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Sample records for moderate brain hypoxia

  1. Selective vulnerability in brain hypoxia

    DEFF Research Database (Denmark)

    Cervos-Navarro, J.; Diemer, Nils Henrik

    1991-01-01

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

  2. Moderate hypoxia followed by reoxygenation results in blood-brain barrier breakdown via oxidative stress-dependent tight-junction protein disruption.

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    Christoph M Zehendner

    Full Text Available Re-canalization of cerebral vessels in ischemic stroke is pivotal to rescue dysfunctional brain areas that are exposed to moderate hypoxia within the penumbra from irreversible cell death. Goal of the present study was to evaluate the effect of moderate hypoxia followed by reoxygenation (MHR on the evolution of reactive oxygen species (ROS and blood-brain barrier (BBB integrity in brain endothelial cells (BEC. BBB integrity was assessed in BEC in vitro and in microvessels of the guinea pig whole brain in situ preparation. Probes were exposed to MHR (2 hours 67-70 mmHg O2, 3 hours reoxygenation, BEC or towards occlusion of the arteria cerebri media (MCAO with or without subsequent reperfusion in the whole brain preparation. In vitro BBB integrity was evaluated using trans-endothelial electrical resistance (TEER and transwell permeability assays. ROS in BEC were evaluated using 2',7'-dichlorodihydrofluorescein diacetate (DCF, MitoSox and immunostaining for nitrotyrosine. Tight-junction protein (TJ integrity in BEC, stainings for nitrotyrosine and FITC-albumin extravasation in the guinea pig brain preparation were assessed by confocal microscopy. Diphenyleneiodonium (DPI was used to investigate NADPH oxidase dependent ROS evolution and its effect on BBB parameters in BEC. MHR impaired TJ proteins zonula occludens 1 (ZO-1 and claudin 5 (Cl5, decreased TEER, and significantly increased cytosolic ROS in BEC. These events were blocked by the NADPH oxidase inhibitor DPI. MCAO with or without subsequent reoxygenation resulted in extravasation of FITC-albumin and ROS generation in the penumbra region of the guinea pig brain preparation and confirmed BBB damage. BEC integrity may be impaired through ROS in MHR on the level of TJ and the BBB is also functionally impaired in moderate hypoxic conditions followed by reperfusion in a complex guinea pig brain preparation. These findings suggest that the BBB is susceptible towards MHR and that ROS play a key role

  3. Brain hypoxia imaging

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    Song, Ho Chun [Chonnam National University Medical School, Gwangju (Korea, Republic of)

    2007-04-15

    The measurement of pathologically low levels of tissue pO{sub 2} is an important diagnostic goal for determining the prognosis of many clinically important diseases including cardiovascular insufficiency, stroke and cancer. The target tissues nowadays have mostly been tumors or the myocardium, with less attention centered on the brain. Radiolabelled nitroimidazole or derivatives may be useful in identifying the hypoxic cells in cerebrovascular disease or traumatic brain injury, and hypoxic-ischemic encephalopathy. In acute stroke, the target of therapy is the severely hypoxic but salvageable tissue. {sup 18}F-MISO PET and {sup 99m}Tc-EC-metronidazole SPECT in patients with acute ischemic stroke identified hypoxic tissues and ischemic penumbra, and predicted its outcome. A study using {sup 123}I-IAZA in patient with closed head injury detected the hypoxic tissues after head injury. Up till now these radiopharmaceuticals have drawbacks due to its relatively low concentration with hypoxic tissues associated with/without low blood-brain barrier permeability and the necessity to wait a long time to achieve acceptable target to background ratios for imaging in acute ischemic stroke. It is needed to develop new hypoxic marker exhibiting more rapid localization in the hypoxic region in the brain. And then, the hypoxic brain imaging with imidazoles or non-imidazoles may be very useful in detecting the hypoxic tissues, determining therapeutic strategies and developing therapeutic drugs in several neurological disease, especially, in acute ischemic stroke.

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

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    Belén Feriche

    Full Text Available 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.

  5. Effects of Acute Systemic Hypoxia and Hypercapnia on Brain Damage in a Rat Model of Hypoxia-Ischemia.

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    Wanchao Yang

    Full Text Available Therapeutic hypercapnia has the potential for neuroprotection after global cerebral ischemia. Here we further investigated the effects of different degrees of acute systemic hypoxia in combination with hypercapnia on brain damage in a rat model of hypoxia and ischemia. Adult wistar rats underwent unilateral common carotid artery (CCA ligation for 60 min followed by ventilation with normoxic or systemic hypoxic gas containing 11%O2,13%O2,15%O2 and 18%O2 (targeted to PaO2 30-39 mmHg, 40-49 mmHg, 50-59 mmHg, and 60-69 mmHg, respectively or systemic hypoxic gas containing 8% carbon dioxide (targeted to PaCO2 60-80 mmHg for 180 min. The mean artery pressure (MAP, blood gas, and cerebral blood flow (CBF were evaluated. The cortical vascular permeability and brain edema were examined. The ipsilateral cortex damage and the percentage of hippocampal apoptotic neurons were evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL assay as well as flow cytometry, respectively. Immunofluorescence and western blotting were performed to determine aquaporin-4 (AQP4 expression. In rats treated with severe hypoxia (PaO2 50 mmHg, hypercapnia protected against these pathophysiological changes. Moreover, hypercapnia treatment significantly reduced brain damage in the ischemic ipsilateral cortex and decreased the percentage of apoptotic neurons in the hippocampus after the CCA ligated rats were exposed to mild or moderate hypoxemia (PaO2 > 50 mmHg; especially under mild hypoxemia (PaO2 > 60 mmHg, hypercapnia significantly attenuated the expression of AQP4 protein with brain edema (p < 0.05. Hypercapnia exerts beneficial effects under mild to moderate hypoxemia and augments detrimental effects under severe hypoxemia on brain damage in a rat model of hypoxia-ischemia.

  6. Extreme hypoxia tolerance of naked mole-rat brain.

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    Larson, John; Park, Thomas J

    2009-12-09

    Mammalian brains have extremely high levels of aerobic metabolism and typically suffer irreversible damage after brief periods of oxygen deprivation such as occur during stroke or cardiac arrest. Here we report that brain tissue from naked mole-rats, rodents that live in a chronically low-oxygen environment, is remarkably resistant to hypoxia: naked mole-rat neurons maintain synaptic transmission much longer than mouse neurons and can recover from periods of anoxia exceeding 30 min. We suggest that brain tolerance to hypoxia may result from slowed or arrested brain development in these extremely long-lived animals.

  7. Increased susceptibility of dystrophin-deficient brain to mild hypoxia

    International Nuclear Information System (INIS)

    Wallis, T.; Rae, C.; Bubb, W.A.; Head, S.I.

    2002-01-01

    Full text: Duchenne muscular dystrophy is an X-linked disorder resulting from total absence of the 427 kDa protein dystrophin. Dystrophin is normally expressed in the brain mainly in a neuronal subpopulation: cortical pyramidal cells, hippocampal CA1 neurons and cerebellar Purkinje cells. One suggested role for dystrophin is in colocalising mitochondrial creatine kinase with ADP translocase and ATP synthase in mitochondria. Brain tissue slices in the murine model of Duchenne dystrophy, the mdx mouse, have been shown to be more sensitive to hypoxia than control. In this work, we used 13 C NMR to monitor the metabolic response of mdx cortical brain tissue slices to normoxia (95%O 2 /5% CO 2 ) and mild hypoxia (95%air/5% CO 2 ). Under normoxic conditions, mdx cortical slices displayed increased net flux through the Krebs cycle and glutamate/glutamine cycle, consistent with the proposed GABA A lesion which results in decreased inhibitory input. By contrast, mild hypoxia resulted in a significant increase in the total pool size of lactate and decreased net flux of 13 C from [3- 13 C]pyruvate into glutamate C4, GABA C2 and Ala C2, as well as decreased anaplerotic activity as measured by the ratio of Asp C2: Asp C3 label. Mild hypoxia has a significantly greater effect on brain oxidative metabolism in mdx mice, than in control

  8. Hypoxic Hypoxia at Moderate Altitudes: State of the Science

    Science.gov (United States)

    2011-05-01

    nature of cognitive appraisal during exercise in environmentally stressful conditions. Psychology of Sport and Exercise. 2: 47-67. Alpern, M...Shukitt-Hale, B. 1993. Effects of altitude on mood, behaviour and cognitive functioning: A review. Sports Medicine. 16(2): 97-125. Balldin, U...exposure to hypoxia in healthy males [Abstract]. Aviation, Space, and Environmental Medicine. 78(3): 399. Chiles , W. D., Iampietro, P. F. and

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    , the results show that increased BF during one-leg exercise in moderate hypoxia is confined only to the contracting muscles, and the working muscle hyperemia appears not to be directly mediated by adenosine. Increased flow heterogeneity in noncontracting muscles likely reflects sympathetic nervous constraints...... healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to approximately 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion...... to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise....

  10. ASYMMETRY OF THE BRAIN AT ADAPTATION TO HYPOXIA

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    V. I. Portnichenko

    2012-11-01

    Full Text Available Association between cerebral blood flow and higher nervous activity in people at different stages of adaptation to the midlands was studied. Investigation were performed before, during and after a three-week stay in the mountains at an altitude of 2100 m, as well as during short-term ups without the physical load on the height of 3900 m. In the initial period of adaptation to hypoxia desynchronization between the nerve processes in the cerebral cortex and brain blood flow was observed. There was an inversion and an increase in the asymmetry of cerebral blood flow in the direction of the dominance of the left hemisphere of the brain. After the three-week stay in the mountains asymmetry of cerebral blood flow was disappeared, blood flow to the brain was reduced, hemispheric symmetry was formed, and blood flow synchronized with the nerve processes in the cerebral cortex again was restored.

  11. NO INFLUENCE OF HYPOXIA ON COORDINATION BETWEEN RESPIRATORY AND LOCOMOTOR RHYTHMS DURING ROWING AT MODERATE INTENSITY

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    Nicolas Fabre

    2007-12-01

    Full Text Available Besides neuro-mechanical constraints, chemical or metabolic stimuli have also been proposed to interfere with the coordination between respiratory and locomotor rhythms. In the light of the conflicting data observed in the literature, this study aimed to assess whether acute hypoxia modifies the degree of coordination between respiratory and locomotor rhythms during rowing exercises in order to investigate competitive interactions between neuro-mechanical (movement and chemical (hypoxia respiratory drives. Nine male healthy subjects performed one submaximal 6-min rowing exercise on a rowing ergometer in both normoxia (altitude: 304 m and acute hypoxia (altitude: 2877 m. The exercise intensity was about 40 % and 35 % (for normoxia and hypoxia conditions, respectively of the individual maximal power output measured during an incremental rowing test to volitional exhaustion carried out in normoxia. Metabolic rate and minute ventilation were continuously collected throughout exercise. Locomotor movement and breathing rhythms were continuously recorded and synchronized cycle-by-cycle. The degree of coordination was expressed as a percentage of breaths starting during the same phase of the locomotor cycle. For a same and a constant metabolic rate, acute hypoxia did not influence significantly the degree of coordination (mean ± SEM, normoxia: 20.0 ± 6.2 %, hypoxia: 21.3 ± 11.1 %, p > 0.05 while ventilation and breathing frequency were significantly greater in hypoxia. Our results may suggest that during rowing exercise at a moderate metabolic load, neuro-mechanical locomotion-linked respiratory stimuli appear "stronger" than peripheral chemoreceptors- linked respiratory stimuli induced by hypoxia, in the context of our study

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

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

    1999-04-01

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

  13. Moderate hypoxia influences potassium outward currents in adipose-derived stem cells.

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    Mayuri Prasad

    Full Text Available Moderate hypoxic preconditioning of adipose-derived stem cells (ASCs enhances properties such as proliferation and secretion of growth factors, representing a valuable strategy to increase the efficiency of cell-based therapies. In a wide variety of cells potassium (K+ channels are key elements involved in the cellular responses to hypoxia, suggesting that ASCs cultured under low oxygen conditions may display altered electrophysiological properties. Here, the effects of moderate hypoxic culture on proliferation, whole-cell currents, and ion channel expression were investigated using human ASCs cultured at 5% and 20% oxygen. Although cell proliferation was greatly enhanced, the dose-dependent growth inhibition by the K+ channel blocker tetraethylammonium (TEA was not significantly affected by hypoxia. Under both normoxic and hypoxic conditions, ASCs displayed outward K+ currents composed by Ca2+-activated, delayed rectifier, and transient components. Hypoxic culture reduced the slope of the current-voltage curves and caused a negative shift in the voltage activation threshold of the whole-cell currents. However, the TEA-mediated shift of voltage activation threshold was not affected by hypoxia. Semiquantitative real-time RT-PCR revealed that expression of genes encoding for various ion channels subunits related to oxygen sensing and proliferation remained unchanged after hypoxic culture. In conclusion, outward currents are influenced by moderate hypoxia in ASCs through a mechanism that is not likely the result of modulation of TEA-sensitive K+ channels.

  14. Hypobaric Hypoxia Imbalances Mitochondrial Dynamics in Rat Brain Hippocampus

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    Khushbu Jain

    2015-01-01

    Full Text Available Brain is predominantly susceptible to oxidative stress and mitochondrial dysfunction during hypobaric hypoxia, and therefore undergoes neurodegeneration due to energy crisis. Evidences illustrate a high degree of association for mitochondrial fusion/fission imbalance and mitochondrial dysfunction. Mitochondrial fusion/fission is a recently reported dynamic mechanism which frequently occurs among cellular mitochondrial network. Hence, the study investigated the temporal alteration and involvement of abnormal mitochondrial dynamics (fusion/fission along with disturbed mitochondrial functionality during chronic exposure to hypobaric hypoxia (HH. The Sprague-Dawley rats were exposed to simulated high altitude equivalent to 25000 ft for 3, 7, 14, 21, and 28 days. Mitochondrial morphology, distribution within neurons, enzyme activity of respiratory complexes, Δψm, ADP: ATP, and expression of fission/fusion key proteins were determined. Results demonstrated HH induced alteration in mitochondrial morphology by damaged, small mitochondria observed in neurons with disturbance of mitochondrial functionality and reduced mitochondrial density in neuronal processes manifested by excessive mitochondrial fragmentation (fission and decreased mitochondrial fusion as compared to unexposed rat brain hippocampus. The study suggested that imbalance in mitochondrial dynamics is one of the noteworthy mechanisms occurring in hippocampal neurons during HH insult.

  15. Comprehensive evaluation of immunomodulation by moderate hypoxia in S. agalactiae vaccinated Nile tilapia.

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    Gallage, Sanchala; Katagiri, Takayuki; Endo, Masato; Maita, Masashi

    2017-07-01

    Streptococcus agalactiae is a major bacterial pathogen in tilapia aquaculture. Vaccines are known to provide protection but S. agalactiae clearance in tilapia can be reduced by marginal environmental conditions. Therefore, the purpose of this study is to examine S. agalactiae clearance in vaccinated Nile tilapia under moderate hypoxic (55± 5% DO) and normoxic (85 ± 5%DO) conditions. Fish were acclimatized to either moderate hypoxia or normoxia and immunized with formalin-inactivated S. agalactiae. Fish were experimentally challenged with S. agalactiae at 30 days post-vaccination. Serum antibody titer was significantly higher in vaccinated fish kept under normoxic condition compared to the moderate hypoxic condition at fifteen and thirty days post-vaccination. The cumulative mortality following challenge was significantly reduced in vaccinated fish kept under normoxic condition compared to those in moderate hypoxic condition reflecting that pre-challenge antibody titer may correlate with survival of fish. Blood and tissue pathogen burden detection of S. agalactiae studies revealed that culturable S. agalactiae cells could not be detected in the blood of normoxic vaccinated fish at all the sampling points. In contrast, fish vaccinated in moderate hypoxic condition had considerable number of culturable S. agalactiae cells in their blood up to 5 days following challenge. Phagocytosis and intracellular reactive oxygen species (ROS) production were lowered by moderate hypoxia in vitro. Furthermore, presence of specific antibodies and higher specific antibody level in the serum increased phagocytosis, ROS production and lowered intracellular survival of S. agalactiae in head kidney leukocytes. Overall this study has highlighted that S. agalactiae clearance in vaccinated Nile tilapia is modulated by moderate hypoxia. One of the possible explanations for this might be less efficient phagocytic activities due to low oxygen availability and lower specific

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

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    Eugenia Mata-Greenwood

    2017-05-01

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

  17. Lipid peroxidation in neonatal mouse brain subjected to two different types of hypoxia.

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    Hasegawa, K; Yoshioka, H; Sawada, T; Nishikawa, H

    1991-01-01

    To elucidate the role of free radicals in the pathogenesis of neonatal hypoxic encephalopathy, we determined the content of thiobarbituric acid reactants (TBARs), as an index of lipid peroxidation related with a free radical reaction, in the brains of newborn mice during hypoxia and recovery from hypoxia. Hypoxic stress was induced by 100% nitrogen gas breathing (N2 group) or 100% carbon dioxide gas breathing (CO2 group). TBARs increased with 20 minutes of hypoxia and returned to the control level during the recovery period in both groups. The increase in TBARs in the CO2 group was greater than that in the N2 group. These results may suggest that free radical reaction occurs during the hypoxic period and that CO2 hypoxia is more effective on free radical production in the newborn brain than N2 hypoxia.

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

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

    2015-01-01

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

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

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    Myriam eBouslama

    2015-11-01

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

  20. Cerebral circulation, metabolism, and blood-brain barrier of rats in hypocapnic hypoxia

    International Nuclear Information System (INIS)

    Beck, T.; Krieglstein, J.

    1987-01-01

    The effects of hypoxic hypoxia on physiological variables, cerebral circulation, cerebral metabolism, and blood-brain barrier were investigated in conscious, spontaneously breathing rats by exposing them to an atmosphere containing 7% O 2 . Hypoxia affected a marked hypotension, hypocapnia and alkalosis. Cortical tissue high-energy phosphates and glucose content were not affected by hypoxia, glucose 6-phosphate lactate, and pyruvate levels were significantly increased. Blood-brain barrier permeability, regional brain glucose content and lumped constant were not changed by hypoxia. Local cerebral glucose utilization (LCGU) rose by 40-70% of control values in gray matter and by 80-90% in white matter. Under hypoxia, columns of increased and decreased LCGU and were detectable in cortical gray matter. Color-coded [ 14 C]2-deoxy-D-glucose autoradiograms of rat brain are shown. Local cerebral blood flow (LCBF) increased by 50-90% in gray matter and by up to 180% in white matter. Coupling between LCGU and LCBF in hypoxia remained unchanged. The data suggests a stimulation of glycolysis, increased glucose transport into the cell, and increased hexokinase activity. The physiological response of gray and white matter to hypoxia obviously differs. Uncoupling of the relation between LCGU and LCBF does not occur

  1. Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain

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    Debora Coimbra-Costa

    2017-08-01

    Full Text Available Acute hypoxia increases the formation of reactive oxygen species (ROS in the brain. However, the effect of reoxygenation, unavoidable to achieve full recovery of the hypoxic organ, has not been clearly established. The aim of the present study was to evaluate the effects of exposition to acute severe respiratory hypoxia followed by reoxygenation on the evolution of oxidative stress and apoptosis in the brain. We investigated the effect of in vivo acute severe normobaric hypoxia (rats exposed to 7% O2 for 6 h and reoxygenation in normoxia (21% O2 for 24 h or 48 h on oxidative stress markers, the antioxidant system and apoptosis in the brain. After respiratory hypoxia we found increased levels of HIF-1α expression, lipid peroxidation, protein oxidation and nitric oxide in brain extracts. Antioxidant defence systems such as superoxide dismutase (SOD, reduced glutathione (GSH and glutathione peroxidase (GPx and the reduced/oxidized glutathione (GSH/GSSG ratio were significantly decreased in the brain. After 24 h of reoxygenation, oxidative stress parameters and the anti-oxidant system returned to control values. Regarding the apoptosis parameters, acute hypoxia increased cytochrome c, AIF and caspase 3 activity in the brain. The apoptotic effect is greatest after 24 h of reoxygenation. Immunohistochemistry suggests that CA3 and dentate gyrus in the hippocampus seem more susceptible to hypoxia than the cortex. Severe acute hypoxia increases oxidative damage, which in turn could activate apoptotic mechanisms. Our work is the first to demonstrate that after 24 h of reoxygenation oxidative stress is attenuated, while apoptosis is maintained mainly in the hippocampus, which may, in fact, be the cause of impaired brain function. Keywords: Antioxidants, Apoptosis, Normobaric hypoxia, Oxidative stress, Reoxygenation

  2. Brain adaptation to hypoxia and hyperoxia in mice

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    Laura Terraneo

    2017-04-01

    Conclusion: Prolonged mild hyperoxia leads to persistent cerebral damage, comparable to that inferred by prolonged mild hypoxia. The underlying mechanism appears related to a model whereby the imbalance between ROS generation and anti-ROS defense is similar, but occurs at higher levels in hypoxia than in hyperoxia.

  3. The Effect of Inspiratory Resistance on Exercise Performance and Perception in Moderate Normobaric Hypoxia.

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    Seo, Yongsuk; Vaughan, Jeremiah; Quinn, Tyler D; Followay, Brittany; Roberge, Raymond; Glickman, Ellen L; Kim, Jung-Hyun

    2017-12-01

    Seo, Yongsuk, Jeremiah Vaughan, Tyler D. Quinn, Brittany Followay, Raymond Roberge, Ellen L. Glickman, and Jung-Hyun Kim. The effect of inspiratory resistance on exercise performance and perception in moderate normobaric hypoxia. High Alt Med Biol. 18:417-424, 2017. Respirators are simple and efficient in protecting workers against toxic airborne substances; however, their use may limit the physical performance of workers. The purpose of this study was to determine the effect of inspiratory resistance on physical performance and breathing perception in normobaric hypoxia. Nine healthy men wore a tight-fitting respiratory mask outfitted with one of four different inspiratory resistors (R) (0, 1.5, 4.5, 7.5 cm H 2 O/L/Sec) while exercising at normobaric hypoxia (17% O 2 ) at submaximal exercise workloads of 50, 100, and 150 W on a cycle ergometer for 10 minutes each, followed by a maximal oxygen uptake (VO 2 max) test to exhaustion. Maximal power output at R7.5 was significantly lower than R0 (p = 0.016) and R1.5 (p = 0.035). Respiration rate was significantly reduced at R4.5 (p = 0.011) and R7.5 (p ≤ 0.001) compared with R0. Minute ventilation was significantly decreased in R7.5 compared with R0 (p = 0.003), R1.5 (p = 0.010), and R4.5 (p = 0.016), whereas VO 2 was not significantly changed. Breathing comfort (BC) and breathing effort (BE) were significantly impaired in R7.5 (BC: p = 0.025, BE: p = 0.001) and R4.5 (BC: p = 0.007, BE: p = 0.001) compared with R0, but rating of perceived exertion (RPE) remained unchanged. Added inspiratory resistance limited maximal power output and increased perceptions of BC and BE in normobaric hypoxia. However, low-to-moderate inspiratory resistance did not have a deleterious effect on VO 2 or RPE at submaximal or maximal exercise. Perceptual and physiological characteristics of respirators of varying inspiratory resistances should be considered by manufacturers and end users during

  4. Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

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    Septelia I. Wanandi

    2011-02-01

    Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

  5. Tetrahydrobiopterin in antenatal brain hypoxia-ischemia-induced motor impairments and cerebral palsy.

    Science.gov (United States)

    Vasquez-Vivar, Jeannette; Shi, Zhongjie; Luo, Kehuan; Thirugnanam, Karthikeyan; Tan, Sidhartha

    2017-10-01

    Antenatal brain hypoxia-ischemia, which occurs in cerebral palsy, is considered a significant cause of motor impairments in children. The mechanisms by which antenatal hypoxia-ischemia causes brain injury and motor deficits still need to be elucidated. Tetrahydrobiopterin is an important enzyme cofactor that is necessary to produce neurotransmitters and to maintain the redox status of the brain. A genetic deficiency of this cofactor from mutations of biosynthetic or recycling enzymes is a well-recognized factor in the development of childhood neurological disorders characterized by motor impairments, developmental delay, and encephalopathy. Experimental hypoxia-ischemia causes a decline in the availability of tetrahydrobiopterin in the immature brain. This decline coincides with the loss of brain function, suggesting this occurrence contributes to neuronal dysfunction and motor impairments. One possible mechanism linking tetrahydrobiopterin deficiency, hypoxia-ischemia, and neuronal injury is oxidative injury. Evidence of the central role of the developmental biology of tetrahydrobiopterin in response to hypoxic ischemic brain injury, especially the development of motor deficits, is discussed. Copyright © 2017. Published by Elsevier B.V.

  6. Phosphorylation of eIF2α is required for mRNA translation inhibition and survival during moderate hypoxia

    International Nuclear Information System (INIS)

    Koritzinsky, Marianne; Rouschop, Kasper M.A.; Beucken, Twan van den; Magagnin, Michael G.; Savelkouls, Kim; Lambin, Philippe; Wouters, Bradly G.

    2007-01-01

    Abstracts: Background and purpose: Human tumors are characterized by temporal fluctuations in oxygen tension. The biological pathways that respond to the dynamic tumor microenvironment represent potential molecular targets for cancer therapy. Anoxic conditions result in eIF2α dependent inhibition of overall mRNA translation, differential gene expression, hypoxia tolerance and tumor growth. The signaling pathway which governs eIF2α phosphorylation has therefore emerged as a potential molecular target. In this study, we investigated the role of eIF2α in regulating mRNA translation and hypoxia tolerance during moderate hypoxia. Since other molecular pathways that regulate protein synthesis are frequently mutated in cancer, we also assessed mRNA translation in a panel of cell lines from different origins. Materials and methods: Immortalized human fibroblast, transformed mouse embryo fibroblasts (MEFs) and cells from six cancer cell lines were exposed to 0.2% or 0.0% oxygen. We assayed global mRNA translation efficiency by polysome analysis, as well as proliferation and clonogenic survival. The role of eIF2α was assessed in MEFs harboring a homozygous inactivating mutation (S51A) as well as in U373-MG cells overexpressing GADD34 (C-term) under a tetracycline-dependent promoter. The involvement of eIF4E regulation was investigated in HeLa cells stably expressing a short hairpin RNA (shRNA) targeting 4E-BP1. Results: All cells investigated inhibited mRNA translation severely in response to anoxia and modestly in response to hypoxia. Two independent genetic cell models demonstrated that inhibition of mRNA translation in response to moderate hypoxia was dependent on eIF2α phosphorylation. Disruption of eIF2α phosphorylation caused sensitivity to hypoxia and anoxia. Conclusions: Disruption of eIF2α phosphorylation is a potential target for hypoxia-directed molecular cancer therapy

  7. Effects of caffeine on neuromuscular fatigue and performance during high-intensity cycling exercise in moderate hypoxia.

    Science.gov (United States)

    Smirmaul, Bruno P C; de Moraes, Antonio Carlos; Angius, Luca; Marcora, Samuele M

    2017-01-01

    To investigate the effects of caffeine on performance, neuromuscular fatigue and perception of effort during high-intensity cycling exercise in moderate hypoxia. Seven adult male participants firstly underwent an incremental exercise test on a cycle ergometer in conditions of acute normobaric hypoxia (fraction inspired oxygen = 0.15) to establish peak power output (PPO). In the following two visits, they performed a time to exhaustion test (78 ± 3% PPO) in the same hypoxic conditions after caffeine ingestion (4 mg kg -1 ) and one after placebo ingestion in a double-blind, randomized, counterbalanced cross-over design. Caffeine significantly improved time to exhaustion by 12%. A significant decrease in subjective fatigue was found after caffeine consumption. Perception of effort and surface electromyographic signal amplitude of the vastus lateralis were lower and heart rate was higher in the caffeine condition when compared to placebo. However, caffeine did not reduce the peripheral and central fatigue induced by high-intensity cycling exercise in moderate hypoxia. The caffeine-induced improvement in time to exhaustion during high-intensity cycling exercise in moderate hypoxia seems to be mediated by a reduction in perception of effort, which occurs despite no reduction in neuromuscular fatigue.

  8. Vitamin E supplementation inhibits muscle damage and inflammation after moderate exercise in hypoxia.

    Science.gov (United States)

    Santos, S A; Silva, E T; Caris, A V; Lira, F S; Tufik, S; Dos Santos, R V T

    2016-08-01

    Exercise under hypoxic conditions represents an additional stress in relation to exercise in normoxia. Hypoxia induces oxidative stress and inflammation as mediated through tumour necrosis factor (TNF)-α release that might be exacerbated through exercise. In addition, vitamin E supplementation might attenuate oxidative stress and inflammation resulting from hypoxia during exercise. The present study aimed to evaluate the effects of vitamin E supplementation (250 mg) on inflammatory parameters and cellular damage after exercise under hypoxia simulating an altitude of 4200 m. Nine volunteers performed three sessions of 60 min of exercise (70% maximal oxygen uptake) interspersed for 1 week under normoxia, hypoxia and hypoxia after vitamin E supplementation 1 h before exercise. Blood was collected before, immediately after and at 1 h after exercise to measure inflammatory parameters and cell damage. Percentage oxygen saturation of haemoglobin decreased after exercise and recovered 1 h later in the hypoxia + vitamin condition (P exercise (P exercise in hypoxia increased interleukin (IL)-6, TNF-α, IL-1ra and IL-10 immediately after exercise (P exercise in hypoxia without supplementation (P exercise reduces cell damage markers after exercise in hypoxia and changes the concentration of cytokines, suggesting a possible protective effect against inflammation induced by hypoxia during exercise. © 2016 The British Dietetic Association Ltd.

  9. Altered aquaporins in the brains of mice submitted to intermittent hypoxia model of sleep apnea.

    Science.gov (United States)

    Baronio, Diego; Martinez, Denis; Fiori, Cintia Zappe; Bambini-Junior, Victorio; Forgiarini, Luiz Felipe; Pase da Rosa, Darlan; Kim, Lenise Jihe; Cerski, Marcelle Reesink

    2013-01-15

    Rostral fluid displacement has been proposed as a pathophysiologic mechanism of both central and obstructive sleep apnea. Aquaporins are membrane proteins that regulate water transport across the cell membrane and are involved in brain edema formation and resolution. The present study investigated the effect of intermittent hypoxia (IH), a model of sleep apnea, on brain aquaporins. Mice were exposed to intermittent hypoxia to a nadir of 7% oxygen fraction. Brain water content, Aquaporin-1 and Aquaporin-3 were measured in the cerebellum and hippocampus. Hematoxylin-eosin and immunohistochemistry stainings were performed to evaluate cell damage. Compared to the sham group, the hypoxia group presented higher brain water content, lower levels of Aquaporin-1 and similar levels of Aquaporin-3. Immunoreactivity to GFAP and S100B was stronger in the hypoxia group in areas of extensive gliosis, compatible with cytotoxic edema. These findings, although preliminary, indicate an effect of IH on aquaporins levels. Further investigation about the relevance of these data on the pathophysiology of OSA is warranted. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Detection of Hypoxia in Human Brain Tumor Xenografts Using a Modified Comet Assay

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    Jingli Wang

    2003-07-01

    Full Text Available We used the standard comet assay successfully to generate in vitro dose-response curves under oxic and hypoxic conditions. We then made mixtures of cells that had been irradiated with 3 and 9 Gy of X-rays to simulate two subpopulations in a tumor, but efforts to accurately detect and quantify the subpopulations using the standard comet assay were unsuccessful. Therefore, we investigated a modified comet assay to determine whether it could be used for measuring hypoxia in our model systems. U251 MG cells were grown as subcutaneous tumors in athymic mice; U251 MG and U87 MG cells were grown as intracerebral (i.c. tumors in athymic rats. Animals were injected with RSU 1069, irradiated, and euthanized. Tumors and normal brains were removed, and the cells were analyzed using a modified comet assay. Differences in comet tail moment distributions between tumor and contralateral normal brain, using tail moments at either the 25th or 50th percentile in each distribution, were taken as measures of the degree of tumor hypoxia. For U251 MG tumors, there was a positive relationship between tumor size and the degree of hypoxia, whereas preliminary data from U87 MG i.c. tumors showed less hypoxia and no apparent relationship between tumor size and hypoxia.

  11. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain

    DEFF Research Database (Denmark)

    Overgaard, Morten; Rasmussen, Peter; Bohm, Aske M

    2012-01-01

    Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions...... were combined. We measured cerebral lactate turnover via a tracer dilution method ([1-(13)C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (F(i)o(2) 10...

  12. Killing of Brain Tumor Cells by Hypoxia-Responsive Element Mediated Expression of BAX

    Directory of Open Access Journals (Sweden)

    Hangjun Ruan

    1999-11-01

    Full Text Available The presence of radioresistant hypoxic cells in human brain tumors limits the overall effectiveness of conventional fractionated radiation therapy. Tumor-specific therapies that target hypoxic cells are clearly needed. We have investigated the expression of suicide genes under hypoxia by a hypoxia-responsive element (HRE, which can be activated through hypoxia-inducible factor-1 (HIF-1. We transfected plasmids containing multiple copies of HIRE into U-87 MG and U-251 MG-NCI human brain tumor cells and tested their ability to induce LacZ gene expression under anoxia. Gene expression under anoxia versus oxia was increased about 12-fold for U-87 MG cells and about fourfold for U-251 MG-NCI cells. At intermediate hypoxic conditions, increased LacZ gene expression in U-87 MG cells was induced by the plasmid that contained three HREs, but not by the plasmid with two HREs. Lastly, when we placed a suicide gene BAX under the control of HREs, cells transfected with the BAX plasmids were preferentially killed through apoptosis under anoxia. Our studies demonstrate that HRE-regulated gene expression is active in brain tumor cells, and that the amount of increased gene expression obtained is dependent on the cell line, the HIRE copy number, and the degree of hypoxia.

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

    Science.gov (United States)

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

    2014-01-01

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

  14. Influence of moderate and severe hypoxia on the diurnal activity pattern of lesser sandeel Ammodytes tobianus

    DEFF Research Database (Denmark)

    Behrens, Jane; Petersen, Jens Kjerulf; Ærtebjerg, G.

    2010-01-01

    , but the behaviour of the fish was also changed. The summed activity (emerging plus burying events) was lower in severe hypoxia compared to normoxia except during hours of dim light. All fish were buried during night-time, regardless of treatment, with the exception of some in severe hypoxia during the first couple...

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

    Science.gov (United States)

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

  16. Mammalian target of rapamycin is required for phrenic long-term facilitation following severe but not moderate acute intermittent hypoxia.

    Science.gov (United States)

    Dougherty, Brendan J; Fields, Daryl P; Mitchell, Gordon S

    2015-09-01

    Phrenic long-term facilitation (pLTF) is a persistent increase in phrenic nerve activity after acute intermittent hypoxia (AIH). Distinct cell-signaling cascades give rise to pLTF depending on the severity of hypoxemia within hypoxic episodes. Moderate AIH (mAIH; three 5-min episodes, PaO2 ∼35-55 mmHG) elicits pLTF by a serotonin (5-HT)-dependent mechanism that requires new synthesis of brain-derived neurotrophic factor (BDNF), activation of its high-affinity receptor (TrkB), and ERK MAPK signaling. In contrast, severe AIH (sAIH; three 5-min episodes, PaO2 ∼25-30 mmHG) elicits pLTF by an adenosine-dependent mechanism that requires new TrkB synthesis and Akt signaling. Although both mechanisms require spinal protein synthesis, the newly synthesized proteins are distinct, as are the neurochemicals inducing plasticity (serotonin vs. adenosine). In many forms of neuroplasticity, new protein synthesis requires translational regulation via mammalian target of rapamycin (mTOR) signaling. Since Akt regulates mTOR activity, we hypothesized that mTOR activity is necessary for sAIH- but not mAIH-induced pLTF. Phrenic nerve activity in anesthetized, paralyzed, and ventilated rats was recorded before, during, and 60 min after mAIH or sAIH. Rats were pretreated with intrathecal injections of 20% DMSO (vehicle controls) or rapamycin (0.1 mM, 12 μl), a selective mTOR complex 1 inhibitor. Consistent with our hypothesis, rapamycin blocked sAIH- but not mAIH-induced pLTF. Thus spinal mTOR activity is required for adenosine-dependent (sAIH) but not serotonin-dependent (mAIH) pLTF, suggesting that distinct mechanisms regulate new protein synthesis in these forms of spinal neuroplasticity. Copyright © 2015 the American Physiological Society.

  17. Synchrotron microbeam radiation therapy induces hypoxia in intracerebral gliosarcoma but not in the normal brain

    International Nuclear Information System (INIS)

    Bouchet, Audrey; Lemasson, Benjamin; Christen, Thomas; Potez, Marine; Rome, Claire; Coquery, Nicolas; Le Clec’h, Céline; Moisan, Anaick; Bräuer-Krisch, Elke; Leduc, Géraldine; Rémy, Chantal; Laissue, Jean A.; Barbier, Emmanuel L.; Brun, Emmanuel; Serduc, Raphaël

    2013-01-01

    Purpose: Synchrotron microbeam radiation therapy (MRT) is an innovative irradiation modality based on spatial fractionation of a high-dose X-ray beam into lattices of microbeams. The increase in lifespan of brain tumor-bearing rats is associated with vascular damage but the physiological consequences of MRT on blood vessels have not been described. In this manuscript, we evaluate the oxygenation changes induced by MRT in an intracerebral 9L gliosarcoma model. Methods: Tissue responses to MRT (two orthogonal arrays (2 × 400 Gy)) were studied using magnetic resonance-based measurements of local blood oxygen saturation (MR S O 2 ) and quantitative immunohistology of RECA-1, Type-IV collagen and GLUT-1, marker of hypoxia. Results: In tumors, MR S O 2 decreased by a factor of 2 in tumor between day 8 and day 45 after MRT. This correlated with tumor vascular remodeling, i.e. decrease in vessel density, increases in half-vessel distances (×5) and GLUT-1 immunoreactivity. Conversely, MRT did not change normal brain MR S O 2 , although vessel inter-distances increased slightly. Conclusion: We provide new evidence for the differential effect of MRT on tumor vasculature, an effect that leads to tumor hypoxia. As hypothesized formerly, the vasculature of the normal brain exposed to MRT remains sufficiently perfused to prevent any hypoxia

  18. Stem cells for brain repair in neonatal hypoxia-ischemia.

    Science.gov (United States)

    Chicha, L; Smith, T; Guzman, R

    2014-01-01

    Neonatal hypoxic-ischemic insults are a significant cause of pediatric encephalopathy, developmental delays, and spastic cerebral palsy. Although the developing brain's plasticity allows for remarkable self-repair, severe disruption of normal myelination and cortical development upon neonatal brain injury are likely to generate life-persisting sensory-motor and cognitive deficits in the growing child. Currently, no treatments are available that can address the long-term consequences. Thus, regenerative medicine appears as a promising avenue to help restore normal developmental processes in affected infants. Stem cell therapy has proven effective in promoting functional recovery in animal models of neonatal hypoxic-ischemic injury and therefore represents a hopeful therapy for this unmet medical condition. Neural stem cells derived from pluripotent stem cells or fetal tissues as well as umbilical cord blood and mesenchymal stem cells have all shown initial success in improving functional outcomes. However, much still remains to be understood about how those stem cells can safely be administered to infants and what their repair mechanisms in the brain are. In this review, we discuss updated research into pathophysiological mechanisms of neonatal brain injury, the types of stem cell therapies currently being tested in this context, and the potential mechanisms through which exogenous stem cells might interact with and influence the developing brain.

  19. Potential Moderators of Physical Activity on Brain Health

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    Regina L. Leckie

    2012-01-01

    Full Text Available Age-related cognitive decline is linked to numerous molecular, structural, and functional changes in the brain. However, physical activity is a promising method of reducing unfavorable age-related changes. Physical activity exerts its effects on the brain through many molecular pathways, some of which are regulated by genetic variants in humans. In this paper, we highlight genes including apolipoprotein E (APOE, brain derived neurotrophic factor (BDNF, and catechol-O-methyltransferase (COMT along with dietary omega-3 fatty acid, docosahexaenoic acid (DHA, as potential moderators of the effect of physical activity on brain health. There are a growing number of studies indicating that physical activity might mitigate the genetic risks for disease and brain dysfunction and that the combination of greater amounts of DHA intake with physical activity might promote better brain function than either treatment alone. Understanding whether genes or other lifestyles moderate the effects of physical activity on neurocognitive health is necessary for delineating the pathways by which brain health can be enhanced and for grasping the individual variation in the effectiveness of physical activity interventions on the brain and cognition. There is a need for future research to continue to assess the factors that moderate the effects of physical activity on neurocognitive function.

  20. Sumoylation of hypoxia-inducible factor-1α ameliorates failure of brain stem cardiovascular regulation in experimental brain death.

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    Julie Y H Chan

    2011-03-01

    Full Text Available One aspect of brain death is cardiovascular deregulation because asystole invariably occurs shortly after its diagnosis. A suitable neural substrate for mechanistic delineation of this aspect of brain death resides in the rostral ventrolateral medulla (RVLM. RVLM is the origin of a life-and-death signal that our laboratory detected from blood pressure of comatose patients that disappears before brain death ensues. At the same time, transcriptional upregulation of heme oxygenase-1 in RVLM by hypoxia-inducible factor-1α (HIF-1α plays a pro-life role in experimental brain death, and HIF-1α is subject to sumoylation activated by transient cerebral ischemia. It follows that sumoylation of HIF-1α in RVLM in response to hypoxia may play a modulatory role on brain stem cardiovascular regulation during experimental brain death.A clinically relevant animal model that employed mevinphos as the experimental insult in Sprague-Dawley rat was used. Biochemical changes in RVLM during distinct phenotypes in systemic arterial pressure spectrum that reflect maintained or defunct brain stem cardiovascular regulation were studied. Western blot analysis, EMSA, ELISA, confocal microscopy and immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1, Ubc9 (the only known conjugating enzyme for the sumoylation pathway or HIF-1α, augmented sumoylation of HIF-1α, nucleus-bound translocation and enhanced transcriptional activity of HIF-1α in RVLM neurons took place preferentially during the pro-life phase of experimental brain death. Furthermore, loss-of-function manipulations by immunoneutralization of SUMO-1, Ubc9 or HIF-1α in RVLM blunted the upregulated nitric oxide synthase I/protein kinase G signaling cascade, which sustains the brain stem cardiovascular regulatory machinery during the pro-life phase.We conclude that sumoylation of HIF-1α in RVLM ameliorates brain stem

  1. Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats.

    Science.gov (United States)

    Shi, Xudan; Doycheva, Desislava Met; Xu, Liang; Tang, Jiping; Yan, Min; Zhang, John H

    2016-11-01

    Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injuries. Rat pups underwent common carotid artery ligation followed by either 150min (severe model) or 100min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) was used to examine their roles on BBB permeability. Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α's effects as a prodeath or prosurvival signal were influenced by the severity of HI injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Modification of radiation changes of the blood-brain barrier by exogenous hypoxia

    International Nuclear Information System (INIS)

    Antipov, V.V.; Fedorov, V.P.; Kordenko, A.N.; Ushakov, I.B.

    1987-01-01

    The authors conducted an experimental study of a radiomodifying effect of exogenous hypoxia on the structures of the blood-brain barrier in rats early after irradiation of the head at a dose of 10 Gy. Histochemical and histological methods were used to assess the status of the endothelium, basal membrane tissue basophils and astrocytic junction. They indicated change of these structures in irradiation and action of GHM-8 gaseous mixture. Exogenous hypoxia was shown to promote the normalization of transport through the capillary wall as a result of the prevention of injury of the structure and metabollic processes in endothelial cells and basal membrane. The astrocytic junction and, to a certain degree, tissue basophils exhibited synergy in the action of the studied fators

  3. Moderate Traumatic Brain Injury: Clinical Characteristics and a Prognostic Model of 12-Month Outcome.

    Science.gov (United States)

    Einarsen, Cathrine Elisabeth; van der Naalt, Joukje; Jacobs, Bram; Follestad, Turid; Moen, Kent Gøran; Vik, Anne; Håberg, Asta Kristine; Skandsen, Toril

    2018-03-31

    Patients with moderate traumatic brain injury (TBI) often are studied together with patients with severe TBI, even though the expected outcome of the former is better. Therefore, we aimed to describe patient characteristics and 12-month outcomes, and to develop a prognostic model based on admission data, specifically for patients with moderate TBI. Patients with Glasgow Coma Scale scores of 9-13 and age ≥16 years were prospectively enrolled in 2 level I trauma centers in Europe. Glasgow Outcome Scale Extended (GOSE) score was assessed at 12 months. A prognostic model predicting moderate disability or worse (GOSE score ≤6), as opposed to a good recovery, was fitted by penalized regression. Model performance was evaluated by area under the curve of the receiver operating characteristics curves. Of the 395 enrolled patients, 81% had intracranial lesions on head computed tomography, and 71% were admitted to an intensive care unit. At 12 months, 44% were moderately disabled or worse (GOSE score ≤6), whereas 8% were severely disabled and 6% died (GOSE score ≤4). Older age, lower Glasgow Coma Scale score, no day-of-injury alcohol intoxication, presence of a subdural hematoma, occurrence of hypoxia and/or hypotension, and preinjury disability were significant predictors of GOSE score ≤6 (area under the curve = 0.80). Patients with moderate TBI exhibit characteristics of significant brain injury. Although few patients died or experienced severe disability, 44% did not experience good recovery, indicating that follow-up is needed. The model is a first step in development of prognostic models for moderate TBI that are valid across centers. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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

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    Nahla Zaghloul

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

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

    OpenAIRE

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

    2015-01-01

    Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH...

  6. Gray Matter Hypoxia in the Brain of the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis

    Science.gov (United States)

    Johnson, Thomas W.; Wu, Ying; Nathoo, Nabeela; Rogers, James A.; Wee Yong, V.; Dunn, Jeff F.

    2016-01-01

    Background Multiple sclerosis (MS) has a significant inflammatory component and may have significant gray matter (GM) pathophysiology. Brain oxygenation is a sensitive measurement of the balance between metabolic need and oxygen delivery. There is evidence that inflammation and hypoxia are interdependent. In this paper, we applied novel, implanted PO2 sensors to measure hypoxia in cortical and cerebellar GM, in an inflammation-induced mouse model of MS. Objective Quantify oxygenation in cortical and cerebellar GM in the awake, unrestrained experimental autoimmune encephalomyelitis (EAE) mouse model and to relate the results to symptom level and disease time-course. Methods C57BL/6 mice were implanted with a fiber-optic sensor in the cerebellum (n = 13) and cortex (n = 24). Animals were induced with stimulation of the immune response and sensitization to myelin oligodendrocyte glycoprotein (MOG). Controls did not have MOG. We measured PO2 in awake, unrestrained animals from pre-induction (baseline) up to 36 days post-induction for EAE and controls. Results There were more days with hypoxia than hyperoxia (cerebellum: 34/67 vs. 18/67 days; cortex: 85/112 vs. 22/112) compared to time-matched controls. The average decline in PO2 on days that were significantly lower than time-matched controls was -8.8±6.0 mmHg (mean ± SD) for the cerebellum and -8.0±4.6 for the cortex. Conversely, the average increase in PO2 on days that were significantly hyperoxic was +3.2±2.8 mmHg (mean ± SD) for the cerebellum and +0.8±2.1 for the cortex. Cortical hypoxia related to increased behavioral deficits. Evidence for hypoxia occurred before measurable behavioral deficits. Conclusions A highly inflammatory condition primed to a white matter (WM) autoimmune response correlates with significant hypoxia and increased variation in oxygenation in GM of both cerebellum and cortex in the mouse EAE model of MS. PMID:27907119

  7. The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia

    Directory of Open Access Journals (Sweden)

    Roehl Anna B

    2012-08-01

    Full Text Available Abstract Backround Neuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown. Methods Transient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg-1 levosimendan followed by a continuous infusion of 0.2 μg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed. Results Levosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03 and delayed flow maximum by 5 minutes (p = 0.002. Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017 and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L-1 were higher in the levosimendan group. The increased expression of IL-6, IL-1ß TNFα and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan. Conclusion Although levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood–brain barrier, the present

  8. Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury

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    Mushfiquddin Khan

    2017-01-01

    Full Text Available Mild traumatic brain injury (TBI, also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide (NO, the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha (HIF-1α, a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1α is regulated by NO via the mechanism of S-nitrosylation of HIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione (GSNO and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1α. Exogenously administered GSNO was found not only to stabilize HIF-1α and to induce HIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.

  9. Cyclosporine treatment reduces oxygen free radical generation and oxidative stress in the brain of hypoxia-reoxygenated newborn piglets.

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    Richdeep S Gill

    Full Text Available Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H(2O(2 production and markers of oxidative stress. Piglets (1-4 d, 1.4-2.5 kg were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation (n = 8/group. At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls or cyclosporine (2.5 or 10 mg/kg i.v. bolus in a blinded-randomized fashion. An additional sham-operated group (n = 4 underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe, cerebral cortical H(2O(2 production (electrochemical sensor, cerebral tissue glutathione (ELISA and cytosolic cytochrome-c (western blot levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40-48% of baseline, hypotension (mean arterial pressure 27-31 mmHg and acidosis (pH 7.04 at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg, significantly attenuated the increase in cortical H(2O(2 concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H(2O(2 production and minimizes oxidative stress in newborn piglets following hypoxia-reoxygenation.

  10. Whole brain radiation-induced impairments in learning and memory are time-sensitive and reversible by systemic hypoxia.

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    Junie P Warrington

    Full Text Available Whole brain radiation therapy (WBRT is commonly used for treatment of primary and metastatic brain tumors; however, cognitive impairment occurs in 40-50% of brain tumor survivors. The etiology of the cognitive impairment following WBRT remains elusive. We recently reported that radiation-induced cerebrovascular rarefaction within hippocampal subregions could be completely reversed by systemic hypoxia. However, the effects of this intervention on learning and memory have not been reported. In this study, we assessed the time-course for WBRT-induced impairments in contextual and spatial learning and the capacity of systemic hypoxia to reverse WBRT-induced deficits in spatial memory. A clinical fractionated series of 4.5Gy WBRT was administered to mice twice weekly for 4 weeks, and after various periods of recovery, behavioral analyses were performed. To study the effects of systemic hypoxia, mice were subjected to 11% (hypoxia or 21% oxygen (normoxia for 28 days, initiated 1 month after the completion of WBRT. Our results indicate that WBRT induces a transient deficit in contextual learning, disruption of working memory, and progressive impairment of spatial learning. Additionally, systemic hypoxia completely reversed WBRT-induced impairments in learning and these behavioral effects as well as increased vessel density persisted for at least 2 months following hypoxia treatment. Our results provide critical support for the hypothesis that cerebrovascular rarefaction is a key component of cognitive impairment post-WBRT and indicate that processes of learning and memory, once thought to be permanently impaired after WBRT, can be restored.

  11. Brain and skin do not contribute to the systemic rise in erythropoietin during acute hypoxia in humans

    DEFF Research Database (Denmark)

    Rasmussen, Peter; Nordsborg, Nikolai; Taudorf, Sarah

    2012-01-01

    these findings apply to humans remains unknown. We exposed healthy young subjects to hypoxia (equivalent to 3800 m) and measured EPO in arterial and jugular venous plasma and in cerebrospinal fluid. To examine the role of the skin for EPO production during hypoxia, subjects were exposed to 8 h of hypobaric......Erythropoietin (EPO) preserves arterial oxygen content by controlling red blood cell and plasma volumes. Synthesis of EPO was long thought to relate inversely to renal oxygenation, but in knockout mice, brain and skin have been identified as essential for the acute hypoxic EPO response. Whether...

  12. Brain Tissue PO2 Measurement During Normoxia and Hypoxia Using Two-Photon Phosphorescence Lifetime Microscopy.

    Science.gov (United States)

    Xu, Kui; Boas, David A; Sakadžić, Sava; LaManna, Joseph C

    2017-01-01

    Key to the understanding of the principles of physiological and structural acclimatization to changes in the balance between energy supply (represented by substrate and oxygen delivery, and mitochondrial oxidative phosphorylation) and energy demand (initiated by neuronal activity) is to determine the controlling variables, how they are sensed and the mechanisms initiated to maintain the balance. The mammalian brain depends completely on continuous delivery of oxygen to maintain its function. We hypothesized that tissue oxygen is the primary sensed variable. In this study two-photon phosphorescence lifetime microscopy (2PLM) was used to determine and define the tissue oxygen tension field within the cerebral cortex of mice to a cortical depth of between 200-250 μm under normoxia and acute hypoxia (FiO 2  = 0.10). High-resolution images can provide quantitative distributions of oxygen and intercapillary oxygen gradients. The data are best appreciated by quantifying the distribution histogram that can then be used for analysis. For example, in the brain cortex of a mouse, at a depth of 200 μm, tissue oxygen tension was mapped and the distribution histogram was compared under normoxic and mild hypoxic conditions. This powerful method can provide for the first time a description of the delivery and availability of brain oxygen in vivo.

  13. Quantitative analysis of brain metabolites concentrations using MR spectroscopy in acute hypoxia ischemic encephalopathy

    International Nuclear Information System (INIS)

    Xiao Yeyu; Wang HaiYu; Shen Zhiwei; Lin Yan; Chen Yaowen; Xiao Gang; Wu Renhua

    2010-01-01

    Objective: To evaluate the absolute quantification of brain metabolites concentrations using external standard MRS in acute hypoxia ischemia encephalopathy (HIE) piglet model. Method: Eight 7-day-old healthy piglets were subjected to insult of hypoxia ischemia (HI). The animals and an external standard phantom containing detectable metabolites of known concentrations were studied on a 1.5 T GE Signa scanner. The single-voxel proton magnetic resonance spectroscopy ( 1 H-MRS) data were processed using LCModel software, and the quantification of N-acetylaspartate (NAA), creatine (Cr) and lactate (Lac) were accomplished. Multivariate analysis of variance was performed to compare the NAA, Cr, Lac concentration differences in the brains of piglets pre- and post-HI (0h). In addition, the dynamic changes of brain metabolites concentrations of 2 HIE piglets were observed at the time points of 0 h and 2 h. Results: One piglet was excluded because it was over anesthetized to death. Seven piglets' data were analyzed. The concentrations of NAA pre- and post-HI were (6.86±0.49) mmol/kg and (5.73±0.88) mmol/kg respectively, they were (4.65±0.73) mmol/kg and (4.40±0.80) mmol/kg for Cr; and were 0.00 mmol/kg and (0.43±0.39) mmol/kg for Lac. After HI, decreased NAA concentration immediately was observed, and it was of statistical significance (F=8.608, P=0.013). The concentration of Cr was insignificantly decreased (F=0.379, P=0.550). The concentration of Lac was increased, and the difference was of statistical significance (F=8.600, P=0.013). Dynamic observation showed a Lac peak immediately after HI and it decreased after 2 h post-HI. Conclusions: External standard MRS using LCModel has great value in the quantitative analysis of brain metabolites. The changes of NAA and Lac concentrations are sensitive to reflect the early metabolic change of acute HIE. (authors)

  14. Transcriptome Analysis Identifies Key Metabolic Changes in the Hooded Seal (Cystophora cristata Brain in Response to Hypoxia and Reoxygenation.

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    Mariana Leivas Müller Hoff

    Full Text Available The brain of diving mammals tolerates low oxygen conditions better than the brain of most terrestrial mammals. Previously, it has been demonstrated that the neurons in brain slices of the hooded seal (Cystophora cristata withstand hypoxia longer than those of mouse, and also tolerate reduced glucose supply and high lactate concentrations. This tolerance appears to be accompanied by a shift in the oxidative energy metabolism to the astrocytes in the seal while in terrestrial mammals the aerobic energy production mainly takes place in neurons. Here, we used RNA-Seq to compare the effect of hypoxia and reoxygenation in vitro on brain slices from the visual cortex of hooded seals. We saw no general reduction of gene expression, suggesting that the response to hypoxia and reoxygenation is an actively regulated process. The treatments caused the preferential upregulation of genes related to inflammation, as found before e.g. in stroke studies using mammalian models. Gene ontology and KEGG pathway analyses showed a downregulation of genes involved in ion transport and other neuronal processes, indicative for a neuronal shutdown in response to a shortage of O2 supply. These differences may be interpreted in terms of an energy saving strategy in the seal's brain. We specifically analyzed the regulation of genes involved in energy metabolism. Hypoxia and reoxygenation caused a similar response, with upregulation of genes involved in glucose metabolism and downregulation of the components of the pyruvate dehydrogenase complex. We also observed upregulation of the monocarboxylate transporter Mct4, suggesting increased lactate efflux. Together, these data indicate that the seal brain responds to the hypoxic challenge by a relative increase in the anaerobic energy metabolism.

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

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    Wardaya Wardaya

    2013-05-01

    antioxidants in Sprague Dawley male mice.Methods: The experimental study was in February-April 2010 consisted of one control group and four exposed groups of male mice Sprague Dawley. Each groups consisted of 5 mice. The control group did not have IHH. The exposed groups (with an interval of one week had once, twice, three, or four times IHH using a chamber flight. All exposed groups were treated hypobaric equivalent to: 35,000 ft altitude (1 minutes, 25,000 ft (5 minutes, and 18,000 ft (25 minutes. All of their brains had 8-OHdG and SOD measured.Results: The 8-OHdG level among three time IHH exposures had already returned to the control value (P = 0.843. The SOD level increased progressively among two, three, and four times IHH. However after the second exposure, it was found that the SOD level was similar to the control value, 0.231 ± 0.042 (P = 0.191.Conclusion: In conclusion, three times of IHH may improve the effect of hypoxia hypobaric on oxidative stress and specific activity of antioxidants in Sprague Dawley male mice. The SOD level was increased at an earlier exposure, which was after one IHH exposure.Keywords: intermittent hypoxia hypobaric, oxidative stress, antioxidants

  16. Social support moderates caregiver life satisfaction following traumatic brain injury.

    Science.gov (United States)

    Ergh, Tanya C; Hanks, Robin A; Rapport, Lisa J; Coleman, Renee D

    2003-12-01

    Social support is an important determinant of adjustment following traumatic brain injury (TBI) sustained by a family member. The present study examined the extent to which social support moderates the influence of characteristics of the person with injury on caregiver subjective well-being. Sixty pairs of individuals who had sustained a moderate to severe TBI and their caregivers (N=120) participated. Years postinjury ranged from 0.3 to 9.9 ( M=4.8, SD=2.6). Cognitive, functional, and neurobehavioral functioning of participants with TBI were assessed using neuropsychological tests and rating scales. Caregiver life satisfaction and perceived social support were assessed using self-report questionnaires. Results indicated that time since injury was unrelated to life satisfaction. Neurobehavioral disturbances showed an inverse relation with life satisfaction. Social support emerged as an important moderator of life satisfaction. Only among caregivers with low social support was cognitive dysfunction adversely related to life satisfaction. Similarly, a trend suggested that patient unawareness of deficit was associated with caregiver life dissatisfaction only among caregivers with low social support. In contrast, these characteristics were unrelated to life satisfaction among caregivers with adequate social support.

  17. Expression of hypoxia-inducible factor 1 alpha and oligodendrocyte lineage gene-1 in cultured brain slices after oxygen-glucose deprivation☆

    OpenAIRE

    Cui, Hong; Han, Weijuan; Yang, Lijun; Chang, Yanzhong

    2013-01-01

    Oligodendrocyte lineage gene-1 expressed in oligodendrocytes may trigger the repair of neuronal myelin impairment, and play a crucial role in myelin repair. Hypoxia-inducible factor 1α, a transcription factor, is of great significance in premature infants with hypoxic-ischemic brain damage. There is little evidence of direct regulatory effects of hypoxia-inducible factor 1α on oligodendrocyte lineage gene-1. In this study, brain slices of Sprague-Dawley rats were cultured and subjected to oxy...

  18. Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia.

    Science.gov (United States)

    Sethy, Niroj Kumar; Singh, Manjulata; Kumar, Rajesh; Ilavazhagan, Govindasamy; Bhargava, Kalpana

    2011-03-01

    Exposure to high altitude (and thus hypobaric hypoxia) induces electrophysiological, metabolic, and morphological modifications in the brain leading to several neurological clinical syndromes. Despite the known fact that hypoxia episodes in brain are a common factor for many neuropathologies, limited information is available on the underlying cellular and molecular mechanisms. In this study, we investigated the temporal effect of short-term (0-12 h) chronic hypobaric hypoxia on global gene expression of rat brain followed by detailed canonical pathway analysis and regulatory network identification. Our analysis revealed significant alteration of 33, 17, 53, 81, and 296 genes (p stress response pathway and genes were detected at all time points suggesting activation of NRF2-ARE antioxidant defense system. The results were further validated by assessing the expression levels of selected genes in temporal as well as brain regions with quantitative RT-PCR and western blot. In conclusion, our whole brain approach with temporal monitoring of gene expression patterns during hypobaric hypoxia has resulted in (1) deciphering sequence of pathways and signaling networks activated during onset of hypoxia, and (2) elucidation of NRF2-orchestrated antioxidant response as a major intrinsic defense mechanism. The results of this study will aid in better understanding and management of hypoxia-induced brain pathologies.

  19. Spatial patterns of progressive brain volume loss after moderate-severe traumatic brain injury

    Science.gov (United States)

    Jolly, Amy; de Simoni, Sara; Bourke, Niall; Patel, Maneesh C; Scott, Gregory; Sharp, David J

    2018-01-01

    Abstract Traumatic brain injury leads to significant loss of brain volume, which continues into the chronic stage. This can be sensitively measured using volumetric analysis of MRI. Here we: (i) investigated longitudinal patterns of brain atrophy; (ii) tested whether atrophy is greatest in sulcal cortical regions; and (iii) showed how atrophy could be used to power intervention trials aimed at slowing neurodegeneration. In 61 patients with moderate-severe traumatic brain injury (mean age = 41.55 years ± 12.77) and 32 healthy controls (mean age = 34.22 years ± 10.29), cross-sectional and longitudinal (1-year follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal brain volume changes were characterized using a novel neuroimaging analysis pipeline that generates a Jacobian determinant metric, reflecting spatial warping between baseline and follow-up scans. Jacobian determinant values were summarized regionally and compared with clinical and neuropsychological measures. Patients with traumatic brain injury showed lower grey and white matter volume in multiple brain regions compared to controls at baseline. Atrophy over 1 year was pronounced following traumatic brain injury. Patients with traumatic brain injury lost a mean (± standard deviation) of 1.55% ± 2.19 of grey matter volume per year, 1.49% ± 2.20 of white matter volume or 1.51% ± 1.60 of whole brain volume. Healthy controls lost 0.55% ± 1.13 of grey matter volume and gained 0.26% ± 1.11 of white matter volume; equating to a 0.22% ± 0.83 reduction in whole brain volume. Atrophy was greatest in white matter, where the majority (84%) of regions were affected. This effect was independent of and substantially greater than that of ageing. Increased atrophy was also seen in cortical sulci compared to gyri. There was no relationship between atrophy and time since injury or age at baseline. Atrophy rates were related to memory performance at the end of the

  20. Acetazolamide during acute hypoxia improves tissue oxygenation in the human brain.

    Science.gov (United States)

    Wang, Kang; Smith, Zachary M; Buxton, Richard B; Swenson, Erik R; Dubowitz, David J

    2015-12-15

    Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O2 metabolism (CMRO2 ) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (PtiO2 ) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral PtiO2 from MRI measurements of cerebral blood flow (CBF) and cerebral venous O2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2 , or PtiO2 . During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml·100 ml(-1)·min(-1) (hypoxia), P effect was improved cerebral tissue PtiO2 during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and PtiO2 during acute hypoxia. Copyright © 2015 the American Physiological Society.

  1. Preferred temperature of juvenile Atlantic cod Gadus morhua with different haemoglobin genotypes at normoxia and moderate hypoxia

    DEFF Research Database (Denmark)

    Petersen, M.F.; Steffensen, J.F.

    2003-01-01

    .2+/-1.5 degrees C while HbI-1 cod preferred 15.4+/-1.1 degrees C, and this preference was significant. The effect of hypoxia (35% oxygen saturation) on the preferred temperature was also measured. Previous studies showed that the preferred temperature of fish decreases during hypoxia, and this was the case for Hb......I-1 cod, which preferred 9.8+/-1.8 degrees C during hypoxia, whereas HbI-2 cod did not show this effect. The results indicate that environmental temperature changes will lead to a distributional change in the different haemoglobin types of Atlantic cod, global warming providing an advantage for HbI-1...... cod. However, since HbI-1 cod prefer a low temperature under hypoxic conditions, a combination of increased water temperature and hypoxia could be unfavourable for Atlantic cod stocks....

  2. The role of glycogen, glucose and lactate in neuronal activity during hypoxia in the hooded seal (Cystophora cristata) brain.

    Science.gov (United States)

    Czech-Damal, N U; Geiseler, S J; Hoff, M L M; Schliep, R; Ramirez, J-M; Folkow, L P; Burmester, T

    2014-09-05

    The brains of diving mammals are repeatedly exposed to hypoxic conditions during diving. Brain neurons of the hooded seal (Cystophora cristata) have been shown to be more hypoxia tolerant than those of mice, but the underlying mechanisms are not clear. Here we investigated the roles of different metabolic substrates for maintenance of neuronal activity and integrity, by comparing the in vitro spontaneous neuronal activity of brain slices from layer V of the visual cortex of hooded seals with those in mice (Mus musculus). Studies were conducted by manipulating the composition of the artificial cerebrospinal fluid (aCSF), containing either 10 mM glucose, or 20 mM lactate, or no external carbohydrate supply (aglycemia). Normoxic, hypoxic and ischemic conditions were applied. The lack of glucose or the application of lactate in the aCSF containing no glucose had little effect on the neuronal activity of seal neurons in either normoxia or hypoxia, while neurons from mice survived in hypoxia only few minutes regardless of the composition of the aCSF. We propose that seal neurons have higher intrinsic energy stores. Indeed, we found about three times higher glycogen stores in the seal brain (∼4.1 ng per μg total protein in the seal cerebrum) than in the mouse brain. Notably, in aCSF containing no glucose, seal neurons can tolerate 20 mM lactate while in mouse neuronal activity vanished after few minutes even in normoxia. This can be considered as an adaptation to long dives, during which lactate accumulates in the blood. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. SPECT brain perfusion findings in mild or moderate traumatic brain injury.

    Science.gov (United States)

    Abu-Judeh, H H; Parker, R; Aleksic, S; Singh, M L; Naddaf, S; Atay, S; Kumar, M; Omar, W; El-Zeftawy, H; Luo, J Q; Abdel-Dayem, H M

    2000-01-01

    The purpose of this manuscript is to present the findings in the largest series of SPECT brain perfusion imaging reported to date for mild or moderate traumatic brain injury. This is a retrospective evaluation of 228 SPECT brain perfusion-imaging studies of patients who suffered mild or moderate traumatic brain injury with or without loss of consciousness (LOC). All patients had no past medical history of previous brain trauma, neurological, or psychiatric diseases, HIV, alcohol or drug abuse. The patient population included 135 males and 93 females. The ages ranged from 11-88 years (mean 40.8). The most common complaints were characteristic of the postconcussion syndrome: headaches 139/228 (61%); dizziness 61/228 (27%); and memory problems 63/228 (28%). LOC status was reported to be positive in 121/228 (53%), negative in 41/228 (18%), and unknown for 63/228 (28%). Normal studies accounted for 52/228 (23%). For abnormal studies (176/228 or 77%) the findings were as follows: basal ganglia hypoperfusion 338 lesions (55.2%); frontal lobe hypoperfusion 146 (23.8%); temporal lobes hypoperfusion 80 (13%); parietal lobes hypoperfusion 20 (3.7%); insular and or occipital lobes hypoperfusion 28 (4.6%). Patients' symptoms correlated with the SPECT brain perfusion findings. The SPECT BPI studies in 122/228 (54%) were done early within 3 months of the date of the accident, and for the remainder, 106/228 (46%) over 3 months and less than 3 years from the date of the injury. In early imaging, 382 lesions were detected; in 92 patients (average 4.2 lesions per study) imaging after 3 months detected 230 lesions: in 84 patients (average 2.7 lesions per study). Basal ganglia hypoperfusion is the most common abnormality following mild or moderate traumatic brain injury (p = 0.006), and is more common in patients complaining of memory problem (p = 0.0005) and dizziness (p = 0.003). Early imaging can detect more lesions than delayed imaging (p = 0.0011). SPECT brain perfusion

  4. SPECT brain perfusion findings in mild or moderate traumatic brain injury

    International Nuclear Information System (INIS)

    Abu-Judeh, H.H.; Parker, R.; Aleksic, S.

    2000-01-01

    Background: The purpose of this manuscript is to present the findings in the largest series of SPECT brain perfusion imaging reported to date for mild or moderate traumatic brain injury. PATIENTS AND METHODS: This is a retrospective evaluation of 228 SPECT brain perfusion-imaging studies of patients who suffered mild or moderate traumatic brain injury with or without loss of consciousness (LOC). All patients had no past medical history of previous brain trauma, neurological, or psychiatric diseases, HIV, alcohol or drug abuse. The patient population included 135 males and 93 females. The ages ranged from 11-88 years (mean 40.8). The most common complaints were characteristic of the postconcussion syndrome: headaches 139/228 (61%); dizziness 61/228 (27%); and memory problems 63/228 (28%). LOC status was reported to be positive in 121/228 (53%), negative in 41/228 (18%), and unknown for 63/228 (28%). RESULTS: Normal studies accounted for 52/228 (23%). For abnormal studies (176/228 or 77%) the findings were as follows: basal ganglia hypoperfusion 338 lesions (55.2%); frontal lobe hypoperfusion 146 (23.8%); temporal lobes hypoperfusion 80 (13%); parietal lobes hypoperfusion 20 (3.7%); insular and or occipital lobes hypoperfusion 28 (4.6%). Patients' symptoms correlated with the SPECT brain perfusion findings. The SPECT BPI studies in 122/228 (54%) were done early within 3 months of the date of the accident, and for the remainder, 106/228 (46%) over 3 months and less than 3 years from the date of the injury. In early imaging, 382 lesions were detected; in 92 patients (average 4.2 lesions per study) imaging after 3 months detected 230 lesions: in 84 patients (average 2.7 lesions per study). CONCLUSIONS: Basal ganglia hypoperfusion is the most common abnormality following mild or moderate traumatic brain injury (p = 0.006), and is more common in patients complaining of memory problem (p = 0.0005) and dizziness (p = 0.003). Early imaging can detect more lesions than

  5. Maternal hypoxia increases the activity of MMPs and decreases the expression of TIMPs in the brain of neonatal rats.

    Science.gov (United States)

    Tong, Wenni; Chen, Wanqiu; Ostrowski, Robert P; Ma, Qingyi; Souvenir, Rhonda; Zhang, Lubo; Zhang, John H; Tang, Jiping

    2010-02-15

    A recent study has shown that increased activity of matrix metalloproteinases-2 and metalloproteinases-9 (MMP-2 and MMP-9) has detrimental effect on the brain after neonatal hypoxia. The present study determined the effect of maternal hypoxia on neuronal survivability and the activity of MMP-2 and MMP-9, as well as the expression of tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2) in the brain of neonatal rats. Pregnant rats were exposed to 10.5% oxygen for 6 days from the gestation day 15 to day 21. Pups were sacrificed at day 0, 4, 7, 14, and 21 after birth. Body weight and brain weight of the pups were measured at each time point. The activity of MMP-2 and MMP-9 and the protein abundance of TIMP-1 and TIMP-2 were determined by zymography and Western blotting, respectively. The tissue distribution of MMPs was examined by immunofluorescence staining. The neuronal death was detected by Nissl staining. Maternal hypoxia caused significant decreases in body and brain size, increased activity of MMP-2 at day 0, and increased MMP-9 at day 0 and 4. The increased activity of the MMPs was accompanied by an overall tendency towards a reduced expression of TIMPs at all ages with the significance observed for TIMPs at day 0, 4, and 7. Immunofluorescence analysis showed an increased expression of MMP-2, MMP-9 in the hippocampus at day 0 and 4. Nissl staining revealed significant cell death in the hippocampus at day 0, 4, and 7. Functional tests showed worse neurobehavioral outcomes in the hypoxic animals.

  6. Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model

    Directory of Open Access Journals (Sweden)

    Dimitrios Angelis

    2017-01-01

    Full Text Available Background. Protein tyrosine phosphatases (PTPs in conjunction with protein tyrosine kinases (PTKs regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks. Methods. Newborn piglets were divided into groups: normoxia, hypoxia, hypoxia followed by 1 day and 15 days in FiO2 0.21, and hypoxia pretreated with Src kinase inhibitor PP2, prior to hypoxia followed by 1 day and 15 days. Hypoxia was achieved by providing 7% FiO2 for 1 hour and PTP-1B expression was measured via immunoblotting. Results. PTP-1B increased posthypoxia by about 30% and persisted for 2 weeks while Src kinase inhibition attenuated the expected PTP-1B-increased expression. Conclusions. Our study suggests that Src kinase mediates a hypoxia-induced increased PTP-1B expression.

  7. [Mechanism of potassium channel in hypoxia-ischemic brain edema: experiment with neonatal rat astrocyte].

    Science.gov (United States)

    Fu, Xue-mei; Xiang, Long; Liao, Da-qing; Feng, Zhi-chun; Mu, De-zhi

    2008-11-04

    To investigate the mechanism of potassium channel in brain edema caused by hypoxia-ischemia (HI). Astrocytes were obtained from 3-day-old SD rats, cultured, and randomly divided into 2 groups: normoxia group, cultured under normoxic condition, and hypoxic-ischemic group, cultured under hypoxic-ischemic condition. The cell volume was measured by radiologic method. Patch-clamp technique was used to observe the electric physiological properties of the voltage-gated potassium channels (Kv) in a whole cell configuration, and the change of voltage-gated potassium channel current (IKv) was recorded in cultured neonatal rat astrocyte during HI. Aquaporin 4 (AQP4) expression vector was constructed from pSUPER vector and transfected into the astrocytes (AQP4 RNAi) to construct AQP4 knockdown (AQP4-/-) cells. cellular volume was determined using [3H]-3-O-methyl-D-glucose uptake in both AQP4-/- and AQP4+/+ cells under the condition of HI. Real time PCR and Western blotting were used to detect the mRNA and protein expression of AQP4. The percentages of the AQP4+/+ and AQP4-/- astrocyte volumes in the condition of HI for 0.5, 1, 2, and 4 h were 104+/-7, 109+/-6, 126+/-12, and 152+/-9 times, and 97+/-7, 105+/-9, 109+/-7, and 132+/-6 times as those of their corresponding control groups (all Pastrocytes significantly increased during HI and the degrees of edema mediated by AQP4 knockdown at different time points were all significantly milder (all Pastrocytes via aquaporin-4 and then cell swelling.

  8. Alterations of monocarboxylate transporter densities during hypoxia in brain and breast tumour cells

    DEFF Research Database (Denmark)

    Cheng, Chang; Edin, Nina F Jeppesen; Lauritzen, Knut H

    2012-01-01

    Tumour cells are characterized by aerobic glycolysis, which provides biomass for tumour proliferation and leads to extracellular acidification through efflux of lactate via monocarboxylate transporters (MCTs). Deficient and spasm-prone tumour vasculature causes variable hypoxia, which favours...

  9. Hypoxia Stress Modifies Na/K-ATPase, H/K-ATPase, , and Isoform Expression in the Brain of Immune-Challenged Air-Breathing Fish

    Directory of Open Access Journals (Sweden)

    MC Subhash Peter

    2017-11-01

    Full Text Available Fishes are equipped to sense stressful stimuli and are able to respond to environmental stressor such as hypoxia with varying pattern of stress response. The functional attributes of brain to hypoxia stress in relation to ion transport and its interaction during immune challenge have not yet delineated in fish. We, therefore, explored the pattern of ion transporter functions and messenger RNA (mRNA expression of α1-subunit isoforms of Na + /K + -ATPase (NKA in the brain segments, namely, prosencephalon (PC, mesencephalon (MC, and metencephalon (MeC in an obligate air-breathing fish exposed either to hypoxia stress (30 minutes forced immersion in water or challenged with zymosan treatment (25-200 ng g −1 for 24 hours or both. Zymosan that produced nonspecific immune responses evoked differential regulation of NKA, H + /K + -ATPase (HKA, and Na + / NH 4 + - ATPase (NNA in the varied brain segments. On the contrary, hypoxia stress that demanded activation of NKA in PC and MeC showed a reversed NKA activity pattern in MeC of immune-challenged fish. A compromised HKA and NNA regulation during hypoxia stress was found in immune-challenged fish, indicating the role of these brain ion transporters to hypoxia stress and immune challenges. The differential mRNA expression of α1-subunit isoforms of NKA, nkaα1a , nkaα1b , and nkaα1c , in hypoxia-stressed brain showed a shift in its expression pattern during hypoxia stress-immune interaction in PC and MC. Evidence is thus presented for the first time that ion transporters such as HKA and NNA along with NKA act as functional brain markers which respond differentially to both hypoxia stress and immune challenges. Taken together, the data further provide evidence for a differential Na + , K + , H + , and NH 4 + ion signaling that exists in brain neuronal clusters during hypoxia stress-immune interaction as a result of modified regulations of NKA, HKA, and NNA transporter functions and nkaα1 isoform

  10. Spatial patterns of progressive brain volume loss after moderate-severe traumatic brain injury.

    Science.gov (United States)

    Cole, James H; Jolly, Amy; de Simoni, Sara; Bourke, Niall; Patel, Maneesh C; Scott, Gregory; Sharp, David J

    2018-01-04

    Traumatic brain injury leads to significant loss of brain volume, which continues into the chronic stage. This can be sensitively measured using volumetric analysis of MRI. Here we: (i) investigated longitudinal patterns of brain atrophy; (ii) tested whether atrophy is greatest in sulcal cortical regions; and (iii) showed how atrophy could be used to power intervention trials aimed at slowing neurodegeneration. In 61 patients with moderate-severe traumatic brain injury (mean age = 41.55 years ± 12.77) and 32 healthy controls (mean age = 34.22 years ± 10.29), cross-sectional and longitudinal (1-year follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal brain volume changes were characterized using a novel neuroimaging analysis pipeline that generates a Jacobian determinant metric, reflecting spatial warping between baseline and follow-up scans. Jacobian determinant values were summarized regionally and compared with clinical and neuropsychological measures. Patients with traumatic brain injury showed lower grey and white matter volume in multiple brain regions compared to controls at baseline. Atrophy over 1 year was pronounced following traumatic brain injury. Patients with traumatic brain injury lost a mean (± standard deviation) of 1.55% ± 2.19 of grey matter volume per year, 1.49% ± 2.20 of white matter volume or 1.51% ± 1.60 of whole brain volume. Healthy controls lost 0.55% ± 1.13 of grey matter volume and gained 0.26% ± 1.11 of white matter volume; equating to a 0.22% ± 0.83 reduction in whole brain volume. Atrophy was greatest in white matter, where the majority (84%) of regions were affected. This effect was independent of and substantially greater than that of ageing. Increased atrophy was also seen in cortical sulci compared to gyri. There was no relationship between atrophy and time since injury or age at baseline. Atrophy rates were related to memory performance at the end of the follow

  11. A method for measuring brain partial pressure of oxygen in unanesthetized unrestrained subjects: the effect of acute and chronic hypoxia on brain tissue PO(2).

    Science.gov (United States)

    Ortiz-Prado, E; Natah, Siraj; Srinivasan, Sathyanarayanan; Dunn, Jeff F

    2010-11-30

    The level of tissue oxygenation provides information related to the balance between oxygen delivery, oxygen utilization, tissue reactivity and morphology during physiological conditions. Tissue partial pressure of oxygen (PtO(2)) is influenced by the use of anesthesia or restraint. These factors may impact the absolute level of PtO(2). In this study we present a novel fiber optic method to measure brain PtO(2). This method can be used in unanesthetized, unrestrained animals, provides absolute values for PO(2), has a stable calibration, does not consume oxygen and is MRI compatible. Brain PtO(2) was studied during acute hypoxia, as well as before and after 28 days of high altitude acclimatization. A sensor was chronically implanted in the frontal cortex of eight Wistar rats. It is comprised of a fiber optic probe with a tip containing material that fluoresces with an oxygen dependent lifetime. Brain PtO(2) declines by 80% and 76% pre- and post-acclimatization, respectively, when the fraction of inspired oxygen declines from 0.21 to 0.08. In addition, a linear relationship between brain PtO(2) and inspired O(2) levels was demonstrated r(2)=0.98 and r(2)=0.99 (pre- and post-acclimatization). Hypoxia acclimatization resulted in an increase in the overall brain PtO(2) by approximately 35%. This paper demonstrates the use of a novel chronically implanted fiber optic based sensor for measuring absolute PtO(2). It shows a very strong linear relationship in awake animals between inspired O(2) and tissue O(2), and shows that there is a proportional increase in PtO(2) over a range of inspired values after exposure to chronic hypoxia. Copyright © 2010 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2014-01-01

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

  13. Early postnatal exposure to intermittent hypoxia in rodents is proinflammatory, impairs white matter integrity, and alters brain metabolism.

    Science.gov (United States)

    Darnall, Robert A; Chen, Xi; Nemani, Krishnamurthy V; Sirieix, Chrystelle M; Gimi, Barjor; Knoblach, Susan; McEntire, Betty L; Hunt, Carl E

    2017-07-01

    BackgroundPreterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury.MethodsRat pups were exposed to IH from P2 to P12. Control animals were exposed to room air. Cytokines were analyzed in plasma and brain tissue at P13 and P18. At P20-P22, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were performed.ResultsPups exposed to IH had increased plasma Gro/CXCL1 and cerebellar IFN-γ and IL-1β at P13, and brainstem enolase at P18. DTI showed a decrease in FA and AD in the corpus callosum (CC) and cingulate gyrus, and an increase in RD in the CC. MRS revealed decreases in NAA/Cho, Cr, Tau/Cr, and Gly/Cr; increases in TCho and GPC in the brainstem; and decreases in NAA/Cho in the hippocampus.ConclusionsWe conclude that early postnatal exposure to IH, similar in magnitude to that experienced in human preterm infants, is associated with evidence for proinflammatory changes, decreases in white matter integrity, and metabolic changes consistent with hypoxia.

  14. Maternal hypertension during pregnancy modifies the response of the immature brain to hypoxia-ischemia: Sequential MRI and behavioral investigations

    International Nuclear Information System (INIS)

    Letourneur, Annelise; Roussel, Simon; Divoux, Didier; Toutain, Jerome; Bernaudin, Myriam; Touzani, Omar; Freret, Thomas; Boulouard, Michel; Schumann-Bard, Pascale; Bouet, Valentine

    2012-01-01

    Hypoxic-ischemic (HI) brain injury occurring during the perinatal period is still a major cause of mortality and morbidity. We assessed the impact of maternal hypertension, the most common medical disorder of pregnancy, on the anatomical and functional consequences of HI insult in the immature brain. Rat pups from spontaneously hypertensive (SHR) and normotensive (Wistar Kyoto - WKY) dams were subjected to HI brain damage at postnatal day 7 (P7). Brain lesion and functional deficits were analyzed from 10 min to 35 days after HI, using magnetic resonance imaging (MRI), sensorimotor and cognitive tests. MRI data revealed that SHR pups displayed less brain damage than WKY, attested by an initial smaller lesion followed by a reduced tissue loss at chronic stage (57.1±21.6 and 31.1±27% ipsilateral hemisphere atrophy in WKY and SHR, respectively). Behavioral analyses showed less HI-induced behavioral deficits in motor coordination (rotarod test) and spatial learning (Morris watermaze test) in pups from hypertensive dams compared to those from normotensive ones. The data suggest that maternal hypertension causes prenatal stress that may render the immature brain more resistant to subsequent hypoxia-ischemia, related to a preconditioning phenomenon. (authors)

  15. Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia

    Science.gov (United States)

    2013-01-01

    Background Hypoxia induces microglial activation which causes damage to the developing brain. Microglia derived inflammatory mediators may contribute to this process. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation and cytokines production in brain injuries; however, its role in hypoxic injury remains uncertain. We investigate here TLR4 expression and its roles in neuroinflammation in neonatal rats following hypoxic injury. Methods One day old Wistar rats were subjected to hypoxia for 2 h. Primary cultured microglia and BV-2 cells were subjected to hypoxia for different durations. TLR4 expression in microglia was determined by RT-PCR, western blot and immunofluorescence staining. Small interfering RNA (siRNA) transfection and antibody neutralization were employed to downregulate TLR4 in BV-2 and primary culture. mRNA and protein expression of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and inducible nitric oxide synthase (iNOS) was assessed. Reactive oxygen species (ROS), nitric oxide (NO) and NF-κB levels were determined by flow cytometry, colorimetric and ELISA assays respectively. Hypoxia-inducible factor-1 alpha (HIF-1α) mRNA and protein expression was quantified and where necessary, the protein expression was depleted by antibody neutralization. In vivo inhibition of TLR4 with CLI-095 injection was carried out followed by investigation of inflammatory mediators expression via double immunofluorescence staining. Results TLR4 immunofluorescence and protein expression in the corpus callosum and cerebellum in neonatal microglia were markedly enhanced post-hypoxia. In vitro, TLR4 protein expression was significantly increased in both primary microglia and BV-2 cells post-hypoxia. TLR4 neutralization in primary cultured microglia attenuated the hypoxia-induced expression of TNF-α, IL-1β and iNOS. siRNA knockdown of TLR4 reduced hypoxia-induced upregulation of TNF-α, IL-1β, iNOS, ROS and NO in BV-2 cells. TLR4

  16. Effect of moderate hypoxia at three acclimation temperatures on stress responses in Atlantic cod with different haemoglobin types

    DEFF Research Database (Denmark)

    Methling, Caroline; Aluru, Neelakanteswar; Vijayan, Mathilakath M

    2010-01-01

    in a difference in stress response to hypoxia exposure. Two hsp70-isoforms (labelled a and b) were detected and they differed in expression in the gills but not in the liver of Atlantic cod. Acclimation temperature significantly affected the expression of hsp70 in the liver, and in an isoform-specific manner...... in the gills. Hypoxia exposure increased the expression of hsp70 in the liver, but not the gills, of cod and this response was not influenced by the acclimation temperature. The expression of hsp70 in both tissues did not differ between fish with different haemoglobin types. Acclimation temperature...... hypoxic exposure influence the organismal and cellular stress responses in Atlantic cod. We hypothesise that HbI-2 fish are more tolerant to short-term hypoxic episodes than HbI-1 fish, and this adaptation may be independent of tissue hsp70 expression....

  17. Cerebellar abnormalities following hypoxia alone compared to hypoxic-ischemic forebrain injury in the developing rat brain

    NARCIS (Netherlands)

    Biran, V.; Heine, V.M.; Verney, C.; Sheldon, R.A.; Spadafora, R.; Vexler, Z.S.; Rowitch, D.H.; Ferriero, D.M.

    2011-01-01

    Two-day-old (P2) rat pups were subjected to either a global hypoxia or to electrocoagulation of the right carotid artery followed by 2.5. h hypoxia. Cellular and regional injury in the cerebellum (CB) was studied at 1, 2 and 19. days using immunohistology. Following hypoxia and hypoxia-ischemia, all

  18. Brain Metabolism Alterations Induced by Pregnancy Swimming Decreases Neurological Impairments Following Neonatal Hypoxia-Ischemia in Very Immature Rats

    Directory of Open Access Journals (Sweden)

    Eduardo F. Sanches

    2018-06-01

    Full Text Available Introduction: Prematurity, through brain injury and altered development is a major cause of neurological impairments and can result in motor, cognitive and behavioral deficits later in life. Presently, there are no well-established effective therapies for preterm brain injury and the search for new strategies is needed. Intra-uterine environment plays a decisive role in brain maturation and interventions using the gestational window have been shown to influence long-term health in the offspring. In this study, we investigated whether pregnancy swimming can prevent the neurochemical metabolic alterations and damage that result from postnatal hypoxic-ischemic brain injury (HI in very immature rats.Methods: Female pregnant Wistar rats were divided into swimming (SW or sedentary (SE groups. Following a period of adaptation before mating, swimming was performed during the entire gestation. At postnatal day (PND3, rat pups from SW and SE dams had right common carotid artery occluded, followed by systemic hypoxia. At PND4 (24 h after HI, the early neurochemical profile was measured by 1H-magnetic resonance spectroscopy. Astrogliosis, apoptosis and neurotrophins protein expression were assessed in the cortex and hippocampus. From PND45, behavioral testing was performed. Diffusion tensor imaging and neurite orientation dispersion and density imaging were used to evaluate brain microstructure and the levels of proteins were quantified.Results: Pregnancy swimming was able to prevent early metabolic changes induced by HI preserving the energetic balance, decreasing apoptotic cell death and astrogliosis as well as maintaining the levels of neurotrophins. At adult age, swimming preserved brain microstructure and improved the performance in the behavioral tests.Conclusion: Our study points out that swimming during gestation in rats could prevent prematurity related brain damage in progeny with high translational potential and possibly interesting cost

  19. SPECT brain perfusion abnormalities in mild or moderate traumatic brain injury.

    Science.gov (United States)

    Abdel-Dayem, H M; Abu-Judeh, H; Kumar, M; Atay, S; Naddaf, S; El-Zeftawy, H; Luo, J Q

    1998-05-01

    The purpose of this atlas is to present a review of the literature showing the advantages of SPECT brain perfusion imaging (BPI) in mild or moderate traumatic brain injury (TBI) over other morphologic imaging modalities such as x-ray CT or MRI. The authors also present the technical recommendations for SPECT brain perfusion currently practiced at their center. For the radiopharmaceutical of choice, a comparison between early and delayed images using Tc-99m HMPAO and Tc-99m ECD showed that Tc-99m HMPAO is more stable in the brain with no washout over time. Therefore, the authors feel that Tc-99m HMPAO is preferable to Tc-99m ECD. Recommendations regarding standardizing intravenous injection, the acquisition, processing parameters, and interpretation of scans using a ten grade color scale, and use of the cerebellum as the reference organ are presented. SPECT images of 228 patients (age range, 11 to 88; mean, 40.8 years) with mild or moderate TBI and no significant medical history that interfered with the results of the SPECT BP were reviewed. The etiology of the trauma was in the following order of frequency: motor vehicle accidents (45%) followed by blow to the head (36%) and a fall (19%). Frequency of the symptoms was headache (60.9%), memory problems (27.6%), dizziness (26.7%), and sleep disorders (8.7%). Comparison between patients imaged early (3 months) from the time of the accident, showed that early imaging detected more lesions (4.2 abnormal lesions per study compared to 2.7 in those imaged more than 3 months after the accident). Of 41 patients who had mild traumatic injury without loss of consciousness and had normal CT, 28 studies were abnormal. Focal areas of hypoperfusion were seen in 77% (176 patients, 612 lesions) of the group of 228 patients. The sites of abnormalities were in the following order: basal ganglia and thalami, 55.2%, frontal lobes, 23.8%, temporal lobes, 13%, parietal, 3.7%, insular and occipital lobes together, 4.6%.

  20. DHA but Not EPA Emulsions Preserve Neurological and Mitochondrial Function after Brain Hypoxia-Ischemia in Neonatal Mice

    Science.gov (United States)

    Sosunov, Sergey A.; Williams, Jill J.; Zirpoli, Hylde; Vlasakov, Iliyan; Deckelbaum, Richard J.; Ten, Vadim S.

    2016-01-01

    Background and Purpose Treatment with triglyceride emulsions of docosahexaenoic acid (tri-DHA) protected neonatal mice against hypoxia-ischemia (HI) brain injury. The mechanism of this neuroprotection remains unclear. We hypothesized that administration of tri-DHA enriches HI-brains with DHA/DHA metabolites. This reduces Ca2+-induced mitochondrial membrane permeabilization and attenuates brain injury. Methods 10-day-old C57BL/6J mice following HI-brain injury received tri-DHA, tri-EPA or vehicle. At 4–5 hours of reperfusion, mitochondrial fatty acid composition and Ca2+ buffering capacity were analyzed. At 24 hours and at 8–9 weeks of recovery, oxidative injury, neurofunctional and neuropathological outcomes were evaluated. In vitro, hyperoxia-induced mitochondrial generation of reactive oxygen species (ROS) and Ca2+ buffering capacity were measured in the presence or absence of DHA or EPA. Results Only post-treatment with tri-DHA reduced oxidative damage and improved short- and long-term neurological outcomes. This was associated with increased content of DHA in brain mitochondria and DHA-derived bioactive metabolites in cerebral tissue. After tri-DHA administration HI mitochondria were resistant to Ca2+-induced membrane permeabilization. In vitro, hyperoxia increased mitochondrial ROS production and reduced Ca2+ buffering capacity; DHA, but not EPA, significantly attenuated these effects of hyperoxia. Conclusions Post-treatment with tri-DHA resulted in significant accumulation of DHA and DHA derived bioactive metabolites in the HI-brain. This was associated with improved mitochondrial tolerance to Ca2+-induced permeabilization, reduced oxidative brain injury and permanent neuroprotection. Interaction of DHA with mitochondria alters ROS release and improves Ca2+ buffering capacity. This may account for neuroprotective action of post-HI administration of tri-DHA. PMID:27513579

  1. DHA but Not EPA Emulsions Preserve Neurological and Mitochondrial Function after Brain Hypoxia-Ischemia in Neonatal Mice.

    Science.gov (United States)

    Mayurasakorn, Korapat; Niatsetskaya, Zoya V; Sosunov, Sergey A; Williams, Jill J; Zirpoli, Hylde; Vlasakov, Iliyan; Deckelbaum, Richard J; Ten, Vadim S

    2016-01-01

    Treatment with triglyceride emulsions of docosahexaenoic acid (tri-DHA) protected neonatal mice against hypoxia-ischemia (HI) brain injury. The mechanism of this neuroprotection remains unclear. We hypothesized that administration of tri-DHA enriches HI-brains with DHA/DHA metabolites. This reduces Ca2+-induced mitochondrial membrane permeabilization and attenuates brain injury. 10-day-old C57BL/6J mice following HI-brain injury received tri-DHA, tri-EPA or vehicle. At 4-5 hours of reperfusion, mitochondrial fatty acid composition and Ca2+ buffering capacity were analyzed. At 24 hours and at 8-9 weeks of recovery, oxidative injury, neurofunctional and neuropathological outcomes were evaluated. In vitro, hyperoxia-induced mitochondrial generation of reactive oxygen species (ROS) and Ca2+ buffering capacity were measured in the presence or absence of DHA or EPA. Only post-treatment with tri-DHA reduced oxidative damage and improved short- and long-term neurological outcomes. This was associated with increased content of DHA in brain mitochondria and DHA-derived bioactive metabolites in cerebral tissue. After tri-DHA administration HI mitochondria were resistant to Ca2+-induced membrane permeabilization. In vitro, hyperoxia increased mitochondrial ROS production and reduced Ca2+ buffering capacity; DHA, but not EPA, significantly attenuated these effects of hyperoxia. Post-treatment with tri-DHA resulted in significant accumulation of DHA and DHA derived bioactive metabolites in the HI-brain. This was associated with improved mitochondrial tolerance to Ca2+-induced permeabilization, reduced oxidative brain injury and permanent neuroprotection. Interaction of DHA with mitochondria alters ROS release and improves Ca2+ buffering capacity. This may account for neuroprotective action of post-HI administration of tri-DHA.

  2. DHA but Not EPA Emulsions Preserve Neurological and Mitochondrial Function after Brain Hypoxia-Ischemia in Neonatal Mice.

    Directory of Open Access Journals (Sweden)

    Korapat Mayurasakorn

    Full Text Available Treatment with triglyceride emulsions of docosahexaenoic acid (tri-DHA protected neonatal mice against hypoxia-ischemia (HI brain injury. The mechanism of this neuroprotection remains unclear. We hypothesized that administration of tri-DHA enriches HI-brains with DHA/DHA metabolites. This reduces Ca2+-induced mitochondrial membrane permeabilization and attenuates brain injury.10-day-old C57BL/6J mice following HI-brain injury received tri-DHA, tri-EPA or vehicle. At 4-5 hours of reperfusion, mitochondrial fatty acid composition and Ca2+ buffering capacity were analyzed. At 24 hours and at 8-9 weeks of recovery, oxidative injury, neurofunctional and neuropathological outcomes were evaluated. In vitro, hyperoxia-induced mitochondrial generation of reactive oxygen species (ROS and Ca2+ buffering capacity were measured in the presence or absence of DHA or EPA.Only post-treatment with tri-DHA reduced oxidative damage and improved short- and long-term neurological outcomes. This was associated with increased content of DHA in brain mitochondria and DHA-derived bioactive metabolites in cerebral tissue. After tri-DHA administration HI mitochondria were resistant to Ca2+-induced membrane permeabilization. In vitro, hyperoxia increased mitochondrial ROS production and reduced Ca2+ buffering capacity; DHA, but not EPA, significantly attenuated these effects of hyperoxia.Post-treatment with tri-DHA resulted in significant accumulation of DHA and DHA derived bioactive metabolites in the HI-brain. This was associated with improved mitochondrial tolerance to Ca2+-induced permeabilization, reduced oxidative brain injury and permanent neuroprotection. Interaction of DHA with mitochondria alters ROS release and improves Ca2+ buffering capacity. This may account for neuroprotective action of post-HI administration of tri-DHA.

  3. Normobaric Hypoxia as a Cognitive Stress Test for Mild Traumatic Brain Injury: Oculometrics, Pulse Oximetry, and the Self Report of Symptom Severity

    Science.gov (United States)

    2011-06-20

    fitness for duty of personnel. Hypoxia and Mild Traumatic Brain Injury The present research was motivated in part by a serendipitous observation made...athletic departments, bicycle shops, fitness and health centers as well as such clubs and organizations as roller derby teams, rodeo clubs, rugby teams

  4. Adult naked mole-rat brain retains the NMDA receptor subunit GluN2D associated with hypoxia tolerance in neonatal mammals.

    Science.gov (United States)

    Peterson, Bethany L; Park, Thomas J; Larson, John

    2012-01-11

    Adult naked mole-rats show a number of systemic adaptations to a crowded underground habitat that is low in oxygen and high in carbon dioxide. Remarkably, brain slice tissue from adult naked mole-rats also is extremely tolerant to oxygen deprivation as indicated by maintenance of synaptic transmission under hypoxic conditions as well as by a delayed neuronal depolarization during anoxia. These characteristics resemble hypoxia tolerance in brain slices from neonates in a variety of mammal species. An important component of neonatal tolerance to hypoxia involves the subunit composition of NMDA receptors. Neonates have a high proportion of NMDA receptors with GluN2D subunits which are protective because they retard calcium entry into neurons during hypoxic episodes. Therefore, we hypothesized that adult naked mole-rats retain a protective, neonatal-like, NMDA receptor subunit profile. We used immunoblotting to assess age-related changes in NMDA receptor subunits in naked mole-rats and mice. The results show that adult naked mole-rat brain retains a much greater proportion of the hypoxia-protective GluN2D subunit compared to adult mice. However, age-related changes in other subunits (GluN2A and GluN2B) from the neonatal period to adulthood were comparable in mice and naked mole-rats. Hence, adult naked mole-rat brain only retains the neonatal NMDA receptor subunit that is associated with hypoxia tolerance. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  5. Hypoxia-induced lipid peroxidation in rat brain and protective effect of carnitine and phosphocreatine

    Czech Academy of Sciences Publication Activity Database

    Rauchová, Hana; Koudelová, J.; Drahota, Zdeněk; Mourek, J.

    2002-01-01

    Roč. 27, č. 9 (2002), s. 899-904 ISSN 0364-3190 R&D Projects: GA MŠk LN00A069 Grant - others:GA UK(XC) 22/2001 Institutional research plan: CEZ:AV0Z5011922 Keywords : hypobaric hypoxia-lipid peroxidation * carnitine * lactate/pyruvate ratio Subject RIV: ED - Physiology Impact factor: 1.672, year: 2002

  6. Hypoxia-Mediated Epigenetic Regulation of Stemness in Brain Tumor Cells.

    Science.gov (United States)

    Prasad, Pankaj; Mittal, Shivani Arora; Chongtham, Jonita; Mohanty, Sujata; Srivastava, Tapasya

    2017-06-01

    Activation of pluripotency regulatory circuit is an important event in solid tumor progression and the hypoxic microenvironment is known to enhance the stemness feature of some cells. The distinct population of cancer stem cells (CSCs)/tumor initiating cells exist in a niche and augment invasion, metastasis, and drug resistance. Previously, studies have reported global hypomethylation and site-specific aberrant methylation in gliomas along with other epigenetic modifications as important contributors to genomic instability during glioma progression. Here, we have demonstrated the role of hypoxia-mediated epigenetic modifications in regulating expression of core pluripotency factors, OCT4 and NANOG, in glioma cells. We observe hypoxia-mediated induction of demethylases, ten-eleven-translocation (TET) 1 and 3, but not TET2 in our cell-line model. Immunoprecipitation studies reveal active demethylation and direct binding of TET1 and 3 at the Oct4 and Nanog regulatory regions. Tet1 and 3 silencing assays further confirmed induction of the pluripotency pathway involving Oct4, Nanog, and Stat3, by these paralogues, although with varying degrees. Knockdown of Tet1 and Tet3 inhibited the formation of neurospheres in hypoxic conditions. We observed independent roles of TET1 and TET3 in differentially regulating pluripotency and differentiation associated genes in hypoxia. Overall, this study demonstrates an active demethylation in hypoxia by TET1 and 3 as a mechanism of Oct4 and Nanog overexpression thus contributing to the formation of CSCs in gliomas. Stem Cells 2017;35:1468-1478. © 2017 AlphaMed Press.

  7. Hypoxia-induced lipid peroxidation in the brain during postnatal ontogenesis

    Czech Academy of Sciences Publication Activity Database

    Rauchová, Hana; Vokurková, Martina; Koudelová, J.

    2012-01-01

    Roč. 61, Suppl.1 (2012), S89-S101 ISSN 0862-8408 R&D Projects: GA MŠk(CZ) 1M0510; GA ČR(CZ) GAP304/12/0259 Institutional research plan: CEZ:AV0Z50110509 Keywords : hypobaric hypoxia * reactive oxygen species (ROS) * polyunsaturated fatty acids * Na * K-ATPase * catalase * L-carnitine Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.531, year: 2012

  8. Evolving changes in fetal heart rate variability and brain injury after hypoxia-ischaemia in preterm fetal sheep.

    Science.gov (United States)

    Yamaguchi, Kyohei; Lear, Christopher A; Beacom, Michael J; Ikeda, Tomoaki; Gunn, Alistair J; Bennet, Laura

    2018-01-08

    Fetal heart rate variability is a critical index of fetal wellbeing. Suppression of heart rate variability may provide prognostic information on the risk of hypoxic-ischaemic brain injury after birth. In the present study, we report the evolution of fetal heart rate variability after both mild and severe hypoxia-ischaemia. Both mild and severe hypoxia-ischaemia were associated with an initial, brief suppression of multiple measures of heart rate variability. This was followed by normal or increased levels of heart rate variability during the latent phase of injury. Severe hypoxia-ischaemia was subsequently associated with the prolonged suppression of measures of heart rate variability during the secondary phase of injury, which is the period of time when brain injury is no longer treatable. These findings suggest that a biphasic pattern of heart rate variability may be an early marker of brain injury when treatment or intervention is probably most effective. Hypoxia-ischaemia (HI) is a major contributor to preterm brain injury, although there are currently no reliable biomarkers for identifying infants who are at risk. We tested the hypothesis that fetal heart rate (FHR) and FHR variability (FHRV) would identify evolving brain injury after HI. Fetal sheep at 0.7 of gestation were subjected to either 15 (n = 10) or 25 min (n = 17) of complete umbilical cord occlusion or sham occlusion (n = 12). FHR and four measures of FHRV [short-term variation, long-term variation, standard deviation of normal to normal R-R intervals (SDNN), root mean square of successive differences) were assessed until 72 h after HI. All measures of FHRV were suppressed for the first 3-4 h in the 15 min group and 1-2 h in the 25 min group. Measures of FHRV recovered to control levels by 4 h in the 15 min group, whereas the 25 min group showed tachycardia and an increase in short-term variation and SDNN from 4 to 6 h after occlusion. The measures of FHRV then progressively

  9. Ageing and chronic intermittent hypoxia mimicking sleep apnea do not modify local brain tissue stiffness in healthy mice.

    Science.gov (United States)

    Jorba, Ignasi; Menal, Maria José; Torres, Marta; Gozal, David; Piñol-Ripoll, Gerard; Colell, Anna; Montserrat, Josep M; Navajas, Daniel; Farré, Ramon; Almendros, Isaac

    2017-07-01

    Recent evidence suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer´s disease (AD), with the latter promoting alterations in brain tissue stiffness, a feature of ageing. Here, we assessed the effects of age and intermittent hypoxia (IH) on brain tissue stiffness in a mouse model of OSA. Two-month-old and 18-month-old mice (N=10 each) were subjected to IH (20% O 2 40s - 6% O 2 20s) for 8 weeks (6h/day). Corresponding control groups for each age were kept under normoxic conditions in room air (RA). After sacrifice, the brain was excised and 200-micron coronal slices were cut with a vibratome. Local stiffness of the cortex and hippocampus were assessed in brain slices placed in an Atomic Force Microscope. For both brain regions, the Young's modulus (E) in each animal was computed as the average values from 9 force-indentation curves. Cortex E mean (±SE) values were 442±122Pa (RA) and 455±120 (IH) for young mice and 433±44 (RA) and 405±101 (IH) for old mice. Hippocampal E values were 376±62 (RA) and 474±94 (IH) for young mice and 486±93 (RA) and 521±210 (IH) for old mice. For both cortex and hippocampus, 2-way ANOVA indicated no statistically significant effects of age or challenge (IH vs. RA) on E values. Thus, neither chronic IH mimicking OSA nor ageing up to late middle age appear to modify local brain tissue stiffness in otherwise healthy mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Hypoxia-ischemia or excitotoxin-induced tissue plasminogen activator- dependent gelatinase activation in mice neonate brain microvessels.

    Directory of Open Access Journals (Sweden)

    Priscilla L Omouendze

    Full Text Available Hypoxia-ischemia (HI and excitotoxicity are validated causes of neonatal brain injuries and tissue plasminogen activator (t-PA participates in the processes through proteolytic and receptor-mediated pathways. Brain microvascular endothelial cells from neonates in culture, contain and release more t-PA and gelatinases upon glutamate challenge than adult cells. We have studied t-PA to gelatinase (MMP-2 and MMP-9 activity links in HI and excitotoxicity lesion models in 5 day-old pups in wild type and in t-PA or its inhibitor (PAI-1 genes inactivated mice. Gelatinolytic activities were detected in SDS-PAGE zymograms and by in situ fluorescent DQ-gelatin microscopic zymographies. HI was achieved by unilateral carotid ligature followed by a 40 min hypoxia (8%O₂. Excitotoxic lesions were produced by intra parenchymal cortical (i.c. injections of 10 µg ibotenate (Ibo. Gel zymograms in WT cortex revealed progressive extinction of MMP-2 and MMP-9 activities near day 15 or day 8 respectively. MMP-2 expression was the same in all strains while MMP-9 activity was barely detectable in t-PA⁻/⁻ and enhanced in PAI-1⁻/⁻ mice. HI or Ibo produced activation of MMP-2 activities 6 hours post-insult, in cortices of WT mice but not in t-PA⁻/⁻ mice. In PAI-1⁻/⁻ mice, HI or vehicle i.c. injection increased MMP-2 and MMP-9 activities. In situ zymograms using DQ-gelatin revealed vessel associated gelatinolytic activity in lesioned areas in PAI-1⁻/⁻ and in WT mice. In WT brain slices incubated ex vivo, glutamate (200 µM induced DQ-gelatin activation in vessels. The effect was not detected in t-PA⁻/⁻ mice, but was restored by concomitant exposure to recombinant t-PA (20 µg/mL. In summary, neonatal brain lesion paradigms and ex vivo excitotoxic glutamate evoked t-PA-dependent gelatinases activation in vessels. Both MMP-2 and MMP-9 activities appeared t-PA-dependent. The data suggest that vascular directed protease inhibition may have

  11. Dynamic changes in glucose metabolism of living rat brain slices induced by hypoxia and neurotoxic chemical-loading revealed by positron autoradiography

    International Nuclear Information System (INIS)

    Omata, N.; Fujibayashi, Y.; Waki, A.; Sadato, N.; Yano, R.; Yoshimoto, M.; Yonekura, Y.; Murata, T.; Yoshida, S.

    1999-01-01

    Fresh rat brain slices were incubated with 2-deoxy-2-[ 18 F]-fluoro-D-glucose ([ 18 F]FDG) in oxygenated Krebs-Ringer solution at 36 degree C, and serial two-dimensional time-resolved images of [ 18 F]FDG uptake were obtained from these specimens on imaging plates. The fractional rate constant (= k3*) of [ 18 F]FDG proportional to the cerebral glucose metabolic rate (CMRglc) was evaluated by applying the Gjedde-Patlak graphical method to the image data. With hypoxia loading (oxygen deprivation) or glucose metabolism inhibitors acting on oxidative phosphorylation, the k3* value increased dramatically suggesting enhanced glycolysis. After relieving hypoxia ≤10-min, the k3* value returned to the pre-loading level. In contrast, with ≥20-min hypoxia only partial or no recovery was observed, indicating that irreversible neuronal damage had been induced. However, after loading with tetrodotoxin (TTX), the k3* value also decreased but returned to the pre-loading level even after 70-min TTX-loading, reflecting a transient inhibition of neuronal activity. This technique provides a new means of quantifying dynamic changes in the regional CMRglc in living brain slices in response to various interventions such as hypoxia and neurotoxic chemical-loading as well as determining the viability and prognosis of brain tissues. (author)

  12. Maternal allopurinol during fetal hypoxia lowers cord blood levels of the brain injury marker S-100B

    NARCIS (Netherlands)

    Torrance, Helen L.; Benders, Manon J.; Derks, Jan B.; Rademaker, Carin M. A.; Bos, Arie F.; Van Den Berg, Paul; Longini, Mariangela; Buonocore, Giuseppe; Venegas, MariaElena; Baquero, Hernando; Visser, Gerard H. A.; Van Bel, Frank

    BACKGROUND: Fetal hypoxia is an important determinant of neonatal encephalopathy caused by birth asphyxia, in which hypoxia-induced free radical formation plays an important role. HYPOTHESIS: Maternal treatment with allopurinol, will cross the placenta during fetal hypoxia (rimary outcome) and

  13. Utilization of D-beta-hydroxybutyrate and oleate as alternate energy fuels in brain cell cultures of newborn mice after hypoxia at different glucose concentrations.

    Science.gov (United States)

    Bossi, E; Kohler, E; Herschkowitz, N

    1989-11-01

    In dissociated whole brain cell cultures from newborn mice, we have previously shown that during glucose deprivation under normoxia, D-beta-hydroxybutyrate and oleic acid are increasingly used for energy production. We now asked whether this glucose dependency of the utilization of D-beta-hydroxybutyrate and oleic acid as alternate energy fuels is also present after a hypoxic phase. 3-Hydroxy[3-14C]butyrate or [U-14C]oleic acid were added to 7- and 14-d-old cultures and 14CO2-production compared after hypoxia in normal and glucose-deprived conditions. After hypoxia, the ability of the cells 7 d in culture to increase D-beta-hydroxybutyrate consumption in response to glucose deprivation is diminished, 14-d-old cells lose this ability. In contrast, after hypoxia, both 7- and 14-d-old cultures maintain or even improve the ability to increase oleate consumption, when glucose is lacking.

  14. A History of Mild Traumatic Brain Injury affects Peripheral Pulse Oximetry during Normobaric Hypoxia

    Directory of Open Access Journals (Sweden)

    Leonard Temme

    2016-09-01

    Full Text Available Introduction: Physiological and emotional stressors increase symptoms of concussion in recently injured individuals and both forms of stress induce symptoms in people recovering from mild traumatic brain injury (mTBI but who are asymptomatic when not stressed or are at rest. Methods: Healthy asymptomatic adults (25.0 ± 5.1 years with a history of mTBI (n = 36 and matched healthy controls (n = 36 with no mTBI history were exposed to three levels of normobaric hypoxic stress generated with the Reduced Oxygen Breathing Device (ROBD (Environics, Inc., Tollande, CT, which reduced the percent oxygen by mixing sea level air with nitrogen. The ROBD reduced the percent oxygen in the breathable air from the normal 21% to 15.5% O2, 14% O2, and 13% O2. Under these conditions: (a a standard pulse oximeter recorded peripheral oxygen saturation (SpO2 and pulse rate (beats per minute, and (b the FIT (PMI, Inc., Rockville, MD recorded saccadic velocity and pupillary response dynamics to a brief light flash. Results: For all three hypoxic stress conditions the mTBI group had significantly higher SpO2 during the final minute of exposure than did the controls F(2.17,151.8 = 5.29, p < .001, η2 = .852 and the rate of SpO2 change over time was significantly shallower for the mTBI than for the controls F(2.3,161.3 = 2.863, p < .001, η2 = .569, Greenhouse-Geisser corrected. Overall, mTBI had lower pulse rate but the difference was only significant for the 14% O2 condition. FIT oculomotor measures were not sensitive to group differences. When exposed to mild or moderate normobaric hypoxic stress (15% O2: (1 SpO2 differences emerged between the mTBI and matched healthy controls, (2 heart rate trended lower in the mTBI group, and (3 FIT measures were not sensitive to group differences. Conclusion: A relatively minor hypoxic challenge can reveal measurable differences in SpO2 and heart rate in otherwise asymptomatic individuals with a history of mTBI.

  15. Mesenchymal stem cells induce T-cell tolerance and protect the preterm brain after global hypoxia-ischemia.

    Directory of Open Access Journals (Sweden)

    Reint K Jellema

    Full Text Available Hypoxic-ischemic encephalopathy (HIE in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 10(6 MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI, in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE.

  16. Tissue oxygenation in brain, muscle, and fat in a rat model of sleep apnea: differential effect of obstructive apneas and intermittent hypoxia.

    Science.gov (United States)

    Almendros, Isaac; Farré, Ramon; Planas, Anna M; Torres, Marta; Bonsignore, Maria R; Navajas, Daniel; Montserrat, Josep M

    2011-08-01

    To test the hypotheses that the dynamic changes in brain oxygen partial pressure (PtO(2)) in response to obstructive apneas or to intermittent hypoxia differ from those in other organs and that the changes in brain PtO(2) in response to obstructive apneas is a source of oxidative stress. Prospective controlled animal study. University laboratory. 98 Sprague-Dawley rats. Cerebral cortex, skeletal muscle, or visceral fat tissues were exposed in anesthetized animals subjected to either obstructive apneas or intermittent hypoxia (apneic and hypoxic events of 15 s each and 60 events/h) for 1 h. Arterial oxygen saturation (SpO(2)) presented a stable pattern, with similar desaturations during both stimuli. The PtO(2) was measured by a microelectrode. During obstructive apneas, a fast increase in cerebral PtO(2) was observed (38.2 ± 3.4 vs. 54.8 ± 5.9 mm Hg) but not in the rest of tissues. This particular cerebral response was not found during intermittent hypoxia. The cerebral content of reduced glutathione was decreased after obstructive apneas (46.2% ± 15.2%) compared to controls (100.0% ± 14.7%), but not after intermittent hypoxia. This antioxidant consumption after obstructive apneas was accompanied by increased cerebral lipid peroxidation under this condition. No changes were observed for these markers in the other tissues. These results suggest that cerebral cortex could be protected in some way from hypoxic periods caused by obstructive apneas. The increased cerebral PtO(2) during obstructive apneas may, however, cause harmful effects (oxidative stress). The obstructive apnea model appears to be more adequate than the intermittent hypoxia model for studying brain changes associated with OSA.

  17. [Changes in phospholipids of the brain grey and white matter during in vitro autolysis in rats subjected to acute hypobaric hypoxic hypoxia].

    Science.gov (United States)

    Gribanov, G A; Leshchenko, D V; Golovko, M Iu

    2004-01-01

    The development of autolysis in grey brain matter of albino rats was accompanied by desintegration of aminophospholipids with parallel increase of glycerophosphates (GLP) and phosphatidic acids (PA) on early stages of incubation and lysophospholipids (LPL) on later stages. Acute hypobaric hypoxic hypoxia decreased the level of phosphatidylethanolamines (PE) with simultaneous accumulation of PA. Previous hypoxia altered the character of autolytic reorganizations of phospholipids. Oscillatory reciprocal reorganizations in the system PE > PS (phosphatidylserine) were observed at early stage (1 h) and at late stages of autolysis (24 h). At the same time increased transformation of phosphatidylcholines (PC) into sphingomyelins (SM) with simultaneous accumulation GLP was registered. During autolysis of brain white matter of control rats opposite oscillatory reorganizations of PE, PC, SM, PA with reduction of PE and simultaneous increase of LPL and PA level after 1 hour of incubation were observed. Reciprocal reactions of biotransformation in system PS > PE were revealed at 4th hour. Previous hypobaric hypoxic hypoxia reduced the level of total phospholipids as well as PS at simultaneous increase of LPL. Acute hypobaric hypoxic hypoxia increased autolytic transformations in system PC > SM and induced hydrolysis of PE, PC into LPL at late stages of autolysis.

  18. A Pilot Study of Inhaled CO Therapy in Neonatal Hypoxia-Ischemia: Carboxyhemoglobin Concentrations and Brain Volumes.

    Science.gov (United States)

    Douglas-Escobar, Martha; Mendes, Monique; Rossignol, Candace; Bliznyuk, Nikolay; Faraji, Ariana; Ahmad, Abdullah S; Doré, Sylvain; Weiss, Michael D

    2018-01-01

    Objective: The objective of this pilot study was to start evaluating the efficacy and the safety (i.e., carboxyhemoglobin concentration of carbon monoxide (CO)) as a putative neuroprotective therapy in neonates. Study Design: Neonatal C57BL/6 mice were exposed to CO at a concentration of either 200 or 250 ppm for a period of 1 h. The pups were then sacrificed at 0, 10, 20, 60, 120, 180, and 240 min after exposure to either concentration of CO, and blood was collected for analysis of carboxyhemoglobin. Following the safety study, 7-day-old pups underwent a unilateral carotid ligation. After recovery, the pups were exposed to a humidified gas mixture of 8% oxygen and 92% nitrogen for 20 min in a hypoxia chamber. One hour after the hypoxia exposure, the pups were randomized to one of two groups: air (HI+A) or carbon monoxide (HI+CO). An inhaled dose of 250 ppm of CO was administered to the pups for 1 h per day for a period of 3 days. At 7 days post-injury, the pups were sacrificed and the brains analyzed for cortical and hippocampal volumes. Results: CO exposure at 200 and 250 ppm produced a peak carboxyhemoglobin concentration of 21.52 ± 1.18% and 27.55 ± 3.58%, respectively. The carboxyhemoglobin concentrations decreased rapidly, reaching control concentrations by 60 min post exposure. At 14 days of age (7 days post injury), the HI+CO (treated with 1 h per day of 250 ppm of CO for 3 days post injury) had significant preservation of the ratio of ipsilateral to contralateral cortex (median 1.07, 25% 0.97, 75% 1.23, n = 10) compared the HI+A group ( p carboxyhemoglobin concentrations which would induce acute neurologic abnormalities and was effective in preserving cortical volumes following hypoxic-ischemic injury.

  19. Nitric oxide induces hypoxia ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism.

    Science.gov (United States)

    Lu, Qing; Harris, Valerie A; Rafikov, Ruslan; Sun, Xutong; Kumar, Sanjiv; Black, Stephen M

    2015-12-01

    We have recently shown that increased hydrogen peroxide (H2O2) generation is involved in hypoxia-ischemia (HI)-mediated neonatal brain injury. H2O2 can react with free iron to form the hydroxyl radical, through Fenton Chemistry. Thus, the objective of this study was to determine if there was a role for the hydroxyl radical in neonatal HI brain injury and to elucidate the underlying mechanisms. Our data demonstrate that HI increases the deposition of free iron and hydroxyl radical formation, in both P7 hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD), and the neonatal rat exposed to HI. Both these processes were found to be nitric oxide (NO) dependent. Further analysis demonstrated that the NO-dependent increase in iron deposition was mediated through increased transferrin receptor expression and a decrease in ferritin expression. This was correlated with a reduction in aconitase activity. Both NO inhibition and iron scavenging, using deferoxamine administration, reduced hydroxyl radical levels and neuronal cell death. In conclusion, our results suggest that increased NO generation leads to neuronal cell death during neonatal HI, at least in part, by altering iron homeostasis and hydroxyl radical generation. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  20. Region-specific effects on brain metabolites of hypoxia and hyperoxia overlaid on cerebral ischemia in young and old rats: a quantitative proton magnetic resonance spectroscopy study

    Directory of Open Access Journals (Sweden)

    Giuliani Patricia

    2010-02-01

    Full Text Available Abstract Background Both hypoxia and hyperoxia, deregulating the oxidative balance, may play a role in the pathology of neurodegenerative disorders underlain by cerebral ischemia. In the present study, quantitative proton magnetic resonance spectroscopy was used to evaluate regional metabolic alterations, following a 24-hour hypoxic or hyperoxic exposure on the background of ischemic brain insult, in two contrasting age-groups of rats: young - 3 months old and aged - 24 months old. Methods Cerebral ischemia was induced by ligation of the right common carotid artery. Concentrations of eight metabolites (alanine, choline-containing compounds, total creatine, γ-aminobutyric acid, glutamate, lactate, myo-inositol and N-acetylaspartate were quantified from extracts in three different brain regions (fronto-parietal and occipital cortices and the hippocampus from both hemispheres. Results In the control normoxic condition, there were significant increases in lactate and myo-inositol concentrations in the hippocampus of the aged rats, compared with the respective values in the young ones. In the ischemia-hypoxia condition, the most prevalent changes in the brain metabolites were found in the hippocampal regions of both young and aged rats; but the effects were more evident in the aged animals. The ischemia-hyperoxia procedure caused less dedicated changes in the brain metabolites, which may reflect more limited tissue damage. Conclusions We conclude that the hippocampus turns out to be particularly susceptible to hypoxia overlaid on cerebral ischemia and that old age further increases this susceptibility.

  1. Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.

    LENUS (Irish Health Repository)

    Presneill, Jeffrey

    2014-01-01

    The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes.

  2. Feasibility of online self-administered cognitive training in moderate-severe brain injury.

    Science.gov (United States)

    Sharma, Bhanu; Tomaszczyk, Jennifer C; Dawson, Deirdre; Turner, Gary R; Colella, Brenda; Green, Robin E A

    2017-07-01

    Cognitive environmental enrichment (C-EE) offers promise for offsetting neural decline that is observed in chronic moderate-severe traumatic brain injury (TBI). Brain games are a delivery modality for C-EE that can be self-administered over the Internet without therapist oversight. To date, only one study has examined the feasibility of self-administered brain games in TBI, and the study focused predominantly on mild TBI. Therefore, the primary purpose of the current study was to examine the feasibility of self-administered brain games in moderate-severe TBI. A secondary and related purpose was to examine the feasibility of remote monitoring of any C-EE-induced adverse symptoms with a self-administered evaluation tool. Ten patients with moderate-severe TBI were asked to complete 12 weeks (60 min/day, five days/week) of online brain games with bi-weekly self-evaluation, intended to measure any adverse consequences of cognitive training (e.g., fatigue, eye strain). There was modest weekly adherence (42.6% ± 4.4%, averaged across patients and weeks) and 70% patient retention; of the seven retained patients, six completed the self-evaluation questionnaire at least once/week for each week of the study. Even patients with moderate-severe TBI can complete a demanding, online C-EE intervention and a self-administered symptom evaluation tool with limited therapist oversight, though at daily rate closer to 30 than 60 min per day. Further self-administered C-EE research is underway in our lab, with more extensive environmental support. Implications for Rehabilitation Online brain games (which may serve as a rehabilitation paradigm that can help offset the neurodegeneration observed in chronic TBI) can be feasibly self-administered by moderate-to-severe TBI patients. Brain games are a promising therapy modality, as they can be accessed by all moderate-to-severe TBI patients irrespective of geographic location, clinic and/or therapist availability, or impairments that

  3. Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral Cytokine Production, Higher Serum Biomarker Levels, and Poor Outcome in Patients with Severe Traumatic Brain Injury

    Science.gov (United States)

    Yan, Edwin B.; Satgunaseelan, Laveniya; Paul, Eldho; Bye, Nicole; Nguyen, Phuong; Agyapomaa, Doreen; Kossmann, Thomas; Rosenfeld, Jeffrey V.

    2014-01-01

    Abstract Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood–brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4–5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment. PMID:24279428

  4. Effect of hypoxia on the incorporation of [2-3H] glycerol and [1-14C[-palmitate into lipids of various brain regions

    International Nuclear Information System (INIS)

    Alberghina, M.; Giuffrida, A.M.

    1981-01-01

    The lipid metabolism in guinea pig brain after intermittent hypoxia, prolonged for 80 hrs, was markedly impaired. The in vivo incorporation of [2-3H] glycerol and [1-14C] palmitate into lipids of microsomes, mitochondria, myelin, and synaptosomes, purified form cerebral hemispheres, was significantly lower in the hypoxic animals than in the controls. The same effect was observed on the incorporation of labeled precursors into lipids of mitochondria purified from cerebellum and brainstem. In particular, the labeling of th major phospholipids present - ie, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) - in the mitochondria of the three brain regions examined decreased after hypoxic treatment

  5. Hypoxia Room

    Data.gov (United States)

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

  6. A Pilot Study of Inhaled CO Therapy in Neonatal Hypoxia-Ischemia: Carboxyhemoglobin Concentrations and Brain Volumes

    Directory of Open Access Journals (Sweden)

    Martha Douglas-Escobar

    2018-05-01

    Full Text Available Objective: The objective of this pilot study was to start evaluating the efficacy and the safety (i.e., carboxyhemoglobin concentration of carbon monoxide (CO as a putative neuroprotective therapy in neonates.Study Design: Neonatal C57BL/6 mice were exposed to CO at a concentration of either 200 or 250 ppm for a period of 1 h. The pups were then sacrificed at 0, 10, 20, 60, 120, 180, and 240 min after exposure to either concentration of CO, and blood was collected for analysis of carboxyhemoglobin. Following the safety study, 7-day-old pups underwent a unilateral carotid ligation. After recovery, the pups were exposed to a humidified gas mixture of 8% oxygen and 92% nitrogen for 20 min in a hypoxia chamber. One hour after the hypoxia exposure, the pups were randomized to one of two groups: air (HI+A or carbon monoxide (HI+CO. An inhaled dose of 250 ppm of CO was administered to the pups for 1 h per day for a period of 3 days. At 7 days post-injury, the pups were sacrificed and the brains analyzed for cortical and hippocampal volumes.Results: CO exposure at 200 and 250 ppm produced a peak carboxyhemoglobin concentration of 21.52 ± 1.18% and 27.55 ± 3.58%, respectively. The carboxyhemoglobin concentrations decreased rapidly, reaching control concentrations by 60 min post exposure. At 14 days of age (7 days post injury, the HI+CO (treated with 1 h per day of 250 ppm of CO for 3 days post injury had significant preservation of the ratio of ipsilateral to contralateral cortex (median 1.07, 25% 0.97, 75% 1.23, n = 10 compared the HI+A group (p < 0.05.Conclusion: CO exposure of 250 ppm did not reach carboxyhemoglobin concentrations which would induce acute neurologic abnormalities and was effective in preserving cortical volumes following hypoxic-ischemic injury.

  7. An Aminopyridazine Inhibitor of Death Associated Protein Kinase Attenuates Hypoxia-Ischemia Induced Brain Damage

    Energy Technology Data Exchange (ETDEWEB)

    Velentza, A.V.; Wainwright, M.S.; Zasadzki, M.; Mirzoeva, S.; Haiech, J.; Focia, P.J.; Egli, M.; Watterson, D.M.

    2010-03-08

    Death associated protein kinase (DAPK) is a calcium and calmodulin regulated enzyme that functions early in eukaryotic programmed cell death, or apoptosis. To validate DAPK as a potential drug discovery target for acute brain injury, the first small molecule DAPK inhibitor was synthesized and tested in vivo. A single injection of the aminopyridazine-based inhibitor administered 6 h after injury attenuated brain tissue or neuronal biomarker loss measured, respectively, 1 week and 3 days later. Because aminopyridazine is a privileged structure in neuropharmacology, we determined the high-resolution crystal structure of a binary complex between the kinase domain and a molecular fragment of the DAPK inhibitor. The co-crystal structure describes a structural basis for interaction and provides a firm foundation for structure-assisted design of lead compounds with appropriate molecular properties for future drug development.

  8. Behavioural, brain and cardiac responses to hypobaric hypoxia in broiler chickens.

    Science.gov (United States)

    Martin, Jessica E; Christensen, Karen; Vizzier-Thaxton, Yvonne; Mitchell, Malcolm A; McKeegan, Dorothy E F

    2016-09-01

    A novel approach to pre-slaughter stunning of chickens has been developed in which birds are rendered unconscious by progressive hypobaric hypoxia. Termed Low Atmospheric Pressure Stunning (LAPS), this approach involves application of gradual decompression lasting 280s according to a prescribed curve. We examined responses to LAPS by recording behaviour, electroencephalogram (EEG) and electrocardiogram (ECG) in individual male chickens, and interpreted these with regard to the welfare impact of the process. We also examined the effect of two temperature adjusted pressure curves on these responses. Broiler chickens were exposed to LAPS in 30 triplets (16 and 14 triplets assigned to each pressure curve). In each triplet, one bird was instrumented for recording of EEG and ECG while the behaviour of all three birds was observed. Birds showed a consistent sequence of behaviours during LAPS (ataxia, loss of posture, clonic convulsions and motionless) which were observed in all birds. Leg paddling, tonic convulsions, slow wing flapping, mandibulation, head shaking, open bill breathing, deep inhalation, jumping and vocalisation were observed in a proportion of birds. Spectral analysis of EEG responses at 2s intervals throughout LAPS revealed progressive decreases in median frequency at the same time as corresponding progressive increases in total power, followed later by decreases in total power as all birds exhibited isoelectric EEG and died. There was a very pronounced increase in total power at 50-60s into the LAPS cycle, which corresponded to dominance of the signal by high amplitude slow waves, indicating loss of consciousness. Slow wave EEG was seen early in the LAPS process, before behavioural evidence of loss of consciousness such as ataxia and loss of posture, almost certainly due to the fact that it was completely dark in the LAPS chamber. ECG recordings showed a pronounced bradycardia (starting on average 49.6s into LAPS), often associated with arrhythmia, until

  9. Teleosts in hypoxia : Aspects of anaerobic metabolism

    NARCIS (Netherlands)

    Van den Thillart, G.; van Waarde, Aren

    1985-01-01

    Moderate hypoxia can be tolerated by many fish species, while only some species survive severe hypoxia or anoxia. Hypoxia usually activates anaerobic glycolysis, which may be temporary when the animals are able to improve their oxygen extraction capacity. Switching over to aerobic metabolism allows

  10. Lesion Size Is Exacerbated in Hypoxic Rats Whereas Hypoxia-Inducible Factor-1 Alpha and Vascular Endothelial Growth Factor Increase in Injured Normoxic Rats: A Prospective Cohort Study of Secondary Hypoxia in Focal Traumatic Brain Injury.

    Science.gov (United States)

    Thelin, Eric Peter; Frostell, Arvid; Mulder, Jan; Mitsios, Nicholas; Damberg, Peter; Aski, Sahar Nikkhou; Risling, Mårten; Svensson, Mikael; Morganti-Kossmann, Maria Cristina; Bellander, Bo-Michael

    2016-01-01

    Hypoxia following traumatic brain injury (TBI) is a severe insult shown to exacerbate the pathophysiology, resulting in worse outcome. The aim of this study was to investigate the effects of a hypoxic insult in a focal TBI model by monitoring brain edema, lesion volume, serum biomarker levels, immune cell infiltration, as well as the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF). Female Sprague-Dawley rats (n = 73, including sham and naive) were used. The rats were intubated and mechanically ventilated. A controlled cortical impact device created a 3-mm deep lesion in the right parietal hemisphere. Post-injury, rats inhaled either normoxic (22% O2) or hypoxic (11% O2) mixtures for 30 min. The rats were sacrificed at 1, 3, 7, 14, and 28 days post-injury. Serum was collected for S100B measurements using ELISA. Ex vivo magnetic resonance imaging (MRI) was performed to determine lesion size and edema volume. Immunofluorescence was employed to analyze neuronal death, changes in cerebral macrophage- and neutrophil infiltration, microglia proliferation, apoptosis, complement activation (C5b9), IgG extravasation, HIF-1α, and VEGF. The hypoxic group had significantly increased blood levels of lactate and decreased pO2 (p hypoxic animals (p hypoxic group at 1 day after trauma (p = 0.0868). No differences were observed between the groups in cytotoxic and vascular edema, IgG extravasation, neutrophils and macrophage aggregation, microglia proliferation, or C5b-9 expression. Hypoxia following focal TBI exacerbated the lesion size and neuronal loss. Moreover, there was a tendency to higher levels of S100B in the hypoxic group early after injury, indicating a potential validity as a biomarker of injury severity. In the normoxic group, the expression of HIF-1α and VEGF was found elevated, possibly indicative of neuro-protective responses occurring in this less severely injured group. Further studies are

  11. Genetic variation in Aquaporin-4 moderates the relationship between sleep and brain Aβ-amyloid burden.

    Science.gov (United States)

    Rainey-Smith, Stephanie R; Mazzucchelli, Gavin N; Villemagne, Victor L; Brown, Belinda M; Porter, Tenielle; Weinborn, Michael; Bucks, Romola S; Milicic, Lidija; Sohrabi, Hamid R; Taddei, Kevin; Ames, David; Maruff, Paul; Masters, Colin L; Rowe, Christopher C; Salvado, Olivier; Martins, Ralph N; Laws, Simon M

    2018-02-26

    The glymphatic system is postulated to be a mechanism of brain Aβ-amyloid clearance and to be most effective during sleep. Ablation of the astrocytic end-feet expressed water-channel protein, Aquaporin-4, in mice, results in impairment of this clearance mechanism and increased brain Aβ-amyloid deposition, suggesting that Aquaporin-4 plays a pivotal role in glymphatic function. Currently there is a paucity of literature regarding the impact of AQP4 genetic variation on sleep, brain Aβ-amyloid burden and their relationship to each other in humans. To address this a cross-sectional observational study was undertaken in cognitively normal older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Genetic variants in AQP4 were investigated with respect to self-reported Pittsburgh Sleep Quality Index sleep parameters, positron emission tomography derived brain Aβ-amyloid burden and whether these genetic variants moderated the sleep-Aβ-amyloid burden relationship. One AQP4 variant, rs72878776, was associated with poorer overall sleep quality, while several SNPs moderated the effect of sleep latency (rs491148, rs9951307, rs7135406, rs3875089, rs151246) and duration (rs72878776, rs491148 and rs2339214) on brain Aβ-amyloid burden. This study suggests that AQP4 genetic variation moderates the relationship between sleep and brain Aβ-amyloid burden, which adds weight to the proposed glymphatic system being a potential Aβ-amyloid clearance mechanism and suggests that AQP4 genetic variation may impair this function. Further, AQP4 genetic variation should be considered when interpreting sleep-Aβ relationships.

  12. Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain.

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    Mun Chiang Chan

    Full Text Available As part of the cellular adaptation to limiting oxygen availability in animals, the expression of a large set of genes is activated by the upregulation of the hypoxia-inducible transcription factors (HIFs. Therapeutic activation of the natural human hypoxic response can be achieved by the inhibition of the hypoxia sensors for the HIF system, i.e. the HIF prolyl-hydroxylases (PHDs. Here, we report studies on tricyclic triazole-containing compounds as potent and selective PHD inhibitors which compete with the 2-oxoglutarate co-substrate. One compound (IOX4 induces HIFα in cells and in wildtype mice with marked induction in the brain tissue, revealing that it is useful for studies aimed at validating the upregulation of HIF for treatment of cerebral diseases including stroke.

  13. Chronic intermittent hypoxia induces changes on the expression and activity of neprilysin (EC 3.4.24.16) in the brain of rats.

    Science.gov (United States)

    de Oliveira, Renato W; Julian, Guilherme S; Perry, Juliana C; Tufik, Sergio; Chagas, Jair R

    2018-04-24

    Obstructive sleep apnea (OSA) is a frequent sleeping breathing disorder associated with cognitive impairments. Neprilysin (NEP) is responsible for degrading several substrates related to cognition; however, the effect of chronic intermittent hypoxia (CIH) on NEP is still unknown. This study aimed to evaluate the expression and activity of NEP under CIH in cognitive-related brain structures. Western blot, qRT-PCR and enzyme activity assay, demonstrated that a six-week intermittent hypoxia increased NEP expression and activity, selectively in temporal cortex, but not in the hippocampus and frontal cortex. The increase in NEP activity and expression was reverted followed by two weeks recovery in normoxia. These data show that CIH protocol increases the expression and activity of NEP selectively in the temporal cortex. Additional mechanisms must be investigated to elucidate the effects of CIH in cognition. Copyright © 2018. Published by Elsevier B.V.

  14. Prodigiosin inhibits gp91{sup phox} and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia

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    Chang, Chia-Che [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan (China); Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan (China); Wang, Yea-Hwey [Department of Nursing, College of Medicine and Nursing, Hungkuang University, Taichung, Taiwan (China); Chern, Chang-Ming [Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Liou, Kuo-Tong [Department of Chinese Martial Arts, Chinese Culture University, Taipei, Taiwan (China); Hou, Yu-Chang [Department of Chinese Medicine, Taoyuan General Hospital, Department of Health, Taiwan (China); Department of Nursing, Yuanpei University, Hsinchu, Taiwan (China); Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan (China); Peng, Yu-Ta [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Shen, Yuh-Chiang, E-mail: yuhcs@nricm.edu.tw [National Research Institute of Chinese Medicine, Taipei, Taiwan (China); Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China)

    2011-11-15

    This study aimed to explore the mechanisms by which prodigiosin protects against hypoxia-induced oxidative/nitrosative brain injury induced by middle cerebral artery occlusion/reperfusion (MCAo/r) injury in mice. Hypoxia in vitro was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone MCAo/r injury with prodigiosin (10 and 100 {mu}g/kg, i.v.) at 1 h after hypoxia ameliorated MCAo/r-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. MCAo/r induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (gp91{sup phox}), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b leukocytes due to breakdown of blood-brain barrier (BBB) by activation of nuclear factor-kappa B (NF-{kappa}B). All these changes were significantly diminished by prodigiosin. In BV-2 cells, OGD induced ROS and nitric oxide production by up-regulating gp91{sup phox} and iNOS via activation of the NF-{kappa}B pathway, and these changes were suppressed by prodigiosin. In conclusion, our results indicate that prodigiosin reduces gp91{sup phox} and iNOS expression possibly by impairing NF-{kappa}B activation. This compromises the activation of microglial and/or inflammatory cells, which then, in turn, mediates prodigiosin's protective effect in the MCAo/r mice. -- Highlights: Black-Right-Pointing-Pointer Prodigiosin ameliorated brain infarction and deficits. Black-Right-Pointing-Pointer Prodigiosin protected against hypoxia/reperfusion-induced brain injury. Black-Right-Pointing-Pointer Prodigiosin diminished oxidative/nitrosativestress and leukocytes infiltration. Black-Right-Pointing-Pointer Prodigiosin reduced BBB breakdown. Black

  15. Observed Parent Behaviors as Time-Varying Moderators of Problem Behaviors Following Traumatic Brain Injury in Young Children

    Science.gov (United States)

    Treble-Barna, Amery; Zang, Huaiyu; Zhang, Nanhua; Taylor, H. Gerry; Stancin, Terry; Yeates, Keith Owen; Wade, Shari L.

    2016-01-01

    Parent behaviors moderate the adverse consequences of pediatric traumatic brain injury (TBI); however, it is unknown how these moderating effects change over time. This study examined the moderating effect of observed parent behaviors over time since injury on the relation between TBI and behavioral outcomes. Participants included children, ages…

  16. Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia-ischemia: a potential marker of neonatal encephalopathy.

    Science.gov (United States)

    Bednarek, Nathalie; Svedin, Pernilla; Garnotel, Roselyne; Favrais, Géraldine; Loron, Gauthier; Schwendiman, Leslie; Hagberg, Henrik; Morville, Patrice; Mallard, Carina; Gressens, Pierre

    2012-01-01

    To implement neuroprotective strategies in newborns, sensitive and specific biomarkers are needed for identifying those who are at risk for brain damage. We evaluated the effectiveness of matrix metalloproteinases (MMPs) and their naturally occurring tissue inhibitors of metalloproteinases (TIMPs) in predicting neonatal encephalopathy (NE) damage in newborns. Plasma MMP-9 and TIMP-1 levels were upregulated as early as 1 h after the HI insult but not did not show such elevations after other types of injury (ibotenate-induced excitotoxicity, hypoxia, lipopolysaccharide-induced inflammation), and brain levels reflected this increase soon thereafter. We confirmed these results by carrying out plasma MMP-9 and TIMP-1 measurements in human newborns with NE. In these infants, protein levels of MMP-9 and TIMP-1 were found to be elevated during a short window up to 6 h after birth. This feature is particularly useful in identifying newborns in need of neuroprotection. A second peak observed 72 h after birth is possibly related to the second phase of energy failure after a HI insult. Our data, although preliminary, support the use of MMP-9 and TIMP-1 as early biomarkers for the presence and extent of perinatal brain injury in human term newborns. We first used a mouse model of neonatal HI injury to explore mechanistic aspects such as the time course of these markers after the hypoxia-ischemia event, and the correlation between the levels of these candidate markers in brain and plasma.

  17. Xenon and sevoflurane provide analgesia during labor and fetal brain protection in a perinatal rat model of hypoxia-ischemia.

    Directory of Open Access Journals (Sweden)

    Ting Yang

    Full Text Available It is not possible to identify all pregnancies at risk of neonatal hypoxic-ischemic encephalopathy (HIE. Many women use some form of analgesia during childbirth and some anesthetic agents have been shown to be neuroprotective when used as analgesics at subanesthetic concentrations. In this study we sought to understand the effects of two anesthetic agents with presumptive analgesic activity and known preconditioning-neuroprotective properties (sevoflurane or xenon, in reducing hypoxia-induced brain damage in a model of intrauterine perinatal asphyxia. The analgesic and neuroprotective effects at subanesthetic levels of sevoflurane (0.35% or xenon (35% were tested in a rat model of intrauterine perinatal asphyxia. Analgesic effects were measured by assessing maternal behavior and spinal cord dorsal horn neuronal activation using c-Fos. In separate experiments, intrauterine fetal asphyxia was induced four hours after gas exposure; on post-insult day 3 apoptotic cell death was measured by caspase-3 immunostaining in hippocampal neurons and correlated with the number of viable neurons on postnatal day (PND 7. A separate cohort of pups was nurtured by a surrogate mother for 50 days when cognitive testing with Morris water maze was performed. Both anesthetic agents provided analgesia as reflected by a reduction in the number of stretching movements and decreased c-Fos expression in the dorsal horn of the spinal cord. Both agents also reduced the number of caspase-3 positive (apoptotic neurons and increased cell viability in the hippocampus at PND7. These acute histological changes were mirrored by improved cognitive function measured remotely after birth on PND 50 compared to control group. Subanesthetic doses of sevoflurane or xenon provided both analgesia and neuroprotection in this model of intrauterine perinatal asphyxia. These data suggest that anesthetic agents with neuroprotective properties may be effective in preventing HIE and should be

  18. Hypoxia Stress Modifies Na+/K+-ATPase, H+/K+-ATPase, Na+/NH4+-ATPase, and nkaα1 Isoform Expression in the Brain of Immune-Challenged Air-Breathing Fish

    Science.gov (United States)

    Peter, MC Subhash; Simi, Satheesan

    2017-01-01

    Fishes are equipped to sense stressful stimuli and are able to respond to environmental stressor such as hypoxia with varying pattern of stress response. The functional attributes of brain to hypoxia stress in relation to ion transport and its interaction during immune challenge have not yet delineated in fish. We, therefore, explored the pattern of ion transporter functions and messenger RNA (mRNA) expression of α1-subunit isoforms of Na+/K+-ATPase (NKA) in the brain segments, namely, prosencephalon (PC), mesencephalon (MC), and metencephalon (MeC) in an obligate air-breathing fish exposed either to hypoxia stress (30 minutes forced immersion in water) or challenged with zymosan treatment (25-200 ng g−1 for 24 hours) or both. Zymosan that produced nonspecific immune responses evoked differential regulation of NKA, H+/K+-ATPase (HKA), and Na+/NH4+-ATPase (NNA) in the varied brain segments. On the contrary, hypoxia stress that demanded activation of NKA in PC and MeC showed a reversed NKA activity pattern in MeC of immune-challenged fish. A compromised HKA and NNA regulation during hypoxia stress was found in immune-challenged fish, indicating the role of these brain ion transporters to hypoxia stress and immune challenges. The differential mRNA expression of α1-subunit isoforms of NKA, nkaα1a, nkaα1b, and nkaα1c, in hypoxia-stressed brain showed a shift in its expression pattern during hypoxia stress-immune interaction in PC and MC. Evidence is thus presented for the first time that ion transporters such as HKA and NNA along with NKA act as functional brain markers which respond differentially to both hypoxia stress and immune challenges. Taken together, the data further provide evidence for a differential Na+, K+, H+, and NH4+ ion signaling that exists in brain neuronal clusters during hypoxia stress-immune interaction as a result of modified regulations of NKA, HKA, and NNA transporter functions and nkaα1 isoform regulation. PMID:29238219

  19. Hypoxia Stress Modifies Na+/K+-ATPase, H+/K+-ATPase, [Formula: see text], and nkaα1 Isoform Expression in the Brain of Immune-Challenged Air-Breathing Fish.

    Science.gov (United States)

    Peter, Mc Subhash; Simi, Satheesan

    2017-01-01

    Fishes are equipped to sense stressful stimuli and are able to respond to environmental stressor such as hypoxia with varying pattern of stress response. The functional attributes of brain to hypoxia stress in relation to ion transport and its interaction during immune challenge have not yet delineated in fish. We, therefore, explored the pattern of ion transporter functions and messenger RNA (mRNA) expression of α1-subunit isoforms of Na + /K + -ATPase (NKA) in the brain segments, namely, prosencephalon (PC), mesencephalon (MC), and metencephalon (MeC) in an obligate air-breathing fish exposed either to hypoxia stress (30 minutes forced immersion in water) or challenged with zymosan treatment (25-200 ng g -1 for 24 hours) or both. Zymosan that produced nonspecific immune responses evoked differential regulation of NKA, H + /K + -ATPase (HKA), and [Formula: see text] (NNA) in the varied brain segments. On the contrary, hypoxia stress that demanded activation of NKA in PC and MeC showed a reversed NKA activity pattern in MeC of immune-challenged fish. A compromised HKA and NNA regulation during hypoxia stress was found in immune-challenged fish, indicating the role of these brain ion transporters to hypoxia stress and immune challenges. The differential mRNA expression of α1-subunit isoforms of NKA, nkaα1a , nkaα1b , and nkaα1c , in hypoxia-stressed brain showed a shift in its expression pattern during hypoxia stress-immune interaction in PC and MC. Evidence is thus presented for the first time that ion transporters such as HKA and NNA along with NKA act as functional brain markers which respond differentially to both hypoxia stress and immune challenges. Taken together, the data further provide evidence for a differential Na + , K + , H + , and [Formula: see text] ion signaling that exists in brain neuronal clusters during hypoxia stress-immune interaction as a result of modified regulations of NKA, HKA, and NNA transporter functions and nkaα1 isoform

  20. Early post-natal exposure to intermittent hypoxia in rodents is pro-inflammatory, impairs white matter integrity and alters brain metabolism

    Science.gov (United States)

    Darnall, Robert A.; Chen, Xi; Nemani, Krishnamurthy V.; Sirieix, Chrystelle M.; Gimi, Barjor; Knoblach, Susan; McEntire, Betty L.; Hunt, Carl E.

    2017-01-01

    Background Preterm infants are frequently exposed to intermittent hypoxia (IH) associated with apnea and periodic breathing that may result in inflammation and brain injury that later manifests as cognitive and executive function deficits. We used a rodent model to determine whether early postnatal exposure to IH would result in inflammation and brain injury. Methods Rat pups were exposed to IH from P2–P12. Control animals were exposed to room air. Cytokines were analyzed in plasma and brain tissue at P13 and P18. At P20–P22, diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were performed. Results Pups exposed to IH had increased plasma Gro/CXCL1 and cerebellar IFN-γ and IL-1β at P13, and brainstem enolase at P18. DTI showed a decrease in FA and AD in the corpus callosum (CC) and cingulate gyrus and an increase in RD in the CC. MRS revealed decreases in NAA/Cho, Cr, Tau/Cr and Gly/Cr and increases in TCho and GPC in the brainstem and decreases in NAA/Cho in the hippocampus. Conclusions We conclude that early postnatal exposure to IH, similar in magnitude experienced in human preterm infants, is associated with evidence for pro-inflammatory changes, decreases in white matter integrity, and metabolic changes consistent with hypoxia. PMID:28388601

  1. The Family Environment as a Moderator of Psychosocial Outcomes Following Traumatic Brain Injury in Young Children

    Science.gov (United States)

    Yeates, Keith Owen; Taylor, H. Gerry; Walz, Nicolay Chertkoff; Stancin, Terry; Wade, Shari L.

    2010-01-01

    Objective This study sought to determine whether the family environment moderates psychosocial outcomes after traumatic brain injury (TBI) in young children. Method Participants were recruited prospectively from consecutive hospital admissions of 3-6 year old children, and included 19 with severe TBI, 56 with complicated mild/moderate TBI, and 99 with orthopedic injuries (OI). They completed four assessments across the first 18 months post-injury. The initial assessment included measures of parenting style, family functioning, and the quality of the home. Children’s behavioral adjustment, adaptive functioning, and social competence were assessed at each occasion. Mixed model analyses examined the relationship of the family environment to psychosocial outcomes across time. Results The OI and TBI groups differed significantly in social competence, but the family environment did not moderate the group difference, which was of medium magnitude. In contrast, group differences in behavioral adjustment became more pronounced across time at high levels of authoritarian and permissive parenting; among children with severe TBI, however, even those with low levels of permissive parenting showed increases in behavioral problems. For adaptive functioning, better home environments provided some protection following TBI, but not over time for the severe TBI group. These three-way interactions of group, family environment, and time post injury were all of medium magnitude. Conclusions The findings indicate that the family environment moderates the psychosocial outcomes of TBI in young children, but the moderating influence may wane with time among children with severe TBI. PMID:20438212

  2. Tensor-Based Morphometry Reveals Volumetric Deficits in Moderate=Severe Pediatric Traumatic Brain Injury.

    Science.gov (United States)

    Dennis, Emily L; Hua, Xue; Villalon-Reina, Julio; Moran, Lisa M; Kernan, Claudia; Babikian, Talin; Mink, Richard; Babbitt, Christopher; Johnson, Jeffrey; Giza, Christopher C; Thompson, Paul M; Asarnow, Robert F

    2016-05-01

    Traumatic brain injury (TBI) can cause widespread and prolonged brain degeneration. TBI can affect cognitive function and brain integrity for many years after injury, often with lasting effects in children, whose brains are still immature. Although TBI varies in how it affects different individuals, image analysis methods such as tensor-based morphometry (TBM) can reveal common areas of brain atrophy on magnetic resonance imaging (MRI), secondary effects of the initial injury, which will differ between subjects. Here we studied 36 pediatric moderate to severe TBI (msTBI) participants in the post-acute phase (1-6 months post-injury) and 18 msTBI participants who returned for their chronic assessment, along with well-matched controls at both time-points. Participants completed a battery of cognitive tests that we used to create a global cognitive performance score. Using TBM, we created three-dimensional (3D) maps of individual and group differences in regional brain volumes. At both the post-acute and chronic time-points, the greatest group differences were expansion of the lateral ventricles and reduction of the lingual gyrus in the TBI group. We found a number of smaller clusters of volume reduction in the cingulate gyrus, thalamus, and fusiform gyrus, and throughout the frontal, temporal, and parietal cortices. Additionally, we found extensive associations between our cognitive performance measure and regional brain volume. Our results indicate a pattern of atrophy still detectable 1-year post-injury, which may partially underlie the cognitive deficits frequently found in TBI.

  3. Tensor-Based Morphometry Reveals Volumetric Deficits in Moderate=Severe Pediatric Traumatic Brain Injury

    Science.gov (United States)

    Hua, Xue; Villalon-Reina, Julio; Moran, Lisa M.; Kernan, Claudia; Babikian, Talin; Mink, Richard; Babbitt, Christopher; Johnson, Jeffrey; Giza, Christopher C.; Thompson, Paul M.; Asarnow, Robert F.

    2016-01-01

    Abstract Traumatic brain injury (TBI) can cause widespread and prolonged brain degeneration. TBI can affect cognitive function and brain integrity for many years after injury, often with lasting effects in children, whose brains are still immature. Although TBI varies in how it affects different individuals, image analysis methods such as tensor-based morphometry (TBM) can reveal common areas of brain atrophy on magnetic resonance imaging (MRI), secondary effects of the initial injury, which will differ between subjects. Here we studied 36 pediatric moderate to severe TBI (msTBI) participants in the post-acute phase (1–6 months post-injury) and 18 msTBI participants who returned for their chronic assessment, along with well-matched controls at both time-points. Participants completed a battery of cognitive tests that we used to create a global cognitive performance score. Using TBM, we created three-dimensional (3D) maps of individual and group differences in regional brain volumes. At both the post-acute and chronic time-points, the greatest group differences were expansion of the lateral ventricles and reduction of the lingual gyrus in the TBI group. We found a number of smaller clusters of volume reduction in the cingulate gyrus, thalamus, and fusiform gyrus, and throughout the frontal, temporal, and parietal cortices. Additionally, we found extensive associations between our cognitive performance measure and regional brain volume. Our results indicate a pattern of atrophy still detectable 1-year post-injury, which may partially underlie the cognitive deficits frequently found in TBI. PMID:26393494

  4. A Prospective Randomized Study of Brain Tissue Oxygen Pressure-Guided Management in Moderate and Severe Traumatic Brain Injury Patients

    Directory of Open Access Journals (Sweden)

    Chien-Min Lin

    2015-01-01

    Full Text Available The purpose of this study was to compare the effect of PbtO2-guided therapy with traditional intracranial pressure- (ICP- guided treatment on the management of cerebral variables, therapeutic interventions, survival rates, and neurological outcomes of moderate and severe traumatic brain injury (TBI patients. From 2009 to 2010, TBI patients with a Glasgow coma scale 20 mmHg, and 27 patients were treated with ICP-guided therapy (ICP 60 mmHg in the neurosurgical intensive care unit (NICU; demographic characteristics were similar across groups. The survival rate in the PbtO2-guided group was also significantly increased at 3 and 6 months after injury. Moreover, there was a significant correlation between the PbtO2 signal and Glasgow outcome scale-extended in patients from 1 to 6 months after injury. This finding demonstrates that therapy directed by PbtO2 monitoring is valuable for the treatment of patients with moderate and severe TBI and that increasing PaO2 to 150 mmHg may be efficacious for preventing cerebral hypoxic events after brain trauma.

  5. Moderate alcohol exposure during early brain development increases stimulus-response habits in adulthood.

    Science.gov (United States)

    Parker, Matthew O; Evans, Alexandra M-D; Brock, Alistair J; Combe, Fraser J; Teh, Muy-Teck; Brennan, Caroline H

    2016-01-01

    Exposure to alcohol during early central nervous system development has been shown variously to affect aspects of physiological and behavioural development. In extreme cases, this can extend to craniofacial defects, severe developmental delay and mental retardation. At more moderate levels, subtle differences in brain morphology and behaviour have been observed. One clear effect of developmental alcohol exposure is an increase in the propensity to develop alcoholism and other addictions. The mechanisms by which this occurs, however, are not currently understood. In this study, we tested the hypothesis that adult zebrafish chronically exposed to moderate levels of ethanol during early brain ontogenesis would show an increase in conditioned place preference for alcohol and an increased propensity towards habit formation, a key component of drug addiction in humans. We found support for both of these hypotheses and found that the exposed fish had changes in mRNA expression patterns for dopamine receptor, nicotinic acetylcholine receptor and μ-opioid receptor encoding genes. Collectively, these data show an explicit link between the increased proclivity for addiction and addiction-related behaviour following exposure to ethanol during early brain development and alterations in the neural circuits underlying habit learning. © 2014 Society for the Study of Addiction.

  6. Trauma center designation correlates with functional independence after severe but not moderate traumatic brain injury.

    Science.gov (United States)

    Brown, Joshua B; Stassen, Nicole A; Cheng, Julius D; Sangosanya, Ayodele T; Bankey, Paul E; Gestring, Mark L

    2010-08-01

    The mortality of traumatic brain injury (TBI) continues to decline, emphasizing functional outcomes. Trauma center designation has been linked to survival after TBI, but the impact on functional outcomes is unclear. The objective was to determine whether trauma center designation influenced functional outcomes after moderate and severe TBI. Trauma subjects presenting to an American College of Surgeons (ACS) Level I or II trauma center with a Glasgow Coma Score (GCS) independence (FI) defined as a modified functional independence measure (FIM) of 12, and independent expression (IE) defined as a FIM component of 4. These were compared between Level I and Level II centers in subjects with both moderate (GCS 9-12) and severe (GCS moderate TBI. ACS trauma center designation is significantly associated with FI and IE after severe, but not moderate TBI. Prospective study is warranted to verify and explore factors contributing to this discrepancy.

  7. Brain metabolism and extracellular space diffusion parameters during and after transient global hypoxia in the rat cortex

    Czech Academy of Sciences Publication Activity Database

    Zoremba, N.; Homola, Aleš; Rossaint, R.; Syková, Eva

    2007-01-01

    Roč. 203, - (2007), s. 34-41 ISSN 0014-4886 R&D Projects: GA MŠk 1M0538; GA MŠk LC554 Institutional research plan: CEZ:AV0Z50390512 Keywords : Hypoxia * Cortex * Recovery Subject RIV: FH - Neurology Impact factor: 3.982, year: 2007

  8. Progesterone treatment shows benefit in a pediatric model of moderate to severe bilateral brain injury.

    Directory of Open Access Journals (Sweden)

    Rastafa I Geddes

    Full Text Available Controlled cortical impact (CCI models in adult and aged Sprague-Dawley (SD rats have been used extensively to study medial prefrontal cortex (mPFC injury and the effects of post-injury progesterone treatment, but the hormone's effects after traumatic brain injury (TBI in juvenile animals have not been determined. In the present proof-of-concept study we investigated whether progesterone had neuroprotective effects in a pediatric model of moderate to severe bilateral brain injury.Twenty-eight-day old (PND 28 male Sprague Dawley rats received sham (n = 24 or CCI (n = 47 injury and were given progesterone (4, 8, or 16 mg/kg per 100 g body weight or vehicle injections on post-injury days (PID 1-7, subjected to behavioral testing from PID 9-27, and analyzed for lesion size at PID 28.The 8 and 16 mg/kg doses of progesterone were observed to be most beneficial in reducing the effect of CCI on lesion size and behavior in PND 28 male SD rats.Our findings suggest that a midline CCI injury to the frontal cortex will reliably produce a moderate TBI comparable to what is seen in the adult male rat and that progesterone can ameliorate the injury-induced deficits.

  9. The effects of exercise under hypoxia on cognitive function.

    Directory of Open Access Journals (Sweden)

    Soichi Ando

    Full Text Available Increasing evidence suggests that cognitive function improves during a single bout of moderate exercise. In contrast, exercise under hypoxia may compromise the availability of oxygen. Given that brain function and tissue integrity are dependent on a continuous and sufficient oxygen supply, exercise under hypoxia may impair cognitive function. However, it remains unclear how exercise under hypoxia affects cognitive function. The purpose of this study was to examine the effects of exercise under different levels of hypoxia on cognitive function. Twelve participants performed a cognitive task at rest and during exercise at various fractions of inspired oxygen (FIO2: 0.209, 0.18, and 0.15. Exercise intensity corresponded to 60% of peak oxygen uptake under normoxia. The participants performed a Go/No-Go task requiring executive control. Cognitive function was evaluated using the speed of response (reaction time and response accuracy. We monitored pulse oximetric saturation (SpO2 and cerebral oxygenation to assess oxygen availability. SpO2 and cerebral oxygenation progressively decreased during exercise as the FIO2 level decreased. Nevertheless, the reaction time in the Go-trial significantly decreased during moderate exercise. Hypoxia did not affect reaction time. Neither exercise nor difference in FIO2 level affected response accuracy. An additional experiment indicated that cognitive function was not altered without exercise. These results suggest that the improvement in cognitive function is attributable to exercise, and that hypoxia has no effects on cognitive function at least under the present experimental condition. Exercise-cognition interaction should be further investigated under various environmental and exercise conditions.

  10. Predictors of cognitive and physical fatigue in post-acute mild-moderate traumatic brain injury.

    Science.gov (United States)

    Schiehser, Dawn M; Delano-Wood, Lisa; Jak, Amy J; Hanson, Karen L; Sorg, Scott F; Orff, Henry; Clark, Alexandra L

    2017-10-01

    Post-traumatic fatigue (PTF) is a common, disabling, and often chronic symptom following traumatic brain injury (TBI). Yet, the impact of chronic cognitive and physical fatigue and their associations with psychiatric, sleep, cognitive, and psychosocial sequelae in mild-moderate TBI remain poorly understood. Sixty Veterans with a history of mild-moderate TBI and 40 Veteran controls (VC) were administered the Modified Fatigue Impact Scale, a validated measure of TBI-related cognitive and physical fatigue as well as measures of neuropsychiatric, psychosocial, sleep, and objective cognitive functioning. Compared to VC, TBI Veterans endorsed significantly greater levels of cognitive and physical fatigue. In TBI, psychiatric symptoms, sleep disturbance, and post-traumatic amnesia (PTA) were associated with both cognitive and physical fatigue, while loss of consciousness (LOC) and poor attention/processing speed were related to elevations in cognitive fatigue only. In regression analyses, anxiety, sleep disturbance, and LOC significantly predicted cognitive fatigue, while only post-traumatic stress symptoms and PTA contributed to physical fatigue. Cognitive and physical fatigue are problematic symptoms following mild-moderate TBI that are differentially associated with specific injury and psychiatric sequelae. Findings provide potential symptom targets for interventions aimed at ameliorating fatigue, and further underscore the importance of assessing and treating fatigue as a multi-dimensional symptom following TBI.

  11. Pituitary and/or hypothalamic dysfunction following moderate to severe traumatic brain injury: Current perspectives

    Directory of Open Access Journals (Sweden)

    Zeeshan Javed

    2015-01-01

    Full Text Available There is an increasing deliberation regarding hypopituitarism following traumatic brain injury (TBI and recent data have suggested that pituitary dysfunction is very common among survivors of patients having moderate-severe TBI which may evolve or resolve over time. Due to high prevalence of pituitary dysfunction after moderate-severe TBI and its association with increased morbidity and poor recovery and the fact that it can be easily treated with hormone replacement, it has been suggested that early detection and treatment is necessary to prevent long-term neurological consequences. The cause of pituitary dysfunction after TBI is still not well understood, but evidence suggests few possible primary and secondary causes. Results of recent studies focusing on the incidence of hypopituitarism in the acute and chronic phases after TBI are varied in terms of severity and time of occurrence. Although the literature available does not show consistent values and there is difference in study parameters and diagnostic tests used, it is clear that pituitary dysfunction is very common after moderate to severe TBI and patients should be carefully monitored. The exact timing of development cannot be predicted but has suggested regular assessment of pituitary function up to 1 year after TBI. In this narrative review, we aim to explore the current evidence available regarding the incidence of pituitary dysfunction in acute and chronic phase post-TBI and recommendations for screening and follow-up in these patients. We will also focus light over areas in this field worthy of further investigation.

  12. 5-HTTLPR moderates the association between interdependence and brain responses to mortality threats.

    Science.gov (United States)

    Luo, Siyang; Yu, Dian; Han, Shihui

    2017-12-01

    While behavioral research suggests an association between cultural worldview and decreased anxiety of death, the underlying neurobiological mechanisms remain unclear. Using functional MRI, we investigated whether and how the serotonin transporter promoter polymorphism (5-HTTLPR), which has been associated with mental disorders such as anxiety and depression, moderates the associations between a cultural trait (i.e., interdependence) and self-report of death anxiety/depression and between interdependence and brain responses to mortality threats. Long/long and short/short allele carriers of the 5-HTTLPR were scanned using fMRI while they performed a one-back task on death-related, death-unrelated negative, and neutral words. Participants' interdependence and death anxiety/depression were assessed using questionnaires after scanning. We found that participants who assessed themselves with greater interdependence reported lower death anxiety/depression and showed decreased neural response to death-related words in emotion-related brain regions including the anterior cingulate, putamen, and thalamus. However, these results were evident in long/long allele carriers of the 5-HTTLPR but not in short/short allele carriers who even showed positive associations between interdependence and neural activities in the anterior cingulate, putamen and thalamus in response to death-related words. Our findings suggest candidate mechanisms for explaining the complex relationship between genotype, cultural traits, and mental/neural responses to mortality threats. Hum Brain Mapp 38:6157-6171, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. The big sell: Managing stigma and workplace discrimination following moderate to severe brain injury.

    Science.gov (United States)

    Stergiou-Kita, Mary; Grigorovich, Alisa; Damianakis, Thecla; Le Dorze, Guylaine; David, Christine; Lemsky, Carolyn; Hebert, Debbie

    2017-01-01

    Misperceptions regarding persons with brain injuries (PWBI) can lead to stigmatization, workplace discrimination and, in turn, influence PWBIs full vocational integration. In this study we explored how stigma may influence return-to-work processes, experiences of stigma and discrimination at the workplace for persons with (moderate to severe) brain injuries, and strategies that can be employed to manage disclosure. Exploratory qualitative study; used in-depth interviews and an inductive thematic analytical approach in data analysis. Ten PWBI and five employment service providers participated. PWBI discussed their work experiences, relationships with supervisors and co-workers and experiences of stigma and/or discrimination at work. Employment service providers discussed their perceptions regarding PWBI's rights and abilities to work, reported incidents of workplace discrimination, and how issues related to stigma, discrimination and disclosure are managed. Three themes were identified: i) public, employer and provider knowledge about brain injury and beliefs about PWBI; ii) incidents of workplace discrimination; iii) disclosure. Misperceptions regarding PWBI persist amongst the public and employers. Incidents of workplace discrimination included social exclusion at the workplace, hiring discrimination, denial of promotion/demotion, harassment, and failure to provide reasonable accommodations. Disclosure decisions required careful consideration of PWBI needs, the type of information that should be shared, and the context in which that information is shared. Public understanding about PWBI remains limited. PWBI require further assistance to manage disclosure and incidents of workplace discrimination.

  14. Alzheimer’s Disease Mutant Mice Exhibit Reduced Brain Tissue Stiffness Compared to Wild-type Mice in both Normoxia and following Intermittent Hypoxia Mimicking Sleep Apnea

    Directory of Open Access Journals (Sweden)

    Maria José Menal

    2018-01-01

    Full Text Available BackgroundEvidence from patients and animal models suggests that obstructive sleep apnea (OSA may increase the risk of Alzheimer’s disease (AD and that AD is associated with reduced brain tissue stiffness.AimTo investigate whether intermittent hypoxia (IH alters brain cortex tissue stiffness in AD mutant mice exposed to IH mimicking OSA.MethodsSix-eight month old (B6C3-Tg(APPswe,PSEN1dE985Dbo/J AD mutant mice and wild-type (WT littermates were subjected to IH (21% O2 40 s to 5% O2 20 s; 6 h/day or normoxia for 8 weeks. After euthanasia, the stiffness (E of 200-μm brain cortex slices was measured by atomic force microscopy.ResultsTwo-way ANOVA indicated significant cortical softening and weight increase in AD mice compared to WT littermates, but no significant effects of IH on cortical stiffness and weight were detected. In addition, reduced myelin was apparent in AD (vs. WT, but no significant differences emerged in the cortex extracellular matrix components laminin and glycosaminoglycans when comparing baseline AD and WT mice.ConclusionAD mutant mice exhibit reduced brain tissue stiffness following both normoxia and IH mimicking sleep apnea, and such differences are commensurate with increased edema and demyelination in AD.

  15. Rejection Sensitivity as a Moderator of Psychosocial Outcomes Following Pediatric Traumatic Brain Injury.

    Science.gov (United States)

    Meadows, Emily A; Owen Yeates, Keith; Rubin, Kenneth H; Taylor, H Gerry; Bigler, Erin D; Dennis, Maureen; Gerhardt, Cynthia A; Vannatta, Kathryn; Stancin, Terry; Hoskinson, Kristen R

    2017-07-01

    The current study examines whether psychosocial outcomes following pediatric traumatic brain injury (TBI) vary as a function of children's rejection sensitivity (RS), defined as their disposition to be hypersensitive to cues of rejection from peers. Children ages 8-13 with a history of severe TBI (STBI, n=16), complicated mild/moderate TBI (n=35), or orthopedic injury (OI, n=49) completed measures assessing self-esteem and RS on average 3.28 years post-injury (SD=1.33, range=1.25-6.34). Parents reported on their child's emotional and behavioral functioning and social participation. Regression analyses found moderation of group differences by RS for three outcomes: social participation, self-perceptions of social acceptance, and externalizing behavior problems. Conditional effects at varying levels of RS indicated that externalizing problems and social participation were significantly worse for children with STBI at high levels of RS, compared to children with OI. Social participation for the STBI group remained significantly lower than the OI group at mean levels of RS, but not at low levels of RS. At high levels of RS, self-perceptions of social acceptance were lower for children with moderate TBI compared to OI, but group differences were not significant at mean or low levels of RS. No evidence of moderation was found for global self-worth, self-perceptions of physical appearance or athletic ability, or internalizing problems. The findings highlight the salient nature of social outcomes in the context of varying levels of RS. These findings may have implications for the design of interventions to improve social outcomes following TBI. (JINS, 2017, 23, 451-459).

  16. Moderate traumatic brain injury causes acute dendritic and synaptic degeneration in the hippocampal dentate gyrus.

    Directory of Open Access Journals (Sweden)

    Xiang Gao

    Full Text Available Hippocampal injury-associated learning and memory deficits are frequent hallmarks of brain trauma and are the most enduring and devastating consequences following traumatic brain injury (TBI. Several reports, including our recent paper, showed that TBI brought on by a moderate level of controlled cortical impact (CCI induces immature newborn neuron death in the hippocampal dentate gyrus. In contrast, the majority of mature neurons are spared. Less research has been focused on these spared neurons, which may also be injured or compromised by TBI. Here we examined the dendrite morphologies, dendritic spines, and synaptic structures using a genetic approach in combination with immunohistochemistry and Golgi staining. We found that although most of the mature granular neurons were spared following TBI at a moderate level of impact, they exhibited dramatic dendritic beading and fragmentation, decreased number of dendritic branches, and a lower density of dendritic spines, particularly the mushroom-shaped mature spines. Further studies showed that the density of synapses in the molecular layer of the hippocampal dentate gyrus was significantly reduced. The electrophysiological activity of neurons was impaired as well. These results indicate that TBI not only induces cell death in immature granular neurons, it also causes significant dendritic and synaptic degeneration in pathohistology. TBI also impairs the function of the spared mature granular neurons in the hippocampal dentate gyrus. These observations point to a potential anatomic substrate to explain, in part, the development of posttraumatic memory deficits. They also indicate that dendritic damage in the hippocampal dentate gyrus may serve as a therapeutic target following TBI.

  17. Social Environmental Moderators of Long-term Functional Outcomes of Early Childhood Brain Injury.

    Science.gov (United States)

    Wade, Shari L; Zhang, Nanhua; Yeates, Keith Owen; Stancin, Terry; Taylor, H Gerry

    2016-04-01

    Pediatric traumatic brain injury (TBI) contributes to impairments in behavior and academic performance. However, the long-term effects of early childhood TBI on functioning across settings remain poorly understood. To examine the long-term functional outcomes of early childhood TBI relative to early childhood orthopedic injuries (OIs). We also examine the moderating role of the social environment as defined by parent report and observational measures of family functioning, parenting practices, and home environment. A prospective, longitudinal, observational cohort study conducted at each child's home, school, and hospital, including 3 children's hospitals and 1 general hospital in the Midwest. Patients were enrolled in the initial study between January 2003 and October 2006. Follow-ups were completed between January 2010 and April 2015. Fifty-eight children who sustained a TBI (67% of original enrolled cohort) and 72 children who sustained an OI (61% of the original enrolled cohort) were prospectively followed up from shortly after injury (between the ages of 3 and 7 years at enrollment) to an average of 6.7 years after injury, with assessments occurring at multiple points. Long-term functional outcomes in everyday settings, as assessed through the Child and Adolescent Functional Assessment Scale (CAFAS). Of the 130 children included, the median age for those with OIs was 11.72 years and 11.97, 12.21, and 11.72 years for those with complicated mild, moderate, and severe TBIs, respectively. Children with moderate and severe TBI were rated as having more functional impairments in multiple domains than those with OIs (P authoritarian (mean CAFAS of 56.45, 41.80, 54.90, and 17.12 for severe TBI, moderate TBI, complicated mild TBI, and OI, respectively, with significant difference between severe TBI and OI [difference = 39.33; P parenting or with fewer home resources (mean CAFAS of 69.57, 47.45, 49.00, and 23.81 for severe TBI, moderate TBI, complicated mild TBI, and OI

  18. Brain reactivity to visual food stimuli after moderate-intensity exercise in children.

    Science.gov (United States)

    Masterson, Travis D; Kirwan, C Brock; Davidson, Lance E; Larson, Michael J; Keller, Kathleen L; Fearnbach, S Nicole; Evans, Alyssa; LeCheminant, James D

    2017-09-19

    Exercise may play a role in moderating eating behaviors. The purpose of this study was to examine the effect of an acute bout of exercise on neural responses to visual food stimuli in children ages 8-11 years. We hypothesized that acute exercise would result in reduced activity in reward areas of the brain. Using a randomized cross-over design, 26 healthy weight children completed two separate laboratory conditions (exercise; sedentary). During the exercise condition, each participant completed a 30-min bout of exercise at moderate-intensity (~ 67% HR maximum) on a motor-driven treadmill. During the sedentary session, participants sat continuously for 30 min. Neural responses to high- and low-calorie pictures of food were determined immediately following each condition using functional magnetic resonance imaging. There was a significant exercise condition*stimulus-type (high- vs. low-calorie pictures) interaction in the left hippocampus and right medial temporal lobe (p visual food stimuli differently following an acute bout of exercise compared to a non-exercise sedentary session in 8-11 year-old children. Specifically, an acute bout of exercise results in greater activation to high-calorie and reduced activation to low-calorie pictures of food in both the left hippocampus and right medial temporal lobe. This study shows that response to external food cues can be altered by exercise and understanding this mechanism will inform the development of future interventions aimed at altering energy intake in children.

  19. Prospective memory after moderate-to-severe traumatic brain injury: a multinomial modeling approach.

    Science.gov (United States)

    Pavawalla, Shital P; Schmitter-Edgecombe, Maureen; Smith, Rebekah E

    2012-01-01

    Prospective memory (PM), which can be understood as the processes involved in realizing a delayed intention, is consistently found to be impaired after a traumatic brain injury (TBI). Although PM can be empirically dissociated from retrospective memory, it inherently involves both a prospective component (i.e., remembering that an action needs to be carried out) and retrospective components (i.e., remembering what action needs to be executed and when). This study utilized a multinomial processing tree model to disentangle the prospective (that) and retrospective recognition (when) components underlying PM after moderate-to-severe TBI. Seventeen participants with moderate to severe TBI and 17 age- and education-matched control participants completed an event-based PM task that was embedded within an ongoing computer-based color-matching task. The multinomial processing tree modeling approach revealed a significant group difference in the prospective component, indicating that the control participants allocated greater preparatory attentional resources to the PM task compared to the TBI participants. Participants in the TBI group were also found to be significantly more impaired than controls in the when aspect of the retrospective component. These findings indicated that the TBI participants had greater difficulty allocating the necessary preparatory attentional resources to the PM task and greater difficulty discriminating between PM targets and nontargets during task execution, despite demonstrating intact posttest recall and/or recognition of the PM tasks and targets.

  20. Dementia After Moderate-Severe Traumatic Brain Injury: Coexistence of Multiple Proteinopathies.

    Science.gov (United States)

    Kenney, Kimbra; Iacono, Diego; Edlow, Brian L; Katz, Douglas I; Diaz-Arrastia, Ramon; Dams-O'Connor, Kristen; Daneshvar, Daniel H; Stevens, Allison; Moreau, Allison L; Tirrell, Lee S; Varjabedian, Ani; Yendiki, Anastasia; van der Kouwe, Andre; Mareyam, Azma; McNab, Jennifer A; Gordon, Wayne A; Fischl, Bruce; McKee, Ann C; Perl, Daniel P

    2018-01-01

    We report the clinical, neuroimaging, and neuropathologic characteristics of 2 patients who developed early onset dementia after a moderate-severe traumatic brain injury (TBI). Neuropathological evaluation revealed abundant β-amyloid neuritic and cored plaques, diffuse β-amyloid plaques, and frequent hyperphosphorylated-tau neurofibrillary tangles (NFT) involving much of the cortex, including insula and mammillary bodies in both cases. Case 1 additionally showed NFTs in both the superficial and deep cortical layers, occasional perivascular and depth-of-sulci NFTs, and parietal white matter rarefaction, which corresponded with decreased parietal fiber tracts observed on ex vivo MRI. Case 2 additionally showed NFT predominance in the superficial layers of the cortex, hypothalamus and brainstem, diffuse Lewy bodies in the cortex, amygdala and brainstem, and intraneuronal TDP-43 inclusions. The neuropathologic diagnoses were atypical Alzheimer disease (AD) with features of chronic traumatic encephalopathy and white matter loss (Case 1), and atypical AD, dementia with Lewy bodies and coexistent TDP-43 pathology (Case 2). These findings support an epidemiological association between TBI and dementia and further characterize the variety of misfolded proteins that may accumulate after TBI. Analyses with comprehensive clinical, imaging, genetic, and neuropathological data are required to characterize the full clinicopathological spectrum associated with dementias occurring after moderate-severe TBI. 2017 American Association of Neuropathologists, Inc. This work is written by US Government employees and is in the public domain in the US.

  1. Tracheostomy is associated with decreased hospital mortality after moderate or severe isolated traumatic brain injury.

    Science.gov (United States)

    Baron, David Marek; Hochrieser, Helene; Metnitz, Philipp G H; Mauritz, Walter

    2016-06-01

    Data regarding the impact and timing of tracheostomy in patients with isolated traumatic brain injury (TBI) are ambiguous. Our goal was to evaluate the impact of tracheostomy on hospital mortality in patients with moderate or severe isolated TBI. We performed a retrospective cohort analysis of data prospectively collected at 87 Austrian intensive care units (ICUs). All patients continuously admitted between 1998 and 2010 were evaluated for the study. In total, 4,735 patients were admitted to ICUs with isolated TBI. Of these patients, 2,156 had a moderate or severe TBI (1,603 patients were endotracheally intubated only, 553 patients underwent tracheostomy). Epidemiological data (trauma severity, treatment, and outcome) of the two groups were compared. Patients with moderate or severe isolated TBI undergoing tracheostomy had a similar Glasgow Coma Scale score, median (interquartile range): 6 (3-8) vs 6 (3-8); p = 0.90, and Simplified Acute Physiology Score II, 45 (37-54) vs 45 (35-56); p = 0.86, compared with intubated patients not undergoing tracheostomy. Furthermore, patients undergoing tracheostomy exhibited higher Abbreviated Injury Scale Head scores and had a longer ICU stay for survivors, 30 (22-42) vs 9 (3-17) days; p tracheostomy compared with patients who remained intubated, observed-to-expected mortality ratio (95 % confidence interval): 0.62 (0.53-0.72) vs 1.00 (0.95-1.05) respectively. Despite the greater severity of head injury, patients with isolated TBI who underwent tracheostomy had a lower risk-adjusted mortality than patients who remained intubated. Reasons for this difference in outcome may be multifactorial and require further investigation.

  2. The Evolution of Post-Traumatic Stress Disorder following Moderate-to-Severe Traumatic Brain Injury.

    Science.gov (United States)

    Alway, Yvette; Gould, Kate Rachel; McKay, Adam; Johnston, Lisa; Ponsford, Jennie

    2016-05-01

    Increasing evidence indicates that post-traumatic stress disorder (PTSD) may develop following traumatic brain injury (TBI), despite most patients having no conscious memory of their accident. This prospective study examined the frequency, timing of onset, symptom profile, and trajectory of PTSD and its psychiatric comorbidities during the first 4 years following moderate-to-severe TBI. Participants were 85 individuals (78.8% male) with moderate or severe TBI recruited following admission to acute rehabilitation between 2005 and 2010. Using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Disorders (SCID-I), participants were evaluated for pre- and post-injury PTSD soon after injury and reassessed at 6 months, 12 months, 2 years, 3 years, and 4 years post-injury. Over the first 4 years post-injury, 17.6% developed injury-related PTSD, none of whom had PTSD prior to injury. PTSD onset peaked between 6 and 12 months post-injury. The majority of PTSD cases (66.7%) had a delayed-onset, which for a third was preceded by subsyndromal symptoms in the first 6 months post-injury. PTSD frequency increased over the first year post-injury, remained stable during the second year, and gradually declined thereafter. The majority of subjects with PTSD experienced a chronic symptom course and all developed one or more than one comorbid psychiatric disorder, with mood, other anxiety, and substance-use disorders being the most common. Despite event-related amnesia, post-traumatic stress symptoms, including vivid re-experiencing phenomena, may develop following moderate-to-severe TBI. Onset is typically delayed and symptoms may persist for several years post-injury.

  3. Social Environmental Moderators of Long-term Functional Outcomes of Early Childhood Brain Injury

    Science.gov (United States)

    Wade, Shari L.; Zhang, Nanhua; Yeates, Keith Owen; Stancin, Terry; Taylor, H. Gerry

    2017-01-01

    IMPORTANCE Pediatric traumatic brain injury (TBI) contributes to impairments in behavior and academic performance. However, the long-term effects of early childhood TBI on functioning across settings remain poorly understood. OBJECTIVE To examine the long-term functional outcomes of early childhood TBI relative to early childhood orthopedic injuries (OIs). We also examine the moderating role of the social environment as defined by parent report and observational measures of family functioning, parenting practices, and home environment. DESIGN, SETTING, AND PARTICIPANTS A prospective, longitudinal, observational cohort study conducted at each child’s home, school, and hospital, including 3 children’s hospitals and 1 general hospital in the Midwest. Patients were enrolled in the initial study between January 2003 and October 2006. Follow-ups were completed between January 2010 and April 2015. Fifty-eight children who sustained a TBI (67%of original enrolled cohort) and 72 children who sustained an OI (61% of the original enrolled cohort) were prospectively followed up from shortly after injury (between the ages of 3 and 7 years at enrollment) to an average of 6.7 years after injury, with assessments occurring at multiple points. MAIN OUTCOMES AND MEASURES Long-term functional outcomes in everyday settings, as assessed through the Child and Adolescent Functional Assessment Scale (CAFAS). RESULTS Of the 130 children included, the median age for those with OIs was 11.72 years and 11.97, 12.21, and 11.72 years for those with complicated mild, moderate, and severe TBIs, respectively. Children with moderate and severe TBI were rated as having more functional impairments in multiple domains than those with OIs (P authoritarian (mean CAFAS of 56.45, 41.80, 54.90, and 17.12 for severe TBI, moderate TBI, complicated mild TBI, and OI, respectively, with significant difference between severe TBI and OI [difference = 39.33; P < .001], moderate TBI and OI [difference = 24

  4. Cerebral Hypoxia

    Science.gov (United States)

    ... Inc. Brain Injury Resource Center Brain Trauma Foundation Easter Seals National Rehabilitation Information Center (NARIC) See all ... Inc. Brain Injury Resource Center Brain Trauma Foundation Easter Seals National Rehabilitation Information Center (NARIC) See all ...

  5. Facilitated transport of glucose from blood to brain in man and the effect of moderate hypoglycaemia on cerebral glucose utilization

    International Nuclear Information System (INIS)

    Blomqvist, G.; Widen, L.; Hellstrand, E.; Gutniak, M.; Grill, V.

    1991-01-01

    The effect of steady-state moderate hypoglycaemia on human brain homeostasis has been studied with positron emission tomography using D-glucose 11 C(ul) as tracer. To rule out any effects of insulin, the plasma insulin concentration was maintained at the same level under normo- and hypoglycaemic conditions. Reduction of blood glucose by 55% increased the glucose clearance through the blood-brain barrier by 50% and reduced brain glucose consumption by 40%. Blood flow was not affected. The results are consistent with facilitated transport of glucose from blood to brain in humans. The maximal transport rate of glucose from blood to brain was found to be 62±19 (mean±SEM) μmol hg -1 min -1 , and the half-saturation constant was found to be 4.1±3.2 mM. (orig.)

  6. Deficits in Facial Emotion Recognition Indicate Behavioral Changes and Impaired Self-Awareness after Moderate to Severe Traumatic Brain Injury

    NARCIS (Netherlands)

    Spikman, Jacoba M.; Milders, Maarten V.; Visser-Keizer, Annemarie C.; Westerhof-Evers, Herma J.; Herben-Dekker, Meike; van der Naalt, Joukje

    2013-01-01

    Traumatic brain injury (TBI) is a leading cause of disability, specifically among younger adults. Behavioral changes are common after moderate to severe TBI and have adverse consequences for social and vocational functioning. It is hypothesized that deficits in social cognition, including facial

  7. Functional level during the first 2 years after moderate and severe traumatic brain injury.

    Science.gov (United States)

    Sandhaug, Maria; Andelic, Nada; Langhammer, Birgitta; Mygland, Aase

    2015-01-01

    Long-term outcomes after TBI are examined to a large extent, but longitudinal studies with more than 1-year follow-up time after injury have been fewer in number. The course of recovery may vary due to a number of factors and it is still somewhat unclear which factors are contributing. The aim of this study was to describe the functional level at four time points up to 24 months after traumatic brain injury (TBI) and to evaluate the predictive impact of pre-injury and injury-related factors. A cohort study. Outpatient. Sixty-five patients with moderate (n = 21) or severe (n = 44) TBI. The patients with TBI were examined with Functional Independence Measure (FIM) and Glasgow Outcome Scale Extended (GOSE) at 3 months, 12 months and 24 months after injury. Possible predictors were analysed in a regression model using FIM total score at 24 months as the outcome measure. FIM scores improved significantly from rehabilitation unit discharge to 24 months after injury, with peak levels at 3 and 24 months after injury (p GOSE scores for the whole group and the moderate group improved significantly over time, but the severe group did not. FIM at admission to the rehabilitation unit and GCS score at admission to the rehabilitation unit were closest to being significant predictors of FIM total scores 24 months after injury (B = 0.265 and 2.883, R(2 )= 0.39, p = 0.073, p = 0.081). FIM levels improved during the period from rehabilitation unit discharge to 3 months follow-up; thereafter, there was a 'plateauing' of recovery. In contrast, GOSE 'plateauing' of recovery was at 12 months. The study results may indicate that two of the most used outcome measures in TBI research are more relevant for assessment of the functional recovery in a sub-acute phase than in later stages of TBI recovery.

  8. Employment Outcome Ten Years after Moderate to Severe Traumatic Brain Injury: A Prospective Cohort Study.

    Science.gov (United States)

    Grauwmeijer, Erik; Heijenbrok-Kal, Majanka H; Haitsma, Ian K; Ribbers, Gerard M

    2017-09-01

    The objective of this prospective cohort study was to evaluate the probability of employment and predictors of employment in patients with moderate- to- severe traumatic brain injury (TBI) over 10-year follow-up. One hundred nine patients (18-67 years) were included with follow-up measurements 3, 6, 12, 18, 24, and 36 months and 10 years post-TBI. Potential predictors of employment probability included patient characteristics, injury severity factors, functional outcome measured at discharge from the hospital with the Glasgow Outcome Scale (GOS), Barthel Index (BI), Functional Independence Measure (FIM), and the Functional Assessment Measure (FAM). Forty-eight patients (42%) completed the 10-year follow-up. Three months post-TBI, 12% were employed, which gradually, but significantly, increased to 57% after 2-years follow-up (p employed persons had less-severe TBI, shorter length of hospital stay (LOS), and higher scores on the GOS, BI, FIM, and FAM at hospital discharge than unemployed persons. No significant differences in age, sex, educational level, living with partner/family or not, pre-injury employment, professional category, psychiatric symptoms, or discharge destination were found. Longitudinal multivariable analysis showed that time, pre-injury employment, FAM, and LOS were independent predictors of employment probability. We concluded that employment probability 10 years after moderate or severe TBI is related to injury severity and pre-injury employment. Future studies on vocational rehabilitation should focus on modifiable factors and take into consideration the effects of national legislation and national labor market forces.

  9. Patients with Moderate and Severe Traumatic Brain Injury: Impact of Preinjury Platelet Inhibitor or Warfarin Treatment.

    Science.gov (United States)

    Tollefsen, Marie Hexeberg; Vik, Anne; Skandsen, Toril; Sandrød, Oddrun; Deane, Susan Frances; Rao, Vidar; Moen, Kent Gøran

    2018-06-01

    We aimed to examine the effect of preinjury antithrombotic medication on clinical and radiologic neuroworsening in traumatic brain injury (TBI) and study the effect on outcome. A total of 184 consecutive patients ≥50 years old with moderate and severe TBI admitted to a level 1 trauma center were included. Neuroworsening was assessed clinically by using the Glasgow Coma Scale (GCS) score and radiologically by using the Rotterdam CT score on repeated time points. Functional outcome was assessed with the Glasgow Outcome Scale Extended 6 months after injury. The platelet inhibitor group (mean age, 77.3 years; n = 43) and the warfarin group (mean age, 73.2 years; n = 20) were significantly older than the nonuser group (mean age, 63.7 years; n = 121; P ≤ 0.001). In the platelet inhibitor group 74% and in the warfarin group, 85% were injured by falls. Platelet inhibitors were not significantly associated with clinical or radiologic neuroworsening (P = 0.37-1.00), whereas warfarin increased the frequency of worsening in GCS score (P = 0.001-0.028) and Rotterdam CT score (P = 0.004). In-hospital mortality was higher in the platelet inhibitor group (28%; P = 0.030) and the warfarin group (50%; P warfarin predicted both mortality and worse outcome. In this study of patients with moderate and severe TBI, preinjury platelet inhibitors did not cause neuroworsening or predict higher mortality or worse outcome. In contrast, preinjury warfarin caused neuroworsening and was an independent risk factor for mortality and worse outcome at 6 months. Hence, fall prevention and liberal use of computed tomography examinations is important in this patient group. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Mechanisms of Neuroprotection from Hypoxia-Ischemia (HI) Brain Injury by Up-regulation of Cytoglobin (CYGB) in a Neonatal Rat Model*

    Science.gov (United States)

    Tian, Shu-Feng; Yang, Han-Hua; Xiao, Dan-Ping; Huang, Yue-Jun; He, Gu-Yu; Ma, Hai-Ran; Xia, Fang; Shi, Xue-Chuan

    2013-01-01

    This study was designed to investigate the expression profile of CYGB, its potential neuroprotective function, and underlying molecular mechanisms using a model of neonatal hypoxia-ischemia (HI) brain injury. Cygb mRNA and protein expression were evaluated within the first 36 h after the HI model was induced using RT-PCR and Western blotting. Cygb mRNA expression was increased at 18 h in a time-dependent manner, and its level of protein expression increased progressively in 24 h. To verify the neuroprotective effect of CYGB, a gene transfection technique was employed. Cygb cDNA and shRNA delivery adenovirus systems were established (Cygb-cDNA-ADV and Cygb-shRNA-ADV, respectively) and injected into the brains of 3-day-old rats 4 days before they were induced with HI treatment. Rats from different groups were euthanized 24 h post-HI, and brain samples were harvested. 2,3,5-Triphenyltetrazolium chloride, TUNEL, and Nissl staining indicated that an up-regulation of CYGB resulted in reduced acute brain injury. The superoxide dismutase level was found to be dependent on expression of CYGB. The Morris water maze test in 28-day-old rats demonstrated that CYGB expression was associated with improvement of long term cognitive impairment. Studies also demonstrated that CYGB can up-regulate mRNA and protein levels of VEGF and increase both the density and diameter of the microvessels but inhibits activation of caspase-2 and -3. Thus, this is the first in vivo study focusing on the neuroprotective role of CYGB. The reduction of neonatal HI injury by CYGB may be due in part to antioxidant and antiapoptotic mechanisms and by promoting angiogenesis. PMID:23585565

  11. White matter disruption in moderate/severe pediatric traumatic brain injury: Advanced tract-based analyses

    Directory of Open Access Journals (Sweden)

    Emily L. Dennis

    2015-01-01

    Full Text Available Traumatic brain injury (TBI is the leading cause of death and disability in children and can lead to a wide range of impairments. Brain imaging methods such as DTI (diffusion tensor imaging are uniquely sensitive to the white matter (WM damage that is common in TBI. However, higher-level analyses using tractography are complicated by the damage and decreased FA (fractional anisotropy characteristic of TBI, which can result in premature tract endings. We used the newly developed autoMATE (automated multi-atlas tract extraction method to identify differences in WM integrity. 63 pediatric patients aged 8–19 years with moderate/severe TBI were examined with cross sectional scanning at one or two time points after injury: a post-acute assessment 1–5 months post-injury and a chronic assessment 13–19 months post-injury. A battery of cognitive function tests was performed in the same time periods. 56 children were examined in the first phase, 28 TBI patients and 28 healthy controls. In the second phase 34 children were studied, 17 TBI patients and 17 controls (27 participants completed both post-acute and chronic phases. We did not find any significant group differences in the post-acute phase. Chronically, we found extensive group differences, mainly for mean and radial diffusivity (MD and RD. In the chronic phase, we found higher MD and RD across a wide range of WM. Additionally, we found correlations between these WM integrity measures and cognitive deficits. This suggests a distributed pattern of WM disruption that continues over the first year following a TBI in children.

  12. A comparison of IQ and memory cluster solutions in moderate and severe pediatric traumatic brain injury.

    Science.gov (United States)

    Thaler, Nicholas S; Terranova, Jennifer; Turner, Alisa; Mayfield, Joan; Allen, Daniel N

    2015-01-01

    Recent studies have examined heterogeneous neuropsychological outcomes in childhood traumatic brain injury (TBI) using cluster analysis. These studies have identified homogeneous subgroups based on tests of IQ, memory, and other cognitive abilities that show some degree of association with specific cognitive, emotional, and behavioral outcomes, and have demonstrated that the clusters derived for children with TBI are different from those observed in normal populations. However, the extent to which these subgroups are stable across abilities has not been examined, and this has significant implications for the generalizability and clinical utility of TBI clusters. The current study addressed this by comparing IQ and memory profiles of 137 children who sustained moderate-to-severe TBI. Cluster analysis of IQ and memory scores indicated that a four-cluster solution was optimal for the IQ scores and a five-cluster solution was optimal for the memory scores. Three clusters on each battery differed primarily by level of performance, while the others had pattern variations. Cross-plotting the clusters across respective IQ and memory test scores indicated that clusters defined by level were generally stable, while clusters defined by pattern differed. Notably, children with slower processing speed exhibited low-average to below-average performance on memory indexes. These results provide some support for the stability of previously identified memory and IQ clusters and provide information about the relationship between IQ and memory in children with TBI.

  13. Does Apolipoprotein e4 Status Moderate the Association of Family Environment with Long-Term Child Functioning following Early Moderate to Severe Traumatic Brain Injury? A Preliminary Study.

    Science.gov (United States)

    Treble-Barna, Amery; Zang, Huaiyu; Zhang, Nanhua; Martin, Lisa J; Yeates, Keith Owen; Taylor, H Gerry; Wade, Shari L; Kurowski, Brad G

    2016-09-01

    To examine whether apolipoprotein e4 (APOE) status moderates the association of family environment with child functioning following early traumatic brain injury (TBI). Sixty-five children with moderate to severe TBI and 70 children with orthopedic injury (OI) completed assessments 6, 12, 18 months, and 3.5 and 6.8 years post injury. DNA was extracted from saliva samples and genotyped for APOE e4 status. Linear mixed models examined moderating effects of APOE e4 status on associations between two family environment factors (parenting style, home environment) and three child outcomes (executive functioning, behavioral adjustment, adaptive functioning). Children with TBI who were carriers of the e4 allele showed poorer adaptive functioning relative to non-carriers with TBI and children with OI in the context of low authoritarianism. At high levels of authoritarianism, non-carriers with TBI showed the poorest adaptive functioning among groups. There were no main effects or interactions involving APOE and executive functioning or behavioral adjustment. The APOE e4 allele was detrimental for long-term adaptive functioning in the context of positive parenting, whereas in less optimal parenting contexts, being a non-carrier was detrimental. We provide preliminary evidence for an interaction of APOE e4 status and parenting style in predicting long-term outcomes following early TBI. (JINS, 2016, 22, 859-864).

  14. Transdiagnostic dimensions of anxiety and depression moderate motivation-related brain networks during goal maintenance.

    Science.gov (United States)

    Spielberg, Jeffrey M; Miller, Gregory A; Warren, Stacie L; Sutton, Bradley P; Banich, Marie; Heller, Wendy

    2014-10-01

    Advancing research on the etiology, prevention, and treatment of psychopathology requires the field to move beyond modular conceptualizations of neural dysfunction toward understanding disturbance in key brain networks. Although some studies of anxiety and depression have begun doing so, they typically suffer from several drawbacks, including: (1) a categorical approach ignoring transdiagnostic processes, (2) failure to account for substantial anxiety and depression comorbidity, (3) examination of networks at rest, which overlooks disruption manifesting only when networks are challenged. Accordingly, the present study examined relationships between transdiagnostic dimensions of anxiety/depression and patterns of functional connectivity while goal maintenance was challenged. Participants (n = 179, unselected community members and undergraduates selected to be high/low on anxiety/depression) performed a task in which goal maintenance was challenged (color-word Stroop) while fMRI data were collected. Analyses examined moderation by anxiety/depression of condition-dependent coupling between regions of dorsolateral prefrontal cortex (dlPFC) previously associated with approach and avoidance motivation and amygdala/orbitofrontal cortex (OFC). Anxious arousal was positively associated with amygdala↔right dlPFC coupling. Depression was positively associated with OFC↔right dlPFC coupling and negatively associated with OFC↔left dlPFC coupling. Findings advance the field toward an integrative model of the neural instantiation of anxiety/depression by identifying specific, distinct dysfunctions associated with anxiety and depression in networks important for maintaining approach and avoidance goals. Specifically, findings shed light on potential neural mechanisms involved in attentional biases in anxiety and valuation biases in depression and underscore the importance of examining transdiagnostic dimensions of anxiety/depression while networks are challenged. © 2014

  15. Socioeconomic status moderates age-related differences in the brain's functional network organization and anatomy across the adult lifespan.

    Science.gov (United States)

    Chan, Micaela Y; Na, Jinkyung; Agres, Phillip F; Savalia, Neil K; Park, Denise C; Wig, Gagan S

    2018-05-14

    An individual's environmental surroundings interact with the development and maturation of their brain. An important aspect of an individual's environment is his or her socioeconomic status (SES), which estimates access to material resources and social prestige. Previous characterizations of the relation between SES and the brain have primarily focused on earlier or later epochs of the lifespan (i.e., childhood, older age). We broaden this work to examine the relationship between SES and the brain across a wide range of human adulthood (20-89 years), including individuals from the less studied middle-age range. SES, defined by education attainment and occupational socioeconomic characteristics, moderates previously reported age-related differences in the brain's functional network organization and whole-brain cortical structure. Across middle age (35-64 years), lower SES is associated with reduced resting-state system segregation (a measure of effective functional network organization). A similar but less robust relationship exists between SES and age with respect to brain anatomy: Lower SES is associated with reduced cortical gray matter thickness in middle age. Conversely, younger and older adulthood do not exhibit consistent SES-related difference in the brain measures. The SES-brain relationships persist after controlling for measures of physical and mental health, cognitive ability, and participant demographics. Critically, an individual's childhood SES cannot account for the relationship between their current SES and functional network organization. These findings provide evidence that SES relates to the brain's functional network organization and anatomy across adult middle age, and that higher SES may be a protective factor against age-related brain decline. Copyright © 2018 the Author(s). Published by PNAS.

  16. Inflammation and oxidative stress biomarkers in neonatal brain hypoxia and prediction of adverse neurological outcome: a review

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    Marianna Varsami

    2013-06-01

    Full Text Available Despite advances in perinatal care, the outcome of newborns with hypoxic-ischemic encephalopathy is poor and the issue still remains challenging in neonatology. The use of an easily approachable and practical biomarker not only could identify neonates with severe brain damage and subsequent adverse outcome, but could also target the group of infants that would benefit from a neuroprotective intervention. Recent studies have suggested interleukin-1b, interleukin-6, tumour necrosis alpha (TNF-a and neuron specific enolase (NSE to be potential biomarkers of brain damage in asphyxiated newborns. S100B, lactate dehydrogenase, nitrated albumin-nitrotyrosine, adrenomedullin, activin-A, non protein bound iron, isoprostanes, vascular endothelial growth factor and metalloproteinases have also been proposed by single-centre studies to play a similar role in the field. With this review we aim to provide an overview of existing data in the literature regarding biomarkers for neonatal brain damage.

  17. Oxidative stress in obstructive sleep apnea and intermittent hypoxia--revisited--the bad ugly and good: implications to the heart and brain.

    Science.gov (United States)

    Lavie, Lena

    2015-04-01

    Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is linked with increased reactive oxygen species/reactive nitrogen species (ROS/RNS) and oxidative stress, which adversely affect the associated cardio-/cerebro-vascular disease in OSA. Yet, animal and a small number of human studies support activation of cardio-/cerebro-protective mechanisms as well. ROS/RNS are intricate and multifaceted molecules with multiple functions. At low-moderate concentrations ROS/RNS are considered "good", by regulating vital cellular functions. At higher levels, they are considered "bad" by promoting oxidative stress and damaging vital macromolecules through ischemia and reperfusion (I/R) injury. Subsequently, ROS/RNS can get "ugly" by eliciting sterile inflammation and a multitude of deadly pathologies. What makes ROS/RNS good, bad, or ugly? A dynamic interplay between a large number of factors determines the outcomes. These include the types of ROS/RNS produced, their quantity, duration, frequency, intracellular localization, micro-environmental antioxidants, as well as the genetic make-up and life style related variables. This review presents the currently available data on redox biology in physiological/pathophysiological conditions and in OSA/IH, in order to better understand the apparently contradictory findings on damage vs. repair. These findings are discussed within the context of the prevailing views on I/R associated ROS/RNS, and their potential implications to OSA. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Effect of equiosmolar solutions of hypertonic sodium lactate versus mannitol in craniectomy patients with moderate traumatic brain injury

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    Muhammad R. Ahmad

    2014-03-01

    Full Text Available Background: Brain relaxation and prevention from cerebral edema are essential in craniectomy. Osmotherapy with 20% mannitol are generally used to withdraw fluid from the brain parenchyma, however may cause hemodynamic fluctuation, due to increase diuresis. On the other hand 0.5 M hypertonic sodium lactate (HSL appeared as an alternative of osmotherapy. This study  aimed to observe the effect of hypertonic sodium lactate (HSL on brain relaxation, blood glucose level and hemodynamic variables in craniectomy due to moderate brain injury.Methods: A randomized controlled study of 42 cases with moderate brain injury, aged 18 - 65 years, ASA 1 - 3, between September-November 2012, was carried out. The patients were divided into group M (n = 21 that received 2.5 mL/kg 20% mannitol and group HSL that received 2.5 mL/kg 0.5M HSL. Mean arterial pressures (MAP, central venous pressures (CVP and urine output were measured after induction, and at 15, 30, 45, 60 min after infusion. Brain relaxation was assessed at a four-point scale after opening the duramater. Blood glucose levels were measured before induction and at 60 min after the infusion. Appropriate statistical tests were used for comparison. Unpaired t-test was used to compare hemodynamic and blood glucose level, and chi-square was used to compare brain relaxation.Results: MAP at 60 minute was significantly higher in HSL group than M group (81.66 ± 7.85 vs 74.33 ± 6.18 mmHg; p = 0.002. There was no difference in brain relaxation (p = 0.988. A significant increase in blood glucose level was observed in group HSL (17.95 ± 11.46 mg/dL; p = 0.001.Conclusion: Half-molar HSL was as effective as 20% mannitol in producing brain relaxation, with better hemodynamic stability and gave significant increase in blood glucose level.Keywords: brain relaxation, hemodynamic, hypertonic sodium lactate, mannitol, traumatic brain injury

  19. Effect of hyperbaric oxygen on lipid peroxidation and visual development in neonatal rats with hypoxia-ischemia brain damage.

    Science.gov (United States)

    Chen, Jing; Chen, Yan-Hui; Lv, Hong-Yan; Chen, Li-Ting

    2016-07-01

    The aim of the present study was to investigate the effect of hyperbaric oxygen (HBO) on lipid peroxidation and visual development in a neonatal rat model of hypoxic-ischemic brain damage (HIBD). The rat models of HIBD were established by delayed uterus dissection and were divided randomly into two groups (10 rats each): HIBD and HBO-treated HIBD (HIBD+HBO) group. Another 20 rats that underwent sham-surgery were also divided randomly into the HBO-treated and control groups. The rats that underwent HBO treatment received HBO (0.02 MPa, 1 h/day) 24 h after the surgery and this continued for 14 days. When rats were 4 weeks old, their flash visual evoked potentials (F-VEPs) were monitored and the ultrastructures of the hippocampus were observed under transmission electron microscope. The levels of superoxide dismutase (SOD) and malonyldialdehyde (MDA) in the brain tissue homogenate were detected by xanthine oxidase and the thiobarbituric acid colorimetric method. Compared with the control group, the ultrastructures of the pyramidal neurons in the hippocampal CA3 area were distorted, the latencies of F-VEPs were prolonged (P0.05). HBO enhances antioxidant capacity and reduces the ultrastructural damage induced by hypoxic-ischemia, which may improve synaptic reconstruction and alleviate immature brain damage to promote the habilitation of brain function.

  20. Effect of methylphenidate on ICU and hospital length of stay in patients with severe and moderate traumatic brain injury.

    Science.gov (United States)

    Moein, Houshang; Khalili, Hossein A; Keramatian, Kamyar

    2006-09-01

    Traumatic brain injury is one of the major causes of death and disability among young people. Methylphenidate, a neural stimulant and protective drug, which has been mainly used for childhood attention deficit/hyperactivity disorder, has shown some benefits in late psychosocial problems in patients with traumatic brain injury. Its effect on arousal and consciousness has been also revealed in the sub-acute phase of traumatic brain injury. We studied its effect on the acute phase of moderate and severe traumatic brain injury (TBI) in relation to the length of ICU and hospital admission. Severely and moderately TBI patients (according to inclusion and exclusion criteria) were randomized to treatment and control groups. The treatment group received methylphenidate 0.3mg/kg per dose PO BID by the second day of admission until the time of discharge, and the control group received a placebo. Admission information and daily Glasgow Coma Scale (GCS) were recorded. Medical, surgical, and discharge plans for patients were determined by the attending physician, blinded to the study. Forty patients with severe TBI (GCS = 5-8) and 40 moderately TBI patients (GCS = 9-12) were randomly divided into treatment and control groups on the day of admission. In the severely TBI patients, both hospital and ICU length of stay, on average, were shorter in the treatment group compared with the control group. In the moderately TBI patients while ICU stay was shorter in the treatment group, there was no significant reduction of the period of hospitalization. There were no significant differences between the treatment and control groups in terms of age, sex, post resuscitation GCS, or brain CT scan findings, in either severely or moderately TBI patients. Methylphenidate was associated with reductions in ICU and hospital length of stay by 23% in severely TBI patients (P = 0.06 for ICU and P = 0.029 for hospital stay time). However, in the moderately TBI patients who received methylphenidate

  1. Deficits in Facial Emotion Recognition Indicate Behavioral Changes and Impaired Self-Awareness after Moderate to Severe Traumatic Brain Injury

    OpenAIRE

    Spikman, Jacoba M.; Milders, Maarten V.; Visser-Keizer, Annemarie C.; Westerhof-Evers, Herma J.; Herben-Dekker, Meike; van der Naalt, Joukje

    2013-01-01

    Traumatic brain injury (TBI) is a leading cause of disability, specifically among younger adults. Behavioral changes are common after moderate to severe TBI and have adverse consequences for social and vocational functioning. It is hypothesized that deficits in social cognition, including facial affect recognition, might underlie these behavioral changes. Measurement of behavioral deficits is complicated, because the rating scales used rely on subjective judgement, often lack specificity and ...

  2. Are Patients Ready for ?EARLYSTIM?? Attitudes towards Deep Brain Stimulation among Female and Male Patients with Moderately Advanced Parkinson's Disease

    OpenAIRE

    Sperens, Maria; Hamberg, Katarina; Hariz, Gun-Marie

    2017-01-01

    Objective. To explore, in female and male patients with medically treated, moderately advanced Parkinson's disease (PD), their knowledge and reasoning about Deep Brain Stimulation (DBS). Methods. 23 patients with PD (10 women), aged 46- 70, were interviewed at a mean of 8 years after diagnosis, with open-ended questions concerning their reflections and considerations about DBS. The interviews were transcribed verbatim and analysed according to the difference and similarity technique in Ground...

  3. Acute Effects of Moderate and Strenuous Running on Trace Element Distribution in the Brain, Liver, and Spleen of Trained Rats

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    Kıvanç Ergen

    2013-03-01

    Full Text Available Objective: Trace elements such as manganese (Mn, cobalt (Co and chromium (Cr play key roles in metabolic reactions and are important in many physiological enzymatic processes. In this study, we aimed to investigate the acute effects of moderate and strenuous running (treadmill exercise on the levels of Mn, Co and Cr in the brain, liver, and spleen of trained rats. Study Design: Animal experiment. Material and Methods: Twenty-one Wistar-Albino adult male rats were used in the study. Rats were grouped as control group (no mandated exercise; n=8, moderate exercise group (30 min exercise duration; n=7, and strenuous exercise group (60 min exercise duration; n=6. The levels of Mn, Co, and Cr in the frontal lobe, temporal lobe, brain stem, liver, and spleen were determined by atomic absorption spectrophotometer. Results: Cr levels in liver of rats increased in parallel to the time course of running supporting the exercise training effect on the action of insulin. Compared to the control group, the level of Co significantly decreased in the brain stem of rats in the moderate exercise group (p=0.009 and in the frontal lobe of rats in the strenuous exercise group (p=0.004. In the strenuous exercise group, an examination of the brain stem revealed that the level of Mn significantly decreased (p=0.001, and levels of Co and Cr were apparently depleted to the extent that these elements were no longer detectable. Conclusion: A notable finding is that during or after single bout strenuous exercise, levels of Co decreased in the spleen and particularly decreased in the brain stem of regularly trained rats. From this study, it can be inferred that sportsmen should aware trace element disturbances among the body parts or depletion of some trace elements after single bout of chronic strenuous running exercise.

  4. 99mTc-HMPAO SPECT of the brain in mild to moderate traumatic brain injury patients: compared with CT--a prospective study.

    Science.gov (United States)

    Nedd, K; Sfakianakis, G; Ganz, W; Uricchio, B; Vernberg, D; Villanueva, P; Jabir, A M; Bartlett, J; Keena, J

    1993-01-01

    Single photon emission computed tomography (SPECT) with Technetium-99m hexamethyl propylenamine oxime (Tc-99m-HMPAO) was used in 20 patients with mild to moderate traumatic brain injury (TBI) to evaluate the effects of brain trauma on regional cerebral blood flow (rCBF). SPECT scan was compared with CT scan in 16 patients. SPECT showed intraparenchymal differences in rCBF more often than lesions diagnosed with CT scans (87.5% vs. 37.5%). In five of six patients with lesions in both modalities, the area of involvement was relatively larger on SPECT scans than on CT scans. Contrecoup changes were seen in five patients on SPECT alone, two patients with CT alone and one patient had contrecoup lesions on CT and SPECT. Of the eight patients (50%) with skull fractures, seven (43.7%) had rCBF findings on SPECT scan and five (31.3%) demonstrated decrease in rCBF in brain underlying the fracture. All these patients with fractures had normal brain on CT scans. Conversely, extra-axial lesions and fractures evident on CT did not visualize on SPECT, but SPECT demonstrated associated changes in rCBF. Although there is still lack of clinical and pathological correlation, SPECT appears to be a promising method for a more sensitive evaluation of axial lesions in patients with mild to moderate TBI.

  5. The relationship of resting cerebral blood flow and brain activation during a social cognition task in adolescents with chronic moderate to severe traumatic brain injury: a preliminary investigation.

    Science.gov (United States)

    Newsome, Mary R; Scheibel, Randall S; Chu, Zili; Hunter, Jill V; Li, Xiaoqi; Wilde, Elisabeth A; Lu, Hanzhang; Wang, Zhiyue J; Lin, Xiaodi; Steinberg, Joel L; Vasquez, Ana C; Cook, Lori; Levin, Harvey S

    2012-05-01

    Alterations in cerebrovascular function are evident acutely in moderate to severe traumatic brain injury (TBI), although less is known about their chronic effects. Adolescent and adult patients with moderate to severe TBI have been reported to demonstrate diffuse activation throughout the brain during functional magnetic resonance imaging (fMRI). Because fMRI is a measure related to blood flow, it is possible that any deficits in blood flow may alter activation. An arterial spin labeling (ASL) perfusion sequence was performed on seven adolescents with chronic moderate to severe TBI and seven typically developing (TD) adolescents during the same session in which they had performed a social cognition task during fMRI. In the TD group, prefrontal CBF was positively related to prefrontal activation and negatively related to non-prefrontal, posterior, brain activation. This relationship was not seen in the TBI group, who demonstrated a greater positive relationship between prefrontal CBF and non-prefrontal activation than the TD group. An analysis of CBF data independent of fMRI showed reduced CBF in the right non-prefrontal region (pflow throughout the right hemisphere in healthy brains. However, the TBI group demonstrated a positive association with activation constrained to the right non-prefrontal region. These data suggest a relationship between impaired non-prefrontal CBF and the presence of non-prefrontal extra-activation, where the region with more limited blood flow is associated with activation limited to that region. In a secondary analysis, pathology associated with hyperintensities on T2-weighted FLAIR imaging over the whole brain was related to whole brain activation, revealing a negative relationship between lesion volume and frontal activation, and a positive relationship between lesion volume and posterior activation. These preliminary data, albeit collected with small sample sizes, suggest that reduced non-prefrontal CBF, and possibly pathological

  6. EFFECTS OF CANNABIDIOL PLUS HYPOTHERMIA ON SHORT-TERM NEWBORN PIG BRAIN DAMAGE AFTER ACUTE HYPOXIA-ISCHEMIA

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    Hector Lafuente

    2016-07-01

    Full Text Available Background: Hypothermia is standard treatment for neonatal encephalopathy, but near 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms to hypothermia and would improve neuroprotection. Cannabidiol could be a good candidate.Objective: To test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets.Methods: Hypoxic-ischemic animals were randomized to receive 30 min after the insult: 1 normothermia- and vehicle-treated group; 2 normothermia- and cannabidiol-treated group; 3 hypothermia- and vehicle-treated group; and 4 hypothermia- and cannabidiol-treated group. Six hours after treatment, brains were processed to qualify the number of neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate and excitotoxicity (glutamate/Nacetyl-aspartate. Western blot studies were performed to quantify protein nitrosylation (oxidative stress and expression of caspase-3 (apoptosis and TNFα (inflammation.Results: Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on histological damage, was greater than either hypothermia or cannabidiol alone.Conclusion: Cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage.

  7. Causes and Consequences of Treatment Variation in Moderate and Severe Traumatic Brain Injury : A Multicenter Study

    NARCIS (Netherlands)

    Criossen, Maryse C.; Polinder, Suzanne; Andriessen, Teuntje M.; van der Naalt, Joukje; Haitsma, Iain; Horn, Janneke; Franschman, Gaby; Vos, Pieter E.; Steyerberg, Ewout W.; Lingsma, Hester

    Objectives: Although guidelines have been developed to standardize care in traumatic brain injury, between-center variation in treatment approach has been frequently reported. We examined variation in treatment for traumatic brain injury by assessing factors influencing treatment and the association

  8. Moderate Ethanol Preconditioning of Rat Brain Cultures Engenders Neuroprotection Against Dementia-Inducing Neuroinflammatory Proteins: Possible Signaling Mechanisms

    Science.gov (United States)

    Neafsey, Edward J.; Wang, Kewei; Achille, Nicholas J.; Mitchell, Robert M.; Sivaswamy, Sreevidya

    2010-01-01

    There is no question that chronic alcohol (ethanol) abuse, a leading worldwide problem, causes neuronal dysfunction and brain damage. However, various epidemiologic studies in recent years have indicated that in comparisons with abstainers or never-drinkers, light/moderate alcohol consumers have lower risks of age-dependent cognitive decline and/or dementia, including Alzheimer’s disease (AD). Such reduced risks have been variously attributed to favorable circulatory and/or cerebrovascular effects of moderate ethanol intake, but they could also involve ethanol “preconditioning” phenomena in brain glia and neurons. Here we summarize our experimental studies showing that moderate ethanol preconditioning (MEP; 20–30 mM ethanol) of rat brain cultures prevents neurodegeneration due to β-amyloid, an important protein implicated in AD, and to other neuroinflammatory proteins such as gp120, the human immunodeficiency virus 1 envelope protein linked to AIDS dementia. The MEP neuroprotection is associated with suppression of neurotoxic protein-evoked initial increases in [Ca+2]i and proinflammatory mediators—e.g., superoxide anion, arachidonic acid, and glutamate. Applying a sensor → transducer → effector model to MEP, we find that onset of neuroprotection correlates temporally with elevations in “effector” heat shock proteins (HSP70, HSP27, and phospho-HSP27). The effector status of HSPs is supported by the fact that inhibiting HSP elevations due to MEP largely restores gp120-induced superoxide potentiation and subsequent neurotoxicity. As upstream mediators, synaptic N-methyl-d-aspartate receptors may be initial prosurvival sensors of ethanol, and protein kinase C epsilon and focal adhesion kinase are likely transducers during MEP that are essential for protective HSP elevations. Regarding human consumption, we speculate that moderate ethanol intake might counter incipient cognitive deterioration during advanced aging or AD by exerting preconditioning

  9. Moderate ethanol preconditioning of rat brain cultures engenders neuroprotection against dementia-inducing neuroinflammatory proteins: possible signaling mechanisms.

    Science.gov (United States)

    Collins, Michael A; Neafsey, Edward J; Wang, Kewei; Achille, Nicholas J; Mitchell, Robert M; Sivaswamy, Sreevidya

    2010-06-01

    There is no question that chronic alcohol (ethanol) abuse, a leading worldwide problem, causes neuronal dysfunction and brain damage. However, various epidemiologic studies in recent years have indicated that in comparisons with abstainers or never-drinkers, light/moderate alcohol consumers have lower risks of age-dependent cognitive decline and/or dementia, including Alzheimer's disease (AD). Such reduced risks have been variously attributed to favorable circulatory and/or cerebrovascular effects of moderate ethanol intake, but they could also involve ethanol "preconditioning" phenomena in brain glia and neurons. Here we summarize our experimental studies showing that moderate ethanol preconditioning (MEP; 20-30 mM ethanol) of rat brain cultures prevents neurodegeneration due to beta-amyloid, an important protein implicated in AD, and to other neuroinflammatory proteins such as gp120, the human immunodeficiency virus 1 envelope protein linked to AIDS dementia. The MEP neuroprotection is associated with suppression of neurotoxic protein-evoked initial increases in [Ca(+2)](i) and proinflammatory mediators--e.g., superoxide anion, arachidonic acid, and glutamate. Applying a sensor --> transducer --> effector model to MEP, we find that onset of neuroprotection correlates temporally with elevations in "effector" heat shock proteins (HSP70, HSP27, and phospho-HSP27). The effector status of HSPs is supported by the fact that inhibiting HSP elevations due to MEP largely restores gp120-induced superoxide potentiation and subsequent neurotoxicity. As upstream mediators, synaptic N-methyl-d-aspartate receptors may be initial prosurvival sensors of ethanol, and protein kinase C epsilon and focal adhesion kinase are likely transducers during MEP that are essential for protective HSP elevations. Regarding human consumption, we speculate that moderate ethanol intake might counter incipient cognitive deterioration during advanced aging or AD by exerting preconditioning

  10. A functional brain-derived neurotrophic factor (BDNF) gene variant increases the risk of moderate-to-severe allergic rhinitis.

    Science.gov (United States)

    Jin, Peng; Andiappan, Anand Kumar; Quek, Jia Min; Lee, Bernett; Au, Bijin; Sio, Yang Yie; Irwanto, Astrid; Schurmann, Claudia; Grabe, Hans Jörgen; Suri, Bani Kaur; Matta, Sri Anusha; Westra, Harm-Jan; Franke, Lude; Esko, Tonu; Sun, Liangdan; Zhang, Xuejun; Liu, Hong; Zhang, Furen; Larbi, Anis; Xu, Xin; Poidinger, Michael; Liu, Jianjun; Chew, Fook Tim; Rotzschke, Olaf; Shi, Li; Wang, De Yun

    2015-06-01

    Brain-derived neurotrophic factor (BDNF) is a secretory protein that has been implicated in the pathogenesis of allergic rhinitis (AR), atopic asthma, and eczema, but it is currently unknown whether BDNF polymorphisms influence susceptibility to moderate-to-severe AR. We sought to identify disease associations and the functional effect of BDNF genetic variants in patients with moderate-to-severe AR. Tagging single nucleotide polymorphisms (SNPs) spanning the BDNF gene were selected from the human HapMap Han Chinese from Beijing (CHB) data set, and associations with moderate-to-severe AR were assessed in 2 independent cohorts of Chinese patients (2216 from Shandong province and 1239 living in Singapore). The functional effects of the BDNF genetic variants were determined by using both in vitro and ex vivo assays. The tagging SNP rs10767664 was significantly associated with the risk of moderate-to-severe AR in both Singapore Chinese (P = .0017; odds ratio, 1.324) and Shandong Chinese populations (P = .039; odds ratio, 1.180). The coding nonsynonymous SNP rs6265 was in perfect linkage with rs10767664 and conferred increased BDNF protein secretion by a human cell line in vitro. Subjects bearing the AA genotype of rs10767664 exhibited increased risk of moderate-to-severe AR and displayed increased BDNF protein and total IgE levels in plasma. Using a large-scale expression quantitative trait locus study, we demonstrated that BDNF SNPs are significantly associated with altered BDNF concentrations in peripheral blood. A common genetic variant of the BDNF gene is associated with increased risk of moderate-to-severe AR, and the AA genotype is associated with increased BDNF mRNA levels in peripheral blood. Together, these data indicate that functional BDNF gene variants increase the risk of moderate-to-severe AR. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  11. Hypoxia: From Placental Development to Fetal Programming.

    Science.gov (United States)

    Fajersztajn, Lais; Veras, Mariana Matera

    2017-10-16

    Hypoxia may influence normal and different pathological processes. Low oxygenation activates a variety of responses, many of them regulated by hypoxia-inducible factor 1 complex, which is mostly involved in cellular control of O 2 consumption and delivery, inhibition of growth and development, and promotion of anaerobic metabolism. Hypoxia plays a significant physiological role in fetal development; it is involved in different embryonic processes, for example, placentation, angiogenesis, and hematopoiesis. More recently, fetal hypoxia has been associated directly or indirectly with fetal programming of heart, brain, and kidney function and metabolism in adulthood. In this review, the role of hypoxia in fetal development, placentation, and fetal programming is summarized. Hypoxia is a basic mechanism involved in different pregnancy disorders and fetal health developmental complications. Although there are scientific data showing that hypoxia mediates changes in the growth trajectory of the fetus, modulates gene expression by epigenetic mechanisms, and determines the health status later in adulthood, more mechanistic studies are needed. Furthermore, if we consider that intrauterine hypoxia is not a rare event, and can be a consequence of unavoidable exposures to air pollution, nutritional deficiencies, obesity, and other very common conditions (drug addiction and stress), the health of future generations may be damaged and the incidence of some diseases will markedly increase as a consequence of disturbed fetal programming. Birth Defects Research 109:1377-1385, 2017.© 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  12. Social communication features in children following moderate to severe acquired brain injury: a cross-sectional pilot study.

    Science.gov (United States)

    Breau, Lynn M; Clark, Brenda; Scott, Ori; Wilkes, Courtney; Reynolds, Shawn; Ricci, Florencia; Sonnenberg, Lyn; Zwaigenbaum, Lonnie; Rashid, Marghalara; Goez, Helly R

    2015-04-01

    We compared the social communication deficits of children with moderate to severe acquired brain injury or autism spectrum disorder, while accounting for the role of attention-deficit hyperactivity disorder (ADHD) symptoms. Parents of 20 children aged 6 to 10 years (10 acquired brain injury; 10 autism spectrum disorder) completed the Social Communication Questionnaire, and Conners 3 Parent Short. A multivariate analysis of covariance revealed significant differences between groups in Social Communication Questionnaire restricted repetitive behavior scores, but not reciprocal social interaction or social communication. Multiple linear regressions indicated diagnosis did not predict reciprocal social interaction or social communication scores and that Conners 3 Parent Short Form hyperactivity scores were the strongest predictor of Social Communication Questionnaire reciprocal social interaction scores after accounting for age and Intelligence Quotient. The lack of difference in social communication deficits between groups may help in understanding the pathophysiology underlying the behavioral consequences of acquired brain injury. The link between hyperactivity and reciprocal interaction suggests that targeting hyperactivity may improve social outcomes in children following acquired brain injury. © The Author(s) 2014.

  13. Community integration 2 years after moderate and severe traumatic brain injury.

    Science.gov (United States)

    Sandhaug, Maria; Andelic, Nada; Langhammer, Birgitta; Mygland, Aase

    2015-01-01

    The aim of this study was to examine community integration by the Community Integration Questionnaire (CIQ) 2 years after injury in a divided TBI sample of moderately and severely injured patients. The second aim was to identify social-demographic, injury-related and rehabilitation associated predictors of CIQ. A cohort study. Outpatient follow-up. Fifty-seven patients with moderate (n = 21) or severe (n = 36) TBI were examined with the Community Integration Questionnaire (CIQ) at 2 years after injury. Possible predictors were analysed in a regression model using CIQ total score at 2 years as the outcome measure. The Community Integration Questionnaire. At 2 years follow-up, there was significant difference between the moderately and severely injured patients in the productivity scores (p productivity level than the severely injured patients. Marital status, injury severity and rehabilitation after injury were associated with community integration 2 years after TBI.

  14. Medical aspects of pediatric rehabilitation after moderate to severe traumatic brain injury.

    Science.gov (United States)

    Cantore, Lisa; Norwood, Kenneth; Patrick, Peter

    2012-01-01

    Recovery from severe traumatic brain injury (TBI) is prolonged, complicated and challenging. Medical rehabilitation is the bridge from acute medical care and stabilization to community reintegration. The process of caring for the recovering brain introduces unknown challenges of neural plasticity with demands to restore and to also move the child and family back to the developmental trajectory they once knew. While the ongoing focus is to maintain and advance medical stability, co- morbid conditions are addressed, and a plan for ongoing health is established. While no one manuscript can cover all of the medical aspects, this article will present in a "systems review" manner the most challenging and demanding medical conditions that children may confront following severe brain injury.

  15. Effects of platelet and plasma transfusion on outcome in traumatic brain injury patients with moderate bleeding diatheses.

    Science.gov (United States)

    Anglin, Catherine O; Spence, Jeffrey S; Warner, Matthew A; Paliotta, Christopher; Harper, Caryn; Moore, Carol; Sarode, Ravi; Madden, Christopher; Diaz-Arrastia, Ramon

    2013-03-01

    Object Coagulopathy and thrombocytopenia are common after traumatic brain injury (TBI), yet transfusion thresholds for mildly to moderately abnormal ranges of international normalized ratio and platelet count remain controversial. This study evaluates associations between fresh frozen plasma (FFP) and platelet transfusions with long-term functional outcome and survival in TBI patients with moderate hemostatic laboratory abnormalities. Methods This study is a retrospective review of prospectively collected data of patients with mild to severe TBI. Data include patient demographics, several initial injury severity metrics, daily laboratory values, Glasgow Outcome Score- Extended (GOSE) scores, Functional Status Examination (FSE) scores, and survival to 6 months. Correlations were evaluated between these variables and transfusion of FFP, platelets, packed red blood cells (RBCs), cryoprecipitate, recombinant factor VIIa, and albumin. Ordinal regression was performed to account for potential confounding variables to further define relationships between transfusion status and long-term outcome. By analyzing collected data, mild to moderate coagulopathy was defined as an international normalized ratio 1.4-2.0, moderate thrombocytopenia as platelet count 50 × 10(9)/L to 107 × 10(9)/L, and moderate anemia as 21%-30% hematocrit. Results In patients with mild to moderate laboratory hematological abnormalities, univariate analysis shows significant correlations between poor outcome scores and FFP, platelet, or packed RBC transfusion; the volume of FFP or packed RBCs transfused also correlated with poor outcome. Several measures of initial injury and laboratory abnormalities also correlated with poor outcome. Patient age, initial Glasgow Coma Scale score, and highest recorded serum sodium were included in the ordinal regression model using backward variable selection. In the moderate coagulopathy subgroup, patients transfused with FFP were more likely to have a lower GOSE

  16. The Prognostic Value of MRI in Moderate and Severe Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Haghbayan, Hourmazd; Boutin, Amélie; Laflamme, Mathieu; Lauzier, François; Shemilt, Michèle; Moore, Lynne; Zarychanski, Ryan; Douville, Vincent; Fergusson, Dean; Turgeon, Alexis F

    2017-12-01

    Traumatic brain injury is a major cause of death and disability, yet many predictors of outcome are not precise enough to guide initial clinical decision-making. Although increasingly used in the early phase following traumatic brain injury, the prognostic utility of MRI remains uncertain. We thus undertook a systematic review and meta-analysis of studies evaluating the predictive value of acute MRI lesion patterns for discriminating clinical outcome in traumatic brain injury. MEDLINE, EMBASE, BIOSIS, and CENTRAL from inception to November 2015. Studies of adults who had MRI in the acute phase following moderate or severe traumatic brain injury. Our primary outcomes were all-cause mortality and the Glasgow Outcome Scale. Two authors independently performed study selection and data extraction. We calculated pooled effect estimates with a random effects model, evaluated the risk of bias using a modified version of Quality in Prognostic Studies and determined the strength of evidence with the Grading of Recommendations, Assessment, Development, and Evaluation. We included 58 eligible studies, of which 27 (n = 1,652) contributed data to meta-analysis. Brainstem lesions were associated with all-cause mortality (risk ratio, 1.78; 95% CI, 1.01-3.15; I = 43%) and unfavorable Glasgow Outcome Scale (risk ratio, 2.49; 95% CI, 1.72-3.58; I = 81%) at greater than or equal to 6 months. Diffuse axonal injury patterns were associated with an increased risk of unfavorable Glasgow Outcome Scale (risk ratio, 2.46; 95% CI, 1.06-5.69; I = 74%). MRI scores based on lesion depth demonstrated increasing risk of unfavorable neurologic outcome as more caudal structures were affected. Most studies were at high risk of methodological bias. MRI following traumatic brain injury yields important prognostic information, with several lesion patterns significantly associated with long-term survival and neurologic outcome. Given the high risk of bias in the current body of literature, large well

  17. Oxytocin effects on complex brain networks are moderated by experiences of maternal love withdrawal

    NARCIS (Netherlands)

    Riem, M.M.E.; van IJzendoorn, M.H.; Tops, M.; Boksem, M.A.S.; Rombouts, S.A.R.B.; Bakermans-Kranenburg, M.J.

    2013-01-01

    The neuropeptide oxytocin has been implicated in a variety of social processes. However, recent studies indicate that oxytocin does not enhance prosocial behavior in all people in all circumstances. Here, we investigate effects of intranasal oxytocin administration on intrinsic functional brain

  18. Blood biomarkers in moderate-to-severe traumatic brain injury: potential utility of a multimarker approach in characterizing outcome

    Directory of Open Access Journals (Sweden)

    Alex P Di Battista

    2015-05-01

    Full Text Available Background: Blood biomarkers are valuable tools for elucidating the complex cellular and molecular mechanisms underlying traumatic brain injury (TBI pathophysiology. Profiling distinct classes of biomarkers could aid in the identification and characterization of both initial injury and secondary pathological processes. The purpose of this study was to characterize the prognostic performance, both individually and combined, of a recently developed multimarker panel of circulating biomarkers reflecting specific pathogenic mechanisms including neuroinflammation, oxidative damage and neuroregeneration, in moderate-to-severe TBI patients. Materials and Methods: Peripheral blood samples were drawn from 85 isolated TBI patients (n=60 severe, n=25 moderate at hospital admission, 6-, 12-, and 24-h post-injury. Mortality and neurological outcome were assessed using the extended Glasgow Outcome Score (GOSE. A multiplex platform was designed on MULTI-SPOT® plates to simultaneously analyze human plasma levels of s100 calcium binding protein (s100B, glial fibrillary acidic protein (GFAP, neuron specific enolase (NSE, brain derived neurotrophic factor (BDNF, monocyte chemoattractant protein (MCP-1, intercellular adhesion molecule (ICAM-5, and peroxiredoxin (PRDX-6. Results: Unfavorable outcome was associated with elevations in s100B, GFAP and MCP-1. Mortality was related to differences in 6 of 7 markers analyzed. Combined admission concentrations of s100B, GFAP and MCP-1 were able to discriminate favorable versus unfavorable outcome (AUC = 0.83, and survival versus death (AUC = 0.87, although not significantly better than s100B alone (AUC = 0.82 and 0.86, respectively. Conclusion: The multimarker panel of TBI-related biomarkers performed well in discriminating between unfavorable and favorable outcomes in the acute period after moderate-to-severe TBI. However, these combined biomarkers did not outperform s100B alone.

  19. Moderating effect of APOE ε4 on the relationship between sleep-wake cycle and brain β-amyloid.

    Science.gov (United States)

    Hwang, Jeong Yeon; Byun, Min Soo; Choe, Young Min; Lee, Jun Ho; Yi, Dahyun; Choi, Jae-Won; Hwang, Su Hwan; Lee, Yu Jin; Lee, Dong Young

    2018-03-27

    To clarify the relationships between sleep-wake cycle and cerebral β-amyloid (Aβ) deposition in cognitively normal (CN) older adults, focusing primarily on the moderating effects of the APOE ε4 allele. The present study included 133 CN older adults who participated in the Korean Brain Aging Study for Early Diagnosis & Prediction of Alzheimer's Disease cohort. All participants underwent [ 11 C] Pittsburgh compound B-PET imaging to quantify Aβ deposition in the brain and blood sampling for APOE genotyping. Sleep and circadian parameters were measured using actigraphy for 8 consecutive days. The APOE ε4 allele had moderating effects on the associations of sleep latency (SL), mesor, and acrophase with cerebral Aβ deposition, and the interactions between APOE ε4 status and SL and between APOE ε4 status and acrophase remained significant after adjusting for multiple comparisons. In APOE ε4 noncarriers, shorter SL, higher mesor, and advanced acrophase were associated with Aβ positivity. In contrast, APOE ε4 carriers showed a relationship between delayed acrophase and Aβ accumulation that approached but did not reach significance. After the Bonferroni correction, the associations of shorter SL and higher mesor with Aβ positivity remained significant for APOE ε4 noncarriers. Our findings suggest that the APOE ε4 allele may act as a moderator in the relationship between the sleep-wake cycle and Aβ accumulation in CN older adults. Thus, APOE ε4 status needs to be considered as a key factor when designing related research or interventions. © 2018 American Academy of Neurology.

  20. Functional outcome and health-related quality of life 10 years after moderate-to-severe traumatic brain injury.

    Science.gov (United States)

    Andelic, N; Hammergren, N; Bautz-Holter, E; Sveen, U; Brunborg, C; Røe, C

    2009-07-01

    To describe the functional outcome and health-related quality of life (HRQL) 10 years after moderate-to-severe traumatic brain injury (TBI). A retrospective, population-based study of 62 survivors of working-age with moderate-to-severe TBI injured in 1995/1996, and hospitalized at the Trauma Referral Center in Eastern Norway. Functional status was measured by the Glasgow Outcome Scale-Extended (GOS-E). HRQL was assessed by the SF-36 questionnaire. The mean current-age was 40.8 years. The frequency of epilepsy was 19% and the depression rate 31%. A majority had good recovery (48%) or moderate disability (44%). Employment rate was 58%. Functional and employment status were associated with initial injury severity in contrast to HRQL. Study patients had significantly lower scores in all SF-36 dimensions when compared with the general Norwegian population. At 10-years follow-up, our study population is still in their most productive years and affected domains should be considered in long-term follow-up and intervention programs.

  1. Sex differences in behavioral outcome following neonatal hypoxia ischemia: insights from a clinical meta-analysis and a rodent model of induced hypoxic ischemic brain injury.

    Science.gov (United States)

    Smith, Amanda L; Alexander, Michelle; Rosenkrantz, Ted S; Sadek, Mona Lisa; Fitch, R Holly

    2014-04-01

    Hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) is one of the most common injuries among preterm infants and term infants with birth complications. Both populations show cognitive/behavioral deficits, including impairments in sensory, learning/memory, and attention domains. Clinical data suggests a sex difference in HI outcomes, with males exhibiting more severe cognitive/behavioral deficits relative to matched females. Our laboratory has also reported more severe behavioral deficits among male rats with induced HI relative to females with comparable injury (Hill et al., 2011a,b). The current study initially examined published clinical studies from the past 20years where long-term IQ outcome scores for matched groups of male and female premature infants were reported separately (IQ being the most common outcome measure). A meta-analysis revealed a female "advantage," as indicated by significantly better scores on performance and full scale IQ (but not verbal IQ) for premature females. We then utilized a rodent model of neonatal HI injury to assess sham and postnatal day 7 (P7) HI male and female rats on a battery of behavioral tasks. Results showed expected deficits in HI male rats, but also showed task-dependent sex differences, with HI males having significantly larger deficits than HI females on some tasks but equivalent deficits on other tasks. In contrast to behavioral results, post mortem neuropathology associated with HI was comparable across sex. These findings suggest: 1) neonatal female "protection" in some behavioral domains, as indexed by superior outcome following early injury relative to males; and 2) female protection may entail sex-specific plasticity or compensation, rather than a reduction in gross neuropathology. Further exploration of the mechanisms underlying this sex effect could aid in neuroprotection efforts for at-risk neonates in general, and males in particular. Moreover, our current report of comparable anatomical

  2. The moderating effects of sex and age on the association between traumatic brain injury and harmful psychological correlates among adolescents.

    Directory of Open Access Journals (Sweden)

    Gabriela Ilie

    Full Text Available Although it is well established that sex is a risk factor in acquiring a traumatic brain injury (TBI among adolescents, it has not been established whether it also moderates the influence of other TBI psychological health correlates.Data were derived from a 2011 population-based cross-sectional school survey, which included 9,288 Ontario 7th-12th graders who completed anonymous self-administered questionnaires in classrooms. Response rate was 62%. Preliminary analyses found no evidence of nonresponse bias in the reporting of TBI. TBI was defined as a hit or blow to the head that resulted in a 5 minutes loss of consciousness or at least one overnight hospitalization due to symptoms associated with it. Reports of lifetime TBI were more common among males than females (23.1%, 95% CI: 20.5, 25.8 vs. 17.1%, 95% CI: 14.7, 19.8. Thirteen correlates were examined and included cigarette smoking, elevated psychological distress, suicide ideation, bully victimization (at school, as well as cyber bullying, bullying others, cannabis use, cannabis dependence and drug use problems, physical injuries, daily smoking, drinking alcohol, binge drinking, use of cannabis, and poor academic performance. Among the outcomes examined, sex moderated the relationship between lifetime TBI and cigarette smoking. In addition, sex and age jointly moderated the relationship between lifetime TBI and daily smoking, alcohol use and physical injuries. Late adolescent males who reported lifetime TBI, relative to females, displayed elevated daily smoking and injuries, whereas their females counterparts displayed elevated past year drinking. Possible bias related to self-report procedures and the preclusion of causal inferences due to the cross-sectional nature of the data are limitations of this study.TBI differences in outcomes need to be assessed for potential moderating effects of sex and age. Results have important implications for more tailored injury prevention efforts.

  3. The moderating effects of sex and age on the association between traumatic brain injury and harmful psychological correlates among adolescents.

    Science.gov (United States)

    Ilie, Gabriela; Adlaf, Edward M; Mann, Robert E; Boak, Angela; Hamilton, Hayley; Asbridge, Mark; Colantonio, Angela; Turner, Nigel E; Rehm, Jürgen; Cusimano, Michael D

    2014-01-01

    Although it is well established that sex is a risk factor in acquiring a traumatic brain injury (TBI) among adolescents, it has not been established whether it also moderates the influence of other TBI psychological health correlates. Data were derived from a 2011 population-based cross-sectional school survey, which included 9,288 Ontario 7th-12th graders who completed anonymous self-administered questionnaires in classrooms. Response rate was 62%. Preliminary analyses found no evidence of nonresponse bias in the reporting of TBI. TBI was defined as a hit or blow to the head that resulted in a 5 minutes loss of consciousness or at least one overnight hospitalization due to symptoms associated with it. Reports of lifetime TBI were more common among males than females (23.1%, 95% CI: 20.5, 25.8 vs. 17.1%, 95% CI: 14.7, 19.8). Thirteen correlates were examined and included cigarette smoking, elevated psychological distress, suicide ideation, bully victimization (at school, as well as cyber bullying), bullying others, cannabis use, cannabis dependence and drug use problems, physical injuries, daily smoking, drinking alcohol, binge drinking, use of cannabis, and poor academic performance. Among the outcomes examined, sex moderated the relationship between lifetime TBI and cigarette smoking. In addition, sex and age jointly moderated the relationship between lifetime TBI and daily smoking, alcohol use and physical injuries. Late adolescent males who reported lifetime TBI, relative to females, displayed elevated daily smoking and injuries, whereas their females counterparts displayed elevated past year drinking. Possible bias related to self-report procedures and the preclusion of causal inferences due to the cross-sectional nature of the data are limitations of this study. TBI differences in outcomes need to be assessed for potential moderating effects of sex and age. Results have important implications for more tailored injury prevention efforts.

  4. Utility of fractional anisotropy imaging analyzed by statistical parametric mapping for detecting minute brain lesions in chronic-stage patients who had mild or moderate traumatic brain injury

    International Nuclear Information System (INIS)

    Asano, Yoshitaka; Shinoda, Jun; Okumura, Ayumi; Aki, Tatsuki; Takenaka, Shunsuke; Miwa, Kazuhiro; Yamada, Mikito; Ito, Takeshi; Yokohama, Kazutoshi

    2012-01-01

    Diffusion tensor imaging (DTI) has recently evolved as valuable technique to investigate diffuse axonal injury (DAI). This study examined whether fractional anisotropy (FA) images analyzed by statistical parametric mapping (FA-SPM images) are superior to T 2 *-weighted gradient recalled echo (T2*GRE) images or fluid-attenuated inversion recovery (FLAIR) images for detecting minute lesions in traumatic brain injury (TBI) patients. DTI was performed in 25 patients with cognitive impairments in the chronic stage after mild or moderate TBI. The FA maps obtained from the DTI were individually compared with those from age-matched healthy control subjects using voxel-based analysis and FA-SPM images (p<0.001). Abnormal low-intensity areas on T2*GRE images (T2* lesions) were found in 10 patients (40.0%), abnormal high-intensity areas on FLAIR images in 4 patients (16.0%), and areas with significantly decreased FA on FA-SPM image in 16 patients (64.0%). Nine of 10 patients with T2* lesions had FA-SPM lesions. FA-SPM lesions topographically included most T2* lesions in the white matter and the deep brain structures, but did not include T2* lesions in the cortex/near-cortex or lesions containing substantial hemosiderin regardless of location. All 4 patients with abnormal areas on FLAIR images had FA-SPM lesions. FA-SPM imaging is useful for detecting minute lesions because of DAI in the white matter and the deep brain structures, which may not be visualized on T2*GRE or FLAIR images, and may allow the detection of minute brain lesions in patients with post-traumatic cognitive impairment. (author)

  5. Unsupervised categorization with individuals diagnosed as having moderate traumatic brain injury: Over-selective responding.

    Science.gov (United States)

    Edwards, Darren J; Wood, Rodger

    2016-01-01

    This study explored over-selectivity (executive dysfunction) using a standard unsupervised categorization task. Over-selectivity has been demonstrated using supervised categorization procedures (where training is given); however, little has been done in the way of unsupervised categorization (without training). A standard unsupervised categorization task was used to assess levels of over-selectivity in a traumatic brain injury (TBI) population. Individuals with TBI were selected from the Tertiary Traumatic Brain Injury Clinic at Swansea University and were asked to categorize two-dimensional items (pictures on cards), into groups that they felt were most intuitive, and without any learning (feedback from experimenter). This was compared against categories made by a control group for the same task. The findings of this study demonstrate that individuals with TBI had deficits for both easy and difficult categorization sets, as indicated by a larger amount of one-dimensional sorting compared to control participants. Deficits were significantly greater for the easy condition. The implications of these findings are discussed in the context of over-selectivity, and the processes that underlie this deficit. Also, the implications for using this procedure as a screening measure for over-selectivity in TBI are discussed.

  6. Oxytocin effects on complex brain networks are moderated by experiences of maternal love withdrawal.

    Science.gov (United States)

    Riem, Madelon M E; van IJzendoorn, Marinus H; Tops, Mattie; Boksem, Maarten A S; Rombouts, Serge A R B; Bakermans-Kranenburg, Marian J

    2013-10-01

    The neuropeptide oxytocin has been implicated in a variety of social processes. However, recent studies indicate that oxytocin does not enhance prosocial behavior in all people in all circumstances. Here, we investigate effects of intranasal oxytocin administration on intrinsic functional brain connectivity with resting state functional magnetic resonance imaging. Participants were 42 women who received a nasal spray containing either 16 IU of oxytocin or a placebo and reported how often their mother used love withdrawal as a disciplinary strategy involving withholding love and affection after a failure or misbehavior. We found that oxytocin changes functional connectivity between the posterior cingulate cortex (PCC) and the brainstem. In the oxytocin group there was a positive connectivity between these regions, whereas the placebo group showed negative connectivity. In addition, oxytocin induced functional connectivity changes between the PCC, the cerebellum and the postcentral gyrus, but only for those participants who experienced low levels of maternal love withdrawal. We speculate that oxytocin enhances prosocial behavior by influencing complex brain networks involved in self-referential processing and affectionate touch, most prominently in individuals with supportive family backgrounds. Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.

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

    Science.gov (United States)

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

    2008-01-01

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

  8. Autobiographical memory and episodic future thinking after moderate to severe traumatic brain injury

    DEFF Research Database (Denmark)

    Rasmussen, Katrine Willemoes; Berntsen, Dorthe

    2014-01-01

    Converging evidence suggests that autobiographical memory and episodic future thinking share a common neurocognitive basis. Although previous research has shown that traumatic brain injury (TBI) can impair the ability to remember the personal past, episodic future thinking has not previously been...... asked to report a series of events that had happened to them in the past and a series of events that might happen to them in the future. Transcriptions were scored according to a reliable system for categorizing internal (episodic) and external (semantic) information. For each event described......, participants also completed two modified Autobiographical Memory Questionnaire items to assess self-reported phenomenal qualities associated with remembering and imagining. In addition, TBI patients underwent neuropsychological assessment. Results revealed that TBI patients recalled/imagined proportionally...

  9. A Novel Preclinical Model of Moderate Primary Blast-Induced Traumatic Brain Injury.

    Science.gov (United States)

    Divani, Afshin A; Murphy, Amanda J; Meints, Joyce; Sadeghi-Bazargani, Homayoun; Nordberg, Jessica; Monga, Manoj; Low, Walter C; Bhatia, Prerana M; Beilman, Greg J; SantaCruz, Karen S

    2015-07-15

    Blast-induced traumatic brain injury (bTBI) is the "signature" injury of the recent Iraq and Afghanistan wars. Here, we present a novel method to induce bTBI using shock wave (SW) lithotripsy. Using a lithotripsy machine, Wistar rats (N = 70; 408.3 ± 93 g) received five SW pulses to the right side of the frontal cortex at 24 kV and a frequency of 60 Hz. Animals were then randomly divided into three study endpoints: 24 h (n = 25), 72 h (n = 19) and 168 h (n = 26). Neurological and behavioral assessments (Garcia's test, beam walking, Rotarod, and elevated plus maze) were performed at the baseline, and further assessments followed at 3, 6, 24, 72, and 168 h post-injury, if applicable. We performed digital subtraction angiography (DSA) to assess presence of cerebral vasospasm due to induced bTBI. Damage to brain tissue was assessed by an overall histological severity (OHS) score based on depth of injury, area of hemorrhage, and extent of axonal injury. Except for beam walking, OHS was significantly correlated with the other three outcome measures with at least one of their assessments during the first 6 h after the experiment. OHS manifested the highest absolute correlation coefficients with anxiety at the baseline and 6 h post-injury (r(baseline) = -0.75, r(6hrs) = 0.85; p<0.05). Median hemispheric differences for contrast peak values (obtained from DSA studies) for 24, 72, and 168 h endpoints were 3.45%, 3.05% and 0.2%, respectively, with statistically significant differences at 1 versus 7 d (p<0.05) and 3 versus 7 d (p<0.01). In this study, we successfully established a preclinical rat model of bTBI with characteristics similar to those observed in clinical cases. This new method may be useful for future investigations aimed at understanding bTBI pathophysiology.

  10. Parent management of the school reintegration needs of children and youth following moderate or severe traumatic brain injury.

    Science.gov (United States)

    Roscigno, Cecelia I; Fleig, Denise K; Knafl, Kathleen A

    2015-01-01

    School reintegration following children's traumatic brain injury (TBI) is still poorly understood from families' perspectives. We aimed to understand how both unique and common experiences during children's school reintegration were explained by parents to influence the family. Data came from an investigation using descriptive phenomenology (2005-2007) to understand parents' experiences in the first five years following children's moderate to severe TBI. Parents (N = 42 from 37 families in the United States) participated in two 90-min interviews (first M = 15 months; second M = 27 months). Two investigators independently coded parents' discussions of school reintegration using content analysis to understand the unique and common factors that parents perceived affected the family. Parents' school negotiation themes included the following: (1) legal versus moral basis for helping the child; (2) inappropriate state and local services that did not consider needs specific to TBI; and (3) involvement in planning, implementing and evaluating the child's education plan. Parents perceived that coordinated and collaboration leadership with school personnel lessened families' workload. Families who home-schooled had unique challenges. School reintegration can add to family workload by changing roles and relationships and by adding to parents' perceived stress in managing of the child's condition. Moderate to severe traumatic brain injury is assumed to be the primary cause of children's morbidities post-injury. Despite laws in the United States meant to facilitate children's school reintegration needs, parents often perceived that policies and practices differed from the intentions of laws and added to the family workload and stress. The school environment of the child (physical, cultural or psychological setting) plays an important long-term role in shaping family roles, relationships and management of the child's condition.

  11. The trajectories of overall disability in the first 5 years after moderate and severe traumatic brain injury.

    Science.gov (United States)

    Forslund, Marit V; Roe, Cecilie; Perrin, Paul B; Sigurdardottir, Solrun; Lu, Juan; Berntsen, Svein; Andelic, Nada

    2017-01-01

    To assess longitudinal trajectories of overall disability after moderate-to-severe traumatic brain injury (TBI) and to examine whether those trajectories could be predicted by socio-demographic and injury characteristics. Demographics and injury characteristics of 105 individuals with moderate-to-severe TBI were extracted from medical records. At the 1-, 2-, and 5-year follow-ups, TBI-related disability was assessed by the GOSE. A hierarchical linear model (HLM) was used to examine functional outcomes up to 5 years following injury and whether those outcomes could be predicted by: time, gender, age, relationship, education, employment pre-injury, occupation, GCS, cause of injury, length of post-traumatic amnesia (PTA), CT findings and injury severity score, as well as the interactions between each of these predictors and time. Higher GOSE trajectories (lower disability) were predicted by younger age at injury and shorter PTA, as well as by the interaction terms of time*PTA and time*employment. Those who had been employed at injury decreased in disability over time, while those who had been unemployed increased in disability. The study results support the view that individual factors generally outweigh injury-related factors as predictors of disability after TBI, except for PTA.

  12. Mild Concussion, but Not Moderate Traumatic Brain Injury, Is Associated with Long-Term Depression-Like Phenotype in Mice.

    Directory of Open Access Journals (Sweden)

    Nikita M Bajwa

    Full Text Available Mild traumatic brain injuries can lead to long-lasting cognitive and motor deficits, increasing the risk of future behavioral, neurological, and affective disorders. Our study focused on long-term behavioral deficits after repeated injury in which mice received either a single mild CHI (mCHI, a repeated mild CHI (rmCHI consisting of one impact to each hemisphere separated by 3 days, or a moderate controlled cortical impact injury (CCI. Shams received only anesthesia. Behavioral tests were administered at 1, 3, 5, 7, and 90 days post-injury (dpi. CCI animals showed significant motor and sensory deficits in the early (1-7 dpi and long-term (90 dpi stages of testing. Interestingly, sensory and subtle motor deficits in rmCHI animals were found at 90 dpi. Most importantly, depression-like behaviors and social passiveness were observed in rmCHI animals at 90 dpi. These data suggest that mild concussive injuries lead to motor and sensory deficits and affective disorders that are not observed after moderate TBI.

  13. Health-related quality of life 3 years after moderate to severe traumatic brain injury: a prospective cohort study.

    Science.gov (United States)

    Grauwmeijer, Erik; Heijenbrok-Kal, Majanka H; Ribbers, Gerard M

    2014-07-01

    To evaluate the time course of health-related quality of life (HRQoL) after moderate to severe traumatic brain injury (TBI) and to identify its predictors. Prospective cohort study with follow-up measurements at 3, 6, 12, 18, 24, and 36 months after TBI. Patients with moderate to severe TBI discharged from 3 level-1 trauma centers. Patients (N=97, 72% men) with a mean age ± SD of 32.8±13.0 years (range, 18-65y), hospitalized with moderate (23%) or severe (77%) TBI. Not applicable. HRQoL was measured with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), functional outcomes with the Glasgow Outcome Scale (GOS), Barthel Index, FIM, and Functional Assessment Measure, and mood with the Wimbledon Self-Report Scale. The SF-36 domains showed significant improvement over time for Physical Functioning (PPhysical (PPhysical Component Summary (PCS) score, whereas the Mental Component Summary (MCS) score remained stable. At 3-year follow-up, HRQoL of patients with TBI was the same as that in the Dutch normative population. Time after TBI, hospital length of stay (LOS), FIM, and GOS were independent predictors of the PCS, whereas LOS and mood were predictors of the MCS. After TBI, the physical component of HRQoL showed significant improvement over time, whereas the mental component remained stable. Problems of disease awareness seem to play a role in self-reported mental HRQoL. After TBI, mood status is a better predictor of the mental component of HRQoL than functional outcome, implying that mood should be closely monitored during and after rehabilitation. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  14. Intranasal insulin treatment of an experimental model of moderate traumatic brain injury.

    Science.gov (United States)

    Brabazon, Fiona; Wilson, Colin M; Jaiswal, Shalini; Reed, John; Frey, William H; Byrnes, Kimberly R

    2017-09-01

    Traumatic brain injury (TBI) results in learning and memory dysfunction. Cognitive deficits result from cellular and metabolic dysfunction after injury, including decreased cerebral glucose uptake and inflammation. This study assessed the ability of intranasal insulin to increase cerebral glucose uptake after injury, reduce lesion volume, improve memory and learning function and reduce inflammation. Adult male rats received a controlled cortical impact (CCI) injury followed by intranasal insulin or saline treatment daily for 14 days. PET imaging of [18F]-FDG uptake was performed at baseline and at 48 h and 10 days post-injury and MRI on days three and nine post injury. Motor function was tested with the beam walking test. Memory function was assessed with Morris water maze. Intranasal insulin after CCI significantly improved several outcomes compared to saline. Insulin-treated animals performed better on beam walk and demonstrated significantly improved memory. A significant increase in [18F]-FDG uptake was observed in the hippocampus. Intranasal insulin also resulted in a significant decrease in hippocampus lesion volume and significantly less microglial immunolabeling in the hippocampus. These data show that intranasal insulin improves memory, increases cerebral glucose uptake and decreases neuroinflammation and hippocampal lesion volume, and may therefore be a viable therapy for TBI.

  15. Executive functioning of complicated-mild to moderate traumatic brain injury patients with frontal contusions.

    Science.gov (United States)

    Ghawami, Heshmatollah; Sadeghi, Sadegh; Raghibi, Mahvash; Rahimi-Movaghar, Vafa

    2017-01-01

    Executive dysfunctions are among the most prevalent neurobehavioral sequelae of traumatic brain injuries (TBIs). Using culturally validated tests from the Delis-Kaplan Executive Function System (D-KEFS: Trail Making, Verbal Fluency, Design Fluency, Sorting, Twenty Questions, and Tower) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS: Rule Shift Cards, Key Search, and Modified Six Elements), the current study was the first to examine executive functioning in a group of Iranian TBI patients with focal frontal contusions. Compared with a demographically matched normative sample, the frontal contusion patients showed substantial impairments, with very large effect sizes (p ≤ .003, 1.56 executive measures. Controlling for respective lower-level/fundamental conditions, the differences on the highest-level executive (cognitive switching) conditions were still significant. The frontal patients also committed more errors. Patients with lateral prefrontal (LPFC) contusions were qualitatively worst. For example, only the LPFC patients committed perseverative repetition errors. Altogether, our results support the notion that the frontal lobes, specifically the lateral prefrontal regions, play a critical role in cognitive executive functioning, over and above the contributions of respective lower-level cognitive abilities. The results provide clinical evidence for validity of the cross-culturally adapted versions of the tests.

  16. Eyeball pressure stimulation induces subtle sympathetic activation in patients with a history of moderate or severe traumatic brain injury.

    Science.gov (United States)

    Wang, Ruihao; Hösl, Katharina M; Ammon, Fabian; Markus, Jörg; Koehn, Julia; Roy, Sankanika; Liu, Mao; de Rojas Leal, Carmen; Muresanu, Dafin; Flanagan, Steven R; Hilz, Max J

    2018-06-01

    After traumatic brain injury (TBI), there may be persistent central-autonomic-network (CAN) dysfunction causing cardiovascular-autonomic dysregulation. Eyeball-pressure-stimulation (EPS) normally induces cardiovagal activation. In patients with a history of moderate or severe TBI (post-moderate-severe-TBI), we determined whether EPS unveils cardiovascular-autonomic dysregulation. In 51 post-moderate-severe-TBI patients (32.7 ± 10.5 years old, 43.1 ± 33.4 months post-injury), and 30 controls (29.1 ± 9.8 years), we recorded respiration, RR-intervals (RRI), systolic and diastolic blood-pressure (BPsys, BPdia), before and during EPS (120 sec; 30 mmHg), using an ocular-pressure-device (Okulopressor®). We calculated spectral-powers of mainly sympathetic low (LF: 0.04-0.15 Hz) and parasympathetic high (HF: 0.15-0.5 Hz) frequency RRI-fluctuations, sympathetically mediated LF-powers of BPsys, and calculated normalized (nu) LF- and HF-powers of RRI. We compared parameters between groups before and during EPS by repeated-measurement-analysis-of-variance with post-hoc analysis (significance: p < 0.05). At rest, sympathetically mediated LF-BPsys-powers were significantly lower in the patients than the controls. During EPS, only controls significantly increased RRIs and parasympathetically mediated HFnu-RRI-powers, but decreased LF-RRI-powers, LFnu-RRI-powers, and LF-BPsys-powers; in contrast, the patients slightly though significantly increased BPsys upon EPS, without changing any other parameter. In post-moderate-severe-TBI patients, autonomic BP-modulation was already compromised at rest. During EPS, our patients failed to activate cardiovagal modulation but slightly increased BPsys, indicating persistent CAN dysregulation. Our findings unveil persistence of subtle cardiovascular-autonomic dysregulation even years after TBI. Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Meiyan Xuan

    2015-01-01

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

  18. Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier: relevance to CNS drug delivery.

    Science.gov (United States)

    Thompson, Brandon J; Sanchez-Covarrubias, Lucy; Slosky, Lauren M; Zhang, Yifeng; Laracuente, Mei-li; Ronaldson, Patrick T

    2014-04-01

    Cerebral hypoxia and subsequent reoxygenation stress (H/R) is a component of several diseases. One approach that may enable neural tissue rescue after H/R is central nervous system (CNS) delivery of drugs with brain protective effects such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins). Our present in vivo data show that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain after H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood-brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB under H/R conditions. In rat brain microvessels, H/R (6% O2, 60 minutes followed by 21% O2, 10 minutes) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate and fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of transforming growth factor-β (TGF-β)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF-β/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.

  19. Facial Emotion Recognition Deficits following Moderate-Severe Traumatic Brain Injury (TBI): Re-examining the Valence Effect and the Role of Emotion Intensity

    NARCIS (Netherlands)

    Rosenberg, H.; McDonald, S.; Dethier, M.; Kessels, R.P.C.; Westbrook, R.F.

    2014-01-01

    Many individuals who sustain moderate-severe traumatic brain injuries (TBI) are poor at recognizing emotional expressions, with a greater impairment in recognizing negative (e.g., fear, disgust, sadness, and anger) than positive emotions (e.g., happiness and surprise). It has been questioned whether

  20. Deficits in facial emotion recognition indicate behavioral changes and impaired self-awareness after moderate to severe traumatic brain injury.

    Science.gov (United States)

    Spikman, Jacoba M; Milders, Maarten V; Visser-Keizer, Annemarie C; Westerhof-Evers, Herma J; Herben-Dekker, Meike; van der Naalt, Joukje

    2013-01-01

    Traumatic brain injury (TBI) is a leading cause of disability, specifically among younger adults. Behavioral changes are common after moderate to severe TBI and have adverse consequences for social and vocational functioning. It is hypothesized that deficits in social cognition, including facial affect recognition, might underlie these behavioral changes. Measurement of behavioral deficits is complicated, because the rating scales used rely on subjective judgement, often lack specificity and many patients provide unrealistically positive reports of their functioning due to impaired self-awareness. Accordingly, it is important to find performance based tests that allow objective and early identification of these problems. In the present study 51 moderate to severe TBI patients in the sub-acute and chronic stage were assessed with a test for emotion recognition (FEEST) and a questionnaire for behavioral problems (DEX) with a self and proxy rated version. Patients performed worse on the total score and on the negative emotion subscores of the FEEST than a matched group of 31 healthy controls. Patients also exhibited significantly more behavioral problems on both the DEX self and proxy rated version, but proxy ratings revealed more severe problems. No significant correlation was found between FEEST scores and DEX self ratings. However, impaired emotion recognition in the patients, and in particular of Sadness and Anger, was significantly correlated with behavioral problems as rated by proxies and with impaired self-awareness. This is the first study to find these associations, strengthening the proposed recognition of social signals as a condition for adequate social functioning. Hence, deficits in emotion recognition can be conceived as markers for behavioral problems and lack of insight in TBI patients. This finding is also of clinical importance since, unlike behavioral problems, emotion recognition can be objectively measured early after injury, allowing for early

  1. Deficits in facial emotion recognition indicate behavioral changes and impaired self-awareness after moderate to severe traumatic brain injury.

    Directory of Open Access Journals (Sweden)

    Jacoba M Spikman

    Full Text Available Traumatic brain injury (TBI is a leading cause of disability, specifically among younger adults. Behavioral changes are common after moderate to severe TBI and have adverse consequences for social and vocational functioning. It is hypothesized that deficits in social cognition, including facial affect recognition, might underlie these behavioral changes. Measurement of behavioral deficits is complicated, because the rating scales used rely on subjective judgement, often lack specificity and many patients provide unrealistically positive reports of their functioning due to impaired self-awareness. Accordingly, it is important to find performance based tests that allow objective and early identification of these problems. In the present study 51 moderate to severe TBI patients in the sub-acute and chronic stage were assessed with a test for emotion recognition (FEEST and a questionnaire for behavioral problems (DEX with a self and proxy rated version. Patients performed worse on the total score and on the negative emotion subscores of the FEEST than a matched group of 31 healthy controls. Patients also exhibited significantly more behavioral problems on both the DEX self and proxy rated version, but proxy ratings revealed more severe problems. No significant correlation was found between FEEST scores and DEX self ratings. However, impaired emotion recognition in the patients, and in particular of Sadness and Anger, was significantly correlated with behavioral problems as rated by proxies and with impaired self-awareness. This is the first study to find these associations, strengthening the proposed recognition of social signals as a condition for adequate social functioning. Hence, deficits in emotion recognition can be conceived as markers for behavioral problems and lack of insight in TBI patients. This finding is also of clinical importance since, unlike behavioral problems, emotion recognition can be objectively measured early after injury

  2. The absence of protective effect of candesartan and angiotensin IV in the moderate brain injury in rats

    International Nuclear Information System (INIS)

    Nasser, M.; Botelle, L.; Javellaud, J.; Oudart, N.; Achard, J-M

    2012-01-01

    Background: angiotensin receptor blockers (ARB) are protective in various models of experimental ischemic stroke. This protective effect is mediated by the stimulation of non-AT1 receptors by angiotensin II and angiotensin IV. Since traumatic brain injury shares with ischemic cerebral injury several common mechanisms, we examined if a pretreatment with the ARB candesartan, or a post-treatment with angiotensin IV are also protective in a rat model of blunt traumatic brain injury (TBI). Methods :adults Sprague Dawley rats were treated for five days with candesartan (0.5 mg/kg/day) or saline by gavage prior to the induction of diffuse moderate TBI using the impact-acceleration model. Two others groups of rats were treated by a daily intraperitoneal injection of angiotensin IV (1.5 mg/kg/day) or saline for five days following TBI. Overall neurological insult were assessed daily by measuring the neurological score. Sensitive deficits (scotch test) and sensorimotor deficits (beam-walking test) were evaluated daily from day 1 to 7 and at day 15; cognitive impairment (object recognition test) was evaluated at day 15. Results : TBI induced significant sensitive and sensorimotor deficits that were maximal at day 1 and spontaneously improved with time. At day 15, traumatised animals had a marked alteration of the working memory. Neither treatment with candesartan, angiotensin IV or with erythropoietin decreased the severity of the initial sensorimotor deficits, nor accelerate the recovery rate. Candesartan, angiotensin IV had likewise no protective effect on the cognitive deficit evaluated to day 15. Conclusion: pretreatment with candesartan and post-treatment with angiotensin IV are both ineffective to protect against sensorimotor and c ognitive impairment in a rat model of impact-acceleration TBI. (author)

  3. Migraine induced by hypoxia

    DEFF Research Database (Denmark)

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

    2016-01-01

    in the visual cortex were measured by proton magnetic resonance spectroscopy. The circumference of cranial arteries was measured by 3 T high-resolution magnetic resonance angiography. Hypoxia induced migraine-like attacks in eight patients compared to one patient after sham (P = 0.039), aura in three...... and possible aura in 4 of 15 patients. Hypoxia did not change glutamate concentration in the visual cortex compared to sham, but increased lactate concentration (P = 0.028) and circumference of the cranial arteries (P ... suggests that hypoxia may provoke migraine headache and aura symptoms in some patients. The mechanisms behind the migraine-inducing effect of hypoxia should be further investigated....

  4. Focused and divided attention abilities in the acute phase of recovery from moderate to severe traumatic brain injury.

    Science.gov (United States)

    Robertson, Kayela; Schmitter-Edgecombe, Maureen

    2017-01-01

    Impairments in attention following traumatic brain injury (TBI) can significantly impact recovery and rehabilitation effectiveness. This study investigated the multi-faceted construct of selective attention following TBI, highlighting the differences on visual nonsearch (focused attention) and search (divided attention) tasks. Participants were 30 individuals with moderate to severe TBI who were tested acutely (i.e. following emergence from PTA) and 30 age- and education-matched controls. Participants were presented with visual displays that contained either two or eight items. In the focused attention, nonsearch condition, the location of the target (if present) was cued with a peripheral arrow prior to presentation of the visual displays. In the divided attention, search condition, no spatial cue was provided prior to presentation of the visual displays. The results revealed intact focused, nonsearch, attention abilities in the acute phase of TBI recovery. In contrast, when no spatial cue was provided (divided attention condition), participants with TBI demonstrated slower visual search compared to the control group. The results of this study suggest that capitalizing on intact focused attention abilities by allocating attention during cognitively demanding tasks may help to reduce mental workload and improve rehabilitation effectiveness.

  5. Are Patients Ready for "EARLYSTIM"? Attitudes towards Deep Brain Stimulation among Female and Male Patients with Moderately Advanced Parkinson's Disease.

    Science.gov (United States)

    Sperens, Maria; Hamberg, Katarina; Hariz, Gun-Marie

    2017-01-01

    Objective . To explore, in female and male patients with medically treated, moderately advanced Parkinson's disease (PD), their knowledge and reasoning about Deep Brain Stimulation (DBS). Methods . 23 patients with PD (10 women), aged 46-70, were interviewed at a mean of 8 years after diagnosis, with open-ended questions concerning their reflections and considerations about DBS. The interviews were transcribed verbatim and analysed according to the difference and similarity technique in Grounded Theory. Results . From the patients' narratives, the core category "Processing DBS: balancing symptoms, fears and hopes" was established. The patients were knowledgeable about DBS and expressed cautious and well considered attitudes towards its outcome but did not consider themselves ill enough to undergo DBS. They were aware of its potential side-effects. They considered DBS as the last option when oral medication is no longer sufficient. There was no difference between men and women in their reasoning and attitudes towards DBS. Conclusion . This study suggests that knowledge about the pros and cons of DBS exists among PD patients and that they have a cautious attitude towards DBS. Our patients did not seem to endorse an earlier implementation of DBS, and they considered that it should be the last resort when really needed.

  6. Moderate-intensity interval training increases serum brain-derived neurotrophic factor level and decreases inflammation in Parkinson's disease patients.

    Science.gov (United States)

    Zoladz, J A; Majerczak, J; Zeligowska, E; Mencel, J; Jaskolski, A; Jaskolska, A; Marusiak, J

    2014-06-01

    It has been demonstrated that physical training increases serum brain-derived neurotrophic factor (BDNF) in healthy people. The aim of this study was to establish the effect of physical training on the basal serum level of the BDNF in the Parkinson's disease patients (PD patients) in relation to their health status. Twelve PD patients (mean ± S.E.M: age 70 ± 3 years; body mass 70 ± 2 kg; height 163 ± 3 cm) performed a moderate-intensity interval training (three 1-hour training sessions weekly), lasting 8 weeks. Basal serum BDNF in the PD patients before training amounted to 10,977 ± 756 pg x mL(-1) and after 8 weeks of training it has increased to 14,206 ± 1256 pg x mL(-1) (i.e. by 34%, P=0.03). This was accompanied by an attenuation of total Unified Parkinson's Disease Rating Scale (UPDRS) (P=0.01). The training resulted also in a decrease of basal serum soluble vascular cell adhesion molecule 1 (sVCAM-1) (P=0.001) and serum tumor necrosis factor-α (TNF-α) (P=0.03) levels. We have concluded that the improvement of health status of the Parkinson's disease patients after training could be related to the increase of serum BDNF level caused by the attenuated inflammation in those patients.

  7. Influence exerted by new pyrimidine derivatives on cerebral circulation auto-regulation and vasodilatating function of vessels endothelium in rats' brains under chronic hemic hypoxia

    Directory of Open Access Journals (Sweden)

    A.V. Voronkov

    2018-03-01

    Full Text Available Our research goal was to examine influences exerted by new pyrimidine derivatives coded as BL0 and BL2 on cerebral hemodynamics auto-regulation parameters and vasodilatating function of vessels endothelium as risk factors causing ischemic and hemorrhagic strokes under chronic hemic hypoxia. We performed an experiment on white Wistar rats to prove that endothelial dysfunction which evolves under chronic hemic hypoxia leads to disorders in endothelium-mediated mechanisms for cerebral circulation auto-regulation in rats. We modeled hypoxia in animals via granting them free access to 0.2 % sodium nitrite solution instead of ordinary drinking water. Endothelial dysfunction was confirmed as per disorders in vasodilatation and vasoconstriction reactions at intravenous introduction of acetyl choline (0.1 mg/kg and methyl ether hydrochloride nitro-L-arginine (10 mg/kg. Cerebral blood flow speed was measured with MM-D-K-Minimax v.2.1. ultrasound Doppler. We assessed cerebral circulation auto-regulation as per compression test results which allowed us to calculate overshoot coefficient and auto-regulation power. Examined pyrimidine derivatives and comparison preparations were introduced orally 60 minutes prior to taking readings. Mexidol doses were calculated on the basis of interspecific recalculation of a maximum daily dose for a man. Nicergoline dose was taken as a most effective one as per literature data. When new pyrimidine derivatives BL0 and BL2 are applied under chronic hemic hypoxia, it causes overshoot coefficient to grow authentically higher than in a negative control group but it doesn't exert any positive influence on collateral reserve parameter, namely auto-regulation power. BL0 and BL2 improve endothelium vasodilatating function at intravenous acetylcholine introduction (0.1 mg/kg and don't exert any influence on vasoconstricting function at L-NAME intravenous introduction (10 mg/kg. The examined substance BL0 has more apparent

  8. Utility of the Croatian translation of the community integration questionnaire-revised in a sample of adults with moderate to severe traumatic brain injury.

    Science.gov (United States)

    Tršinski, Dubravko; Tadinac, Meri; Bakran, Žarko; Klepo, Ivana

    2018-02-23

    To examine the utility of the Community Integration Questionnaire-Revised, translated into Croatian, in a sample of adults with moderate to severe traumatic brain injury. The Community Integration Questionnaire-Revised was administered to a sample of 88 adults with traumatic brain injury and to a control sample matched by gender, age and education. Participants with traumatic brain injury were divided into four subgroups according to injury severity. The internal consistency of the Community Integration Questionnaire-Revised was satisfactory. The differences between the group with traumatic brain injury and the control group were statistically significant for the overall Community Integration Questionnaire-Revised score, as well as for all the subscales apart from the Home Integration subscale. The community Integration Questionnaire-Revised score varied significantly for subgroups with different severity of traumatic brain injury. The results show that the Croatian translation of the Community Integration Questionnaire-Revised is useful in assessing participation in adults with traumatic brain injury and confirm previous findings that severity of injury predicts community integration. Results of the new Electronic Social Networking scale indicate that persons who are more active on electronic social networks report better results for other domains of community integration, especially social activities. Implications for rehabilitation The Croatian translation of the Community Integration Questionnaire-Revised is a valid tool for long-term assessment of participation in various domains in persons with moderate to severe traumatic brain injury Persons with traumatic brain injury who are more active in the use of electronic social networking are also more integrated into social and productivity domains. Targeted training in the use of new technologies could enhance participation after traumatic brain injury.

  9. Nitroimidazoles and imaging hypoxia

    International Nuclear Information System (INIS)

    Nunn, A.; Linder, K.; Strauss, H.W.

    1995-01-01

    A class of compounds known to undergo different intracellular metabolism depending on the availability of oxygen in tissue, the nitroimidazoles, have been advocated for imaging hypoxic tissue. In the presence of normal oxygen levels the molecule is immediately reoxidized. In hypoxic tissue the low oxygen concentration is not able to effectively compete to reoxidize the molecule and further reduction appears to take place. The association is not irreversible. Nitroimidazoles for in vivo imaging using radiohalogenated derivatives of misonidazole have recently been employed in patients. Two major problems with fluoromisonidazole are its relatively low concentration within the lesion and the need to wait several hours to permit clearance of the agent from the normoxic background tissue. Even with high-resolution positron emission tomographic imaging, this combination of circumstances makes successful evaluation of hypoxic lesions a challenge. Single-photon agents, with their longer half-lives and comparable biological properties, offer a greater opportunity for successful imaging. In 1992 technetium-99m labeled nitroimidazoles were described that seem to have at least comparable in vivo characteristics. Laboratory studies have demonstrated preferential binding of these agents to hypoxic tissue in the myocardium, in the brain, and in tumors. These investigations indicate that imaging can provide direct evidence of tissue with low oxygen levels that is viable. Even from this early vantage point the utility of measuring tissue oxygen levels with external imaging suggests that hypoxia imaging could play a major role in clinical decision making. (orig./MG)

  10. Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H2S system: Role of oxidative stress and endoplasmic reticulum stress.

    Science.gov (United States)

    Liu, Song; Xin, Danqing; Wang, Lingxiao; Zhang, Tiantian; Bai, Xuemei; Li, Tong; Xie, Yunkai; Xue, Hao; Bo, Shishi; Liu, Dexiang; Wang, Zhen

    2017-10-01

    Neonatal hypoxic-ischemic (HI) injury is a major cause of neonatal death and neurological dysfunction. H 2 S has been shown to protect against hypoxia-induced injury and apoptosis of neurons. L-Cysteine is catalyzed by cystathionine-β-synthase (CBS) in the brain and sequentially produces endogenous H 2 S. The present study was designed to investigate whether L-Cysteine could attenuate the acute brain injury and improve neurobehavioral outcomes following HI brain injury in neonatal mice by releasing endogenous H 2 S. L-Cysteine treatment significantly attenuated brain edema and decreased infarct volume and neuronal cell death, as shown by a decrease in the Bax/Bcl-2 ratio, suppression of caspase-3 activation, and reduced phosphorylation of Akt and ERK at 72h after HI. Additionally, L-Cysteine substantially up-regulated NF-E2-related factor 2 and heme oxygenase-1 expression. L-Cysteine also decreased endoplasmic reticulum (ER) stress-associated pro-apoptotic protein expression. Furthermore, L-Cysteine had long-term effects by protecting against the loss of ipsilateral brain tissue and improving neurobehavioral outcomes. Importantly, pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI insult. Thus, L-Cysteine exerts neuroprotection against HI-induced injury in neonates via the CBS/H 2 S pathway, mediated in part by anti-apoptotic effects and reduced oxidative stress and ER stress. Thus, L-Cysteine may be a promising treatment for HI. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  11. Healthy body, healthy mind: A mixed methods study of outcomes, barriers and supports for exercise by people who have chronic moderate-to-severe acquired brain injury.

    Science.gov (United States)

    Lorenz, Laura S; Charrette, Ann L; O'Neil-Pirozzi, Therese M; Doucett, Julia M; Fong, Jeffrey

    2018-01-01

    Few people with chronic moderate-to-severe brain injury are following recommended physical activity guidelines. Investigate effects of planned, systematic physical activity while cultivating social and emotional well-being of people with chronic moderate-to-severe brain injury. Moderate-to-intensive physical activity would be associated with improvements in impairment and activity limitation measures (endurance, mobility, gait speed) immediately post-intervention and six weeks later (study week 12). The intervention was a single group pre-/post-intervention study with 14 people with chronic moderate-to-severe brain injury who live in brain injury group homes and exercised 60-90 min, 3 days per week for 6 weeks at a maximum heart rate of 50-80%. Pre-post measures (administered weeks 0, 6 and 12) were the 6 Minute Walk Test, High-level Mobility Assessment Tool and 10 Meter Walk Test. The qualitative component used a brief survey and semi-structured interview guide with participants, family members, and staff. Following program completion, post-intervention group changes were noted on all outcome measures and greater than minimal detectable change for people with brain injury. Three transitioned from low to high ambulatory status and maintained this change at 12 weeks. During interviews, participants agreed the program was stimulating. More than eighty percent liked working out in a group and felt better being active. Program impact included physical, cognitive and social/emotional aspects. Social aspects (group format, trainers) were highly motivating and supported by residents, family, and staff. Investments in transportation and recruiting and training interns to assist participants are critical to program sustainability and expansion. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Very Early Administration of Progesterone Does Not Improve Neuropsychological Outcomes in Subjects with Moderate to Severe Traumatic Brain Injury

    Science.gov (United States)

    Caveney, Angela F.; Hertzberg, Vicki S; Silbergleit, Robert; Yeatts, Sharon D.; Palesch, Yuko Y.; Levin, Harvey S.; Wright, David W.

    2017-01-01

    Abstract A Phase III, double-blind, placebo-controlled trial (ProTECT III) found that administration of progesterone did not reduce mortality or improve functional outcome as measured by the Glasgow Outcome Scale Extended (GOSE) in subjects with moderate to severe traumatic brain injury. We conducted a secondary analysis of neuropsychological outcomes to evaluate whether progesterone is associated with improved recovery of cognitive and motor functioning. ProTECT III was conducted at 49 level I trauma centers in the United States. Adults with moderate to severe TBI were randomized to receive intravenous progesterone or placebo within 4 h of injury for a total of 4 days. At 6 months, subjects underwent evaluation of memory, attention, executive functioning, language, and fine motor coordination/dexterity. Chi-square analysis revealed no significant difference in the proportion of subjects (263/280 progesterone, 283/295 placebo) with Galveston Orientation and Amnesia Test scores ≥75. Analyses of covariance did not reveal significant treatment effects for memory (Buschke immediate recall, p = 0.53; delayed recall, p = 0.94), attention (Trails A speed, p = 0.81 and errors, p = 0.22; Digit Span Forward length, p = 0.66), executive functioning (Trails B speed, p = 0.97 and errors, p = 0.93; Digit Span Backward length, p = 0.60), language (timed phonemic fluency, p = 0.05), and fine motor coordination/dexterity (Grooved Pegboard dominant hand time, p = 0.75 and peg drops, p = 0.59; nondominant hand time, p = 0.74 and peg drops, p = 0.61). Pearson Product Moment Correlations demonstrated significant (p GOSE scores. Similar to the ProTECT III trial's results of the primary outcome, the secondary outcomes do not provide evidence of a neuroprotective effect of progesterone. PMID:26973025

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

    Science.gov (United States)

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

    2015-05-01

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

  14. Exercise performed at hypoxia influences mood state and anxiety symptoms

    Directory of Open Access Journals (Sweden)

    Jorge Fernando Tavares de Souza

    2015-06-01

    Full Text Available During hypoxia conditions, psychological states can be worsened. However, little information is available regarding the effect of physical exercise performed in hypoxia conditions on mood state and anxiety symptoms. The aim of the present study was to elucidate the acute effect of moderate physical exercise performed at hypoxia on mood states and anxiety symptoms in healthy young subjects. Ten volunteers were subjected to the following conditions: a normoxic condition (NC and a hypoxic condition (HC. They performed 45 min of physical exercise. Their anxiety symptoms and mood states were evaluated at the initial time point as well as immediately following and 30 and 60 min after the exercise session. Our results showed a significant increase in post-exercise anxiety symptoms and a significant decrease in mood scores immediately after and 30 min after exercise performed in the HC. Moderate physical activity performed at hypoxia condition increased post-exercise anxiety and worsened mood state.

  15. Treatment with a GLP-1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders

    DEFF Research Database (Denmark)

    Mansur, Rodrigo B; Zugman, Andre; Ahmed, Juhie

    2017-01-01

    regions (e.g. RR: 1.011, p=0.049 in the left rostral middle frontal area). Changes in regional volumes were associated with improvement in executive function (e.g. r=0.698, p=0.003 for the right superior frontal area). Adjunctive liraglutide results in clinically significant weight loss......, with corresponding improvement in cognitive function; changes in cognitive function were partially moderated by changes in brain morphometry, underscoring the interrelationship between weight and brain structure/function.......Cognitive deficits are a core feature across psychiatric disorders. Emerging evidence indicates that metabolic pathways are highly relevant for the substrates and phenomenology of the cognitive domain. Herein, we aimed to determine the effects of liraglutide, a GLP-1R agonist, on brain structural...

  16. Knockdown of long noncoding antisense RNA brain-derived neurotrophic factor attenuates hypoxia/reoxygenation-induced nerve cell apoptosis through the BDNF-TrkB-PI3K/Akt signaling pathway.

    Science.gov (United States)

    Zhong, Jian-Bin; Li, Xie; Zhong, Si-Ming; Liu, Jiu-Di; Chen, Chi-Bang; Wu, Xiao-Yan

    2017-09-27

    Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal cell apoptosis. The antisense RNA of brain-derived neurotrophic factor (BDNF-AS) is a natural antisense transcript that is transcribed opposite the gene that encodes BDNF. The aim of this study was to determine whether knockdown of BDNF-AS can suppress hypoxia/reoxygenation (H/R)-induced neuronal cell apoptosis and whether this is mediated by the BDNF-TrkB-PI3K/Akt pathway. We detected the expression of BDNF and BDNF-AS in brain tissue from 20 patients with cerebral infarction and five patients with other diseases (but no cerebral ischemia). We found that BDNF expression was significantly downregulated in patients with cerebral infarction, whereas the expression of BDNF-AS was significantly upregulated. In both human cortical neurons (HCN2) and human astrocytes, H/R significantly induced the expression of BDNF-AS, but significantly decreased BDNF expression. H/R also significantly induced apoptosis and reduced the mitochondrial membrane potential in these cells. Following downregulation of BDNF-AS by siRNA in human cortical neurons and human astrocyte cells, BDNF expression was significantly upregulated and the H/R-induced upregulation of BDNF-AS was significantly attenuated. BDNF-AS siRNA inhibited H/R-induced cell apoptosis and ameliorated the H/R-induced suppression of mitochondrial membrane potential. H/R inhibited the expression of BDNF, p-AKT/AKT, and TrKB, and this inhibition was recovered by BDNF-AS siRNA. In summary, this study indicates that BDNF-AS siRNA induces activation of the BDNF-TrkB-PI3K/Akt pathway following H/R-induced neurotoxicity. These findings will be useful toward the application of BDNF-AS siRNA for the treatment of neurodegenerative diseases.

  17. Exercise preconditioning reduces brain damage and inhibits TNF-alpha receptor expression after hypoxia/reoxygenation: an in vivo and in vitro study.

    Science.gov (United States)

    Ding, Yun-Hong; Mrizek, Michael; Lai, Qin; Wu, Yimin; Reyes, Raul; Li, Jie; Davis, William W; Ding, Yuchuan

    2006-11-01

    Exercise reduces ischemia and reperfusion injury in rat stroke models. We investigated whether gradual increases in tumor necrosis factor-alpha (TNF-alpha) reported during exercise down-regulates expression of TNF-alpha receptors I and II (TNFRI and II) in stroke, leading to reduced brain damage. Adult male Sprague Dawley rats were subjected to 30 minutes of exercise on a treadmill each day for 3 weeks. Then, stroke was induced by a 2-hour middle cerebral artery (MCA) occlusion using an intra-luminal filament. Expressions of TNFRI and II mRNA in the brain were detected using a real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Protein expressions of TNFRI and II were determined by enzyme-linked immunoabsorbant assay (ELISA) in serum and brain homogenates. Spatial distribution of TNF-alpha receptors in brain regions was determined with immunocytochemistry. In human umbilical vein endothelial cells (HUVEC), we addressed the causal effect of TNF-alpha pretreatment on TNF I and II expression using ELISA and real-time PCR. In exercised rats after stroke, brain infarct was significantly (p<0.01) reduced in the entire MCA supplied regions, associated with a mild expression of TNFRI and II mRNA and protein. The TNF-alpha receptors were restricted to the ischemic core. In contrast, a robust expression of TNFRI and II molecules was found in non-exercised rats subjected to similar ischemia/reperfusion insults. An in vitro study revealed a causal link between TNF-alpha pretreatment and reduced cellular expression of TNF-alpha receptors under hypoxic/reoxygenated conditions. Our results suggest that reduced-brain damage in ischemic rats after exercise preconditioning may be attributable to the reduced expression of TNF-alpha receptors. Chronically increased TNF-alpha expression was also found to reduce TNFI and II responding to acute ischemia/reperfusion insult.

  18. Quantitative in vivo detection of brain cell death after hypoxia ischemia using the lipid peak at 1.3 ppm of proton magnetic resonance spectroscopy in neonatal rats.

    Science.gov (United States)

    Ahn, So Yoon; Yoo, Hye Soo; Lee, Jang Hoon; Sung, Dong Kyung; Jung, Yu Jin; Sung, Se In; Lim, Keun Ho; Chang, Yun Sil; Lee, Jung Hee; Kim, Ki Soo; Park, Won Soon

    2013-07-01

    This study was performed to determine the accuracy of proton magnetic spectroscopy ((1)H-MRS) lipid peak as a noninvasive tool for quantitative in vivo detection of brain cell death. Seven day-old Sprague Dawley rats were subjected to 8% oxygen following a unilateral carotid artery ligation. For treatment, cycloheximide was given immediately after hypoxic ischemia (HI). Lipid peak was measured using (1)H-MRS at 24 hr after HI, and then brains were harvested for fluorocytometric analyses with annexin V/propidium iodide (PI) and fluorescent probe JC-1, and for adenosine-5'-triphosphate (ATP) and lactate. Increased lipid peak at 1.3 ppm measured with (1)H-MRS, apoptotic and necrotic cells, and loss of mitochondrial membrane potential (ΔΨ) at 24 hr after HI were significantly improved with cycloheximide treatment. Significantly reduced brain ATP and increased lactate levels observed at 24 hr after HI showed a tendency to improve without statistical significance with cycloheximide treatment. Lipid peak at 1.3 ppm showed significant positive correlation with both apoptotic and necrotic cells and loss of ΔΨ, and negative correlation with normal live cells. Lipid peak at 1.3 ppm measured by (1)H-MRS might be a sensitive and reliable diagnostic tool for quantitative in vivo detection of brain cell death after HI.

  19. Effects of atorvastatin on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injury; a randomized double-blind placebo-controlled clinical trial.

    Science.gov (United States)

    Farzanegan, Gholam Reza; Derakhshan, Nima; Khalili, Hosseinali; Ghaffarpasand, Fariborz; Paydar, Shahram

    2017-10-01

    The aim of the current study was to investigate the effects of atorvastatin on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injury (TBI). The study was conducted as a randomized clinical trial during a 16-month period from May 2015 and August 2016 in a level I trauma center in Shiraz, Southern Iran. We included 65 patients with moderate (GCS: 9-13) to severe (GCS: 5-8) TBI who had brain contusions of less than 30cc volume. We excluded those who required surgical intervention. Patients were randomly assigned to receive daily 20mg atorvastatin for 10days (n=21) or placebo in the same dosage (n=23). The brain contusion volumetry was performed on days 0, 3 and 7 utilizing spiral thin-cut brain CT-Scan (1-mm thickness). The outcome measured included modified Rankin scale (MRS), Glasgow Outcome Scale (GOS) and Disability rating Scale (DRS) which were all evaluated 3months post-injury. There was no significant difference between two study group regarding the baseline, 3rd day and 7th day of the contusion volume and the rate of contusion expansion. However, functional outcome scales of GOS, MRS and DRS at 3-months post-injury were significantly better in atorvastatin arm of the study compared to placebo (p values of 0.043, 0.039 and 0.030 respectively). Even though atorvastatin was not found to be more effective than placebo in reducing contusion expansion rate, it was associated with improved functional outcomes at 3-months following moderate to severe TBI. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. How functional connectivity between emotion regulation structures can be disrupted: preliminary evidence from adolescents with moderate to severe traumatic brain injury.

    Science.gov (United States)

    Newsome, Mary R; Scheibel, Randall S; Mayer, Andrew R; Chu, Zili D; Wilde, Elisabeth A; Hanten, Gerri; Steinberg, Joel L; Lin, Xiaodi; Li, Xiaoqi; Merkley, Tricia L; Hunter, Jill V; Vasquez, Ana C; Cook, Lori; Lu, Hanzhang; Vinton, Kami; Levin, Harvey S

    2013-09-01

    Outcome of moderate to severe traumatic brain injury (TBI) includes impaired emotion regulation. Emotion regulation has been associated with amygdala and rostral anterior cingulate (rACC). However, functional connectivity between the two structures after injury has not been reported. A preliminary examination of functional connectivity of rACC and right amygdala was conducted in adolescents 2 to 3 years after moderate to severe TBI and in typically developing (TD)control adolescents, with the hypothesis that the TBI adolescents would demonstrate altered functional connectivity in the two regions. Functional connectivity was determined by correlating fluctuations in the blood oxygen level dependent(BOLD) signal of the rACC and right amygdala with that of other brain regions. In the TBI adolescents, the rACC was found to be significantly less functionally connected to medial prefrontal cortices and to right temporal regions near the amygdala (height threshold T = 2.5, cluster level p functional connectivity with the rACC (height threshold T = 2.5, cluster level p = .06, FDR corrected). Data suggest disrupted functional connectivity in emotion regulation regions. Limitations include small sample sizes. Studies with larger sample sizes are necessary to characterize the persistent neural damage resulting from moderate to severe TBI during development.

  1. Hypoxia targeting copper complexes

    International Nuclear Information System (INIS)

    Dearling, J.L.

    1998-11-01

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

  2. Catechol-O-Methyltransferase Genotypes and Parenting Influence on Long-Term Executive Functioning After Moderate to Severe Early Childhood Traumatic Brain Injury: An Exploratory Study.

    Science.gov (United States)

    Kurowski, Brad G; Treble-Barna, Amery; Zang, Huaiyu; Zhang, Nanhua; Martin, Lisa J; Yeates, Keith Owen; Taylor, H Gerry; Wade, Shari L

    To examine catechol-O-methyltransferase (COMT) rs4680 genotypes as moderators of the effects of parenting style on postinjury changes in parent behavior ratings of executive dysfunction following moderate to severe early childhood traumatic brain injury. Research was conducted in an outpatient setting. Participants included children admitted to hospital with moderate to severe traumatic brain injury (n = 55) or orthopedic injuries (n = 70) between ages 3 and 7 years. Prospective cohort followed over 7 years postinjury. Parenting Practices Questionnaire and the Behavior Rating Inventory of Executive Functioning obtained at baseline, 6, 12, and 18 months, and 3.5 and 6.8 years postinjury. DNA was collected from saliva samples, purified using the Oragene (DNA Genotek, Ottawa, Ontario, Canada) OG-500 self-collection tubes, and analyzed using TaqMan (Applied Biosystems, Thermo Fisher Scientific, Waltham, Massachusetts) assay protocols to identify the COMT rs4680 polymorphism. Linear mixed models revealed a significant genotype × parenting style × time interaction (F = 5.72, P = .02), which suggested that the adverse effects of authoritarian parenting on postinjury development of executive functioning were buffered by the presence of the COMT AA genotype (lower enzyme activity, higher dopamine levels). There were no significant associations of executive functioning with the interaction between genotype and authoritative or permissive parenting ratings. The lower activity COMT rs4680 genotype may buffer the negative effect of authoritarian parenting on long-term executive functioning following injury in early childhood. The findings provide preliminary evidence for associations of parenting style with executive dysfunction in children and for a complex interplay of genetic and environmental factors as contributors to decreases in these problems after traumatic injuries in children. Further investigation is warranted to understand the interplay among genetic and

  3. Elevation of hypoxia resistance with the use of gutimine

    Energy Technology Data Exchange (ETDEWEB)

    Vinogradov, V.M.; Pastushenkov, L.V.; Sumina, E.N.

    Experimental data demonstrating the protection from the adverse effects of hypoxia offered by the antioxidant gutimine and its analogs are presented. The experiments included preliminary studies of hypoxia resistance and recovery under simulated altitude, studies of circulatory hypoxia in the brain and in intrauterine fetuses, studies of myocardial ischemia during acute and chronic experiments and studies where cardiac, kidney and limb circulation is cut off. The compound was also found to be effective in cases of hemorrhagic hypotension, complex hypoxia in peritonitis, meningococcal meningitis, and the weakening of uterine muscle contractility during prolonged deliveries, and in cranial-cerebral trauma. Mechanisms of the antihypoxic action of gutimine and its analogs have been found to include the reduction of oxygen utilization, the activation of aerobic and anaerobic metabolism, the acceleration of lactate utilization, the inhibition of lipolysis in fat tissue, and stabilization of cell membranes. Clinical observations also support the experimental data.

  4. Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study.

    Science.gov (United States)

    Courchesne-Loyer, Alexandre; Croteau, Etienne; Castellano, Christian-Alexandre; St-Pierre, Valérie; Hennebelle, Marie; Cunnane, Stephen C

    2017-07-01

    Ketones (principally β-hydroxybutyrate and acetoacetate (AcAc)) are an important alternative fuel to glucose for the human brain, but their utilisation by the brain remains poorly understood. Our objective was to use positron emission tomography (PET) to assess the impact of diet-induced moderate ketosis on cerebral metabolic rate of acetoacetate (CMRa) and glucose (CMRglc) in healthy adults. Ten participants (35 ± 15 y) received a very high fat ketogenic diet (KD) (4.5:1; lipid:protein plus carbohydrates) for four days. CMRa and CMRglc were quantified by PET before and after the KD with the tracers, 11 C-AcAc and 18 F-fluorodeoxyglucose ( 18 F-FDG), respectively. During the KD, plasma ketones increased 8-fold ( p = 0.005) while plasma glucose decreased by 24% ( p = 0.005). CMRa increased 6-fold ( p = 0.005), whereas CMRglc decreased by 20% ( p = 0.014) on the KD. Plasma ketones were positively correlated with CMRa (r = 0.93; p < 0.0001). After four days on the KD, CMRa represented 17% of whole brain energy requirements in healthy adults with a 2-fold difference across brain regions (12-24%). The CMR of ketones (AcAc and β-hydroxybutyrate combined) while on the KD was estimated to represent about 33% of brain energy requirements or approximately double the CMRa. Whether increased ketone availability raises CMR of ketones to the same extent in older people as observed here or in conditions in which chronic brain glucose hypometabolism is present remains to be determined.

  5. Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia

    Science.gov (United States)

    Lafuente, Hector; Pazos, Maria R.; Alvarez, Antonia; Mohammed, Nagat; Santos, Martín; Arizti, Maialen; Alvarez, Francisco J.; Martinez-Orgado, Jose A.

    2016-01-01

    Hypothermia is a standard treatment for neonatal encephalopathy, but nearly 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms with hypothermia improving neuroprotection. Cannabidiol could be a good candidate. Our aim was to test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets. Hypoxic-ischemic animals were randomly divided into four groups receiving 30 min after the insult: (1) normothermia and vehicle administration; (2) normothermia and cannabidiol administration; (3) hypothermia and vehicle administration; and (4) hypothermia and cannabidiol administration. Six hours after treatment, brains were processed to quantify the number of damaged neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate) and excitotoxicity (glutamate/Nacetyl-aspartate). Western blot studies were performed to quantify protein nitrosylation (oxidative stress), content of caspase-3 (apoptosis) and TNFα (inflammation). Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on cell damage, was greater than either hypothermia or cannabidiol alone. The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult. PMID:27462203

  6. Effects of hypoxia-ischemia and MK-801 treatment on the binding of a phencyclidine analogue in the developing rat brain

    International Nuclear Information System (INIS)

    Silverstein, F.S.; McDonald, J.W. III; Bommarito, M.; Johnston, M.V.

    1990-01-01

    The phencyclidine analogue [ 3 H](1-[2-thienyl]cyclohexyl)piperidine ( 3 H-TCP) binds to the ion channel associated with the N-methyl-D-aspartate receptor channel complex. In vitro autoradiography indicates that the distribution of 3 H-TCP binding in brain closely parallels that of [ 3 H]glutamate binding to the N-methyl-D-aspartate receptor. In nine 7-day-old rats, an acute focal hypoxic-ischemic insult produced by unilateral carotid artery ligation and subsequent exposure to 8% oxygen acutely reduced 3 H-TCP binding ipsilateral to the ligation by 30% in the CA1, by 27% in the CA3, by 26% in the dentate gyrus, and by 17% in the striatum compared with values from the contralateral hemisphere. In 10 littermates that received 1 mg/kg of the neuroprotective noncompetitive N-methyl-D-aspartate antagonist MK-801 immediately before hypoxic exposure, the regional distribution of 3 H-TCP binding in hypoxic-ischemic brain was relatively preserved and there were no interhemispheric asymmetries in 3 H-TCP binding densities. In addition, in three unoperated rats decapitated 24 hours after MK-801 treatment, 3 H-TCP binding was reduced by 15-35%; similar bilateral suppression of 3 H-TCP binding was detected in MK-801-treated ligates. Our data indicate that 3 H-TCP autoradiography can be used to assay the efficacy of neuroprotective agents in this experimental model of perinatal stroke

  7. Prospective longitudinal MRI study of brain volumes and diffusion changes during the first year after moderate to severe traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Veronika Brezova

    2014-01-01

    Higher ADC values were detected in the cortex in individuals with severe TBI, DAI and PTA > 2 weeks, from 3 months. There were no associations between ADC values and brain volumes, and ADC values did not predict outcome.

  8. Prognosis in moderate and severe traumatic brain injury: External validation of the IMPACT models and the role of extracranial injuries

    NARCIS (Netherlands)

    Lingsma, Hester; Andriessen, Teuntje M. J. C.; Haitsema, Iain; Horn, Janneke; van der Naalt, Joukje; Franschman, Gaby; Maas, Andrew I. R.; Vos, Pieter E.; Steyerberg, Ewout W.

    2013-01-01

    BACKGROUND: Several prognostic models to predict outcome in traumatic brain injury (TBI) have been developed, but few are externally validated. We aimed to validate the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) prognostic models in a recent unselected patient

  9. Psychomotor skills learning under chronic hypoxia.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    Wang, Bin; Wang, Xiaoqin

    2015-08-01

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

  11. A pilot randomized controlled trial of on-line interventions to improve sleep quality in adults after mild or moderate traumatic brain injury.

    Science.gov (United States)

    Theadom, Alice; Barker-Collo, Suzanne; Jones, Kelly; Dudley, Margaret; Vincent, Norah; Feigin, Valery

    2018-05-01

    To explore feasibility and potential efficacy of on-line interventions for sleep quality following a traumatic brain injury (TBI). A two parallel-group, randomized controlled pilot study. Community-based. In all, 24 participants (mean age: 35.9 ± 11.8 years) who reported experiencing sleep difficulties between 3 and 36 months after a mild or moderate TBI. Participants were randomized to receive either a cognitive behaviour therapy or an education intervention on-line. Both interventions were self-completed for 20-30 minutes per week over a six-week period. The Pittsburgh Sleep Quality Index assessed self-reported sleep quality with actigraphy used as an objective measure of sleep quality. The CNS Vital Signs on-line neuropsychological test assessed cognitive functioning and the Rivermead Post-concussion Symptoms and Quality of Life after Brain Injury questionnaires were completed pre and post intervention. Both programmes demonstrated feasibility for use post TBI, with 83.3% of participants completing the interventions. The cognitive behaviour therapy group experienced significant reductions ( F = 5.47, p = 0.04) in sleep disturbance (mean individual change = -4.00) in comparison to controls post intervention (mean individual change = -1.50) with a moderate effect size of 1.17. There were no significant group differences on objective sleep quality, cognitive functioning, post-concussion symptoms or quality of life. On-line programmes designed to improve sleep are feasible for use for adults following mild-to-moderate TBI. Based on the effect size identified in this pilot study, 128 people (64 per group) would be needed to determine clinical effectiveness.

  12. Symptoms of gonadal dysfunction are more predictive of hypopituitarism than nonspecific symptoms in screening for pituitary dysfunction following moderate or severe traumatic brain injury.

    Science.gov (United States)

    Cuesta, Martín; Hannon, Mark J; Crowley, Rachel K; Behan, Lucy Ann; Tormey, William; Rawluk, Daniel; Delargy, Mark; Agha, Amar; Thompson, Christopher J

    2016-01-01

    The economic and logistic burden of screening for hypopituitarism following moderate/severe traumatic brain injury (TBI) is considerable. A key recommendation in published guidelines is to prioritize for screening those patients with symptoms suggestive of pituitary dysfunction. The purpose of this study was to evaluate the utility of targeted screening for hypopituitarism in long-term survivors after moderate/severe TBI using referrals on the basis of symptoms. In group 1 (G1), consecutive, unselected patients were screened from the Irish National Neurosurgery Centre, whereas in group 2 (G2) patients were targeted based on the presence of symptoms suggestive of pituitary dysfunction. A total of 137 patients (113 male) were systematically screened (G1) and compared to 112 patients (77 male) referred for pituitary evaluation on the basis of suggestive symptoms (G2). The rate of GH, ACTH, gonadotrophin (GT), TSH and ADH deficiency was compared among groups. Patients referred with menstrual dysfunction had more GH (50% vs 11%, P = 0·001), ACTH (60% vs 14%, P hypopituitarism than those consecutively screened. Symptoms of hypogonadism are sufficiently predictive of hypopituitarism to justify screening for hypopituitarism after moderate/severe TBI. Nonspecific symptoms of hypopituitarism are no more predictive than unselected screening. © 2015 John Wiley & Sons Ltd.

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

    Science.gov (United States)

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

    2006-04-01

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

  14. Hypoxia tolerance in coral-reef triggerfishes (Balistidae)

    Science.gov (United States)

    Wong, Corrie C.; Drazen, Jeffrey C.; Callan, Chatham K.; Korsmeyer, Keith E.

    2018-03-01

    Despite high rates of photosynthetic oxygen production during the day, the warm waters of coral reefs are susceptible to hypoxia at night due to elevated respiration rates at higher temperatures that also reduce the solubility of oxygen. Hypoxia may be a challenge for coral-reef fish that hide in the reef to avoid predators at night. Triggerfishes (Balistidae) are found in a variety of reef habitats, but they also are known to find refuge in reef crevices and holes at night, which may expose them to hypoxic conditions. The critical oxygen tension ( P crit) was determined as the point below which oxygen uptake could not be maintained to support standard metabolic rate (SMR) for five species of triggerfish. The triggerfishes exhibited similar levels of hypoxia tolerance as other coral-reef and coastal marine fishes that encounter low oxygen levels in their environment. Two species, Rhinecanthus rectangulus and R. aculeatus, had the lowest P crit ( 3.0 kPa O2), comparable to the most hypoxia-tolerant obligate coral-dwelling gobies, while Odonus niger and Sufflamen bursa were moderately tolerant to hypoxia ( P crit 4.5 kPa), and Xanthichthys auromarginatus was intermediate ( P crit 3.7 kPa). These differences in P crit were not due to differences in oxygen demand, as all the species had a similar SMR once mass differences were taken into account. The results suggest that triggerfish species are adapted for different levels of hypoxia exposure during nocturnal sheltering within the reef.

  15. Radiation-induced hypoxia may perpetuate late normal tissue injury

    International Nuclear Information System (INIS)

    Vujaskovic, Zeljko; Anscher, Mitchell S.; Feng, Q.-F.; Rabbani, Zahid N.; Amin, Khalid; Samulski, Thaddeus S.; Dewhirst, Mark W.; Haroon, Zishan A.

    2001-01-01

    Purpose: The purpose of this study was to determine whether or not hypoxia develops in rat lung tissue after radiation. Methods and Materials: Fisher-344 rats were irradiated to the right hemithorax using a single dose of 28 Gy. Pulmonary function was assessed by measuring the changes in respiratory rate every 2 weeks, for 6 months after irradiation. The hypoxia marker was administered 3 h before euthanasia. The tissues were harvested at 6 weeks and 6 months after irradiation and processed for immunohistochemistry. Results: A moderate hypoxia was detected in the rat lungs at 6 weeks after irradiation, before the onset of functional or histopathologic changes. The more severe hypoxia, that developed at the later time points (6 months) after irradiation, was associated with a significant increase in macrophage activity, collagen deposition, lung fibrosis, and elevation in the respiratory rate. Immunohistochemistry studies revealed an increase in TGF-β, VEGF, and CD-31 endothelial cell marker, suggesting a hypoxia-mediated activation of the profibrinogenic and proangiogenic pathways. Conclusion: A new paradigm of radiation-induced lung injury should consider postradiation hypoxia to be an important contributing factor mediating a continuous production of a number of inflammatory and fibrogenic cytokines

  16. Fluoro-Jade and TUNEL staining as useful tools to identify ischemic brain damage following moderate extradural compression of sensorimotor cortex.

    Science.gov (United States)

    Kundrotiene, Jurgita; Wägner, Anna; Liljequist, Sture

    2004-01-01

    Cerebral ischemia was produced by moderate compression for 30 min of a specific brain area in the sensorimotor cortex of Sprague-Dawley rats. On day 1, that is 24 h after the transient sensorimotor compression, ischemia-exposed animals displayed a marked focal neurological deficit documented as impaired beam walking performance. This functional disturbance was mainly due to contralateral fore- and hind-limb paresis. As assessed by daily beam walking tests it was shown that there was a spontaneous recovery of motor functions over a period of five to seven days after the ischemic event. Using histopathological analysis (Nissl staining) we have previously reported that the present experimental paradigm does not produce pannecrosis (tissue cavitation) despite the highly reproducible focal neurological deficit. We now show how staining with fluorescent markers for neuronal death, that is Fluoro-Jade and TUNEL, respectively, identifies regional patterns of selective neuronal death. These observations add further support to the working hypothesis that the brain damage caused by cortical compression-induced ischemia consists of scattered, degenerating neurons in specific brain regions. Postsurgical administration of the AMPA receptor specific antagonist, LY326325 (30 mg/kg; i.p., 70 min after compression), not only improved beam walking performance on day 1 to 3, respectively but also significantly reduced the number of Fluoro-Jade stained neurons on day 5. These results suggest that enhanced AMPA/glutamate receptor activity is at least partially responsible for the ischemia-produced brain damage detected by the fluorescent marker Fluoro-Jade.

  17. Regional Brain Volumes Moderate, but Do Not Mediate, the Effects of Group-Based Exercise Training on Reductions in Loneliness in Older Adults.

    Science.gov (United States)

    Ehlers, Diane K; Daugherty, Ana M; Burzynska, Agnieszka Z; Fanning, Jason; Awick, Elizabeth A; Chaddock-Heyman, Laura; Kramer, Arthur F; McAuley, Edward

    2017-01-01

    Introduction: Despite the prevalence of and negative health consequences associated with perceived loneliness in older adults, few studies have examined interactions among behavioral, psychosocial, and neural mechanisms. Research suggests that physical activity and improvements in perceived social support and stress are related to reductions in loneliness. Yet, the influence of brain structure on these changes is unknown. The present study examined whether change in regional brain volume mediated the effects of changes in social support and stress on change in perceived loneliness after an exercise intervention. We also examined the extent to which baseline brain volumes moderated the relationship between changes in social support, stress, and loneliness. Methods: Participants were 247 older adults (65.4 ± 4.6 years-old) enrolled in a 6-month randomized controlled trial comprised of four exercise conditions: Dance ( n = 69), Strength/Stretching/Stability ( n = 70), Walk ( n = 54), and Walk Plus ( n = 54). All groups met for 1 h, three times weekly. Participants completed questionnaires assessing perceived social support, stress, and loneliness at baseline and post-intervention. Regional brain volumes (amygdala, prefrontal cortex [PFC], hippocampus) before and after intervention were measured with automatic segmentation of each participant's T1-weighted structural MRI. Data were analyzed in a latent modeling framework. Results: Perceived social support increased ( p = 0.003), while stress ( p loneliness ( p = 0.001) decreased over the intervention. Increased social support directly (-0.63, p loneliness. Changes in amygdala, PFC, and hippocampus volumes were unrelated to change in psychosocial variables (all p ≥ 0.44). However, individuals with larger baseline amygdalae experienced greater decreases in loneliness due to greater reductions in stress (0.35, p = 0.02). Further, individuals with larger baseline PFC volumes experienced greater reductions in stress due

  18. Regional Brain Volumes Moderate, but Do Not Mediate, the Effects of Group-Based Exercise Training on Reductions in Loneliness in Older Adults

    Directory of Open Access Journals (Sweden)

    Diane K. Ehlers

    2017-04-01

    Full Text Available Introduction: Despite the prevalence of and negative health consequences associated with perceived loneliness in older adults, few studies have examined interactions among behavioral, psychosocial, and neural mechanisms. Research suggests that physical activity and improvements in perceived social support and stress are related to reductions in loneliness. Yet, the influence of brain structure on these changes is unknown. The present study examined whether change in regional brain volume mediated the effects of changes in social support and stress on change in perceived loneliness after an exercise intervention. We also examined the extent to which baseline brain volumes moderated the relationship between changes in social support, stress, and loneliness.Methods: Participants were 247 older adults (65.4 ± 4.6 years-old enrolled in a 6-month randomized controlled trial comprised of four exercise conditions: Dance (n = 69, Strength/Stretching/Stability (n = 70, Walk (n = 54, and Walk Plus (n = 54. All groups met for 1 h, three times weekly. Participants completed questionnaires assessing perceived social support, stress, and loneliness at baseline and post-intervention. Regional brain volumes (amygdala, prefrontal cortex [PFC], hippocampus before and after intervention were measured with automatic segmentation of each participant's T1-weighted structural MRI. Data were analyzed in a latent modeling framework.Results: Perceived social support increased (p = 0.003, while stress (p < 0.001, and loneliness (p = 0.001 decreased over the intervention. Increased social support directly (−0.63, p < 0.01 and indirectly, through decreased stress (−0.10, p = 0.02, predicted decreased loneliness. Changes in amygdala, PFC, and hippocampus volumes were unrelated to change in psychosocial variables (all p ≥ 0.44. However, individuals with larger baseline amygdalae experienced greater decreases in loneliness due to greater reductions in stress (0.35, p = 0

  19. Brain oxidative metabolism of the newborn dog: correlation between 31P NMR spectroscopy and pyridine nucleotide redox state.

    Science.gov (United States)

    Mayevsky, A; Nioka, S; Subramanian, V H; Chance, B

    1988-04-01

    The effects of both anoxia and short- and long-term hypoxia on brain oxidative metabolism were studied in newborn dogs. Oxidative metabolism was evaluated by two independent measures: in vivo continuous monitoring of mitochondrial NADH redox state and energy stores as calculated from the phosphocreatine (PCr)/Pi levels measured by 31P nuclear magnetic resonance (NMR) spectroscopy. The hemodynamic response to low oxygen supply was further evaluated by measuring the changes in the reflected light intensity at 366 nm (the excitation wavelength for NADH). The animal underwent surgery and was prepared for monitoring of the two signals (NADH and PCr/Pi). It was then placed inside a Phosphoenergetics 260-80 NMR spectrometer magnet with a 31-cm bore. Each animal (1-21 days old) was exposed to short-term anoxia or hypoxia as well as to long-term hypoxia (1-2 h). The results can be summarized as follow: (a) In the normoxic brain, the ratio between PCr and Pi was greater than 1 (1.2-1.4), while under hypoxia or asphyxia a significant decrease that was correlated to the FiO2 levels was recorded. (b) A clear correlation was found between the decrease in PCr/Pi values and the increased NADH redox state developed under decreased O2 supply to the brain. (c) Exposing the animal to moderately long-term hypoxia led to a stabilized low-energy state of the brain with a good recovery after rebreathing normal air. (d) Under long-term and severe hypoxia, the microcirculatory autoregulatory mechanism was damaged and massive vasoconstriction was optically recorded simultaneously with a significant decrease in PCr/Pi values.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. The moderator's moderator

    International Nuclear Information System (INIS)

    Williamson, G.K.

    1990-01-01

    A brief account is given of the development of graphite moderators for Magnox and advanced gas cooled reactors. The accident at Windscale in 1957 brought to worldwide attention the importance of irradiation damage in graphite and the consequent storage of Wigner energy. In spite of the Windscale setback, preparations for the civil programme of Magnox reactors went ahead apace. Some of the background to the disastrous Dungeness B tender is presented. In spite of all the difficulties and uncertainties, the graphite in UK reactors has performed well. In all cases, as far as the author is aware, the behaviour of the graphite moderators will not prevent design life being achieved. (author)

  1. Health-related quality of life after mild, moderate and severe traumatic brain injury: patterns and predictors of suboptimal functioning during the first year after injury.

    Science.gov (United States)

    Scholten, A C; Haagsma, J A; Andriessen, T M J C; Vos, P E; Steyerberg, E W; van Beeck, E F; Polinder, S

    2015-04-01

    The Glasgow Outcome Scale Extended (GOSE) is the established functional outcome scale to assess disability following traumatic brain injury (TBI), however does not capture the patient's subjective perspective. Health-related quality of life (HRQL) does capture the individual's perception of disability after TBI, and has therefore been recognized as an important outcome in TBI. In contrast to GOSE, HRQL enables comparison of health outcome across various disease states and with healthy individuals. We aimed to assess functional outcome, HRQL, recovery, and predictors of 6 and 12-month outcome in a comprehensive sample of patients with mild, moderate or severe TBI, and to examine the relationship between functional impairment (GOSE) and HRQL. A prospective cohort study was conducted among a sample of 2066 adult TBI patients who attended the emergency department (ED). GOSE was determined through questionnaires or structured interviews. Questionnaires 6 and 12 months after ED treatment included socio-demographic information and HRQL measured with Short-Form Health Survey (SF-36; reflecting physical, mental and social functioning) and Perceived Quality of Life Scale (PQoL; measuring degree of satisfaction with functioning). 996 TBI survivors with mild, moderate or severe TBI completed the 6-month questionnaire. Functional outcome and HRQL after moderate or severe TBI was significantly lower than after mild TBI. Patients with moderate TBI showed greatest improvement. After one year, the mild TBI group reached outcomes comparable to population norms. TBI of all severities highly affected SF-36 domains physical and social functioning, and physical and emotional role functioning. GOSE scores were highly related to all SF-36 domains and PQoL scores. Female gender, older age, co-morbidity and high ISS were strongest independent predictors of decreased HRQL at 6 and 12 months after TBI. HRQL and recovery patterns differ for mild, moderate and severe TBI. This study indicates

  2. Effects of hypoxia and ocean acidification on the upper thermal niche boundaries of coral reef fishes.

    Science.gov (United States)

    Ern, Rasmus; Johansen, Jacob L; Rummer, Jodie L; Esbaugh, Andrew J

    2017-07-01

    Rising ocean temperatures are predicted to cause a poleward shift in the distribution of marine fishes occupying the extent of latitudes tolerable within their thermal range boundaries. A prevailing theory suggests that the upper thermal limits of fishes are constrained by hypoxia and ocean acidification. However, some eurythermal fish species do not conform to this theory, and maintain their upper thermal limits in hypoxia. Here we determine if the same is true for stenothermal species. In three coral reef fish species we tested the effect of hypoxia on upper thermal limits, measured as critical thermal maximum (CT max ). In one of these species we also quantified the effect of hypoxia on oxygen supply capacity, measured as aerobic scope (AS). In this species we also tested the effect of elevated CO 2 (simulated ocean acidification) on the hypoxia sensitivity of CT max We found that CT max was unaffected by progressive hypoxia down to approximately 35 mmHg, despite a substantial hypoxia-induced reduction in AS. Below approximately 35 mmHg, CT max declined sharply with water oxygen tension ( P w O 2 ). Furthermore, the hypoxia sensitivity of CT max was unaffected by elevated CO 2 Our findings show that moderate hypoxia and ocean acidification do not constrain the upper thermal limits of these tropical, stenothermal fishes. © 2017 The Author(s).

  3. Hypoxia-inducible factor-1 alpha has a key role in hypoxic preconditioning.

    Science.gov (United States)

    Taie, Satoshi; Ono, Junichiro; Iwanaga, Yasuyuki; Tomita, Shuhei; Asaga, Takehiko; Chujo, Kosuke; Ueki, Masaaki

    2009-08-01

    Sublethal hypoxia induces tolerance to subsequent hypoxic insults in a process known as hypoxic preconditioning (HP). Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a key transcription protein involved in the mechanism of HP. In this study, we investigated the effects of HP on tissue oxygenation and expression of HIF-1 alpha gene targets in the brain using neural cell-specific HIF-1 alpha-deficient mice. The animals were exposed to 8% oxygen for 3 hours. Twenty-four hours later, the oxygen partial pressure (pO(2)) of brain tissue and gene expression were measured during hypoxia. HP improved the pO(2) of brain tissue during subsequent hypoxia with upregulated inducible nitric oxide synthase in wild-type mice, whereas HP had no detectable effect in the mutant mice. Our results indicate that the protective effects of HP may be partially mediated by improving tissue oxygenation via HIF-1 alpha and inducible nitric oxide synthase.

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

    Science.gov (United States)

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

    2012-04-01

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

  5. How impulsivity relates to compulsive buying and the burden perceived by caregivers after moderate-to-severe traumatic brain injury.

    Science.gov (United States)

    Rochat, Lucien; Beni, Catia; Billieux, Joël; Annoni, Jean-Marie; Van der Linden, Martial

    2011-01-01

    Impulsivity is a core feature in patients with traumatic brain injury (TBI). The aim of the study is to investigate how a specific dimension of impulsivity, namely urgency (the tendency to act rashly when distressed), might shed new light on the aetiology of compulsive buying proneness in patients with TBI and to explore how urgency and compulsive buying relate to the burden perceived by the caregivers. Caregivers of 74 patients with TBI were given 3 questionnaires in order to assess their subjective burden as well as patients' impulsivity and compulsive buying proneness. Both urgency and compulsive buying tendencies significantly increased after TBI. Furthermore, path analyses revealed that current urgency was both directly and indirectly related to the subjective burden perceived by the caregivers, and this indirect pathway was mediated by compulsive buying. Urgency plays a central role in understanding specific problematic behaviours after TBI and their impact on caregivers. These findings are discussed in light of the cognitive processes underlying the urgency component of impulsivity in relation to the occurrence of compulsive buying behaviours after TBI. Copyright © 2011 S. Karger AG, Basel.

  6. Effects of neurofeedback on the short-term memory and continuous attention of patients with moderate traumatic brain injury: A preliminary randomized controlled clinical trial

    Directory of Open Access Journals (Sweden)

    Reza Rostami

    2017-10-01

    Full Text Available Purpose: There are some studies which showed neurofeedback therapy (NFT can be effective in clients with traumatic brain injury (TBI history. However, randomized controlled clinical trials are still needed for evaluation of this treatment as a standard option. This preliminary study was aimed to evaluate the effect of NFT on continuous attention (CA and short-term memory (STM of clients with moderate TBI using a randomized controlled clinical trial (RCT. Methods: In this preliminary RCT, seventeen eligible patients with moderate TBI were randomly allocated in two intervention and control groups. All the patients were evaluated for CA and STM using the visual continuous attention test and Wechsler memory scale-4th edition (WMS-IV test, respectively, both at the time of inclusion to the project and four weeks later. The intervention group participated in 20 sessions of NFT through the first four weeks. Conversely, the control group participated in the same NF sessions from the fifth week to eighth week of the project. Results: Eight subjects in the intervention group and five subjects in the control group completed the study. The mean and standard deviation of participants' age were (26.75 ± 15.16 years and (27.60 ± 8.17 years in experiment and control groups, respectively. All of the subjects were male. No significant improvement was observed in any variables of the visual continuous attention test and WMS-IV test between two groups (p ≥ 0.05. Conclusion: Based on our literature review, it seems that our study is the only study performed on the effect of NFT on TBI patients with control group. NFT has no effect on CA and STM in patients with moderate TBI. More RCTs with large sample sizes, more sessions of treatment, longer time of follow-up and different protocols are recommended. Keywords: Neurofeedback, Brain injuries, Attention, Short-term memory

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

    Science.gov (United States)

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

    2017-09-01

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

  8. Cerebral Perfusion Pressure Targets Individualized to Pressure-Reactivity Index in Moderate to Severe Traumatic Brain Injury: A Systematic Review.

    Science.gov (United States)

    Needham, Edward; McFadyen, Charles; Newcombe, Virginia; Synnot, Anneliese J; Czosnyka, Marek; Menon, David

    2017-03-01

    Traumatic brain injury (TBI) frequently triggers a disruption of cerebral autoregulation. The cerebral perfusion pressure (CPP) at which autoregulation is optimal ("CPPopt") varies between individuals, and can be calculated based on fluctuations between arterial blood pressure and intracranial pressure. This review assesses the effect of individualizing CPP targets to pressure reactivity index (a measure of autoregulation) in patients with TBI. Cochrane Central Register of Controlled Trials, MEDLINE®, Embase, and Cumulative Index of Nursing and Allied Health Literature were searched in March 2015 for studies assessing the effect of targeting CPPopt in TBI. We included all studies that assessed the impact of targeting CPPopt on outcomes including mortality, neurological outcome, and physiological changes. Risk of bias was assessed using the RTI Item Bank and evidence quality was considered using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Eight cohort studies (based on six distinct data sets) assessing the association between CPPopt and mortality, Glasgow Outcome Scale and physiological measures in TBI were included. The quality of evidence was deemed very low based on the GRADE criteria. Although the data suggest an association between variation from CPPopt and poor clinical outcome at 6 months, the quality of evidence prevents firm conclusions, particularly regarding causality, from being drawn. Available data suggest that targeting CPPopt might represent a technique to improve outcomes following TBI, but currently there is insufficient high-quality data to support a recommendation for use in clinical practice. Further prospective, randomized controlled studies should be undertaken to clarify its role in the acute management of TBI.

  9. The expanding universe of hypoxia.

    Science.gov (United States)

    Zhang, Huafeng; Semenza, Gregg L

    2008-07-01

    Reduced oxygen availability (hypoxia) is sensed and transduced into changes in the activity or expression of cellular macromolecules. These responses impact on virtually all areas of biology and medicine. In this meeting report, we summarize major developments in the field that were presented at the 2008 Keystone Symposium on Cellular, Physiological, and Pathogenic Responses to Hypoxia.

  10. Hypoxia-inducible factor-1α upregulation in microglia following hypoxia protects against ischemia-induced cerebral infarction.

    Science.gov (United States)

    Huang, Tao; Huang, Weiyi; Zhang, Zhiqiang; Yu, Lei; Xie, Caijun; Zhu, Dongan; Peng, Zizhuang; Chen, Jiehan

    2014-10-01

    Activated microglia were considered to be the toxic inflammatory mediators that induce neuron degeneration after brain ischemia. Hypoxia can enhance the expression of hypoxia-inducible factor-1α (HIF-1α) in microglia and cause microglial activation. However, intermittent hypoxia has been reported recently to be capable of protecting the body from myocardial ischemia. We established a high-altitude environment as the hypoxic condition in this study. The hypoxic condition displayed a neuroprotective effect after brain ischemia, and mice exposed to this condition presented better neurological performance and smaller infarct size. At the same time, a high level of HIF-1α, low level of isoform of nitric oxide synthase, and a reduction in microglial activation were also seen in ischemic focus of hypoxic mice. However, this neuroprotective effect could be blocked by 2-methoxyestradiol, the HIF-1α inhibitor. Our finding suggested that HIF-1α expression was involved in microglial activation in vitro and was regulated by oxygen supply. The microglia were inactivated by re-exposure to hypoxia, which might be due to overexpression of HIF-1α. These results indicated that hypoxic conditions can be exploited to achieve maximum neuroprotection after brain ischemia. This mechanism possibly lies in microglial inactivation through regulation of the expression of HIF-1α.

  11. Weakening of the radioprotective action of gas hypoxia with growth of ascitic tumors

    Energy Technology Data Exchange (ETDEWEB)

    Aytmagambetova, B Z; Shmakova, N L; Fadeyeva, T A

    1975-06-27

    It was shown previously that moderate hypoxia induced by breathing oxygen-poor air (5 percent O/sub 2/) reduces the lethal effect of the total irradiation of mice, while with local irradiation of tumors reduction of tumor growth rate is even more marked in hypoxia-protected animals than with irradiation of mice in normal air. This suggests the possible therapeutic application of hypoxia. It was found that acute gas hypoxia strongly retards radiation damage to bone marrow, both qualitatively (type of cells affected) and quantitatively. In addition, a definite weakening of the protective effect of hypoxia was observed, this being proportional to increase in tumor size. Planned future tests involving direct dynamic measurement of oxygen stress as a function of amount of ascites are expected to supply further information on reduction of radiosensitivity of normal tissues and on the selective intensification of tumor regression. Graphic data accompany the paper. (JPRS)

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

    Science.gov (United States)

    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. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Midcervical neuronal discharge patterns during and following hypoxia

    Science.gov (United States)

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

    2014-01-01

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

  14. A genetically encoded biosensor for visualising hypoxia responses in vivo

    Directory of Open Access Journals (Sweden)

    Tvisha Misra

    2017-02-01

    Full Text Available Cells experience different oxygen concentrations depending on location, organismal developmental stage, and physiological or pathological conditions. Responses to reduced oxygen levels (hypoxia rely on the conserved hypoxia-inducible factor 1 (HIF-1. Understanding the developmental and tissue-specific responses to changing oxygen levels has been limited by the lack of adequate tools for monitoring HIF-1 in vivo. To visualise and analyse HIF-1 dynamics in Drosophila, we used a hypoxia biosensor consisting of GFP fused to the oxygen-dependent degradation domain (ODD of the HIF-1 homologue Sima. GFP-ODD responds to changing oxygen levels and to genetic manipulations of the hypoxia pathway, reflecting oxygen-dependent regulation of HIF-1 at the single-cell level. Ratiometric imaging of GFP-ODD and a red-fluorescent reference protein reveals tissue-specific differences in the cellular hypoxic status at ambient normoxia. Strikingly, cells in the larval brain show distinct hypoxic states that correlate with the distribution and relative densities of respiratory tubes. We present a set of genetic and image analysis tools that enable new approaches to map hypoxic microenvironments, to probe effects of perturbations on hypoxic signalling, and to identify new regulators of the hypoxia response.

  15. BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: a prospective study.

    Science.gov (United States)

    Buchmann, Arlette F; Hellweg, Rainer; Rietschel, Marcella; Treutlein, Jens; Witt, Stephanie H; Zimmermann, Ulrich S; Schmidt, Martin H; Esser, Günter; Banaschewski, Tobias; Laucht, Manfred; Deuschle, Michael

    2013-08-01

    Recent studies have emphasized an important role for neurotrophins, such as brain-derived neurotrophic factor (BDNF), in regulating the plasticity of neural circuits involved in the pathophysiology of stress-related diseases. The aim of the present study was to examine the interplay of the BDNF Val⁶⁶Met and the serotonin transporter promoter (5-HTTLPR) polymorphisms in moderating the impact of early-life adversity on BDNF plasma concentration and depressive symptoms. Participants were taken from an epidemiological cohort study following the long-term outcome of early risk factors from birth into young adulthood. In 259 individuals (119 males, 140 females), genotyped for the BDNF Val⁶⁶Met and the 5-HTTLPR polymorphisms, plasma BDNF was assessed at the age of 19 years. In addition, participants completed the Beck Depression Inventory (BDI). Early adversity was determined according to a family adversity index assessed at 3 months of age. Results indicated that individuals homozygous for both the BDNF Val and the 5-HTTLPR L allele showed significantly reduced BDNF levels following exposure to high adversity. In contrast, BDNF levels appeared to be unaffected by early psychosocial adversity in carriers of the BDNF Met or the 5-HTTLPR S allele. While the former group appeared to be most susceptible to depressive symptoms, the impact of early adversity was less pronounced in the latter group. This is the first preliminary evidence indicating that early-life adverse experiences may have lasting sequelae for plasma BDNF levels in humans, highlighting that the susceptibility to this effect is moderated by BDNF Val⁶⁶Met and 5-HTTLPR genotype. Copyright © 2013. Published by Elsevier B.V.

  16. Effect of Memantine on Serum Levels of Neuron-Specific Enolase and on the Glasgow Coma Scale in Patients With Moderate Traumatic Brain Injury.

    Science.gov (United States)

    Mokhtari, Majid; Nayeb-Aghaei, Hossein; Kouchek, Mehran; Miri, Mir Mohammad; Goharani, Reza; Amoozandeh, Arash; Akhavan Salamat, Sina; Sistanizad, Mohammad

    2018-01-01

    Traumatic brain injury (TBI) is a major cause of disability and death globally. Despite significant progress in neuromonitoring and neuroprotection, pharmacological interventions have failed to generate favorable results. We examined the effect of memantine on serum levels of neuron-specific enolase (NSE), a marker of neuronal damage, and the Glasgow Coma Scale (GCS) in patients with moderate TBI. Patients were randomly assigned to the control group (who received standard TBI management) and the treatment group (who, alongside their standard management, received enteral memantine 30 mg twice daily for 7 days). Patients' clinical data, GCS, findings of head computed tomography, and serum NSE levels were collected during the study. Forty-one patients were randomized into the control and treatment groups, 19 and 22 patients respectively. Baseline characteristics and serum NSE levels were not significantly different between the 2 groups. The mean serum NSE levels for the memantine and the control groups on day 3 were 7.95 ± 2.86 and 12.33 ± 7.09 ng/mL, respectively (P = .05), and on day 7 were 5.03 ± 3.25 and 10.04 ± 5.72 ng/mL, respectively (P = .003). The mean GCS on day 3 was 12.3 ± 2.0 and 10.9 ± 1.9 in the memantine and control groups, respectively (P = .03). Serum NSE levels and GCS changes were negatively correlated (r = -0.368, P = .02). Patients with moderate TBI who received memantine had significantly reduced serum NSE levels by day 7 and marked improvement in their GCS scores on day 3 of the study. © 2017, The American College of Clinical Pharmacology.

  17. Facial emotion recognition deficits following moderate-severe Traumatic Brain Injury (TBI): re-examining the valence effect and the role of emotion intensity.

    Science.gov (United States)

    Rosenberg, Hannah; McDonald, Skye; Dethier, Marie; Kessels, Roy P C; Westbrook, R Frederick

    2014-11-01

    Many individuals who sustain moderate-severe traumatic brain injuries (TBI) are poor at recognizing emotional expressions, with a greater impairment in recognizing negative (e.g., fear, disgust, sadness, and anger) than positive emotions (e.g., happiness and surprise). It has been questioned whether this "valence effect" might be an artifact of the wide use of static facial emotion stimuli (usually full-blown expressions) which differ in difficulty rather than a real consequence of brain impairment. This study aimed to investigate the valence effect in TBI, while examining emotion recognition across different intensities (low, medium, and high). Twenty-seven individuals with TBI and 28 matched control participants were tested on the Emotion Recognition Task (ERT). The TBI group was more impaired in overall emotion recognition, and less accurate recognizing negative emotions. However, examining the performance across the different intensities indicated that this difference was driven by some emotions (e.g., happiness) being much easier to recognize than others (e.g., fear and surprise). Our findings indicate that individuals with TBI have an overall deficit in facial emotion recognition, and that both people with TBI and control participants found some emotions more difficult than others. These results suggest that conventional measures of facial affect recognition that do not examine variance in the difficulty of emotions may produce erroneous conclusions about differential impairment. They also cast doubt on the notion that dissociable neural pathways underlie the recognition of positive and negative emotions, which are differentially affected by TBI and potentially other neurological or psychiatric disorders.

  18. Coastal hypoxia and sediment biogeochemistry

    Directory of Open Access Journals (Sweden)

    J. J. Middelburg

    2009-07-01

    Full Text Available The intensity, duration and frequency of coastal hypoxia (oxygen concentration <63 μM are increasing due to human alteration of coastal ecosystems and changes in oceanographic conditions due to global warming. Here we provide a concise review of the consequences of coastal hypoxia for sediment biogeochemistry. Changes in bottom-water oxygen levels have consequences for early diagenetic pathways (more anaerobic at expense of aerobic pathways, the efficiency of re-oxidation of reduced metabolites and the nature, direction and magnitude of sediment-water exchange fluxes. Hypoxia may also lead to more organic matter accumulation and burial and the organic matter eventually buried is also of higher quality, i.e. less degraded. Bottom-water oxygen levels also affect the organisms involved in organic matter processing with the contribution of metazoans decreasing as oxygen levels drop. Hypoxia has a significant effect on benthic animals with the consequences that ecosystem functions related to macrofauna such as bio-irrigation and bioturbation are significantly affected by hypoxia as well. Since many microbes and microbial-mediated biogeochemical processes depend on animal-induced transport processes (e.g. re-oxidation of particulate reduced sulphur and denitrification, there are indirect hypoxia effects on biogeochemistry via the benthos. Severe long-lasting hypoxia and anoxia may result in the accumulation of reduced compounds in sediments and elimination of macrobenthic communities with the consequences that biogeochemical properties during trajectories of decreasing and increasing oxygen may be different (hysteresis with consequences for coastal ecosystem dynamics.

  19. Effects of neurofeedback on the short-term memory and continuous attention of patients with moderate traumatic brain injury: A preliminary randomized controlled clinical trial.

    Science.gov (United States)

    Rostami, Reza; Salamati, Payman; Yarandi, Kourosh Karimi; Khoshnevisan, Alireza; Saadat, Soheil; Kamali, Zeynab Sadat; Ghiasi, Somaie; Zaryabi, Atefeh; Ghazi Mir Saeid, Seyed Shahab; Arjipour, Mehdi; Rezaee-Zavareh, Mohammad Saeid; Rahimi-Movaghar, Vafa

    2017-10-01

    There are some studies which showed neurofeedback therapy (NFT) can be effective in clients with traumatic brain injury (TBI) history. However, randomized controlled clinical trials are still needed for evaluation of this treatment as a standard option. This preliminary study was aimed to evaluate the effect of NFT on continuous attention (CA) and short-term memory (STM) of clients with moderate TBI using a randomized controlled clinical trial (RCT). In this preliminary RCT, seventeen eligible patients with moderate TBI were randomly allocated in two intervention and control groups. All the patients were evaluated for CA and STM using the visual continuous attention test and Wechsler memory scale-4th edition (WMS-IV) test, respectively, both at the time of inclusion to the project and four weeks later. The intervention group participated in 20 sessions of NFT through the first four weeks. Conversely, the control group participated in the same NF sessions from the fifth week to eighth week of the project. Eight subjects in the intervention group and five subjects in the control group completed the study. The mean and standard deviation of participants' age were (26.75 ± 15.16) years and (27.60 ± 8.17) years in experiment and control groups, respectively. All of the subjects were male. No significant improvement was observed in any variables of the visual continuous attention test and WMS-IV test between two groups (p ≥ 0.05). Based on our literature review, it seems that our study is the only study performed on the effect of NFT on TBI patients with control group. NFT has no effect on CA and STM in patients with moderate TBI. More RCTs with large sample sizes, more sessions of treatment, longer time of follow-up and different protocols are recommended. Copyright © 2017 Daping Hospital and the Research Institute of Surgery of the Third Military Medical University. Production and hosting by Elsevier B.V. All rights reserved.

  20. Comparing the effect of hypercapnia and hypoxia on the electroencephalogram during wakefulness.

    Science.gov (United States)

    Wang, David; Yee, Brendon J; Wong, Keith K; Kim, Jong Won; Dijk, Derk-Jan; Duffin, James; Grunstein, Ronald R

    2015-01-01

    Hypoxia has been postulated as a key mechanism for neurocognitive impairment in sleep-disordered breathing. However, the effect of hypoxia on the electroencephalogram (EEG) is not clear. We examined quantitative EEG recordings from 20 normal volunteers under three 5-min ventilatory control protocols: progressive hypercapnia with iso-hyperoxia (pO2=150mmHg) (Protocol 1), progressive hypercapnia with iso-hypoxia (pO2=50mmHg) (Protocol 2), and progressive hypoxia with a CO2 scrubber in the circuit (Protocol 3). Each protocol started with a 5-min session of breathing room air as baseline. In Protocol 1, compared to its baseline, iso-hyperoxia hypercapnia led to a lower Alpha% and higher Delta/Alpha (D/A) ratio. Similarly, in Protocol 2, the iso-hypoxia hypercapnia induced a higher Delta%, a lower Alpha% and higher D/A ratio. No difference was found in any EEG spectral band including the D/A ratio when Protocols 1 & 2 were compared. In Protocol 3, the Delta%, Alpha% and D/A ratio recorded during hypoxia were not significantly different from baseline. We found that hypercapnia, but not hypoxia, may play a key role in slowing of the EEG in healthy humans. Hypercapnia may be a greater influence than hypoxia on brain neuroelectrical activities. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  1. Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus.

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    Bethany L Peterson

    Full Text Available Naked mole-rats are highly social and strictly subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. Brain slices from naked mole-rats show extreme tolerance to hypoxia compared to slices from other mammals, as indicated by maintenance of synaptic transmission under more hypoxic conditions and three fold longer latency to anoxic depolarization. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death may be the elevation of intracellular calcium concentration. In the present study, we used fluorescent imaging techniques to measure relative intracellular calcium changes in CA1 pyramidal cells of hippocampal slices during hypoxia. We found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from naked mole-rats compared to slices from laboratory mice. This was the case for both neonatal (postnatal day 6 and older (postnatal day 20 age groups. Furthermore, while both species demonstrated more calcium accumulation at older ages, the older naked mole-rats showed a smaller calcium accumulation response than even the younger mice. A blunted intracellular calcium response to hypoxia may contribute to the extreme hypoxia tolerance of naked mole-rat neurons. The results are discussed in terms of a general hypothesis that a very prolonged or arrested developmental process may allow adult naked mole-rat brain to retain the hypoxia tolerance normally only seen in neonatal mammals.

  2. Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus.

    Science.gov (United States)

    Peterson, Bethany L; Larson, John; Buffenstein, Rochelle; Park, Thomas J; Fall, Christopher P

    2012-01-01

    Naked mole-rats are highly social and strictly subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. Brain slices from naked mole-rats show extreme tolerance to hypoxia compared to slices from other mammals, as indicated by maintenance of synaptic transmission under more hypoxic conditions and three fold longer latency to anoxic depolarization. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death may be the elevation of intracellular calcium concentration. In the present study, we used fluorescent imaging techniques to measure relative intracellular calcium changes in CA1 pyramidal cells of hippocampal slices during hypoxia. We found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from naked mole-rats compared to slices from laboratory mice. This was the case for both neonatal (postnatal day 6) and older (postnatal day 20) age groups. Furthermore, while both species demonstrated more calcium accumulation at older ages, the older naked mole-rats showed a smaller calcium accumulation response than even the younger mice. A blunted intracellular calcium response to hypoxia may contribute to the extreme hypoxia tolerance of naked mole-rat neurons. The results are discussed in terms of a general hypothesis that a very prolonged or arrested developmental process may allow adult naked mole-rat brain to retain the hypoxia tolerance normally only seen in neonatal mammals.

  3. Hypoxic preconditioning induces neuroprotective stanniocalcin-1 in brain via IL-6 signaling

    DEFF Research Database (Denmark)

    Westberg, Johan A; Serlachius, Martina; Lankila, Petri

    2007-01-01

    BACKGROUND AND PURPOSE: Exposure of animals for a few hours to moderate hypoxia confers relative protection against subsequent ischemic brain damage. This phenomenon, known as hypoxic preconditioning, depends on new RNA and protein synthesis, but its molecular mechanisms are poorly understood...... originally reported expression of mammalian STC-1 in brain neurons and showed that STC-1 guards neurons against hypercalcemic and hypoxic damage. METHODS: We treated neural Paju cells with IL-6 and measured the induction of STC-1 mRNA. In addition, we quantified the effect of hypoxic preconditioning on Stc-1...... mRNA levels in brains of wild-type and IL-6 deficient mice. Furthermore, we monitored the Stc-1 response in brains of wild-type and transgenic mice, overexpressing IL-6 in the astroglia, before and after induced brain injury. RESULTS: Hypoxic preconditioning induced an upregulated expression of Stc...

  4. Baseline performance and learning rate of conceptual and perceptual skill-learning tasks: the effect of moderate to severe traumatic brain injury.

    Science.gov (United States)

    Vakil, Eli; Lev-Ran Galon, Carmit

    2014-01-01

    Existing literature presents a complex and inconsistent picture of the specific deficiencies involved in skill learning following traumatic brain injury (TBI). In an attempt to address this difficulty, individuals with moderate to severe TBI (n = 29) and a control group (n = 29) were tested with two different skill-learning tasks: conceptual (i.e., Tower of Hanoi Puzzle, TOHP) and perceptual (i.e., mirror reading, MR). Based on previous studies of the effect of divided attention on these tasks and findings regarding the effect of TBI on conceptual and perceptual priming tasks, it was predicted that the group with TBI would show impaired baseline performance compared to controls in the TOHP task though their learning rate would be maintained, while both baseline performance and learning rate on the MR task would be maintained. Consistent with our predictions, overall baseline performance of the group with TBI was impaired in the TOHP test, while the learning rate was not. The learning rate on the MR task was preserved but, contrary to our prediction, response time of the group with TBI was slower than that of controls. The pattern of results observed in the present study was interpreted to possibly reflect an impairment of both the frontal lobes as well as that of diffuse axonal injury, which is well documented as being affected by TBI. The former impairment affects baseline performance of the conceptual learning skill, while the latter affects the overall slower performance of the perceptual learning skill.

  5. Are Patients Ready for “EARLYSTIM”? Attitudes towards Deep Brain Stimulation among Female and Male Patients with Moderately Advanced Parkinson's Disease

    Science.gov (United States)

    2017-01-01

    Objective. To explore, in female and male patients with medically treated, moderately advanced Parkinson's disease (PD), their knowledge and reasoning about Deep Brain Stimulation (DBS). Methods. 23 patients with PD (10 women), aged 46–70, were interviewed at a mean of 8 years after diagnosis, with open-ended questions concerning their reflections and considerations about DBS. The interviews were transcribed verbatim and analysed according to the difference and similarity technique in Grounded Theory. Results. From the patients' narratives, the core category “Processing DBS: balancing symptoms, fears and hopes” was established. The patients were knowledgeable about DBS and expressed cautious and well considered attitudes towards its outcome but did not consider themselves ill enough to undergo DBS. They were aware of its potential side-effects. They considered DBS as the last option when oral medication is no longer sufficient. There was no difference between men and women in their reasoning and attitudes towards DBS. Conclusion. This study suggests that knowledge about the pros and cons of DBS exists among PD patients and that they have a cautious attitude towards DBS. Our patients did not seem to endorse an earlier implementation of DBS, and they considered that it should be the last resort when really needed. PMID:28458943

  6. Are Patients Ready for “EARLYSTIM”? Attitudes towards Deep Brain Stimulation among Female and Male Patients with Moderately Advanced Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Maria Sperens

    2017-01-01

    Full Text Available Objective. To explore, in female and male patients with medically treated, moderately advanced Parkinson’s disease (PD, their knowledge and reasoning about Deep Brain Stimulation (DBS. Methods. 23 patients with PD (10 women, aged 46–70, were interviewed at a mean of 8 years after diagnosis, with open-ended questions concerning their reflections and considerations about DBS. The interviews were transcribed verbatim and analysed according to the difference and similarity technique in Grounded Theory. Results. From the patients’ narratives, the core category “Processing DBS: balancing symptoms, fears and hopes” was established. The patients were knowledgeable about DBS and expressed cautious and well considered attitudes towards its outcome but did not consider themselves ill enough to undergo DBS. They were aware of its potential side-effects. They considered DBS as the last option when oral medication is no longer sufficient. There was no difference between men and women in their reasoning and attitudes towards DBS. Conclusion. This study suggests that knowledge about the pros and cons of DBS exists among PD patients and that they have a cautious attitude towards DBS. Our patients did not seem to endorse an earlier implementation of DBS, and they considered that it should be the last resort when really needed.

  7. Combining hypobaric hypoxia or hyperbaric oxygen postconditioning with memantine reduces neuroprotection in 7-day-old rat hypoxia-ischemia.

    Science.gov (United States)

    Gamdzyk, Marcin; Ziembowicz, Apolonia; Bratek, Ewelina; Salinska, Elzbieta

    2016-10-01

    Perinatal hypoxia-ischemia causes brain injury in neonates, but a fully successful treatment to prevent changes in the brain has yet to be developed. The aim of this study was to evaluate the effect of combining memantine treatment with HBO (2.5 ATA) or HH (0.47 ATA) on neonatal hypoxia-ischemia brain injury. 7-day old rats were subjected to hypoxia-ischemia (H-I) and treated with combination of memantine and HBO or HH. The brain damage was evaluated by examination of infarct area and the number of apoptotic cells in CA1 region of hippocampus. Additionally, the level of reactive oxygen species (ROS) was measured. Memantine, HBO or HH postconditioning applied at short time (1-6h) after H-I, and repeated for two subsequent days, resulted in significant neuroprotection. The reduction in ipsilateral hemisphere weight deficit and in the size of infarct area was observed 14days after H-I. A reduction in apoptosis and ROS level was also observed. Combining memantine with HBO or HH resulted in a loss of neuroprotection. Our results show that, combining HBO or HH postconditioning with memantine produce no additive increase in the neuroprotective effect. On the contrary, combining the treatments resulted in lower neuroprotection in comparison to the effects of memantine, HBO or HH alone. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. Chronic Intermittent Hypoxia Induces Atherosclerosis

    OpenAIRE

    Savransky, Vladimir; Nanayakkara, Ashika; Li, Jianguo; Bevans, Shannon; Smith, Philip L.; Rodriguez, Annabelle; Polotsky, Vsevolod Y.

    2007-01-01

    Rationale: Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is associated with hyperlipidemia, atherosclerosis, and a high cardiovascular risk. A causal link between obstructive sleep apnea and atherosclerosis has not been established.

  9. Inflames of confined space-hypoxia syndrome on riboflavin and its coenzymes content in white rat tissues

    OpenAIRE

    Федорко, Наталія Леонідівна; Прокоф’єва, Наталія Юріївна; Келар, Анастасія Едуардівна; Петров, Сергій Анатолійович

    2015-01-01

    During confined space-hypoxia syndrome it is observed a significant increase of riboflavin in all organs of rats, but more in the heart and brain. High level of flavin adenine dinucleotide is observed in rat liver and kidney, and significant increase of flavin mononucleotide is observed only in the brain. The data reflect the metabolism of riboflavin under conditions of confined space-hypoxia syndrome, and change of the flavin content in the bodies of animals indicates different compensatory ...

  10. Disruption of the Serotonergic System after Neonatal Hypoxia-Ischemia in a Rodent Model

    Directory of Open Access Journals (Sweden)

    Kathryn M. Buller

    2012-01-01

    Full Text Available Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury.

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

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    Malik Assaf

    2012-11-01

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

  12. Effect of Age on Glasgow Coma Scale in Patients with Moderate and Severe Traumatic Brain Injury: An Approach with Propensity Score-Matched Population

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    Cheng-Shyuan Rau

    2017-11-01

    Full Text Available Background: The most widely used methods of describing traumatic brain injury (TBI are the Glasgow Coma Scale (GCS and the Abbreviated Injury Scale (AIS. Recent evidence suggests that presenting GCS in older patients may be higher than that in younger patients for an equivalent anatomical severity of TBI. This study aimed to assess these observations with a propensity-score matching approach using the data from Trauma Registry System in a Level I trauma center. Methods: We included all adult patients (aged ≥20 years old with moderate to severe TBI from 1 January 2009 to 31 December 2016. Patients were categorized into elderly (aged ≥65 years and young adults (aged 20–64 years. The severity of TBI was defined by an AIS score in the head (AIS 3‒4 and 5 indicate moderate and severe TBI, respectively. We examined the differences in the GCS scores by age at each head AIS score. Unpaired Student’s t- and Mann–Whitney U-tests were used to analyze normally and non-normally distributed continuous data, respectively. Categorical data were compared using either the Pearson chi-square or two-sided Fisher’s exact tests. Matched patient populations were allocated in a 1:1 ratio according to the propensity scores calculated using NCSS software with the following covariates: sex, pre-existing chronic obstructive pulmonary disease, systolic blood pressure, hemoglobin, sodium, glucose, and alcohol level. Logistic regression was used to evaluate the effects of age on the GCS score in each head AIS stratum. Results: The study population included 2081 adult patients with moderate to severe TBI. These patients were categorized into elderly (n = 847 and young adults (n = 1234: each was exclusively further divided into three groups of patients with head AIS of 3, 4, or 5. In the 162 well-balanced pairs of TBI patients with head AIS of 3, the elderly demonstrated a significantly higher GCS score than the young adults (14.1 ± 2.2 vs. 13.1 ± 3

  13. Hypoxia, Oxidative Stress and Fat

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    Nikolaus Netzer

    2015-06-01

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

  14. Hypoxia Impacts on Food Web Linkages in a Pelagic Ecosystem

    Science.gov (United States)

    Sato, M.; Horne, J. K.; Parker-Stetter, S. L.; Essington, T.; Keister, J. E.; Moriarty, P.; Li, L.

    2016-02-01

    Low dissolved oxygen (DO), or hypoxia, causes significant disturbances on aquatic organisms, but the consequences for key food web linkages is not well understood. Here, we tested how the intensity of low DO events governs the degree of spatial overlap between pelagic zooplanktivorous fish and their zooplankton prey, fish feeding rates, and community compositions of zooplankton. We hypothesized that the greater sensitivity of fish to DO compared to zooplankton would lead to diminished spatial overlap at moderate DO and reduced feeding rates of fish, while severe hypoxia would amplify spatial overlap by preventing zooplankton from using deep refuge habitats leading to increased fish feeding rates. We also hypothesized shifts in zooplankton community composition towards less energetically profitable taxa such as small copepods and gelatinous species. We used a combination of multifrequency acoustic and net sampling for detecting distributions and abundance of zooplankton and pelagic fish in Hood Canal, WA, a seasonally hypoxic fjord. We employed a sampling design which paired hypoxic regions of Hood Canal with normoxic regions sampled prior to, during, and after the onset of hypoxia in two years. Contrary to our hypotheses, we found that fish and zooplankton did not change their horizontal and vertical distributions during periods and in locations with low DO levels. Consequently, the vertical overlap between fish and zooplankton did not change with DO. Fish feeding rates and the dominant zooplankton prey did not change with hypoxia events. The apparent resilience of fish to low DO in our system may be explained by decreased metabolic oxygen demand due to cool temperatures, increased availability and accessibility to their prey in low DO waters, or potential increase in predation risk at shallower depth. This study highlights the importance of both temperature and DO, instead of hypoxia threshold alone, in evaluating the impacts of hypoxia on pelagic communities.

  15. The effect of hypobaric hypoxia on multichannel EEG signal complexity.

    Science.gov (United States)

    Papadelis, Christos; Kourtidou-Papadeli, Chrysoula; Bamidis, Panagiotis D; Maglaveras, Nikos; Pappas, Konstantinos

    2007-01-01

    The objective of this study was the development and evaluation of nonlinear electroencephalography parameters which assess hypoxia-induced EEG alterations, and describe the temporal characteristics of different hypoxic levels' residual effect upon the brain electrical activity. Multichannel EEG, pO2, pCO2, ECG, and respiration measurements were recorded from 10 subjects exposed to three experimental conditions (100% oxygen, hypoxia, recovery) at three-levels of reduced barometric pressure. The mean spectral power of EEG under each session and altitude were estimated for the standard bands. Approximate Entropy (ApEn) of EEG segments was calculated, and the ApEn's time-courses were smoothed by a moving average filter. On the smoothed diagrams, parameters were defined. A significant increase in total power and power of theta and alpha bands was observed during hypoxia. Visual interpretation of ApEn time-courses revealed a characteristic pattern (decreasing during hypoxia and recovering after oxygen re-administration). The introduced qEEG parameters S1 and K1 distinguished successfully the three hypoxic conditions. The introduced parameters based on ApEn time-courses are assessing reliably and effectively the different hypoxic levels. ApEn decrease may be explained by neurons' functional isolation due to hypoxia since decreased complexity corresponds to greater autonomy of components, although this interpretation should be further supported by electrocorticographic animal studies. The introduced qEEG parameters seem to be appropriate for assessing the hypoxia-related neurophysiological state of patients in the hyperbaric chambers in the treatment of decompression sickness, carbon dioxide poisoning, and mountaineering.

  16. Nitric oxide in the rat cerebellum after hypoxia/ischemia.

    Science.gov (United States)

    Rodrigo, José; Fernández, Ana Patricia; Alonso, David; Serrano, Julia; Fernández-Vizarra, Paula; Martínez-Murillo, Ricardo; Bentura, María Luisa; Martinez, Alfredo

    2004-01-01

    Nitric oxide is a regulatory biological substance and an important intracellular messenger that acts as a specific mediator of various neuropathological disorders. In mammals and invertebrates, nitric oxide is synthesized from L-arginine in the central and peripheral neural structures by the endothelial, neuronal and inducible enzymatic isoforms of nitric oxide synthase. Nitric oxide may affect the function of various neurotransmitter-specific systems, and is involved in neuromodulation, reproductive function, immune response, and regulation of the cerebral blood circulation. This makes nitric oxide the main candidate in brain responses to brain ischemia/hypoxia. The cerebellum has been reported to be the area of the brain that has the highest nitric oxide synthase activity and the highest concentration of glutamate and aspartate. By glutamate receptors and physiological action of nitric oxide, cyclic guanisine-5'-monophosphate may be rapidly increased. The cerebellum significantly differs with respect to ischemia and hypoxia, this response being directly related to the duration and intensity of the injury. The cerebellum could cover the eventual need for nitric oxide during the hypoxia, boosting the nitric oxide synthase activity, but overall ischemia would require de novo protein synthesis, activating the inducible nitric oxide synthase to cope with the new situation. The specific inhibitors of nitric oxide synthesis show neuroprotective effects.

  17. Developmental trajectories of infants and toddlers with good initial presentation following moderate or severe traumatic brain injury: a pilot clinical assessment project.

    Science.gov (United States)

    Pomerleau, Geneviève; Hurteau, Anne-Marie; Parent, Line; Doucet, Katrine; Corbin-Berrigan, Laurie-Ann; Gagnon, Isabelle

    2012-01-01

    The purpose of this study was to review the feasibility and usefulness of instituting a clinical protocol of scheduled assessments for children after a moderate or severe traumatic brain injury (TBI) sustained before the age of 2 years and showing no immediate deficits at hospital discharge, as well as to explore the early developmental trajectories of these children. Exploratory analytical cohort study. Pediatric Trauma Center Out-patient services. 31 children were followed within the clinical protocol of scheduled assessments. The protocol included an immediate post-injury clinical assessment of infants who sustained a TBI and follow-up assessments at the ages of 9 months, 18 months (if injured prior to that age), 30 months, and 42 months. Domains assessed at each scheduled visit included hearing, speech and language, motor performance, personal social abilities, and adaptive behaviors. Clinicians reported few difficulties with scheduling or administering the assessments, maintaining a 67% participation rate at the end of the follow-up period, thus demonstrating the feasibility of the protocol in this population. Scores on the majority of formal tests showed high variability and 15-20% of children presented with clinically significant motor and/or language delays. By 42 months of age, difficulties with adaptive behavior and personal social abilities were identified in our sample of children when compared to published norms. Qualitative clinical findings from professionals identified between 25-50% of children with potential attentional difficulties throughout the follow-up period. Findings from this study demonstrate the feasibility of implementing a clinical protocol of assessment for infants and toddlers who sustain a TBI before the age of 2 years and present with no impairments at the time of discharge from hospital. Developmental problems in this population appear to be easier to identify later in the toddler years as opposed to immediately following the TBI

  18. Altered metabolites of the rat hippocampus after mild and moderate traumatic brain injury - a combined in vivo and in vitro 1 H-MRS study.

    Science.gov (United States)

    Singh, Kavita; Trivedi, Richa; Verma, Ajay; D'souza, Maria M; Koundal, Sunil; Rana, Poonam; Baishya, Bikash; Khushu, Subash

    2017-10-01

    Traumatic brain injury (TBI) has been shown to affect hippocampus-associated learning, memory and higher cognitive functions, which may be a consequence of metabolic alterations. Hippocampus-associated disorders may vary depending on the severity of injury [mild TBI (miTBI) and moderate TBI (moTBI)] and time since injury. The underlying hippocampal metabolic irregularities may provide an insight into the pathological process following TBI. In this study, in vivo and in vitro proton magnetic resonance spectroscopy ( 1 H-MRS) data were acquired from the hippocampus region of controls and TBI groups (miTBI and moTBI) at D0 (pre-injury), 4 h, Day 1 and Day 5 post-injury (PI). In vitro MRS results indicated trauma-induced changes in both miTBI and moTBI; however, in vivo MRS showed metabolic alterations in moTBI only. miTBI and moTBI showed elevated levels of osmolytes indicating injury-induced edema. Altered levels of citric acid cycle intermediates, glutamine/glutamate and amino acid metabolism indicated injury-induced aberrant bioenergetics, excitotoxicity and oxidative stress. An overall similar pattern of pathological process was observed in both miTBI and moTBI, with the distinction of depleted N-acetylaspartate levels (indicating neuronal loss) at 4 h and Day 1 and enhanced lactate production (indicating heightened energy depletion leading to the commencement of the anaerobic pathway) at Day 5 in moTBI. To the best of our knowledge, this is the first study to investigate the hippocampus metabolic profile in miTBI and moTBI simultaneously using in vivo and in vitro MRS. Copyright © 2017 John Wiley & Sons, Ltd.

  19. Molecular and biochemical responses of hypoxia exposure in Atlantic croaker collected from hypoxic regions in the northern Gulf of Mexico.

    Science.gov (United States)

    Rahman, Md Saydur; Thomas, Peter

    2017-01-01

    A major impact of global climate change has been the marked increase worldwide in the incidence of coastal hypoxia (dissolved oxygen, DOhypoxic waters as well as their molecular and physiological responses to environmental hypoxia exposure are largely unknown. A suite of potential hypoxia exposure biomarkers was evaluated in Atlantic croaker collected from hypoxic and normoxic regions in the northern Gulf of Mexico (nGOM), and in croaker after laboratory exposure to hypoxia (DO: 1.7 mg l-1). Expression of hypoxia-inducible factor-α, hif-α; neuronal nitric oxide synthase, nNOS; and insulin-like growth factor binding protein, igfbp mRNAs and protein carbonyl (PC, an oxidative stress indicator) content were elevated several-fold in brain and liver tissues of croaker collected from nGOM hypoxic sites. All of these molecular and biochemical biomarkers were also upregulated ~3-10-fold in croaker brain and liver tissues within 1-2 days of hypoxia exposure in controlled laboratory experiments. These results suggest that hif-αs, nNOS and igfbp-1 transcripts and PC contents are useful biomarkers of environmental hypoxia exposure and some of its physiological effects, making them important components for improved assessments of long-term impacts of environmental hypoxia on fish populations.

  20. Physiological determinants of human acute hypoxia tolerance.

    Science.gov (United States)

    2013-11-01

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

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

    Science.gov (United States)

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

    2017-01-01

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

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

    Science.gov (United States)

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

    1996-04-01

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

  3. Alterations in Cortical Thickness and White Matter Integrity in Mild-to-Moderate Communicating Hydrocephalic School-Aged Children Measured by Whole-Brain Cortical Thickness Mapping and DTI

    Directory of Open Access Journals (Sweden)

    Siyu Zhang

    2017-01-01

    Full Text Available Follow-up observation is required for mild-to-moderate hydrocephalic patients because of the potential damage to brain. However, effects of mild-to-moderate hydrocephalus on gray and white matter remain unclear in vivo. Using structural MRI and diffusion tensor imaging (DTI, current study compared the cortical thickness and white matter integrity between children with mild-to-moderate communicating hydrocephalus and healthy controls. The relationships between cortical changes and intelligence quota were also examined in patients. We found that cortical thickness in the left middle temporal and left rostral middle frontal gyrus was significantly lower in the hydrocephalus group compared with that of controls. Fractional anisotropy in the right corpus callosum body was significantly lower in the hydrocephalus group compared with that of controls. In addition, there was no association of cortical thinning or white matter fractional anisotropy with intelligence quota in either group. Thus, our findings provide clues to that mild-to-moderate hydrocephalus could lead to structural brain deficits especially in the middle temporal and middle frontal gyrus prior to the behavior changes.

  4. Self-perceived health care needs and delivery of health care services 5 years after moderate-to-severe traumatic brain injury.

    Science.gov (United States)

    Andelic, Nada; Soberg, Helene L; Berntsen, Svein; Sigurdardottir, Solrun; Roe, Cecilie

    2014-11-01

    To describe the self-perceived health care needs of patients with moderate-to-severe traumatic brain injury (TBI) and to assess the impact of the functional level at 1 year after injury on patients' unmet needs at the 5-year follow-up. A prospective follow-up study. Clinical research. A total of 93 patients participated in the 5-year follow-up. We registered demographic and injury-related data at the time of admission and the scores for the Disability Rating Scale, Glasgow Outcome Scale-Extended, and Short Form 36 subscales for physical functioning and mental health at 1 and 5 years. The patients' self-perceived health care needs and use of health care services at 5 years were the main outcome measurements. At the 5-year follow-up, 70% of patients reported at least 1 perceived need. The self-perceived health care needs were met for 39% of the patients. The patients with unmet needs (n = 29 [31%]) reported frequent needs in emotional (65%), vocational (62%), and cognitive (58%) domains. These patients were significantly more likely to present a less severe disability on the Disability Rating Scale at the 1-year follow-up (odds ratio [OR] 0.11 [95% confidence interval {CI}, 0.02-0.7]; P = .02). Worse mental health at the 1-year follow-up and a younger age (16-29 years) largely predicted unmet needs at the 5-year follow-up (OR 3.28 [95% CI, 1.1-10.04], P = .04; and OR 4.93 [95% CI, 0.16-15.2], P = .005, respectively). Gaps between self-perceived health care needs and health care services received at the 5-year follow-up were found. An important message to clinicians who provide health care services in the late TBI phase is that they should be aware of patients' long-term needs regarding cognitive and emotional difficulties. Of equal importance is an emphasis on long-term vocational rehabilitation services. To ensure the appropriateness of health care service delivery, health care services after TBI should be better targeted at less-severe TBI population as well

  5. Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT

    Science.gov (United States)

    Leszczynska, Katarzyna B.; Foskolou, Iosifina P.; Abraham, Aswin G.; Anbalagan, Selvakumar; Tellier, Céline; Haider, Syed; Span, Paul N.; O’Neill, Eric E.; Buffa, Francesca M.; Hammond, Ester M.

    2015-01-01

    Restoration of hypoxia-induced apoptosis in tumors harboring p53 mutations has been proposed as a potential therapeutic strategy; however, the transcriptional targets that mediate hypoxia-induced p53-dependent apoptosis remain elusive. Here, we demonstrated that hypoxia-induced p53-dependent apoptosis is reliant on the DNA-binding and transactivation domains of p53 but not on the acetylation sites K120 and K164, which, in contrast, are essential for DNA damage–induced, p53-dependent apoptosis. Evaluation of hypoxia-induced transcripts in multiple cell lines identified a group of genes that are hypoxia-inducible proapoptotic targets of p53, including inositol polyphosphate-5-phosphatase (INPP5D), pleckstrin domain–containing A3 (PHLDA3), sulfatase 2 (SULF2), B cell translocation gene 2 (BTG2), cytoplasmic FMR1-interacting protein 2 (CYFIP2), and KN motif and ankyrin repeat domains 3 (KANK3). These targets were also regulated by p53 in human cancers, including breast, brain, colorectal, kidney, bladder, and melanoma cancers. Downregulation of these hypoxia-inducible targets associated with poor prognosis, suggesting that hypoxia-induced apoptosis contributes to p53-mediated tumor suppression and treatment response. Induction of p53 targets, PHLDA3, and a specific INPP5D transcript mediated apoptosis in response to hypoxia through AKT inhibition. Moreover, pharmacological inhibition of AKT led to apoptosis in the hypoxic regions of p53-deficient tumors and consequently increased radiosensitivity. Together, these results identify mediators of hypoxia-induced p53-dependent apoptosis and suggest AKT inhibition may improve radiotherapy response in p53-deficient tumors. PMID:25961455

  6. An examination of the Wechsler Adult Intelligence Scales, Fourth Edition (WAIS-IV) in individuals with complicated mild, moderate and Severe traumatic brain injury (TBI).

    Science.gov (United States)

    Carlozzi, Noelle E; Kirsch, Ned L; Kisala, Pamela A; Tulsky, David S

    2015-01-01

    This study examined the clinical utility of the Wechsler Adult Intelligence Scales-Fourth Edition (WAIS-IV) in individuals with complicated mild, moderate or severe TBI. One hundred individuals with TBI (n = 35 complicated mild or moderate TBI; n = 65 severe TBI) and 100 control participants matched on key demographic variables from the WAIS-IV normative dataset completed the WAIS-IV. Univariate analyses indicated that participants with severe TBI had poorer performance than matched controls on all index scores and subtests (except Matrix Reasoning). Individuals with complicated mild/moderate TBI performed more poorly than controls on the Working Memory Index (WMI), Processing Speed Index (PSI), and Full Scale IQ (FSIQ), and on four subtests: the two processing speed subtests (SS, CD), two working memory subtests (AR, LN), and a perceptual reasoning subtest (BD). Participants with severe TBI had significantly lower scores than the complicated mild/moderate TBI on PSI, and on three subtests: the two processing speed subtests (SS and CD), and the new visual puzzles test. Effect sizes for index and subtest scores were generally small-to-moderate for the group with complicated mild/moderate and moderate-to-large for the group with severe TBI. PSI also showed good sensitivity and specificity for classifying individuals with severe TBI versus controls. Findings provide support for the clinical utility of the WAIS-IV in individuals with complicated mild, moderate, and severe TBI.

  7. Systemic Hypoxia Changes the Organ-Specific Distribution of Vascular Endothelial Growth Factor and Its Receptors

    Science.gov (United States)

    Marti, Hugo H.; Risau, Werner

    1998-12-01

    Vascular endothelial growth factor (VEGF) plays a key role in physiological blood vessel formation and pathological angiogenesis such as tumor growth and ischemic diseases. Hypoxia is a potent inducer of VEGF in vitro. Here we demonstrate that VEGF is induced in vivo by exposing mice to systemic hypoxia. VEGF induction was highest in brain, but also occurred in kidney, testis, lung, heart, and liver. In situ hybridization analysis revealed that a distinct subset of cells within a given organ, such as glial cells and neurons in brain, tubular cells in kidney, and Sertoli cells in testis, responded to the hypoxic stimulus with an increase in VEGF expression. Surprisingly, however, other cells at sites of constitutive VEGF expression in normal adult tissues, such as epithelial cells in the choroid plexus and kidney glomeruli, decreased VEGF expression in response to the hypoxic stimulus. Furthermore, in addition to VEGF itself, expression of VEGF receptor-1 (VEGFR-1), but not VEGFR-2, was induced by hypoxia in endothelial cells of lung, heart, brain, kidney, and liver. VEGF itself was never found to be up-regulated in endothelial cells under hypoxic conditions, consistent with its paracrine action during normoxia. Our results show that the response to hypoxia in vivo is differentially regulated at the level of specific cell types or layers in certain organs. In these tissues, up- or down-regulation of VEGF and VEGFR-1 during hypoxia may influence their oxygenation after angiogenesis or modulate vascular permeability.

  8. Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice.

    Science.gov (United States)

    Cahill, Lindsay S; Gazdzinski, Lisa M; Tsui, Albert Ky; Zhou, Yu-Qing; Portnoy, Sharon; Liu, Elaine; Mazer, C David; Hare, Gregory Mt; Kassner, Andrea; Sled, John G

    2017-03-01

    Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO 2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

  9. The role of sympathetic reflex control of cerebral blood flow and microcirculation during normoxia and hypoxia

    International Nuclear Information System (INIS)

    Kissen, I.

    1989-01-01

    The purpose of this study was to investigate the hypothesis that there is sympathetic reflex regulation of the cerebral blood flow (CBF) and the utilization of microvessels during normoxia and hypoxia. Regional CBF was determined in conscious Long Evans rats with 4-iodo[N-methyl- 14 C]antipyrine. The percentage of the microvessels perfused as determined by comparing perfused microvessels (FITC-dextran), with the total microvasculature (alkaline phosphatase stain). To test this hypothesis, arcs of the proposed reflex were eliminated. The first experiment examined the effect of bilateral superior cervical ganglionectomy on CBF and microcirulation during normoxia and hypoxia. CBF increased during hypoxia from 67 ± 2 to 115 ± 3 ml/min/100 g in control, and from 77 ± 2 to 155 ± 6 ml/min/100 g in ganglionectomized animals. In control, hypoxic flow to caudal areas was higher than to rostral areas and that difference was prevented by ganglionectomy. Utilization of arterioles during hypoxia increased from 51 ± 2% to 63 ± 2% in control, and from 52 ± 1% to 77 ± 2% in ganglionectomized group. The percent perfused capillaries during normoxia was 49 ± 2% in control, and 52 ± 1% in ganglionectomized group, and during hypoxia it was 73 ± 2% in both groups. In the second study, cerebral vascular responses to hypoxia were determined after administration of alpha-adrenoceptor antagonists N-methyl chlorpromazine (does not cross the blood-brain barrier), and phenoxybenzamine (crosses the blood-brain barrier). Neither phenoxybenzamine nor N-methyl chlorpromazine affected CBF and microcirculation during normoxia. During hypoxia, they similarly reversed the rostral to caudal gradient of flow, increased utilization of arterioles in rostral brain areas, and did not affect capillaries

  10. Andrographolide protects mouse astrocytes against hypoxia injury by promoting autophagy and S100B expression

    Directory of Open Access Journals (Sweden)

    Juan Du

    2018-04-01

    Full Text Available Andrographolide (ANDRO has been studied for its immunomodulation, anti-inflammatory, and neuroprotection effects. Because brain hypoxia is the most common factor of secondary brain injury after traumatic brain injury, we studied the role and possible mechanism of ANDRO in this process using hypoxia-injured astrocytes. Mouse cortical astrocytes C8-D1A (astrocyte type I clone from C57/BL6 strains were subjected to 3 and 21% of O2 for various times (0–12 h to establish an astrocyte hypoxia injury model in vitro. After hypoxia and ANDRO administration, the changes in cell viability and apoptosis were assessed using CCK-8 and flow cytometry. Expression changes in apoptosis-related proteins, autophagy-related proteins, main factors of JNK pathway, ATG5, and S100B were determined by western blot. Hypoxia remarkably damaged C8-D1A cells evidenced by reduction of cell viability and induction of apoptosis. Hypoxia also induced autophagy and overproduction of S100B. ANDRO reduced cell apoptosis and promoted cell autophagy and S100B expression. After ANDRO administration, autophagy-related proteins, S-100B, JNK pathway proteins, and ATG5 were all upregulated, while autophagy-related proteins and s100b were downregulated when the jnk pathway was inhibited or ATG5 was knocked down. ANDRO conferred a survival advantage to hypoxia-injured astrocytes by reducing cell apoptosis and promoting autophagy and s100b expression. Furthermore, the promotion of autophagy and s100b expression by ANDRO was via activation of jnk pathway and regulation of ATG5.

  11. Plasma volume in acute hypoxia

    DEFF Research Database (Denmark)

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

    1998-01-01

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

  12. Preeclampsia, Hypoxia, Thrombosis, and Inflammation

    Directory of Open Access Journals (Sweden)

    Amir A. Shamshirsaz

    2012-01-01

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

  13. Hepcidin: A Critical Regulator Of Iron Metabolism During Hypoxia

    Science.gov (United States)

    2011-01-01

    inducible factor (HIF)/hypoxia response element ( HRE ) system, as well as recent evidence indicating that localized adipose hypoxia due to obesity may...mechanisms by which hypoxia affects hepcidin expression, to include a review of the hypoxia inducible factor (HIF)/hypoxia response element ( HRE ) system, as...a battery of genes are induced by the hypoxia inducible factor (HIF)/hypoxia response element ( HRE ) system. The HIF system senses O2 levels through

  14. Cerebral hypoxia and ischemia in preterm infants

    Directory of Open Access Journals (Sweden)

    Alberto Ravarino

    2014-06-01

    Full Text Available Premature birth is a major public health issue internationally affecting 13 million babies worldwide. Hypoxia and ischemia is probably the commonest type of acquired brain damage in preterm infants. The clinical manifestations of hypoxic-ischemic injury in survivors of premature birth include a spectrum of cerebral palsy and intellectual disabilities. Until recently, the extensive brain abnormalities in preterm neonates appeared to be related mostly to destructive processes that lead to substantial deletion of neurons, axons, and glia from necrotic lesions in the developing brain. Advances in neonatal care coincide with a growing body of evidence that the preterm gray and white matter frequently sustain less severe insults, where tissue destruction is the minor component. Periventricular leukomalacia (PVL is the major form of white matter injury and consists classically of focal necrotic lesions, with subsequent cyst formation, and a less severe but more diffuse injury to cerebral white mater, with prominent astrogliosis and microgliosis but without overt necrosis. With PVL a concomitant injury occurs to subplate neurons, located in the subcortical white matter. Severe hypoxic-ischemic insults that trigger significant white matter necrosis are accompanied by neuronal degeneration in cerebral gray and white matter. This review aims to illustrate signs of cerebral embryology of the second half of fetal life and correlate hypoxic-ischemic brain injury in the premature infant. This should help us better understand the symptoms early and late and facilitate new therapeutic strategies. Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014 · Cagliari (Italy · October 25th, 2014 · The role of the clinical pathological dialogue in problem solving Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken

  15. Multi-Vitamin B Supplementation Reverses Hypoxia-Induced Tau Hyperphosphorylation and Improves Memory Function in Adult Mice.

    Science.gov (United States)

    Yu, Lixia; Chen, Yuan; Wang, Weiguang; Xiao, Zhonghai; Hong, Yan

    2016-08-04

    Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia.

  16. Effects of prenatal hypoxia on schizophrenia-related phenotypes in heterozygous reeler mice: a gene × environment interaction study.

    Science.gov (United States)

    Howell, Kristy R; Pillai, Anilkumar

    2014-08-01

    Both genetic and environmental factors play important roles in the pathophysiology of schizophrenia. Although prenatal hypoxia is a potential environmental factor implicated in schizophrenia, very little is known about the consequences of combining models of genetic risk factor with prenatal hypoxia. Heterozygous reeler (haploinsufficient for reelin; HRM) and wild-type (WT) mice were exposed to prenatal hypoxia (9% oxygen for two hour) or normoxia at embryonic day 17 (E17). Behavioral (Prepulse inhibition, Y-maze and Open field) and functional (regional volume in frontal cortex and hippocampus as well as hippocampal blood flow) tests were performed at 3 months of age. The levels of hypoxia and stress-related molecules such as hypoxia-inducible factor-1 α (HIF-1α), vascular endothelial factor (VEGF), VEGF receptor-2 (VEGFR2/Flk1) and glucocorticoid receptor (GR) were examined in frontal cortex and hippocampus at E18, 1 month and 3 months of age. In addition, serum VEGF and corticosterone levels were also examined. Prenatal hypoxia induced anxiety-like behavior in both HRM and WT mice. A significant reduction in hippocampal blood flow, but no change in brain regional volume was observed following prenatal hypoxia. Significant age and region-dependent changes in HIF-1α, VEGF, Flk1 and GR were found following prenatal hypoxia. Serum VEGF and corticosterone levels were found decreased following prenatal hypoxia. None of the above prenatal hypoxia-induced changes were either diminished or exacerbated due to reelin deficiency. These results argue against any gene-environment interaction between hypoxia and reelin deficiency. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  17. Effect of hypoxia on cerebral blood flow regulation during rest and exercise : role of cerebral oxygen delivery on performance

    OpenAIRE

    Fan, J.-L.

    2014-01-01

    Adequate supply of oxygen to the brain is critical for maintaining normal brain function. Severe hypoxia, such as that experienced during high altitude ascent, presents a unique challenge to brain oxygen (O2) supply. During high-intensity exercise, hyperventilation-induced hypocapnia leads to cerebral vasoconstriction, followed by reductions in cerebral blood flow (CBF), oxygen delivery (DO2), and tissue oxygenation. This reduced O2 supply to the brain could potentially account for the reduce...

  18. Emotion perception after moderate-severe traumatic brain injury: The valence effect and the role of working memory, processing speed, and nonverbal reasoning

    NARCIS (Netherlands)

    Rosenberg, H.; Dethier, M.; Kessels, R.P.C.; Westbrook, R.F.; McDonald, S.

    2015-01-01

    OBJECTIVE: Traumatic brain injury (TBI) impairs emotion perception. Perception of negative emotions (sadness, disgust, fear, and anger) is reportedly affected more than positive (happiness and surprise) ones. It has been argued that this reflects a specialized neural network underpinning negative

  19. Characterization of the concurrent metabolic changes in brain and plasma during insulin-induced moderate hypoglycemia using 1H NMR spectroscopy in juvenile rats.

    Science.gov (United States)

    Ennis, Kathleen; Lusczek, Elizabeth; Rao, Raghavendra

    2017-07-13

    Treatment of hypoglycemia in children is currently based on plasma glucose measurements. This approach may not ensure neuroprotection since plasma glucose does not reflect the dynamic state of cerebral energy metabolism. To determine whether cerebral metabolic changes during hypoglycemia could be better characterized using plasma metabolomic analysis, insulin-induced acute hypoglycemia was induced in 4-week-old rats. Brain tissue and concurrent plasma samples were collected from hypoglycemic (N=7) and control (N=7) rats after focused microwave fixation to prevent post-mortem metabolic changes. The concentration of 29 metabolites in brain and 34 metabolites in plasma were determined using 1 H NMR spectroscopy at 700MHz and examined using partial least squares-discriminant analysis. The sensitivity of plasma glucose for detecting cerebral energy failure was assessed by determining its relationship to brain phosphocreatine. The brain and plasma metabolite profiles of the hypoglycemia group were distinct from the control group (brain: R 2 =0.92, Q 2 =0.31; plasma: R 2 =0.95, Q 2 =0.74). Concentration differences in glucose, ketone bodies and amino acids were responsible for the intergroup separation. There was 45% concordance between the brain and plasma metabolite profiles. Brain phosphocreatine correlated with brain glucose (control group: R 2 =0.86; hypoglycemia group: R 2 =0.59; pplasma glucose. The results confirm that plasma glucose is an insensitive biomarker of cerebral energy changes during hypoglycemia and suggest that a plasma metabolite profile is superior for monitoring cerebral metabolism. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Ageing and cardiorespiratory response to hypoxia.

    Science.gov (United States)

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

    2012-11-01

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

  1. Exercise Improves Mood State in Normobaric Hypoxia.

    Science.gov (United States)

    Seo, Yongsuk; Fennell, Curtis; Burns, Keith; Pollock, Brandon S; Gunstad, John; McDaniel, John; Glickman, Ellen

    2015-11-01

    The purpose of this study was to quantify the efficacy of using exercise to alleviate the impairments in mood state associated with hypoxic exposure. Nineteen young, healthy men completed Automated Neuropsychological Assessment Metrics-4(th) Edition (ANAM4) versions of the mood state test before hypoxia exposure, after 60 min of hypoxia exposure (12.5% O(2)), and during and after two intensities of cycling exercise (40% and 60% adjusted Vo(2max)) under the same hypoxic conditions. Peripheral oxygen saturation (Spo(2)) and regional cerebral oxygen saturation (rSo(2)) were continuously monitored. At rest in hypoxia, Total Mood Disturbance (TMD) was significantly increased compared to baseline in both the 40% and 60% groups. TMD was significantly decreased during exercise compared to rest in hypoxia. TMD was also significantly decreased during recovery compared to rest in hypoxia. Spo(2) significantly decreased at 60 min rest in hypoxia, during exercise, and recovery compared to baseline. Regional cerebral oxygen saturation was also reduced at 60 min rest in hypoxia, during exercise, and recovery compared to baseline. The current study demonstrated that exercise at 40% and 60% of adjusted Vo(2max) attenuated the adverse effects of hypoxia on mood. These findings may have significant applied value, as negative mood states are known to impair performance in hypoxia. Further studies are needed to replicate the current finding and to clarify the possible mechanisms associated with the potential benefits of exercise on mood state in normobaric hypoxia.

  2. Approximate Simulation of Acute Hypobaric Hypoxia with Normobaric Hypoxia

    Science.gov (United States)

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

    2011-01-01

    INTRODUCTION. Some manufacturers of reduced oxygen (O2) breathing devices claim a comparable hypobaric hypoxia (HH) training experience by providing F(sub I) O2 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.

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

    Directory of Open Access Journals (Sweden)

    Tatiana V. Serebrovskaya

    2015-05-01

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

  4. Postoperative hypoxia and length of intensive care unit stay after cardiac surgery: the underweight paradox?

    Directory of Open Access Journals (Sweden)

    Marco Ranucci

    Full Text Available Cardiac operations with cardiopulmonary bypass can be associated with postoperative lung dysfunction. The present study investigates the incidence of postoperative hypoxia after cardiac surgery, its relationship with the length of intensive care unit stay, and the role of body mass index in determining postoperative hypoxia and intensive care unit length of stay.Single-center, retrospective study.University Hospital. Patients. Adult patients (N = 5,023 who underwent cardiac surgery with CPB.None.According to the body mass index, patients were attributed to six classes, and obesity was defined as a body mass index >30. POH was defined as a PaO2/FiO2 ratio <200 at the arrival in the intensive care unit. Postoperative hypoxia was detected in 1,536 patients (30.6%. Obesity was an independent risk factor for postoperative hypoxia (odds ratio 2.4, 95% confidence interval 2.05-2.78, P = 0.001 and postoperative hypoxia was a determinant of intensive care unit length of stay. There is a significant inverse correlation between body mass index and PaO2/FiO2 ratio, with the risk of postoperative hypoxia increasing by 1.7 folds per each incremental body mass index class. The relationship between body mass index and intensive care unit length of stay is U-shaped, with longer intensive care unit stay in underweight patients and moderate-morbid obese patients.Obese patients are at higher risk for postoperative hypoxia, but this leads to a prolonged intensive care unit stay only for moderate-morbid obese patients. Obese patients are partially protected against the deleterious effects of hemodilution and transfusions. Underweight patients present the "paradox" of a better lung gas exchange but a longer intensive care unit stay. This is probably due to a higher severity of their cardiac disease.

  5. Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia

    Science.gov (United States)

    Saez, Isabel; Duran, Jordi; Sinadinos, Christopher; Beltran, Antoni; Yanes, Oscar; Tevy, María F; Martínez-Pons, Carlos; Milán, Marco; Guinovart, Joan J

    2014-01-01

    Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that—against general belief—neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress. PMID:24569689

  6. Neurons have an active glycogen metabolism that contributes to tolerance to hypoxia.

    Science.gov (United States)

    Saez, Isabel; Duran, Jordi; Sinadinos, Christopher; Beltran, Antoni; Yanes, Oscar; Tevy, María F; Martínez-Pons, Carlos; Milán, Marco; Guinovart, Joan J

    2014-06-01

    Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that-against general belief-neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress.

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

    International Nuclear Information System (INIS)

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

    2009-01-01

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

  8. Effect of ovariectomy on inflammation induced by intermittent hypoxia in a mouse model of sleep apnea.

    Science.gov (United States)

    Torres, Marta; Palomer, Xavier; Montserrat, Josep M; Vázquez-Carrera, Manel; Farré, Ramon

    2014-10-01

    Patient data report marked gender and pre-vs-postmenopausal differences in obstructive sleep apnea (OSA). However, no experimental data are available on how sexual hormones modulate OSA consequences. Here we report novel results on estrogen-modulated heart and brain inflammation in female mice subjected to intermittent hypoxia, a major injurious challenge in OSA. C57BL/6J (14-week old) intact and ovariectomized mice (n=6 each) were subjected to intermittent hypoxia (20 s at 5% and 40s at 21%, 60 cycles/h; 6 h/day). Identical intact and ovariectomized groups breathing room air were controls. After 30 days, the gene expressions of interleukins 6 and 8 (IL-6, IL-8) in the brain and heart tissues were measured. Whereas, compared with normoxia, intermittent hypoxia considerably increased IL-6 and IL-8 gene expressions in intact females, no change was found in ovariectomized mice when comparing normoxia and intermittent hypoxia. These data suggest that estrogens modulate the inflammatory effects of intermittent hypoxia and point to further studies on the role played by sex hormones in OSA. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Zinc promotes the death of hypoxic astrocytes by upregulating hypoxia-induced hypoxia-inducible factor-1alpha expression via poly(ADP-ribose) polymerase-1.

    Science.gov (United States)

    Pan, Rong; Chen, Chen; Liu, Wen-Lan; Liu, Ke-Jian

    2013-07-01

    Pathological release of excess zinc ions has been implicated in ischemic brain cell death. However, the underlying mechanisms remain to be elucidated. In stroke, ischemia-induced zinc release and hypoxia-inducible factor-1 (HIF-1) accumulation concurrently occur in the ischemic tissue. The present study tests the hypothesis that the presence of high intracellular zinc concentration is a major cause of modifications to PARP-1 and HIF-1α during hypoxia, which significantly contributes to cell death during ischemia. Primary cortical astrocytes and C8-D1A cells were exposed to different concentrations of zinc chloride. Cell death rate and protein expression of HIF-1 and Poly(ADP-ribose) polymerase (PARP)-1 were examined after 3-h hypoxic treatment. Although 3-h hypoxia or 100 μM of zinc alone did not induce noticeable cytotoxicity, their combination led to a dramatic increase in astrocytic cell death in a zinc-concentration-dependent manner. Exposure of astrocytes to hypoxia for 3 h remarkably increased the levels of intracellular zinc and HIF-1α protein, which was further augmented by added exogenous zinc. Notably, HIF-1α knockdown blocked zinc-induced astrocyte death. Moreover, knockdown of PARP-1, another important protein in the response of hypoxia, attenuated the overexpression of HIF-1α and reduced the cell death rate. Our studies show that zinc promotes hypoxic cell death through overexpression of the hypoxia response factor HIF-1α via the cell fate determine factor PARP-1 modification, which provides a novel mechanism for zinc-mediated ischemic brain injury. © 2013 John Wiley & Sons Ltd.

  10. Gill and lung ventilation responses to steady-state aquatic hypoxia and hyperoxia in the bullfrog tadpole.

    Science.gov (United States)

    West, N H; Burggren, W W

    1982-02-01

    Gill ventilation frequency (fG), the pressure amplitude (PBC) and stroke volume (VS) of buccal ventilation cycles, the frequency of air breaths (fL), water flow over the gills (VW), gill oxygen uptake (MGO2), oxygen utilization (U), and heart frequency (fH) have been measured in unanaesthetized, air breathing Rana catesbeiana tadpoles (stage XVI-XIX). The animals were unrestrained except for ECG leads or cannulae, and were able to surface voluntarily for air breathing. They were subjected to aquatic normoxia, hyperoxia and three levels of aquatic hypoxia, and their respiratory responses recorded in the steady state. The experiments were performed at 20 +/- 0.5 degrees C. In hyperoxia there was an absence of air breathing, and fG, PBC and VW fell from the normoxic values, while U increased, resulting in no significant change in MGO2. Animals in normoxia showed a very low fL which increased in progressively more hypoxic states. VW increased from the normoxic value in mild hypoxia (PO2 = 96 +/- 2 mm Hg), but fell, associated with a reduction in PBC, in moderate (PO2 = 41 +/- 1 mm Hg) and severe (PO2 = 21 +/- 3 mm Hg) hypoxia in the presence of lung ventilation. Gill MGO2 was not significantly different from the normoxic value in mild hypoxia but fell in moderate hypoxia, while in severe hypoxia oxygen was lost to the ventilating water from the blood perfusing the gills. There was no significant change in fH from the normoxic value in either hypoxia or hyperoxia. These data indicate, that in the bimodally breathing bullfrog tadpole, aquatic PO2 exerts a strong control over both gill and lung ventilation. Furthermore, there is an interaction between gill and lung ventilation such that the onset of a high frequency of lung ventilation in moderate and severe hypoxia promotes a suppression of gill ventilation cycles.

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

    Science.gov (United States)

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

    2017-07-01

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

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

    NARCIS (Netherlands)

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

    2004-01-01

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

  13. Moderate and late preterm infants exhibit widespread brain white matter microstructure alterations at term-equivalent age relative to term-born controls

    NARCIS (Netherlands)

    Kelly, Claire E.; Cheong, Jeanie L Y; Gabra Fam, Lillian; Leemans, Alexander; Seal, Marc L.; Doyle, Lex W.; Anderson, Peter J.; Spittle, Alicia J.; Thompson, Deanne K.

    2016-01-01

    Despite the many studies documenting cerebral white matter microstructural alterations associated with very preterm birth (<32 weeks’ gestation), there is a dearth of similar research in moderate and late preterm infants (born 32–36 weeks’ gestation), who experience higher rates of

  14. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val(66)Met

    NARCIS (Netherlands)

    Elzinga, Bernet M.; Molendijk, Marc L.; Voshaar, Richard C. Oude; Bus, Boudewijn A. A.; Prickaerts, Jos; Spinhoven, Philip; Penninx, Brenda J. W. H.

    Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, the effects

  15. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val(66)Met

    NARCIS (Netherlands)

    Elzinga, B.M.; Molendijk, M.L.; Voshaar, R.C.O.; Bus, B.A.A.; Prickaerts, J.; Spinhoven, P.; Penninx, B.W.J.H.

    2011-01-01

    Rationale: Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover,

  16. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met

    NARCIS (Netherlands)

    Elzinga, B.M.; Molendijk, M.L.; Oude Voshaar, R.C.; Bus, B.A.A.; Prickaerts, J.; Spinhoven, P.; Penninx, B.J.

    2011-01-01

    RATIONALE: Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover,

  17. Moderate whisky consumption in combination with an evening meal reduces tryptophan availability to the brain but does not influence performance in healthy volunteers

    NARCIS (Netherlands)

    Markus, C.R.; Sierksma, A.; Verbeek, C.; Rooijen, J.J.M. van; Patel, H.J.; Brand, A.N.; Hendriks, H.F.J.

    2004-01-01

    Brain serotonin (5-HT) synthesis is controlled by nutrients that influence the availability of plasma tryptophan (Trp) as compared with the sum of the other large neutral amino acids (LNAA; Trp:LNAA). Alcohol consumption is found to change mood and performance and this might well be due to

  18. Mouse Intermittent Hypoxia Mimicking Apnea of Prematurity: Effects on Myelinogenesis and Axonal Maturation

    Science.gov (United States)

    CAI, JUN; TUONG, CHI MINH; ZHANG, YIPING; SHIELDS, CHRISTOPHER B.; GUO, GANG; FU, HUI; GOZAL, DAVID

    2014-01-01

    Premature babies are at high risk for both infantile apnea and long-term neurobehavioral deficits. Recent studies suggest that diffuse structural changes in brain white matter are a positive predictor of poor cognitive outcomes. Since oligodendrocyte maturation, myelination, axon development and synapse formation mainly occur in the 3rd trimester of gestation and 1st postnatal year, infantile apnea could lead to and/or exaggerate white matter impairments in preterm neonates. Therefore, we investigated oligodendroglia and axon development in a neonatal mouse model of intermittent hypoxia between postnatal days 2 to 10. During critical phases of central nervous system development, intermittent hypoxia induced hypomyelination in the corpus callosum, striatum, fornix and cerebellum, but not the pons or spinal cord. Intermittent hypoxia-elicited alterations in myelin-forming processes were reflected by decreased expression of myelin proteins, including MBP, PLP, MAG and CNPase, possibly due to arrested maturation of oligodendrocytes. Ultra-structural abnormalities were apparent in the myelin sheath and axon. Immature oligodendrocytes were more vulnerable to neonatal intermittent hypoxia exposures than developing axons, suggesting that hypomyelination may contribute, at least partially, to axonal deficits. Insufficient neurofilament synthesis with anomalous components of neurofilament subunits, β-tubulin and MAP2 isoforms indicated immaturity of axons in intermittent hypoxia-exposed mouse brains. In addition, down-regulation of Synapsin I, Synaptophysin and Gap-43 phosphorylation suggested a potential stunt in axonogenesis and synaptogenesis. The region-selective and complex impairment in brain white matter induced by intermittent hypoxia was further associated with electrophysiological changes that may underlie long-term neurobehavioral sequelae. PMID:21953180

  19. Moderate Bravery

    DEFF Research Database (Denmark)

    Majgaard, Klaus

    2016-01-01

    Purpose: The ability to act in a purposeful and effective way amid institutional tensions and paradoxes is, right now, a highly prized quality in public leadership. The purpose of this chapter is to qualify moderately brave acts as a learning format that combines the analytical and performative...

  20. Restraint stress intensifies interstitial K+ accumulation during severe hypoxia

    Directory of Open Access Journals (Sweden)

    Christian eSchnell

    2012-03-01

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

  1. Moderately delayed post-insult treatment with normobaric hyperoxia reduces excitotoxin-induced neuronal degeneration but increases ischemia-induced brain damage

    Directory of Open Access Journals (Sweden)

    Haelewyn Benoit

    2011-04-01

    Full Text Available Abstract Background The use and benefits of normobaric oxygen (NBO in patients suffering acute ischemic stroke is still controversial. Results Here we show for the first time to the best of our knowledge that NBO reduces both NMDA-induced calcium influxes in vitro and NMDA-induced neuronal degeneration in vivo, but increases oxygen and glucose deprivation-induced cell injury in vitro and ischemia-induced brain damage produced by middle cerebral artery occlusion in vivo. Conclusions Taken together, these results indicate that NBO reduces excitotoxin-induced calcium influx and subsequent neuronal degeneration but favors ischemia-induced brain damage and neuronal death. These findings highlight the complexity of the mechanisms involved by the use of NBO in patients suffering acute ischemic stroke.

  2. Hyperbaric Oxygen Therapy in the Treatment of Chronic Mild-Moderate Blast-Induced Traumatic Brain Injury Post-Concussion Syndrome (PCS) and Post Traumatic Stress Disorder (PTSD)

    Science.gov (United States)

    2017-10-01

    Post-Concussion Syndrome (PCS) and Post Traumatic Stress Disorder (PTSD) PRINCIPAL INVESTIGATOR: Paul G. Harch, M.D. CONTRACTING ORGANIZATION...Traumatic Brain Injury Post-Concussion Syndrome (PCS) and Post Traumatic Stress Disorder (PTSD) 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR...injury (TBI) and post-traumatic stress disorder (PTSD) affect 11-28% and 13-17%, respectively, of U.S. combat troops returning from Iraq and

  3. Ethanol extract of Portulaca oleracea L. protects against hypoxia-induced neuro damage through modulating endogenous erythropoietin expression.

    Science.gov (United States)

    Wanyin, Wang; Liwei, Dong; Lin, Jia; Hailiang, Xin; Changquan, Ling; Min, Li

    2012-04-01

    In addition to its role in erythropoiesis, erythropoietin is also appreciated for its neuroprotective effects, and it has been suggested for treatment of some ischemic-hypoxic neurovascular diseases. The protective effects of endogenous erythropoietin in the brain give rise to the hypothesis that modulating erythropoietin expression might be a better way for treatment of ischemia-hypoxia neurovascular diseases. We have found that ethanol extract of Portulaca oleracea L. (EEPO) could increase erythropoietin expression in hypoxic mouse brain in our previous study. The present study is to investigate whether EEPO exerts its neuroprotective effects against hypoxia injury through regulating endogenous erythropoietin expression. The results demonstrated that EEPO decreased the serum neuron specific enolase level in hypoxia mice and the activity of caspase-3 in neuron, increased the neuron viability and attenuated the pathological damages caused by the hypoxia condition. Importantly, we also found that EEPO stimulated the endogenous erythropoietin expression at both mRNA and protein levels. Using the conditioned medium containing soluble erythropoietin receptor, we found that the neuroprotective effects of EEPO were dependent, at least partly, on erythropoietin expression. Although EEPO did not affect transcription of hypoxia inducible factor-1α (HIF-1α), it did stabilize expression of HIF-1α. It is concluded that EEPO has neuroprotective effects against hypoxia injury, which is at least partly through stimulating endogenous erythropoietin expression by stabilizing HIF-1α. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Inflames of confined space-hypoxia syndrome on riboflavin and its coenzymes content in white rat tissues

    Directory of Open Access Journals (Sweden)

    Наталія Леонідівна Федорко

    2015-08-01

    Full Text Available During confined space-hypoxia syndrome it is observed a significant increase of riboflavin in all organs of rats, but more in the heart and brain. High level of flavin adenine dinucleotide is observed in rat liver and kidney, and significant increase of flavin mononucleotide is observed only in the brain. The data reflect the metabolism of riboflavin under conditions of confined space-hypoxia syndrome, and change of the flavin content in the bodies of animals indicates different compensatory processes

  5. [Impact of hypoxia in different periods of prenatal ontogenesis on ECoG of rabbit fetus].

    Science.gov (United States)

    Guseĭnov, A G; Mamedov, Kh B

    2012-10-01

    Sensitivity of ECoG of sensorimotor cortex of 28-day rabbit foetus in different periods (prefetal and fetal) of embryogenesis to hypoxia impact was studied. In the foetus subjected to hypoxia during prefetal period (8-18th days) in the spectrum of the general activity the increase of slow waves, occupying little portion of the spectrum, is noticed, while the main delta-rhythm has more clear pattern. At the same time, hypoxia, undertaken in the fetal period (18-28th days) does not have significant effect on ECoG indexes. On the basis of our own and literature data one can propose tha high sensitivity of ECoG to oxygen deficiency is due to low stability of the brain cortex itself and subcortical white matter to hypoxic inpairement in early embriogenesis.

  6. Alterations of parenchymal microstructure, neuronal connectivity and cerebrovascular resistance at adolescence following mild to moderate traumatic brain injury in early development.

    Science.gov (United States)

    Parent, Maxime; Li, Ying; Santhakumar, Vijayalakshmi; Hyder, Fahmeed; Sanganahalli, Basavaraju G; Kannurpatti, Sridhar

    2018-06-01

    TBI is a leading cause of morbidity in children. To investigate outcome of early developmental TBI during adolescence, a rat model of fluid percussion injury was developed, where previous work reported deficits in sensorimotor behavior and cortical blood flow at adolescence. 1 Based on the non-localized outcome, we hypothesized that multiple neurophysiological components of brain function, namely neuronal connectivity, synapse/axonal microstructural integrity and neurovascular function are altered and magnetic resonance imaging (MRI) methods could be used to determine regional alterations. Adolescent outcomes of developmental TBI were studied 2-months after injury, using functional MRI (fMRI) and Diffusion Tensor Imaging (DTI). fMRI based resting state functional connectivity (RSFC), representing neural connectivity, was significantly altered between sham and TBI. RSFC strength decreased in the cortex, hippocampus and thalamus accompanied by decrease in the spatial extent of their corresponding RSFC networks and inter-hemispheric asymmetry. Cerebrovascular reactivity to arterial CO2 changes diminished after TBI across both hemispheres, with a more pronounced decrease in the ipsilateral hippocampus, thalamus and motor cortex. DTI measures of fractional anisotropy (FA) and apparent diffusion coefficient (ADC), reporting on axonal and microstructural integrity of the brain, indicated similar inter-hemispheric asymmetry, with highest change in the ipsilateral hippocampus and regions adjoining the ipsilateral thalamus, hypothalamus and amygdala. TBI-induced corpus callosal microstructural alterations indicated measurable changes in inter-hemispheric structural connectivity. Hippocampus, thalamus and select cortical regions were most consistently affected in multiple imaging markers. The multi-modal MRI results demonstrate cortical and subcortical alterations in neural connectivity, cerebrovascular resistance and parenchymal microstructure in the adolescent brain

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

    Directory of Open Access Journals (Sweden)

    Dora Polšek

    Full Text Available Sleep apnea is a chronic, widely underdiagnosed condition characterized by disruption of sleep architecture and intermittent hypoxia due to short cessations of breathing. It is a major independent risk factor for myocardial infarction, congestive heart failure and stroke as well as one of the rare modifiable risk factors for Alzheimer's Dementia. Reliable animal disease models are needed to understand the link between sleep apnea and the various clinically linked disorders.An automated system for inducing hypoxia was developed, in which the major improvement was the possibility to efficiently adjust the length and intensity of hypoxia in two different periods. The chamber used a small volume of gas allowing for fast exchanges of different oxygen levels. The mice were kept in their cages adapted with the system on the cage lid. As a proof of principle, they were exposed to a three week period of intermittent hypoxia for 8 hours a day, with 90 s intervals of 5, 7% and 21% oxygen to validate the model. Treated (n = 8 and control mice (no hypoxia, n = 7 were handled in the same manner and their hippocampal brain regions compared by histology.The chamber provided a fast, reliable and precise intermittent hypoxia, without inducing noticeable side effects to the animals. The validation experiment showed that apoptotic neurons in the hippocampus were more numerous in the mice exposed to intermittent hypoxia than in the control group, in all tested hippocampal regions (cornu ammonis 1 (CA1 P <0.001; cornu ammonis 3 (CA3 P <0.001; and dentate gyrus (DG P = 0.023. In both, control and hypoxic conditions, there was a significantly higher number of apoptotic neurons in the DG compared to the CA1 and CA3 subfields (P <0.001.The new design of a hypoxic chamber provides a fast, adjustable and reliable model of obstructive sleep apnea, which was validated by apoptosis of hippocampal neurons.

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

    Science.gov (United States)

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

    2018-01-10

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

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

    Science.gov (United States)

    Voronina, T A

    2000-01-01

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

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

    Science.gov (United States)

    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

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

    International Nuclear Information System (INIS)

    Steckbauer, A; Duarte, C M; Vaquer-Sunyer, R; Carstensen, J; Conley, D J

    2011-01-01

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

  12. Loss aversion and hypoxia: less loss aversion in oxygen-depleted environment.

    Science.gov (United States)

    Pighin, Stefania; Bonini, Nicolao; Savadori, Lucia; Hadjichristidis, Constantinos; Schena, Federico

    2014-03-01

    Hypoxia, the deprivation of adequate oxygen supply, constitutes a direct threat to survival by disrupting cardiovascular or respiratory homeostasis and eliciting a respiratory distress. Although hypoxia has been shown to increase brain vulnerability and impair basic cognitive functions, only one study has examined its effect on decision-making. The present study examined the effect of mild hypoxia on individual's loss aversion, that is, the tendency to be more affected by losses than equal sized gains. A sample of 26 participants were asked to either accept or reject a series of mixed gambles once in an oxygen-depleted environment (14.1% oxygen concentration) and once in a normoxic environment (20.9% oxygen concentration). Each gamble involved a 50-50 chance of winning or losing specified amounts of money. Mild hypoxia decreased loss aversion: on average in the normoxic condition participants accepted gambles if the gain was at least 2.4 times as large as the loss, whereas in the oxygen-depleted condition participants accepted gambles if the gain was at least 1.7 times as large as the loss. Mild hypoxia may push individuals to be less cautious in daily decisions that involve a trade-off between a gain and a loss.

  13. Inflammatory cytokine tumor necrosis factor α suppresses neuroprotective endogenous erythropoietin from astrocytes mediated by hypoxia-inducible factor-2α.

    Science.gov (United States)

    Nagaya, Yoshiaki; Aoyama, Mineyoshi; Tamura, Tetsuya; Kakita, Hiroki; Kato, Shin; Hida, Hideki; Saitoh, Shinji; Asai, Kiyofumi

    2014-12-01

    Interest in erythropoietin (EPO) as a neuroprotective mediator has grown since it was found that systemically administered EPO is protective in several animal models of disease. However, given that the blood-brain barrier limits EPO entry into the brain, alternative approaches that induce endogenous EPO production in the brain may be more effective clinically and associated with fewer untoward side-effects. Astrocytes are the main source of EPO in the central nervous system. In the present study we investigated the effect of the inflammatory cytokine tumor necrosis factor α (TNFα) on hypoxia-induced upregulation of EPO in rat brain. Hypoxia significantly increased EPO mRNA expression in the brain and kidney, and this increase was suppressed by TNFα in vivo. In cultured astrocytes exposed to hypoxic conditions for 6 and 12 h, TNFα suppressed the hypoxia-induced increase in EPO mRNA expression in a concentration-dependent manner. TNFα inhibition of hypoxia-induced EPO expression was mediated primarily by hypoxia-inducible factor (HIF)-2α rather than HIF-1α. The effects of TNFα in reducing hypoxia-induced upregulation of EPO mRNA expression probably involve destabilization of HIF-2α, which is regulated by the nuclear factor (NF)-κB signaling pathway. TNFα treatment attenuated the protective effects of astrocytes on neurons under hypoxic conditions via EPO signaling. The effective blockade of TNFα signaling may contribute to the maintenance of the neuroprotective effects of EPO even under hypoxic conditions with an inflammatory response. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  14. Hippocampal mitogen-activated protein kinase activation is associated with intermittent hypoxia in a rat model of obstructive sleep apnea syndrome.

    Science.gov (United States)

    Zhao, Ya-Ning; Wang, Hong-Yang; Li, Jian-Min; Chen, Bao-Yuan; Xia, Guo; Zhang, Pan-Pan; Ge, Yan-Lei

    2016-01-01

    Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/re‑oxygenation, may impair the cerebral system. Although mitogen‑activated protein kinase (MAPK) signaling was observed to have a key role in hypoxia‑induced brain injury, the intracellular events and their underlying mechanisms for intermittent hypoxia/re‑oxygenation-associated damage to hippocamal MAPKs, including extracellular signal‑regulated kinase (ERK)1/2, P38MAPK and c‑Jun N‑terminal kinase (JNK) remain to be elucidated and require further investigation. A total of five rats in each sub‑group were exposed to intermittent hypoxia or continued hypoxia for 2, 4, 6 or 8 weeks. Histological, immunohistochemical and biological analyses were performed to assess nerve cell injury in the hippocampus. Surviving CA1 pyramidal cells were identified by hematoxylin and eosin staining. The levels of phosphorylated ERK1/2, P38MAPK and JNK were detected by western blotting. B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax) in neural cells were examined by immunohistochemistry. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities were measured by thiobarbituric acid and xanthine oxidation methods, respectively. Under continued hypoxia, the levels of phospho‑ERK1/2 peaked at the fourth week and then declined, whereas phospho‑P38MAPK and JNK were detected only in the late stages. By contrast, under intermittent hypoxia, ERK1/2, P38MAPK and JNK were activated at all time-points assessed (2, 4, 6 and 8 weeks). The levels of phospho‑ERK1/2, P38MAPK and JNK were all higher in the intermittent hypoxia groups than those in the corresponding continued hypoxia groups. Bcl‑2 was mainly increased and reached the highest level at six weeks in the continued hypoxia group. Of note, Bcl‑2 rapidly increased to the peak level at four weeks, followed by a decrease to the lowest level at the eighth week in the intermittent hypoxia group. Bax was

  15. Emotion perception after moderate-severe traumatic brain injury: The valence effect and the role of working memory, processing speed, and nonverbal reasoning.

    Science.gov (United States)

    Rosenberg, Hannah; Dethier, Marie; Kessels, Roy P C; Westbrook, R Frederick; McDonald, Skye

    2015-07-01

    Traumatic brain injury (TBI) impairs emotion perception. Perception of negative emotions (sadness, disgust, fear, and anger) is reportedly affected more than positive (happiness and surprise) ones. It has been argued that this reflects a specialized neural network underpinning negative emotions that is vulnerable to brain injury. However, studies typically do not equate for differential difficulty between emotions. We aimed to examine whether emotion recognition deficits in people with TBI were specific to negative emotions, while equating task difficulty, and to determine whether perception deficits might be accounted for by other cognitive processes. Twenty-seven people with TBI and 28 matched control participants identified 6 basic emotions at 2 levels of intensity (a) the conventional 100% intensity and (b) "equated intensity"-that is, an intensity that yielded comparable accuracy rates across emotions in controls. (a) At 100% intensity, the TBI group was impaired in recognizing anger, fear, and disgust but not happiness, surprise, or sadness and performed worse on negative than positive emotions. (b) At equated intensity, the TBI group was poorer than controls overall but not differentially poorer in recognizing negative emotions. Although processing speed and nonverbal reasoning were associated with emotion accuracy, injury severity by itself was a unique predictor. When task difficulty is taken into account, individuals with TBI show impairment in recognizing all facial emotions. There was no evidence for a specific impairment for negative emotions or any particular emotion. Impairment was accounted for by injury severity rather than being a secondary effect of reduced neuropsychological functioning. (c) 2015 APA, all rights reserved).

  16. Sexually Dimorphic Outcomes after Neonatal Stroke and Hypoxia-Ischemia

    Directory of Open Access Journals (Sweden)

    Christiane Charriaut-Marlangue

    2017-12-01

    Full Text Available Cohort studies have demonstrated a higher vulnerability in males towards ischemic and/or hypoxic-ischemic injury in infants born near- or full-term. Male sex was also associated with limited brain repair following neonatal stroke and hypoxia-ischemia, leading to increased incidence of long-term cognitive deficits compared to females with similar brain injury. As a result, the design of pre-clinical experiments considering sex as an important variable was supported and investigated because neuroprotective strategies to reduce brain injury demonstrated sexual dimorphism. While the mechanisms underlining these differences between boys and girls remain unclear, several biological processes are recognized to play a key role in long-term neurodevelopmental outcomes: gonadal hormones across developmental stages, vulnerability to oxidative stress, modulation of cell death, and regulation of microglial activation. This review summarizes the current evidence for sex differences in neonatal hypoxic-ischemic and/or ischemic brain injury, considering the major pathways known to be involved in cognitive and behavioral deficits associated with damages of the developing brain.

  17. Exposure to acute severe hypoxia leads to increased urea loss and disruptions in acid-base and ionoregulatory balance in dogfish sharks (Squalus acanthias).

    Science.gov (United States)

    Zimmer, Alex M; Wood, Chris M

    2014-01-01

    The effects of acute moderate (20% air O2 saturation; 6-h exposure) and severe (5% air O2 saturation; 4-h exposure) hypoxia on N-waste, acid-base, and ion balance in dogfish sharks (Squalus acanthias suckleyi) were evaluated. We predicted that the synthesis and/or retention of urea, which are active processes, would be inhibited by hypoxia. Exposure to moderate hypoxia had negligible effects on N-waste fluxes or systemic physiology, except for a modest rise in plasma lactate. Exposure to severe hypoxia led to a significant increase in urea excretion (Jurea), while plasma, liver, and muscle urea concentrations were unchanged, suggesting a loss of urea retention. Ammonia excretion (Jamm) was elevated during normoxic recovery. Moreover, severe hypoxia led to disruptions in acid-base balance, indicated by a large increase in plasma [lactate] and substantial decreases in arterial pHa and plasma [Formula: see text], as well as loss of ionic homeostasis, indicated by increases in plasma [Mg(2+)], [Ca(2+)], and [Na(+)]. We suggest that severe hypoxia in dogfish sharks leads to a reduction in active gill homeostatic processes, such as urea retention, acid-base regulation and ionoregulation, and/or an osmoregulatory compromise due to increased functional gill surface area. Overall, the results provide a comprehensive picture of the physiological responses to a severe degree of hypoxia in an ancient fish species.

  18. The role of GABA in the hypoxia tolerance of the epaulette shark

    International Nuclear Information System (INIS)

    Wise, G.; Mulvey, J.; Renshaw, G.M.C.; Dodd, P.R.

    1998-01-01

    Full text: The epaulette shark responds to hypoxia with brain hypometabolism which is correlated with increased levels of gamma-aminobutyric acid (GABA). We examined GABA-like immunoreactivity (GABA-IR) and the density and binding characteristics of GABA A receptors in the Epaulette shark brainstem. These studies were conducted to investigate changes in response to hypoxia. Experimental animals were exposed to eight cycles of an extreme hypoxic regimen (5% of normoxia). Animals were anaesthetised with 80mg/L of MS222 and the brain was dissected and processed either for immunohistochemistry or receptor ligand binding. Membranes were prepared at 4 deg C according to a previously reported protocol and the binding characteristics of [ 3 H]flunitrazeparn ([ 3 H]FNZ) were examined using an in vitro centrifugation assay. We report on the effect of hypoxia on specific [ 3 H]FNZ binding characteristics. GABA-IR was detected using a primary antibody dilution of 1:15 000 and the Vector ABC method. We report that an overall increase in the optical density of GABA-IR occurs with significant increases in three out of the four brainstem nuclei examined in experimental animals. The results of these studies are discussed in conjunction with the hypoxia-tolerance .of the epaulette shark. Copyright (1998) Australian Neuroscience Society

  19. CO2-O2 interactions in extension of tolerance to acute hypoxia

    Science.gov (United States)

    Lambertsen, C. J.

    1995-01-01

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

  20. Kinetic modeling in PET imaging of hypoxia

    DEFF Research Database (Denmark)

    Li, Fan; Jørgensen, Jesper Tranekjær; Hansen, Anders E

    2014-01-01

    be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET......Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can...... analysis for PET imaging of hypoxia....

  1. Stem cells to regenerate the newborn brain

    NARCIS (Netherlands)

    van Velthoven, C.T.J.

    2011-01-01

    Perinatal hypoxia-ischemia (HI) is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. In this thesis we investigate whether mesenchymal stem cells (MSC) regenerate the neonatal brain after HI injury. We show that transplantation of MSC after neonatal brain injury

  2. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M

    1996-01-01

    exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVA P = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other...... (10% Co2 with 10% O2) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVA P > 0.05). Hypocapnic normoxia, produced...

  3. Evaluation of coping resources and self-esteem as moderators of the relationship between threat appraisals and avoidance of activities after traumatic brain injury.

    Science.gov (United States)

    Riley, Gerard A; Dennis, Rebecca K; Powell, Theresa

    2010-12-01

    It is not uncommon for people after a traumatic brain injury (TBI) to develop anxieties about possible negative outcomes (i.e., threat appraisals) in relation to participating in valued activities. Some respond to this anxiety by avoiding the activities, but others maintain their participation. The present study investigated two factors that may help explain this variation across individuals in their response to threat appraisals - self-esteem and the evaluation of coping resources. Forty-one individuals with a TBI completed the Avoidance and Threat Appraisals Questionnaire, the Rosenberg Self-Esteem Scale and the Coping Resources Questionnaire. The study's hypotheses were supported: Those low in self-esteem, and those with a negative evaluation of their ability to cope with the TBI, were significantly more likely to respond to threat appraisals with avoidance. Those whose injury was more recent and those whose injury was the result of an assault were also more likely to respond with avoidance. The theoretical and therapeutic implications of these results are discussed.

  4. Parents and teachers reporting on a child's emotional and behavioural problems following severe traumatic brain injury (TBI): the moderating effect of time.

    Science.gov (United States)

    Silberg, Tamar; Tal-Jacobi, Dana; Levav, Miriam; Brezner, Amichai; Rassovsky, Yuri

    2015-01-01

    Gathering information from parents and teachers following paediatric traumatic brain injury (TBI) has substantial clinical value for diagnostic decisions. Yet, a multi-informant approach has rarely been addressed when evaluating children at the chronic stage post-injury. In the current study, the goals were to examine (1) differences between parents' and teachers' reports on a child's emotional and behavioural problems and (2) the effect of time elapsed since injury on each rater's report. A sample of 42 parents and 42 teachers of children following severe TBI completed two standard rating scales. Receiver Operating Characteristic (ROC) curves were used to determine whether time elapsed since injury reliably distinguished children falling above and below clinical levels. Emotional-behavioural scores of children following severe TBI fell within normal range, according to both teachers and parents. Significant differences were found between parents' reports relatively close to the time of injury and 2 years post-injury. However, no such differences were observed in teachers' ratings. Parents and teachers of children following severe TBI differ in their reports on a child's emotional and behavioural problems. The present study not only underscores the importance of multiple informants, but also highlights, for the first time, the possibility that informants' perceptions may vary across time.

  5. Effect of hypoxia on the activity and binding of glycolytic and associated enzymes in sea scorpion tissues

    Directory of Open Access Journals (Sweden)

    Lushchak V.I.

    1998-01-01

    Full Text Available The effect of hypoxia on the levels of glycogen, glucose and lactate as well as the activities and binding of glycolytic and associated enzymes to subcellular structures was studied in brain, liver and white muscle of the teleost fish, Scorpaena porcus. Hypoxia exposure decreased glucose levels in liver from 2.53 to 1.70 µmol/g wet weight and in muscle led to its increase from 3.64 to 25.1 µmol/g wet weight. Maximal activities of several enzymes in brain were increased by hypoxia: hexokinase by 23%, phosphoglucoisomerase by 47% and phosphofructokinase (PFK by 56%. However, activities of other enzymes in brain as well as enzymes in liver and white muscle were largely unchanged or decreased during experimental hypoxia. Glycolytic enzymes in all three tissues were partitioned between soluble and particulate-bound forms. In several cases, the percentage of bound enzymes was reduced during hypoxia; bound aldolase in brain was reduced from 36.4 to 30.3% whereas glucose-6-phosphate dehydrogenase fell from 55.7 to 28.7% bound. In muscle PFK was reduced from 57.4 to 41.7% bound. Oppositely, the proportion of bound aldolase and triosephosphate isomerase increased in hypoxic muscle. Phosphoglucomutase did not appear to occur in a bound form in liver and bound phosphoglucomutase disappeared in muscle during hypoxia exposure. Anoxia exposure also led to the disappearance of bound fructose-1,6-bisphosphatase in liver, whereas a bound fraction of this enzyme appeared in white muscle of anoxic animals. The possible function of reversible binding of glycolytic enzymes to subcellular structures as a regulatory mechanism of carbohydrate metabolism is discussed.

  6. Improvement of oxygen supply by an artificial carrier in combination with normobaric oxygenation decreases the volume of tissue hypoxia and tissue damage from transient focal cerebral ischemia

    NARCIS (Netherlands)

    Seiffge, David J.; Lapina, Natalia E.; Tsagogiorgas, Charalambos; Theisinger, Bastian; Henning, Robert H.; Schilling, Lothar

    Tissue hypoxia may play an important role in the development of ischemic brain damage. In the present study we investigated in a rat model of transient focal brain ischemia the neuroprotective effects of increasing the blood oxygen transport capacity by applying a semifluorinated alkane

  7. Hypoxia and the heart of poikilotherms

    Czech Academy of Sciences Publication Activity Database

    Ošťádal, Bohuslav

    2014-01-01

    Roč. 1, č. 1 (2014), s. 28-32 Institutional support: RVO:67985823 Keywords : blood supply heart * poikilotherms * tolerance to hypoxia Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  8. Redox signaling during hypoxia in mammalian cells

    Directory of Open Access Journals (Sweden)

    Kimberly A. Smith

    2017-10-01

    Full Text Available Hypoxia triggers a wide range of protective responses in mammalian cells, which are mediated through transcriptional and post-translational mechanisms. Redox signaling in cells by reactive oxygen species (ROS such as hydrogen peroxide (H2O2 occurs through the reversible oxidation of cysteine thiol groups, resulting in structural modifications that can change protein function profoundly. Mitochondria are an important source of ROS generation, and studies reveal that superoxide generation by the electron transport chain increases during hypoxia. Other sources of ROS, such as the NAD(PH oxidases, may also generate oxidant signals in hypoxia. This review considers the growing body of work indicating that increased ROS signals during hypoxia are responsible for regulating the activation of protective mechanisms in diverse cell types.

  9. Hypoxia, HIF-1 Regulation and Cancer Therapy

    NARCIS (Netherlands)

    Groot, A.J.

    2008-01-01

    Oxygen insufficiency (hypoxia) is a common feature of human cancer and associated with tumor aggressiveness and poor clinical outcome. Furthermore, hypoxic tumors are more resistant to ionizing radiation and chemotherapy contributing to their unfavorable prognosis. The oxygen sensing pathway is

  10. 2007 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  11. 2004 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  12. 2005 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  13. 2002 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  14. 2003 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  15. 2001 Hypoxia Watch Bottom CTD Station Locations

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The NOAA Hypoxia Watch project provides near-real-time, web-based maps of dissolved oxygen near the sea floor over the Texas-Louisiana continental shelf during a...

  16. Cognition Effects of Low-Grade Hypoxia

    Science.gov (United States)

    2016-07-01

    human short-term memory . Br J Anaesth. 1971; 43(6):548–552. 3. Crow TJ, Kelman GR. Psychological effects of mild acute hypoxia. Br J Anaesth. 1973; 45...Journal Article 3. DATES COVERED (From – To) Jan 2003 – Sep 2005 4. TITLE AND SUBTITLE Cognition Effects of Low-Grade Hypoxia 5a. CONTRACT NUMBER... cognitive function are reported in this paper. The study compared cognitive function during short exposures at four different altitudes. Ninety-one

  17. Hypoxia independent drivers of melanoma angiogenesis

    Directory of Open Access Journals (Sweden)

    Svenja eMeierjohann

    2015-05-01

    Full Text Available Tumor angiogenesis is a process which is traditionally regarded as the tumor`s response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a prerequisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia independent mechanisms of tumor angiogenesis in melanoma.

  18. Activity of lactate dehydrogenase in serum and cerebral cortex of immature and mature rats after hypobaric hypoxia

    Czech Academy of Sciences Publication Activity Database

    Koudelová, J.; Rauchová, Hana; Vokurková, Martina

    2006-01-01

    Roč. 31, č. 7 (2006), s. 915-919 ISSN 0364-3190 R&D Projects: GA ČR(CZ) GA305/04/0500; GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : brain * lactate dehydrogenase * hypoxia Subject RIV: ED - Physiology Impact factor: 2.139, year: 2006

  19. Moderate effects of noninvasive brain stimulation of the frontal cortex for improving negative symptoms in schizophrenia: Meta-analysis of controlled trials.

    Science.gov (United States)

    Aleman, André; Enriquez-Geppert, Stefanie; Knegtering, Henderikus; Dlabac-de Lange, Jozarni J

    2018-06-01

    studies as yet with tDCS. More research is needed to establish moderator variables that may affect response to neurostimulation and to optimize treatment parameters in order to achieve stable and durable (and thus clinically relevant) effects. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling

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    Annika Bettina Foehrenbacher

    2013-12-01

    Full Text Available Hypoxia contributes to resistance of tumors to some cytotoxic drugs and to radiotherapy, but can in principle be exploited with hypoxia-activated prodrugs (HAP. HAP in clinical development fall into two broad groups. Class I HAP (like the benzotriazine N-oxides tirapazamine and SN30000, are activated under relatively mild hypoxia. In contrast, Class II HAP (such as the nitro compounds PR-104A or TH-302 are maximally activated only under extreme hypoxia, but their active metabolites (effectors diffuse to cells at intermediate O2 and thus also eliminate moderately hypoxic cells. Here, we use a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD model to compare these two strategies and to identify the features required in an optimal Class II HAP. The model uses a Green’s function approach to calculate spatial and longitudinal gradients of O2, prodrug and effector concentrations, and resulting killing in a digitized 3D tumor microregion to estimate activity as monotherapy and in combination with radiotherapy. An analogous model for a normal tissue with mild hypoxia and short intervesssel distances (based on a cremaster muscle microvessel network was used to estimate tumor selectivity of cell killing. This showed that Class II HAP offer advantages over Class I including higher tumor selectivity and greater freedom to vary prodrug diffusibility and rate of metabolic activation. The model suggests that the largest gains in class II HAP antitumor activity could be realized by optimizing effector stability and prodrug activation rates. We also use the model to show that diffusion of effector into blood vessels is unlikely to materially increase systemic exposure for realistic tumor burdens and effector clearances. However, we show that the tumor selectivity achievable by hypoxia-dependent prodrug activation alone is limited if dose-limiting normal tissues are even mildly hypoxic

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

    Science.gov (United States)

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

    2016-03-01

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

  2. The effect of aprotinin on hypoxia-reoxygenation-induced changes in neutrophil and endothelial function.

    LENUS (Irish Health Repository)

    Harmon, D

    2012-02-03

    BACKGROUND AND OBJECTIVE: An acute inflammatory response associated with cerebral ischaemia-reperfusion contributes to the development of brain injury. Aprotinin has potential, though unexplained, neuroprotective effects in patients undergoing cardiac surgery. METHODS: Human neutrophil CD11 b\\/CD18, endothelial cell intercellular adhesion molecule-1 (ICAM-1) expression and endothelial interleukin (IL)-1beta supernatant concentrations in response to in vitro hypoxia-reoxygenation was studied in the presence or absence of aprotinin (1600 KIU mL(-1)). Adhesion molecule expression was quantified using flow cytometry and IL-1beta concentrations by enzyme-linked immunosorbent assay. Data were analysed using ANOVA and post hoc Student-Newman-Keuls test as appropriate. RESULTS: Exposure to 60-min hypoxia increased neutrophil CD11b expression compared to normoxia (170+\\/-46% vs. 91+\\/-27%, P = 0.001) (percent intensity of fluorescence compared to time 0) (n = 8). Hypoxia (60 min) produced greater upregulation of CD11b expression in controls compared to aprotinin-treated neutrophils [(170+\\/-46% vs. 129+\\/-40%) (P = 0.04)] (n = 8). Hypoxia-reoxygenation increased endothelial cell ICAM-1 expression (155+\\/-3.7 vs. 43+\\/-21 mean channel fluorescence, P = 0.0003) and IL-1beta supernatant concentrations compared to normoxia (3.4+\\/-0.4 vs. 2.6+\\/-0.2, P = 0.02) (n = 3). Hypoxia-reoxygenation produced greater upregulation of ICAM- 1 expression [(155+\\/-3.3 vs. 116+\\/-0.7) (P = 0.001)] and IL-1beta supernatant concentrations [(3.4+\\/-0.3 vs. 2.6+\\/-0.1) (P = 0.01)] in controls compared to aprotinin-treated endothelial cell preparation (n = 3). CONCLUSIONS: Hypoxia-reoxygenation-induced upregulation of neutrophil CD11b, endothelial cell ICAM-1 expression and IL-1beta concentrations is decreased by aprotinin at clinically relevant concentrations.

  3. Role of Carotid Body in Intermittent Hypoxia-Related Hypertension.

    Science.gov (United States)

    Iturriaga, Rodrigo; Oyarce, María Paz; Dias, Ana Carolina Rodrigues

    2017-05-01

    Obstructive sleep apnea (OSA), a common breathing disorder, is recognized as an independent risk factor for systemic hypertension. Among the alterations induced by OSA, the chronic intermittent hypoxia (CIH) is considered the main factor for the hypertension. Exposure of rodents to CIH is the gold-standard method to study the mechanisms involved in the cardiovascular alterations induced by OSA. Although it is well known that CIH produces hypertension, the underlying mechanisms are not totally elucidated. It is likely that the CIH-induced systemic oxidative stress and inflammation may elicit endothelial dysfunction and increase the arterial blood pressure. In addition, OSA patients and animals exposed to CIH show sympathetic hyperactivity and potentiated cardiorespiratory responses to acute hypoxia, suggesting that CIH enhances the peripheral hypoxic chemoreflex. Recent experimental evidences support the proposal that CIH selectively enhances carotid body (CB) chemosensory reactivity to oxygen, which in turn increases sympathetic outflow leading to neurogenic hypertension. In this review, we will discuss the supporting evidence for a critical role of the CB in the generation and maintenance of the hypertension induced by CIH, also, the contribution of oxidative stress to enhance CB chemosensory drive and the activation of sympathetic-related centers in the brain.

  4. Chapter 8 Military Personnel With Traumatic Brain Injuries and Insomnia Have Reductions in PTSD and Improved Perceived Health Following Sleep Restoration: A Relationship Moderated by Inflammation.

    Science.gov (United States)

    Barr, Taura; Livingston, Whitney; Guardado, Pedro; Baxter, Tristin; Mysliwiec, Vincent; Gill, Jessica

    2015-01-01

    Up to one-third of deployed military personnel sustain a traumatic brain injury (TBI). TBIs and the stress of deployment contribute to the vulnerability for chronic sleep disturbance, resulting in high rates of insomnia diagnoses as well as symptoms of posttraumatic stress disorder (PTSD), depression, and declines in health-related quality of life (HRQOL). Inflammation is associated with insomnia; however, the impact of sleep changes on comorbid symptoms and inflammation in this population is unknown. In this study, we examined the relationship between reported sleep changes and the provision of the standard of care, which could include one or more of the following: cognitive behavioral therapy (CBT), medications, and continuous positive airway pressure (CPAP). We compared the following: (a) the group with a decrease in the Pittsburgh Sleep Quality Index (PSQI; restorative sleep) and (b) the group with no change or increase in PSQI (no change). Independent t tests and chi-square tests were used to compare the groups on demographic and clinical characteristics, and mixed between-within subjects analysis of variance tests were used to determine the effect of group differences on changes in comorbid symptoms. Linear regression models were used to examine the role of inflammation in changes in symptoms and HRQOL. The sample included 70 recently deployed military personnel with TBI, seeking care for sleep disturbances. Thirty-seven participants reported restorative sleep and 33 reported no sleep changes or worse sleep. The two groups did not differ in demographic characteristics or clinical symptoms at baseline. The TBI+restored sleep group had significant reductions in PTSD and depression over the 3-month period, whereas the TBI+no change group had a slight increase in both PTSD and depression. The TBI+restored sleep group also had significant changes in HRQOL, including the following HRQOL subcomponents: physical functioning, role limitations in physical health

  5. Thirty Minutes of Hypobaric Hypoxia Provokes Alterations of Immune Response, Haemostasis, and Metabolism Proteins in Human Serum

    Directory of Open Access Journals (Sweden)

    Jochen Hinkelbein

    2017-08-01

    Full Text Available Hypobaric hypoxia (HH during airline travel induces several (patho- physiological reactions in the human body. Whereas severe hypoxia is investigated thoroughly, very little is known about effects of moderate or short-term hypoxia, e.g. during airline flights. The aim of the present study was to analyse changes in serum protein expression and activation of signalling cascades in human volunteers staying for 30 min in a simulated altitude equivalent to airline travel. After approval of the local ethics committee, 10 participants were exposed to moderate hypoxia (simulation of 2400 m or 8000 ft for 30 min in a hypobaric pressure chamber. Before and after hypobaric hypoxia, serum was drawn, centrifuged, and analysed by two-dimensional gel electrophoresis (2-DIGE and matrix-assisted laser desorption/ionization followed by time-of-flight mass spectrometry (MALDI-TOF. Biological functions of regulated proteins were identified using functional network analysis (GeneMania®, STRING®, and Perseus® software. In participants, oxygen saturation decreased from 98.1 ± 1.3% to 89.2 ± 1.8% during HH. Expression of 14 spots (i.e., 10 proteins: ALB, PGK1, APOE, GAPDH, C1QA, C1QB, CAT, CA1, F2, and CLU was significantly altered. Bioinformatic analysis revealed an association of the altered proteins with the signalling cascades “regulation of haemostasis” (four proteins, “metabolism” (five proteins, and “leukocyte mediated immune response” (five proteins. Even though hypobaric hypoxia was short and moderate (comparable to an airliner flight, analysis of protein expression in human subjects revealed an association to immune response, protein metabolism, and haemostasis

  6. Tumor Hypoxia: Causative Mechanisms, Microregional Heterogeneities, and the Role of Tissue-Based Hypoxia Markers.

    Science.gov (United States)

    Vaupel, Peter; Mayer, Arnulf

    Tumor hypoxia is a hallmark of solid malignant tumor growth, profoundly influences malignant progression and contributes to the development of therapeutic resistance. Pathogenesis of tumor hypoxia is multifactorial, with contributions from both acute and chronic factors. Spatial distribution of hypoxia within tumors is markedly heterogeneous and often changes over time, e.g., during a course of radiotherapy. Substantial changes in the oxygenation status can occur within the distance of a few cell layers, explaining the inability of currently used molecular imaging techniques to adequately assess this crucial trait. Due to the possible importance of tumor hypoxia for clinical decision-making, there is a great demand for molecular tools which may provide the necessary resolution down to the single cell level. Exogenous and endogenous markers of tumor hypoxia have been investigated for this purpose. Their potential use may be greatly enhanced by multiparametric in situ methods in experimental and human tumor tissue.

  7. Hypoxia and hypoxia inducible factor-1α are required for normal endometrial repair during menstruation.

    Science.gov (United States)

    Maybin, Jacqueline A; Murray, Alison A; Saunders, Philippa T K; Hirani, Nikhil; Carmeliet, Peter; Critchley, Hilary O D

    2018-01-23

    Heavy menstrual bleeding (HMB) is common and debilitating, and often requires surgery due to hormonal side effects from medical therapies. Here we show that transient, physiological hypoxia occurs in the menstrual endometrium to stabilise hypoxia inducible factor 1 (HIF-1) and drive repair of the denuded surface. We report that women with HMB have decreased endometrial HIF-1α during menstruation and prolonged menstrual bleeding. In a mouse model of simulated menses, physiological endometrial hypoxia occurs during bleeding. Maintenance of mice under hyperoxia during menses decreases HIF-1α induction and delays endometrial repair. The same effects are observed upon genetic or pharmacological reduction of endometrial HIF-1α. Conversely, artificial induction of hypoxia by pharmacological stabilisation of HIF-1α rescues the delayed endometrial repair in hypoxia-deficient mice. These data reveal a role for HIF-1 in the endometrium and suggest its pharmacological stabilisation during menses offers an effective, non-hormonal treatment for women with HMB.

  8. Functional magnetic resonance imaging (fMRI) for fetal oxygenation during maternal hypoxia: initial results

    International Nuclear Information System (INIS)

    Wedegaertner, U.; Adam, G.; Tchirikov, M.; Schroeder, H.; Koch, M.

    2002-01-01

    Purpose: To investigate the potential of fMRI to measure changes in fetal tissue oxygenation during acute maternal hypoxia in fetal lambs. Material and Methods: Two ewes carrying singleton fetuses (gestational age 125 and 131 days) underwent MR imaging under inhalation anesthesia. BOLD imaging of the fetal brain, liver and myocardium was performed during acute maternal hypoxia (oxygen replaced by N 2 O). Maternal oxygen saturation and heart rate were monitored by a pulse-oxymeter attached to the maternal tongue. Results: Changes of fetal tissue oxygenation during maternal hypoxia were clearly visible with BOLD MRI. Signal intensity decreases were more distinct in liver and heart (∝40%) from control than in the fetal brain (∝10%). Conclusions: fMRI is a promising diagnostic tool to determine fetal tissue oxygenation and may open new opportunities in monitoring fetal well being in high risk pregnancies complicated by uteroplacentar insufficiency. Different signal changes in liver/heart and brain may reflect a centralization of the fetal blood flow. (orig.) [de

  9. Hypoxia training: symptom replication in experienced military aircrew.

    Science.gov (United States)

    Johnston, Ben J; Iremonger, Gareth S; Hunt, Sheena; Beattie, Elizabeth

    2012-10-01

    Military aircrew are trained to recognize the signs and symptoms of hypoxia in a safe environment using a variety of methods to simulate altitude. In order to investigate the effectiveness of hypoxia training, this study compared the recall of hypoxia symptoms in military aircrew between two consecutive hypobaric chamber hypoxia training sessions conducted, on average, 4.5 yr apart. Previously trained subjects completed a questionnaire immediately before and after they underwent refresher hypoxia training and recorded the occurrence, order, and severity of symptoms experienced. Responses from refresher training were compared with their recall of symptoms experienced during previous training. There was no difference in the recall of most hypoxia symptoms between training sessions. Slurred speech was recalled more frequently from previous training compared to refresher training (14 vs. 4 subjects), whereas hot/cold flushes were recalled less frequently from previous training compared to refresher training (5 vs. 17 subjects). There was a statistically significant difference in overall hypoxia score (10.3 vs. 8.3), suggesting that from memory subjects may underestimate the level of hypoxia experienced in previous training. A high level of similarity between the recall of previously experienced hypoxia symptoms and recent experience supports the effectiveness of hypoxia training. These results replicate the finding of a 'hypoxia signature' reported by a previous study. Small differences in the recall of some symptoms and in overall hypoxia score highlight the importance of drawing attention to the more subtle symptoms of early hypoxia, and of using training techniques which optimize aircrew recall.

  10. Protective effect of astrocyte-conditioned medium on neurons following hypoxia and mechanical injury

    Directory of Open Access Journals (Sweden)

    YAN Ji-wen

    2013-02-01

    Full Text Available 【Abstract】Objective: To investigate the protec-tive effect of mouse astrocyte-conditioned medium (ACM on hypoxic and mechanically injured neurons by a cell model in vitro, and to explore the possible mechanism. Methods: The model of hypoxic neuronal injury was caused by 3% O 2 in three-gas incubator. Neurons were cul-tured with ordinary medium or 20% ACM respectively and randomly divided into hypoxic group (hypoxia for 4, 8, 24 h and marked as H4R0, H8R0, H24R0 and hypoxia reoxygenation group (H4R24, H8R24, H24R24. Mechanical injury model was developed by scratching neurons cultured in 20% ACM or ordinary medium to different degrees. Neu-rons in both medium were divided into normal control group, mild, moderate and severe injury groups. The 20% ACM was added 24 h before hypoxia/reoxygenation or mechanical injury. The morphology and survival of neurons were observed and counted by trypan blue staining. The concentration of NO, lactic dehydrogenase (LDH and membrane ATPase activity were detected by corresponding kits. Results: It was showed that 20% ACM can obviously promote the survival rate of hypoxia/reoxygenated neurons and scratched neurons as well. The morphology and num-ber of neurons exposed to hypoxia or scratch injury showed great difference between groups with or without ACM treatment. Compared with control group, the concentration of NO and LDH was much lower in hypoxic/reoxygenated neurons treated with 20% ACM, and the ATPase activity was higher. For the mechanical injury model, neurons with moderate injury also revealed a lower NO and LDH concen-tration than the control group. All the differences were sta-tistically significant (P<0.05. Conclusion: ACM can promote the survival and func-tional recovery of neurons following hypoxia or scratching to a certain degree. The mechanism may be associated with reducing the synthesis and release of NO and LDH as well as increasing the activity of membrane ATPase. Key words: Glial cell line

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

    Science.gov (United States)

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

    2018-01-01

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

  12. Normobaric, intermittent hypoxia conditioning is cardio- and vasoprotective in rats.

    Science.gov (United States)

    Manukhina, Eugenia B; Belkina, Ludmila M; Terekhina, Olga L; Abramochkin, Denis V; Smirnova, Elena A; Budanova, Olga P; Mallet, Robert T; Downey, H Fred

    2013-12-01

    Favorable versus detrimental cardiovascular responses to intermittent hypoxia conditioning (IHC) are heavily dependent on experimental or pathological conditions, including the duration, frequency and intensity of the hypoxia exposures. Recently, we demonstrated that a program of moderate, normobaric IHC (FIO2 9.5-10% for 5-10 min/cycle, with intervening 4 min normoxia, 5-8 cycles/day for 20 days) in dogs afforded robust cardioprotection against infarction and arrhythmias induced by coronary artery occlusion-reperfusion, but this protection has not been verified in other species. Accordingly, in this investigation cardio- as well as vasoprotection were examined in male Wistar rats completing the normobaric IHC program or a sham program in which the rats continuously breathed atmospheric air. Myocardial ischemia and reperfusion (IR) was imposed by occlusion and reperfusion of the left anterior descending coronary artery in in situ experiments and by subjecting isolated, perfused hearts to global ischemia-reperfusion. Cardiac arrhythmias and myocardial infarct size were quantified in in situ experiments. Endothelial function was evaluated from the relaxation to acetylcholine of norepinephrine-precontracted aortic rings taken from in situ IR experiments, and from the increase in coronary flow produced by acetylcholine in isolated hearts. IHC sharply reduced cardiac arrhythmias during ischemia and decreased infarct size by 43% following IR. Endothelial dysfunction in aorta was marked after IR in sham rats, but not significant in IHC rats. Similar findings were found for the coronary circulations of isolated hearts. These findings support the hypothesis that moderate, normobaric IHC is cardio- and vasoprotective in a rat model of IR.

  13. Association between the Osteoporosis Self-Assessment Tool for Asians Score and Mortality in Patients with Isolated Moderate and Severe Traumatic Brain Injury: A Propensity Score-Matched Analysis.

    Science.gov (United States)

    Rau, Cheng-Shyuan; Kuo, Pao-Jen; Wu, Shao-Chun; Chen, Yi-Chun; Hsieh, Hsiao-Yun; Hsieh, Ching-Hua

    2016-12-03

    Background: The purpose of this study was to use a propensity score-matched analysis to investigate the association between the Osteoporosis Self-Assessment Tool for Asians (OSTA) scores and clinical outcomes of patients with isolated moderate and severe traumatic brain injury (TBI). Methods: The study population comprised 7855 patients aged ≥40 years who were hospitalized for treatment of isolated moderate and severe TBI (an Abbreviated Injury Scale (AIS) ≥3 points only in the head and not in other regions of the body) between 1 January 2009 and 31 December 2014. Patients were categorized as high-risk (OSTA score -1; n = 5359). Two-sided Pearson's chi-squared, or Fisher's exact tests were used to compare categorical data. Unpaired Student's t -test and Mann-Whitney U test were performed to analyze normally and non-normally distributed continuous data, respectively. Propensity score-matching in a 1:1 ratio was performed using NCSS software, with adjustment for covariates. Results: Compared to low-risk patients, high- and medium-risk patients were significantly older and injured more severely. The high- and medium-risk patients had significantly higher mortality rates, longer hospital length of stay, and a higher proportion of admission to the intensive care unit than low-risk patients. Analysis of propensity score-matched patients with adjusted covariates, including gender, co-morbidity, blood alcohol concentration level, Glasgow Coma Scale score, and Injury Severity Score revealed that high- and medium-risk patients still had a 2.4-fold (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.39-4.15; p = 0.001) and 1.8-fold (OR, 1.8; 95% CI, 1.19-2.86; p = 0.005) higher mortality, respectively, than low-risk patients. However, further addition of age as a covariate for the propensity score-matching demonstrated that there was no significant difference between high-risk and low-risk patients or between medium-risk and low-risk patients, implying that older age

  14. Plasma metabolite score correlates with Hypoxia time in a newly born piglet model for asphyxia

    Directory of Open Access Journals (Sweden)

    Julia Kuligowski

    2017-08-01

    Full Text Available Hypoxic-ischemic encephalopathy (HIE secondary to perinatal asphyxia is a leading cause of mortality and acquired long-term neurologic co-morbidities in the neonate. The most successful intervention for the treatment of moderate to severe HIE is moderate whole body hypothermia initiated within 6 h from birth. The objective and prompt identification of infants who are at risk of developing moderate to severe HIE in the critical first hours still remains a challenge. This work proposes a metabolite score calculated based on the relative intensities of three metabolites (choline, 6,8-dihydroxypurine and hypoxanthine that showed maximum correlation with hypoxia time in a consolidated piglet model for neonatal hypoxia-ischemia. The metabolite score's performance as a biomarker for perinatal hypoxia and its usefulness for clinical grading and decision making have been assessed and compared to the performance of lactate which is currently considered the gold standard. For plasma samples withdrawn before and directly after a hypoxic insult, the metabolite score performed similar to lactate. However, it provided an enhanced predictive capacity at 2 h after resuscitation. The present study evidences the usefulness of the metabolite score for improving the early assessment of the severity of the hypoxic insult based on serial determinations in a minimally invasive biofluid. The applicability of the metabolite score for clinical diagnosis and patient stratification for hypothermia treatment has to be confirmed in multicenter trials involving newborns suffering from HIE. Keywords: Hypoxia, Perinatal asphyxia, Newborn, Metabolic biomarker, Neonatal piglet model, Liquid Chromatography – Time-of-Flight Mass Spectrometry (LC-TOF-MS

  15. Diagnostic efficiency of demographically corrected Wechsler Adult Intelligence Scale-III and Wechsler Memory Scale-III indices in moderate to severe traumatic brain injury and lower education levels.

    Science.gov (United States)

    Walker, Alexandra J; Batchelor, Jennifer; Shores, E Arthur; Jones, Mike

    2009-11-01

    Despite the sensitivity of neuropsychological tests to educational level, improved diagnostic accuracy for demographically corrected scores has yet to be established. Diagnostic efficiency statistics of Wechsler Adult Intelligence Scale-III (WAIS-III) and Wechsler Memory Scale-III (WMS-III) indices that were corrected for education, sex, and age (demographically corrected) were compared with age corrected indices in individuals aged 16 to 75 years with moderate to severe traumatic brain injury (TBI) and 12 years or less education. TBI participants (n = 100) were consecutive referrals to an outpatient rehabilitation service and met careful selection criteria. Controls (n = 100) were obtained from the WAIS-III/WMS-III standardization sample. Demographically corrected indices did not provide higher diagnostic efficiency than age corrected indices and this result was supported by reanalysis of the TBI group against a larger and unmatched control group. Processing Speed Index provided comparable diagnostic accuracy to that of combined indices. Demographically corrected indices were associated with higher cut-scores to maximize overall classification, reflecting the upward adjustment of those scores in a lower education sample. This suggests that, in clinical practice, the test results of individuals with limited education may be more accurately interpreted with the application of demographic corrections. Diagnostic efficiency statistics are presented, and future research directions are discussed.

  16. Inflammation and hypoxia in the kidney: friends or foes?

    Science.gov (United States)

    Haase, Volker H

    2015-08-01

    Hypoxic injury is commonly associated with inflammatory-cell infiltration, and inflammation frequently leads to the activation of cellular hypoxia response pathways. The molecular mechanisms underlying this cross-talk during kidney injury are incompletely understood. Yamaguchi and colleagues identify CCAAT/enhancer-binding protein δ as a cytokine- and hypoxia-regulated transcription factor that fine-tunes hypoxia-inducible factor-1 signaling in renal epithelial cells and thus provide a novel molecular link between hypoxia and inflammation in kidney injury.

  17. Modification of bacterial cell survival by postirradiation hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Vexler, F B; Eidus, L Kh

    1986-01-27

    It is shown that postirradiation hypoxia affects the survival of E.coli. Hypoxic conditions immediately after a single-dose irradiation diminish cell survival in nutrient medium. Increasing time intervals between irradiation and hypoxia decrease the efficiency of the latter, while 1 h after irradiation hypoxia does not modify the survival of irradiated cells. These findings reveal that the mechanisms of action of postirradiation hypoxia on eu- and prokaryotic cells are similar.

  18. Overexpression of Hypoxia-Inducible Factor-1α Exacerbates Endothelial Barrier Dysfunction Induced by Hypoxia

    Directory of Open Access Journals (Sweden)

    Pei Wang

    2013-09-01

    Full Text Available Background/Aims: The mechanisms involved in endothelial barrier dysfunction induced by hypoxia are incompletely understood. There is debate about the role of hypoxia-inducible factor-1α (HIF-1α in endothelial barrier disruption. The aim of this study was to investigate the effect of genetic overexpression of HIF-1α on barrier function and the underlying mechanisms in hypoxic endothelial cells. Methods: The plasmid pcDNA3.1/V5-His-HIF-1α was stably transfected into human endothelial cells. The cells were exposed to normoxia or hypoxia. The mRNA and protein expressions of HIF-1α were detected by RT-PCR and Western blot respectively. The barrier function was assessed by measuring the transendothelial electrical resistance (TER. The Western blot analysis was used to determine the protein expression of glucose transporter-1 (GLUT-1, zonular occludens-1 (ZO-1, occludin, and myosin light chain kinase (MLCK in endothelial cells. The mRNA expression of proinflammatory cytokines was detected by qRT-PCR. Results: Genetic overexpression of HIF-1α significantly increased the mRNA and protein expression of HIF-1α in endothelial cells. The overexpression of HIF-1α enhanced the hypoxia-induced increase of HIF-1α and GLUT-1 protein expression. HIF-1α overexpression not only exacerbated hypoxia-induced endothelial barrier dysfunction but also augmented hypoxia-induced up-regulation of MLCK protein expression. HIF-1α overexpression also enhanced IL-1β, IL-6 and TNF-α mRNA expression. Conclusion: We provide evidence that genetic overexpression of HIF-1α aggravates the hypoxia-induced endothelial barrier dysfunction via enhancing the up-regulation of MLCK protein expression caused by hypoxia, suggesting a potential role for HIF-1α in the pathogenesis of endothelial barrier dysfunction in hypoxia.

  19. Analysis of hypoxia and hypoxia-like states through metabolite profiling.

    Directory of Open Access Journals (Sweden)

    Julie E Gleason

    Full Text Available In diverse organisms, adaptation to low oxygen (hypoxia is mediated through complex gene expression changes that can, in part, be mimicked by exposure to metals such as cobalt. Although much is known about the transcriptional response to hypoxia and cobalt, little is known about the all-important cell metabolism effects that trigger these responses.Herein we use a low molecular weight metabolome profiling approach to identify classes of metabolites in yeast cells that are altered as a consequence of hypoxia or cobalt exposures. Key findings on metabolites were followed-up by measuring expression of relevant proteins and enzyme activities. We find that both hypoxia and cobalt result in a loss of essential sterols and unsaturated fatty acids, but the basis for these changes are disparate. While hypoxia can affect a variety of enzymatic steps requiring oxygen and heme, cobalt specifically interferes with diiron-oxo enzymatic steps for sterol synthesis and fatty acid desaturation. In addition to diiron-oxo enzymes, cobalt but not hypoxia results in loss of labile 4Fe-4S dehydratases in the mitochondria, but has no effect on homologous 4Fe-4S dehydratases in the cytosol. Most striking, hypoxia but not cobalt affected cellular pools of amino acids. Amino acids such as aromatics were elevated whereas leucine and methionine, essential to the strain used here, dramatically decreased due to hypoxia induced down-regulation of amino acid permeases.These studies underscore the notion that cobalt targets a specific class of iron proteins and provide the first evidence for hypoxia effects on amino acid regulation. This research illustrates the power of metabolite profiling for uncovering new adaptations to environmental stress.

  20. Effects of intermittent hypoxia on running economy.

    Science.gov (United States)

    Burtscher, M; Gatterer, H; Faulhaber, M; Gerstgrasser, W; Schenk, K

    2010-09-01

    We investigated the effects of two 5-wk periods of intermittent hypoxia on running economy (RE). 11 male and female middle-distance runners were randomly assigned to the intermittent hypoxia group (IHG) or to the control group (CG). All athletes trained for a 13-wk period starting at pre-season until the competition season. The IHG spent additionally 2 h at rest on 3 days/wk for the first and the last 5 weeks in normobaric hypoxia (15-11% FiO2). RE, haematological parameters and body composition were determined at low altitude (600 m) at baseline, after the 5 (th), the 8 (th) and the 13 (th) week of training. RE, determined by the relative oxygen consumption during submaximal running, (-2.3+/-1.2 vs. -0.3+/-0.7 ml/min/kg, Ptraining phase. Georg Thieme Verlag KG Stuttgart . New York.

  1. Kinetic modeling in PET imaging of hypoxia

    Science.gov (United States)

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

    2014-01-01

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

  2. Hypoxic stress up-regulates Kir2.1 expression and facilitates cell proliferation in brain capillary endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Yamamura, Hideto; Suzuki, Yoshiaki; Yamamura, Hisao [Department of Molecular & Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (Japan); Asai, Kiyofumi [Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya (Japan); Imaizumi, Yuji, E-mail: yimaizum@phar.nagoya-cu.ac.jp [Department of Molecular & Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya (Japan)

    2016-08-05

    The blood-brain barrier (BBB) is mainly composed of brain capillary endothelial cells (BCECs), astrocytes and pericytes. Brain ischemia causes hypoxic encephalopathy and damages BBB. However, it remains still unclear how hypoxia affects BCECs. In the present study, t-BBEC117 cells, an immortalized bovine brain endothelial cell line, were cultured under hypoxic conditions at 4–5% oxygen for 72 h. This hypoxic stress caused hyperpolarization of resting membrane potential. Patch-clamp recordings revealed a marked increase in Ba{sup 2+}-sensitive inward rectifier K{sup +} current in t-BBEC117 cells after hypoxic culture. Western blot and real-time PCR analyses showed that Kir2.1 expression was significantly up-regulated at protein level but not at mRNA level after the hypoxic culture. Ca{sup 2+} imaging study revealed that the hypoxic stress enhanced store-operated Ca{sup 2+} (SOC) entry, which was significantly reduced in the presence of 100 μM Ba{sup 2+}. On the other hand, the expression of SOC channels such as Orai1, Orai2, and transient receptor potential channels was not affected by hypoxic stress. MTT assay showed that the hypoxic stress significantly enhanced t-BBEC117 cell proliferation, which was inhibited by approximately 60% in the presence of 100 μM Ba{sup 2+}. We first show here that moderate cellular stress by cultivation under hypoxic conditions hyperpolarizes membrane potential via the up-regulation of functional Kir2.1 expression and presumably enhances Ca{sup 2+} entry, resulting in the facilitation of BCEC proliferation. These findings suggest potential roles of Kir2.1 expression in functional changes of BCECs in BBB following ischemia. -- Highlights: •Hypoxic culture of brain endothelial cells (BEC) caused membrane hyperpolarization. •This hyperpolarization was due to the increased expression of Kir2.1 channels. •Hypoxia enhanced store-operated Ca{sup 2+} (SOC) entry via Kir2.1 up-regulation. •Expression levels of putative SOC

  3. Hypoxic stress up-regulates Kir2.1 expression and facilitates cell proliferation in brain capillary endothelial cells

    International Nuclear Information System (INIS)

    Yamamura, Hideto; Suzuki, Yoshiaki; Yamamura, Hisao; Asai, Kiyofumi; Imaizumi, Yuji

    2016-01-01

    The blood-brain barrier (BBB) is mainly composed of brain capillary endothelial cells (BCECs), astrocytes and pericytes. Brain ischemia causes hypoxic encephalopathy and damages BBB. However, it remains still unclear how hypoxia affects BCECs. In the present study, t-BBEC117 cells, an immortalized bovine brain endothelial cell line, were cultured under hypoxic conditions at 4–5% oxygen for 72 h. This hypoxic stress caused hyperpolarization of resting membrane potential. Patch-clamp recordings revealed a marked increase in Ba 2+ -sensitive inward rectifier K + current in t-BBEC117 cells after hypoxic culture. Western blot and real-time PCR analyses showed that Kir2.1 expression was significantly up-regulated at protein level but not at mRNA level after the hypoxic culture. Ca 2+ imaging study revealed that the hypoxic stress enhanced store-operated Ca 2+ (SOC) entry, which was significantly reduced in the presence of 100 μM Ba 2+ . On the other hand, the expression of SOC channels such as Orai1, Orai2, and transient receptor potential channels was not affected by hypoxic stress. MTT assay showed that the hypoxic stress significantly enhanced t-BBEC117 cell proliferation, which was inhibited by approximately 60% in the presence of 100 μM Ba 2+ . We first show here that moderate cellular stress by cultivation under hypoxic conditions hyperpolarizes membrane potential via the up-regulation of functional Kir2.1 expression and presumably enhances Ca 2+ entry, resulting in the facilitation of BCEC proliferation. These findings suggest potential roles of Kir2.1 expression in functional changes of BCECs in BBB following ischemia. -- Highlights: •Hypoxic culture of brain endothelial cells (BEC) caused membrane hyperpolarization. •This hyperpolarization was due to the increased expression of Kir2.1 channels. •Hypoxia enhanced store-operated Ca 2+ (SOC) entry via Kir2.1 up-regulation. •Expression levels of putative SOC channels were not affected by hypoxia.

  4. Morphological evaluation of the cerebral blood vessels in the late gestation fetal sheep following hypoxia in utero.

    Science.gov (United States)

    Baburamani, Ana A; Lo, Camden; Castillo-Melendez, Margie; Walker, David W

    2013-01-01

    Hypoxia can significantly contribute to the development of permanent brain injury in the term neonate; however the response of cerebral blood vessels is not well understood. This study aimed to quantitatively measure vascular density and morphology using laminin immunohistochemistry as a marker of blood vessels, and determine the effects of a single, severe bout of hypoxia (umbilical cord occlusion, UCO) late in gestation on the developing cerebrovasculature in fetal sheep. At 124-126 days gestation singleton fetal sheep underwent surgery for implantation of catheters and placement of an inflatable cuff around the umbilical cord. A 10 min UCO or sham UCO (n=5) occurred at 132 days gestation. Fetal brains were collected at 24 h (n=5) or 48 h (n=4) after UCO for vascular density and morphology analysis of laminin immunohistochemistry. 48 h following a single, brief bout of severe hypoxia late in gestation decreased vascular density was seen in the caudate nucleus and no changes in vascular morphology occurred. However closer analysis revealed a significant shift in the frequency of smaller (≤10 μm) to larger (≤100 μm) perimeter blood vessels in periventricular and subcortical white matter. Close examination of the frequency distribution of vascular perimeter highlights that alterations in vascular morphology persist in the near term fetal brain for up to 48 h following a brief (10 min) hypoxia in white but not gray matter. These findings suggest that the near term brain may still be vulnerable to white matter injury following in utero hypoxia. Copyright © 2012 Elsevier Inc. All rights reserved.

  5. Response of skeletal muscle mitochondria to hypoxia.

    Science.gov (United States)

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

    2003-01-01

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

  6. The impact of hypoxia on oncolytic virotherapy

    Directory of Open Access Journals (Sweden)

    Guo ZS

    2011-11-01

    Full Text Available Z Sheng GuoUniversity of Pittsburgh Cancer Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAAbstract: The hypoxic tumor microenvironment plays significant roles in tumor cell metabolism and survival, tumor growth, and progression. Hypoxia modulates target genes in target cells mainly through an oxygen-sensing signaling pathway mediated by hypoxia-inducible factor of transcription factors. As a result, hypoxic tumor cells are resistant to conventional therapeutics such as radiation and chemotherapy. Oncolytic virotherapy may be a promising novel therapeutic for hypoxic cancer. Some oncolytic viruses are better adapted than others to the hypoxic tumor environment. Replication of adenoviruses from both groups B and C is inhibited, yet replication of herpes simplex virus is enhanced. Hypoxia seems to exert little or no effect on the replication of other oncolytic viruses. Vaccinia virus displayed increased cytotoxicity in some hypoxic cancer cells even though viral protein synthesis and transgene expression were not affected. Vesicular stomatitis virus replicated to similar levels in both hypoxic and normoxic conditions, and is effective for killing hypoxic cancer cells. However, vesicular stomatitis virus and reovirus, but not encephalomyocarditis virus, are sensitive to elevated levels of hypoxia-inducible factor-1α in renal cancer cells with the loss of von Hippel–Lindau tumor suppressor protein, because elevated hypoxia-inducible factor activity confers dramatically enhanced resistance to cytotoxicity mediated by vesicular stomatitis virus or reovirus. A variety of hypoxia-selective and tumor-type-specific oncolytic adenoviruses, generated by incorporating hypoxia-responsive elements into synthetic promoters to control essential genes for viral replication or therapeutic genes, have been shown to be safe and efficacious. Hypoxic tumor-homing macrophages can function effectively as carrier

  7. Neuroprotection via RNA-binding protein RBM3 expression is regulated by hypothermia but not by hypoxia in human SK-N-SH neurons

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    Rosenthal LM

    2017-05-01

    Full Text Available Lisa-Maria Rosenthal,1 Giang Tong,1 Christoph Walker,1 Sylvia J Wowro,1 Jana Krech,1 Constanze Pfitzer,1,2 Georgia Justus,1 Felix Berger,1,3 Katharina Rose Luise Schmitt1 1Department of Congenital Heart Disease/Pediatric Cardiology, German Heart Institute Berlin, 2Berlin Institute of Health (BIH, 3Department of Pediatric Cardiology, Charité – University Medical Center, Berlin, Germany Objective: Therapeutic hypothermia is an established treatment for perinatal asphyxia. Yet, many term infants continue to die or suffer from neurodevelopmental disability. Several experimental studies have demonstrated a beneficial effect of mild-to-moderate hypothermia after hypoxic injury, but the understanding of hypothermia-induced neuroprotection remains incomplete. In general, global protein synthesis is attenuated by hypothermia, but a small group of RNA-binding proteins including the RNA-binding motif 3 (RBM3 is upregulated in response to cooling. The aim of this study was to establish an in vitro model to investigate the effects of hypoxia and hypothermia on neuronal cell survival, as well as to examine the kinetics of concurrent cold-shock protein RBM3 gene expression. Methods: Experiments were performed by using human SK-N-SH neurons exposed to different oxygen concentrations (21%, 8%, or 0.2% O2 for 24 hours followed by moderate hypothermia (33.5°C or normothermia for 24, 48, or 72 hours. Cell death was determined by quantification of lactate dehydrogenase and neuron-specific enolase releases into the cell cultured medium, and cell morphology was assessed by using immunofluorescence staining. The regulation of RBM3 gene expression was assessed by reverse transcriptase-quantitative polymerase chain reaction and Western blot analysis.Results: Exposure to hypoxia (0.2% O2 for 24 hours resulted in significantly increased cell death in SK-N-SH neurons, whereas exposure to 8% O2 had no significant impact on cell viability. Post-hypoxia treatment with

  8. The interactive effect of cooling and hypoxia on forearm fatigue development.

    Science.gov (United States)

    Lloyd, Alex; Hodder, Simon; Havenith, George

    2015-09-01

    To examine the effect of separate and combined exposure to hypoxia [normoxia (FIO2 = 0.21) vs. moderate altitude (FIO2 = 0.13)] and temperature [thermoneutral (22 °C) vs. cold (5 °C)] on muscle fatigue development in the forearm, after repeated low-resistance contractions. Eight males were exposed for 70 min to four separate conditions in a balanced order. Conditions were normoxic-thermoneutral (N), hypoxic-thermoneutral, normoxic-cold and hypoxic-cold. After 15-min seated rest, participants carried out intermittent dynamic forearm exercise at 15 % maximal isometric voluntary contraction (MVC) for eight consecutive, 5-min work bouts. Each bout was separated by 110 s rest during which MVC force was collected. When exposed to hypoxia and cold independently, the exercise protocol decreased MVC force of the finger flexors by 8.1 and 13.9 %, respectively, compared to thermoneutral normoxia. When hypoxia and cold were combined, the decrease in MVC force was 21.4 % more than thermoneutral normoxia, reflecting an additive effect and no interaction. EMG relative to force produced during MVC, increased by 2 and 1.2 μV per kg (36 and 23 % of N) for cold and hypoxia, respectively. When the stressors were combined the effect was additive, increasing to 3.1 μV per kg (56 % of N). When compared to exercise in thermoneutral normoxic conditions, both cold and hypoxia significantly reduce brief MVC force output. This effect appears to be of mechanical origin, not a failure in muscle fibre recruitment per se. Additionally, the reduction in force is greater when the stressors are combined, showing an additive effect.

  9. Expression patterns of the hypoxia-related genes osteopontin, CA9, erythropoietin, VEGF and HIF-1α in human glioma in vitro and in vivo

    International Nuclear Information System (INIS)

    Said, Harun M.; Hagemann, Carsten; Staab, Adrian; Stojic, Jelena; Kuehnel, Siglinde; Vince, Giles H.; Flentje, Michael; Roosen, Klaus; Vordermark, Dirk

    2007-01-01

    Background and purpose: To identify molecular markers of tumor hypoxia and potential therapeutic targets in glioblastoma (GBM), we investigated the hypoxia-related expression of osteopontin (OPN), carbonic anhydrase 9 (CA9), erythropoietin (EPO), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) in vitro in human GBM cell lines and in vivo in human tumor samples of GBM, compared to low-grade astrocytoma (LGA). Materials and methods: Expression of the hypoxia-induced genes OPN, CA9, EPO, VEGF and HIF-1α was analyzed in three GBM cell lines, GaMG, U373 and U251, under in vitro hypoxia (1, 6 or 24 h at 5%, 1% or 0.1% O 2 ) and in tumor samples from two patient groups with LGA and GBM (n = 15 each), at the mRNA level (semiquantitative RT-PCR). Selected conditions and representative tumor samples were also evaluated at the protein level by Western blot. Results: OPN and CA9 mRNA was most consistently upregulated in relation to severity and duration of in vitro hypoxia. In tumor samples, mean expression levels (LGA vs. GBM, normalized to mean expression in normal brain) were 1.71 vs. 4.57 (p < 0.001) for OPN, 1.11 vs. 3.35 (p < 0.001) for CA9, 2.79 vs. 5.28 (not significant, n.s.) for Epo, 1.13 vs. 2.0 (p = 0.007) for VEGF and 0.97 vs. 0.97 (n.s.) for HIF-1α. In tumor samples, GBM showed a particularly strong protein expression of OPN. Conclusions: Among a panel of known hypoxia-inducible genes, OPN and CA9 emerge as most consistently induced by in vitro hypoxia in human GBM cell lines and most specifically expressed in patient GBM tumor tissue, rendering these two genes attractive targets for hypoxia-directed treatment approaches

  10. Role of hypoxia and hypoxia inducible factor in physiological and pathological conditions

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    Mozhgan Jahani

    2017-11-01

    Full Text Available Introduction: Organisms are exposed to oxygen deprivation (Hypoxia in various physiological and pathological conditions. There are different conserve evolutionary responses to counterview with this stress that primary transcriptional response to stress related to hypoxia is interceded by hypoxia-inducible factor (HIF-1 in mammals. This factor can regulate different genes that have essential roles in adaptation to this condition. In this review, the role of this factor in physiological and pathological conditions under hypoxic condition has been evaluated after examining structural features and regulation characteristics of HIF-1. Methods: First, articles related to the keywords of hypoxia and HIF-1 (from 1991-2016 were searched from valid databases such as Springer Link, Google Scholar, PubMed and Science direct. Then, the articles correlated with hypoxia, HIF-1 and their roles in physiological and pathological conditions (120 articles were searched and just 64 articles were selected for this study. Result: According to studies, there are different genes in cells and organs that can be regulated by HIF-1. Activation of genes expression by this protein occurs through its linkage to cis-acting of 50 base pair hypoxia response element (HRE region located in their promotor and enhancer. Depending on circumstances, activation of these genes can be beneficial or harmful. Conclusion: Activation of different genes in hypoxia by HIF-1 has different effects on physiological and pathological conditions. Therefore, HIF-1, as a hypoxia-inducible factor in hypoxic conditions, plays an essential role in the adaptation of cells and organs to changes related to the presence of oxygen.

  11. Frequently asked questions in hypoxia research

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    Wenger RH

    2015-09-01

    Full Text Available Roland H Wenger,1,2 Vartan Kurtcuoglu,1,2 Carsten C Scholz,1,2 Hugo H Marti,3 David Hoogewijs1,2,4 1Institute of Physiology and Zurich Center for Human Physiology (ZIHP, University of Zurich, 2National Center of Competence in Research “Kidney.CH”, Zurich, Switzerland; 3Institute of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, 4Institute of Physiology, University of Duisburg-Essen, Essen, Germany Abstract: “What is the O2 concentration in a normoxic cell culture incubator?” This and other frequently asked questions in hypoxia research will be answered in this review. Our intention is to give a simple introduction to the physics of gases that would be helpful for newcomers to the field of hypoxia research. We will provide background knowledge about questions often asked, but without straightforward answers. What is O2 concentration, and what is O2 partial pressure? What is normoxia, and what is hypoxia? How much O2 is experienced by a cell residing in a culture dish in vitro vs in a tissue in vivo? By the way, the O2 concentration in a normoxic incubator is 18.6%, rather than 20.9% or 20%, as commonly stated in research publications. And this is strictly only valid for incubators at sea level. Keywords: gas laws, hypoxia-inducible factor, Krogh tissue cylinder, oxygen diffusion, partial pressure, tissue oxygen levels

  12. Hypoxanthine as a measurement of hypoxia.

    Science.gov (United States)

    Saugstad, O D

    1975-04-01

    The hypoxanthine concentration in plasma was found to be a sensitive parameter of hypoxia of the fetus and the newborn infant. The plasma level of hypoxanthine in the umbilical cord in 29 newborn infants with normal delivery varied between 0 and 11.0 mumol/liter with a mean of 5.8 mumol/liter, SD 3.0 mumol/liter. Compared with this reference group the hypoxanthine concentration in plasma of the umbilical cord in 10 newborn infants with clinical signs of intrauterine hypoxia during labor was found to be significantly higher, with a range of 11.0-61.5 mumol/liter, with a mean of 25.0 mumol/liter, SD 18.0 mumol/liter. The plasma level of hypoxanthine in two premature babies developing an idiopathic respiratory distress syndrome was monitored. The metabolite was found to be considerably increased, in one of them more than 24 hr after a period of hypoxia necessitating artificial ventilation. The hypoxanthine level in plasma of umbilical arterial blood was followed about 2 hr postpartum in three newborn infants with clinical signs of intrauterine hypoxia. The decrease of the plasma concentration of the metabolite seemed to be with a constant velocity, as it was about 10 mumol/liter/hr in these cases. A new method was used for the determination of hypoxanthine in plasma, based on the principle that PO2 decreased when hypoxanthine is oxidized to uric acid.

  13. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

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    Nicole Horrée

    2007-01-01

    Full Text Available Background: Hypoxia-inducible factor 1α (HIF-1α plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. Methods: Expression of HIF-1α and proteins in the HIF-1α pathway (Glut-1, CAIX, VEGF in paraffin-embedded specimens of normal (n = 17, premalignant (n = 17 and endometrioid endometrial carcinoma (n = 39 was explored by immunohistochemistry, in relation to microvessel density (MVD. Results: HIF-1α overexpression was absent in inactive endometrium but present in hyperplasia (61% and carcinoma (87%, with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium, in contrast with expression in hyperplasia (Glut-1 0%, CAIX 61%, only focal and diffuse and carcinoma (Glut-1 94.6%, CAIX 92%, both mostly perinecrotically. Diffuse HIF-1α was accompanied by activation of downstream targets. VEGF was significantly higher expressed in hyperplasias and carcinomas compared to inactive endometrium. MVD was higher in hyperplasias and carcinomas than in normal endometrium (p < 0.001. Conclusion: HIF-1α and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1α in endometrial carcinogenesis.

  14. Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: a historical overview and future perspectives

    Science.gov (United States)

    Bishop, Tammie; Ratcliffe, Peter J

    2014-01-01

    By the early 1900s, the close matching of oxygen supply with demand was recognized to be a fundamental requirement for physiological function, and multiple adaptive responses to environment hypoxia had been described. Nevertheless, the widespread operation of mechanisms that directly sense and respond to levels of oxygen in animal cells was not appreciated for most of the twentieth century with investigators generally stressing the regulatory importance of metabolic products. Work over the last 25 years has overturned that paradigm. It has revealed the existence of a set of “oxygen-sensing” 2-oxoglutarate dependent dioxygenases that catalyze the hydroxylation of specific amino acid residues and thereby control the stability and activity of hypoxia-inducible factor. The hypoxia-inducible factor hydroxylase pathway regulates a massive transcriptional cascade that is operative in essentially all animal cells. It transduces a wide range of responses to hypoxia, extending well beyond the classical boundaries of hypoxia physiology. Here we review the discovery and elucidation of these pathways, and consider the opportunities and challenges that have been brought into focus by the findings, including new implications for the integrated physiology of hypoxia and therapeutic approaches to ischemic/hypoxic disease. PMID:27774477

  15. Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

    DEFF Research Database (Denmark)

    Bailey, Damian M; Taudorf, Sarah; Berg, Ronan M G

    2009-01-01

    This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein...... paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide metabolites. Neuron-specific enolase (NSE), S100beta, and 3-nitrotyrosine (3-NT) were determined by ELISA. Hypoxia increased the arterio-jugular venous...... concentration difference (a-v(D)) and net cerebral output of lipid-derived alkoxyl-alkyl free radicals and lipid hydroperoxides (P

  16. Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia

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    Korry J. Hintze

    2011-01-01

    Full Text Available Iron status affects cognitive and physical performance in humans. Recent evidence indicates that iron balance is a tightly regulated process affected by a series of factors other than diet, to include hypoxia. Hypoxia has profound effects on iron absorption and results in increased iron acquisition and erythropoiesis when humans move from sea level to altitude. The effects of hypoxia on iron balance have been attributed to hepcidin, a central regulator of iron homeostasis. This paper will focus on the molecular mechanisms by which hypoxia affects hepcidin expression, to include a review of the hypoxia inducible factor (HIF/hypoxia response element (HRE system, as well as recent evidence indicating that localized adipose hypoxia due to obesity may affect hepcidin signaling and organismal iron metabolism.

  17. Protective action of tetramethylpyrazine on the medulla oblongata in rats with chronic hypoxia.

    Science.gov (United States)

    Ding, Yan; Hou, Xuefei; Chen, Li; Li, Hui; Tang, Yuhong; Zhou, Hua; Zhao, Shu; Zheng, Yu

    2013-01-01

    Tetramethylpyrazine (TMP), one of the active ingredients of the Chinese herb Lingusticum Wallichii Frantchat (Chuan Xiong), plays an important role in neuroprotection. However, the protective effect of TMP on the medulla oblongata, the most important region of the brain for cardiovascular and respiratory control, during chronic hypoxia remains unclear. In this study, we examined the neuroprotective effect of TMP on the medulla oblongata after chronic hypoxic injury in rats. Male Sprague-Dawley rats were randomly divided into four groups: control group, TMP group, chronic hypoxia group, and chronic hypoxia+TMP group. Rats were exposed to hypoxia (10% (v/v) O₂) or normoxia for 6 h daily for 14 days. TMP (80 mg/kg) or vehicle (saline) was injected intraperitoneally 30 min before experimentation. Loss of neurons in the pre-Bötzinger complex, the nucleus ambiguus, the nucleus tractus solitarius, the hypoglossal nucleus and the facial nucleus were evaluated by Nissl staining. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured, and apoptosis was monitored using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method. The level of Bcl-2 mRNA and Bax mRNA was quantitatively measured by RT-PCR analysis. TMP protected Nissl bodies of neurons from injury in all nuclei observed, and reduced the loss of neurons in the nucleus ambiguus, the nucleus tractus solitarius, and the hypoglossal nucleus in rats subjected to chronic hypoxia. TMP upregulated SOD activity and inhibited the increase in MDA content in the medulla oblongata of hypoxic rats. In addition, TMP decreased the rate of apoptosis index (the percentage of apoptotic cells against the total number of cells) in all medullary structures examined, excepting the nucleus ambiguus and inhibited the decrease in Bcl-2 mRNA levels in the medulla oblongata following hypoxia. Our findings indicate that TMP may protect the medullary structures that are involved in

  18. Air breathing and aquatic gas exchange during hypoxia in armoured catfish.

    Science.gov (United States)

    Scott, Graham R; Matey, Victoria; Mendoza, Julie-Anne; Gilmour, Kathleen M; Perry, Steve F; Almeida-Val, Vera M F; Val, Adalberto L

    2017-01-01

    Air breathing in fish is commonly believed to have arisen as an adaptation to aquatic hypoxia. The effectiveness of air breathing for tissue O 2 supply depends on the ability to avoid O 2 loss as oxygenated blood from the air-breathing organ passes through the gills. Here, we evaluated whether the armoured catfish (Hypostomus aff. pyreneusi)-a facultative air breather-can avoid branchial O 2 loss while air breathing in aquatic hypoxia, and we measured various other respiratory and metabolic traits important for O 2 supply and utilization. Fish were instrumented with opercular catheters to measure the O 2 tension (PO 2 ) of expired water, and air breathing and aquatic respiration were measured during progressive stepwise hypoxia in the water. Armoured catfish exhibited relatively low rates of O 2 consumption and gill ventilation, and gill ventilation increased in hypoxia due primarily to increases in ventilatory stroke volume. Armoured catfish began air breathing at a water PO 2 of 2.5 kPa, and both air-breathing frequency and hypoxia tolerance (as reflected by PO 2 at loss of equilibrium, LOE) was greater in individuals with a larger body mass. Branchial O 2 loss, as reflected by higher PO 2 in expired than in inspired water, was observed in a minority (4/11) of individuals as water PO 2 approached that at LOE. Armoured catfish also exhibited a gill morphology characterized by short filaments bearing short fused lamellae, large interlamellar cell masses, low surface area, and a thick epithelium that increased water-to-blood diffusion distance. Armoured catfish had a relatively low blood-O 2 binding affinity when sampled in normoxia (P 50 of 3.1 kPa at pH 7.4), but were able to rapidly increase binding affinity during progressive hypoxia exposure (to a P 50 of 1.8 kPa). Armoured catfish also had low activities of several metabolic enzymes in white muscle, liver, and brain. Therefore, low rates of metabolism and gill ventilation, and a reduction in branchial gas

  19. Glucose and Intermediary Metabolism and Astrocyte-Neuron Interactions Following Neonatal Hypoxia-Ischemia in Rat.

    Science.gov (United States)

    Brekke, Eva; Berger, Hester Rijkje; Widerøe, Marius; Sonnewald, Ursula; Morken, Tora Sund

    2017-01-01

    Neonatal hypoxia-ischemia (HI) and the delayed injury cascade that follows involve excitotoxicity, oxidative stress and mitochondrial failure. The susceptibility to excitotoxicity of the neonatal brain may be related to the capacity of astrocytes for glutamate uptake. Furthermore, the neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance for limiting this kind of injury. Also, in the neonatal brain, neurons depend upon de novo synthesis of neurotransmitters via pyruvate carboxylase in astrocytes to increase neurotransmitter pools during normal brain development. Several recent publications describing intermediary brain metabolism following neonatal HI have yielded interesting results: (1) Following HI there is a prolonged depression of mitochondrial metabolism in agreement with emerging evidence of mitochondria as vulnerable targets in the delayed injury cascade. (2) Astrocytes, like neurons, are metabolically impaired following HI, and the degree of astrocytic malfunction may be an indicator of the outcome following hypoxic and hypoxic-ischemic brain injury. (3) Glutamate transfer from neurons to astrocytes is not increased following neonatal HI, which may imply that astrocytes fail to upregulate glutamate uptake in response to the massive glutamate release during HI, thus contributing to excitotoxicity. (4) In the neonatal brain, the activity of the PPP is reduced following HI, which may add to the susceptibility of the neonatal brain to oxidative stress. The present review aims to discuss the metabolic temporal alterations observed in the neonatal brain following HI.

  20. Pimonidazole: a novel hypoxia marker for complementary study of tumor hypoxia and tumor biology

    International Nuclear Information System (INIS)

    Varia, Mahesh A.; Kennedy, Andrew S.; Calkins-Adams, Dennise P.; Rinker, Lillian; Novotny, Debra; Fowler, Wesley C.; Raleigh, James A.

    1997-01-01

    Purpose/Objectives: Tumor hypoxia appears to be associated with treatment resistance and with gene expression that may lead to hypoxia-mediated selection of tumor cells as a source for cell growth and metastases. The objective of this study was to develop complementary techniques of hypoxia detection with molecular markers of cell proliferation and metastases in order to investigate the role of tumor hypoxia in tumor biology. Materials and Methods: Pimonidazole is a 2-nitroimidazole which is reductively-activated and becomes covalently bound to thiol-containing proteins only in hypoxic cells. These adducts can be detected using immunohistochemistry, enzyme linked immunosorbent assay or flow cytometry as a measure of hypoxia in tumors. Quantitative immunohistochemical analysis has been completed for five patients with squamous cell carcinoma of the cervix who were given pimonidazole hydrochloride (0.5 g/m 2 intravenously) followed by cervical biopsies 24 hours later. Informed consent was obtained according to a protocol approved by the Institutional Review Board. A minimum of 3 random biopsies were obtained from the tumors and at least four sections examined from each biopsy site. Formalin fixed, paraffin embedded tissue sections were immunostained for pimonidazole binding using a mouse monoclonal antibody. Commercially available monoclonal antibodies were used to detect cell proliferation markers MIB-1 (Ki-67) and to detect vascular endothelial growth factor (VEGF) in tumor cells in contiguous sections. The extent of immunostaining was expressed as the percent of immunostained to total tumor cells as determined by Chalkley point counting. Results: No clinical toxicities were associated with pimonidazole infusion. Immunostaining with pimonidazole antibody was observed in all patients indicating the presence of tumor hypoxia. Qualitatively there is little or no overlap between the areas of hypoxia and proliferation. Quantitative data tabulated below show the

  1. Regulation of mRNA translation influences hypoxia tolerance

    International Nuclear Information System (INIS)

    Koritzinsky, M.; Wouters, B.G.; Koumenis, C.

    2003-01-01

    Hypoxia is a heterogenous but common characteristic of human tumours and poor oxygenation is associated with poor prognosis. We believe that the presence of viable hypoxic tumor cells reflects in part an adaptation and tolerance of these cells to oxygen deficiency. Since oxidative phosphorylation is compromized during hypoxia, adaptation may involve both the upregulation of glycolysis as well as downregulation of energy consumption. mRNA translation is one of the most energy costly cellular processes, and we and others have shown that global mRNA translation is rapidly inhibited during hypoxia. However, some mRNAs, including those coding for HIF-1 α and VEGF, remain efficiently translated during hypoxia. Clearly, the mechanisms responsible for the overall inhibition of translation during hypoxia does not compromize the translation of certain hypoxia-induced mRNA species. We therefore hypothesize that the inhibition of mRNA translation serves to promote hypoxia tolerance in two ways: i) through conservation of energy and ii) through differential gene expression involved in hypoxia adaptation. We have recently identified two pathways that are responsible for the global inhibition of translation during hypoxia. The phosphorylation of the eukaryotic initiation factor eIF2 α by the ER resident kinase PERK results in down-regulation of protein synthesis shortly after the onset of hypoxia. In addition, the initiation complex eIF4F is disrupted during long lasting hypoxic conditions. The identification of the molecular pathways responsible for the inhibition of overall translation during hypoxia has rendered it possible to investigate their importance for hypoxia tolerance. We have found that mouse embryo fibroblasts that are knockout for PERK and therefore not able to inhibit protein synthesis efficiently during oxygen deficiency are significantly less tolerant to hypoxia than their wildtype counterparts. We are currently also investigating the functional significance

  2. Stress-Induced Hyperglycemia, but Not Diabetic Hyperglycemia, Is Associated with Higher Mortality in Patients with Isolated Moderate and Severe Traumatic Brain Injury: Analysis of a Propensity Score-Matched Population.

    Science.gov (United States)

    Rau, Cheng-Shyuan; Wu, Shao-Chun; Chen, Yi-Chun; Chien, Peng-Chen; Hsieh, Hsiao-Yun; Kuo, Pao-Jen; Hsieh, Ching-Hua

    2017-11-03

    Background : Admission hyperglycemia is associated with higher morbidity and mortality in patients with traumatic brain injury (TBI). Stress-induced hyperglycemia (SIH), a form of hyperglycemia induced by the stress response, is associated with increased patient mortality following TBI. However, admission hyperglycemia occurs not only in SIH but also in patients with diabetic hyperglycemia (DH). Current information regarding whether trauma patients with SIH represent a distinct group with differential outcomes compared to those with DH remains limited. Methods : Serum glucose concentration ≥200 mg/dL upon arrival at the emergency department was defined as hyperglycemia. Presence of diabetes mellitus (DM) was determined by patient history and/or admission glycated hemoglobin (HbA1c) level ≥6.5%. In the present study, the patient cohort included those with moderate and severe TBI, as defined by an Abbreviated Injury Scale (AIS) score ≥3 points in the head, and excluded those who had additional AIS scores ≥3 points in any other region of the body. A total of 1798 adult patients with isolated moderate to severe TBI were allocated into four groups: SIH ( n = 140), DH ( n = 187), diabetic normoglycemia (DN, n = 186), and non-diabetic normoglycemia (NDN, n = 1285). Detailed patient information was retrieved from the Trauma Registry System at a level I trauma center between 1 January 2009, and 31 December 2015. Unpaired Student's t - and Mann-Whitney U -tests were used to analyze normally and non-normally distributed continuous data, respectively. Categorical data were compared using the Pearson chi-square or two-sided Fisher's exact tests. Matched patient populations were allocated in a 1:1 ratio according to propensity scores calculated by NCSS software. Logistic regression was used to evaluate the effect of SIH and DH on the adjusted mortality outcome. Results : In patients with isolated moderate to severe TBI, the presence of SIH and DH led to 9.1-fold and 2

  3. Hypoxia regulates microRNA expression in the human carotid body

    International Nuclear Information System (INIS)

    Mkrtchian, Souren; Lee, Kian Leong; Kåhlin, Jessica; Ebberyd, Anette; Poellinger, Lorenz; Fagerlund, Malin Jonsson; Eriksson, Lars I.

    2017-01-01

    The carotid body (CB) is the key sensing organ for physiological oxygen levels in the body. Under conditions of low oxygen (hypoxia), the CB plays crucial roles in signaling to the cardiorespiratory center in the medulla oblongata for the restoration of oxygen homeostasis. How hypoxia regulates gene expression in the human CB remains poorly understood. While limited information on transcriptional regulation in animal CBs is available, the identity and impact of important post-transcriptional regulators such as non-coding RNAs, and in particular miRNAs are not known. Here we show using ex vivo experiments that indeed a number of miRNAs are differentially regulated in surgically removed human CB slices when acute hypoxic conditions were applied. Analysis of the hypoxia-regulated miRNAs shows that they target biological pathways with upregulation of functions related to cell proliferation and immune response and downregulation of cell differentiation and cell death functions. Comparative analysis of the human CB miRNAome with the global miRNA expression patterns of a large number of different human tissues showed that the CB miRNAome had a unique profile which reflects its highly specialized functional status. Nevertheless, the human CB miRNAome is most closely related to the miRNA expression pattern of brain tissues indicating that they may have the most similar developmental origins. - Highlights: • Hypoxia triggers differential expression of many miRNAs in the human carotid body. • This can lead to the upregulation of proliferation and immune response functions. • CB expression profile in the carotid body resembles the miRNA expression pattern in the brain. • miRNAs are involved in the regulation of carotid body functions including oxygen sensing.

  4. Hypoxia regulates microRNA expression in the human carotid body

    Energy Technology Data Exchange (ETDEWEB)

    Mkrtchian, Souren, E-mail: souren.mkrtchian@ki.se [Section for Anesthesiology and Intensive Care Medicine, Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm (Sweden); Lee, Kian Leong, E-mail: csilkl@nus.edu.sg [Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore (Singapore); Kåhlin, Jessica [Section for Anesthesiology and Intensive Care Medicine, Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm (Sweden); Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, SE-171 76 Stockholm (Sweden); Ebberyd, Anette [Section for Anesthesiology and Intensive Care Medicine, Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm (Sweden); Poellinger, Lorenz [Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore (Singapore); Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm (Sweden); Fagerlund, Malin Jonsson; Eriksson, Lars I. [Section for Anesthesiology and Intensive Care Medicine, Department of Physiology and Pharmacology, Karolinska Institute, SE-171 77 Stockholm (Sweden); Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, SE-171 76 Stockholm (Sweden)

    2017-03-15

    The carotid body (CB) is the key sensing organ for physiological oxygen levels in the body. Under conditions of low oxygen (hypoxia), the CB plays crucial roles in signaling to the cardiorespiratory center in the medulla oblongata for the restoration of oxygen homeostasis. How hypoxia regulates gene expression in the human CB remains poorly understood. While limited information on transcriptional regulation in animal CBs is available, the identity and impact of important post-transcriptional regulators such as non-coding RNAs, and in particular miRNAs are not known. Here we show using ex vivo experiments that indeed a number of miRNAs are differentially regulated in surgically removed human CB slices when acute hypoxic conditions were applied. Analysis of the hypoxia-regulated miRNAs shows that they target biological pathways with upregulation of functions related to cell proliferation and immune response and downregulation of cell differentiation and cell death functions. Comparative analysis of the human CB miRNAome with the global miRNA expression patterns of a large number of different human tissues showed that the CB miRNAome had a unique profile which reflects its highly specialized functional status. Nevertheless, the human CB miRNAome is most closely related to the miRNA expression pattern of brain tissues indicating that they may have the most similar developmental origins. - Highlights: • Hypoxia triggers differential expression of many miRNAs in the human carotid body. • This can lead to the upregulation of proliferation and immune response functions. • CB expression profile in the carotid body resembles the miRNA expression pattern in the brain. • miRNAs are involved in the regulation of carotid body functions including oxygen sensing.

  5. Sodium Pyruvate Reduced Hypoxic-Ischemic Injury to Neonatal Rat Brain

    OpenAIRE

    Pan, Rui; Rong, Zhihui; She, Yun; Cao, Yuan; Chang, Li-Wen; Lee, Wei-Hua

    2012-01-01

    Background Neonatal hypoxia-ischemia (HI) remains a major cause of severe brain damage and is often associated with high mortality and lifelong disability. Immature brains are extremely sensitive to hypoxia-ischemia, shown as prolonged mitochondrial neuronal death. Sodium pyruvate (SP), a substrate of the tricarboxylic acid cycle and an extracellular antioxidant, has been considered as a potential treatment for hypoxic-ischemic encephalopathy (HIE), but its effects have not been evaluated in ...

  6. Inhibition of calcium uptake during hypoxia in developing zebrafish is mediated by hypoxia-inducible factor.

    Science.gov (United States)

    Kwong, Raymond W M; Kumai, Yusuke; Tzaneva, Velislava; Azzi, Estelle; Hochhold, Nina; Robertson, Cayleih; Pelster, Bernd; Perry, Steve F

    2016-12-15

    The present study investigated the potential role of hypoxia-inducible factor (HIF) in calcium homeostasis in developing zebrafish (Danio rerio). It was demonstrated that zebrafish raised in hypoxic water (30 mmHg; control, 155 mmHg P O 2 ) until 4 days post-fertilization exhibited a substantial reduction in whole-body Ca 2+ levels and Ca 2+ uptake. Ca 2+ uptake in hypoxia-treated fish did not return to pre-hypoxia (control) levels within 2 h of transfer back to normoxic water. Results from real-time PCR showed that hypoxia decreased the whole-body mRNA expression levels of the epithelial Ca 2+ channel (ecac), but not plasma membrane Ca 2+ -ATPase (pmca2) or Na + /Ca 2+ -exchanger (ncx1b). Whole-mount in situ hybridization revealed that the number of ecac-expressing ionocytes was reduced in fish raised in hypoxic water. These findings suggested that hypoxic treatment suppressed the expression of ecac, thereby reducing Ca 2+ influx. To further evaluate the potential mechanisms for the effects of hypoxia on Ca 2+ regulation, a functional gene knockdown approach was employed to prevent the expression of HIF-1αb during hypoxic treatment. Consistent with a role for HIF-1αb in regulating Ca 2+ balance during hypoxia, the results demonstrated that the reduction of Ca 2+ uptake associated with hypoxic exposure was not observed in fish experiencing HIF-1αb knockdown. Additionally, the effects of hypoxia on reducing the number of ecac-expressing ionocytes was less pronounced in HIF-1αb-deficient fish. Overall, the current study revealed that hypoxic exposure inhibited Ca 2+ uptake in developing zebrafish, probably owing to HIF-1αb-mediated suppression of ecac expression. © 2016. Published by The Company of Biologists Ltd.

  7. Initial brain aging

    DEFF Research Database (Denmark)

    Thomsen, Kirsten; Yokota, Takashi; Hasan-Olive, Md Mahdi

    2018-01-01

    Brain aging is accompanied by declining mitochondrial respiration. We hypothesized that mitochondrial morphology and dynamics would reflect this decline. Using hippocampus and frontal cortex of a segmental progeroid mouse model lacking Cockayne syndrome protein B (CSB(m/m)) and C57Bl/6 (WT......) controls and comparing young (2-5 months) to middle-aged mice (13-14 months), we found that complex I-linked state 3 respiration (CI) was reduced at middle age in CSB(m/m) hippocampus, but not in CSB(m/m) cortex or WT brain. In hippocampus of both genotypes, mitochondrial size heterogeneity increased....... Mitochondrial DNA content was lower, and hypoxia-induced factor 1α mRNA was greater at both ages in CSB(m/m) compared to WT brain. Our findings show that decreased CI and increased mitochondrial size heterogeneity are highly associated and point to declining mitochondrial quality control as an initial event...

  8. Decreased extracellular adenosine levels lead to loss of hypoxia-induced neuroprotection after repeated episodes of exposure to hypoxia.

    Directory of Open Access Journals (Sweden)

    Mei Cui

    Full Text Available Achieving a prolonged neuroprotective state following transient ischemic attacks (TIAs is likely to effectively reduce the brain damage and neurological dysfunction associated with recurrent stroke. HPC is a phenomenon in which advanced exposure to mild hypoxia reduces the stroke volume produced by a subsequent TIA. However, this neuroprotection is not long-lasting, with the effects reaching a peak after 3 days. Therefore, in this study, we investigated the use of multiple episodes of hypoxic exposure at different time intervals to induce longer-term protection in a mouse stroke model. C57BL/6 mice were subjected to different hypoxic preconditioning protocols: a single episode of HPC or five identical episodes at intervals of 3 days (E3d HPC or 6 days (E6d HPC. Three days after the last hypoxic exposure, temporary middle cerebral artery occlusion (MCAO was induced. The effects of these HPC protocols on hypoxia-inducible factor (HIF regulated gene mRNA expression were measured by quantitative PCR. Changes in extracellular adenosine concentrations, known to exert neuroprotective effects, were also measured using in vivo microdialysis and high pressure liquid chromatography (HPLC. Neuroprotection was provided by E6d HPC but not E3d HPC. HIF-regulated target gene expression increased significantly following all HPC protocols. However, E3d HPC significantly decreased extracellular adenosine and reduced cerebral blood flow in the ischemic region with upregulated expression of the adenosine transporter, equilibrative nucleoside transporter 1 (ENT1. An ENT1 inhibitor, propentofylline increased the cerebral blood flow and re-established neuroprotection in E3d HPC. Adenosine receptor specific antagonists showed that adenosine mainly through A1 receptor mediates HPC induced neuroprotection. Our data indicate that cooperation of HIF-regulated genes and extracellular adenosine is necessary for HPC-induced neuroprotection.

  9. Hypoxia induces adipogenic differentitation of myoblastic cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Itoigawa, Yoshiaki [Tohoku University School of Medicine, Sendai (Japan); Juntendo University School of Medicine, Tokyo (Japan); Kishimoto, Koshi N., E-mail: kishimoto@med.tohoku.ac.jp [Tohoku University School of Medicine, Sendai (Japan); Okuno, Hiroshi; Sano, Hirotaka [Tohoku University School of Medicine, Sendai (Japan); Kaneko, Kazuo [Juntendo University School of Medicine, Tokyo (Japan); Itoi, Eiji [Tohoku University School of Medicine, Sendai (Japan)

    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.

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

    Science.gov (United States)

    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. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Neuroglobin-deficiency exacerbates Hif1A and c-FOS response, but does not affect neuronal survival during severe hypoxia in vivo

    DEFF Research Database (Denmark)

    Hundahl, Christian Ansgar; Luuk, Hendrik; Ilmjärv, Sten

    2011-01-01

    Neuroglobin (Ngb), a neuron-specific globin that binds oxygen in vitro, has been proposed to play a key role in neuronal survival following hypoxic and ischemic insults in the brain. Here we address whether Ngb is required for neuronal survival following acute and prolonged hypoxia in mice...

  12. Oroxylin A regulates glucose metabolism in response to hypoxic stress with the involvement of Hypoxia-inducible factor-1 in human hepatoma HepG2 cells.

    Science.gov (United States)

    Dai, Qinsheng; Yin, Qian; Wei, Libin; Zhou, Yuxin; Qiao, Chen; Guo, Yongjian; Wang, Xiaotang; Ma, Shiping; Lu, Na

    2016-08-01

    Metabolic alteration in cancer cells is one of the most conspicuous characteristics that distinguish cancer cells from normal cells. In this study, we investigated the influence and signaling ways of oroxylin A affecting cancer cell energy metabolism under hypoxia. The data showed that oroxylin A remarkably reduced the generation of lactate and glucose uptake under hypoxia in HepG2 cells. Moreover, oroxylin A inhibited HIF-1α expression and its stability. The downstream targets (PDK1, LDHA, and HK II), as well as their mRNA levels were also suppressed by oroxylin A under hypoxia. The silencing or the overexpression of HIF-1α assays suggested that HIF-1α is required for metabolic effect of oroxylin A in HepG2 cells during hypoxia. Furthermore, oroxylin A could reduce the expression of complex III in mitochondrial respiratory chain, and then decrease the accumulation of ROS at moderate concentrations (0-50 µM) under hypoxia, which was benefit for its inhibition on glycolytic activity by decreasing ROS-mediated HIF-1 expression. Besides, oroxylin A didn't cause the loss of MMP under hypoxia and had no obvious effects on the expression of OXPHOS complexes, suggesting that oroxylin A did not affect mitochondrial mass at the moderate stress of oroxylin A. The suppressive effect of oroxylin A on glycolysis led to a significantly repress of ATP generation, for ATP generation mostly depends on glycolysis in HepG2 cells. This study revealed a new aspect of glucose metabolism regulation of oroxylin A under hypoxia, which may contribute to its new anticancer mechanism. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  13. Circulating levels of cell-derived microparticles are reduced by mild hypobaric hypoxia: data from a randomised controlled trial.

    Science.gov (United States)

    Ayers, Lisa; Stoewhas, Anne-Christin; Ferry, Berne; Latshang, Tsogyal D; Lo Cascio, Christian M; Sadler, Ross; Stadelmann, Katrin; Tesler, Noemi; Huber, Reto; Achermann, Peter; Bloch, Konrad E; Kohler, Malcolm

    2014-05-01

    Hypoxia is known to induce the release of microparticles in vitro. However, few publications have addressed the role of hypoxia in vivo on circulating levels of microparticles. This randomised, controlled, crossover trial aimed to determine the effect of mild hypoxia on in vivo levels of circulating microparticles in healthy individuals. Blood was obtained from 51 healthy male volunteers (mean age of 26.9 years) at baseline altitude (490 m) and after 24 and 48 h at moderate altitude (2,590 m). The order of altitude exposure was randomised. Flow cytometry was used to assess platelet-poor plasma for levels of circulating microparticles derived from platelets, endothelial cells, leucocytes, granulocytes, monocytes, red blood cells and procoagulant microparticles. Mean (standard deviation) oxygen saturation was significantly lower on the first and second day after arrival at 2,590 m, 91.0 (2.0) and 92.0 (2.0) %, respectively, compared to 490 m, 96 (1.0) %, p microparticles (annexin V+ -221/μl 95 % CI -370.8/-119.0, lactadherin+ -202/μl 95 % CI -372.2/-93.1), platelet-derived microparticles (-114/μl 95 % CI -189.9/-51.0) and red blood cell-derived microparticles (-81.4 μl 95 % CI -109.9/-57.7) after 48 h at moderate altitude was found. Microparticles derived from endothelial cells, granulocytes, monocytes and leucocytes were not significantly altered by exposure to moderate altitude. In healthy male individuals, mild hypobaric hypoxia, induced by a short-term stay at moderate altitude, is associated with lower levels of procoagulant microparticles, platelet-derived microparticles and red blood cell-derived microparticles, suggesting a reduction in thrombotic potential.

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

    Directory of Open Access Journals (Sweden)

    Jitesh D Kawedia

    Full Text Available 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.

  15. Hypoxia and Hypoxia Mimetics Decrease Aquaporin 5 (AQP5) Expression through Both Hypoxia Inducible Factor-1α and Proteasome-Mediated Pathways

    Science.gov (United States)

    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

  16. Characterization and functional analysis of hypoxia-inducible factor HIF1α and its inhibitor HIF1αn in tilapia.

    Science.gov (United States)

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

    2017-01-01

    Hypoxia is a major cause of fish morbidity and mortality in the aquatic environment. Hypoxia-inducible factors are very important modulators in the transcriptional response to hypoxic stress. In this study, we characterized and conducted functional analysis of hypoxia-inducible factor HIF1α and its inhibitor HIF1αn in Nile tilapia (Oreochromis niloticus). By cloning and Sanger sequencing, we obtained the full length cDNA sequences for HIF1α (2686bp) and HIF1αn (1308bp), respectively. The CDS of HIF1α includes 15 exons encoding 768 amino acid residues and the CDS of HIF1αn contains 8 exons encoding 354 amino acid residues. The complete CDS sequences of HIF1α and HIF1αn cloned from tilapia shared very high homology with known genes from other fishes. HIF1α show differentiated expression in different tissues (brain, heart, gill, spleen, liver) and at different hypoxia exposure times (6h, 12h, 24h). HIF1αn expression level under hypoxia is generally increased (6h, 12h, 24h) and shows extremely highly upregulation in brain tissue under hypoxia. A functional determination site analysis in the protein sequences between fish and land animals identified 21 amino acid sites in HIF1α and 2 sites in HIF1αn as significantly associated sites (α = 0.05). Phylogenetic tree-based positive selection analysis suggested 22 sites in HIF1α as positively selected sites with a p-value of at least 95% for fish lineages compared to the land animals. Our study could be important for clarifying the mechanism of fish adaptation to aquatic hypoxia environment.

  17. An innovative intermittent hypoxia model for cell cultures allowing fast Po2 oscillations with minimal gas consumption.

    Science.gov (United States)

    Minoves, Mélanie; Morand, Jessica; Perriot, Frédéric; Chatard, Morgane; Gonthier, Brigitte; Lemarié, Emeline; Menut, Jean-Baptiste; Polak, Jan; Pépin, Jean-Louis; Godin-Ribuot, Diane; Briançon-Marjollet, Anne

    2017-10-01

    Performing hypoxia-reoxygenation cycles in cell culture with a cycle duration accurately reflecting what occurs in obstructive sleep apnea (OSA) patients is a difficult but crucial technical challenge. Our goal was to develop a novel device to expose multiple cell culture dishes to intermittent hypoxia (IH) cycles relevant to OSA with limited gas consumption. With gas flows as low as 200 ml/min, our combination of plate holders with gas-permeable cultureware generates rapid normoxia-hypoxia cycles. Cycles alternating 1 min at 20% O 2 followed by 1 min at 2% O 2 resulted in Po 2 values ranging from 124 to 44 mmHg. Extending hypoxic and normoxic phases to 10 min allowed Po 2 variations from 120 to 25 mmHg. The volume of culture medium or the presence of cells only modestly affected the Po 2 variations. In contrast, the nadir of the hypoxia phase increased when measured at different heights above the membrane. We validated the physiological relevance of this model by showing that hypoxia inducible factor-1α expression was significantly increased by IH exposure in human aortic endothelial cells, murine breast carcinoma (4T1) cells as well as in a blood-brain barrier model (2.5-, 1.5-, and 6-fold increases, respectively). In conclusion, we have established a new device to perform rapid intermittent hypoxia cycles in cell cultures, with minimal gas consumption and the possibility to expose several culture dishes simultaneously. This device will allow functional studies of the consequences of IH and deciphering of the molecular biology of IH at the cellular level using oxygen cycles that are clinically relevant to OSA. Copyright © 2017 the American Physiological Society.

  18. Hypoxia: Exposure Time Until Significant Performance Effects

    Science.gov (United States)

    2016-03-07

    three alcoholic beverages per day (on average), or were taking any prescription medication (besides oral contraceptives). Likewise, those who were...or tested positively for pregnancy were disqualified from the study, as the risks of hypoxia to a human fetus are currently unknown. Also, those...that could impact inclusion in the study. After the questionnaire, all female participants provided a urine sample for pregnancy testing. Participants

  19. NASA Gulf of Mexico Initiative Hypoxia Research

    Science.gov (United States)

    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.

  20. Activity of aminotransferases in organs of rats during hypoxia of enclosed space of the action of thiamine bromide

    Directory of Open Access Journals (Sweden)

    Сніжана Сергіївна Чернадчук

    2015-05-01

    Full Text Available It is studied an aminotransferase activity during injection of thiamin bromide in rat tissues in normal and hypoxic enclosed space. After injection of thiamine bromide we have set reduction of AST and ALT activity, relative to control, except by the brain tissue, where there was an increase of investigated indicators. The decrease of activity of the investigated elements is occurred in animals which before hypoxia were injection of thiamine bromide

  1. Optical imaging of tumor hypoxia dynamics

    Science.gov (United States)

    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.

  2. Hypoxia in the changing marine environment

    International Nuclear Information System (INIS)

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

    2013-01-01

    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). (synthesis and review)

  3. Hypoxia in the changing marine environment

    Science.gov (United States)

    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).

  4. Intrauterine hypoxia: clinical consequences and therapeutic perspectives

    Directory of Open Access Journals (Sweden)

    Thompson LP

    2015-09-01

    Full Text Available Loren P Thompson,1 Sarah Crimmins,1 Bhanu P Telugu,2 Shifa Turan1 1Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA; 2Department of Animal Sciences, University of Maryland, College Park, MD, USA Abstract: Intrauterine hypoxia is a significant clinical challenge in obstetrics that affects both the pregnant mother and fetus. Intrauterine hypoxia can occur in pregnant women living at high altitude and/or with cardiovascular disease. In addition, placental hypoxia can be generated by altered placental development and spiral artery remodeling leading to placental insufficiency and dysfunction. Both conditions can impact normal maternal cardiovascular homeostasis leading to preeclampsia and/or impair transfer of O2/nutrient supply resulting in fetal growth restriction. This review discusses the mechanisms underlying altered placental vessel remodeling, maternal and fetal consequences, patient management, and potential future therapies for improving these conditions. Keywords: fetal growth restriction, oxidative stress, extravillous trophoblast invasion, Doppler ultrasound, pulsatility index, preeclampsia 

  5. Hypoxia symptoms during altitude training in professional Iranian fighter pilots.

    Science.gov (United States)

    Alagha, Babak; AhmadBeygi, Shervin; Ahmadbeigy, Shervin; Moosavi, Seyed Ali Javad; Jalali, Seyed Mahmood

    2012-01-01

    Susceptibility to hypoxia is influenced by a multitude of factors, including fatigue, physical activity, illnesses, ambient temperature, rate of ascent, destination altitude, medications, and alcohol. Anecdotally, several reports have been made regarding changes in the form of hypoxia presentation in Iranian fighter pilots in the absence of these factors. This study focused specifically on the effect of pilot age on susceptibility to hypoxia and its initial presentation. We assumed that a pilot's age may increase his susceptibility to hypoxia and consequently reduce the amount of time it takes for hypoxia to present. Because our literature review did not reveal any previous study addressing the possible relationship between age and susceptibility to hypoxia, the purpose of this study is to address and clarify this relationship. In this retrospective study, we collected information from Iranian fighter pilots (n = 30) through an anonymous questionnaire in 2000. The form of hypoxia presentation of each subject was evaluated during five altitude chamber training (ACT) sessions that were conducted routinely from 1972 to 1984. To enhance the accuracy of the study's results, confounding factors such as prior hypoxia experience in an ACT session have been taken into consideration. The results revealed a statistically significant relationship between age and a change in the form of hypoxia presentation in our subjects. Increased age reduced the amount of time before the first individual hypoxia symptom appeared (P < .000002). Although having previous hypoxia experience may help pilots to recognize their symptoms earlier, its effect was not statistically significant (P < .18). A few changes in the nature of individual symptoms were observed; however, we did not find a meaningful statistical correlation between pilot age and change in the nature of symptoms. Susceptibility ot hypoxia increases with pilot age. Copyright © 2012 Air Medical Journal Associates. Published by

  6. Endogenous markers of tumor hypoxia. Predictors of clinical radiation resistance?

    International Nuclear Information System (INIS)

    Vordermark, D.; Brown, J.M.

    2003-01-01

    Background: Eppendorf electrode measurements of tumor oxygenation have defined an adverse effect of tumor hypoxia on prognosis after radiotherapy and other treatment modalities, in particular in head and neck and cervix carcinomas as well as soft tissue sarcomas. Recently, the immunohistochemical detection of proteins involved in the ''hypoxic response'' of tumor cells has been discussed as a method to estimate hypoxia in clinical tumor specimens. Material and Methods: This review focuses on clinical and experimental data, regarding prognostic impact and comparability with other methods of hypoxia detection, for three proteins suggested as endogenous markers of tumor hypoxia: hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase 9 (CA 9), and glucose transporter 1 (GLUT1). Results: None of the three potential hypoxia markers is exclusively hypoxia-specific, and in each case protein can be detected under normoxic conditions in vitro. HIF-1α responds rapidly to hypoxia but also to reoxygenation, making this marker quite unstable in the context of clinical sample collection. The perinecrotic labeling pattern typical of chronic hypoxia and a reasonable agreement with injectable hypoxia markers such as pimonidazole have most consistently been described for CA 9. All three markers showed correlation with Eppendorf electrode measurements of tumor oxygenation in carcinoma of the cervix. In nine of 13 reports, among them all three that refer to curative radiotherapy for head and neck cancer, HIF-1α overexpression was associated with poor outcome. CA 9 was an adverse prognostic factor in cervix, head and neck and lung cancer, but not in two other head and neck cancer reports. GLUT1 predicted for poor survival in colorectal, cervix and lung cancer. Conclusion: Endogenous markers have the potential to indicate therapeutically relevant levels of hypoxia within tumors. Clinical trials assessing a marker's ability to predict a benefit from specific hypoxia

  7. Molecular evolution of myoglobin in the Tibetan Plateau endemic schizothoracine fish (Cyprinidae, Teleostei) and tissue-specific expression changes under hypoxia.

    Science.gov (United States)

    Qi, Delin; Chao, Yan; Zhao, Yongli; Xia, Mingzhe; Wu, Rongrong

    2018-04-01

    Myoglobin (Mb) is an oxygen-binding hemoprotein that was once thought to be exclusively expressed in oxidative myocytes of skeletal and cardiac muscle where it serves in oxygen storage and facilitates intracellular oxygen diffusion. In this study, we cloned the coding sequence of the Mb gene from four species, representing three groups, of the schizothoracine fish endemic to the Qinghai-Tibetan Plateau (QTP), then conducted molecular evolution analyses. We also investigated tissue expression patterns of Mb and the expression response to moderate and severe hypoxia at the mRNA and protein levels in a representative of the highly specialized schizothoracine fish species, Schizopygopsis pylzovi. Molecular evolution analyses showed that Mb from the highly specialized schizothoracine fish have undergone positive selection and one positively selected residue (81L) was identified, which is located in the F helix, close to or in contact with the heme. We present tentative evidence that the Mb duplication event occurred in the ancestor of the schizothoracine and Cyprininae fish (common carp and goldfish), and that the Mb2 paralog was subsequently lost in the schizothoracine fish. In S. pylzovi, Mb mRNA is expressed in various tissues with the exception of the intestine and gill, but all such tissues, including the liver, muscle, kidney, brain, eye, and skin, expressed very low levels of Mb mRNA (Tibetan Plateau fish.

  8. Intermittent but not sustained hypoxia activates orexin-containing neurons in mice.

    Science.gov (United States)

    Yamaguchi, Keiji; Futatsuki, Takahiro; Ushikai, Jumpei; Kuroki, Chiharu; Minami, Toshiaki; Kakihana, Yasuyuki; Kuwaki, Tomoyuki

    2015-01-15

    Hypothalamic orexin-containing neurons are activated by CO2 and contribute to hypercapnic ventilatory activation. However, their role in oxygen-related regulation of breathing is not well defined. In this study, we examined whether an experimental model mimicking apnea-induced repetitive hypoxemia (intermittent hypoxia [IH]) activates orexin-containing neurons. Mice were exposed to IH (5×5min at 10% O2), intermittent hyperoxia (IO; 5×5min at 50% O2), sustained hypoxia (SH; 25min at 10% O2), or sham stimulation. Their brains were examined using double immunohistochemical staining for orexin and c-Fos. The results indicated that IH (25.8±3.0%), but not SH (9.0±1.5%) activated orexin-containing neurons when compared to IO (5.5±0.6%) and sham stimulation (5.9±1.4%). These results correlate with those of our previous work showing that IH-induced respiratory long-term facilitation is dependent on orexin-containing neurons. Taken together, orexin contributes to repetitive hypoxia-induced respiratory activation and the hypoxic activation of orexin-containing neurons is pattern dependent. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. A neonatal mouse model of intermittent hypoxia associated with features of apnea in premature infants.

    Science.gov (United States)

    Cai, Jun; Tuong, Chi Minh; Gozal, David

    2011-09-15

    A neonatal mouse model of intermittent hypoxia (IH) simulating the recurring hypoxia/reoxygenation episodes of apnea of prematurity (AOP) was developed. C57BL/6 P2 pups were culled for exposure to either intermittent hypoxia or intermittent air as control. The IH paradigms consisted of alternation cycles of 20.9% O2 and either 8.0% or 5.7% O2 every 120 or 140s for 6h a day during daylight hours from day 2 to day 10 postnatally, i.e., roughly equivalent to human brain development in the perinatal period. IH exposures elicited modest to severe decrease in oxygen saturation along with bradycardia in neonatal mice, which were severity-dependent. Hypomyelination in both central and peripheral nervous systems was observed despite the absence of visible growth retardation. The neonatal mouse model of IH in this study partially fulfills the current diagnostic criteria with features of AOP, and provides opportunities to reproduce in rodents some of the pathophysiological changes associated with this disorder, such as alterations in myelination. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial.

    Science.gov (United States)

    Okonkwo, David O; Shutter, Lori A; Moore, Carol; Temkin, Nancy R; Puccio, Ava M; Madden, Christopher J; Andaluz, Norberto; Chesnut, Randall M; Bullock, M Ross; Grant, Gerald A; McGregor, John; Weaver, Michael; Jallo, Jack; LeRoux, Peter D; Moberg, Dick; Barber, Jason; Lazaridis, Christos; Diaz-Arrastia, Ramon R

    2017-11-01

    A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study. Randomized prospective clinical trial. Ten ICUs in the United States. One hundred nineteen severe traumatic brain injury patients. Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended. A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy. Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess

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

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    Priti Azad

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

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

    Directory of Open Access Journals (Sweden)

    Neuhaus C

    2014-11-01

    Full Text Available Christopher Neuhaus,1,2 Jochen Hinkelbein2,31Department of Anesthesiology, Heidelberg University Hospital, Ruprecht Karls University of Heidelberg, Heidelberg, 2Emergency Medicine and Air Rescue Working Group, German Society of Aviation and Space Medicine (DGLRM, Munich, 3Department of Anesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, GermanyAbstract: 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.Keywords: cognitive response, aviation training, pilot, hypoxia, oxygen, loss of consciousness

  13. Fetal brain damage following maternal carbon monoxide intoxication: an experimental study

    Energy Technology Data Exchange (ETDEWEB)

    Ginsberg, M D; Myers, R E

    1974-01-01

    Techniques of fetal monitoring, including fetal blood sampling in utero, were employed to study the physiological effects of acute maternal carbon monoxide intoxication on nine term-pregnant female rhesus monkeys exposed to 0.1 to 0.3% inspired carbon monoxide over 1 to 3 hr. The mothers tolerated carboxyhemoglobin levels exceeding 60% without clinical sequelae, whereas the fetuses promptly developed profound hypoxia upon exposure of the mothers to CO. The fetal COHb levels rose only gradually over 1 to 3 hr, and thus contributed only slightly to the development of early fetal hypoxia. The fetal hypoxia was associated with bradycardia, hypotension, and metabolic and respiratory acidosis. Severity of intrauterine hypoxia was closely correlated with the appearance of brain damage. Brain swelling associated with hemorrhagic necrosis of the cerebral hemispheres (severe brain damage) appeared only in fetuses whose arterial oxygen content was reduced below 1.0 ml/100 ml for at least 45 min during the maternal CO intoxication.

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

    Science.gov (United States)

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

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

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Neetu Kushwah

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

  17. Disparate roles of zinc in chemical hypoxia-induced neuronal death

    Directory of Open Access Journals (Sweden)

    Sujeong eKim

    2015-01-01

    Full Text Available Accumulating evidence has provided a causative role of zinc (Zn2+ in neuronal death following ischemic brain injury. Using a hypoxia model of primary cultured cortical neurons with hypoxia-inducing chemicals, cobalt chloride (1 mM CoCl2, deferoxamine (3 mM DFX, and sodium azide (2 mM NaN3, we evaluated whether Zn2+ is involved in hypoxic neuronal death. The hypoxic chemicals rapidly elicited intracellular Zn2+ release/accumulation in viable neurons. The immediate addition of the Zn2+ chelator, CaEDTA or N,N,N’N’-tetrakis-(2-pyridylmethyl ethylenediamine (TPEN, prevented the intracellular Zn2+ load and CoCl2-induced neuronal death, but neither 3-hour-later Zn2+ chelation nor a non-Zn2+ chelator ZnEDTA (1 mM demonstrated any effects. However, neither CaEDTA nor TPEN rescued neurons from cell death following DFX- or NaN3-induced hypoxia, whereas ZnEDTA rendered them resistant to the hypoxic injury. Instead, the immediate supplementation of Zn2+ rescued DFX- and NaN3-induced neuronal death. The iron supplementation also afforded neuroprotection against DFX-induced hypoxic injury. Thus, although intracellular Zn2+ release/accumulation is common during chemical hypoxia, Zn2+ might differently influence the subsequent fate of neurons; it appears to play a neurotoxic or neuroprotective role depending on the hypoxic chemical used. These results also suggest that different hypoxic chemicals may induce neuronal death via distinct mechanisms.

  18. Disparate roles of zinc in chemical hypoxia-induced neuronal death.

    Science.gov (United States)

    Kim, Sujeong; Seo, Jung-Woo; Oh, Shin Bi; Kim, So Hee; Kim, Inki; Suh, Nayoung; Lee, Joo-Yong

    2015-01-01

    Accumulating evidence has provided a causative role of zinc (Zn(2+)) in neuronal death following ischemic brain injury. Using a hypoxia model of primary cultured cortical neurons with hypoxia-inducing chemicals, cobalt chloride (1 mM CoCl2), deferoxamine (3 mM DFX), and sodium azide (2 mM NaN3), we evaluated whether Zn(2+) is involved in hypoxic neuronal death. The hypoxic chemicals rapidly elicited intracellular Zn(2+) release/accumulation in viable neurons. The immediate addition of the Zn(2+) chelator, CaEDTA or N,N,N'N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN), prevented the intracellular Zn(2+) load and CoCl2-induced neuronal death, but neither 3 hour later Zn(2+) chelation nor a non-Zn(2+) chelator ZnEDTA (1 mM) demonstrated any effects. However, neither CaEDTA nor TPEN rescued neurons from cell death following DFX- or NaN3-induced hypoxia, whereas ZnEDTA rendered them resistant to the hypoxic injury. Instead, the immediate supplementation of Zn(2+) rescued DFX- and NaN3-induced neuronal death. The iron supplementation also afforded neuroprotection against DFX-induced hypoxic injury. Thus, although intracellular Zn(2+) release/accumulation is common during chemical hypoxia, Zn(2+) might differently influence the subsequent fate of neurons; it appears to play a neurotoxic or neuroprotective role depending on the hypoxic chemical used. These results also suggest that different hypoxic chemicals may induce neuronal death via distinct mechanisms.

  19. Efficient Cryosolid Positron Moderators

    Science.gov (United States)

    2012-08-01

    table layout Figure 21 shows the integration of the IR spectroscopy optics with the positron Moderation and Annihilation vacuum chambers on the...Characterization of Cryogenic Moderators The application of Matrix Isolation Spectroscopy (MIS) to characterizing cryogenic solid positron ...Matrix Isolation Spectroscopy capability into our Positron Moderation apparatus, which enables spectroscopic characterization of the cryogenic

  20. Brain sites mediating corticosteroid feedback inhibition of stimulated ACTH secretion

    International Nuclear Information System (INIS)

    Jacobson, L.

    1989-01-01

    There is substantial evidence that the brain mediates stress-induced and circadian increases in ACTH secretion and that corticosteroid concentrations which normalize basal plasma ACTH are insufficient to normalize ACTH responses to circadian or stressful stimuli in adrenalectomized rats. To identify brain sites mediating corticosteroid inhibition of stimulated ACTH secretion, two approaches were used. The first compared brain [ 14 C]-2-deoxyglucose uptake in rats with differential ACTH responses to stress. Relative to sham-adrenalectomized (SHAM) rats, adrenalectomized rats replaced with low, constant corticosterone levels via a subcutaneous corticosterone pellet (B-PELLET) exhibited elevated and prolonged ACTH responses to a variety of stimuli. Adrenalectomized rate given a circadian corticosterone rhythm via corticosterone in their drinking water exhibited elevated ACTH levels immediately after stress, but unlike B-PELLET rats, terminated stress induced ACTH secretion normally relative to SHAMS. Therefore, the abnormal ACTH responses to stress in B-PELLET rats were due to the lack of both circadian variations and stress-induced increases in corticosterone. Hypoxia was selected as a standardized stimulus for correlating brain [ 14 C]-2-deoxyglucose uptake with ACTH secretion. In intact rats, increases in plasma ACTH and decreases in arterial PO 2 correlated with the severity of hypoxia at arterial PCO 2 below 60 mm Hg. Hypoxia PELLET vs. SHAM rats. However, in preliminary experiments, although hypoxia increased brain 2-deoxyglucose uptake in most brain regions, plasma ACTH correlated poorly with 2-deoxyglucose uptake at 12% and 10% O 2

  1. Chronic intermittent but not constant hypoxia decreases NAA/Cr ratios in neonatal mouse hippocampus and thalamus.

    Science.gov (United States)

    Douglas, Robert M; Miyasaka, Naoyuki; Takahashi, Kan; Latuszek-Barrantes, Adrianna; Haddad, Gabriel G; Hetherington, Hoby P

    2007-03-01

    Chronic constant hypoxia (CCH) and chronic intermittent hypoxia (CIH) are known to have deleterious effects on the central nervous system. Because of the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity, and this can be noninvasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either CCH, where the Fi(O(2)) was maintained at 11% continuously or to CIH, where the Fi(O(2)) was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 wk demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 wk of normoxia. Meanwhile, mice exposed to 4 wk of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases, such as obstructive sleep apnea, have the potential for inducing significant neurocognitive recovery in these patients.

  2. Hypobaric hypoxia impairs cued and contextual fear memory in rats.

    Science.gov (United States)

    Kumari, Punita; Kauser, Hina; Wadhwa, Meetu; Roy, Koustav; Alam, Shahnawaz; Sahu, Surajit; Kishore, Krishna; Ray, Koushik; Panjwani, Usha

    2018-04-26

    Fear memory is essential for survival, and its dysregulation leads to disorders. High altitude hypobaric hypoxia (HH) is known to induce cognitive decline. However, its effect on fear memory is still an enigma. We aimed to investigate the temporal effect of HH on fear conditioning and the underlying mechanism. Adult male Sprague-Dawley rats were trained for fear conditioning and exposed to simulated HH equivalent to 25,000 ft for different durations (1, 3, 7, 14 and 21 days). Subsequently, rats were tested for cued and contextual fear conditioning. Neuronal morphology, apoptosis and DNA fragmentation were studied in the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). We observed significant deficit in cued and contextual fear acquisition (at 1, 3 and 7 days) and consolidation (cued at 1 and 3 days and contextual fear at 1, 3 and 7 days) under HH. HH exposure with retraining showed the earlier restoration of contextual fear memory. Further, we found a gradual increase in the number of pyknotic and apoptotic neurons together with the increase in DNA fragmentation in mPFC, hippocampus, and BLA up to 7 days of HH exposure. The present study concludes that HH exposure equivalent to 25000 ft induced cued and contextual fear memory deficit (acquisition and consolidation) which is found to be correlated with the neurodegenerative changes in the limbic brain regions. Copyright © 2018. Published by Elsevier B.V.

  3. Hypoxia positron emission tomography imaging: combining information on perfusion and tracer retention to improve hypoxia specificity

    DEFF Research Database (Denmark)

    Busk, Morten; Munk, Ole L; Jakobsen, Steen S

    2017-01-01

    BACKGROUND: Static positron emission tomography (PET) allows mapping of tumor hypoxia, but low resolution and slow tracer retention/clearance results in poor image contrast and the risk of missing areas where hypoxic cells and necrosis are intermixed. Fully dynamic PET may improve accuracy but scan...

  4. Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

    DEFF Research Database (Denmark)

    Klausen, T; Christensen, H; Hansen, J M

    1996-01-01

    This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were...