavioral tests before and after an extended training period. The tests were complemented by questionnaires and interviews. This newly supplied information improved performance on different time scales. In a pointing task we demonstrate an instant improvement of performance based on the signal provided by the device. Furthermore, the signal was helpful in relevant daily tasks, often complicated for the blind, such as keeping a direction over longer distances or taking shortcuts in familiar environments. A homing task with an additional attentional load demonstrated a significant improvement after training. The subject found the directional information highly expedient for the adjustment of his inner maps of familiar environments and describes an increase in his feeling of security when exploring unfamiliar environments with the belt. The results give evidence for a firm integration of the newly supplied signals into the behavior of this late blind subject with better navigational performance and more courageous behavior in unfamiliar environments. Most importantly, the complementary information provided by the belt lead to a positive emotional impact with enhanced feeling of security. The present experimental approach demonstrates the positive potential of sensory augmentation devices for the help of handicapped people. PMID:22403535

  19. Hypoxia-Inducible Factor 1–Dependent Induction of Intestinal Trefoil Factor Protects Barrier Function during Hypoxia

    PubMed Central

    Furuta, Glenn T.; Turner, Jerrold R.; Taylor, Cormac T.; Hershberg, Robert M.; Comerford, Katrina; Narravula, Sailaja; Podolsky, Daniel K.; Colgan, Sean P.

    2001-01-01

    Mucosal organs such as the intestine are supported by a rich and complex underlying vasculature. For this reason, the intestine, and particularly barrier-protective epithelial cells, are susceptible to damage related to diminished blood flow and concomitant tissue hypoxia. We sought to identify compensatory mechanisms that protect epithelial barrier during episodes of intestinal hypoxia. Initial studies examining T84 colonic epithelial cells revealed that barrier function is uniquely resistant to changes elicited by hypoxia. A search for intestinal-specific, barrier-protective factors revealed that the human intestinal trefoil factor (ITF) gene promoter bears a previously unappreciated binding site for hypoxia-inducible factor (HIF)-1. Hypoxia resulted in parallel induction of ITF mRNA and protein. Electrophoretic mobility shift assay analysis using ITF-specific, HIF-1 consensus motifs resulted in a hypoxia-inducible DNA binding activity, and loading cells with antisense oligonucleotides directed against the α chain of HIF-1 resulted in a loss of ITF hypoxia inducibility. Moreover, addition of anti-ITF antibody resulted in a loss of barrier function in epithelial cells exposed to hypoxia, and the addition of recombinant human ITF to vascular endothelial cells partially protected endothelial cells from hypoxia-elicited barrier disruption. Extensions of these studies in vivo revealed prominent hypoxia-elicited increases in intestinal permeability in ITF null mice. HIF-1–dependent induction of ITF may provide an adaptive link for maintenance of barrier function during hypoxia. PMID:11342587

  20. Augmented Reality for Close Quarters Combat

    ScienceCinema

    None

    2014-06-23

    Sandia National Laboratories has developed a state-of-the-art augmented reality training system for close-quarters combat (CQB). This system uses a wearable augmented reality system to place the user in a real environment while engaging enemy combatants in virtual space (Boston Dynamics DI-Guy). Umbra modeling and simulation environment is used to integrate and control the AR system.

  1. From Augmentation Media to Meme Media.

    ERIC Educational Resources Information Center

    Tanaka, Yuzuru

    Computers as meta media are now evolving from augmentation media vehicles to meme media vehicles. While an augmentation media system provides a seamlessly integrated environment of various tools and documents, meme media system provides further functions to edit and distribute tools and documents. Documents and tools on meme media can easily…

  2. Vertebral Augmentation for Osteoporotic Compression Fractures.

    PubMed

    Richmond, Bradford J

    2016-01-01

    Vertebral augmentation procedures such as vertebroplasty and kyphoplasty were developed to reduce pain and improve quality of life for patients with osteoporotic vertebral compression fractures. However, the use of vertebral augmentation has been debated and questioned since its inception. This article addresses some of these issues. PMID:26490134

  3. Enhancing Education through Mobile Augmented Reality

    ERIC Educational Resources Information Center

    Joan, D. R. Robert

    2015-01-01

    In this article, the author has discussed about the Mobile Augmented Reality and enhancing education through it. The aim of the present study was to give some general information about mobile augmented reality which helps to boost education. Purpose of the current study reveals the mobile networks which are used in the institution campus as well…

  4. Status report of RMS active damping augmentation

    NASA Technical Reports Server (NTRS)

    Gilbert, Mike; Demeo, Martha E.

    1993-01-01

    A status report of Remote Manipulator System (RMS) active damping augmentation is presented. Topics covered include: active damping augmentation; benefits of RMS ADA; simulated payload definition; sensor and actuator definition; ADA control law design; Shuttle Engineering Simulator (SES) real-time simulation; and astronaut evaluation.

  5. Augmented Reality for Close Quarters Combat

    SciTech Connect

    2013-09-20

    Sandia National Laboratories has developed a state-of-the-art augmented reality training system for close-quarters combat (CQB). This system uses a wearable augmented reality system to place the user in a real environment while engaging enemy combatants in virtual space (Boston Dynamics DI-Guy). Umbra modeling and simulation environment is used to integrate and control the AR system.

  6. Irradiated homologous costal cartilage for augmentation rhinoplasty

    SciTech Connect

    Lefkovits, G. )

    1990-10-01

    Although the ideal reconstructive material for augmentation rhinoplasty continues to challenge plastic surgeons, there exists no report in the literature that confines the use of irradiated homologous costal cartilage, first reported by Dingman and Grabb in 1961, to dorsal nasal augmentation. The purpose of this paper is to present a retrospective analysis of the author's experience using irradiated homologous costal cartilage in augmentation rhinoplasty. Twenty-seven dorsal nasal augmentations were performed in 24 patients between 16 and 49 years of age with a follow-up ranging from 1 to 27 months. Good-to-excellent results were achieved in 83.3% (20 of 24). Poor results requiring revision were found in 16.7% (4 of 24). Complication rates included 7.4% infection (2 of 27) and 14.8% warping (4 of 27). The resorption rate was zero. These results compare favorably with other forms of nasal augmentation. Advantages and disadvantages of irradiated homologous costal cartilage are discussed.

  7. Performance of a self-augmented railgun

    SciTech Connect

    Burton, R.L.; Witherspoon, F.D.; Goldstein, S.A. )

    1991-10-01

    The accelerating force of a railgun 1/2{ital L}{prime}{ital I}{sup 2}{sub {ital a}} can be increased by augmenting the self-induced magnetic field created by the armature current. Augmentation fields can be produced by external current coils or, as is done here, by shorting the railgun muzzle, and using the gun rails as the augmentation coil. Experimental results are presented for a 3.6-m railgun operated in this self-augmented mode, and effective inductance gradients are achieved which are as much as 9.3 times that of the unaugmented gun. A circuit model is presented which explains features of the measured shunt current and voltage. It is concluded that self-augmentation is an effective way to reduce ohmic heating in the armature of a railgun.

  8. Hypoxia induces adipogenic differentitation of myoblastic cell lines

    SciTech Connect

    Itoigawa, Yoshiaki; Kishimoto, Koshi N.; Okuno, Hiroshi; Sano, Hirotaka; Kaneko, Kazuo; Itoi, Eiji

    2010-09-03

    Research highlights: {yields} C2C12 and G8 myogenic cell lines treated by hypoxia differentiate into adipocytes. {yields} The expression of C/EBP{beta}, {alpha} and PPAR{gamma} were increased under hypoxia. {yields} Myogenic differentiation of C2C12 was inhibited under hypoxia. -- Abstract: Muscle atrophy usually accompanies fat accumulation in the muscle. In such atrophic conditions as back muscles of kyphotic spine and the rotator cuff muscles with torn tendons, blood flow might be diminished. It is known that hypoxia causes trans-differentiation of mesenchymal stem cells derived from bone marrow into adipocytes. However, it has not been elucidated yet if hypoxia turned myoblasts into adipocytes. We investigated adipogenesis in C2C12 and G8 murine myogenic cell line treated by hypoxia. Cells were also treated with the cocktail of insulin, dexamethasone and IBMX (MDI), which has been known to inhibit Wnt signaling and promote adipogenesis. Adipogenic differentiation was seen in both hypoxia and MDI. Adipogenic marker gene expression was assessed in C2C12. CCAAT/enhancer-binding protein (C/EBP) {beta}, {alpha} and peroxisome proliferator activating receptor (PPAR) {gamma} were increased by both hypoxia and MDI. The expression profile of Wnt10b was different between hypoxia and MDI. The mechanism for adipogenesis of myoblasts in hypoxia might be regulated by different mechanism than the modification of Wnt signaling.

  9. Cycling hypoxia: A key feature of the tumor microenvironment.

    PubMed

    Michiels, Carine; Tellier, Céline; Feron, Olivier

    2016-08-01

    A compelling body of evidence indicates that most human solid tumors contain hypoxic areas. Hypoxia is the consequence not only of the chaotic proliferation of cancer cells that places them at distance from the nearest capillary but also of the abnormal structure of the new vasculature network resulting in transient blood flow. Hence two types of hypoxia are observed in tumors: chronic and cycling (intermittent) hypoxia. Most of the current work aims at understanding the role of chronic hypoxia in tumor growth, response to treatment and metastasis. Only recently, cycling hypoxia, with spatial and temporal fluctuations in oxygen levels, has emerged as another key feature of the tumor environment that triggers different responses in comparison to chronic hypoxia. Either type of hypoxia is associated with distinct effects not only in cancer cells but also in stromal cells. In particular, cycling hypoxia has been demonstrated to favor, to a higher extent than chronic hypoxia, angiogenesis, resistance to anti-cancer treatments, intratumoral inflammation and tumor metastasis. These review details these effects as well as the signaling pathway it triggers to switch on specific transcriptomic programs. Understanding the signaling pathways through which cycling hypoxia induces these processes that support the development of an aggressive cancer could convey to the emergence of promising new cancer treatments. PMID:27343712

  10. Hypoxia reduces the effect of photoreceptor bleaching.

    PubMed

    Lin, Yun-Bin; Liu, Jorn-Hon; Chang, Yin

    2012-07-01

    Hypoxia and light illumination can both decrease oxygen consumption in the photoreceptor layers. The purpose of the present study was to investigate whether the mutual effects of hypoxia and intense illumination to the photoreceptors are additive. The a-wave of flash electroretinogram (fERG) was recorded to indirectly measure the photoreceptors function under given conditions. Six normal healthy subjects, mean age 34.0 ± 3.8 years, all of whom had high-altitude (>3,000 m) mountain hiking experience, were recruited for the study. Flash a-wave electroretinography was examined under four conditions: (1) normal (D/N); (2) systemic hypoxia induced by inhaling a mixture of O(2) and N(2) gases, which caused oxyhemoglobin saturation (SaO(2)) ≈ 80% (D/H); (3) intense light illumination, which resulted in photoreceptor bleaching (B/N); and (4) a combination of conditions b and c (B/H). Thirty light stimuli, each with a 20-ms ON and 1,980-ms OFF cycle, were given and ERG performed to probe the photoreceptor function. The results showed that a-wave at the various conditions did not respond to all stimuli. The average a-wave amplitudes were 91.4 ± 46.5, 22.8 ± 42.5, 15.5 ± 28.9, and 35.2 ± 41.1 μV for D/N, D/H, B/N, and B/H, respectively. Nonparametric Friedman test for a-wave amplitude indicated that significant differences occurred in D/N-D/H, D/N-B/N, D/N-B/H, D/H-B/H, and B/N-B/H (all p values were <0.001, but D/H-B/N was 0.264). Thus, systemic hypoxia or strong illumination to the retina can cause an absence of the ERG a-wave or change its response, although individual differences were observed. In this study, systemic hypoxia appeared to reduce photoreceptor bleaching, an interesting finding in itself. The mechanisms underlying the disappearance of the ERG a-wave following hypoxia or intense illumination to the photoreceptors seem to differ. PMID:22544448

  11. Clinical consequences of altered chemoreflex control

    PubMed Central

    Plataki, Maria; Sands, Scott A.; Malhotra, Atul

    2015-01-01

    Control of ventilation dictates various breathing patterns. The respiratory control system consists of a central pattern generator and several feedback mechanisms that act to maintain ventilation at optimal levels. The concept of loop gain has been employed to describe its stability and variability. Synthesizing all interactions under a general model that could account for every behavior has been challenging. Recent insight into the importance of these feedback systems may unveil therapeutic strategies for common ventilatory disturbances. In this review we will address the major mechanisms that have been proposed as mediators of some of the breathing patterns in health and disease that have raised controversies and discussion on ventilatory control over the years. PMID:23681082

  12. Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.

    PubMed

    Fang, Hsin-Yu; Hughes, Russell; Murdoch, Craig; Coffelt, Seth B; Biswas, Subhra K; Harris, Adrian L; Johnson, Randall S; Imityaz, Hongxia Z; Simon, M Celeste; Fredlund, Erik; Greten, Florian R; Rius, Jordi; Lewis, Claire E

    2009-07-23

    Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate 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 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-kappaB (NF-kappaB) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1alpha and 2alpha or NF-kappaB in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-kappaB, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors. PMID:19454749

  13. Hypoxia inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

    PubMed Central

    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.

    2010-01-01

    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 the potent, tumor-promoting cytokines, VEGFA, interleukins 1β and 8, adrenomedullin, CXCR4 and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the NF-κB signalling pathway. We then used both genetic and pharmacological methods to manipulate the levels of HIFs 1α and 2α or NF-κB in primary macrophages in order to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIFs 1 and 2, but not NF-κB, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues like malignant tumors. PMID:19454749

  14. Chronic intermittent hypoxia exposure-induced atherosclerosis: a brief review.

    PubMed

    Song, Dongmei; Fang, Guoqiang; Greenberg, Harly; Liu, Shu Fang

    2015-12-01

    Obstructive sleep apnea (OSA) is highly prevalent in the USA and is recognized as an independent risk factor for atherosclerotic cardiovascular disease. Identification of atherosclerosis risk factor attributable to OSA may provide opportunity to develop preventive measures for cardiovascular risk reduction. Chronic intermittent hypoxia (CIH) is a prominent feature of OSA pathophysiology and may be a major mechanism linking OSA to arteriosclerosis. Animal studies demonstrated that CIH exposure facilitated high-cholesterol diet (HCD)-induced atherosclerosis, accelerated the progression of existing atherosclerosis, and induced atherosclerotic lesions in the absence of other atherosclerosis risk factors, demonstrating that CIH is an independent causal factor of atherosclerosis. Comparative studies revealed major differences between CIH-induced and the classic HCD-induced atherosclerosis. Systemically, CIH was a much weaker inducer of atherosclerosis. CIH and HCD differentially activated inflammatory pathways. Histologically, CIH-induced atherosclerotic plaques had no clear necrotic core, contained a large number of CD31+ endothelial cells, and had mainly elastin deposition, whereas HCD-induced plaques had typical necrotic cores and fibrous caps, contained few endothelial cells, and had mainly collagen deposition. Metabolically, CIH caused mild, but HCD caused more severe dyslipidemia. Mechanistically, CIH did not, but HCD did, cause macrophage foam cell formation. NF-κB p50 gene deletion augmented CIH-induced, but not HCD-induced atherosclerosis. These differences reflect the intrinsic differences between the two types of atherosclerosis in terms of pathological nature and underlying mechanisms and support the notion that CIH-induced atherosclerosis is a new paradigm that differs from the classic HCD-induced atherosclerosis. PMID:26407987

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

    PubMed

    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

  16. Postauricular fascia in augmentation rhinoplasty.

    PubMed

    Guerra, Aldo Benjamin

    2014-06-01

    Ten rhinoplasty operations performed using postauricular fascia for the purpose of augmenting the radix and dorsum of the nose were analyzed retrospectively. All the operations were performed over a 1-year period, between 2005 and 2006. The fascia of the postauricular area has been used as a source of pliable soft-tissue grafts in primary and revision rhinoplasty. It may be easily accessed using a single sulcus incision that also enables harvesting of ear cartilage grafts. Deficiency in the radix is an overlooked abnormality seen in many patients undergoing primary as well as revision rhinoplasty after aggressive hump removal. Recent trends in rhinoplasty have been to avoid the overly reduced nasal skeleton and to create a more balanced nasal surgery result. This article presents the use of the postauricular fascia as a radix graft that has been found to be simple to carry out, reliable, and long lasting. In addition, the fascia graft is useful in the camouflage of various nasal deformities in the dorsum and sidewalls. The average patient follow-up for the study was 24 months. PMID:24932819

  17. Augmented reality: past, present, future

    NASA Astrophysics Data System (ADS)

    Inzerillo, Laura

    2013-03-01

    A great opportunity has permitted to carry out a cultural, historical, architectural and social research with great impact factor on the international cultural interest. We are talking about the realization of a museum whose the main theme is the visit and the discovery of a monument of great prestige: the monumental building the "Steri" in Palermo. The museum is divided into sub themes including the one above all, that has aroused the international interest so much that it has been presented the instance to include the museum in the cultural heritage of UNESCO. It is the realization of a museum path that regards the cells of the Inquisition, which are located just inside of some buildings of the monumental building. The project, as a whole, is faced, in a total view, between the various competences implicated: historic, chemic, architectonic, topographic, drawing, representation, virtual communication, informatics. The birth of the museum will be a sum of the results of all these disciplines involved. Methodology, implementation, fruition, virtual museum, goals, 2D graphic restitution, effects on the cultural heritage and landscape environmental, augmented reality, Surveying 2D and 3D, hi-touch screen, Photogrammetric survey, Photographic survey, representation, drawing 3D and more than this has been dealt with this research.

  18. Wireless Augmented Reality Prototype (WARP)

    NASA Technical Reports Server (NTRS)

    Devereaux, A. S.

    1999-01-01

    Initiated in January, 1997, under NASA's Office of Life and Microgravity Sciences and Applications, the Wireless Augmented Reality Prototype (WARP) is a means to leverage recent advances in communications, displays, imaging sensors, biosensors, voice recognition and microelectronics to develop a hands-free, tetherless system capable of real-time personal display and control of computer system resources. Using WARP, an astronaut may efficiently operate and monitor any computer-controllable activity inside or outside the vehicle or station. The WARP concept is a lightweight, unobtrusive heads-up display with a wireless wearable control unit. Connectivity to the external system is achieved through a high-rate radio link from the WARP personal unit to a base station unit installed into any system PC. The radio link has been specially engineered to operate within the high- interference, high-multipath environment of a space shuttle or space station module. Through this virtual terminal, the astronaut will be able to view and manipulate imagery, text or video, using voice commands to control the terminal operations. WARP's hands-free access to computer-based instruction texts, diagrams and checklists replaces juggling manuals and clipboards, and tetherless computer system access allows free motion throughout a cabin while monitoring and operating equipment.

  19. Augmented reality in surgical procedures

    NASA Astrophysics Data System (ADS)

    Samset, E.; Schmalstieg, D.; Vander Sloten, J.; Freudenthal, A.; Declerck, J.; Casciaro, S.; Rideng, Ø.; Gersak, B.

    2008-02-01

    Minimally invasive therapy (MIT) is one of the most important trends in modern medicine. It includes a wide range of therapies in videoscopic surgery and interventional radiology and is performed through small incisions. It reduces hospital stay-time by allowing faster recovery and offers substantially improved cost-effectiveness for the hospital and the society. However, the introduction of MIT has also led to new problems. The manipulation of structures within the body through small incisions reduces dexterity and tactile feedback. It requires a different approach than conventional surgical procedures, since eye-hand co-ordination is not based on direct vision, but more predominantly on image guidance via endoscopes or radiological imaging modalities. ARIS*ER is a multidisciplinary consortium developing a new generation of decision support tools for MIT by augmenting visual and sensorial feedback. We will present tools based on novel concepts in visualization, robotics and haptics providing tailored solutions for a range of clinical applications. Examples from radio-frequency ablation of liver-tumors, laparoscopic liver surgery and minimally invasive cardiac surgery will be presented. Demonstrators were developed with the aim to provide a seamless workflow for the clinical user conducting image-guided therapy.

  20. Augmented reality for wafer prober

    NASA Astrophysics Data System (ADS)

    Gilgenkrantz, Pascal

    2011-03-01

    The link between wafer manufacturing and wafer test is often weak: without common information system, Test engineers have to read locations of test structures from reference documents and search them on the wafer prober screen. Mask Data Preparation team is ideally placed to fill this gap, given its relationship with both design and manufacturing sides. With appropriate design extraction scripts and design conventions, mask engineers can provide exact wafer locations of all embedded test structures to avoid a painful camera search. Going a step further, it would be a great help to provide to wafer probers a "map" of what was build on wafers. With this idea in mind, mask design database can simply be provided to Test engineers; but the real added value would come from a true integration of real-wafer camera views and design database used for wafer manufacturing. As proven by several augmented reality applications, like Google Maps' mixed Satellite/Map view, mixing a real-world view with its theoretical model is very useful to understand the reality. The creation of such interface can only be made by a wafer prober manufacturer, given the high integration of these machines with their control panel. But many existing software libraries could be used to plot the design view matching the camera view. Standard formats for mask design are usually GDSII and OASIS (SEMI P39 standard); multiple free software and commercial viewers/editors/libraries for these formats are available.

  1. Hypoxia and hypoxia mimetics decrease aquaporin 5 (AQP5) expression through both hypoxia inducible factor-1α and proteasome-mediated pathways.

    PubMed

    Kawedia, Jitesh D; Yang, Fan; Sartor, Maureen A; Gozal, David; Czyzyk-Krzeska, Maria; 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 AQP5 mRNA and protein expression in the mouse lung epithelial cell line MLE-12. The action of hypoxia and cobalt on AQP5 transcription was demonstrated by directly quantifying heternonuclear RNA by real-time PCR. Dominant negative mutants of Hypoxia Inducible Factor (HIF-1α) and HIF-1α siRNA blocked the action of cobalt, showing that HIF-1α is a key component in this mechanism. The proteasome inhibitors, lactacystin or proteasome inhibitor-III completely abolished the effect of hypoxia and cobalt both at the protein and mRNA level indicating that the proteasome pathway is probably involved not only for the stability of HIF-1α protein, but for the stability of unidentified transcription factors that regulate AQP5 transcription. These studies reveal a potentially important physiological mechanism linking hypoxic stress and membrane water channels. PMID:23469202

  2. Psychomotor skills learning under chronic hypoxia.

    PubMed

    Bouquet, C A; Gardette, B; Gortan, C; Abraini, J H

    1999-09-29

    Psychomotor deficits are a prominent feature in subjects exposed to hypoxia. Eight subjects exposed to chronic hypoxia during a simulated climb to 8848 m (Everest-Comex 97) were investigated using both a simple psychomotor task (Purdue pegboard) and two complex psychomotor tasks including a recognition task of either a color stimulus (high semantic level) or an abstract sign (low semantic level). Exposure to hypoxic stress mainly produced psychomotor skills learning deficits compared to control study, with greater deficits in the complex psychomotor task. The pattern of results suggests disruptions of motor strategic process. Our data further suggest that the relative strength of implicit or automatic memory processes associated with semantic information processing may increase when disturbances occur in brain functions. PMID:10549829

  3. Regulation of cell proliferation by hypoxia-inducible factors.

    PubMed

    Hubbi, Maimon E; Semenza, Gregg L

    2015-12-15

    Hypoxia is a physiological cue that impacts diverse physiological processes, including energy metabolism, autophagy, cell motility, angiogenesis, and erythropoiesis. One of the key cell-autonomous effects of hypoxia is as a modulator of cell proliferation. For most cell types, hypoxia induces decreased cell proliferation, since an increased number of cells, with a consequent increase in O2 demand, would only exacerbate hypoxic stress. However, certain cell populations maintain cell proliferation in the face of hypoxia. This is a common pathological hallmark of cancers, but can also serve a physiological function, as in the maintenance of stem cell populations that reside in a hypoxic niche. This review will discuss major molecular mechanisms by which hypoxia regulates cell proliferation in different cell populations, with a particular focus on the role of hypoxia-inducible factors. PMID:26491052

  4. Hypoxia Responsive Drug Delivery Systems in Tumor Therapy.

    PubMed

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

    2016-01-01

    Hypoxia is a common characteristic of solid tumors. It is mainly determined by low levels of oxygen resulting from imperfect vascular networks supplying most tumors. In an attempt to improve the present chemotherapeutic treatment and reduce associated side effects, several prodrug strategies have been introduced to achieve hypoxia-specific delivery of cytotoxic anticancer agents. With the advances in nanotechnology, novel delivery systems activated by the consequent outcomes of hypoxia have been developed. However, developing hypoxia responsive drug delivery systems (which only depend on low oxygen levels) is currently naïve. This review discusses four main hypoxia responsive delivery systems: polymeric based drug delivery systems, oxygen delivery systems combined with radiotherapy and chemotherapy, anaerobic bacteria which are used for delivery of genes to express anticancer proteins such as tumor necrosis alpha (TNF-α) and hypoxia-inducible transcription factors 1 alpha (HIF1α) responsive gene delivery systems. PMID:26898739

  5. Sustained hypoxia modulates mitochondrial DNA content in the neonatal rat brain.

    PubMed

    Lee, Heung M; Greeley, George H; Englander, Ella W

    2008-03-01

    The effects of placental insufficiency and preterm birth on neurodevelopment can be modeled in experimental settings of neonatal hypoxia in rodents. Here, rat pups were reared in reduced oxygen (9.5%) for 11 days, starting on postnatal day 3 (P3). This led to a significant reduction in brain and body weight gain in hypoxic pups compared to age-matched normoxia-reared controls, plausibly reflecting an inability to fulfill the energetic needs of normal growth and development. Adaptive processes designed to augment energetic capacity in eukaryotes include stimulation of mitochondrial biogenesis. We show that after 11 days of sustained hypoxia, the levels of nuclear respiratory factor-1 and mitochondrial transcription factor A are elevated and the content of mitochondrial DNA (mtDNA) is greater in the hypoxic P14 pup brain compared to normoxic conditions. Corresponding immunohistochemical analyses reveal increased density of mtDNA in large cortical neurons. In contrast, no changes in mtDNA content are observed in the brain of pups reared for 24 h (P3-P4) under hypoxic conditions. Together, these data suggest that prolonged inadequate oxygenation may trigger a compensatory increase in neuronal mitochondrial DNA content to partially mitigate compromised energy homeostasis and reduced energetic capacity in the developing hypoxic brain. PMID:18078825

  6. [Complications of breast augmentation - a case report].

    PubMed

    Zedníková, I; Třešková, I; Schmiedhuber, P; Hes, O

    2012-08-01

    As with any surgery, breast augmentation does have certain risks and complications. The aim of this article is to point out a rare complication of breast augmentation - axillary silicone lymphadenopathy (defined as the presence of silicone in the lymph nodes). The authors present a case report of silicone lymphadenopathy in a young woman after the rupture of a silicone breast implant. As the number of women with breast implants is increasing, it is necessary to bear this rare complication of breast augmentation in mind in differential diagnosis of axillary lymphadenopathy. PMID:23153428

  7. Augmented railgun using a permanent magnet

    SciTech Connect

    Katsuki, S.; Akiyama, H.; Eguchi, N.; Sueda, T.; Soejima, M.; Maeda, S.; Sato, K.N.

    1995-08-01

    The use of a permanent magnet instead of an electromagnet has been proposed for the augmentation of the magnetic field of a railgun driven by a current of approximately 20 kA. A permanent magnet has the following advantages in comparison with conventional augmentations using additional turns: (1) simple configuration of the system, (2) temporally and spatially constant magnetic fields, and (3) high efficiency. Here, the operation of a conventional railgun and that of an augmented railgun using a permanent magnet are compared experimentally, and the usefulness of the permanent magnet is described. {copyright} {ital 1995} {ital American} {ital Institute} {ital of} {ital Physics}.

  8. Pathophysiology and clinical effects of chronic hypoxia.

    PubMed

    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

  9. Hypoxia and Dysregulated Angiogenesis in Kidney Disease

    PubMed Central

    Tanaka, Shinji; Tanaka, Tetsuhiro; Nangaku, Masaomi

    2015-01-01

    Background Accumulating evidence has demonstrated that renal hypoxia has a crucial role in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and AKI-to-CKD transition, ultimately culminating in end-stage kidney disease. Renal hypoxia in progressive CKD is intricately linked to persisting capillary loss, which is mainly due to dysregulated angiogenesis. Summary In CKD, hypoxia-inducible factor (HIF) accumulates in the ischemic tubulointerstitium but fails to sufficiently stimulate angiogenic responses, partly because of blunted activation of HIF, which is best exemplified in diabetic kidney disease. In addition, vascular endothelial growth factor (VEGF) expression is downregulated, possibly because injured tubules are not able to express sufficient VEGF and inflammatory circumstances inhibit VEGF expression. The upregulation of antiangiogenic factors and the incompetence of endothelial progenitor cells (EPCs) may also play some roles in the inadequacy of capillary restoration. Administration of VEGF or angiopoietin-1 maintains peritubular capillaries in several kidney diseases; however, administration of a single angiogenic factor may lead to the formation of abnormal vessels and induce inflammation, resulting in worsening of hypoxia and tubulointerstitial fibrosis. HIF stabilization, which aims to achieve the formation of mature and stable vessels by inducing coordinated angiogenesis, is a promising strategy. Given that the effect of systemic HIF activation is highly context-dependent, further studies are needed to elucidate the precise roles of HIF in various kidney diseases. The adoptive transfer of EPCs or mesenchymal stem cells (MSCs) is a fascinating alternative strategy to restore the peritubular capillaries. Key Message Suppressed HIF activation and VEGF expression may be responsible for the dysregulated angiogenesis in progressive CKD. Administration of a single angiogenic factor can cause abnormal vessel formation and

  10. NASA Gulf of Mexico Initiative Hypoxia Research

    NASA Technical Reports Server (NTRS)

    Armstrong, Curtis D.

    2012-01-01

    The Applied Science & Technology Project Office at Stennis Space Center (SSC) manages NASA's Gulf of Mexico Initiative (GOMI). Addressing short-term crises and long-term issues, GOMI participants seek to understand the environment using remote sensing, in-situ observations, laboratory analyses, field observations and computational models. New capabilities are transferred to end-users to help them make informed decisions. Some GOMI activities of interest to the hypoxia research community are highlighted.

  11. Humans In Hypoxia: A Conspiracy Of Maladaptation?!

    PubMed

    Dempsey, Jerome A; Morgan, Barbara J

    2015-07-01

    We address adaptive vs. maladaptive responses to hypoxemia in healthy humans and hypoxic-tolerant species during wakefulness, sleep, and exercise. Types of hypoxemia discussed include short-term and life-long residence at high altitudes, the intermittent hypoxemia attending sleep apnea, or training regimens prescribed for endurance athletes. We propose that hypoxia presents an insult to O2 transport, which is poorly tolerated in most humans because of the physiological cost. PMID:26136544

  12. Humans In Hypoxia: A Conspiracy Of Maladaptation?!

    PubMed Central

    Morgan, Barbara J.

    2015-01-01

    We address adaptive vs. maladaptive responses to hypoxemia in healthy humans and hypoxic-tolerant species during wakefulness, sleep, and exercise. Types of hypoxemia discussed include short-term and life-long residence at high altitudes, the intermittent hypoxemia attending sleep apnea, or training regimens prescribed for endurance athletes. We propose that hypoxia presents an insult to O2 transport, which is poorly tolerated in most humans because of the physiological cost. PMID:26136544

  13. Effects of hypoxia on sympathetic neural control in humans

    NASA Technical Reports Server (NTRS)

    Smith, M. L.; Muenter, N. K.

    2000-01-01

    This special issue is principally focused on the time domain of the adaptive mechanisms of ventilatory responses to short-term, long-term and intermittent hypoxia. The purpose of this review is to summarize the limited literature on the sympathetic neural responses to sustained or intermittent hypoxia in humans and attempt to discern the time domain of these responses and potential adaptive processes that are evoked during short and long-term exposures to hypoxia.

  14. Optical imaging of tumor hypoxia dynamics

    NASA Astrophysics Data System (ADS)

    Palmer, Gregory M.; Fontanella, Andrew N.; Zhang, Guoqing; Hanna, Gabi; Fraser, Cassandra L.; Dewhirst, Mark W.

    2010-11-01

    The influence of the tumor microenvironment and hypoxia plays a significant role in determining cancer progression, treatment response, and treatment resistance. That the tumor microenvironment is highly heterogeneous with significant intratumor and intertumor variability presents a significant challenge in developing effective cancer therapies. Critical to understanding the role of the tumor microenvironment is the ability to dynamically quantify oxygen levels in the vasculature and tissue in order to elucidate the roles of oxygen supply and consumption, spatially and temporally. To this end, we describe the use of hyperspectral imaging to characterize hemoglobin absorption to quantify hemoglobin content and oxygen saturation, as well as dual emissive fluorescent/phosphorescent boron nanoparticles, which serve as ratiometric indicators of tissue oxygen tension. Applying these techniques to a window-chamber tumor model illustrates the role of fluctuations in hemoglobin saturation in driving changes in tissue oxygenation, the two being significantly correlated (r = 0.77). Finally, a green-fluorescence-protein reporter for hypoxia inducible factor-1 (HIF-1) provides an endpoint for hypoxic stress in the tumor, which is used to demonstrate a significant association between tumor hypoxia dynamics and HIF-1 activity in an in vivo demonstration of the technique.

  15. Nutrient Enrichment Drives Gulf of Mexico Hypoxia

    NASA Astrophysics Data System (ADS)

    Boesch, Donald F.; Boynton, Walter R.; Crowder, Larry B.; Diaz, Robert J.; Howarth, Robert W.; Mee, Laurence D.; Nixon, Scott W.; Rabalais, Nancy N.; Rosenberg, Rutger; Sanders, James G.; Scavia, Donald; Turner, R. Eugene

    2009-04-01

    During most summers over the past 30 years, bottom dissolved oxygen across a large area of the Louisiana and upper Texas continental shelf declined to concentrations too low (hypoxia) for most fish and large invertebrate animals to survive. This area is one of the best known “dead zones” proliferating around the world [Diaz and Rosenberg, 2008]. During July 2008, hypoxic bottom waters extended across 20,720 square kilometers (Figure 1), but they were probably even more extensive because winds from Hurricane Dolly mixed the waters off Texas before the survey could be completed. Increased inputs of nutrients (principally nitrogen and phosphorus) from the U.S. agricultural heartland within the Mississippi-Atchafalaya River Basin (MARB) are implicated in the development and spread of hypoxia in the Gulf of Mexico. Consequently, the causes of, and solutions for, hypoxia have been subjects of extensive debate and analysis. An integrated scientific assessment led to a 2001 Action Plan [Mississippi River/Gulf of Mexico Watershed Nutrient Task Force, 2001] with a goal of reducing the area of the hypoxic zone to less than 5000 square kilometers by reducing nitrogen loading [Rabalais et al., 2007].

  16. Hypoxia in the changing marine environment

    NASA Astrophysics Data System (ADS)

    Zhang, J.; Cowie, G.; Naqvi, S. W. A.

    2013-03-01

    The predicted future of the global marine environment, as a combined result of forcing due to climate change (e.g. warming and acidification) and other anthropogenic perturbation (e.g. eutrophication), presents a challenge to the sustainability of ecosystems from tropics to high latitudes. Among the various associated phenomena of ecosystem deterioration, hypoxia can cause serious problems in coastal areas as well as oxygen minimum zones in the open ocean (Diaz and Rosenberg 2008 Science 321 926-9, Stramma et al 2008 Science 320 655-8). The negative impacts of hypoxia include changes in populations of marine organisms, such as large-scale mortality and behavioral responses, as well as variations of species distributions, biodiversity, physiological stress, and other sub-lethal effects (e.g. growth and reproduction). Social and economic activities that are related to services provided by the marine ecosystems, such as tourism and fisheries, can be negatively affected by the aesthetic outcomes as well as perceived or real impacts on seafood quality (STAP 2011 (Washington, DC: Global Environment Facility) p 88). Moreover, low oxygen concentration in marine waters can have considerable feedbacks to other compartments of the Earth system, like the emission of greenhouse gases to the atmosphere, and can affect the global biogeochemical cycles of nutrients and trace elements. It is of critical importance to prediction and adaptation strategies that the key processes of hypoxia in marine environments be precisely determined and understood (cf Zhang et al 2010 Biogeosciences 7 1-24).

  17. Multiple sphingolipid abnormalities following cerebral microendothelial hypoxia

    PubMed Central

    Testai, Fernando D.; Kilkus, John P.; Berdyshev, Evgeny; Gorshkova, Irina; Natarajan, Viswanathan; Dawson, Glyn

    2015-01-01

    Hypoxia has been previously shown to inhibit the dihydroceramide (DHC) desaturase, leading to the accumulation of DHC. In this study, we used metabolic labeling with [3H]-palmitate, HPLC/MS/MS analysis, and specific inhibitors to show numerous sphingolipid changes after oxygen deprivation in cerebral microendothelial cells. The increased DHC, particularly long-chain forms, was observed in both whole cells and detergent-resistant membranes. This was reversed by reoxygenation and blocked by the de novo sphingolipid synthesis inhibitor myriocin, but not by the neutral sphingomyelinase inhibitor GW-4869. Furthermore, oxygen deprivation of microendothelial cells increased levels of dihydro-sphingosine (DH-Sph), DH-sphingosine1-phosphate (DH-S1P), DH-sphingomyelin (DH-SM), DH-glucosylceramide (DH-GlcCer), and S1P levels. In vitro assays revealed no changes in the activity of sphingomyelinases or sphingomyelin synthase, but resulted in reduced S1P lyase activity and 40% increase in glucosylceramide synthase (GCS) activity, which was reversed by reoxygenation. Inhibition of the de novo sphingolipid pathway (myriocin) or GCS (EtPoD4) induced endothelial barrier dysfunction and increased caspase 3-mediated cell death in response to hypoxia. Our findings suggest that hypoxia induces synthesis of S1P and multiple dihydrosphingolipids, including DHC, DH-SM, DH-GlcCer, DH-Sph and DH-S1P, which may be involved in ameliorating the effects of stroke. PMID:25060904

  18. Hypoxia, therapeutic resistance, and sphingosine 1-phosphate.

    PubMed

    Cuvillier, Olivier; Ader, Isabelle; Bouquerel, Pierre; Brizuela, Leyre; Gstalder, Cécile; Malavaud, Bernard

    2013-01-01

    Hypoxia, defined as a poor oxygenation, has been long recognized as a hallmark of solid tumors and a negative prognostic factor for response to therapeutics and survival of patients. Cancer cells have evolved biochemical mechanisms that allow them to react and adapt to hypoxia. At the cellular level, this adaptation is under the control of two related transcription factors, HIF-1 and HIF-2 (hypoxia-inducible factor), that respond rapidly to decreased oxygen levels to activate the expression of a broad range of genes promoting neoangiogenesis, glycolysis, metastasis, increased tumor growth, and resistance to treatments. Recent studies have identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway-which elicits various cellular processes including cell proliferation, cell survival, or angiogenesis-as a new regulator of HIF-1 or HIF-2 activity. In this review, we will focus on how the inhibition/neutralization of the SphK1/S1P signaling could be exploited for cancer therapy. PMID:23290779

  19. ATM activation in hypoxia - causes and consequences

    PubMed Central

    Olcina, Monica M; Grand, Roger JA; Hammond, Ester M

    2014-01-01

    The DNA damage response is a complex signaling cascade that is triggered by cellular stress. This response is essential for the maintenance of genomic integrity and is considered to act as a barrier to the early stages of tumorigenesis. The integral role of ataxia telangiectasia mutated (ATM) kinase in the response to DNA damaging agents is well characterized; however, ATM can also be activated by non-DNA damaging agents. In fact, much has been learnt recently about the mechanism of ATM activation in response to physiologic stresses such as hypoxia that do not induce DNA damage. Regions of low oxygen concentrations that occur in solid tumors are associated with a poor prognostic outcome irrespective of treatment modality. Severe levels of hypoxia induce replication stress and trigger the activation of DNA damage response pathways including ataxia telangiectasia and Rad3-related (ATR)- and ATM-mediated signaling. In this review, we discuss hypoxia-driven ATM signaling and the possible contribution of ATM activation in this context to tumorigenesis. PMID:27308313

  20. The role of hypoxia in intestinal inflammation.

    PubMed

    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

  1. Imaging hypoxia using 3D photoacoustic spectroscopy

    NASA Astrophysics Data System (ADS)

    Stantz, Keith M.

    2010-02-01

    Purpose: The objective is to develop a multivariate in vivo hemodynamic model of tissue oxygenation (MiHMO2) based on 3D photoacoustic spectroscopy. Introduction: Low oxygen levels, or hypoxia, deprives cancer cells of oxygen and confers resistance to irradiation, some chemotherapeutic drugs, and oxygen-dependent therapies (phototherapy) leading to treatment failure and poor disease-free and overall survival. For example, clinical studies of patients with breast carcinomas, cervical cancer, and head and neck carcinomas (HNC) are more likely to suffer local reoccurrence and metastasis if their tumors are hypoxic. A novel method to non invasively measure tumor hypoxia, identify its type, and monitor its heterogeneity is devised by measuring tumor hemodynamics, MiHMO2. Material and Methods: Simulations are performed to compare tumor pO2 levels and hypoxia based on physiology - perfusion, fractional plasma volume, fractional cellular volume - and its hemoglobin status - oxygen saturation and hemoglobin concentration - based on in vivo measurements of breast, prostate, and ovarian tumors. Simulations of MiHMO2 are performed to assess the influence of scanner resolutions and different mathematic models of oxygen delivery. Results: Sensitivity of pO2 and hypoxic fraction to photoacoustic scanner resolution and dependencies on model complexity will be presented using hemodynamic parameters for different tumors. Conclusions: Photoacoustic CT spectroscopy provides a unique ability to monitor hemodynamic and cellular physiology in tissue, which can be used to longitudinally monitor tumor oxygenation and its response to anti-angiogenic therapies.

  2. Regulation of gene expression by hypoxia.

    PubMed

    Millhorn, D E; Czyzyk-Krzeska, M; Bayliss, D A; Lawson, E E

    1993-12-01

    The present study was undertaken to determine if gene expression for tyrosine hydroxylase (TH), the rate limiting enzyme in the biosynthesis of catecholamines, is regulated in the carotid body, sympathetic ganglia and adrenal medulla by hypoxia. We found that a reduction in oxygen tension from 21% to 10% caused a substantial increase (200% at 1 hour and 500% at 6 hours exposure) in the concentration of TH mRNA in carotid body type I cells but not in either the sympathetic ganglia or adrenal gland. In addition, we found that hypercapnia, another natural stimulus of carotid body activity, failed to enhance TH mRNA in type I cells. Removal of the sensory and sympathetic innervation of the carotid body failed to prevent the induction of TH mRNA by hypoxia in type I cells. Our results show that TH gene expression is regulated by hypoxia in the carotid body but not in other peripheral catecholamine synthesizing tissue and that the regulatory mechanism is intrinsic to type I cells. PMID:7909954

  3. Structural integration in hypoxia-inducible factors

    SciTech Connect

    Wu, Dalei; Potluri, Nalini; Lu, Jingping; Kim, Youngchang; Rastinejad, Fraydoon

    2015-08-20

    The hypoxia-inducible factors (HIFs) coordinate cellular adaptations to low oxygen stress by regulating transcriptional programs in erythropoiesis, angiogenesis and metabolism. These programs promote the growth and progression of many tumours, making HIFs attractive anticancer targets. Transcriptionally active HIFs consist of HIF-alpha and ARNT (also called HIF-1 beta) subunits. Here we describe crystal structures for each of mouse HIF-2 alpha-ARNT and HIF-1 alpha-ARNT heterodimers in states that include bound small molecules and their hypoxia response element. A highly integrated quaternary architecture is shared by HIF-2 alpha-ARNT and HIF-1 alpha-ARNT, wherein ARNT spirals around the outside of each HIF-alpha subunit. Five distinct pockets are observed that permit small-molecule binding, including PAS domain encapsulated sites and an interfacial cavity formed through subunit heterodimerization. The DNA-reading head rotates, extends and cooperates with a distal PAS domain to bind hypoxia response elements. HIF-alpha mutations linked to human cancers map to sensitive sites that establish DNA binding and the stability of PAS domains and pockets.

  4. Hypoxia inhibits abdominal expiratory nerve activity.

    PubMed

    Fregosi, R F; Knuth, S L; Ward, D K; Bartlett, D

    1987-07-01

    Our purpose was to examine the influence of steady-state changes in chemical stimuli, as well as discrete peripheral chemoreceptor stimulation, on abdominal expiratory motor activity. In decerebrate, paralyzed, vagotomized, and ventilated cats that had bilateral pneumothoraces, we recorded efferent activity from a phrenic nerve and from an abdominal nerve (cranial iliohypogastric nerve, L1). All cats showed phasic expiratory abdominal nerve discharge at normocapnia [end-tidal PCO2 38 +/- 2 Torr], but small doses (2-6 mg/kg) of pentobarbital sodium markedly depressed this activity. Hyperoxic hypercapnia consistently enhanced abdominal expiratory activity and shortened the burst duration. Isocapnic hypoxia caused inhibition of abdominal nerve discharge in 11 of 13 cats. Carotid sinus nerve denervation (3 cats) exacerbated the hypoxic depression of abdominal nerve activity and depressed phrenic motor output. Stimulation of peripheral chemoreceptors with NaCN increased abdominal nerve discharge in 7 of 10 cats, although 2 cats exhibited marked inhibition. Four cats with intact neuraxis, but anesthetized with ketamine, yielded qualitatively similar results. We conclude that when cats are subjected to steady-state chemical stimuli in isolation (no interference from proprioceptive inputs), hypercapnia potentiates, but hypoxia attenuates, abdominal expiratory nerve activity. Mechanisms to explain the selective inhibition of expiratory motor activity by hypoxia are proposed, and physiological implications are discussed. PMID:3624126

  5. Chronic hypoxia alters mitochondrial composition in human macrophages.

    PubMed

    Fuhrmann, Dominik Christian; Wittig, Ilka; Heide, Heinrich; Dehne, Nathalie; Brüne, Bernhard

    2013-12-01

    Hypoxia inducible factors (HIFs) are important mediators of the cellular adaptive response during acute hypoxia. The role of HIF-1 and HIF-2 during prolonged periods of hypoxia, i.e. chronic hypoxia is less defined. Therefore, we used human THP-1 macrophages with a knockdown of either HIF-1α, HIF-2α, or both HIFα-subunits, incubated them for several days under hypoxia (1% O2), and analyzed responses to hypoxia using 2D-DIGE coupled to MS/MS-analysis. Chronic hypoxia was defined as a time point when the early but transient accumulation of HIFα-subunits and mRNA expression of classical HIF target genes returned towards basal levels, with a new steady state that was constant from 72h onwards. From roughly 800 spots, that were regulated comparing normoxia to chronic hypoxia, about 100 proteins were unambiguously assigned during MS/MS-analysis. Interestingly, a number of glycolytic proteins were up-regulated, while a number of inner mitochondrial membrane proteins were down-regulated independently of HIF-1α or HIF-2α. Chronic hypoxic conditions depleted the mitochondrial mass by autophagy, which occurred independently of HIF proteins. Macrophages tolerate periods of chronic hypoxia very well and adaptive responses occur, at least in part, independently of HIF-1α and/or HIF-2α and comprise mitophagy as a pathway of particular importance. PMID:24140568

  6. Diastolic dysfunction precedes hypoxia-induced mortality in dystrophic mice

    PubMed Central

    Townsend, DeWayne

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a progressive striated muscle disease that is characterized by skeletal muscle weakness with progressive respiratory and cardiac failure. Together respiratory and cardiac disease account for the majority of mortality in the DMD patient population. However, little is known regarding the effects of respiratory dysfunction on the dystrophic heart. The studies described here examine the effects of acute hypoxia on cardiac function. These studies demonstrate, for the first time, that a mouse model of DMD displays significant mortality following acute exposure to hypoxia. This mortality is characterized by a steady decline in systolic function. Retrospective analysis reveals that significant decreases in diastolic dysfunction, especially in the right ventricle, precede the decline in systolic pressure. The initial hemodynamic response to acute hypoxia in the mouse is similar to that observed in larger species, with significant increases in right ventricular afterload and decreases in left ventricular preload being observed. Significant increases in heart rate and contractility suggest hypoxia-induced activation of the sympathetic nervous system. These studies provide evidence that while hypoxia presents significant hemodynamic challenges to the dystrophic right ventricle, global cardiac dysfunction precedes hypoxia-induced mortality in the dystrophic heart. These findings are clinically relevant as the respiratory insufficiency evident in patients with DMD results in significant bouts of hypoxia. The results of these studies indicate that hypoxia may contribute to the acceleration of the heart disease in DMD patients. Importantly, hypoxia can be avoided through the use of ventilatory support. PMID:26311833

  7. Prolonged lobar hypoxia in vivo enhances the responsivity of isolated pulmonary veins to hypoxia

    NASA Technical Reports Server (NTRS)

    Sheehan, D. W.; Farhi, L. E.; Russell, J. A.

    1992-01-01

    The hypoxic response of pulmonary vessels isolated from eight sheep whose right apical lobes (RAL) had inspired 100% N2 for 20 h was studied. The RAL of these conscious sheep inspired hypoxic gas and the remainder of the lung inspired air. During hypoxia, RAL perfusion was 33 +/- 3% of its air value, carotid arterial PO2 averaged 86 +/- 3 mm Hg and pulmonary perfusion pressure was not significantly different from the initial control period when the RAL inspired air. At the end of the hypoxic exposure, the sheep were killed, and pulmonary artery and vein rings (0.5 to 2 mm inner diameter) were isolated from both the RAL and the right cardiac lobe, which served as the control lobe (CL). Arteries from the RAL and CL did not contract in response to 6% O2/6% CO2/88% N2 (hypoxia). In contrast, RAL veins did contract vigorously in response to hypoxia, whereas CL veins did not contract or contracted only minimally. Rubbing of the endothelium or prior incubation of RAL veins with catalase (1,200 units/ml), indomethacin (10(-5) M), or the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist, SQ 29,548 (3 X 10(-6) M) each significantly reduced the response to hypoxia. RAL veins were also found to be more reactive than CL veins to the prostaglandin endoperoxide analogue U46619. We conclude that prolonged lobar hypoxia in vivo increases the responsivity of isolated pulmonary veins to hypoxia. These contractions may result from an increase in reactive O2 species, which in turn modify production of, metabolism of, and/or tissue responsivity to TxA2/PGH2.

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

    PubMed

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

    2015-05-01

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

  9. Repeated acute hypoxia temporarily attenuates the ventilatory respiratory response to hypoxia in conscious newborn rats.

    PubMed

    Matsuoka, T; Yoda, T; Ushikubo, S; Matsuzawa, S; Sasano, T; Komiyama, A

    1999-07-01

    We asked whether repeated hypoxic exposures during the early neonatal periods could affect the ventilatory control, such as the lung volume-dependent ventilatory inhibition (HBR), pulmonary ventilation (VE), and CO2 production (VCO2). Within each litter of rats, one group of pups (experimental group H) was exposed to 6% O2 (30-min duration twice a day from postnatal d 1 to 4). The other group (control group C) was exposed to air. At 5 d after birth, the HBR was triggered by lung inflation via negative body surface pressure (10 cm H2O). Measurements of VE and VCO2 were done by plethysmography and the inflow-outflow CO2 difference, respectively. At 2 wk of age, VE and VCO2 measurements were repeated by the barometric technique and the inflow-outflow CO2 difference, respectively. Each conscious pup was breathing normoxia (21% O2) and then hypoxia (10% O2). Results were as follows: 1) during normoxia, HBR was stronger and both VE and VCO2 were higher in H pups than in C pups; 2) during hypoxia, the HBR of C was as in normoxia, whereas that of H was increased above the normoxic value; 3) during hypoxia, C maintained VE, whereas H decreased it; 4) in hypoxia, VCO2 was reduced significantly in both groups; 5) at 2 wk of age, VE and VCO2 did not differ between H and C during normoxia or in response to 10% hypoxia. We conclude that in rat pups, repeated hypoxic episodes can modify the HBR and, at least temporarily, reduce the VE response to hypoxia with a decrease in VCO2. The findings are in agreement with the view that repeated hypoxic exposures in the neonatal period could interfere with the development of respiratory control and could possibly be involved in the mechanisms of neonatal apnea or sudden infant death syndrome. PMID:10400145

  10. Improved diffuser for augmenting a wind turbine

    DOEpatents

    Foreman, K.M.; Gilbert, B.L.

    A diffuser for augmenting a wind turbine having means for energizing the boundary layer at several locations along the diffuser walls is improved by the addition of a short collar extending radially outward from the outlet of the diffuser.

  11. Augmented Reality Simulations on Handheld Computers

    ERIC Educational Resources Information Center

    Squire, Kurt; Klopfer, Eric

    2007-01-01

    Advancements in handheld computing, particularly its portability, social interactivity, context sensitivity, connectivity, and individuality, open new opportunities for immersive learning environments. This article articulates the pedagogical potential of augmented reality simulations in environmental engineering education by immersing students in…

  12. Muzzle shunt augmentation of conventional railguns

    SciTech Connect

    Parker, J.V. . Physics Div.)

    1991-01-01

    This paper reports on augmentation which is a technique for reducing the armature current and hence the armature power dissipation in a plasma armature railgun. In spite of the advantages, no large augmented railguns have been built, primarily due to the mechanical and electrical complexity introduced by the extra conductors required. it is possible to achieve some of the benefits of augmentation in a conventional railgun by diverting a fraction {phi} of the input current through a shunt path at the muzzle of the railgun. In particular, the relation between force and armature current is the same as that obtained in an n-turn, series-connected augmented railgun with n = 1/(1 {minus} {phi}). The price of this simplification is a reduction in electrical efficiency and some additional complexity in the external electrical system.

  13. A parametric evaluation of railgun augmentation

    NASA Astrophysics Data System (ADS)

    Kotas, J. F.; Guderjahn, C. A.; Littman, F. D.

    1986-11-01

    A general dynamic system model of an augmented electromagnetic launch (EML) system was developed. This model was used to characterize the augmentation effect on EML system performance by a direct comparison to a nonaugmented or simple railgun system. The results of these calculations indicate that increasing rail augmentation increases both Joule heating losses and total EML system inductance. These losses and the larger system inductance were shown to decrease system efficiency despite the lower peak rail current required to induce the same Lorentz force on the projectile in the simple EML system. The Joule heating loss was shown to be reduced by decreasing the initial augmentor rail temperature or by increasing the augmentor rail area. This paper discusses the augmented EML system model and reports the results of the parametric calculations.

  14. The ELF-I augmented electromagnetic launcher

    NASA Astrophysics Data System (ADS)

    Fikse, D. A.; Wu, J. L.; Thio, Y. C.

    1984-03-01

    Augmenting an electromagnetic launcher barrel with one or more turns can theoretically increase the launcher system performance more than twice that of a simple EML. This is accomplished by increasing the amount of magnetic flux in the bore and thus increasing the electromagnetic accelerating force. The potential for augmented barrels had yet to be evaluated, therefore a one meter long test barrel was designed and constructed. This barrel was tested in the ELF-I electromagnetic test facility and the results compared with the theoretically predicted performance of a simple barrel design. This comparison shows an increase in muzzle velocity of 83 percent for the augmented case over the simple launcher case. It was also found that the augmented barrel could be fabricated in a simple manner within the physical limitations of a conventional barrel size, and that its solid armatures provided an excellent method of achieving longer rail life, averaging 20 shots per rail set.

  15. Diffuser for augmenting a wind turbine

    DOEpatents

    Foreman, Kenneth M.; Gilbert, Barry L.

    1984-01-01

    A diffuser for augmenting a wind turbine having means for energizing the boundary layer at several locations along the diffuser walls is improved by the addition of a short collar extending radially outward from the outlet of the diffuser.

  16. Breast augmentation with an unknown substance

    PubMed Central

    Ebrahim, Lamya; Morrison, David; Kop, Alan; Taylor, Donna

    2014-01-01

    Before the widespread use of silicone implants various foreign substances were injected directly into the breasts. The nature of these materials sometimes remains unknown and can cause various complications requiring surgical intervention. Preoperative diagnostic imaging can help characterise the type and distribution of the injected material, thereby assisting in making decisions regarding treatment. We report a case of breast augmentation with an unknown substance, aiming to highlight some imaging characteristics of different breast augmentation substances. PMID:24957586

  17. Regulation of glycolytic enzyme activity during chronic hypoxia by changes in rate-limiting enzyme content. Use of monoclonal antibodies to quantitate changes in pyruvate kinase content.

    PubMed Central

    Hance, A J; Robin, E D; Simon, L M; Alexander, S; Herzenberg, L A; Theodore, J

    1980-01-01

    Monoclonal antibodies were prepared against pyruvate kinase (PyKi; ATP: pyruvate phosphotransferase, EC 2.7.1.40) and used to quantitate PyKi content in L2 lung cells and WI-38 fibroblasts cultivated under hypoxic and normoxic conditions. After 96 h of hypoxic cultivation, PyKi activity was significantly increased in both cell types (L2: normoxia [Po2 = 142 torr], 0.11 +/- 0.01 [SD]; hypoxia [Po2 = 14 torr], 0.25 +/- 0.04 U/microgram DNA, P < 0.01). PyKi content increased proportionately in both cell lines (L2: normoxia, 0.44 +/- 0.13; hypoxia, 0.94 +/- 0.13 microgram enzyme protein/microgram DNA). Specific activity was not significantly different after 96 h (L2: normoxia, 261 +/- 11; hypoxia, 261 +/- 14 U/mg enzyme protein). These results indicate that regulation of glycolysis during chronic hypoxia occurs at the level of enzyme content. Chronic O2 depletion leads to either an increased rate of biosynthesis or a decreased rate of biodegradation of PyKi, causing augmented glycolytic capacity. Monoclonal antibodies provide a highly specific, convenient approach to charcterizing enzymes, as well as quantitating cellular enzyme content. PMID:7440714

  18. Muzzle shunt augmentation of conventional railguns

    SciTech Connect

    Parker, J.V.

    1990-01-01

    Augmentation is a well-known technique for reducing the armature current and hence the armature power dissipation in a plasma armature railgun. In spite of the advantages, no large augmented railguns have been built, primarily due to the mechanical and electrical complexity introduce by the extra conductors required. It is possible to achieve some of the benefits of augmentation in conventional railgun by diverting a fraction {phi} of the input current through a shunt path at the muzzle of the railgun. In particular, the relation between force and armature current is the same as that obtained in an n-turn, series connected augmented railgun with n = 1/(1-{phi}). The price of this simplification is a reduction in electrical efficiency and some additional complexity in the external electrical system. Additions to the electrical system are required to establish the shunt current and to control its magnitude during projectile acceleration. The relationship between muzzle shunt augmentation and conventional series augmentation is developed and various techniques is developed and various techniques for establishing and controlling the shunt current are illustrated with a practical example. 5 refs., 8 figs., 2 tabs.

  19. Augmenting digital displays with computation

    NASA Astrophysics Data System (ADS)

    Liu, Jing

    As we inevitably step deeper and deeper into a world connected via the Internet, more and more information will be exchanged digitally. Displays are the interface between digital information and each individual. Naturally, one fundamental goal of displays is to reproduce information as realistically as possible since humans still care a lot about what happens in the real world. Human eyes are the receiving end of such information exchange; therefore it is impossible to study displays without studying the human visual system. In fact, the design of displays is rather closely coupled with what human eyes are capable of perceiving. For example, we are less interested in building displays that emit light in the invisible spectrum. This dissertation explores how we can augment displays with computation, which takes both display hardware and the human visual system into consideration. Four novel projects on display technologies are included in this dissertation: First, we propose a software-based approach to driving multiview autostereoscopic displays. Our display algorithm can dynamically assign views to hardware display zones based on multiple observers' current head positions, substantially reducing crosstalk and stereo inversion. Second, we present a dense projector array that creates a seamless 3D viewing experience for multiple viewers. We smoothly interpolate the set of viewer heights and distances on a per-vertex basis across the arrays field of view, reducing image distortion, crosstalk, and artifacts from tracking errors. Third, we propose a method for high dynamic range display calibration that takes into account the variation of the chrominance error over luminance. We propose a data structure for enabling efficient representation and querying of the calibration function, which also allows user-guided balancing between memory consumption and the amount of computation. Fourth, we present user studies that demonstrate that the ˜ 60 Hz critical flicker fusion

  20. Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation

    PubMed Central

    Day, Trevor A; Wilson, Richard J A

    2007-01-01

    Inputs from central (brainstem) and peripheral (carotid body) respiratory chemoreceptors are coordinated to protect blood gases against potentially deleterious fluctuations. However, the mathematics of the steady-state interaction between chemoreceptors has been difficult to ascertain. Further, how this interaction affects time-dependent phenomena (in which chemoresponses depend upon previous experience) is largely unknown. To determine how central PCO2 modulates the response to peripheral chemostimulation in the rat, we utilized an in situ arterially perfused, vagotomized, decerebrate preparation, in which central and peripheral chemoreceptors were perfused separately (i.e. dual perfused preparation (DPP)). We carried out two sets of experiments: in Experiment 1, we alternated steady-state brainstem PCO2 between 25 and 50 Torr in each preparation, and applied specific carotid body hypoxia (60 Torr PO2 and 40 Torr PCO2) under both conditions; in Experiment 2, we applied four 5 min bouts (separated by 5 min) of specific carotid body hypoxia (60 Torr PO2 and 40 Torr PCO2) while holding the brainstem at either 30 Torr or 50 Torr PCO2. We demonstrate that the level of brainstem PCO2 modulates (a) the magnitude of the phrenic responses to a single step of specific carotid body hypoxia and (b) the magnitude of time-dependent phenomena. We report that the interaction between chemoreceptors is negative (i.e. hypo-additive), whereby a lower brainstem PCO2 augments phrenic responses resulting from specific carotid body hypoxia. A negative interaction may underlie the pathophysiology of central sleep apnoea in populations that are chronically hypocapnic. PMID:17082232

  1. Inhibition of peripheral dopamine metabolism and the ventilatory response to hypoxia in the rat.

    PubMed

    Bialkowska, Monika; Zajac, Dominika; Mazzatenta, Andrea; Di Giulio, Camillo; Pokorski, Mieczyslaw

    2015-01-01

    Dopamine (DA) is a putative neurotransmitter in the carotid body engaged in the generation of the hypoxic ventilatory response (HVR). However, the action of endogenous DA is unsettled. This study seeks to determine the ventilatory effects of increased availability of endogenous DA caused by inhibition of DA enzymatic breakdown. The peripheral inhibitor of MAO - debrisoquine, or COMT - entacapone, or both combined were injected to conscious rats. Ventilation and its responses to acute 8 % O(2) in N(2) were investigated in a whole body plethysmograph. We found that inhibition of MAO augmented the hyperventilatory response to hypoxia. Inhibition of COMT failed to influence the hypoxic response. However, simultaneous inhibition of both enzymes, the case in which endogenous availability of DA should increase the most, reversed the hypoxic augmentation of ventilation induced by MAO-inhibition. The inference is that when MAO alone is blocked, COMT takes over DA degradation in a compensatory way, which lowers the availability of DA, resulting in a higher intensity of the HVR. We conclude that MAO is the enzyme predominantly engaged in the chemoventilatory effects of DA. Furthermore, the findings imply that endogenous DA is inhibitory, rather than stimulatory, for hypoxic ventilation. PMID:25310955

  2. The physiological effects of hypobaric hypoxia versus normobaric hypoxia: a systematic review of crossover trials.

    PubMed

    Coppel, Jonny; Hennis, Philip; Gilbert-Kawai, Edward; Grocott, Michael Pw

    2015-01-01

    Much hypoxia research has been carried out at high altitude in a hypobaric hypoxia (HH) environment. Many research teams seek to replicate high-altitude conditions at lower altitudes in either hypobaric hypoxic conditions or normobaric hypoxic (NH) laboratories. Implicit in this approach is the assumption that the only relevant condition that differs between these settings is the partial pressure of oxygen (PO2), which is commonly presumed to be the principal physiological stimulus to adaptation at high altitude. This systematic review is the first to present an overview of the current available literature regarding crossover studies relating to the different effects of HH and NH on human physiology. After applying our inclusion and exclusion criteria, 13 studies were deemed eligible for inclusion. Several studies reported a number of variables (e.g. minute ventilation and NO levels) that were different between the two conditions, lending support to the notion that true physiological difference is indeed present. However, the presence of confounding factors such as time spent in hypoxia, temperature, and humidity, and the limited statistical power due to small sample sizes, limit the conclusions that can be drawn from these findings. Standardisation of the study methods and reporting may aid interpretation of future studies and thereby improve the quality of data in this area. This is important to improve the quality of data that is used for improving the understanding of hypoxia tolerance, both at altitude and in the clinical setting. PMID:25722851

  3. REST is a hypoxia-responsive transcriptional repressor.

    PubMed

    Cavadas, Miguel A S; Mesnieres, Marion; Crifo, Bianca; Manresa, Mario C; Selfridge, Andrew C; Keogh, Ciara E; Fabian, Zsolt; Scholz, Carsten C; Nolan, Karen A; Rocha, Liliane M A; Tambuwala, Murtaza M; Brown, Stuart; Wdowicz, Anita; Corbett, Danielle; Murphy, Keith J; Godson, Catherine; Cummins, Eoin P; Taylor, Cormac T; Cheong, Alex

    2016-01-01

    Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia. PMID:27531581

  4. Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Induced Transcription

    NASA Astrophysics Data System (ADS)

    Chandel, N. S.; Maltepe, E.; Goldwasser, E.; Mathieu, C. E.; Simon, M. C.; Schumacker, P. T.

    1998-09-01

    Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl2) in Hep3B cells. However, neither the mechanism of cellular O2 sensing nor that of cobalt is fully understood. We tested whether mitochondria act as O2 sensors during hypoxia and whether hypoxia and cobalt activate transcription by increasing generation of reactive oxygen species (ROS). Results show (i) wild-type Hep3B cells increase ROS generation during hypoxia (1.5% O2) or CoCl2 incubation, (ii) Hep3B cells depleted of mitochondrial DNA (ρ 0 cells) fail to respire, fail to activate mRNA for erythropoietin, glycolytic enzymes, or vascular endothelial growth factor during hypoxia, and fail to increase ROS generation during hypoxia; (iii) ρ 0 cells increase ROS generation in response to CoCl2 and retain the ability to induce expression of these genes; and (iv) the antioxidants pyrrolidine dithiocarbamate and ebselen abolish transcriptional activation of these genes during hypoxia or CoCl2 in wild-type cells, and abolish the response to CoCl2 in ρ 0 cells. Thus, hypoxia activates transcription via a mitochondria-dependent signaling process involving increased ROS, whereas CoCl2 activates transcription by stimulating ROS generation via a mitochondria-independent mechanism.

  5. Efficient utilization of aerobic metabolism helps Tibetan locusts conquer hypoxia

    PubMed Central

    2013-01-01

    Background Responses to hypoxia have been investigated in many species; however, comparative studies between conspecific geographical populations at different altitudes are rare, especially for invertebrates. The migratory locust, Locusta migratoria, is widely distributed around the world, including on the high-altitude Tibetan Plateau (TP) and the low-altitude North China Plain (NP). TP locusts have inhabited Tibetan Plateau for over 34,000 years and thus probably have evolved superior capacity to cope with hypoxia. Results Here we compared the hypoxic responses of TP and NP locusts from morphological, behavioral, and physiological perspectives. We found that TP locusts were more tolerant of extreme hypoxia than NP locusts. To evaluate why TP locusts respond to extreme hypoxia differently from NP locusts, we subjected them to extreme hypoxia and compared their transcriptional responses. We found that the aerobic metabolism was less affected in TP locusts than in NP locusts. RNAi disruption of PDHE1β, an entry gene from glycolysis to TCA cycle, increased the ratio of stupor in TP locusts and decreased the ATP content of TP locusts in hypoxia, confirming that aerobic metabolism is critical for TP locusts to maintain activity in hypoxia. Conclusions Our results indicate that TP and NP locusts have undergone divergence in hypoxia tolerance. These findings also indicate that insects can adapt to hypoxic pressure by modulating basic metabolic processes. PMID:24047108

  6. REST is a hypoxia-responsive transcriptional repressor

    PubMed Central

    Cavadas, Miguel A. S.; Mesnieres, Marion; Crifo, Bianca; Manresa, Mario C.; Selfridge, Andrew C.; Keogh, Ciara E.; Fabian, Zsolt; Scholz, Carsten C.; Nolan, Karen A.; Rocha, Liliane M. A.; Tambuwala, Murtaza M.; Brown, Stuart; Wdowicz, Anita; Corbett, Danielle; Murphy, Keith J.; Godson, Catherine; Cummins, Eoin P.; Taylor, Cormac T.; Cheong, Alex

    2016-01-01

    Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up- or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia. PMID:27531581

  7. Blockade of processing/activation of caspase-3 by hypoxia

    SciTech Connect

    Han, Sang Hee; Kim, Moonil; Park, Kyoungsook; Kim, Tae-Hyoung; Seol, Dai-Wu

    2008-10-31

    Tumor hypoxia, which is caused by the rapid proliferation of tumor cells and aberrant vasculature in tumors, results in inadequate supplies of oxygen and nutrients to tumor cells. Paradoxically, these unfavorable growth conditions benefit tumor cell survival, although the mechanism is poorly understood. We have demonstrated for the first time that hypoxia inhibits TRAIL-induced apoptosis by blocking translocation of Bax from cytosol to the mitochondria in tumor cells. However, it is largely unknown how hypoxia-inhibited Bax translocation attenuates TRAIL-induced apoptosis. Here, we demonstrate that despite its inhibitory activity in TRAIL-induced apoptosis, hypoxia does not affect TRAIL-triggered proximal apoptotic signaling events, including caspase-8 activation and Bid cleavage. Instead, hypoxia inhibited processing of caspase-3, leading to incomplete activation of the caspase. Importantly, hypoxia-blocked translocation of Bax to the mitochondria significantly inhibited releasing the mitochondrial factors, such as cytochrome c and Smac/DIABLO, to the cytosol in response to TRAIL. It is well-known that complete processing/activation of caspase-3 requires Smac/DIABLO released from mitochondria. Therefore, our data indicate that an engagement of the apoptotic mitochondrial events leading to caspase-3 activation is blocked by hypoxia. Our data shed new light on understanding of the apoptotic signal transduction and targets regulated by tumor hypoxia.

  8. Cognitive responses to hypobaric hypoxia: implications for aviation training

    PubMed Central

    Neuhaus, Christopher; Hinkelbein, Jochen

    2014-01-01

    The aim of this narrative review is to provide an overview on cognitive responses to hypobaric hypoxia and to show relevant implications for aviation training. A principal element of hypoxia-awareness training is the intentional evocation of hypoxia symptoms during specific training sessions within a safe and controlled environment. Repetitive training should enable pilots to learn and recognize their personal hypoxia symptoms. A time span of 3–6 years is generally considered suitable to refresh knowledge of the more subtle and early symptoms especially. Currently, there are two different technical approaches available to induce hypoxia during training: hypobaric chamber training and reduced-oxygen breathing devices. Hypoxia training for aircrew is extremely important and effective, and the hypoxia symptoms should be emphasized clearly to aircrews. The use of tight-fitting masks, leak checks, and equipment checks should be taught to all aircrew and reinforced regularly. It is noteworthy that there are major differences in the required quality and quantity of hypoxia training for both military and civilian pilots. PMID:25419162

  9. Transcriptional response to hypoxia in the aquatic fungus Blastocladiella emersonii.

    PubMed

    Camilo, César M; Gomes, Suely L

    2010-06-01

    Global gene expression analysis was carried out with Blastocladiella emersonii cells subjected to oxygen deprivation (hypoxia) using cDNA microarrays. In experiments of gradual hypoxia (gradual decrease in dissolved oxygen) and direct hypoxia (direct decrease in dissolved oxygen), about 650 differentially expressed genes were observed. A total of 534 genes were affected directly or indirectly by oxygen availability, as they showed recovery to normal expression levels or a tendency to recover when cells were reoxygenated. In addition to modulating many genes with no putative assigned function, B. emersonii cells respond to hypoxia by readjusting the expression levels of genes responsible for energy production and consumption. At least transcriptionally, this fungus seems to favor anaerobic metabolism through the upregulation of genes encoding glycolytic enzymes and lactate dehydrogenase and the downregulation of most genes coding for tricarboxylic acid (TCA) cycle enzymes. Furthermore, genes involved in energy-costly processes, like protein synthesis, amino acid biosynthesis, protein folding, and transport, had their expression profiles predominantly downregulated during oxygen deprivation, indicating an energy-saving effort. Data also revealed similarities between the transcriptional profiles of cells under hypoxia and under iron(II) deprivation, suggesting that Fe(2+) ion could have a role in oxygen sensing and/or response to hypoxia in B. emersonii. Additionally, treatment of fungal cells prior to hypoxia with the antibiotic geldanamycin, which negatively affects the stability of mammalian hypoxia transcription factor HIF-1alpha, caused a significant decrease in the levels of certain upregulated hypoxic genes. PMID:20418381

  10. Thermoregulatory and metabolic responses of Japanese quail to hypoxia

    PubMed Central

    Atchley, Dylan S.; Foster, Jennifer A.; Bavis, Ryan W.

    2008-01-01

    Common responses to hypoxia include decreased body temperature (Tb) and decreased energy metabolism. In this study, the effects of hypoxia and hypercapnia on Tb and metabolic oxygen consumption (V̇o2) were investigated in Japanese quail (Coturnix japonica). When exposed to hypoxia (15, 13, 11 and 9% O2), Tb decreased only at 11% and 9% O2 compared to normoxia; quail were better able to maintain Tb during acute hypoxia after a one-week acclimation to 10% O2. V̇o2 also decreased during hypoxia, but at 9% O2 this was partially offset by increased anaerobic metabolism. Tb and V̇o2 responses to 9% O2 were exaggerated at lower ambient temperature (Ta), reflecting a decreased lower critical temperature during hypoxia. Conversely, hypoxia had little effect on Tb or V̇o2 at higher Ta (36°C). We conclude that Japanese quail respond to hypoxia in much the same way as mammals, by reducing both Tb and V̇o2. No relationship was found between the magnitudes of decreases in Tb and V̇o2 during 9% O2, however. Since metabolism is the source of heat generation, this suggests that Japanese quail increase thermolysis to reduce Tb. During hypercapnia (3, 6 and 9% CO2), Tb was reduced only at 9% CO2 while V̇o2 was unchanged. PMID:18727957

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  13. 2014 Gulf of Mexico Hypoxia Forecast

    USGS Publications Warehouse

    Scavia, Donald; Evans, Mary Anne; Obenour, Dan

    2014-01-01

    The Gulf of Mexico annual summer hypoxia forecasts are based on average May total nitrogen loads from the Mississippi River basin for that year. The load estimate, recently released by USGS, is 4,761 metric tons per day. Based on that estimate, we predict the area of this summer’s hypoxic zone to be 14,000 square kilometers (95% credible interval, 8,000 to 20,000) – an “average year”. Our forecast hypoxic volume is 50 km3 (95% credible interval, 20 to 77).

  14. 2013 Gulf of Mexico Hypoxia Forecast

    USGS Publications Warehouse

    Scavia, Donald; Evans, Mary Anne; Obenour, Dan

    2013-01-01

    The Gulf of Mexico annual summer hypoxia forecasts are based on average May total nitrogen loads from the Mississippi River basin for that year. The load estimate, recently released by USGS, is 7,316 metric tons per day. Based on that estimate, we predict the area of this summer’s hypoxic zone to be 18,900 square kilometers (95% credible interval, 13,400 to 24,200), the 7th largest reported and about the size of New Jersey. Our forecast hypoxic volume is 74.5 km3 (95% credible interval, 51.5 to 97.0), also the 7th largest on record.

  15. Hypoxia causes transgenerational impairments in reproduction of fish.

    PubMed

    Wang, Simon Yuan; Lau, Karen; Lai, Keng-Po; Zhang, Jiang-Wen; Tse, Anna Chung-Kwan; Li, Jing-Woei; Tong, Yin; Chan, Ting-Fung; Wong, Chris Kong-Chu; Chiu, Jill Man-Ying; Au, Doris Wai-Ting; Wong, Alice Sze-Tsai; Kong, Richard Yuen-Chong; Wu, Rudolf Shiu-Sun

    2016-01-01

    Hypoxia is amongst the most widespread and pressing problems in aquatic environments. Here we demonstrate that fish (Oryzias melastigma) exposed to hypoxia show reproductive impairments (retarded gonad development, decrease in sperm count and sperm motility) in F1 and F2 generations despite these progenies (and their germ cells) having never been exposed to hypoxia. We further show that the observed transgenerational reproductive impairments are associated with a differential methylation pattern of specific genes in sperm of both F0 and F2 coupled with relevant transcriptomic and proteomic alterations, which may impair spermatogenesis. The discovered transgenerational and epigenetic effects suggest that hypoxia might pose a dramatic and long-lasting threat to the sustainability of fish populations. Because the genes regulating spermatogenesis and epigenetic modifications are highly conserved among vertebrates, these results may also shed light on the potential transgenerational effects of hypoxia on other vertebrates, including humans. PMID:27373813

  16. Hypoxia causes transgenerational impairments in reproduction of fish

    PubMed Central

    Wang, Simon Yuan; Lau, Karen; Lai, Keng-Po; Zhang, Jiang-Wen; Tse, Anna Chung-Kwan; Li, Jing-Woei; Tong, Yin; Chan, Ting-Fung; Wong, Chris Kong-Chu; Chiu, Jill Man-Ying; Au, Doris Wai-Ting; Wong, Alice Sze-Tsai; Kong, Richard Yuen-Chong; Wu, Rudolf Shiu-Sun

    2016-01-01

    Hypoxia is amongst the most widespread and pressing problems in aquatic environments. Here we demonstrate that fish (Oryzias melastigma) exposed to hypoxia show reproductive impairments (retarded gonad development, decrease in sperm count and sperm motility) in F1 and F2 generations despite these progenies (and their germ cells) having never been exposed to hypoxia. We further show that the observed transgenerational reproductive impairments are associated with a differential methylation pattern of specific genes in sperm of both F0 and F2 coupled with relevant transcriptomic and proteomic alterations, which may impair spermatogenesis. The discovered transgenerational and epigenetic effects suggest that hypoxia might pose a dramatic and long-lasting threat to the sustainability of fish populations. Because the genes regulating spermatogenesis and epigenetic modifications are highly conserved among vertebrates, these results may also shed light on the potential transgenerational effects of hypoxia on other vertebrates, including humans. PMID:27373813

  17. Hypoxia-inducible factors as key regulators of tumor inflammation.

    PubMed

    Mamlouk, Soulafa; Wielockx, Ben

    2013-06-15

    Low levels of oxygen or hypoxia is often an obstacle in health, particularly in pathological disorders like cancer. The main family of transcription factors responsible for cell survival and adaptation under strenuous conditions of hypoxia are the "hypoxia-inducible factors" (HIFs). Together with prolyl hydroxylase domain enzymes (PHDs), HIFs regulates tumor angiogenesis, proliferation, invasion, metastasis, in addition to resistance to radiation and chemotherapy. Additionally, the entire HIF transcription cascade is involved in the "seventh" hallmark of cancer; inflammation. Studies have shown that hypoxia can influence tumor associated immune cells toward assisting in tumor proliferation, differentiation, vessel growth, distant metastasis and suppression of the immune response via cytokine expression alterations. These changes are not necessarily analogous to HIF's role in non-cancer immune responses, where hypoxia often encourages a strong inflammatory response. PMID:23055435

  18. The Role of Hypoxia Inducible Factor-1 in Hepatocellular Carcinoma

    PubMed Central

    Luo, Dongjun; Wang, Zhongxia; Wu, Junyi; Jiang, Chunping

    2014-01-01

    Hypoxia is a common feature of many solid tumors, including hepatocellular carcinoma (HCC). Hypoxia can promote tumor progression and induce radiation and chemotherapy resistance. As one of the major mediators of hypoxic response, hypoxia inducible factor-1 (HIF-1) has been shown to activate hypoxia-responsive genes, which are involved in multiple aspects of tumorigenesis and cancer progression, including proliferation, metabolism, angiogenesis, invasion, metastasis and therapy resistance. It has been demonstrated that a high level of HIF-1 in the HCC microenvironment leads to enhanced proliferation and survival of HCC cells. Accordingly, overexpression, of HIF-1 is associated with poor prognosis in HCC. In this review, we described the mechanism by which HIF-1 is regulated and how HIF-1 mediates the biological effects of hypoxia in tissues. We also summarized the latest findings concerning the role of HIF-1 in the development of HCC, which could shed light on new therapeutic approaches for the treatment of HCC. PMID:25101278

  19. HypoxamiRs: regulators of cardiac hypoxia and energy metabolism.

    PubMed

    Azzouzi, Hamid El; Leptidis, Stefanos; Doevendans, Pieter A; De Windt, Leon J

    2015-09-01

    Hypoxia and its intricate regulation are at the epicenter of cardiovascular research. Mediated by hypoxia-inducible factors as well as by several microRNAs, recently termed 'hypoxamiRs', hypoxia affects several cardiac pathophysiological processes. Hypoxia is the driving force behind the regulation of the characteristic metabolic switch from predominant fatty acid oxidation in the healthy heart to glucose utilization in the failing myocardium, but also instigates reactivation of the fetal gene program, induces the cardiac hypertrophy response, alters extracellular matrix composition, influences mitochondrial biogenesis, and impacts upon myocardial contractility. HypoxamiR regulation adds a new level of complexity to this multitude of hypoxia-mediated effects, rendering the understanding of the hypoxic response a fundamental piece in solving the cardiovascular disease puzzle. PMID:26197955

  20. Common responses of tumors and wounds to hypoxia.

    PubMed

    Payen, Valéry L; Brisson, Lucie; Dewhirst, Mark W; Sonveaux, Pierre

    2015-01-01

    Hypoxia is a characteristic of tumors and wounds. Hypoxic cells develop 2 common strategies to face hypoxia: the glycolytic switch and the angiogenic switch. At the onset of hypoxia, alleviation of the Pasteur effect ensures short-term cell survival. Long-term hypoxic cell survival requires a further acceleration of the glycolytic flux under the control of hypoxia-inducible factor 1 that stimulates the expression of most glycolytic transporters and enzymes, uncouples glycolysis from the TCA cycle, and rewires glycolysis to lactic fermentation. Hypoxic cells also trigger angiogenesis, a process that aims to restore normal microenvironmental conditions. Transcription factors (hypoxia-inducible factor 1, nuclear factor κB, activator protein 1) and lactate cooperate to stimulate the expression of proangiogenic agents. Cancer cells differ from normal hypoxic cells by their proliferative agenda and by a high metabolic heterogeneity. These effects in tumor account for further molecular and metabolic changes and for a persistent stimulation of angiogenesis. PMID:25815847

  1. Hypoxia: developments in basic science, physiology and clinical studies.

    PubMed

    Ward, D S; Karan, S B; Pandit, J J

    2011-12-01

    Airway management is primarily designed to avoid hypoxia, yet hypoxia remains the main ultimate cause of anaesthetic-related death and morbidity. Understanding some of the physiology of hypoxia is therefore essential as part of a 'holistic' approach to airway management. Furthermore, it is strategically important that national specialist societies dedicated to airway management do not only focus upon the technical aspects of airway management, but also embrace some of the relevant scientific questions. There has been a great deal of research into causation of hypoxia and the body's natural protective mechanisms and responses to it. This enables us to think of ways in which we might manipulate the cellular and molecular responses to confer greater protection against hypoxia-induced tissue injury. This article reviews some of those aspects. PMID:22074075

  2. ARSC: Augmented Reality Student Card--An Augmented Reality Solution for the Education Field

    ERIC Educational Resources Information Center

    El Sayed, Neven A. M.; Zayed, Hala H.; Sharawy, Mohamed I.

    2011-01-01

    Augmented Reality (AR) is the technology of adding virtual objects to real scenes through enabling the addition of missing information in real life. As the lack of resources is a problem that can be solved through AR, this paper presents and explains the usage of AR technology we introduce Augmented Reality Student Card (ARSC) as an application of…

  3. Augmented Reality for the Improvement of Remote Laboratories: An Augmented Remote Laboratory

    ERIC Educational Resources Information Center

    Andujar, J. M.; Mejias, A.; Marquez, M. A.

    2011-01-01

    Augmented reality (AR) provides huge opportunities for online teaching in science and engineering, as these disciplines place emphasis on practical training and unsuited to completely nonclassroom training. This paper proposes a new concept in virtual and remote laboratories: the augmented remote laboratory (ARL). ARL is being tested in the first…

  4. The transareolar incision for breast augmentation revisited.

    PubMed

    Kompatscher, Peter; Schuler, Christine; Beer, Gertrude M

    2004-01-01

    Of the various possible incisions for breast augmentation, the transareolar access has gained only limited popularity. The potential side effects of this incision are said to be altered nipple sensation, impaired lactation, an increased rate of infections with capsular fibrosis, well visible scar formation with hypopigmentation, and the need for an additional access in case a breast ptosis correction should prove necessary at a later date. The purpose of this retrospective study was to judge advantages and limitations of transareolar breast augmentation, and to verify whether the reluctant attitude toward this surgical approach is justified. A sample of 18 patients with a transareolar, retropectoral breast augmentation was selected for a retrospective evaluation. The suitability of the technique in general was examined together with early postoperative complications, sensory changes, and late complications on the basis of an evaluation system for cosmetic surgical results. The study showed that only women with an areolar diameter of 3.5 cm or more without pronounced breast ptosis were suitable for the transareolar access. No early infections were noted. The rate of capsular fibrosis was 11%. Two years after breast augmentation, 16 women (89%) judged their breast sensation to be normal, but objective assessment showed that mean pressure and vibration sensation were moderately compromised in all parts of the breast. The scars were of good quality, with very little hypopigmentation. With appropriate patient selection, respecting the advantages and limitations, the transareolar incision has its definite place among the different incisions for breast augmentation. PMID:15164231

  5. AB027. Penile augmentation: informed text briefing

    PubMed Central

    Park, Nam Cheol

    2016-01-01

    The men’s desire to have larger and longer penis have created endless medical demands throughout human history. Until up to date, various medical skills for penile augmentation have developed in aspect of experimental and clinical outcome. Recently with throwing away socially unacceptable ideas, the need for penile augmentation is considered as equivalent level with mammoplasty for breast augmentation in women for cosmetic and psychological reason. Concurrently advanced technologies in medical material and tissue engineering provide a variety of options to features functional plastic surgery as well as defected tissue compensation procedures. This creative description works accordingly presents state of art knowledge on the penile augmentation with more than 100 full-colored helpful illustrations clarifying penile surgical anatomy, operative procedures by experienced surgeon from the traditional fat transfer to the penile disassembly technique, the newest tissue engineering techniques by researchers with valuable data of world top level, auxiliary medical devices, and how to reconstruct for damaged penis by a quack or accident. Obviously this text book will be a great guidebook in clinical practice for all who are involved or interested in the penile augmentation procedure.

  6. Key technologies of outdoor augmented reality GIS

    NASA Astrophysics Data System (ADS)

    Ren, Fu; Du, Qingyun; Wu, Xueling

    2008-12-01

    Augmented Reality (AR) is a growing research area in virtual reality and generates a composite view for the user. It is combination of the real scene viewed by the user and a virtual scene generated by the computer that augments the scene with additional information. About 80 percent information in the real world is related with spatial location. The combination of Geographical information system (GIS) and AR technologies would promote the development of outdoor AR systems, and also would explore a new research direction for GIS. The key technologies of outdoor augmented reality GIS, including basic tracking methods, display devices, typical applications and registration processes, are discussed. In indoor augmented reality's closed environments the tracking of position and head orientation as well as the presentation of information is much more unproblematic than the same task in an outdoor environment. The main application task of outdoor augmented reality GIS is the presentation of information to a user while moving through an unknown region. The system helps to detect automatically objects in sight of a person who need its information. It compares the conventional solutions of 3D registration with, while it discusses their algorithm procedure to basic parameters to give out their advantages and disadvantages at different condition. While affine transformation approach uses the idea of computer graphics and vision technology for reference. Its accuracy is mainly based on the precision and speed of scene feature point extracted from natural or artificial feature.

  7. Stability-Augmentation Devices for Miniature Aircraft

    NASA Technical Reports Server (NTRS)

    Wood, RIchard M.

    2005-01-01

    Non-aerodynamic mechanical devices are under consideration as means to augment the stability of miniature autonomous and remotely controlled aircraft. Such aircraft can be used for diverse purposes, including military reconnaissance, radio communications, and safety-related monitoring of wide areas. The need for stability-augmentation devices arises because adverse meteorological conditions generally affect smaller aircraft more strongly than they affect larger aircraft: Miniature aircraft often become uncontrollable under conditions that would not be considered severe enough to warrant grounding of larger aircraft. The need for the stability-augmentation devices to be non-aerodynamic arises because there is no known way to create controlled aerodynamic forces sufficient to counteract the uncontrollable meteorological forces on miniature aircraft. A stability-augmentation device of the type under consideration includes a mass pod (a counterweight) at the outer end of a telescoping shaft, plus associated equipment to support the operation of the aircraft. The telescoping shaft and mass pod are stowed in the rear of the aircraft. When deployed, they extend below the aircraft. Optionally, an antenna for radio communication can be integrated into the shaft. At the time of writing this article, the deployment of the telescoping shaft and mass pod was characterized as passive and automatic, but information about the deployment mechanism(s) was not available. The feasibility of this stability-augmentation concept was demonstrated in flights of hand-launched prototype aircraft.

  8. PRDX2 and PRDX4 are negative regulators of hypoxia-inducible factors under conditions of prolonged hypoxia

    PubMed Central

    Luo, Weibo; Chen, Ivan; Chen, Yan; Alkam, Duah; Wang, Yingfei; Semenza, Gregg L.

    2016-01-01

    Hypoxia-inducible factors (HIFs) control the transcription of genes that are crucial for the pathogenesis of cancer and other human diseases. The transcriptional activity of HIFs is rapidly increased upon exposure to hypoxia, but expression of some HIF target genes decreases during prolonged hypoxia. However, the underlying mechanism for feedback inhibition is not completely understood. Here, we report that peroxiredoxin 2 (PRDX2) and PRDX4 interact with HIF-1α and HIF-2α in vitro and in hypoxic HeLa cells. Prolonged hypoxia increases the nuclear translocation of PRDX2 and PRDX4. As a result, PRDX2 and PRDX4 impair HIF-1 and HIF-2 binding to the hypoxia response elements of a subset of HIF target genes, thereby inhibiting gene transcription in cells exposed to prolonged hypoxia. PRDX2 and PRDX4 have no effect on the recruitment of p300 and RNA polymerase II to HIF target genes and the enzymatic activity of PRDX2 and PRDX4 is not required for inhibition of HIF-1 and HIF-2. We also demonstrate that PRDX2 is a direct HIF target gene and that PRDX2 expression is induced by prolonged hypoxia. These findings uncover a novel feedback mechanism for inhibition of HIF transcriptional activity under conditions of prolonged hypoxia. PMID:26837221

  9. Orthobiologics in the augmentation of osteoporotic fractures.

    PubMed

    Watson, J Tracy; Nicolaou, Daemeon A

    2015-02-01

    Many orthobiologic adjuvants are available and widely utilized for general skeletal restoration. Their use for the specific task of osteoporotic fracture augmentation is less well recognized. Common conductive materials are reviewed for their value in this patient population including the large group of allograft adjuvants categorically known as the demineralized bone matrices (DBMs). Another large group of alloplastic materials is also examined-the calcium phosphate and sulfate ceramics. Both of these materials, when used for the proper indications, demonstrate efficacy for these patients. The inductive properties of bone morphogenic proteins (BMPs) and platelet concentrates show no clear advantages for this group of patients. Systemic agents including bisphosphonates, receptor activator of nuclear factor κβ ligand (RANKL) inhibitors, and parathyroid hormone augmentation all demonstrate positive effects with this fracture cohort. Newer modalities, such as trace ion bioceramic augmentation, are also reviewed for their positive effects on osteoporotic fracture healing. PMID:25431160

  10. News about VDAC1 in Hypoxia

    PubMed Central

    Mazure, N. M.

    2016-01-01

    The voltage-dependent anion channel (VDAC) is the main interface between the cytosol and mitochondria of cells. It plays a crucial role in both mitochondrial metabolism and cell death. The main basic function of this channel is to mediate and gate the flux of small ions, metabolites, and adenosine triphosphate. Changes in its structure, and thus conformation, are expected to affect its activity and modulate the ability of cancer cells to expand. In this review, we describe a novel mechanism by which mitochondria of cells in hypoxia, a low level of oxygen, protects from apoptosis. In hypoxia, some mitochondria become enlarged due to hyperfusion. These mitochondria possess a truncated form of VDAC1 (VDAC1-ΔC), which is linked to the higher metabolic capacity and the greater resistance to cell death of hypoxic cells. However, not all of the VDAC1 protein is truncated, but the amount of the full-length form is diminished compared to the amount in normoxic cells. First, we describe how such a decrease effects cell proliferation, respiration, glycolysis, and other processes. Second, we report on a novel mitochondrial-endolysosomal crosstalk that leads to VDAC1 truncation. By pharmacological targeting of VDAC1-ΔC, the production of energy could be turned off and the sensitivity to cell death restored. This could counteract the favorable microenvironment that gives cancer cells a growth advantage and thereby disrupts the balance between life and death, which is controlled by VDAC1. PMID:27625993

  11. Mechanisms of intermittent hypoxia induced hypertension

    PubMed Central

    Bosc, Laura V González; Resta, Thomas; Walker, Benjimen; Kanagy, Nancy L

    2010-01-01

    Abstract Exposing rodents to brief episodes of hypoxia mimics the hypoxemia and the cardiovascular and metabolic effects observed in patients with obstructive sleep apnoea (OSA), a condition that affects between 5% and 20% of the population. Apart from daytime sleepiness, OSA is associated with a high incidence of systemic and pulmonary hypertension, peripheral vascular disease, stroke and sudden cardiac death. The development of animal models to study sleep apnoea has provided convincing evidence that recurrent exposure to intermittent hypoxia (IH) has significant vascular and haemodynamic impact that explain much of the cardiovascular morbidity and mortality observed in patients with sleep apnoea. However, the molecular and cellular mechanisms of how IH causes these changes is unclear and under investigation. This review focuses on the most recent findings addressing these mechanisms. It includes a discussion of the contribution of the nervous system, circulating and vascular factors, inflammatory mediators and transcription factors to IH-induced cardiovascular disease. It also highlights the importance of reactive oxygen species as a primary mediator of the systemic and pulmonary hypertension that develops in response to exposure to IH. PMID:19818095

  12. Maternal nicotine exposure leads to impaired disulfide bond formation and augmented endoplasmic reticulum stress in the rat placenta.

    PubMed

    Wong, Michael K; Nicholson, Catherine J; Holloway, Alison C; Hardy, Daniel B

    2015-01-01

    Maternal nicotine exposure has been associated with many adverse fetal and placental outcomes. Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper disulfide bond formation--a partially oxygen-dependent process mediated by protein disulfide isomerase (PDI) and ER oxidoreductases. Given that nicotine compromised placental development in the rat, and placental insufficiency has been associated with poor disulfide bond formation and ER stress, we hypothesized that maternal nicotine exposure leads to both placental ER stress and impaired disulfide bond formation. To test this hypothesis, female Wistar rats received daily subcutaneous injections of either saline (vehicle) or nicotine bitartrate (1 mg/kg) for 14 days prior to mating and during pregnancy. Placentas were harvested on embryonic day 15 for analysis. Protein and mRNA expression of markers involved in ER stress (e.g., phosphorylated eIF2α, Grp78, Atf4, and CHOP), disulfide bond formation (e.g., PDI, QSOX1, VKORC1), hypoxia (Hif1α), and amino acid deprivation (GCN2) were quantified via Western blot and/or Real-time PCR. Maternal nicotine exposure led to increased expression of Grp78, phosphorylated eIF2α, Atf4, and CHOP (p<0.05) in the rat placenta, demonstrating the presence of augmented ER stress. Decreased expression of PDI and QSOX1 (p<0.05) reveal an impaired disulfide bond formation pathway, which may underlie nicotine-induced ER stress. Finally, elevated expression of Hif1α and GCN2 (p<0.05) indicate hypoxia and amino acid deprivation in nicotine-exposed placentas, respectively, which may also cause impaired disulfide bond formation and augmented ER stress. This study is the first to link maternal nicotine exposure with both placental ER stress and disulfide bond impairment in vivo, providing novel insight into the mechanisms underlying nicotine

  13. Maternal Nicotine Exposure Leads to Impaired Disulfide Bond Formation and Augmented Endoplasmic Reticulum Stress in the Rat Placenta

    PubMed Central

    Wong, Michael K.; Nicholson, Catherine J.; Holloway, Alison C.; Hardy, Daniel B.

    2015-01-01

    Maternal nicotine exposure has been associated with many adverse fetal and placental outcomes. Although underlying mechanisms remain elusive, recent studies have identified that augmented endoplasmic reticulum (ER) stress is linked to placental insufficiency. Moreover, ER function depends on proper disulfide bond formation—a partially oxygen-dependent process mediated by protein disulfide isomerase (PDI) and ER oxidoreductases. Given that nicotine compromised placental development in the rat, and placental insufficiency has been associated with poor disulfide bond formation and ER stress, we hypothesized that maternal nicotine exposure leads to both placental ER stress and impaired disulfide bond formation. To test this hypothesis, female Wistar rats received daily subcutaneous injections of either saline (vehicle) or nicotine bitartrate (1 mg/kg) for 14 days prior to mating and during pregnancy. Placentas were harvested on embryonic day 15 for analysis. Protein and mRNA expression of markers involved in ER stress (e.g., phosphorylated eIF2α, Grp78, Atf4, and CHOP), disulfide bond formation (e.g., PDI, QSOX1, VKORC1), hypoxia (Hif1α), and amino acid deprivation (GCN2) were quantified via Western blot and/or Real-time PCR. Maternal nicotine exposure led to increased expression of Grp78, phosphorylated eIF2α, Atf4, and CHOP (p<0.05) in the rat placenta, demonstrating the presence of augmented ER stress. Decreased expression of PDI and QSOX1 (p<0.05) reveal an impaired disulfide bond formation pathway, which may underlie nicotine-induced ER stress. Finally, elevated expression of Hif1α and GCN2 (p<0.05) indicate hypoxia and amino acid deprivation in nicotine-exposed placentas, respectively, which may also cause impaired disulfide bond formation and augmented ER stress. This study is the first to link maternal nicotine exposure with both placental ER stress and disulfide bond impairment in vivo, providing novel insight into the mechanisms underlying nicotine

  14. Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) contains hypoxia response elements: relevance to lytic induction by hypoxia.

    PubMed

    Haque, Muzammel; Davis, David A; Wang, Victoria; Widmer, Isabelle; Yarchoan, Robert

    2003-06-01

    Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), also known as human herpesvirus 8, is an etiologic agent of KS, primary effusion lymphoma (PEL), and multicentric Castleman's disease. We recently demonstrated that hypoxia can induce lytic replication of KSHV in PEL cell lines. Hypoxia induces the accumulation of hypoxia-inducible factors (HIF), and we hypothesized that the KSHV genome may respond to hypoxia through functional hypoxia response elements (HREs). Here, we demonstrate the presence of at least two promoters within the KSHV genome that are activated by hypoxia or hypoxia mimics. One is in the promoter region of the gene for Rta, the main lytic switch gene, and the other is within the promoter region of ORF34, a lytic gene of unknown function. The ORF34 promoter contains three putative consensus HREs oriented in the direction of the gene. Dissection and site-directed mutagenesis studies confirmed that one of the HREs of the ORF34 promoter is functional. Under conditions of hypoxia, the ORF34 promoter was strongly upregulated by HIF-1 alpha and HIF-2 alpha. By contrast, the promoter of the gene for Rta appeared to be preferentially upregulated by HIF-2 alpha. Reverse transcription-PCR analysis revealed that specific messages for ORF34 and ORF50 are upregulated in BCBL-1 cells exposed to hypoxia. An HIF-1 binding and competition assay demonstrated that the HRE sequence from the ORF34 promoter can compete for HIF-1 alpha binding to an erythropoietin HRE oligonucleotide while a mutant sequence cannot. Thus, we demonstrated that a viral gene can be activated by hypoxia through activation of a functional viral HRE. To our knowledge, this is the first example of a functional HRE in a viral promoter. PMID:12767996

  15. The augmentation algorithm and molecular phylogenetic trees

    NASA Technical Reports Server (NTRS)

    Holmquist, R.

    1978-01-01

    Moore's (1977) augmentation procedure is discussed, and it is concluded that the procedure is valid for obtaining estimates of the total number of fixed nucleotide substitutions both theoretically and in practice, for both simulated and real data, and in agreement, for experimentally dense data sets, with stochastic estimates of the divergence, provided the restrictions on codon mutability resulting from natural selection are explicitly allowed for. Tateno and Nei's (1978) critique that the augmentation procedure has a systematic bias toward overestimation of the total number of nucleotide replacements is disputed, and a data analysis suggests that ancestral sequences inferred by the method of parsimony contain a large number of incorrectly assigned nucleotides.

  16. Minimal inframammary incision for breast augmentation

    PubMed Central

    Fanous, Nabil; Tawilé, Caroline; Brousseau, Valérie J

    2008-01-01

    The inframammary approach in breast augmentation, still the most popular technique among plastic surgeons, has always been hampered by the undesirable appearance of its scar. The present paper describes a modified approach to inframammary augmentation with saline-filled prostheses. This approach uses a very short incision, thus resulting in a much less noticeable scar. The surgical technique is easy to learn, simple to execute, does not necessitate any special equipment and gives consistent results. Decreasing the scar length to an absolute minimum ensures higher patient and surgeon satisfaction. PMID:19554159

  17. Shuffle-exchanges on augmented meshes

    NASA Technical Reports Server (NTRS)

    Bokhari, S. H.

    1984-01-01

    A mesh connected array of size N = two to the Kth power, K an integer, can be augmented by adding at most one edge per node such that it can perform a shuffle-exchange of size N/2 in constant time. A shuffle-exchange of size N is performed on this augmented array in constant time. This is done by combining the available perfect shuffle of size N/2 with the existing nearest neighbor connections of the mesh. By carefully scheduling the different permutations that are composed in order to achieve the shuffle, the time required is reduced to 5 steps, which is optimal for this network.

  18. Estradiol-17beta protects against hypoxia-induced hepatocyte injury through ER-mediated upregulation of Bcl-2 as well as ER-independent antioxidant effects.

    PubMed

    Lee, Min Young; Jung, Sun Chul; Lee, Jang Hern; Han, Ho Jae

    2008-04-01

    Although many previous studies have suggested that estrogen functions as a cytoprotective agent under oxidative stress conditions, the underlying mechanism by which this effect is exerted remains to be elucidated. This study assessed the effects of estradiol-17beta (E(2)) (10(-8) M) on hypoxia-induced cell injury and its related signaling in primary cultured chicken hepatocytes. Hypoxic conditions were found to augment the level of DNA damage and to reduce cell viability and the level of [(3)H]-thymidine incorporation, and these phenomena were prevented through treatment with E(2). Hypoxia also increased caspase-3 expression, but showed no evidence of an influence on the expression of Bcl-2. However, E(2) induced an increase in the level of Bcl-2 expression under hypoxic conditions and reduced the level of caspase-3 expression. The effects of E(2) on Bcl-2 and caspase expression were blocked by ICI 182780 (E(2) receptor (ER) antagonist, 10(-7) M). In addition, hypoxia resulted in an increase in the intracellular reactive oxygen species (ROS) generated. These effects were blocked by E(2), but not by E(2)-BSA and ICI 182780. Hypoxia also activated p38 mitogen-activated protein kinase (MAPK), c-JUN N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and nuclear factor-kappaB (NF-kappaB). These effects were blocked by E(2), but not by ICI 182780. The inhibition of p38 MAPK and JNK/SAPK blocked NF-kappaB activation. In conclusion, E(2) was found to protect against hypoxia-induced cell injury in chicken hepatocytes through ER-mediated upregulation of Bcl-2 expression and through reducing the activity of ROS-dependent p38 MAPK, JNK/SAPK and NF-kappaB. PMID:18379592

  19. Glycolysis determines dichotomous regulation of T cell subsets in hypoxia.

    PubMed

    Xu, Yang; Chaudhury, Arindam; Zhang, Ming; Savoldo, Barbara; Metelitsa, Leonid S; Rodgers, John; Yustein, Jason T; Neilson, Joel R; Dotti, Gianpietro

    2016-07-01

    Hypoxia occurs in many pathological conditions, including chronic inflammation and tumors, and is considered to be an inhibitor of T cell function. However, robust T cell responses occur at many hypoxic inflammatory sites, suggesting that functions of some subsets are stimulated under low oxygen conditions. Here, we investigated how hypoxic conditions influence human T cell functions and found that, in contrast to naive and central memory T cells (TN and TCM), hypoxia enhances the proliferation, viability, and cytotoxic action of effector memory T cells (TEM). Enhanced TEM expansion in hypoxia corresponded to high hypoxia-inducible factor 1α (HIF1α) expression and glycolytic activity compared with that observed in TN and TCM. We determined that the glycolytic enzyme GAPDH negatively regulates HIF1A expression by binding to adenylate-uridylate-rich elements in the 3'-UTR region of HIF1A mRNA in glycolytically inactive TN and TCM. Conversely, active glycolysis with decreased GAPDH availability in TEM resulted in elevated HIF1α expression. Furthermore, GAPDH overexpression reduced HIF1α expression and impaired proliferation and survival of T cells in hypoxia, indicating that high glycolytic metabolism drives increases in HIF1α to enhance TEM function during hypoxia. This work demonstrates that glycolytic metabolism regulates the translation of HIF1A to determine T cell responses to hypoxia and implicates GAPDH as a potential mechanism for controlling T cell function in peripheral tissue. PMID:27294526

  20. Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis

    PubMed Central

    Morfoisse, Florent; Renaud, Edith; Hantelys, Fransky; Prats, Anne-Catherine; Garmy-Susini, Barbara

    2014-01-01

    Hypoxia is known to be a major factor in the induction of angiogenesis during tumor development but its role in lymphangiogenesis remains unclear. Blood and lymphatic vasculatures are stimulated by the vascular endothelial family of growth factors – the VEGFs. In this review, we investigate the role of hypoxia in the molecular regulation of synthesis of the lymphangiogenic growth factors VEGF-A, VEGF-C, and VEGF-D. Gene expression can be regulated by hypoxia at either transcriptional or translational levels. In contrast to strong induction of DNA transcription by hypoxia-inducible factors (HIFs), the majority of cellular stresses such as hypoxia lead to inhibition of cap-dependent translation of mRNA and downregulation of protein synthesis. Here, we describe how initiation of translation of VEGF mRNA is induced by hypoxia through an internal ribosome entry site (IRES)-dependent mechanism. Considering the implications of the lymphatic vasculature for metastatic dissemination, it is crucial to understand the molecular regulation of lymphangiogenic growth factors by hypoxia to obtain new insights into cancer therapy. PMID:27308316

  1. Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis

    PubMed Central

    Morfoisse, Florent; Renaud, Edith; Hantelys, Fransky; Prats, Anne-Catherine; Garmy-Susini, Barbara

    2015-01-01

    Hypoxia is a major condition for the induction of angiogenesis during tumor development but its role in lymphangiogenesis remains unclear. Blood and lymphatic vasculatures are stimulated by growth factors from the vascular endothelial family: the VEGFs. In this review, we investigate the role of hypoxia in the molecular regulation of synthesis of lymphangiogenic growth factors VEGF-A, VEGF-C, and VEGF-D. Gene expression can be regulated at transcriptional and translational levels by hypoxia. Despite strong regulation of DNA transcription induced by hypoxia-inducible factors (HIFs), the majority of cellular stresses such as hypoxia lead to inhibition of cap-dependent translation of the mRNA, resulting in downregulation of protein synthesis. Here, we describe how translation initiation of VEGF mRNAs is induced by hypoxia through an internal ribosome entry site (IRES)-dependent mechanism. Considering the implication of the lymphatic vasculature in metastatic dissemination, it seems crucial to understand the hypoxia-induced molecular regulation of lymphangiogenic growth factors to obtain new insights for cancer therapy. PMID:27308508

  2. Thermoneutrality modifies the impact of hypoxia on lipid metabolism.

    PubMed

    Jun, Jonathan C; Shin, Mi-Kyung; Yao, Qiaoling; Devera, Ronald; Fonti-Bevans, Shannon; Polotsky, Vsevolod Y

    2013-02-15

    Hypoxia has been shown to rapidly increase triglycerides in mice by decreasing plasma lipoprotein clearance. However, the usual temperature of hypoxic exposure is below thermoneutrality for mice, which may increase thermogenesis and energy requirements, resulting in higher tissue lipid uptake. We hypothesize that decreased lipid clearance and ensuing hyperlipidemia are caused by hypoxic suppression of metabolism at cold temperatures and, therefore, would not occur at thermoneutrality. Twelve-week-old, male C57BL6/J mice were exposed to 6 h of 10% O₂ at the usual temperature (22°C) or thermoneutrality (30°C). Acclimation to 22°C increased lipid uptake in the heart, lungs, and brown adipose tissue, resulting in lower plasma triglyceride and cholesterol levels. At this temperature, hypoxia attenuated lipid uptake in most tissues, thereby raising plasma triglycerides and LDL cholesterol. Thermoneutrality decreased tissue lipid uptake, and hypoxia did not cause a further reduction in lipid uptake in any organs. Consequently, hypoxia at thermoneutrality did not affect plasma triglyceride levels. Unexpectedly, plasma HDL cholesterol increased. The effect of hypoxia on white adipose tissue lipolysis was also modified by temperature. Independent of temperature, hypoxia increased heart rate and glucose and decreased activity, body temperature, and glucose sensitivity. Our study underscores the importance of ambient temperature for hypoxia research, especially in studies of lipid metabolism. PMID:23249698

  3. Snail1 Mediates Hypoxia-Induced Melanoma Progression

    PubMed Central

    Liu, Shujing; Kumar, Suresh M.; Martin, James S.; Yang, Ruifeng; Xu, Xiaowei

    2011-01-01

    Tumor hypoxia is a known adverse prognostic factor, and the hypoxic dermal microenvironment participates in melanomagenesis. High levels of hypoxia inducible factor (HIF) expression in melanoma cells, particularly HIF-2α, is associated with poor prognosis. The mechanism underlying the effect of hypoxia on melanoma progression, however, is not fully understood. We report evidence that the effects of hypoxia on melanoma cells are mediated through activation of Snail1. Hypoxia increased melanoma cell migration and drug resistance, and these changes were accompanied by increased Snail1 and decreased E-cadherin expression. Snail1 expression was regulated by HIF-2α in melanoma. Snail1 overexpression led to more aggressive tumor phenotypes and features associated with stem-like melanoma cells in vitro and increased metastatic capacity in vivo. In addition, we found that knockdown of endogenous Snail1 reduced melanoma proliferation and migratory capacity. Snail1 knockdown also prevented melanoma metastasis in vivo. In summary, hypoxia up-regulates Snail1 expression and leads to increased metastatic capacity and drug resistance in melanoma cells. Our findings support that the effects of hypoxia on melanoma are mediated through Snail1 gene activation and suggest that Snail1 is a potential therapeutic target for the treatment of melanoma. PMID:21996677

  4. Hypoxia-induced alterations of G2 checkpoint regulators.

    PubMed

    Hasvold, Grete; Lund-Andersen, Christin; Lando, Malin; Patzke, Sebastian; Hauge, Sissel; Suo, ZhenHe; Lyng, Heidi; Syljuåsen, Randi G

    2016-05-01

    Hypoxia promotes an aggressive tumor phenotype with increased genomic instability, partially due to downregulation of DNA repair pathways. However, genome stability is also surveilled by cell cycle checkpoints. An important issue is therefore whether hypoxia also can influence the DNA damage-induced cell cycle checkpoints. Here, we show that hypoxia (24 h 0.2% O2) alters the expression of several G2 checkpoint regulators, as examined by microarray gene expression analysis and immunoblotting of U2OS cells. While some of the changes reflected hypoxia-induced inhibition of cell cycle progression, the levels of several G2 checkpoint regulators, in particular Cyclin B, were reduced in G2 phase cells after hypoxic exposure, as shown by flow cytometric barcoding analysis of individual cells. These effects were accompanied by decreased phosphorylation of a Cyclin dependent kinase (CDK) target in G2 phase cells after hypoxia, suggesting decreased CDK activity. Furthermore, cells pre-exposed to hypoxia showed increased G2 checkpoint arrest upon treatment with ionizing radiation. Similar results were found following other hypoxic conditions (∼0.03% O2 20 h and 0.2% O2 72 h). These results demonstrate that the DNA damage-induced G2 checkpoint can be altered as a consequence of hypoxia, and we propose that such alterations may influence the genome stability of hypoxic tumors. PMID:26791779

  5. Resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation.

    PubMed

    Zhang, Qun; Yuan, Lin; Zhang, Qingrui; Gao, Yan; Liu, Guangheng; Xiu, Meng; Wei, Xiang; Wang, Zhen; Liu, Dexiang

    2015-09-01

    Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has been found to afford neuroprotective effects against neuroinflammation in the brain. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic brain injuries. The aim of this study is to investigate the potential role of resveratrol in attenuating hypoxia-induced neurotoxicity via its anti-inflammatory actions through in vitro models of the BV-2 microglial cell line and primary microglia. We found that resveratrol significantly inhibited hypoxia-induced microglial activation and reduced subsequent release of pro-inflammatory factors. In addition, resveratrol inhibited the hypoxia-induced degradation of IκB-alpha and phosphorylation of p65 NF-κB protein. Hypoxia-induced ERK1/2 and JNK phosphorylation was also strongly inhibited by resveratrol, whereas resveratrol had no effect on hypoxia-stimulated p38 MAPK phosphorylation. Importantly, treating primary cortical neurons with conditioned medium (CM) from hypoxia-stimulated microglia induced neuronal apoptosis, which was reversed by CM co-treated with resveratrol. Taken together, resveratrol exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effects in microglia. These effects were mediated, at least in part, by suppressing the activation of NF-ĸB, ERK and JNK MAPK signaling pathways. PMID:26225925

  6. Melatonin modulates the fetal cardiovascular defense response to acute hypoxia.

    PubMed

    Thakor, Avnesh S; Allison, Beth J; Niu, Youguo; Botting, Kimberley J; Serón-Ferré, Maria; Herrera, Emilio A; Giussani, Dino A

    2015-08-01

    Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability. PMID:25908097

  7. Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia.

    PubMed

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

    2006-04-01

    Hypoxia is one of the most frequently encountered stresses in health and disease. The duration, frequency, and severity of hypoxic episodes are critical factors determining whether hypoxia is beneficial or harmful. Adaptation to intermittent hypoxia has been demonstrated to confer cardiovascular protection against more severe and sustained hypoxia, and, moreover, to protect against other stresses, including ischemia. Thus, the direct and cross protective effects of adaptation to intermittent hypoxia have been used for treatment and prevention of a variety of diseases and to increase efficiency of exercise training. Evidence is mounting that nitric oxide (NO) plays a central role in these adaptive mechanisms. NO-dependent protective mechanisms activated by intermittent hypoxia include stimulation of NO synthesis as well as restriction of NO overproduction. In addition, alternative, nonenzymic sources of NO and negative feedback of NO synthesis are important factors in optimizing NO concentrations. The adaptive enhancement of NO synthesis and/or availability activates or increases expression of other protective factors, including heat shock proteins, antioxidants and prostaglandins, making the protection more robust and sustained. Understanding the role of NO in mechanisms of adaptation to hypoxia will support development of therapies to prevent and treat hypoxic or ischemic damage to organs and cells and to increase adaptive capabilities of the organism. PMID:16565431

  8. Evolutionary Genetics of Hypoxia Tolerance in Cetaceans during Diving

    PubMed Central

    Tian, Ran; Wang, Zhengfei; Niu, Xu; Zhou, Kaiya; Xu, Shixia; Yang, Guang

    2016-01-01

    Hypoxia was a major challenge faced by cetaceans during the course of secondary aquatic adaptation. Although physiological traits of hypoxia tolerance in cetaceans have been well characterized, the underlying molecular mechanisms remain unknown. We investigated the sequences of 17 hypoxia-tolerance-related genes in representative cetaceans to provide a comprehensive insight into the genetic basis of hypoxia tolerance in these animals. Genes involved in carrying and transporting oxygen in the blood and muscle (hemoglobin-α and β, myoglobin), and genes involved in the regulation of vasoconstriction (endothelin-1, -2, and -3; endothelin receptor type A and B; adrenergic receptor α-1D; and arginine vasopressin) appear to have undergone adaptive evolution, evidence for positive selection on their particular sites, and radical physiochemical property changes of selected condons. Interestingly, “long-diving” cetaceans had relatively higher ω (dN/dS) values than “short-diving” cetaceans for the hemoglobin β gene, indicating divergent selective pressure presented in cetacean lineages with different diving abilities. Additionally, parallel positive selection or amino acid changes (ADRA1D: P50A, A53G, AVPR1B: I/V270T) among animals exposed to different hypoxia habitats reflect functional convergence or similar genetic mechanisms of hypoxia tolerance. In summary, positive selection, divergent selective pressures, and parallel evolution at the molecular level provided some new insights into the genetic adaptation of hypoxia tolerance. PMID:26912402

  9. Thermoneutrality modifies the impact of hypoxia on lipid metabolism

    PubMed Central

    Shin, Mi-Kyung; Yao, Qiaoling; Devera, Ronald; Fonti-Bevans, Shannon; Polotsky, Vsevolod Y.

    2013-01-01

    Hypoxia has been shown to rapidly increase triglycerides in mice by decreasing plasma lipoprotein clearance. However, the usual temperature of hypoxic exposure is below thermoneutrality for mice, which may increase thermogenesis and energy requirements, resulting in higher tissue lipid uptake. We hypothesize that decreased lipid clearance and ensuing hyperlipidemia are caused by hypoxic suppression of metabolism at cold temperatures and, therefore, would not occur at thermoneutrality. Twelve-week-old, male C57BL6/J mice were exposed to 6 h of 10% O2 at the usual temperature (22°C) or thermoneutrality (30°C). Acclimation to 22°C increased lipid uptake in the heart, lungs, and brown adipose tissue, resulting in lower plasma triglyceride and cholesterol levels. At this temperature, hypoxia attenuated lipid uptake in most tissues, thereby raising plasma triglycerides and LDL cholesterol. Thermoneutrality decreased tissue lipid uptake, and hypoxia did not cause a further reduction in lipid uptake in any organs. Consequently, hypoxia at thermoneutrality did not affect plasma triglyceride levels. Unexpectedly, plasma HDL cholesterol increased. The effect of hypoxia on white adipose tissue lipolysis was also modified by temperature. Independent of temperature, hypoxia increased heart rate and glucose and decreased activity, body temperature, and glucose sensitivity. Our study underscores the importance of ambient temperature for hypoxia research, especially in studies of lipid metabolism. PMID:23249698

  10. Melatonin modulates the fetal cardiovascular defense response to acute hypoxia

    PubMed Central

    Thakor, Avnesh S; Allison, Beth J; Niu, Youguo; Botting, Kimberley J; Serón-Ferré, Maria; Herrera, Emilio A; Giussani, Dino A

    2015-01-01

    Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability. PMID:25908097

  11. Role of hypoxia and vascular endothelial growth factors in lymphangiogenesis.

    PubMed

    Morfoisse, Florent; Renaud, Edith; Hantelys, Fransky; Prats, Anne-Catherine; Garmy-Susini, Barbara

    2015-01-01

    Hypoxia is a major condition for the induction of angiogenesis during tumor development but its role in lymphangiogenesis remains unclear. Blood and lymphatic vasculatures are stimulated by growth factors from the vascular endothelial family: the VEGFs. In this review, we investigate the role of hypoxia in the molecular regulation of synthesis of lymphangiogenic growth factors VEGF-A, VEGF-C, and VEGF-D. Gene expression can be regulated at transcriptional and translational levels by hypoxia. Despite strong regulation of DNA transcription induced by hypoxia-inducible factors (HIFs), the majority of cellular stresses such as hypoxia lead to inhibition of cap-dependent translation of the mRNA, resulting in downregulation of protein synthesis. Here, we describe how translation initiation of VEGF mRNAs is induced by hypoxia through an internal ribosome entry site (IRES)-dependent mechanism. Considering the implication of the lymphatic vasculature in metastatic dissemination, it seems crucial to understand the hypoxia-induced molecular regulation of lymphangiogenic growth factors to obtain new insights for cancer therapy. PMID:27308508

  12. Evolutionary Genetics of Hypoxia Tolerance in Cetaceans during Diving.

    PubMed

    Tian, Ran; Wang, Zhengfei; Niu, Xu; Zhou, Kaiya; Xu, Shixia; Yang, Guang

    2016-03-01

    Hypoxia was a major challenge faced by cetaceans during the course of secondary aquatic adaptation. Although physiological traits of hypoxia tolerance in cetaceans have been well characterized, the underlying molecular mechanisms remain unknown. We investigated the sequences of 17 hypoxia-tolerance-related genes in representative cetaceans to provide a comprehensive insight into the genetic basis of hypoxia tolerance in these animals. Genes involved in carrying and transporting oxygen in the blood and muscle (hemoglobin-α and β, myoglobin), and genes involved in the regulation of vasoconstriction (endothelin-1, -2, and -3; endothelin receptor type A and B; adrenergic receptor α-1D; and arginine vasopressin) appear to have undergone adaptive evolution, evidence for positive selection on their particular sites, and radical physiochemical property changes of selected condons. Interestingly, "long-diving" cetaceans had relatively higher ω (dN/dS) values than "short-diving" cetaceans for the hemoglobin β gene, indicating divergent selective pressure presented in cetacean lineages with different diving abilities. Additionally, parallel positive selection or amino acid changes (ADRA1D: P50A, A53G,AVPR1B: I/V270T) among animals exposed to different hypoxia habitats reflect functional convergence or similar genetic mechanisms of hypoxia tolerance. In summary, positive selection, divergent selective pressures, and parallel evolution at the molecular level provided some new insights into the genetic adaptation of hypoxia tolerance. PMID:26912402

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

    PubMed

    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

  14. Regulation of CREB by moderate hypoxia in PC12 cells.

    PubMed

    Beitner-Johnson, D; Rust, R T; Hsieh, T; Millhorn, D E

    2000-01-01

    The mechanisms by which excitable cells adapt and respond to changes in O2 levels remain largely unknown. We have investigated the effect of hypoxia on the cyclic AMP response element binding protein (CREB) transcription factor. PC12 cells were exposed to moderate levels of hypoxia (5% O2) for various times between 20 min and 6 hr. We found that hypoxia rapidly and persistently induced ser133 phosphorylation of CREB. This effect was more robust than that produced by exposing PC12 cells to either forskolin, KCl, or NGF. This effect was not due to activation of any of the previously known CREB kinases, including PKA, CaMK, PKC, p70s6k, or MAPKAP kinase-2. Thus, hypoxia may induce activation of a novel CREB kinase. To test whether phosphorylation of CREB was associated with an activation of CRE-dependent gene expression, cells were transfected with wild type and mutated regions of the 5'-flanking region of the tyrosine hydroxylase (TH) gene fused to a CAT reporter gene. Mutation of the CRE element in a TH reporter gene reduced, but did not abolish, the effects of hypoxia on TH gene expression. However, hypoxia did not induce transactivation of a GAL4-luciferase reporter by a GAL4-CREB fusion protein. Thus, the mechanism by which hypoxia regulates CREB is distinct, and more complex, than that induced by forskolin, depolarization, or nerve growth factor. PMID:10849656

  15. Cardiac responses to hypoxia and reoxygenation in Drosophila.

    PubMed

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

    2015-12-01

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

  16. Hypoxia in human colorectal adenocarcinoma: Comparison between extrinsic and potential intrinsic hypoxia markers

    SciTech Connect

    Goethals, Laurence; Debucquoy, Annelies; Perneel, Christiaan; Geboes, Karel; Ectors, Nadine; De Schutter, Harlinde; Penninckx, Freddy; McBride, William H.; Begg, Adrian C.; Haustermans, Karin M. . E-mail: karin.haustermans@uzleuven.be

    2006-05-01

    Purpose: To detect and quantify hypoxia in colorectal adenocarcinomas by use of pimonidazole and iododeoxyuridine (IdUrd) as extrinsic markers and carbonic anhydrase IX (CA IX), microvessel density (MVD), epidermal growth-factor receptor (EGFR), and vascular endothelial growth factor (VEGF) as intrinsic markers of hypoxia. Methods and Material: Twenty patients with an adenocarcinoma of the left colon and rectum treated by primary surgery were injected with pimonidazole and IdUrd. Serial sections of tumor biopsies were single stained for VEGF, EGFR, Ki67, and double stained for blood vessels in combination with either pimonidazole, IdUrd, or CA IX. Percentage of expression was scored as well as colocalization of pimonidazole with CA IX. Results: The median percentage of hypoxia, as judged by pimonidazole staining, was 16.7% (range, 0-52.4%). The expression of pimonidazole correlated inversely with the total MVD and endothelial cord MVD (R = -0.55, p = 0.01; R = -0.47, p = 0.04). Good colocalization was found between pimonidazole and CA IX in only 30% of tumors, with no correlation overall between pimonidazole and CA IX, VEGF, or EGFR or between the different intrinsic markers. Cells around some vessels (0.08-11%) were negative for IdUrd but positive for Ki 67, which indicated their lack of perfusion at the time of injection. Conclusion: Chronic and acute hypoxic regions are present in colorectal tumors, as shown by pimonidazole and IdUrd staining. Only in a minority of tumors did an association exist between the areas stained by pimonidazole and those positive for CA IX. Pimonidazole also did not correlate with expression of other putative intrinsic hypoxia markers (VEGF, EGFR)

  17. MURINE PULMONARY RESPONSE TO CHRONIC HYPOXIA IS STRAIN SPECIFIC

    PubMed Central

    Tada, Yuji; Laudi, Sven; Harral, Julie; Carr, Michelle; Ivester, Charles; Tanabe, Nobuhiro; Takiguchi, Yuichi; Tatsumi, Koichiro; Kuriyama, Takayuki; Nichols, William C.; West, James

    2013-01-01

    Information concerning the effects of genetic variation between different background strains on hemodynamic, morphometric, and gene expression response to hypoxia would be useful. Three strains of mice were kept in hypoxia and phenotyped followed by gene profiling analysis. Among the variables examined, hematocrit, right heart muscularization, and right ventricular systolic pressure showed a strain-specific effect. Increased gene expression of inflammatory, muscle, and angiogenesis genes were seen in all strains, though the specific genes changed varied among groups. These results suggest that different strains use different gene expression mechanisms to adapt to the challenge of chronic hypoxia, resulting in modified phenotypic changes. PMID:18600498

  18. Developing vascular and hypoxia based theranostics in solid tumors

    NASA Astrophysics Data System (ADS)

    Koonce, Nathan A.

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

  19. Investigation of the combined effects of bedrest and mild hypoxia

    NASA Technical Reports Server (NTRS)

    Waligora, J. M.; Horrigan, D. J., Jr.; Bungo, M. W.; Conkin, J.

    1982-01-01

    Subjects were exposed to an 8-h mild hypoxia exposure (8000 ft. equivalent, 2438 m) with and without a 28-h period of 6 deg headdown bedrest. Anticipated responses to the bedrest and the hypoxia were observed. There was no indication that bedrest affected the arterial oxygenation or the oxygen gradient across the lungs of the subjects undergoing mild hypoxia. It is concluded that there is no evidence that would preclude an alveolar O2 pressure as low as 69 torr during contingency spacecraft operation.

  20. Modulation of human sinus node function by systemic hypoxia

    NASA Technical Reports Server (NTRS)

    Eckberg, D. L.; Bastow, H., III; Scruby, A. E.

    1982-01-01

    The present study was conducted to determine whether bradycardia develops during systemic hypoxia in supine conscious human volunteers when respiratory frequency and tidal volume are maintained at constant levels. The obtained results suggest that mild hypoxia provokes cardioacceleration in humans, independent of changes of ventilation or baroreflex responsiveness. The earliest cardioacceleration is more prominent in the inspiratory than in the expiratory phase of respiration, and occurs with very small reductions of arterial oxygen saturation. Moderate systemic hypoxia dampens fluctuations of heart rate during the respiratory cycle.

  1. Hypoxia inducible factor-1 alpha and multiple myeloma

    PubMed Central

    Tiwary, Bhupendra Nath

    2016-01-01

    Rapid tumor growth creates a state of hypoxia in the tumor microenvironment and results in release of hypoxia inducible factor-1 alpha (HiF-1α) in the local milieu. Hypoxia inducible factor activity is deregulated in many human cancers, especially those that are highly hypoxic. In multiple myeloma (MM) in initial stages of disease establishment, the hypoxic bone marrow microenvironment supports the initial survival and growth of the myeloma cells. Hypoxic tumour cells are usually resistant to radiotherapy and most conventional chemotherapeutic agents, rendering them highly aggressive and metastatic. Therefore, HIF is an attractive, although challenging, therapeutic target in MM directly or indirectly in recent years. PMID:26900575

  2. Augmentative Communication: Assessment, System Selection, and Usage.

    ERIC Educational Resources Information Center

    DeRuyter, Frank; Becker, Mary R.

    1988-01-01

    Augmentative communication systems for the nonspeaking brain-injured should be carefully selected to serve a variety of functions. These include the utilization of systems for communication purposes, assessment of cognitive-linguistic deficits, integration and participation by the individual in the rehabilitation program, and improvement in an…

  3. Personalized augmented reality for anatomy education.

    PubMed

    Ma, Meng; Fallavollita, Pascal; Seelbach, Ina; Von Der Heide, Anna Maria; Euler, Ekkehard; Waschke, Jens; Navab, Nassir

    2016-05-01

    Anatomy education is a challenging but vital element in forming future medical professionals. In this work, a personalized and interactive augmented reality system is developed to facilitate education. This system behaves as a "magic mirror" which allows personalized in-situ visualization of anatomy on the user's body. Real-time volume visualization of a CT dataset creates the illusion that the user can look inside their body. The system comprises a RGB-D sensor as a real-time tracking device to detect the user moving in front of a display. In addition, the magic mirror system shows text information, medical images, and 3D models of organs that the user can interact with. Through the participation of 7 clinicians and 72 students, two user studies were designed to respectively assess the precision and acceptability of the magic mirror system for education. The results of the first study demonstrated that the average precision of the augmented reality overlay on the user body was 0.96 cm, while the results of the second study indicate 86.1% approval for the educational value of the magic mirror, and 91.7% approval for the augmented reality capability of displaying organs in three dimensions. The usefulness of this unique type of personalized augmented reality technology has been demonstrated in this paper. PMID:26646315

  4. Augmenting the ADDIE Paradigm for Instructional Design

    ERIC Educational Resources Information Center

    Ni, Xiaopeng; Branch, Robert Maribe

    2008-01-01

    The authors discuss topics appropriate for augmenting the ADDIE paradigm for instructional design. The topics selected are based on data from a study of working professionals who successfully completed an instructional design and technology certificate program and who identified related topics that they regarded as beneficial. The participants…

  5. APITRON ELECTROSTATICALLY AUGMENTED FABRIC FILTER EVALUATION

    EPA Science Inventory

    The report gives results of fractional and overall mass efficiency tests of two Apitron electrostatically augmented fabric filter dust collectors. The tests were performed on a mobile pilot-scale system collecting flyash produced by a pulverized-coal-fired industrial boiler and o...

  6. A Universal Logging Format for Augmentative Communication.

    ERIC Educational Resources Information Center

    Lesher, Gregory W.; Moulton, Bryan J.; Rinkus, Gerard; Higginbotham, D. Jeffery

    This report discusses how technical and technological advances in alternative and augmentative communication (AAC) have outstripped the ability to assess their impact on actual communication and argues that this is due in part to the lack of a consistent and reliable method to measure long-term communicative efficacy. The report proposes a…

  7. Location-Based Learning through Augmented Reality

    ERIC Educational Resources Information Center

    Chou, Te-Lien; Chanlin, Lih-Juan

    2014-01-01

    A context-aware and mixed-reality exploring tool cannot only effectively provide an information-rich environment to users, but also allows them to quickly utilize useful resources and enhance environment awareness. This study integrates Augmented Reality (AR) technology into smartphones to create a stimulating learning experience at a university…

  8. CARE: Creating Augmented Reality in Education

    ERIC Educational Resources Information Center

    Latif, Farzana

    2012-01-01

    This paper explores how Augmented Reality using mobile phones can enhance teaching and learning in education. It specifically examines its application in two cases, where it is identified that the agility of mobile devices and the ability to overlay context specific resources offers opportunities to enhance learning that would not otherwise exist.…

  9. Get Real: Augmented Reality for the Classroom

    ERIC Educational Resources Information Center

    Mitchell, Rebecca; DeBay, Dennis

    2012-01-01

    Kids love augmented reality (AR) simulations because they are like real-life video games. AR simulations allow students to learn content while collaborating face to face and interacting with a multimedia-enhanced version of the world around them. Although the technology may seem advanced, AR software makes it easy to develop content-based…

  10. Intelligent Augmented Reality Training for Motherboard Assembly

    ERIC Educational Resources Information Center

    Westerfield, Giles; Mitrovic, Antonija; Billinghurst, Mark

    2015-01-01

    We investigate the combination of Augmented Reality (AR) with Intelligent Tutoring Systems (ITS) to assist with training for manual assembly tasks. Our approach combines AR graphics with adaptive guidance from the ITS to provide a more effective learning experience. We have developed a modular software framework for intelligent AR training…

  11. Design Principles for Augmented Reality Learning

    ERIC Educational Resources Information Center

    Dunleavy, Matt

    2014-01-01

    Augmented reality is an emerging technology that utilizes mobile, context-aware devices (e.g., smartphones, tablets) that enable participants to interact with digital information embedded within the physical environment. This overview of design principles focuses on specific strategies that instructional designers can use to develop AR learning…

  12. Introduction to augmented and virtual reality

    NASA Astrophysics Data System (ADS)

    Caudell, Thomas P.

    1995-12-01

    This paper introduces the field of augmented reality as a prolog to the body of papers in the remainder of this session. I describe the use of head-mounted display technologies to improve the efficiency and quality of human workers in their performance of engineering design, manufacturing, construction, testing, and maintenance activities. This technology is used to `augment' the visual field of the wearer with information necessary in the performance of the current task. The enabling technology is head-up (see-through) display head sets (HUDsets) combined with head position sensing, real world registration systems, and database access software. A primary difference between virtual reality (VR) and `augmented reality' (AR) is in the complexity of the perceived graphical objects. In AR systems, only simple wire frames, template outlines, designators, and text is displayed. An immediate result of this difference is that augmented reality systems can be driven by standard and inexpensive microprocessors. Many research issues must be addressed before this technology can be widely used, including tracking and registration, human 3D perception and reasoning, and human task performance issues.

  13. E-Learning: Between Augmentation and Disruption?

    ERIC Educational Resources Information Center

    Heilesen, Simon B.; Josephsen, Jens

    2008-01-01

    Based on a framework for analysis combining diffusion theory, content layer analysis and sense making, this paper discusses the theme of "e-learning as augmentation or disruption" from the point of view of technological innovation. Two cases of on-campus blended learning at Roskilde University, Denmark, are introduced to illustrate the discussion.…

  14. An Asynchronous Augmentation to Traditional Course Delivery.

    ERIC Educational Resources Information Center

    Wolverton, Marvin L.; Wolverton, Mimi

    Asynchronous augmentation facilitates distributed learning, which relies heavily on technology and self-learning. This paper reports the results of delivering a real estate principles course using an asynchronous course delivery format. It highlights one of many ways to enhance learning using technology, and it provides information concerning how…

  15. Toward natural fiducials for augmented reality

    NASA Astrophysics Data System (ADS)

    Kitchin, Paul; Martinez, Kirk

    2005-03-01

    Augmented Reality (AR) requires a mapping between the camera(s) and the world, so that virtual objects can be correctly registered. Current AR applications either use pre-prepared fiducial markers or specialist equipment or impose significant constraints on lighting and background. Each of these approaches has significant drawbacks. Fiducial markers are susceptible to loss or damage, can be awkward to work with and may require significant effort to prepare an area for Augmented interaction. Use of such markers may also present an imposition to non-augmented observers, especially in environments such as museums or historical landmarks. Specialist equipment is expensive and not universally available. Lighting and background constraints are often impractical for real-world applications. This paper presents initial results in using the palm of the hand as a pseudo-fiducial marker in a natural real-world environment, through colour, feature and edge analysis. The eventual aim of this research is to enable fiducial marker cards to be dispensed with entirely in some situations in order to allow more natural interaction in Augmented environments. Examples of this would be allowing users to "hold" virtual 3D objects in the palm of their hand or use gestures to interact with virtual objects.

  16. [Interaction of hypoxia and haemostasis--hypoxia as a prothrombotic factor at high altitude?].

    PubMed

    Schobersberger, Wolfgang; Hoffmann, Georg; Gunga, Hanns-Christian

    2005-04-01

    For an extended period of time various research projects have been conducted on the relationship of hypoxia and haemostasis. The enclosed article contains the conclusion to which extent lack of oxygen can activate the coagulation system and induce a prothrombotic state. The majority of studies proved a shortening of coagulation times during acute exposure to hypoxia, whereas activated parameters of coagulation and fibrinolysis like prothrombin fragment F1+2 as well as thrombin-antithrombin III complexes and D-dimer remained mostly unmodified. It is suggested that a prolonged sojourn at high altitudes could lead to activation of the coagulation system through an increase of haematocrit and blood viscosity. Recently it was proven that people living at high altitudes show an enhanced risk of stroke incidents. The significance of the change in haemostasis on that outcome has not yet been part of the research. However, it has been proven that the activity of the coagulation system does not play a pathophysiological part in the development of acute mountain sickness and high altitude pulmonary edema. Recent studies also demonstrated that moderate hypoxia during long haul flights may not be the main trigger in inducing deep vein thrombosis in passengers. PMID:15966261

  17. Adipose differentiation-related protein is not involved in hypoxia inducible factor-1-induced lipid accumulation under hypoxia

    PubMed Central

    SHEN, GUOMIN; NING, NING; ZHAO, XINGSHENG; LIU, XI; WANG, GUANGYU; WANG, TIANZHEN; ZHAO, RAN; YANG, CHAO; WANG, DONGMEI; GONG, PINGYUAN; SHEN, YAN; SUN, YONGJIAN; ZHAO, XIAO; JIN, YINJI; YANG, WEIWEI; HE, YAN; ZHANG, LEI; JIN, XIAOMING; LI, XIAOBO

    2015-01-01

    Increasing evidence has showed that hypoxia inducible factor-1 (HIF1) has an important role in hypoxia-induced lipid accumulation, a common feature of solid tumors; however, its role remains to be fully elucidated. Adipose differentiation-related protein (ADRP), a structural protein of lipid droplets, is found to be upregulated under hypoxic conditions. In the present study, an MCF7 breast cancer cell line was used to study the role of ADRP in hypoxia-induced lipid accumulation. It was demonstrated that hypoxia induced the gene expression of ADRP in a HIF1-dependent manner. Increases in the mRNA and protein levels of ADRP was accompanied by increased HIF1A activity. In addition, a significant decrease in the mRNA and protein levels of ADRP were detected in presence of siRNA targeting HIF1A. Using a dual-luciferase reporting experiment and chromatin immunoprecipitation assay, the present study demonstrated that ADRP is a direct target gene of HIF1, and identified a functional hypoxia response element localized 33 bp upstream of the transcriptional start site of the ADRP gene. Furthermore, the present study demonstrated the role of ADRP in low density liporotein (LDL) and very-LDL uptake-induced lipid accumulation under hypoxia. The knockdown of ADRP did not reduce HIF1-induced lipid accumulation under hypoxia. Together, these results showed that ADRP may be not involved in HIF1-induced lipid accumulation. PMID:26498183

  18. GABA representation in hypoxia sensing: a ventilatory study in the rat.

    PubMed

    Tarakanov, I; Tikhomirova, L; Tarasova, N; Safonov, V; Bialkowska, M; Pokorski, M

    2011-01-01

    Phenibut, a nonspecific GABA derivative, is clinically used as an anxiolytic and tranquilizer in psychosomatic conditions. A GABA-ergic inhibitory pathway is engaged in respiratory control at both central and peripheral levels. However, the potential of phenibut to affect the O2-related chemoreflexes has not yet been studied. In this study we seek to determine the ventilatory responses to changes in inspired O2 content in anesthetized, spontaneously-breathing rats. Steady-state 5-min responses to 10% O2 in N2 and 100% O2 were taken in each animal before and 1 h after phenibut administration in a dose 450 mg/kg, i.p. Minute ventilation and its frequency and tidal components were obtained from the respiratory flow signal. We found that after a period of irregular extension of the respiratory cycle, phenibut stabilized resting ventilation at a lower level [20.0±3.3 (SD) vs 31.1±5.2 ml/min before phenibut; P<0.01]. The ventilatory depressant effect of phenibut was not reflected in the hypoxic response. In relative terms, this response was actually accentuated after phenibut; the peak hypoxic ventilation increased by 164% from baseline vs the 100% increase before phenibut. Regarding hyperoxia, its inhibitory effect on breathing was more expressed after phenibut. In conclusion, the GABA-mimetic phenibut did not curtail hypoxic ventilatory responsiveness, despite the presence of GABA-ergic pathways in both central and peripheral, carotid body mechanisms mediating the hypoxic chemoreflex. Thus, GABA-mediated synaptic inhibition may be elaborated in a way to sustain the primarily defensive ventilatory chemoreflex. PMID:21880205

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

    PubMed

    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

  20. Heat acclimation and cross tolerance to hypoxia

    PubMed Central

    Ely, Brett R; Lovering, Andrew T; Horowitz, Michal; Minson, Christopher T

    2014-01-01

    Recent research has suggested a potential for some of the physiological and cellular responses to heat acclimation to carry over to improved tolerance of the novel stresses of another environment. This cross-tolerance is evident in heat-acclimated animals that exhibit enhanced tolerance to either hypoxic or ischemic stress, and is primarily attributed to shared cellular stress response pathways. These pathways include Hypoxia-Inducible Factor-1 (HIF-1) and Heat Shock Proteins (HSP). Whether these shared cellular stress response pathways translate to systemic cross-tolerance (improved exercise tolerance, reduced risk of environment-associated illness) has not been clearly shown, particularly in humans. This review highlights the HIF-1 and HSP pathways and their relationship with systemic acclimation responses, and further examines the potential cellular and systemic adaptations that may result in cross-tolerance between hot and hypoxic environments.

  1. Hypoxia-Specific Cytotoxins in Cancer Therapy.

    PubMed

    Brown; Siim

    1996-01-01

    Hypoxic-specific cytotoxins are a new, and as yet clinically untested, mode of treatment of solid tumors. If they can be given at high enough concentrations and sufficiently often, they should prove extremely effective both in combination with standard radiotherapy and also with certain chemotherapeutic drugs. It is likely that their optimum use will turn hypoxic cells in solid tumors from a therapeutic disadvantage to an advantage. In this report, we review the rationale for the use of hypoxia- cytotoxins, including both the theoretical basis for combining them with fractionated radiation and the preclinical results that have been obtained to date combing these agents with fractionated radiation. We also discuss the three major classes of bioreductive drugs, including the quinones (mitomycin C, porfiromycin, and E09), notroaromatic compounds (including RB6145 and various deoxyribonucleic acid [DNA] targeted aromatics), and finally the n-oxides of which tirapazamine is the lead compound. We also briefly discuss new approaches to bioreductive drug development. The best ways to use these agents are also covered. These include using them in combination with radiation, in combination with chemotherapy, and in combination with agents that increase tumor hypoxia. Finally, the importance of the selection of patients for clinical trials is illustrated by showing how dramatically the number of patients for clinical trials is illustrated by showing how dramatically the number of patients in a clinical trial has to increase to obtain statistical significance for a procedure targeted towards hypoxic cells if some of the patients in the trials have well-oxygenated tumors. PMID:10717159

  2. The Effect of Prenatal Hypoxia on Brain Development: Short- and Long-Term Consequences Demonstrated in Rodent Models

    ERIC Educational Resources Information Center

    Golan, Hava; Huleihel, Mahmoud

    2006-01-01

    Hypoxia (H) and hypoxia-ischemia (HI) are major causes of foetal brain damage with long-lasting behavioral implications. The effect of hypoxia has been widely studied in human and a variety of animal models. In the present review, we summarize the latest studies testing the behavioral outcomes following prenatal hypoxia/hypoxia-ischemia in rodent…

  3. 3D photography in the objective analysis of volume augmentation including fat augmentation and dermal fillers.

    PubMed

    Meier, Jason D; Glasgold, Robert A; Glasgold, Mark J

    2011-11-01

    The authors present quantitative and objective 3D data from their studies showing long-term results with facial volume augmentation. The first study analyzes fat grafting of the midface and the second study presents augmentation of the tear trough with hyaluronic filler. Surgeons using 3D quantitative analysis can learn the duration of results and the optimal amount to inject, as well as showing patients results that are not demonstrable with standard, 2D photography. PMID:22004863

  4. In vivo release of glutamate in nucleus tractus solitarii of the rat during hypoxia.

    PubMed Central

    Mizusawa, A; Ogawa, H; Kikuchi, Y; Hida, W; Kurosawa, H; Okabe, S; Takishima, T; Shirato, K

    1994-01-01

    1. An attempt has been made to test the hypothesis that, in the caudal part of nucleus tractus solitarii (NTS) where carotid sinus nerve (CSN) afferents project, L-glutamate (Glut) modulates the hypoxic ventilatory response. 2. Unanaesthetized, peripherally chemodenervated (carotid body denervated; CBD) and sham-operated, freely moving rats were used. During peripheral chemoreceptor stimulation by hypoxia (10% O2 for 30 min) or doxapram (Dox) infusion (2 mg kg-1 (30 min)-1), ventilation was recorded and successively, under the same conditions, the extracellular Glut concentration ([Glut]o) in the caudal NTS was measured by in vivo microdialysis. [Glut]o was also measured during hyperoxic hypercapnia (10% CO2-30% O2 for 30 min). 3. Furthermore, the effects on ventilation of exogenous Glut, the NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 or the ionotropic receptor antagonist kynurenate microinjected into the caudal NTS were investigated in sham-operated rats. 4. In sham-operated rats, both ventilation and [Glut]o in NTS were increased during peripheral chemoreceptor stimulation. On the other hand, no increases in either ventilation or Glut release were observed in CBD rats. In spite of ventilatory augmentation during hypercapnia, no response of [Glut]o to hypercapnia was observed in either group. 5. Local Glut application into NTS increased ventilation. Pretreatment with MK-801 or kynurenate reduced the hypoxic ventilatory response. This reduction in ventilation was mainly due to the decrease in tidal volume. 6. These results suggest that hypoxia induced the release of Glut in NTS and that this effect was mediated by arterial chemosensory input. Images Figure 2 PMID:7965835

  5. Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension

    PubMed Central

    Nitta, Carlos H.; Osmond, David A.; Herbert, Lindsay M.; Beasley, Britta F.; Resta, Thomas C.; Walker, Benjimen R.

    2013-01-01

    Chronic hypoxia (CH) associated with respiratory disease results in elevated pulmonary vascular intracellular Ca2+ concentration, which elicits enhanced vasoconstriction and promotes vascular arterial remodeling and thus has important implications in the development of pulmonary hypertension (PH). Store-operated Ca2+ entry (SOCE) contributes to this elevated intracellular Ca2+ concentration and has also been linked to acute hypoxic pulmonary vasoconstriction (HPV). Since our laboratory has recently demonstrated an important role for acid-sensing ion channel 1 (ASIC1) in mediating SOCE, we hypothesized that ASIC1 contributes to both HPV and the development of CH-induced PH. To test this hypothesis, we examined responses to acute hypoxia in isolated lungs and assessed the effects of CH on indexes of PH, arterial remodeling, and vasoconstrictor reactivity in wild-type (ASIC1+/+) and ASIC1 knockout (ASIC1−/−) mice. Restoration of ASIC1 expression in pulmonary arterial smooth muscle cells from ASIC1−/− mice rescued SOCE, confirming the requirement for ASIC1 in this response. HPV responses were blunted in lungs from ASIC1−/− mice. Both SOCE and receptor-mediated Ca2+ entry, along with agonist-dependent vasoconstrictor responses, were diminished in small pulmonary arteries from control ASIC−/− mice compared with ASIC+/+ mice. The effects of CH to augment receptor-mediated vasoconstrictor and SOCE responses in vessels from ASIC1+/+ mice were not observed after CH in ASIC1−/− mice. In addition, ASIC1−/− mice exhibited diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling in response to CH compared with ASIC1+/+ mice. Taken together, these data demonstrate an important role for ASIC1 in both HPV and the development of CH-induced PH. PMID:24186095

  6. Augmented skeletal muscle hyperaemia during hypoxic exercise in humans is blunted by combined inhibition of nitric oxide and vasodilating prostaglandins.

    PubMed

    Crecelius, Anne R; Kirby, Brett S; Voyles, Wyatt F; Dinenno, Frank A

    2011-07-15

    Exercise hyperaemia in hypoxia is augmented relative to the same level of exercise in normoxia. At moderate exercise intensities, the mechanism(s) underlying this augmented response are currently unclear. We tested the hypothesis that endothelium-derived nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute to the augmented muscle blood flow during hypoxic exercise relative to normoxia. In 10 young healthy adults, we measured forearm blood flow (FBF; Doppler ultrasound) and calculated the vascular conductance (FVC) responses during 5 min of rhythmic handgrip exercise at 20% maximal voluntary contraction in normoxia (NormEx) and isocapnic hypoxia (HypEx; O2 saturation ∼85%) before and after local intra-brachial combined blockade of NO synthase (NOS; via N(G)-monomethyl-L-arginine: L-NMMA) and cyclooxygenase (COX; via ketorolac). All trials were performed during local α- and β-adrenoceptor blockade to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatation. Arterial and deep venous blood gases were measured and oxygen consumption (VO2) was calculated. In control (saline) conditions, FBF after 5 min of exercise in hypoxia was greater than in normoxia (345 ± 21 ml min(−1) vs. 297 ± 18 ml min(−1); P < 0.05). After NO–PG block, the compensatory increase in FBF during hypoxic exercise was blunted ∼50% and thus was reduced compared with control hypoxic exercise (312 ± 19 ml min(−1); P < 0.05), but this was not the case in normoxia (289 ± 15 ml min(−1); P = 0.33). The lower FBF during hypoxic exercise was associated with a compensatory increase in O2 extraction, and thus VO2 was maintained at normal control levels (P = 0.64–0.99). We conclude that under the experimental conditions employed, NO and PGs have little role in normoxic exercise hyperaemia whereas combined NO–PG inhibition reduces hypoxic exercise hyperaemia and abolishes hypoxic vasodilatation at rest. Additionally, VO2 of the tissue was

  7. DUBs, New Members in the Hypoxia Signaling clUb

    PubMed Central

    Schober, Amelie S.; Berra, Edurne

    2016-01-01

    Cellular protein homeostasis is tightly regulated by ubiquitination. Responsible for target protein ubiquitination is a class of enzymes, the so-called ubiquitin E3 ligases. They are opposed to a second class of enzymes, called deubiquitinating enzymes (DUBs), which can remove polyubiquitin chains from their specific target proteins. The coaction of the two sets of enzymes allows the cell to adapt its overall protein content and the abundance of particular proteins to a variety of cellular and environmental stresses, including hypoxia. In recent years, DUBs have been highlighted to play major roles in many diseases, including cancer, both as tumor suppressors and oncogenes. Therefore, DUBs are emerging as promising targets for cancer-cell specific treatment. Here, we will review the current understanding of DUBs implicated in the control of hypoxia-inducible factor, the regulation of DUBs by hypoxia, and the use of DUB-specific drugs to target tumor hypoxia-signaling. PMID:27014628

  8. Vascular Endothelial growth factor signaling in hypoxia and Inflammation

    PubMed Central

    Ramakrishnan, S.; Anand, Vidhu; Roy, Sabita

    2014-01-01

    Infection, cancer and cardiovascular diseases are the major causes for morbidity and mortality in the United States according to the Center for Disease Control. The underlying etiology that contributes to the severity of these diseases is either hypoxia induced inflammation or inflammation resulting in hypoxia. Therefore, molecular mechanisms that regulate hypoxia-induced adaptive responses in cells are important areas of investigation. Oxygen availability is sensed by molecular switches which regulate synthesis and secretion of growth factors and inflammatory mediators. As a consequence, tissue microenvironment is altered by reprogramming metabolic pathways, angiogenesis, vascular permeability, pH homeostasis to facilitate tissue remodeling. Hypoxia inducible factor (HIF) is the central mediator of hypoxic response. HIF regulates several hundred genes and vascular endothelial growth factor (VEGF) is one of the primary target genes. Understanding the regulation of HIF and its influence on inflammatory response offers unique opportunities for drug development to modulate inflammation and ischemia in pathological conditions. PMID:24610033

  9. Hypoxia-inducible factor 1 in autoimmune diseases.

    PubMed

    Deng, Wei; Feng, Xuebing; Li, Xia; Wang, Dandan; Sun, Lingyun

    2016-05-01

    Autoimmune disorders are a complicated and varied group of diseases arising from inappropriate immune responses. Recent studies have demonstrated that ongoing inflammatory and immune responses are associated with increased oxygen consumption, a process resulting in localized tissue hypoxia within inflammatory lesions ("inflammatory hypoxia"), in which hypoxia-inducible factor 1 (HIF-1), an oxygen-sensitive transcription factor that allows adaptation to hypoxia environments, has been shown to play an important function. HIF-1 is a regulator of angiogenesis and immune system. Besides, HIF-1-mediated metabolic shift and fibrosis may also play crucial roles in some autoimmune disorders. Firstly, we briefly summarize the role of HIF-1 in angiogenesis, immune responses and fibrosis. Secondly, we will show the major recent findings demonstrating a role for HIF-1 signaling in autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, systemic sclerosis and multiple sclerosis. The growing evidences may prompt HIF-1 to be a new target for treatment of autoimmune diseases. PMID:27071377

  10. Rearing of silkworm under hypobaric and hypoxia conditions

    NASA Astrophysics Data System (ADS)

    Hashimoto, Hirofumi; Nakayama, Shin; Yamashita, Masamichi; Space Agriculture Task Force, J.

    In order to investigate of a possibility of utilizing silkworm for the space agriculture, rearing of silkworms was examined under hypobaric and hypoxia conditions. In terms of structural mechanics, the lower inner pressure of Martian greenhouse has advantage to reduce requirements on physical properties of mechanical member of the pressurized structure. The main objective of this study is to know the influence of lower total pressure and hypoxia condition on silkworm. Silkworms are reared under following four hypobaric and hypoxia conditions, 10kPa pure oxygen, 20kPa pure oxygen, 10kPa oxygen and 10kPa nitrogen, and 10kPa oxygen and 90kPa nitrogen. After rearing them to pupa stage, growth of silkworms was found poor under all hypobaric hypoxia conditions compared to those grown under the normal atmospheric condition; the control group. The growth under total pressure of 20kPa is slightly fast.

  11. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

    PubMed Central

    Dewhirst, Mark W.; Cao, Yiting; Moeller, Benjamin

    2014-01-01

    Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia–reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit. PMID:18500244

  12. Role of posterior hypothalamus in hypobaric hypoxia induced pulmonary edema.

    PubMed

    Sharma, R K; Choudhary, R C; Reddy, M K; Ray, A; Ravi, K

    2015-01-01

    To investigate the role of posterior hypothalamus and central neurotransmitters in the pulmonary edema due to hypobaric hypoxia, rats were placed in a high altitude simulation chamber (barometric pressure-294.4 mmHg) for 24 h. Exposure to hypobaric hypoxia resulted in increases in mean arterial blood pressure, renal sympathetic nerve activity, right ventricular systolic pressure, lung wet to dry weight ratio and Evans blue dye leakage. There was a significant attenuation in these responses to hypobaric hypoxia (a) after lesioning posterior hypothalamus and (b) after chronic infusion of GABAA receptor agonist muscimol into posterior hypothalamus. No such attenuation was evident with the chronic infusion of the nitric oxide donor SNAP into the posterior hypothalamus. It is concluded that in hypobaric hypoxia, there is over-activity of posterior hypothalamic neurons probably due to a local decrease in GABA-ergic inhibition which increases the sympathetic drive causing pulmonary hypertension and edema. PMID:25448396

  13. Distribution of hypoxia and pycnocline off the Changjiang Estuary, China

    NASA Astrophysics Data System (ADS)

    Zhu, Jianrong; Zhu, Zhuoyi; Lin, Jun; Wu, Hui; Zhang, Jing

    2016-02-01

    The distributions of hypoxia and the pycnocline off the Changjiang Estuary were investigated by making several field observations from June 2 to 11, from July 18 to 23, from August 20 to 30, from October 3 to 13, 2006, and from August 27 to September 3, 2009. The observations from July 18 to 23, 2006, mainly focused on analyzing the relationship between hypoxia and the extension of the river plume and vertical stratification. In July, the Changjiang diluted water (CDW) was influenced by the easterly typhoon winds, causing it to extend northward rather than northeastward. By using the maximum vertical density gradient as a stratification intensity index, we found that the area of low (< 3 mg/L) dissolved oxygen (DO) was similar to the area of the pycnocline (> 2.0 kg/m4), which indicated that the summer pycnocline can effectively block vertical DO exchange and maintain hypoxia near the bottom. The observed hypoxic area was 500 km2, which was much smaller than the hypoxic areas observed in previous studies, and occurred because of the enhanced mixing that resulted from Typhoon Bill. During the observation period of August 20-30, 2006, the maximum density gradient was weaker due to distinct low river discharge. No hypoxia was observed in the eastern and southeastern sea off the Changjiang Estuary where hypoxia often occurs. However, hypoxia occurred over a large area of 15,400 km2 in the northern observation domain where hypoxia rarely occurs. During June 2-11 and October 3-13, 2006, the maximum density gradient was weaker, and the area with low DO was smaller than in July 2006. This finding resulted from relatively low river discharge and weaker solar heating. Consequently, no hypoxia occurred in the bottom layer. The area of low DO was similar to that of the maximum vertical density gradient. From August 27 to September 3, 2009, high river discharge and strong solar heating produced a larger and more intense pycnocline. The hypoxic area reached 3735 km2 and was very

  14. Upregulated Copper Transporters in Hypoxia-Induced Pulmonary Hypertension

    PubMed Central

    Zimnicka, Adriana M.; Tang, Haiyang; Guo, Qiang; Kuhr, Frank K.; Oh, Myung-Jin; Wan, Jun; Chen, Jiwang; Smith, Kimberly A.; Fraidenburg, Dustin R.; Choudhury, Moumita S. R.; Levitan, Irena; Machado, Roberto F.; Kaplan, Jack H.; Yuan, Jason X.-J.

    2014-01-01

    Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness. PMID:24614111

  15. Hypoxia-Induced Alternative Splicing in Endothelial Cells

    PubMed Central

    Weigand, Julia E.; Boeckel, Jes-Niels; Gellert, Pascal; Dimmeler, Stefanie

    2012-01-01

    Background Adaptation to low oxygen by changing gene expression is vitally important for cell survival and tissue development. The sprouting of new blood vessels, initiated from endothelial cells, restores the oxygen supply of ischemic tissues. In contrast to the transcriptional response induced by hypoxia, which is mainly mediated by members of the HIF family, there are only few studies investigating alternative splicing events. Therefore, we performed an exon array for the genome-wide analysis of hypoxia-related changes of alternative splicing in endothelial cells. Methodology/Principal findings Human umbilical vein endothelial cells (HUVECs) were incubated under hypoxic conditions (1% O2) for 48 h. Genome-wide transcript and exon expression levels were assessed using the Affymetrix GeneChip Human Exon 1.0 ST Array. We found altered expression of 294 genes after hypoxia treatment. Upregulated genes are highly enriched in glucose metabolism and angiogenesis related processes, whereas downregulated genes are mainly connected to cell cycle and DNA repair. Thus, gene expression patterns recapitulate known adaptations to low oxygen supply. Alternative splicing events, until now not related to hypoxia, are shown for nine genes: six which are implicated in angiogenesis-mediated cytoskeleton remodeling (cask, itsn1, larp6, sptan1, tpm1 and robo1); one, which is involved in the synthesis of membrane-anchors (pign) and two universal regulators of gene expression (cugbp1 and max). Conclusions/Significance For the first time, this study investigates changes in splicing in the physiological response to hypoxia on a genome-wide scale. Nine alternative splicing events, until now not related to hypoxia, are reported, considerably expanding the information on splicing changes due to low oxygen supply. Therefore, this study provides further knowledge on hypoxia induced gene expression changes and presents new starting points to study the hypoxia adaptation of endothelial cells

  16. International hypoxia symposium XVIII: 26 February-02 March 2013.

    PubMed

    Pun, Matiram; Basnyat, Buddha

    2013-01-01

    The 18th International Hypoxia Symposia, Lake Louise, Alberta, Canada, February 26-March 02, 2013, covered molecular basis of hypoxic responses (e.g., hypoxia inducible factor, nitrite, nitrate, and hemoglobin) and integrative physiology (e.g., exercise physiology, cerebral blood flow responses, live-high train-low, and population genetics). Free communications and poster sessions covered scientific areas from controlled lab settings to field settings of high altitudes (Andes to Himalayas). PMID:24229461

  17. Circulatory responses to hypoxia in experimental myocardial infarction.

    NASA Technical Reports Server (NTRS)

    Schroll, M.; Robison, S. C.; Harrison, D. C.

    1971-01-01

    Three levels of decreased arterial oxygen saturation elicited a graded circulatory response in dogs, manifested by stepwise increases in cardiac output, left ventricular dp/dt, and stroke volume, and decreases in systemic vascular resistance. Responses to similar hypoxia challenges after experimental myocardial infarction were qualitatively similar but quantitatively less. Although the circulatory compensation for hypoxia was less effective after myocardial infarction, no further deterioration of the haemodynamics was noted.

  18. International hypoxia symposium XVIII: 26 February–02 March 2013

    PubMed Central

    2013-01-01

    The 18th International Hypoxia Symposia, Lake Louise, Alberta, Canada, February 26–March 02, 2013, covered molecular basis of hypoxic responses (e.g., hypoxia inducible factor, nitrite, nitrate, and hemoglobin) and integrative physiology (e.g., exercise physiology, cerebral blood flow responses, live-high train-low, and population genetics). Free communications and poster sessions covered scientific areas from controlled lab settings to field settings of high altitudes (Andes to Himalayas). PMID:24229461

  19. Glycogen metabolism in rat heart muscle cultures after hypoxia.

    PubMed

    Vigoda, Ayelet; Mamedova, Liaman K; Shneyvays, Vladimir; Katz, Abram; Shainberg, Asher

    2003-12-01

    Elevated glycogen levels in heart have been shown to have cardioprotective effects against ischemic injury. We have therefore established a model for elevating glycogen content in primary rat cardiac cells grown in culture and examined potential mechanisms for the elevation (glycogen supercompensation). Glycogen was depleted by exposing the cells to hypoxia for 2 h in the absence of glucose in the medium. This was followed by incubating the cells with 28 mM glucose in normoxia for up to 120 h. Hypoxia decreased glycogen content to about 15% of control, oxygenated cells. This was followed by a continuous increase in glycogen in the hypoxia treated cells during the 120 h recovery period in normoxia. By 48 h after termination of hypoxia, the glycogen content had returned to baseline levels and by 120 h glycogen was about 150% of control. The increase in glycogen at 120 h was associated with comparable relative increases in glucose uptake (approximately 180% of control) and the protein level of the glut-1 transporter (approximately 170% of control), whereas the protein level of the glut-4 transporter was decreased to < 10% of control. By 120 h, the hypoxia-treated cells also exhibited marked increases in the total (approximately 170% of control) and fractional activity of glycogen synthase (control, approximately 15%; hypoxia-treated, approximately 30%). Concomitantly, the hypoxia-treated cells also exhibited marked decreases in the total (approximately 50% of control) and fractional activity of glycogen phosphorylase (control, approximately 50%; hypoxia-treated, approximately 25%). Thus, we have established a model of glycogen supercompensation in cultures of cardiac cells that is explained by concerted increases in glucose uptake and glycogen synthase activity and decreases in phosphorylase activity. This model should prove useful in studying the cardioprotective effects of glycogen. PMID:14674711

  20. Hypoxia-induced carbonic anhydrase IX facilitates lactate flux in human breast cancer cells by non-catalytic function

    PubMed Central

    Jamali, Somayeh; Klier, Michael; Ames, Samantha; Felipe Barros, L.; McKenna, Robert; Deitmer, Joachim W.; Becker, Holger M.

    2015-01-01

    The most aggressive tumour cells, which often reside in hypoxic environments, rely on glycolysis for energy production. Thereby they release vast amounts of lactate and protons via monocarboxylate transporters (MCTs), which exacerbates extracellular acidification and supports the formation of a hostile environment. We have studied the mechanisms of regulated lactate transport in MCF-7 human breast cancer cells. Under hypoxia, expression of MCT1 and MCT4 remained unchanged, while expression of carbonic anhydrase IX (CAIX) was greatly enhanced. Our results show that CAIX augments MCT1 transport activity by a non-catalytic interaction. Mutation studies in Xenopus oocytes indicate that CAIX, via its intramolecular H+-shuttle His200, functions as a “proton-collecting/distributing antenna” to facilitate rapid lactate flux via MCT1. Knockdown of CAIX significantly reduced proliferation of cancer cells, suggesting that rapid efflux of lactate and H+, as enhanced by CAIX, contributes to cancer cell survival under hypoxic conditions. PMID:26337752

  1. The Effect of Hypoxia on Mesenchymal Stem Cell Biology

    PubMed Central

    Ejtehadifar, Mostafa; Shamsasenjan, Karim; Movassaghpour, Aliakbar; Akbarzadehlaleh, Parvin; Dehdilani, Nima; Abbasi, Parvaneh; Molaeipour, Zahra; Saleh, Mahshid

    2015-01-01

    Although physiological and pathological role of hypoxia have been appreciated in mammalians for decades however the cellular biology of hypoxia more clarified in the past 20 years. Discovery of the transcription factor hypoxia-inducible factor (HIF)-1, in the 1990s opened a new window to investigate the mechanisms behind hypoxia. In different cellular contexts HIF-1 activation show variable results by impacting various aspects of cell biology such as cell cycle, apoptosis, differentiation and etc. Mesenchymal stem cells (MSC) are unique cells which take important role in tissue regeneration. They are characterized by self-renewal capacity, multilineage potential, and immunosuppressive property. Like so many kind of cells, hypoxia induces different responses in MSCs by HIF- 1 activation. The activation of this molecule changes the growth, multiplication, differentiation and gene expression profile of MSCs in their niche by a complex of signals. This article briefly discusses the most important effects of hypoxia in growth kinetics, signalling pathways, cytokine secretion profile and expression of chemokine receptors in different conditions. PMID:26236651

  2. Mesenchymal Stem Cells Respond to Hypoxia by Increasing Diacylglycerols.

    PubMed

    Lakatos, Kinga; Kalomoiris, Stefanos; Merkely, Béla; Nolta, Jan A; Fierro, Fernando A

    2016-02-01

    Mesenchymal stem cells (MSC) are currently being tested clinically for a plethora of conditions, with most approaches relying on the secretion of paracrine signals by MSC to modulate the immune system, promote wound healing, and induce angiogenesis. Hypoxia has been shown to affect MSC proliferation, differentiation, survival and secretory profile. Here, we investigate changes in the lipid composition of human bone marrow-derived MSC after exposure to hypoxia. Using mass spectrometry, we compared the lipid profiles of MSC derived from five different donors, cultured for two days in either normoxia (control) or hypoxia (1% oxygen). Hypoxia induced a significant increase of total triglycerides, fatty acids and diacylglycerols (DG). Remarkably, reduction of DG levels using the phosphatidylcholine-specific phospholipase C inhibitor D609 inhibited the secretion of VEGF and Angiopoietin-2, but increased the secretion of interleukin-8, without affecting significantly their respective mRNA levels. Functionally, incubation of MSC in hypoxia with D609 inhibited the potential of the cells to promote migration of human endothelial cells in a wound/scratch assay. Hence, we show that hypoxia induces in MSC an increase of DG that may affect the angiogenic potential of these cells. PMID:26212931

  3. PET imaging of cardiac hypoxia: Opportunities and challenges

    PubMed Central

    Handley, M.G.; Medina, R.A.; Nagel, E.; Blower, P.J.; Southworth, R.

    2012-01-01

    Myocardial hypoxia is a major factor in the pathology of cardiac ischemia and myocardial infarction. Hypoxia also occurs in microvascular disease and cardiac hypertrophy, and is thought to be a prime determinant of the progression to heart failure, as well as the driving force for compensatory angiogenesis. The non-invasive delineation and quantification of hypoxia in cardiac tissue therefore has the potential to be an invaluable experimental, diagnostic and prognostic biomarker for applications in cardiology. However, at this time there are no validated methodologies sufficiently sensitive or reliable for clinical use. PET imaging provides real-time spatial information on the biodistribution of injected radiolabeled tracer molecules. Its inherent high sensitivity allows quantitative imaging of these tracers, even when injected at sub-pharmacological (≥pM) concentrations, allowing the non-invasive investigation of biological systems without perturbing them. PET is therefore an attractive approach for the delineation and quantification of cardiac hypoxia and ischemia. In this review we discuss the key concepts which must be considered when imaging hypoxia in the heart. We summarize the PET tracers which are currently available, and we look forward to the next generation of hypoxia-specific PET imaging agents currently being developed. We describe their potential advantages and shortcomings compared to existing imaging approaches, and what is needed in terms of validation and characterization before these agents can be exploited clinically. PMID:21781973

  4. Pronounced kidney hypoxia precedes albuminuria in type 1 diabetic mice.

    PubMed

    Franzén, Stephanie; Pihl, Liselotte; Khan, Nadeem; Gustafsson, Håkan; Palm, Fredrik

    2016-05-01

    Intrarenal tissue hypoxia has been proposed as a unifying mechanism for the development of chronic kidney disease, including diabetic nephropathy. However, hypoxia has to be present before the onset of kidney disease to be the causal mechanism. To establish whether hypoxia precedes the onset of diabetic nephropathy, we implemented a minimally invasive electron paramagnetic resonance oximetry technique using implanted oxygen sensing probes for repetitive measurements of in vivo kidney tissue oxygen tensions in mice. Kidney cortex oxygen tensions were measured before and up to 15 days after the induction of insulinopenic diabetes in male mice and compared with normoglycemic controls. On day 16, urinary albumin excretions and conscious glomerular filtration rates were determined to define the temporal relationship between intrarenal hypoxia and disease development. Diabetic mice developed pronounced intrarenal hypoxia 3 days after the induction of diabetes, which persisted throughout the study period. On day 16, diabetic mice had glomerular hyperfiltration, but normal urinary albumin excretion. In conclusion, intrarenal tissue hypoxia in diabetes precedes albuminuria thereby being a plausible cause for the onset and progression of diabetic nephropathy. PMID:26936871

  5. The tumour hypoxia induced non-coding transcriptome.

    PubMed

    Choudhry, Hani; Harris, Adrian L; McIntyre, Alan

    2016-01-01

    Recent investigations have highlighted the importance of the non-coding genome in regions of hypoxia in tumours. Such regions are frequently found in solid tumours, and are associated with worse patient survival and therapy resistance. Hypoxia stabilises the transcription factors, hypoxia inducible factors (HIF1α and HIF2α) which coordinate transcriptomic changes that occur in hypoxia. The changes in gene expression induced by HIF1α and HIF2α contribute to many of the hallmarks of cancer phenotypes and enable tumour growth, survival and invasion in the hypoxic tumour microenvironment. Non-coding RNAs, in particular microRNAs (miRNAs), which regulate mRNA stability and translation, and long-non-coding RNAs (lncRNAs), which have diverse functions including chromatin modification and transcriptional regulation, are also important in enabling the key hypoxia regulated processes. They have roles in the regulation of metabolism, angiogenesis, autophagy, invasion and metastasis in the hypoxic microenvironment. Furthermore, HIF1α and HIF2α expression and stabilisation are also regulated by both miRNAs and lncRNAs. Here we review the recent developments in the expression, regulation and functions of miRNAs, lncRNAs and other non-coding RNA classes in tumour hypoxia. PMID:26806607

  6. FemHab: The effects of bed rest and hypoxia on oxidative stress in healthy women.

    PubMed

    Debevec, Tadej; Pialoux, Vincent; Ehrström, Sabine; Ribon, Alexandra; Eiken, Ola; Mekjavic, Igor B; Millet, Grégoire P

    2016-04-15

    Independently, both inactivity and hypoxia augment oxidative stress. This study, part of the FemHab project, investigated the combined effects of bed rest-induced unloading and hypoxic exposure on oxidative stress and antioxidant status. Healthy, eumenorrheic women were randomly assigned to the following three 10-day experimental interventions: normoxic bed rest (NBR;n= 11; PiO2 = 133 mmHg), normobaric hypoxic bed rest (HBR;n= 12; PiO2 = 90 mmHg), and ambulatory hypoxic confinement (HAMB;n= 8: PiO2 = 90 mmHg). Plasma samples, obtained before (Pre), during (D2, D6), immediately after (Post) and 24 h after (Post+1) each intervention, were analyzed for oxidative stress markers [advanced oxidation protein products (AOPP), malondialdehyde (MDA), and nitrotyrosine], antioxidant status [superoxide dismutase (SOD), catalase, ferric-reducing antioxidant power (FRAP), glutathione peroxidase (GPX), and uric acid (UA)], NO metabolism end-products (NOx), and nitrites. Compared with baseline, AOPP increased in NBR and HBR on D2 (+14%; +12%;P< 0.05), D6 (+19%; +15%;P< 0.05), and Post (+22%; +21%;P< 0.05), respectively. MDA increased at Post+1 in NBR (+116%;P< 0.01) and D2 in HBR (+114%;P< 0.01) and HAMB (+95%;P< 0.05). Nitrotyrosine decreased (-45%;P< 0.05) and nitrites increased (+46%;P< 0.05) at Post+1 in HAMB only. Whereas SOD was higher at D6 (+82%) and Post+1 (+67%) in HAMB only, the catalase activity increased on D6 (128%) and Post (146%) in HBR and HAMB, respectively (P< 0.05). GPX was only reduced on D6 (-20%;P< 0.01) and Post (-18%;P< 0.05) in HBR. No differences were observed in FRAP and NOx. UA was higher at Post in HBR compared with HAMB (P< 0.05). These data indicate that exposure to combined inactivity and hypoxia impairs prooxidant/antioxidant balance in healthy women. Moreover, habitual activity levels, as opposed to inactivity, seem to blunt hypoxia-related oxidative stress via antioxidant system upregulation. PMID:26796757

  7. HYPOXIA IN THE NORTHERN GULF OF MEXICO: DOES THE SCIENCE SUPPORT THE PLAN TO REDUCE, MITIGATE, AND CONTROL HYPOXIA?

    EPA Science Inventory

    We update and reevaluate the scientific information on the distribution, history and causes of continental shelf hypoxia that supports the 2001 "Action Plan for Reducing, Mitigating, and Controlling Hypoxiain the Northern Gulf of Mexico," incorporating data, publications, and res...

  8. Hypoxia and Exercise Increase the Transpulmonary Passage of 99mTc-Labeled Albumin Particles in Humans

    PubMed Central

    Bates, Melissa L.; Farrell, Emily T.; Drezdon, Alyssa; Jacobson, Joseph E.; Perlman, Scott B.; Eldridge, Marlowe W.

    2014-01-01

    Intrapulmonary arteriovenous anastomoses (IPAVs) are large diameter connections that allow blood to bypass the lung capillaries and may provide a route for right-to-left embolus transmission. These anastomoses are recruited by exercise and catecholamines and hypoxia. Yet, whether IPAVs are recruited via direct, oxygen sensitive regulatory mechanisms or indirect effects secondary to redistribution pulmonary blood flow is unknown. Here, we hypothesized that the addition of exercise to hypoxic gas breathing, which increases cardiac output, would augment IPAVs recruitment in healthy humans. To test this hypothesis, we measured the transpulmonary passage of 99mTc-macroaggregated albumin particles (99mTc-MAA) in seven healthy volunteers, at rest and with exercise at 85% of volitional max, with normoxic (FIO2 = 0.21) and hypoxic (FIO2 = 0.10) gas breathing. We found increased 99mTc-MAA passage in both exercise conditions and resting hypoxia. However, contrary to our hypothesis, we found the greatest 99mTc-MAA passage with resting hypoxia. As an additional, secondary endpoint, we also noted that the transpulmonary passage of 99mTc-MAA was well-correlated with the alveolar-arterial oxygen difference (A-aDO2) during exercise. While increased cardiac output has been proposed as an important modulator of IPAVs recruitment, we provide evidence that the modulation of blood flow through these pathways is more complex and that increasing cardiac output does not necessarily increase IPAVs recruitment. As we discuss, our data suggest that the resistance downstream of IPAVs is an important determinant of their perfusion. PMID:25013985

  9. TCDD Induces the Hypoxia-Inducible Factor (HIF)-1α Regulatory Pathway in Human Trophoblastic JAR Cells

    PubMed Central

    Liao, Tien-Ling; Chen, Su-Chee; Tzeng, Chii-Reuy; Kao, Shu-Huei

    2014-01-01

    The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α) stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS) and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or N-acetylcysteine (a ROS scavenger). The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development. PMID:25272228

  10. TCDD induces the hypoxia-inducible factor (HIF)-1α regulatory pathway in human trophoblastic JAR cells.

    PubMed

    Liao, Tien-Ling; Chen, Su-Chee; Tzeng, Chii-Reuy; Kao, Shu-Huei

    2014-01-01

    The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α) stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS) and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or N-acetylcysteine (a ROS scavenger). The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development. PMID:25272228

  11. Alterations in left ventricular function during intermittent hypoxia: Possible involvement of O-GlcNAc protein and MAPK signaling.

    PubMed

    Guo, Xueling; Shang, Jin; Deng, Yan; Yuan, Xiao; Zhu, Die; Liu, Huiguo

    2015-07-01

    Obstructive sleep apnea, characterized by recurrent episodes of hypoxia [intermittent hypoxia (IH)], has been identified as a risk factor for cardiovascular diseases. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of proteins has important regulatory implications on the pathophysiology of cardiovascular disorders. In this study, we examined the role of O-GlcNAcylation in cardiac architecture and left ventricular function following IH. Rats were randomly assigned to a normoxia and IH group (2 min 21% O2; 2 min 6-8% O2). Left ventricular function, myocardial morphology and the levels of signaling molecules were then measured. IH induced a significant increase in blood pressure, associated with a gradually abnormal myocardial architecture. The rats exposed to 2 or 3 weeks of IH presented with augmented left ventricular systolic and diastolic function, which declined at week 4. Consistently, the O-GlcNAc protein and O-GlcNAcase (OGA) levels in the left ventricular tissues steadily increased following IH, reaching peak levels at week 3. The O-GlcNAc transferase (OGT), extracellular signal-regulated kinase 1/2 (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation levels were affected in an opposite manner. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) remained unaltered. In parallel, compared with exposure to normoxia, 4 weeks of IH augmented the O-GlcNAc protein, OGT, phosphorylated ERK1/2 and p38 MAPK levels, accompanied by a decrease in OGA levels and an increase in the levels of myocardial nuclear factor-κB (NF-κB), inflammatory cytokines, caspase-3 and cardiomyocyte apoptosis. Taken together, our suggest a possible involvement of O-GlcNAc protein and MAPK signaling in the alterations of left ventricular function and cardiac injury following IH. PMID:25936416

  12. Alterations in left ventricular function during intermittent hypoxia: Possible involvement of O-GlcNAc protein and MAPK signaling

    PubMed Central

    GUO, XUELING; SHANG, JIN; DENG, YAN; YUAN, XIAO; ZHU, DIE; LIU, HUIGUO

    2015-01-01

    Obstructive sleep apnea, characterized by recurrent episodes of hypoxia [intermittent hypoxia (IH)], has been identified as a risk factor for cardiovascular diseases. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of proteins has important regulatory implications on the pathophysiology of cardiovascular disorders. In this study, we examined the role of O-GlcNAcylation in cardiac architecture and left ventricular function following IH. Rats were randomly assigned to a normoxia and IH group (2 min 21% O2; 2 min 6–8% O2). Left ventricular function, myocardial morphology and the levels of signaling molecules were then measured. IH induced a significant increase in blood pressure, associated with a gradually abnormal myocardial architecture. The rats exposed to 2 or 3 weeks of IH presented with augmented left ventricular systolic and diastolic function, which declined at week 4. Consistently, the O-GlcNAc protein and O-GlcNAcase (OGA) levels in the left ventricular tissues steadily increased following IH, reaching peak levels at week 3. The O-GlcNAc transferase (OGT), extracellular signal-regulated kinase 1/2 (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation levels were affected in an opposite manner. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) remained unaltered. In parallel, compared with exposure to normoxia, 4 weeks of IH augmented the O-GlcNAc protein, OGT, phosphorylated ERK1/2 and p38 MAPK levels, accompanied by a decrease in OGA levels and an increase in the levels of myocardial nuclear factor-κB (NF-κB), inflammatory cytokines, caspase-3 and cardiomyocyte apoptosis. Taken together, our suggest a possible involvement of O-GlcNAc protein and MAPK signaling in the alterations of left ventricular function and cardiac injury following IH. PMID:25936416

  13. An Augmentation of G-Guidance Algorithms

    NASA Technical Reports Server (NTRS)

    Carson, John M. III; Acikmese, Behcet

    2011-01-01

    The original G-Guidance algorithm provided an autonomous guidance and control policy for small-body proximity operations that took into account uncertainty and dynamics disturbances. However, there was a lack of robustness in regards to object proximity while in autonomous mode. The modified GGuidance algorithm was augmented with a second operational mode that allows switching into a safety hover mode. This will cause a spacecraft to hover in place until a mission-planning algorithm can compute a safe new trajectory. No state or control constraints are violated. When a new, feasible state trajectory is calculated, the spacecraft will return to standard mode and maneuver toward the target. The main goal of this augmentation is to protect the spacecraft in the event that a landing surface or obstacle is closer or further than anticipated. The algorithm can be used for the mitigation of any unexpected trajectory or state changes that occur during standard mode operations

  14. Augmenting Probabilistic Risk Assesment with Malevolent Initiators

    SciTech Connect

    Curtis Smith; David Schwieder

    2011-11-01

    As commonly practiced, the use of probabilistic risk assessment (PRA) in nuclear power plants only considers accident initiators such as natural hazards, equipment failures, and human error. Malevolent initiators are ignored in PRA, but are considered the domain of physical security, which uses vulnerability assessment based on an officially specified threat (design basis threat). This paper explores the implications of augmenting and extending existing PRA models by considering new and modified scenarios resulting from malevolent initiators. Teaming the augmented PRA models with conventional vulnerability assessments can cost-effectively enhance security of a nuclear power plant. This methodology is useful for operating plants, as well as in the design of new plants. For the methodology, we have proposed an approach that builds on and extends the practice of PRA for nuclear power plants for security-related issues. Rather than only considering 'random' failures, we demonstrated a framework that is able to represent and model malevolent initiating events and associated plant impacts.

  15. Detonation wave augmentation of gas turbines

    NASA Technical Reports Server (NTRS)

    Wortman, A.

    1984-01-01

    The results of a feasibility study that examined the effects of using detonation waves to augment the performance of gas turbines are reported. The central ideas were to reduce compressor requirements and to maintain high performance in jet engines. Gasdynamic equations were used to model the flows associated with shock waves generated by the detonation of fuel in detonator tubes. Shock wave attenuation to the level of Mach waves was found possible, thus eliminating interference with the compressor and the necessity of valves and seals. A preliminary parametric study of the performance of a compressor working at a 4:1 ratio in a conceptual design of a detonation wave augmented jet engine in subsonic flight indicated a clear superiority over conventional designs in terms of fuel efficiency and thrust.

  16. Vertebral Augmentation: State of the Art.

    PubMed

    Sebaaly, Amer; Nabhane, Linda; Issa El Khoury, Fouad; Kreichati, Gaby; El Rachkidi, Rami

    2016-04-01

    Osteoporotic vertebral compression fractures (OVF) are an increasing public health problem. Cement augmentation (vertebroplasty of kyphoplasty) helps stabilize painful OVF refractory to medical treatment. This stabilization is thought to improve pain and functional outcome. Vertebroplasty consists of injecting cement into a fractured vertebra using a percutaneous transpedicular approach. Balloon kyphoplasty uses an inflatable balloon prior to injecting the cement. Although kyphoplasty is associated with significant improvement of local kyphosis and less cement leakage, this does not result in long-term clinical and functional improvement. Moreover, vertebroplasty is favored by some due to the high cost of kyphoplasty. The injection of cement increases the stiffness of the fracture vertebrae. This can lead, in theory, to adjacent OVF. However, many studies found no increase of subsequent fracture when comparing medical treatment to cement augmentation. Kyphoplasty can have a protective effect due to restoration of sagittal balance. PMID:27114782

  17. Tests on Thrust Augmenters for Jet Propulsion

    NASA Technical Reports Server (NTRS)

    Jacobs, Eastman N; Shoemaker, James M

    1932-01-01

    This series of tests was undertaken to determine how much the reaction thrust of a jet could be increased by the use of thrust augmenters and thus to give some indication as to the feasibility of jet propulsion for airplanes. The tests were made during the first part of 1927 at the Langley Memorial Aeronautical Laboratory. A compressed air jet was used in connection with a series of annular guides surrounding the jet to act as thrust augmenters. The results show that, although it is possible to increase the thrust of a jet, the increase is not large enough to affect greatly the status of the problem of the application of jet propulsion to airplanes.

  18. Vertebral Augmentation: State of the Art

    PubMed Central

    Nabhane, Linda; Issa El Khoury, Fouad; Kreichati, Gaby; El Rachkidi, Rami

    2016-01-01

    Osteoporotic vertebral compression fractures (OVF) are an increasing public health problem. Cement augmentation (vertebroplasty of kyphoplasty) helps stabilize painful OVF refractory to medical treatment. This stabilization is thought to improve pain and functional outcome. Vertebroplasty consists of injecting cement into a fractured vertebra using a percutaneous transpedicular approach. Balloon kyphoplasty uses an inflatable balloon prior to injecting the cement. Although kyphoplasty is associated with significant improvement of local kyphosis and less cement leakage, this does not result in long-term clinical and functional improvement. Moreover, vertebroplasty is favored by some due to the high cost of kyphoplasty. The injection of cement increases the stiffness of the fracture vertebrae. This can lead, in theory, to adjacent OVF. However, many studies found no increase of subsequent fracture when comparing medical treatment to cement augmentation. Kyphoplasty can have a protective effect due to restoration of sagittal balance. PMID:27114782

  19. Improved approximations for control augmented structural synthesis

    NASA Technical Reports Server (NTRS)

    Thomas, H. L.; Schmit, L. A.

    1990-01-01

    A methodology for control-augmented structural synthesis is presented for structure-control systems which can be modeled as an assemblage of beam, truss, and nonstructural mass elements augmented by a noncollocated direct output feedback control system. Truss areas, beam cross sectional dimensions, nonstructural masses and rotary inertias, and controller position and velocity gains are treated simultaneously as design variables. The structural mass and a control-system performance index can be minimized simultaneously, with design constraints placed on static stresses and displacements, dynamic harmonic displacements and forces, structural frequencies, and closed-loop eigenvalues and damping ratios. Intermediate design-variable and response-quantity concepts are used to generate new approximations for displacements and actuator forces under harmonic dynamic loads and for system complex eigenvalues. This improves the overall efficiency of the procedure by reducing the number of complete analyses required for convergence. Numerical results which illustrate the effectiveness of the method are given.

  20. H2S Regulates Hypobaric Hypoxia-Induced Early Glio-Vascular Dysfunction and Neuro-Pathophysiological Effects

    PubMed Central

    Kumar, Gaurav; Chhabra, Aastha; Mishra, Shalini; Kalam, Haroon; Kumar, Dhiraj; Meena, Ramniwas; Ahmad, Yasmin; Bhargava, Kalpana; Prasad, Dipti N.; Sharma, Manish

    2016-01-01

    Hypobaric Hypoxia (HH) is an established risk factor for various neuro-physiological perturbations including cognitive impairment. The origin and mechanistic basis of such responses however remain elusive. We here combined systems level analysis with classical neuro-physiological approaches, in a rat model system, to understand pathological responses of brain to HH. Unbiased ‘statistical co-expression networks’ generated utilizing temporal, differential transcriptome signatures of hippocampus—centrally involved in regulating cognition—implicated perturbation of Glio-Vascular homeostasis during early responses to HH, with concurrent modulation of vasomodulatory, hemostatic and proteolytic processes. Further, multiple lines of experimental evidence from ultra-structural, immuno-histological, substrate-zymography and barrier function studies unambiguously supported this proposition. Interestingly, we show a significant lowering of H2S levels in the brain, under chronic HH conditions. This phenomenon functionally impacted hypoxia-induced modulation of cerebral blood flow (hypoxic autoregulation) besides perturbing the strength of functional hyperemia responses. The augmentation of H2S levels, during HH conditions, remarkably preserved Glio-Vascular homeostasis and key neuro-physiological functions (cerebral blood flow, functional hyperemia and spatial memory) besides curtailing HH-induced neuronal apoptosis in hippocampus. Our data thus revealed causal role of H2S during HH-induced early Glio-Vascular dysfunction and consequent cognitive impairment. PMID:27211559

  1. Hypoxia Promotes Osteogenesis but Suppresses Adipogenesis of Human Mesenchymal Stromal Cells in a Hypoxia-Inducible Factor-1 Dependent Manner

    PubMed Central

    Lohanatha, Ferenz L.; Hahne, Martin; Strehl, Cindy; Fangradt, Monique; Tran, Cam Loan; Schönbeck, Kerstin; Hoff, Paula; Ode, Andrea; Perka, Carsten; Duda, Georg N.; Buttgereit, Frank

    2012-01-01

    Background Bone fracture initiates a series of cellular and molecular events including the expression of hypoxia-inducible factor (HIF)-1. HIF-1 is known to facilitate recruitment and differentiation of multipotent human mesenchymal stromal cells (hMSC). Therefore, we analyzed the impact of hypoxia and HIF-1 on the competitive differentiation potential of hMSCs towards adipogenic and osteogenic lineages. Methodology/Principal Findings Bone marrow derived primary hMSCs cultured for 2 weeks either under normoxic (app. 18% O2) or hypoxic (less than 2% O2) conditions were analyzed for the expression of MSC surface markers and for expression of the genes HIF1A, VEGFA, LDHA, PGK1, and GLUT1. Using conditioned medium, adipogenic or osteogenic differentiation as verified by Oil-Red-O or von-Kossa staining was induced in hMSCs under either normoxic or hypoxic conditions. The expression of HIF1A and VEGFA was measured by qPCR. A knockdown of HIF-1α by lentiviral transduction was performed, and the ability of the transduced hMSCs to differentiate into adipogenic and osteogenic lineages was analyzed. Hypoxia induced HIF-1α and HIF-1 target gene expression, but did not alter MSC phenotype or surface marker expression. Hypoxia (i) suppressed adipogenesis and associated HIF1A and PPARG gene expression in hMSCs and (ii) enhanced osteogenesis and associated HIF1A and RUNX2 gene expression. shRNA-mediated knockdown of HIF-1α enhanced adipogenesis under both normoxia and hypoxia, and suppressed hypoxia-induced osteogenesis. Conclusions/Significance Hypoxia promotes osteogenesis but suppresses adipogenesis of human MSCs in a competitive and HIF-1-dependent manner. We therefore conclude that the effects of hypoxia are crucial for effective bone healing, which may potentially lead to the development of novel therapeutic approaches. PMID:23029528

  2. Hypoxia and hypoglycaemia in Ewing's sarcoma and osteosarcoma: regulation and phenotypic effects of Hypoxia-Inducible Factor

    PubMed Central

    2010-01-01

    Background Hypoxia regulates gene expression via the transcription factor HIF (Hypoxia-Inducible Factor). Little is known regarding HIF expression and function in primary bone sarcomas. We describe HIF expression and phenotypic effects of hypoxia, hypoglycaemia and HIF in Ewing's sarcoma and osteosarcoma. Methods HIF-1α and HIF-2α immunohistochemistry was performed on a Ewing's tumour tissue array. Ewing's sarcoma and osteosarcoma cell lines were assessed for HIF pathway induction by Western blot, luciferase assay and ELISA. Effects of hypoxia, hypoglycaemia and isoform-specific HIF siRNA were assessed on proliferation, apoptosis and migration. Results 17/56 Ewing's tumours were HIF-1α-positive, 15 HIF-2α-positive and 10 positive for HIF-1α and HIF-2α. Expression of HIF-1α and cleaved caspase 3 localised to necrotic areas. Hypoxia induced HIF-1α and HIF-2α in Ewing's and osteosarcoma cell lines while hypoglycaemia specifically induced HIF-2α in Ewing's. Downstream transcription was HIF-1α-dependent in Ewing's sarcoma, but regulated by both isoforms in osteosarcoma. In both cell types hypoglycaemia reduced cellular proliferation by ≥ 45%, hypoxia increased apoptosis and HIF siRNA modulated hypoxic proliferation and migration. Conclusions Co-localisation of HIF-1α and necrosis in Ewing's sarcoma suggests a role for hypoxia and/or hypoglycaemia in in vivo induction of HIF. In vitro data implicates hypoxia as the primary HIF stimulus in both Ewing's and osteosarcoma, driving effects on proliferation and apoptosis. These results provide a foundation from which to advance understanding of HIF function in the pathobiology of primary bone sarcomas. PMID:20637078

  3. Ligament reconstruction tendon interposition with mersilene augmentation.

    PubMed

    Stein, Andrew J; Schofield, Jennifer L; Marsh, Mike; Paulo, Jerry

    2011-03-01

    Many surgical procedures have been described for the treatment of thumb basilar joint osteoarthritis. Augmentation of the standard ligament reconstruction tendon interposition procedure with the use of a Mersilene suture tape suspension-plasty, to recreate the stability provided by the anterior oblique ligament and increase pinch strength, will be described. Satisfaction with this procedure was evaluated through surveys completed by patients. In addition, independent physical assessments were performed to demonstrate stability, range of motion, and strength. PMID:21358518

  4. Asian Breast Augmentation: A Systematic Review

    PubMed Central

    Zelken, Jonathan

    2015-01-01

    Background: Economic, cultural, and regulatory phenomena may explain recent popularization of implant-based augmentation in Asia; but the collective Eastern experience remains limited. Asian surgeons and their patients rely on evidence-based medicine that originates elsewhere and may not be entirely relevant. Distinct anatomic and cultural features of Asian women warrant a tailored approach to breast augmentation. We explore the Asian experience with a thorough exploration of the recent literature. Methods: A literature search was performed for articles written after 2000, of Asian women who underwent augmentation mammoplasty using MEDLINE, Embase, and Pubmed Databases. Technique and outcomes data were summarized. Results: Twelve articles reported outcomes of 2089 women. Korea contributed most series (English language, 7), followed by China (3), Taiwan (1), and Japan (1). Silicone implants were used in 82.1% of women studied, and almost exclusively after 2009. More round (68.9%) than anatomic implants (31.1%) were placed. Non-inframammary (axillary, areolar, and umbilical) incisions were used in 96.9% of cases. Nearly all implants were positioned below the muscle or fascia; subglandular placement accounted for 1.1% of cases. Implant/nipple malposition (1.3%), capsular contracture (1.9%), hematoma (0.6%), and infection (0.2%) rates were reported in most series. Undesirable scarring was the most frequent complication (7.3%), but was reported only in 4 of 12 series. Conclusions: Studies of Asian women undergoing augmentation mammoplasty are limited, often with ill-defined outcomes and inadequate follow-up. As experience accumulates, an expanding literature relevant to Asian women will provide evidence-based guidelines that improve outcomes and patient satisfaction, and foster innovation. PMID:26893980

  5. Primary Breast Augmentation with Fat Grafting.

    PubMed

    Coleman, Sydney R; Saboeiro, Alesia P

    2015-07-01

    The controversy over fat grafting to the breasts has now been settled. In 2009, the American Society of Plastic Surgeons Fat Graft Task Force stated that "Fat grafting may be considered for breast augmentation and correction of defects associated with medical conditions and previous breast surgeries; however, results are dependent on technique and surgeon expertise." This article discusses the history, indications, planning, complications, and present technique of fat grafting to the breast using the Coleman technique. PMID:26116935

  6. Augmentation Mammaplasty Using Implants: A Review

    PubMed Central

    2012-01-01

    One of the techniques for augmentation mammaplasty is the procedure using implants. Even though this technique has been used for many years, there are still several controversial issues to be discussed and overcome for patient safety. In this review article, capsular contracture, leak or rupture of the implants, possible systemic disease, relation with breast cancer, and recent problems with Poly Implant Prothese implants are described and discussed. PMID:23094237

  7. Augmented reality visualization for thoracoscopic spine surgery

    NASA Astrophysics Data System (ADS)

    Sauer, Frank; Vogt, Sebastian; Khamene, Ali; Heining, Sandro; Euler, Ekkehard; Schneberger, Marc; Zuerl, Konrad; Mutschler, Wolf

    2006-03-01

    We are developing an augmented reality (AR) image guidance system in which information derived from medical images is overlaid onto a video view of the patient. The centerpiece of the system is a head-mounted display custom fitted with two miniature color video cameras that capture the stereo view of the scene. Medical graphics is overlaid onto the video view and appears firmly anchored in the scene, without perceivable time lag or jitter. We have been testing the system for different clinical applications. In this paper we discuss minimally invasive thoracoscopic spine surgery as a promising new orthopedic application. In the standard approach, the thoracoscope - a rigid endoscope - provides visual feedback for the minimally invasive procedure of removing a damaged disc and fusing the two neighboring vertebrae. The navigation challenges are twofold. From a global perspective, the correct vertebrae on the spine have to be located with the inserted instruments. From a local perspective, the actual spine procedure has to be performed precisely. Visual feedback from the thoracoscope provides only limited support for both of these tasks. In the augmented reality approach, we give the surgeon additional anatomical context for the navigation. Before the surgery, we derive a model of the patient's anatomy from a CT scan, and during surgery we track the location of the surgical instruments in relation to patient and model. With this information, we can help the surgeon in both the global and local navigation, providing a global map and 3D information beyond the local 2D view of the thoracoscope. Augmented reality visualization is a particularly intuitive method of displaying this information to the surgeon. To adapt our augmented reality system to this application, we had to add an external optical tracking system, which works now in combination with our head-mounted tracking camera. The surgeon's feedback to the initial phantom experiments is very positive.

  8. Ceramic augmentation of the lower jaw.

    PubMed

    Bunte, M; Strunz, V

    1977-11-01

    Atrophy of the lower jaw is essentially a manifestation of vertical bone resorption and must be treated in a compensatory manner. Animal experiments have shown the value of the bioactive glass ceramic Ceravital as a bone replacement material. After box-shaped or step-shaped osteotomies, we perform interpositional plastic operations with glass ceramic in order to augment the atrophied human lower jaw. Results, advantages and dangers of the method are shown in 12 patients. PMID:271190

  9. Percutaneous Vertebral Body Augmentation: An Updated Review

    PubMed Central

    Omidi-Kashani, Farzad

    2014-01-01

    There are many medical conditions like osteoporosis, tumor, or osteonecrosis that weaken the structural strength of the vertebral body and prone it to fracture. Percutaneous vertebral augmentation that is usually applied by polymethylmethacrylate is a relatively safe, effective, and long lasting procedure commonly performed in these situations. In this paper, we updated a review of biomechanics, indications, contraindications, surgical techniques, complications, and overall prognosis of these minimally invasive spinal procedures. PMID:25379561

  10. Silicone-induced Granuloma After Buttock Augmentation

    PubMed Central

    Singh, Mansher; Solomon, Isaac H.; Calderwood, Michael S.

    2016-01-01

    Summary: Liquid silicone is inexpensive, minimally antigenic, and likely noncarcinogenic. Its simplicity of use has made it popular as a soft-tissue filler in some parts of the world for patients seeking rapid soft-tissue augmentation of the face, breast, and buttocks. However, multiple reports describe the complications of silicone injections such as cellulitis, abscess, ulceration, and foreign body migration. We present an unusual complication of granulomatous reaction secondary to silicone injection for buttock augmentation, with a literature review of this entity and treatment options. Our patient was a 54-year-old woman who underwent bilateral buttock augmentation in the Dominican Republic using percutaneous injection of liquid silicone. She presented to our facility 1 year after this procedure with pain and inflammation of both buttocks. She was diagnosed with multiple silicone granulomas. Her symptoms completely resolved with a 3-week course of minocycline. Granulomatous reactions to silicone may occur months to years after the silicone injection. The incidence of such complications may be increased when nonmedical-grade silicone is used, and hence, when these procedures are performed in developing countries. Tetracycline antibiotics, especially minocycline, may be used to achieve sustained remission. PMID:27014553

  11. Augmented classical least squares multivariate spectral analysis

    DOEpatents

    Haaland, David M.; Melgaard, David K.

    2004-02-03

    A method of multivariate spectral analysis, termed augmented classical least squares (ACLS), provides an improved CLS calibration model when unmodeled sources of spectral variation are contained in a calibration sample set. The ACLS methods use information derived from component or spectral residuals during the CLS calibration to provide an improved calibration-augmented CLS model. The ACLS methods are based on CLS so that they retain the qualitative benefits of CLS, yet they have the flexibility of PLS and other hybrid techniques in that they can define a prediction model even with unmodeled sources of spectral variation that are not explicitly included in the calibration model. The unmodeled sources of spectral variation may be unknown constituents, constituents with unknown concentrations, nonlinear responses, non-uniform and correlated errors, or other sources of spectral variation that are present in the calibration sample spectra. Also, since the various ACLS methods are based on CLS, they can incorporate the new prediction-augmented CLS (PACLS) method of updating the prediction model for new sources of spectral variation contained in the prediction sample set without having to return to the calibration process. The ACLS methods can also be applied to alternating least squares models. The ACLS methods can be applied to all types of multivariate data.

  12. Augmented Classical Least Squares Multivariate Spectral Analysis

    DOEpatents

    Haaland, David M.; Melgaard, David K.

    2005-01-11

    A method of multivariate spectral analysis, termed augmented classical least squares (ACLS), provides an improved CLS calibration model when unmodeled sources of spectral variation are contained in a calibration sample set. The ACLS methods use information derived from component or spectral residuals during the CLS calibration to provide an improved calibration-augmented CLS model. The ACLS methods are based on CLS so that they retain the qualitative benefits of CLS, yet they have the flexibility of PLS and other hybrid techniques in that they can define a prediction model even with unmodeled sources of spectral variation that are not explicitly included in the calibration model. The unmodeled sources of spectral variation may be unknown constituents, constituents with unknown concentrations, nonlinear responses, non-uniform and correlated errors, or other sources of spectral variation that are present in the calibration sample spectra. Also, since the various ACLS methods are based on CLS, they can incorporate the new prediction-augmented CLS (PACLS) method of updating the prediction model for new sources of spectral variation contained in the prediction sample set without having to return to the calibration process. The ACLS methods can also be applied to alternating least squares models. The ACLS methods can be applied to all types of multivariate data.

  13. Augmented Classical Least Squares Multivariate Spectral Analysis

    DOEpatents

    Haaland, David M.; Melgaard, David K.

    2005-07-26

    A method of multivariate spectral analysis, termed augmented classical least squares (ACLS), provides an improved CLS calibration model when unmodeled sources of spectral variation are contained in a calibration sample set. The ACLS methods use information derived from component or spectral residuals during the CLS calibration to provide an improved calibration-augmented CLS model. The ACLS methods are based on CLS so that they retain the qualitative benefits of CLS, yet they have the flexibility of PLS and other hybrid techniques in that they can define a prediction model even with unmodeled sources of spectral variation that are not explicitly included in the calibration model. The unmodeled sources of spectral variation may be unknown constituents, constituents with unknown concentrations, nonlinear responses, non-uniform and correlated errors, or other sources of spectral variation that are present in the calibration sample spectra. Also, since the various ACLS methods are based on CLS, they can incorporate the new prediction-augmented CLS (PACLS) method of updating the prediction model for new sources of spectral variation contained in the prediction sample set without having to return to the calibration process. The ACLS methods can also be applied to alternating least squares models. The ACLS methods can be applied to all types of multivariate data.

  14. Ridge augmentation in an organ transplant patient.

    PubMed

    Dalla Torre, D; Burtscher, D

    2016-05-01

    With the continuing progress in medicine, the number of successful organ transplantations has continued to increase, a fact that also concerns dentists and implantologists. Implantology after organ transplantation remains controversial due to the patient's immunocompromised situation and the corresponding risk of infection. Only a few studies on this topic have been reported, with all of them showing the dental implant success rates in transplant patients to be similar to those in healthy subjects. However, immunosuppression has been identified as a contraindication to bone augmentation. Consequently, there is still a lack of knowledge regarding pre-implantology bone grafting procedures. The following case report describes the use of ridge augmentation and extended bilateral sinus lift procedures in a liver transplant patient. The patient was treated with an implant-supported fixed prosthesis in the upper jaw and was followed up for a total of 28 months after implant insertion. According to the findings presented, pre-implantology augmentation procedures may be performed successfully in immunosuppressed organ transplant patients. Stable peri-implant conditions were shown over a period of more than 2 years. Nevertheless, further investigations are needed to define a safe treatment protocol for these high-risk patients. PMID:26711250

  15. Service connectivity architecture for mobile augmented reality

    NASA Astrophysics Data System (ADS)

    Turunen, Tuukka; Pyssysalo, Tino; Roening, Juha

    2001-06-01

    Mobile augmented reality can be utilized in a number of different services, and it provides a lot of added value compared to the interfaces used in mobile multimedia today. Intelligent service connectivity architecture is needed for the emerging commercial mobile augmented reality services, to guarantee mobility and interoperability on a global scale. Some of the key responsibilities of this architecture are to find suitable service providers, to manage the connection with and utilization of such providers, and to allow smooth switching between them whenever the user moves out of the service area of the service provider she is currently connected to. We have studied the potential support technologies for such architectures and propose a way to create an intelligent service connectivity architecture based on current and upcoming wireless networks, an Internet backbone, and mechanisms to manage service connectivity in the upper layers of the protocol stack. In this paper, we explain the key issues of service connectivity, describe the properties of our architecture, and analyze the functionality of an example system. Based on these, we consider our proposition a good solution to the quest for global interoperability in mobile augmented reality services.

  16. Silicone-induced Granuloma After Buttock Augmentation.

    PubMed

    Singh, Mansher; Solomon, Isaac H; Calderwood, Michael S; Talbot, Simon G

    2016-02-01

    Liquid silicone is inexpensive, minimally antigenic, and likely noncarcinogenic. Its simplicity of use has made it popular as a soft-tissue filler in some parts of the world for patients seeking rapid soft-tissue augmentation of the face, breast, and buttocks. However, multiple reports describe the complications of silicone injections such as cellulitis, abscess, ulceration, and foreign body migration. We present an unusual complication of granulomatous reaction secondary to silicone injection for buttock augmentation, with a literature review of this entity and treatment options. Our patient was a 54-year-old woman who underwent bilateral buttock augmentation in the Dominican Republic using percutaneous injection of liquid silicone. She presented to our facility 1 year after this procedure with pain and inflammation of both buttocks. She was diagnosed with multiple silicone granulomas. Her symptoms completely resolved with a 3-week course of minocycline. Granulomatous reactions to silicone may occur months to years after the silicone injection. The incidence of such complications may be increased when nonmedical-grade silicone is used, and hence, when these procedures are performed in developing countries. Tetracycline antibiotics, especially minocycline, may be used to achieve sustained remission. PMID:27014553

  17. A novel family of fluorescent hypoxia sensors reveal strong heterogeneity in tumor hypoxia at the cellular level.

    PubMed

    Erapaneedi, Raghu; Belousov, Vsevolod V; Schäfers, Michael; Kiefer, Friedemann

    2016-01-01

    Hypoxia is an intensively investigated condition with profound effects on cell metabolism, migration, and angiogenesis during development and disease. Physiologically, hypoxia is linked to tissue homeostasis and maintenance of pluripotency. Hypoxia also contributes to pathologies including cardiovascular diseases and cancer. Despite its importance, microscopic visualization of hypoxia is largely restricted to the detection of reductively activated probes by immunostaining. Here, we describe a novel family of genetically encoded fluorescent sensors that detect the activation of HIF transcription factors reported by the oxygen-independent fluorescent protein UnaG. It comprises sensors with different switching and memory behavior and combination sensors that allow the distinction of hypoxic and reoxygenated cells. We tested these sensors on orthotopically transplanted glioma cell lines. Using a cranial window, we could visualize hypoxia intravitally at cellular resolution. In tissue samples, sensor activity was detected in regions, which were largely devoid of blood vessels, correlated with HIF-1α stabilization, and were highly heterogeneous at a cellular level. Frequently, we detected recently reoxygenated cells outside hypoxic areas in the proximity of blood vessels, suggestive of hypoxia-promoted cell migration. PMID:26598532

  18. Induction of WNT11 by hypoxia and hypoxia-inducible factor-1α regulates cell proliferation, migration and invasion

    PubMed Central

    Mori, Hiroyuki; Yao, Yao; Learman, Brian S.; Kurozumi, Kazuhiko; Ishida, Joji; Ramakrishnan, Sadeesh K.; Overmyer, Katherine A.; Xue, Xiang; Cawthorn, William P.; Reid, Michael A.; Taylor, Matthew; Ning, Xiaomin; Shah, Yatrik M.; MacDougald, Ormond A.

    2016-01-01

    Changes in cellular oxygen tension play important roles in physiological processes including development and pathological processes such as tumor promotion. The cellular adaptations to sustained hypoxia are mediated by hypoxia-inducible factors (HIFs) to regulate downstream target gene expression. With hypoxia, the stabilized HIF-α and aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF-β) heterodimer bind to hypoxia response elements (HREs) and regulate expression of target genes. Here, we report that WNT11 is induced by hypoxia in many cell types, and that transcription of WNT11 is regulated primarily by HIF-1α. We observed induced WNT11 expression in the hypoxic area of allograft tumors. In addition, in mice bearing orthotopic malignant gliomas, inhibition with bevacizumab of vascular endothelial growth factor, which is an important stimulus for angiogenesis, increased nuclear HIF-1α and HIF-2α, and expression of WNT11. Gain- and loss-of-function approaches revealed that WNT11 stimulates proliferation, migration and invasion of cancer-derived cells, and increases activity of matrix metalloproteinase (MMP)-2 and 9. Since tumor hypoxia has been proposed to increase tumor aggressiveness, these data suggest WNT11 as a possible target for cancer therapies, especially for tumors treated with antiangiogenic therapy. PMID:26861754

  19. Gene expression promoted by the SV40 DNA targeting sequence and the hypoxia-responsive element under normoxia and hypoxia.

    PubMed

    Sacramento, C B; Moraes, J Z; Denapolis, P M A; Han, S W

    2010-08-01

    The main objective of the present study was to find suitable DNA-targeting sequences (DTS) for the construction of plasmid vectors to be used to treat ischemic diseases. The well-known Simian virus 40 nuclear DTS (SV40-DTS) and hypoxia-responsive element (HRE) sequences were used to construct plasmid vectors to express the human vascular endothelial growth factor gene (hVEGF). The rate of plasmid nuclear transport and consequent gene expression under normoxia (20% O2) and hypoxia (less than 5% O2) were determined. Plasmids containing the SV40-DTS or HRE sequences were constructed and used to transfect the A293T cell line (a human embryonic kidney cell line) in vitro and mouse skeletal muscle cells in vivo. Plasmid transport to the nucleus was monitored by real-time PCR, and the expression level of the hVEGF gene was measured by ELISA. The in vitro nuclear transport efficiency of the SV40-DTS plasmid was about 50% lower under hypoxia, while the HRE plasmid was about 50% higher under hypoxia. Quantitation of reporter gene expression in vitro and in vivo, under hypoxia and normoxia, confirmed that the SV40-DTS plasmid functioned better under normoxia, while the HRE plasmid was superior under hypoxia. These results indicate that the efficiency of gene expression by plasmids containing DNA binding sequences is affected by the concentration of oxygen in the medium. PMID:20640386

  20. Hypoxia in tumors: pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications.

    PubMed

    Vaupel, Peter; Mayer, Arnulf

    2014-01-01

    Hypoxia is a hallmark of tumors leading to (mal-)adaptive processes, development of aggressive phenotypes and treatment resistance. Based on underlying mechanisms and their duration, two main types of hypoxia have been identified, coexisting with complex spatial and temporal heterogeneities. Chronic hypoxia is mainly caused by diffusion limitations due to enlarged diffusion distances and adverse diffusion geometries (e.g., concurrent vs. countercurrent microvessels, Krogh- vs. Hill-type diffusion geometry) and, to a lesser extent, by hypoxemia (e.g., in anemic patients, HbCO formation in heavy smokers), and a compromised perfusion or flow stop (e.g., due to disturbed Starling forces or intratumor solid stress). Acute hypoxia mainly results from transient disruptions in perfusion (e.g., vascular occlusion by cell aggregates), fluctuating red blood cell fluxes or short-term contractions of the interstitial matrix. In each of these hypoxia subtypes oxygen supply is critically reduced, but perfusion-dependent nutrient supply, waste removal, delivery of anticancer or diagnostic agents, and repair competence can be impaired or may not be affected. This detailed differentiation of tumor hypoxia may impact on our understanding of tumor biology and may aid in the development of novel treatment strategies, tumor detection by imaging and tumor targeting, and is thus of great clinical relevance. PMID:24729210

  1. ADAPTIVE AND MALADAPTIVE CARDIORESPIRATORY RESPONSES TO CONTINUOUS AND INTERMITTENT HYPOXIA MEDIATED BY HYPOXIA-INDUCIBLE FACTORS 1 AND 2

    PubMed Central

    Prabhakar, Nanduri R.; Semenza, Gregg L.

    2014-01-01

    Hypoxia is a fundamental stimulus that impacts cells, tissues, organs, and physiological systems. The discovery of hypoxia-inducible factor-1 (HIF-1) and subsequent identification of other members of the HIF family of transcriptional activators has provided insight into the molecular underpinnings of oxygen homeostasis. This review focuses on the mechanisms of HIF activation and their roles in physiological and pathophysiological responses to hypoxia, with an emphasis on the cardiorespiratory systems. HIFs are heterodimers comprised of an O2-regulated HIF-1α or HIF-2α subunit and a constitutively expressed HIF-1β subunit. Induction of HIF activity under conditions of reduced O2 availability requires stabilization of HIF-1α and HIF-2α due to reduced prolyl hydroxylation, dimerization with HIF-1β, and interaction with coactivators due to decreased asparaginyl hydroxylation. Stimuli other than hypoxia, such as nitric oxide and reactive oxygen species, can also activate HIFs. HIF-1 and HIF-2 are essential for acute O2 sensing by the carotid body, and their coordinated transcriptional activation is critical for physiological adaptations to chronic hypoxia including erythropoiesis, vascularization, metabolic reprogramming, and ventilatory acclimatization. In contrast, intermittent hypoxia, which occurs in association with sleep-disordered breathing, results in an imbalance between HIF-1α and HIF-2α that causes oxidative stress, leading to cardiorespiratory pathology. PMID:22811423

  2. Is carbonic anhydrase IX a validated target for molecular imaging of cancer and hypoxia?

    PubMed Central

    Li, Jianbo; Zhang, Guojian; Wang, Xuemei; Li, Xiao-Feng

    2015-01-01

    ABSTRACT  The presence of hypoxia is a general feature of most solid malignancies, and hypoxia is considered as one of major factors for anticancer therapy failure. Carbonic anhydrase IX (CAIX) has been reported to be an endogenous hypoxia marker, CAIX monoclonal antibodies, their segments and inhibitors are developed for CAIX imaging. However, growing evidence indicates that CAIX expression under hypoxia condition may be cancer cell lines or cancer-type dependent. Here we review the current literature on CAIX and discuss the advantage and limitation of CAIX as a target for tumor hypoxia imaging. Accordingly, CAIX would be unreliable as a universal target for cancer and tumor hypoxia visualization. PMID:25963430

  3. Distinct Regulatory Mechanisms of the Human Ferritin Gene by Hypoxia and Hypoxia Mimetic Cobalt Chloride at the Transcriptional and Post-transcriptional Levels

    PubMed Central

    Huang, Bo-Wen; Miyazawa, Masaki; Tsuji, Yoshiaki

    2014-01-01

    Cobalt chloride has been used as a hypoxia mimetic because it stabilizes hypoxia inducible factor-1α (HIF1-α) and activates gene transcription through a hypoxia responsive element (HRE). However, differences between hypoxia and hypoxia mimetic cobalt chloride in gene regulation remain elusive. Expression of ferritin, the major iron storage protein, is regulated at the transcriptional and posttranscriptional levels through DNA and RNA regulatory elements. Here we demonstrate that hypoxia and cobalt chloride regulate ferritin heavy chain (ferritin H) expression by two distinct mechanisms. Both hypoxia and cobalt chloride increased HIF1-α but a putative HRE in the human ferritin H gene was not activated. Instead, cobalt chloride but not hypoxia activated ferritin H transcription through an antioxidant responsive element (ARE), to which Nrf2 was recruited. Intriguingly, cobalt chloride downregulated ferritin H protein expression while upregulated other ARE-regulated antioxidant genes in K562 cells. Further characterization demonstrated that cobalt chloride increased interaction between iron regulatory proteins (IRP1 and IRP2) and iron responsive element (IRE) in the 5′UTR of ferritin H mRNA, resulting in translational block of the accumulated ferritin H mRNA. In contrast, hypoxia had marginal effect on ferritin H transcription but increased its translation through decreased IRP1-IRE interaction. These results suggest that hypoxia and hypoxia mimetic cobalt chloride employ distinct regulatory mechanisms through the interplay between DNA and mRNA elements at the transcriptional and post-transcriptional levels. PMID:25172425

  4. Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function.

    PubMed

    Kelly, Caleb J; Zheng, Leon; Campbell, Eric L; Saeedi, Bejan; Scholz, Carsten C; Bayless, Amanda J; Wilson, Kelly E; Glover, Louise E; Kominsky, Douglas J; Magnuson, Aaron; Weir, Tiffany L; Ehrentraut, Stefan F; Pickel, Christina; Kuhn, Kristine A; Lanis, Jordi M; Nguyen, Vu; Taylor, Cormac T; Colgan, Sean P

    2015-05-13

    Interactions between the microbiota and distal gut are fundamental determinants of human health. Such interactions are concentrated at the colonic mucosa and provide energy for the host epithelium through the production of the short-chain fatty acid butyrate. We sought to determine the role of epithelial butyrate metabolism in establishing the austere oxygenation profile of the distal gut. Bacteria-derived butyrate affects epithelial O2 consumption and results in stabilization of hypoxia-inducible factor (HIF), a transcription factor coordinating barrier protection. Antibiotic-mediated depletion of the microbiota reduces colonic butyrate and HIF expression, both of which are restored by butyrate supplementation. Additionally, germ-free mice exhibit diminished retention of O2-sensitive dyes and decreased stabilized HIF. Furthermore, the influences of butyrate are lost in cells lacking HIF, thus linking butyrate metabolism to stabilized HIF and barrier function. This work highlights a mechanism where host-microbe interactions augment barrier function in the distal gut. PMID:25865369

  5. Nutritional status in chronic obstructive pulmonary disease: role of hypoxia.

    PubMed

    Raguso, Comasia A; Luthy, Christophe

    2011-02-01

    In patients with chronic obstructive pulmonary disease (COPD), malnutrition and limited physical activity are very common and contribute to disease prognosis, whereas a balance between caloric intake and exercise allows body weight stability and muscle mass preservation. The goal of this review is to analyze the implications of chronic hypoxia on three key elements involved in energy homeostasis and its role in COPD cachexia. The first one is energy intake. Body weight loss, often observed in patients with COPD, is related to lack of appetite. Inflammatory cytokines are known to be involved in anorexia and to be correlated to arterial partial pressure of oxygen. Recent studies in animals have investigated the role of hypoxia in peptides involved in food consumption such as leptin, ghrelin, and adenosine monophosphate activated protein kinase. The second element is muscle function, which is strongly related to energy use. In COPD, muscle atrophy and muscle fiber shift to the glycolytic type might be an adaptation to chronic hypoxia to preserve the muscle from oxidative stress. Muscle atrophy could be the result of a marked activation of the ubiquitin-proteasome pathway as found in muscle of patients with COPD. Hypoxia, via hypoxia inducible factor-1, is implicated in mitochondrial biogenesis and autophagy. Third, hormonal control of energy balance seems to be affected in patients with COPD. Insulin resistance has been described in this group of patients as well as a sort of "growth hormone resistance." Hypoxia, by hypoxia inducible factor-1, accelerates the degradation of tri-iodothyronine and thyroxine, decreasing cellular oxygen consumption, suggesting an adaptive mechanism rather than a primary cause of COPD cachexia. COPD rehabilitation aimed at maintaining function and quality of life needs to address body weight stabilization and, in particular, muscle mass preservation. PMID:21145207

  6. No Detectable Hypoxia in Malignant Salivary Gland Tumors: Preliminary Results

    SciTech Connect

    Wijffels, Karien; Hoogsteen, Ilse J.; Lok, Jasper; Rijken, Paulus F.J.W.; Marres, Henri A.M.; Wilde, Peter C.M. de; Kogel, Albert J. van der; Kaanders, Johannes H.A.M.

    2009-04-01

    Purpose: Hypoxia is detected in most solid tumors and is associated with malignant progression and adverse treatment outcomes. However, the oxygenation status of malignant salivary gland tumors has not been previously studied. The aim of this study was to investigate the potential clinical relevance of hypoxia in this tumor type. Methods and Materials: Twelve patients scheduled for surgical resection of a salivary gland tumor were preoperatively injected with the hypoxia marker pimonidazole and the proliferation marker iododeoxyuridine. Tissue samples of the dissected tumor were immunohistochemically stained for blood vessels, pimonidazole, carbonic anhydrase-IX, glucose transporters-1 and -3 (Glut-1, Glut-3), hypoxia-inducible factor-1{alpha}, iododeoxyuridine, and epidermal growth factor receptor. The tissue sections were quantitatively assessed by computerized image analysis. Results: The tissue material from 8 patients was of sufficient quality for quantitative analysis. All tumors were negative for pimonidazole binding, as well as for carbonic anhydrase-IX, Glut-1, Glut-3, and hypoxia-inducible factor-1{alpha}. The vascular density was high, with a median value of 285 mm{sup -2} (range, 209-546). The iododeoxyuridine-labeling index varied from <0.1% to 12.2% (median, 2.2%). Epidermal growth factor receptor expression levels were mostly moderate to high. In one-half of the cases, nuclear expression of epidermal growth factor receptor was observed. Conclusion: The absence of detectable pimonidazole binding, as well as the lack of expression of hypoxia-associated proteins in all tumors, indicates that malignant salivary gland tumors are generally well oxygenated. It is unlikely that hypoxia is a relevant factor for their clinical behavior and treatment responsiveness.

  7. Temporal Onset of Hypoxia and Oxidative Stress After Pulmonary Irradiation

    SciTech Connect

    Fleckenstein, Katharina; Zgonjanin, Larisa; Chen Liguang; Rabbani, Zahid; Jackson, Isabel L.; Thrasher, Bradley; Kirkpatrick, John; Foster, W. Michael; Vujaskovic, Zeljko . E-mail: vujas@radonc.duke.edu

    2007-05-01

    Purpose: To investigate the temporal onset of hypoxia following irradiation, and to show how it relates to pulmonary vascular damage, macrophage accumulation, and the production of reactive oxygen species and cytokines. Our previous studies showed that tissue hypoxia in the lung after irradiation contributed to radiation-induced injury. Methods and Materials: Female Fisher 344 rats were irradiated to the right hemithorax with a single dose of 28 Gy. Serial studies were performed up to 20 weeks following irradiation. Radionuclide lung-perfusion studies were performed to detect changes in pulmonary vasculature. Immunohistochemical studies were conducted to study macrophages, tissue hypoxia (carbonic anhydrase-9 marker), oxidative stress (8-hydroxy-2'-deoxyguanosine), and the expression of profibrogenic (transforming growth factor-{beta} [TGF-{beta}]) and proangiogenic (vascular endothelial growth factor [VEGF]) cytokines. Results: Significant changes in lung perfusion along with tissue hypoxia were observed 3 days after irradiation. Significant oxidative stress was detected 1 week after radiation, whereas macrophages started to accumulate at 4 weeks. A significant increase in TGF-{beta} expression was seen within 1 day after radiation, and for VEGF at 2 weeks after radiation. Levels of hypoxia, oxidative stress, and both cytokines continued to rise with time after irradiation. The steepest increase correlated with vast macrophage accumulation. Conclusions: Early changes in lung perfusion, among other factors initiate, the development of hypoxia and chronic oxidative stress after irradiation. Tissue hypoxia is associated with a significant increase in the activation of macrophages and their continuous production of reactive oxygen species, stimulating the production of fibrogenic and angiogenic cytokines, and maintaining the development of chronic radiation-induced lung injury.

  8. Relaxin Protects Astrocytes from Hypoxia In Vitro

    PubMed Central

    Willcox, Jordan M.; Summerlee, Alastair J. S.

    2014-01-01

    The peptide relaxin has recently been shown to protect brain tissues from the detrimental effects of ischemia. To date, the mechanisms for this remain unclear. In order to investigate the neuroprotective mechanisms by which relaxin may protect the brain, we investigated the possibility that relaxin protects astrocytes from hypoxia or oxygen/glucose deprivation (OGD). Cultured astrocytes were pre-treated with either relaxin-2 or relaxin-3 and exposed to OGD for 24 or 48 hours. Following OGD exposure, viability assays showed that relaxin-treated cells exhibited a higher viability when compared to astrocytes that experienced OGD-alone. Next, to test whether relaxin reduced the production of reactive oxygen species (ROS) astrocytes were exposed to the same conditions as the previous experiment and a commercially available ROS detection kit was used to detect ROS production. Astrocytes that were treated with relaxin-2 and relaxin-3 showed a marked decrease in ROS production when compared to control astrocytes that were exposed only to OGD. Finally, experiments were performed to determine whether or not the mitochondrial membrane potential was affected by relaxin treatment during 24 hour OGD. Mitochondrial membrane potential was higher in astrocytes that were treated with relaxin-2 and relaxin-3 compared to untreated OGD-alone astrocytes. Taken together, these data present novel findings that show relaxin protects astrocytes from ischemic conditions through the reduction of ROS production and the maintenance of mitochondrial membrane potential. PMID:24598861

  9. PH2O and simulated hypobaric hypoxia.

    PubMed

    Conkin, Johnny

    2011-12-01

    Some manufacturers of reduced oxygen (O2) breathing devices claim a comparable hypobaric hypoxia (HH) training experience by providing F1O2 < 0.209 at or near sea level pressure to match the ambient oxygen partial pressure (iso-PO2) of the target altitude. I conclude after a review of literature from investigators and manufacturers that these devices may not properly account for the 47 mmHg of water vapor partial pressure that reduces the inspired partial pressure of oxygen (P1O2), which is substantial at higher altitude relative to sea level. Consequently, some devices claiming an equivalent HH experience under normobaric conditions would significantly overestimate the HH condition, especially when simulating altitudes above 10,000 ft (3048 m). 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. An approach to reduce the overestimation and standardize the operation is to at least provide machines that create the same P1O2 conditions at sea level as at the target altitude, a simple software upgrade. PMID:22195399

  10. The cerebral venous system and hypoxia.

    PubMed

    Wilson, Mark H; Imray, Christopher H E

    2016-01-15

    Most hypobaric hypoxia studies have focused on oxygen delivery and therefore cerebral blood inflow. Few have studied venous outflow. However, the volume of blood entering and leaving the skull (∼700 ml/min) is considerably greater than cerebrospinal fluid production (0.35 ml/min) or edema formation rates and slight imbalances of in- and outflow have considerable effects on intracranial pressure. This dynamic phenomenon is not necessarily appreciated in the currently taught static "Monro-Kellie" doctrine, which forms the basis of the "Tight-Fit" hypothesis thought to underlie high altitude headache, acute mountain sickness, and high altitude cerebral edema. Investigating both sides of the cerebral circulation was an integral part of the 2007 Xtreme Everest Expedition. The results of the relevant studies performed as part of and subsequent to this expedition are reviewed here. The evidence from recent studies suggests a relative venous outflow insufficiency is an early step in the pathogenesis of high altitude headache. Translation of knowledge gained from high altitude studies is important. Many patients in a critical care environment develop hypoxemia akin to that of high altitude exposure. An inability to drain the hypoxemic induced increase in cerebral blood flow could be an underappreciated regulatory mechanism of intracranial pressure. PMID:26294747

  11. RUNX1 and NF-E2 upregulation is not specific for MPNs, but is seen in polycythemic disorders with augmented HIF signaling.

    PubMed

    Kapralova, Katarina; Lanikova, Lucie; Lorenzo, Felipe; Song, Jihyun; Horvathova, Monika; Divoky, Vladimir; Prchal, Josef T

    2014-01-16

    Overexpression of transcription factors runt-related transcription factor 1 (RUNX1) and nuclear factor, erythroid-derived 2 (NF-E2) was reported in granulocytes of patients with polycythemia vera and other myeloproliferative neoplasms (MPNs). Further, a transgenic mouse overexpressing the NF-E2 transgene was reported to be a model of MPN. We hypothesized that increased transcripts of RUNX1 and NF-E2 might characterize other polycythemic states with primary polycythemic features, that is, those with exaggerated erythropoiesis due to augmented erythropoietin (EPO) sensitivity. We tested the expression of RUNX1 and NF-E2 in polycythemic patients of diverse phenotypes and molecular causes. We report that RUNX1 and NF-E2 overexpression is not specific for MPN; these transcripts were also significantly elevated in polycythemias with augmented hypoxia-inducible factor activity whose erythroid progenitors were hypersensitive to EPO. RUNX1 and NF-E2 overexpression was not detected in patients with EPO receptor (EPOR) gain-of-function, suggesting distinct mechanisms by which erythroid progenitors in polycythemias with defects of hypoxia sensing and EPOR mutations exert their EPO hypersensitivity. PMID:24297870

  12. Neuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insults.

    PubMed

    Chio, Chung-Ching; Wei, Li; Chen, Tyng Guey; Lin, Chien-Min; Shieh, Ja-Ping; Yeh, Poh-Shiow; Chen, Ruei-Ming

    2016-06-01

    OBJECT Hypoxia can induce cell death or trigger adaptive mechanisms to guarantee cell survival. Neuron-derived orphan receptor 1 (NOR-1) works as an early-response protein in response to a variety of environmental stresses. In this study, the authors evaluated the roles of NOR-1 in hypoxia-induced neuronal insults. METHODS Neuro-2a cells were exposed to oxygen/glucose deprivation (OGD). Cell viability, cell morphology, cas-pase-3 activity, DNA fragmentation, and cell apoptosis were assayed to determine the mechanisms of OGD-induced neuronal insults. RNA and protein analyses were carried out to evaluate the effects of OGD on expressions of NOR-1, cAMP response element-binding (CREB), and cellular inhibitor of apoptosis protein 2 (cIAP2) genes. Translations of these gene expressions were knocked down using RNA interference. Mice subjected to traumatic brain injury (TBI) and NOR-1 was immunodetected. RESULTS Exposure of neuro-2a cells to OGD decreased cell viability in a time-dependent manner. Additionally, OGD led to cell shrinkage, DNA fragmentation, and cell apoptosis. In parallel, treatment of neuro-2a cells with OGD time dependently increased cellular NOR-1 mRNA and protein expressions. Interestingly, administration of TBI also augmented NOR-1 levels in the impacted regions of mice. As to the mechanism, exposure to OGD increased nuclear levels of the transcription factor CREB protein. Downregulating CREB expression using RNA interference simultaneously inhibited OGD-induced NOR-1 mRNA expression. Also, levels of cIAP2 mRNA and protein in neuro-2a cells were augmented by OGD. After reducing cIAP2 translation, OGD-induced cell death was reduced. Sequentially, application of NOR-1 small interfering RNA to neuro-2a cells significantly inhibited OGD-induced cIAP2 mRNA expression and concurrently alleviated hypoxia-induced alterations in cell viability, caspase-3 activation, DNA damage, and cell apoptosis. CONCLUSIONS This study shows that NOR-1 can transduce survival

  13. Exposure to hypobaric hypoxia results in higher oxidative stress compared to normobaric hypoxia.

    PubMed

    Ribon, A; Pialoux, V; Saugy, J J; Rupp, T; Faiss, R; Debevec, T; Millet, G P

    2016-03-01

    Sixteen healthy exercise trained participants underwent the following three, 10-h exposures in a randomized manner: (1) Hypobaric hypoxia (HH; 3450m terrestrial altitude) (2) Normobaric hypoxia (NH; 3450m simulated altitude) and (3) Normobaric normoxia (NN). Plasma oxidative stress (malondialdehyde, MDA; advanced oxidation protein products, AOPP) and antioxidant markers (superoxide dismutase, SOD; glutathione peroxidase, GPX; catalase; ferric reducing antioxidant power, FRAP) were measured before and after each exposure. MDA was significantly higher after HH compared to NN condition (+24%). SOD and GPX activities were increased (vs. before; +29% and +54%) while FRAP was decreased (vs. before; -34%) only after 10h of HH. AOPP significantly increased after 10h for NH (vs. before; +83%), and HH (vs. before; +99%) whereas it remained stable in NN. These results provide evidence that prooxidant/antioxidant balance was impaired to a greater degree following acute exposure to terrestrial (HH) vs. simulated altitude (NH) and that the chamber confinement (NN) did likely not explain these differences. PMID:26732282

  14. Hypoxia imaging predicts success of hypoxia-induced cytosine deaminase/5-fluorocytosine gene therapy in a murine lung tumor model.

    PubMed

    Lee, B-F; Lee, C-H; Chiu, N-T; Hsia, C-C; Shen, L-H; Shiau, A-L

    2012-04-01

    Tc-99m-HL91 is a hypoxia imaging biomarker. The aim of this study was to investigate the value of Tc-99m-HL91 imaging for hypoxia-induced cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy in a murine lung tumor model. C57BL/6 mice were implanted with Lewis lung carcinoma cells transduced with the hypoxia-inducible promoter-driven CD gene (LL2/CD) or luciferase gene (LL2/Luc) serving as the control. When tumor volumes reached 100 mm(3), pretreatment images were acquired after injection of Tc-99m-HL91. The mice were divided into low and high hypoxic groups based on the tumor-to-non-tumor ratio of Tc-99m-HL91. They were injected daily with 5-FC (500 mg kg(-1)) or the vehicle for 1 week. When tumor volumes reached 1000 mm(3), autoradiography and histological examinations were performed. Treatment with 5-FC delayed tumor growth and enhanced the survival of mice bearing high hypoxic LL2/CD tumors. The therapeutic effect of hypoxia-induced CD/5-FC gene therapy was more pronounced in high hypoxic tumors than in low hypoxic tumors. This study provides the first evidence that Tc-99m-HL91 can serve as an imaging biomarker for predicting the treatment responses of hypoxia-regulated CD/5-FC gene therapy in animal tumor models. Our results suggest that hypoxia imaging using Tc-99m-HL91 has the predictive value for the success of hypoxia-directed treatment regimens. PMID:22281757

  15. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen induction by hypoxia and hypoxia-inducible factors.

    PubMed

    Veeranna, Ravindra P; Haque, Muzammel; Davis, David A; Yang, Min; Yarchoan, Robert

    2012-01-01

    Hypoxia and hypoxia-inducible factors (HIFs) play an important role in the Kaposi's sarcoma-associated herpesvirus (KSHV) life cycle. In particular, hypoxia can activate lytic replication of KSHV and specific lytic genes, including the replication and transcription activator (RTA), while KSHV infection in turn can increase the levels and activity of HIFs. In the present study, we show that hypoxia increases the levels of mRNAs encoding KSHV latency-associated nuclear antigen (LANA) in primary effusion lymphoma (PEL) cell lines and also increases the levels of LANA protein. Luciferase reporter assays in Hep3B cells revealed a moderate activation of the LANA promoter region by hypoxia as well as by cotransfection with degradation-resistant HIF-1α or HIF-2α expression plasmids. Computer analysis of a 1.2-kb sequence upstream of the LANA translational start site identified six potential hypoxia-responsive elements (HRE). Sequential deletion studies revealed that much of this activity was mediated by one of these HREs (HRE 4R) oriented in the 3' to 5' direction and located between the constitutive (LTc) and RTA-inducible (LTi) mRNA start sites. Site-directed mutation of this HRE substantially reduced the response to both HIF-1α and HIF-2α in a luciferase reporter assay. Electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated binding of both HIF-1α and HIF-2α to this region. Also, HIF-1α was found to associate with RTA, and HIFs enhanced the activation of LTi by RTA. These results provide evidence that hypoxia and HIFs upregulate both latent and lytic KSHV replication and play a central role in the life cycle of this virus. PMID:22090111

  16. Effect of Organic Enrichment and Hypoxia on the Biodiversity of Benthic Communities in Narragansett Bay

    EPA Science Inventory

    Excessive input of nitrogen to coastal waters leads to eutrophication and hypoxia that reduce biodiversity and impair key ecosystem services provided by benthic communities; for example, fish and shellfish production, bioturbation, nutrient cycling, and water filtration. Hypoxia ...

  17. Effects of Hypoxia on Animal Burrow Construction and Consequent Effects on Sediment Redox Profiles

    EPA Science Inventory

    Previous studies investigating the effects of hypoxia on benthic infauna and consequent effects on sediment chemistry provide only correlative results from the field. In order to establish causation and isolate effects of hypoxia on individual species, we conducted a laboratory ...

  18. Tumor hypoxia: a new PET imaging biomarker in clinical oncology.

    PubMed

    Tamaki, Nagara; Hirata, Kenji

    2016-08-01

    Tumor hypoxia is associated with tumor progression and resistance to various treatments. Noninvasive imaging using positron emission tomography (PET) and F-18-labeled fluoromisonidazole (FMISO) was recently introduced in order to define and quantify tumor hypoxia. The FMISO uptake was closely correlated with pimonidazole immunohistochemistry and hypoxia-inducible factor 1 expression in basic studies. Tumor hypoxia in head and neck cancers and other tumors in a clinical setting may also indicate resistance to radiation and/or chemotherapy. Hypoxic imaging may thus play a new and important role for suitable radiation planning, including dose escalation and dose reduction based on the image findings. Such radiation-dose painting based on the findings of hypoxia may require high-performance PET imaging to provide high target-to-background ratio images and an optimal quantitative parameter to define the hypoxic region. A multicenter prospective study using data from a large number of patients is also warranted to test the clinical value of hypoxic imaging. PMID:26577447

  19. Modelling macrofaunal biomass in relation to hypoxia and nutrient loading

    NASA Astrophysics Data System (ADS)

    Timmermann, Karen; Norkko, Joanna; Janas, Urszula; Norkko, Alf; Gustafsson, Bo G.; Bonsdorff, Erik

    2012-12-01

    Nutrient loading of aquatic ecosystems results in more food for benthic macrofaunal communities but also increases the risk of hypoxia, resulting in a reduction or complete loss of benthic biomass. This study investigates the interaction between eutrophication, hypoxia and benthic biomass with emphasis on the balance between gains and loss of benthic biomass due to changes in nutrient loadings. A physiological fauna model with 5 functional groups was linked to a 3D coupled hydrodynamic-ecological Baltic Sea model. Model results revealed that benthic biomass increased between 0 and 700% after re-oxygenating bottom waters. Nutrient reduction scenarios indicated improved oxygen concentrations in bottom waters and decreased sedimentation of organic matter up to 40% after a nutrient load reduction following the Baltic Sea Action Plan. The lower food supply to benthos reduced the macrofaunal biomass up to 35% especially in areas not currently affected by hypoxia, whereas benthic biomass increased up to 200% in areas affected by eutrophication-induced hypoxia. The expected changes in benthic biomass resulting from nutrient load reductions and subsequent reduced hypoxia may not only increase the food supply for benthivorous fish, but also significantly affect the biogeochemical functioning of the ecosystem.

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

    PubMed

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

    2014-01-01

    The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia. PMID:25015802

  1. Metabolic adaptation to chronic hypoxia in cardiac mitochondria.

    PubMed

    Heather, Lisa C; Cole, Mark A; Tan, Jun-Jie; Ambrose, Lucy J A; Pope, Simon; Abd-Jamil, Amira H; Carter, Emma E; Dodd, Michael S; Yeoh, Kar Kheng; Schofield, Christopher J; Clarke, Kieran

    2012-05-01

    Chronic hypoxia decreases cardiomyocyte respiration, yet the mitochondrial mechanisms remain largely unknown. We investigated the mitochondrial metabolic pathways and enzymes that were decreased following in vivo hypoxia, and questioned whether hypoxic adaptation was protective for the mitochondria. Wistar rats were housed in hypoxia (7 days acclimatisation and 14 days at 11% oxygen), while control rats were housed in normoxia. Chronic exposure to physiological hypoxia increased haematocrit and cardiac vascular endothelial growth factor, in the absence of weight loss and changes in cardiac mass. In both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria isolated from hypoxic hearts, state 3 respiration rates with fatty acid were decreased by 17-18%, and with pyruvate were decreased by 29-15%, respectively. State 3 respiration rates with electron transport chain (ETC) substrates were decreased only in hypoxic SSM, not in hypoxic IFM. SSM from hypoxic hearts had decreased activities of ETC complexes I, II and IV, which were associated with decreased reactive oxygen species generation and protection against mitochondrial permeability transition pore (MPTP) opening. In contrast, IFM from hypoxic hearts had decreased activity of the Krebs cycle enzyme, aconitase, which did not modify ROS production or MPTP opening. In conclusion, cardiac mitochondrial respiration was decreased following chronic hypoxia, associated with downregulation of different pathways in the two mitochondrial populations, determined by their subcellular location. Hypoxic adaptation was not deleterious for the mitochondria, in fact, SSM acquired increased protection against oxidative damage under the oxygen-limited conditions. PMID:22538979

  2. Vitamin C supplementation does not improve hypoxia-induced erythropoiesis.

    PubMed

    Martinez-Bello, Vladimir E; Sanchis-Gomar, Fabian; Martinez-Bello, Daniel; Olaso-Gonzalez, Gloria; Gomez-Cabrera, Mari Carmen; Viña, Jose

    2012-12-01

    Hypoxia induces reactive oxygen species production. Supplements with antioxidant mixtures can compensate for the decline in red cell membrane stability following intermittent hypobaric hypoxia by decreasing protein and lipid oxidation. We aimed to determine whether supplementation with vitamin C is implicated in the regulation of erythropoiesis and in the oxygen-carrying capacity of the blood, and also whether antioxidant supplementation prevents the oxidative stress associated to intermittent hypoxia. Twenty-four male Wistar rats were randomly divided into four experimental groups: normoxia control (n=6), normoxia + vitamin C (n=6), hypoxia control (12 h pO(2) 12%/12 h pO(2) 21%) (n=6), and hypoxia + vitamin C (n=6). Animals were supplemented with vitamin C at a dose of 250 mg·kg(-1)·day(-1) for 21 days. Red blood cell count, hemoglobin, hematocrit, reticulocytes, erythropoietin, and oxidative stress parameters such as malondialdehyde and protein oxidation in plasma were analyzed at two different time points: basal sample (day zero) and final sample (day 21). Similar RBC, Hb, Hct, and Epo increments were observed in both hypoxic groups regardless of the vitamin C supplementation. There was no change on MDA levels after intermittent hypoxic exposure in any experimental group. However, we found an increase in plasma protein oxidation in both hypoxic groups. Vitamin C does not affect erythropoiesis and protein oxidation in rats submitted to intermittent hypoxic exposure. PMID:23270444

  3. Circulating factors are involved in hypoxia-induced hepcidin suppression.

    PubMed

    Ravasi, Giulia; Pelucchi, Sara; Greni, Federico; Mariani, Raffaella; Giuliano, Andrea; Parati, Gianfranco; Silvestri, Laura; Piperno, Alberto

    2014-12-01

    Hepcidin transcription is strongly down-regulated under hypoxic conditions, however whether hypoxia inhibits hepcidin directly or indirectly is still unknown. We investigated the time course of hypoxia-mediated hepcidin down-regulation in vivo in healthy volunteers exposed to hypobaric hypoxia at high altitude and, based on the hypothesis that circulating factors are implicated in hepcidin inhibition, we analyzed the effect of sera of these volunteers exposed to normoxia and hypoxia on hepcidin expression in Huh-7 cell lines. Hypoxia led to a significant hepcidin down-regulation in vivo that was almost complete within 72h of exposure and followed erythropoietin induction. This delay in hepcidin down-regulation suggests the existence of soluble factor/s regulating hepcidin production. We then stimulated HuH-7 cells with normoxic and hypoxic sera to analyze the effects of sera on hepcidin regulation. Hypoxic sera had a significant inhibitory effect on hepcidin promoter activity assessed by a luciferase assay, although the amount of such decrease was not as relevant as that observed in vivo. Cellular mRNA analysis showed that a number of volunteers' sera inhibited hepcidin expression, concurrently with ID1 inhibition, suggesting that inhibitory factor(s) may act through the SMAD-pathway. PMID:25065484

  4. Could mild hypoxia impair pilot decision making in emergencies?

    PubMed

    Legg, Stephen; Hill, Stephen; Mundel, Toby; Gilbey, Andrew; Schlader, Zac; Raman, Aaron

    2012-01-01

    The decreased pressure in the cabin of a pressurised aircraft (typically equivalent to ~8000 ft) reduces the oxygen level so that the blood oxygen saturation of all occupants falls from >97% (normoxia) at sea-level to below 92% (mild hypoxia). Although exposure to mild hypoxia does not affect well-learned cognitive and motor performance of aircrew, it has been proposed that it can affect the performance of some complex cognitive performance tasks involving multiple demands typical of emergency tasks that may have to be performed by pilots. In order to simulate some of these complex cognitive demands, 25 student volunteers participated in an experiment which assessed performance of complex logical reasoning and and multiple memory tasks before and after 2 hours of exposure to normoxia and mild hypoxia. Performance for the more difficult components of the complex reasoning task, especially involving conflict decisions, were marginally significantly degraded by mild hypoxia. Since the effects were only marginally significant future studies should investigate the effects of mild hypoxia on more subtle complex decision-making tasks. PMID:22316722

  5. Intermittent hypoxia induces functional recovery following cervical spinal injury

    PubMed Central

    Vinit, Stéphane; Lovett-Barr, Mary Rachael; Mitchell, Gordon S.

    2009-01-01

    Respiratory-related complications are the leading cause of death in spinal cord injury (SCI) patients. Few effective SCI treatments are available after therapeutic interventions are performed in the period shortly after injury (e.g. spine stabilization and prevention of further spinal damage). In this review we explore the capacity to harness endogenous spinal plasticity induced by intermittent hypoxia to optimize function of surviving (spared) neural pathways associated with breathing. Two primary questions are addressed: 1) does intermittent hypoxia induce plasticity in spinal synaptic pathways to respiratory motor neurons following experimental SCI? and 2) can this plasticity improve respiratory function? In normal rats, intermittent hypoxia induces serotonin-dependent plasticity in spinal pathways to respiratory motor neurons. Early experiments suggest that intermittent hypoxia also enhances respiratory motor output in experimental models of cervical SCI, (cervical hemisection) and that the capacity to induce functional recovery is greater with longer durations post-injury. Available evidence suggests that intermittent hypoxia-induced spinal plasticity has considerable therapeutic potential to treat respiratory insufficiency following chronic cervical spinal injury. PMID:19651247

  6. Neuroprotective effects of PKC inhibition against chemical hypoxia.

    PubMed

    Pavlaković, G; Eyer, C L; Isom, G E

    1995-04-01

    The effect of potassium cyanide-induced chemical hypoxia on protein kinase C (PKC) translocation and cell injury was studied in differentiated PC12 cells. The cellular distribution of PKC in control cells and cells exposed to 100 microM and 1 mM KCN for 30 min. was visualized by use of an anti-PKC antibody and confocal laser scanning microscope. In control differentiated PC12 cells, PKC was localized perinuclearly, while following 12-phorbol 13-myristate acetate (PMA) or KCN it was translocated to the plasma and organelle membranes. Western blot analysis was used to quantify the translocation. Chemical hypoxia increased the membrane-bound PKC to 210% of control levels, while chelerythrine, a PKC inhibitor, and block of calcium influx into the cells (with calcium channel blocker and calcium-free medium) prevented this effect. Cyanide-induced PKC translocation persisted for at least 120 min. Cell injury was monitored by measuring lactate dehydrogenase (LDH) efflux from the cells 24 hr after addition of cyanide. PKC activation plays a role in hypoxic damage, since PKC down-regulation (by overnight exposure to PMA) or inhibition (with chelerythrine or staurosporine) conferred protection against KCN-induced cytotoxicity. Ca2+ channel blocker nifedipine also protected against chemical hypoxia. None of the pretreatments rendered complete protection against cyanide-induced hypoxia, indicating that PKC-independent mechanism(s) are also activated during chemical hypoxia and contribute to cell injury. PMID:7796171

  7. Cardiosphere-derived cell sheet primed with hypoxia improves left ventricular function of chronically infarcted heart

    PubMed Central

    Hosoyama, Tohru; Samura, Makoto; Kudo, Tomoaki; Nishimoto, Arata; Ueno, Koji; Murata, Tomoaki; Ohama, Takashi; Sato, Koichi; Mikamo, Akihito; Yoshimura, Koichi; Li, Tao-Sheng; Hamano, Kimikazu

    2015-01-01

    Cardiosphere-derived cells (CDCs) isolated from postnatal heart tissue are a convenient and efficientresource for the treatment of myocardial infarction. However, poor retention of CDCs in infarcted hearts often causes less than ideal therapeutic outcomes. Cell sheet technology has been developed as a means of permitting longer retention of graft cells, and this therapeutic strategy has opened new avenues of cell-based therapy for severe ischemic diseases. However, there is still scope for improvement before this treatment can be routinely applied in clinical settings. In this study, we investigated whether hypoxic preconditioning enhances the therapeutic efficacy of CDC monolayer sheets. To induce hypoxia priming, CDC monolayer sheets were placed in an incubator adjusted to 2% oxygen for 24 hours, and then preconditioned mouse CDC sheets were implanted into the infarcted heart of old myocardial infarction mouse models. Hypoxic preconditioning of CDC sheets remarkably increased the expression of vascular endothelial growth factor through the PI3-kinase/Akt signaling pathway. Implantation of preconditioned CDC sheets improved left ventricular function inchronically infarcted hearts and reduced fibrosis. The therapeutic efficacy of preconditioned CDC sheets was higher than the CDC sheets that were cultured under normaxia condition. These results suggest that hypoxic preconditioning augments the therapeutic angiogenic and anti-fibrotic activity of CDC sheets. A combination of cell sheets and hypoxic preconditioning offers an attractive therapeutic protocol for CDC transplantation into chronically infarcted hearts. PMID:26885271

  8. Cardiosphere-derived cell sheet primed with hypoxia improves left ventricular function of chronically infarcted heart.

    PubMed

    Hosoyama, Tohru; Samura, Makoto; Kudo, Tomoaki; Nishimoto, Arata; Ueno, Koji; Murata, Tomoaki; Ohama, Takashi; Sato, Koichi; Mikamo, Akihito; Yoshimura, Koichi; Li, Tao-Sheng; Hamano, Kimikazu

    2015-01-01

    Cardiosphere-derived cells (CDCs) isolated from postnatal heart tissue are a convenient and efficientresource for the treatment of myocardial infarction. However, poor retention of CDCs in infarcted hearts often causes less than ideal therapeutic outcomes. Cell sheet technology has been developed as a means of permitting longer retention of graft cells, and this therapeutic strategy has opened new avenues of cell-based therapy for severe ischemic diseases. However, there is still scope for improvement before this treatment can be routinely applied in clinical settings. In this study, we investigated whether hypoxic preconditioning enhances the therapeutic efficacy of CDC monolayer sheets. To induce hypoxia priming, CDC monolayer sheets were placed in an incubator adjusted to 2% oxygen for 24 hours, and then preconditioned mouse CDC sheets were implanted into the infarcted heart of old myocardial infarction mouse models. Hypoxic preconditioning of CDC sheets remarkably increased the expression of vascular endothelial growth factor through the PI3-kinase/Akt signaling pathway. Implantation of preconditioned CDC sheets improved left ventricular function inchronically infarcted hearts and reduced fibrosis. The therapeutic efficacy of preconditioned CDC sheets was higher than the CDC sheets that were cultured under normaxia condition. These results suggest that hypoxic preconditioning augments the therapeutic angiogenic and anti-fibrotic activity of CDC sheets. A combination of cell sheets and hypoxic preconditioning offers an attractive therapeutic protocol for CDC transplantation into chronically infarcted hearts. PMID:26885271

  9. Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases.

    PubMed

    Tsai, Shih-Hung; Huang, Po-Hsun; Hsu, Yu-Juei; Peng, Yi-Jen; Lee, Chien-Hsing; Wang, Jen-Chun; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Hypoxia inducible factor-1α (HIF-1α) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1α expression could be found at the rupture edge at human abdominal aortic aneurysm (AAA) tissues. While our initial in vitro experiments had shown that deferoxamine (DFO) could attenuate angiotensin II (AngII) induced endothelial activations; we unexpectedly found that DFO augmented the severity of AngII-induced AAA, at least partly through increased accumulation of HIF-1α. The findings promoted us to test whether aneurysmal prone factors could up-regulate the expression of MMP-2 and MMP-9 through aberrantly increased HIF-1α and promote AAA development. AngII induced AAA in hyperlipidemic mice model was used. DFO, as a prolyl hydroxylase inhibitor, stabilized HIF-1α and augmented MMPs activities. Aneurysmal-prone factors induced HIF-1α can cause overexpression of MMP-2 and MMP-9 and promote aneurysmal progression. Pharmacological HIF-1α inhibitors, digoxin and 2-ME could ameliorate AngII induced AAA in vivo. HIF-1α is pivotal for the development of AAA. Our study provides a rationale for using HIF-1α inhibitors as an adjunctive medical therapy in addition to current cardiovascular risk-reducing regimens. PMID:27363580

  10. Inhibition of hypoxia inducible factor-1α attenuates abdominal aortic aneurysm progression through the down-regulation of matrix metalloproteinases

    PubMed Central

    Tsai, Shih-Hung; Huang, Po-Hsun; Hsu, Yu-Juei; Peng, Yi-Jen; Lee, Chien-Hsing; Wang, Jen-Chun; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Hypoxia inducible factor-1α (HIF-1α) pathway is associated with many vascular diseases, including atherosclerosis, arterial aneurysms, pulmonary hypertension and chronic venous diseases. Significant HIF-1α expression could be found at the rupture edge at human abdominal aortic aneurysm (AAA) tissues. While our initial in vitro experiments had shown that deferoxamine (DFO) could attenuate angiotensin II (AngII) induced endothelial activations; we unexpectedly found that DFO augmented the severity of AngII-induced AAA, at least partly through increased accumulation of HIF-1α. The findings promoted us to test whether aneurysmal prone factors could up-regulate the expression of MMP-2 and MMP-9 through aberrantly increased HIF-1α and promote AAA development. AngII induced AAA in hyperlipidemic mice model was used. DFO, as a prolyl hydroxylase inhibitor, stabilized HIF-1α and augmented MMPs activities. Aneurysmal-prone factors induced HIF-1α can cause overexpression of MMP-2 and MMP-9 and promote aneurysmal progression. Pharmacological HIF-1α inhibitors, digoxin and 2-ME could ameliorate AngII induced AAA in vivo. HIF-1α is pivotal for the development of AAA. Our study provides a rationale for using HIF-1α inhibitors as an adjunctive medical therapy in addition to current cardiovascular risk-reducing regimens. PMID:27363580

  11. Heat transfer augmentation in nanofluids via nanofins.

    PubMed

    Vadasz, Peter

    2011-01-01

    Theoretical results derived in this article are combined with experimental data to conclude that, while there is no improvement in the effective thermal conductivity of nanofluids beyond the Maxwell's effective medium theory (J.C. Maxwell, Treatise on Electricity and Magnetism, 1891), there is substantial heat transfer augmentation via nanofins. The latter are formed as attachments on the hot wire surface by yet an unknown mechanism, which could be related to electrophoresis, but there is no conclusive evidence yet to prove this proposed mechanism. PMID:21711695

  12. Flow Augmentation in Acute Ischemic Stroke.

    PubMed

    Yadollahikhales, Golnaz; Borhani-Haghighi, Afshin; Torabi-Nami, Mohammad; Edgell, Randall; Cruz-Flores, Salvador

    2016-01-01

    There is an urgent need for additional therapeutic options for acute ischemic stroke considering the major pitfalls of the options available. Herein, we briefly review the role of cerebral blood flow, collaterals, vasoreactivity, and reperfusion injury in acute ischemic stroke. Then, we reviewed pharmacological and interventional measures such as volume expansion and induced hypertension, intra-aortic balloon counterpulsation, partial aortic occlusion, extracranial-intracranial carotid bypass surgery, sphenopalatine ganglion stimulation, and transcranial laser therapy with regard to their effects on flow augmentation and neuroprotection. PMID:25475112

  13. Heat transfer augmentation in nanofluids via nanofins

    PubMed Central

    2011-01-01

    Theoretical results derived in this article are combined with experimental data to conclude that, while there is no improvement in the effective thermal conductivity of nanofluids beyond the Maxwell's effective medium theory (J.C. Maxwell, Treatise on Electricity and Magnetism, 1891), there is substantial heat transfer augmentation via nanofins. The latter are formed as attachments on the hot wire surface by yet an unknown mechanism, which could be related to electrophoresis, but there is no conclusive evidence yet to prove this proposed mechanism. PMID:21711695

  14. Simple bone augmentation for alveolar ridge defects.

    PubMed

    Haggerty, Christopher J; Vogel, Christopher T; Fisher, G Rawleigh

    2015-05-01

    Dental implant procedures, both surgical placement and preimplant bone augmentation, have become an integral aspect of the oral and maxillofacial surgeon's practice. The number of dental implants placed each year continues to increase as a result of increasing patient exposure and awareness of dental implants, the increased functional and esthetic dental demands of general practitioners and patients, the overall increase in age of the US patient population, and expanded insurance coverage of dental implant-related procedures. This article outlines relevant surgical procedures aimed toward reconstructing alveolar ridge defects to restore intra-arch alveolar discrepancies before restoration-driven dental implant placement. PMID:25951957

  15. Dose audit failures and dose augmentation

    NASA Astrophysics Data System (ADS)

    Herring, C.

    1999-01-01

    Standards EN 552 and ISO 11137, covering radiation sterilization, are technically equivalent in their requirements for the selection of the sterilization dose. Dose Setting Methods 1 and 2 described in Annex B of ISO 11137 can be used to meet these requirements for the selection of the sterilization dose. Both dose setting methods require a dose audit every 3 months to determine the continued validity of the sterilization dose. This paper addresses the subject of dose audit failures and investigations into their cause. It also presents a method to augment the sterilization dose when the number of audit positives exceeds the limits imposed by ISO 11137.

  16. Wind energy converter utilizing vortex augmentation

    SciTech Connect

    Edwards, S. S.

    1985-05-14

    A wind energy conversion apparatus is disclosed herein for converting the linear momentum of wind energy into a pair of concentrated, counter-rotating and side-by-side regions of high angular momentum which includes a wing having variable angle of attack positionable forward of the entrance to an elongated duct having a bell mouth including an upper, inner reflex angular surface leading into a bifurcated duct section terminating in a diffuser augmenter at the aft facing area of the duct and which includes propellors operable to extract energy from the angular momentum in the established regions for driving electric generators or generator therefrom.

  17. B-52 stability augmentation system reliability

    NASA Technical Reports Server (NTRS)

    Bowling, T. C.; Key, L. W.

    1976-01-01

    The B-52 SAS (Stability Augmentation System) was developed and retrofitted to nearly 300 aircraft. It actively controls B-52 structural bending, provides improved yaw and pitch damping through sensors and electronic control channels, and puts complete reliance on hydraulic control power for rudder and elevators. The system has experienced over 300,000 flight hours and has exhibited service reliability comparable to the results of the reliability test program. Development experience points out numerous lessons with potential application in the mechanization and development of advanced technology control systems of high reliability.

  18. Lean stability augmentation for premixing, prevaporizing combustors

    NASA Technical Reports Server (NTRS)

    Mcvey, J. B.; Kennedy, J. B.

    1979-01-01

    An experimental program was conducted to investigate techniques for improving the lean combustion limits of premixing, prevaporizing combustors applicable to gas turbine engine main burners. Augmented flameholders employing recessed perforated plates, catalyzed tube bundles, and configurations in which pilot fuel was injected into the wakes of V-gutters or perforated plates were designed and tested. Stable operation of the piloted designs was achieved at equivalence ratios as low as 0.25; NOx emissions of less than 1.0 g/kg at simulated turbine engine cruise conditions were obtained. A piloted perforated plate employing four percent pilot fuel flow produced the best performance while meeting severe NOx constraints.

  19. Augmented virtuality for arthroscopic knee surgery.

    PubMed

    Li, John M; Bardana, Davide D; Stewart, A James

    2011-01-01

    This paper describes a computer system to visualize the location and alignment of an arthroscope using augmented virtuality. A 3D computer model of the patient's joint (from CT) is shown, along with a model of the tracked arthroscopic probe and the projection of the camera image onto the virtual joint. A user study, using plastic bones instead of live patients, was made to determine the effectiveness of this navigated display; the study showed that the navigated display improves target localization in novice residents. PMID:22003616

  20. Entrainment and mixing in thrust augmenting ejectors

    NASA Technical Reports Server (NTRS)

    Bernal, L.; Sarohia, V.

    1983-01-01

    An experimental investigation of two-dimensional thrust augmenting ejector flows has been conducted. Measurements of the shroud surface pressure distribution, mean velocity, turbulent intensities and Reynolds stresses were made in two shroud geometries at various primary nozzle pressure ratios. The effects of shroud geometry and primary nozzle pressure ratio on the shroud surface pressure distribution, mean flow field and turbulent field were determined. From these measurements the evolution of mixing within the shroud of the primary flow and entrained fluid was obtained. The relationship between the mean flow field, the turbulent field and the shroud surface pressure distribution is discussed.

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

    PubMed

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

    2014-10-01

    Obstructive sleep apnea (OSA) consists of sleep-related repetitive obstructions of upper airways that generate episodes of recurrent or intermittent hypoxia (IH). OSA commonly generates cardiovascular and metabolic pathologies defining the obstructive sleep apnea syndrome (OSAS). Literature usually links OSA-associated pathologies to IH episodes that would cause an oxidative status and a carotid body-mediated sympathetic hyperactivity. Because cardiovascular and metabolic pathologies in obese patients and those with OSAS are analogous, we used models (24-wk-old Wistar rats) of IH (applied from weeks 22 to 24) and diet-induced obesity (O; animals fed a high-fat diet from weeks 12 to 24) to define the effect of each individual maneuver and their combination on the oxidative status and sympathetic tone of animals, and to quantify cardiovascular and metabolic parameters and their deviation from normality. We found that IH and O cause an oxidative status (increased lipid peroxides and diminished activities of superoxide dismutases), an inflammatory status (augmented C-reactive protein and nuclear factor kappa-B activation), and sympathetic hyperactivity (augmented plasma and renal artery catecholamine levels and synthesis rate); combined treatments worsened those alterations. IH and O augmented liver lipid content and plasma cholesterol, triglycerides, leptin, glycemia, insulin levels, and HOMA index, and caused hypertension; most of these parameters were aggravated when IH and O were combined. IH diminished ventilatory response to hypoxia, and hypercapnia and O created a restrictive ventilatory pattern; a combination of treatments led to restrictive hypoventilation. Data demonstrate that IH and O cause comparable metabolic and cardiovascular pathologies via misregulation of the redox status and sympathetic hyperactivity. PMID:25103975

  2. Ubiquitin-specific Protease 19 (USP19) Regulates Hypoxia-inducible Factor 1α (HIF-1α) during Hypoxia*

    PubMed Central

    Altun, Mikael; Zhao, Bin; Velasco, Kelly; Liu, Haiyin; Hassink, Gerco; Paschke, Julia; Pereira, Teresa; Lindsten, Kristina

    2012-01-01

    A proper cellular adaptation to low oxygen levels is essential for processes such as development, growth, metabolism, and angiogenesis. The response to decrease in oxygen supply, referred to as hypoxia, is also involved in numerous human diseases including cancer, inflammatory conditions, and vascular disease. The hypoxia-inducible factor 1-α (HIF-1α), a key player in the hypoxic response, is kept under stringent regulation. At normoxia, the levels are kept low as a consequence of the efficient degradation by the ubiquitin-proteasome system, and in response to hypoxia, the degradation is blocked and the accumulating HIF-1α promotes a transcriptional response essential for proper adaptation and survival. Here we show that the ubiquitin-specific protease-19 (USP19) interacts with components of the hypoxia pathway including HIF-1α and rescues it from degradation independent of its catalytic activity. In the absence of USP19, cells fail to mount an appropriate response to hypoxia, indicating an important role for this enzyme in normal or pathological conditions. PMID:22128162

  3. Tasting arterial blood: what do the carotid chemoreceptors sense?

    PubMed Central

    Prabhakhar, Nanduri R.; Joyner, Michael J.

    2015-01-01

    The carotid bodies are sensory organs that detect the chemical composition of the arterial blood. The carotid body sensory activity increases in response to arterial hypoxemia and the ensuing chemoreflex regulates vital homeostatic functions. Recent studies suggest that the carotid bodies might also sense arterial blood glucose and circulating insulin levels. This review focuses on how the carotid bodies sense O2, glucose, and insulin and some potential implications of these sensory functions on physiological regulation and in pathophysiological conditions. Emerging evidence suggests that carbon monoxide (CO)-regulated hydrogen sulfide (H2S), stemming from hypoxia, depolarizes type I cells by inhibiting certain K+ channels, facilitates voltage-gated Ca2+ influx leading to sensory excitation of the carotid body. Elevated CO and decreased H2S renders the carotid bodies insensitive to hypoxia resulting in attenuated ventilatory adaptations to high altitude hypoxia, whereas reduced CO and high H2S result in hypersensitivity of the carotid bodies to hypoxia and hypertension. Acute hypoglycemia augments the carotid body responses to hypoxia but that a prolonged lack of glucose in the carotid bodies can lead to a failure to sense hypoxia. Emerging evidence also indicates that carotid bodies might sense insulin directly independent of its effect on glucose, linking the carotid bodies to the pathophysiological consequences of the metabolic syndrome. How glucose and insulin interact with the CO-H2S signaling is an area of ongoing study. PMID:25642193

  4. A possible role for hypoxia-induced apelin expression in enteric cell proliferation.

    PubMed

    Han, Song; Wang, Guiyun; Qi, Xiang; Lee, Heung M; Englander, Ella W; Greeley, George H

    2008-06-01

    Apelin is the endogenous ligand for the APJ receptor, and apelin and APJ are expressed in the gastrointestinal (GI) tract. Intestinal inflammation increases intestinal hypoxia-inducible factor (HIF) and apelin expression. Hypoxia and inflammation are closely linked cellular insults. The purpose of these studies was to investigate the influence of hypoxia on enteric apelin expression. Exposure of rat pups to acute hypoxia increased hepatic, stomach-duodenal, and colonic apelin mRNA levels 10-, 2-, and 2-fold, respectively (P < 0.05 vs. controls). Hypoxia also increased colonic APJ mRNA levels, and apelin treatment during hypoxia exposure enhanced colonic APJ mRNA levels further. In vitro hypoxia also increased apelin and APJ mRNA levels. The hypoxia-induced elevation in apelin expression is most likely mediated by HIF, since HIF-activated apelin transcriptional activity is dependent on an intact, putative HIF binding site in the rat apelin promoter. Acute exposure of rat pups to hypoxia lowered gastric and colonic epithelial cell proliferation; hypoxia in combination with apelin treatment increased epithelial proliferation by 50%. In vitro apelin treatment of enteric cells exposed to hypoxia increased cell proliferation. Apelin treatment during normoxia was ineffective. Our studies imply that the elevation in apelin expression during hypoxia and inflammation in the GI tract functions in part to stimulate epithelial cell proliferation. PMID:18367654

  5. Cyclic hypoxia does not alter RAD51 expression or PARP inhibitor cell kill in tumor cells.

    PubMed

    Kumareswaran, Ramya; Chaudary, Naz; Jaluba, Karolina; Meng, Alice; Sykes, Jenna; Borhan, Asm; Hill, Richard P; Bristow, Robert G

    2015-09-01

    Solid tumors contain regions of chronic and cyclic hypoxia. Chronic hypoxia can downregulate RAD51 and sensitize cells to PARP inhibition. Herein, we show that RAD51 expression, cell survival and toxicity to PARP inhibition is not affected under cyclic hypoxic conditions. This suggests that PARP inhibition may be selectively toxic in tumor sub-regions associated with chronic hypoxia. PMID:25842967

  6. Modulation of the sympathetic response to acute hypoxia by the caudal ventrolateral medulla in rats

    PubMed Central

    Mandel, Daniel A; Schreihofer, Ann M

    2009-01-01

    Hypoxia elevates splanchnic sympathetic nerve activity (SNA) with differential effects during inspiration and expiration by unresolved central mechanisms. We examined the hypothesis that cardiovascular-related neurones in the caudal ventrolateral medulla (CVLM) contribute to the complex sympathetic response to hypoxia. In chloralose-anaesthetized, ventilated, vagotomized rats, acute hypoxia (10% O2, 60 s) evoked an increase in SNA (103 ± 12%) that was characterized by a decrease in activity during early inspiration followed by a prominent rise during expiration. Some recorded baro-activated CVLM neurones (n= 13) were activated by hypoxia, and most of these neurones displayed peak activity during inspiration that was enhanced during hypoxia. In contrast, other baro-activated CVLM neurones were inhibited during hypoxia (n= 6), and most of these neurones showed peak activity during expiration prior to the onset of hypoxia. Microinjection of the glutamate antagonist kynurenate into the CVLM eliminated the respiratory-related fluctuations in SNA during hypoxia and exaggerated the magnitude of the sympathetic response. In contrast, microinjection of a GABAA antagonist (bicuculline or gabazine) into the CVLM dramatically attenuated the sympathetic response to hypoxia. These data suggest the response to hypoxia in baro-activated CVLM neurones is related to their basal pattern of respiratory-related activity, and changes in the activity of these neurones is consistent with a contribution to the respiratory-related sympathetic responses to hypoxia. Furthermore, both glutamate and GABA in the CVLM contribute to the complex sympathetic response to acute hypoxia. PMID:19047207

  7. Metabolic and locomotor responses of juvenile paddlefish Polyodon spathula to hypoxia and temperature

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hypoxia is an increasing problem in the natural habitats that the paddlefish (Polyodon spathula) has historically inhabited, and a potential problem in managed culture conditions. However, the effects of hypoxia on paddlefish are not well understood. In order to understand the effects of hypoxia on ...

  8. Changes in enzyme activities in tissues of rats exposed to hypoxia (Short Communication)

    PubMed Central

    Cryer, Anthony; Bartley, Walter

    1973-01-01

    Rats were exposed to various degrees of hypoxia and enzyme activities in their tissues were determined. In general, oxidative metabolism was not increased in response to hypoxia, nor was anaerobic metabolism. Physiological and anatomical changes were concluded to be more important than changes in cellular enzyme activities in the overall adaptation to acute hypoxia. PMID:4357712

  9. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia

    PubMed Central

    Guise, Christopher P.; Mowday, Alexandra M.; Ashoorzadeh, Amir; Yuan, Ran; Lin, Wan-Hua; Wu, Dong-Hai; Smaill, Jeff B.; Patterson, Adam V.; Ding, Ke

    2014-01-01

    Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples. PMID:23845143

  10. Bioreductive fluorescent imaging agents: applications to tumour hypoxia.

    PubMed

    Elmes, Robert B P

    2016-07-12

    Large tumours contain regions with very low intracellular O2 concentrations. Known as hypoxia, this feature of tumours yields a highly reducing environment owing to the presence of numerous oxygen sensitive reductase enzymes. The development of new optical chemosensors for these various reductases presents an ideal approach to visualise areas of hypoxia or highly reducing environments. Critical to the success of such chemosensors is the design of probes containing a bioreductively activated moiety that either ensures the selective retention of fluorescence within a hypoxic tissue or a probe that irreversibly releases a reporter fluorophore. This Feature Article aims to summarise the fluorescent tools that have been developed to image tumour hypoxia and the various reductase enzymes associated with the bioreduction process. PMID:26924320

  11. Obstructive sleep apnea and cancer: effects of intermittent hypoxia?

    PubMed

    Kukwa, Wojciech; Migacz, Ewa; Druc, Karolina; Grzesiuk, Elzbieta; Czarnecka, Anna M

    2015-01-01

    Obstructive sleep apnea (OSA) is a common disorder characterized by pauses in regular breathing. Apneic episodes lead to recurrent hypoxemia-reoxygenation cycles with concomitant cellular intermittent hypoxia. Studies suggest that intermittent hypoxia in OSA may influence tumorigenesis. This review presents recent articles on the potential role of OSA in cancer development. Relevant research has focused on: molecular pathways mediating the influence of intermittent hypoxia on tumor physiology, animal and epidemiological human studies linking OSA and cancer. Current data relating OSA to risk of neoplastic disease remain scarce, but recent studies reveal the potential for a strong relation. More work is, therefore, needed on the impact of OSA on many cancer-related aspects. Results may offer enlightenment for improved cancer diagnosis and treatment. PMID:26562000

  12. Relationships between Cycling Hypoxia, HIF-1, Angiogenesis and Oxidative Stress

    PubMed Central

    Dewhirst, Mark W.

    2009-01-01

    This Failla Lecture focused on the inter-relationships between tumor angiogenesis, HIF-1 expression and radiotherapy responses. A common thread that bonds all of these factors together is microenvironmental stress caused by reactive oxygen and nitrogen species formed during tumor growth and angiogenesis or in response to cytotoxic treatment. In this review we focus on one aspect of the crossroad between oxidative stress and angiogenesis, namely cycling hypoxia. Understanding of the relative importance of this feature of the tumor microenvironment has recently expanded; it influences tumor biology in ways that are separate from chronic hypoxia. Cycling hypoxia can influence angiogenesis, treatment responses and metastatic behavior. It represents an important and relatively less well understood feature of tumor biology that requires additional research. PMID:19929412

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

    PubMed

    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

  14. Hypoxia-inducible factors and sphingosine 1-phosphate signaling.

    PubMed

    Cuvillier, Olivier; Ader, Isabelle

    2011-11-01

    Hypoxia, defined as reduced tissue oxygen concentration, is a characteristic of solid tumors and is an indicator of unfavorable diagnosis in patients. At the cellular level, the adaptation to hypoxia is under the control of two related transcription factors, HIF-1α and HIF-2α (Hypoxia-Inducible Factor), which activate expression of genes promoting angiogenesis, metastasis, increased tumor growth and resistance to treatments. A role for HIF-1α and HIF-2α is also emerging in hematologic malignancies such as lymphoma and l eukemia. Recent studies have identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway - which elicits various cellular processes including cell proliferation, cell survival or angiogenesis - as a new regulator of HIF-1α or HIF-2α activity. This review will consider how targeting the SphK1/S1P signaling could represent an attractive strategy for therapeutic intervention in cancer. PMID:21707486

  15. Hypoxia-mediated regulation of gene expression in mammalian cells

    PubMed Central

    Shih, Shu-Ching; Claffey, Kevin P.

    1998-01-01

    The molecular mechanism underlying oxygen sensing in mammalian cells has been extensively investigated in the areas of glucose transport, glycolysis, erythropoiesis, angiogenesis and catecholamine metabolism. Expression of functionally operative representative proteins in these specific areas, such as the glucose transporter 1, glycolytic enzymes, erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase are all induced by hypoxia. Recent studies demonstrated that both transcriptional activation and post-transcriptional mechanisms are important to the hypoxia-mediated regulation of gene expression. In this article, the cis-acting elements and trans-acting factors involved in the transcriptional activation of gene expression will be reviewed. In addition, the mechanisms of post-transcriptional mRNA stabilization will also be addressed. We will discuss whether these two processes of regulation of hypoxia-responsive genes are mechanistically linked and co-operative in nature. PMID:10319016

  16. Calcium-dependent activation of Pyk2 by hypoxia.

    PubMed

    Beitner-Johnson, Dana; Ferguson, Tsuneo; Rust, Randy T; Kobayashi, Shuichi; Millhorn, David E

    2002-02-01

    The Pyk2 tyrosine kinase can be activated by both calcium-dependent and calcium-independent mechanisms. Exposure to moderate hypoxia (5% O(2)) induced a rapid and persistent tyrosine phosphorylation of Pyk2 in pheochromocytoma (PC12) cells. Hypoxia and KCl-depolarization increased the phosphotyrosine content of Pyk2 by twofold and fourfold, respectively. Both of these effects were abolished in the absence of extracellular calcium. There was a modest activation of MAPK in parallel with the onset of Pyk2 phosphorylation. However, there was no detectable activation of either JNK or c-src, two other known downstream targets of Pyk2. Thus, exposure to hypoxia may selectively target specific subsets of Pyk2 signalling pathways. PMID:11781137

  17. Augmenting Your Own Reality: Student Authoring of Science-Based Augmented Reality Games

    ERIC Educational Resources Information Center

    Klopfer, Eric; Sheldon, Josh

    2010-01-01

    Augmented Reality (AR) simulations superimpose a virtual overlay of data and interactions onto a real-world context. The simulation engine at the heart of this technology is built to afford elements of game play that support explorations and learning in students' natural context--their own community and surroundings. In one of the more recent…

  18. Aging, Tolerance to High Altitude, and Cardiorespiratory Response to Hypoxia.

    PubMed

    Richalet, Jean-Paul; Lhuissier, François J

    2015-06-01

    Richalet, Jean-Paul, and François J. Lhuissier. Aging, tolerance to high altitude, and cardiorespiratory response to hypoxia. High Alt Med Biol. 16:117-124, 2015.--It is generally accepted that aging is rather protective, at least at moderate altitude. Some anecdotal reports even mention successful ascent of peaks over 8000 m and even Everest by elderly people. However, very few studies have explored the influence of aging on tolerance to high altitude and prevalence of acute high altitude related diseases, taking into account all confounding factors such as speed of ascent, altitude reached, sex, training status, and chemo-responsiveness. Changes in physiological responses to hypoxia with aging were assessed through a cross-sectional 20-year study including 4675 subjects (2789 men, 1886 women; 14-85 yrs old) and a longitudinal study including 30 subjects explored at a mean 10.4-year interval. In men, ventilatory response to hypoxia increased, while desaturation was less pronounced with aging. Cardiac response to hypoxia was blunted with aging in both genders. Similar results were found in the longitudinal study, with a decrease in cardiac and an increase in ventilatory response to hypoxia with aging. These adaptive responses were less pronounced or absent in post-menopausal untrained women. In conclusion, in normal healthy and active subjects, aging has no deleterious effect on cardiac and ventilatory responses to hypoxia, at least up to the eighth decade. Aging is not a contraindication for high altitude, as far as no pathological condition interferes and physical fitness is compatible with the intensity of the expected physical demand of one's individual. Physiological evaluation through hypoxic exercise testing before going to high altitude is helpful to detect risk factors of severe high altitude-related diseases. PMID:25946570

  19. Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

    PubMed Central

    Neusser, Matthias A.; Lindenmeyer, Maja T.; Moll, Anton G.; Segerer, Stephan; Edenhofer, Ilka; Sen, Kontheari; Stiehl, Daniel P.; Kretzler, Matthias; Gröne, Hermann-Josef; Schlöndorff, Detlef; Cohen, Clemens D.

    2010-01-01

    In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or “hypertensive nephropathy.” In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1α only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC. PMID:20019191

  20. Vitamin C Supplementation Does not Improve Hypoxia-Induced Erythropoiesis

    PubMed Central

    Sanchis-Gomar, Fabian; Martinez-Bello, Daniel; Olaso-Gonzalez, Gloria; Gomez-Cabrera, Mari Carmen; Viña, Jose

    2012-01-01

    Abstract Martinez-Bello,Vladimir E., Fabian Sanchis-Gomar, Daniel Martinez-Bello, Gloria Olaso-Gonzalez, Mari Carmen Gomez-Cabrera, and Jose Viña. Vitamin C Supplementation Does Not Improve Hypoxia-Induced Erythropoiesis. High Alt Med Biol 13:269–274, 2012.—Hypoxia induces reactive oxygen species production. Supplements with antioxidant mixtures can compensate for the decline in red cell membrane stability following intermittent hypobaric hypoxia by decreasing protein and lipid oxidation. We aimed to determine whether supplementation with vitamin C is implicated in the regulation of erythropoiesis and in the oxygen-carrying capacity of the blood, and also whether antioxidant supplementation prevents the oxidative stress associated to intermittent hypoxia. Twenty-four male Wistar rats were randomly divided into four experimental groups: normoxia control (n=6), normoxia + vitamin C (n=6), hypoxia control (12 h pO2 12%/12 h pO2 21%) (n=6), and hypoxia + vitamin C (n=6). Animals were supplemented with vitamin C at a dose of 250 mg·kg−1·day−1 for 21 days. Red blood cell count, hemoglobin, hematocrit, reticulocytes, erythropoietin, and oxidative stress parameters such as malondialdehyde and protein oxidation in plasma were analyzed at two different time points: basal sample (day zero) and final sample (day 21). Similar RBC, Hb, Hct, and Epo increments were observed in both hypoxic groups regardless of the vitamin C supplementation. There was no change on MDA levels after intermittent hypoxic exposure in any experimental group. However, we found an increase in plasma protein oxidation in both hypoxic groups. Vitamin C does not affect erythropoiesis and protein oxidation in rats submitted to intermittent hypoxic exposure. PMID:23270444