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Sample records for ischemic preconditioning ip

  1. Ischemic preconditioning protects against ischemic brain injury.

    PubMed

    Ma, Xiao-Meng; Liu, Mei; Liu, Ying-Ying; Ma, Li-Li; Jiang, Ying; Chen, Xiao-Hong

    2016-05-01

    In this study, we hypothesized that an increase in integrin αvβ3 and its co-activator vascular endothelial growth factor play important neuroprotective roles in ischemic injury. We performed ischemic preconditioning with bilateral common carotid artery occlusion for 5 minutes in C57BL/6J mice. This was followed by ischemic injury with bilateral common carotid artery occlusion for 30 minutes. The time interval between ischemic preconditioning and lethal ischemia was 48 hours. Histopathological analysis showed that ischemic preconditioning substantially diminished damage to neurons in the hippocampus 7 days after ischemia. Evans Blue dye assay showed that ischemic preconditioning reduced damage to the blood-brain barrier 24 hours after ischemia. This demonstrates the neuroprotective effect of ischemic preconditioning. Western blot assay revealed a significant reduction in protein levels of integrin αvβ3, vascular endothelial growth factor and its receptor in mice given ischemic preconditioning compared with mice not given ischemic preconditioning 24 hours after ischemia. These findings suggest that the neuroprotective effect of ischemic preconditioning is associated with lower integrin αvβ3 and vascular endothelial growth factor levels in the brain following ischemia. PMID:27335560

  2. Ischemic preconditioning protects against ischemic brain injury

    PubMed Central

    Ma, Xiao-meng; Liu, Mei; Liu, Ying-ying; Ma, Li-li; Jiang, Ying; Chen, Xiao-hong

    2016-01-01

    In this study, we hypothesized that an increase in integrin αvβ3 and its co-activator vascular endothelial growth factor play important neuroprotective roles in ischemic injury. We performed ischemic preconditioning with bilateral common carotid artery occlusion for 5 minutes in C57BL/6J mice. This was followed by ischemic injury with bilateral common carotid artery occlusion for 30 minutes. The time interval between ischemic preconditioning and lethal ischemia was 48 hours. Histopathological analysis showed that ischemic preconditioning substantially diminished damage to neurons in the hippocampus 7 days after ischemia. Evans Blue dye assay showed that ischemic preconditioning reduced damage to the blood-brain barrier 24 hours after ischemia. This demonstrates the neuroprotective effect of ischemic preconditioning. Western blot assay revealed a significant reduction in protein levels of integrin αvβ3, vascular endothelial growth factor and its receptor in mice given ischemic preconditioning compared with mice not given ischemic preconditioning 24 hours after ischemia. These findings suggest that the neuroprotective effect of ischemic preconditioning is associated with lower integrin αvβ3 and vascular endothelial growth factor levels in the brain following ischemia. PMID:27335560

  3. Adenosine and Ischemic Preconditioning

    PubMed Central

    Liang, Bruce T.; Swierkosz, Tomasz A.; Herrmann, Howard C.; Kimmel, Stephen; Jacobson, Kenneth A.

    2012-01-01

    Adenosine is released in large amounts during myocardial ischemia and is capable of exerting potent cardioprotective effects in the heart. Although these observations on adenosine have been known for a long time, how adenosine acts to achieve its anti-ischemic effect remains incompletely understood. However, recent advances on the chemistry and pharmacology of adenosine receptor ligands have provided important and novel information on the function of adenosine receptor subtypes in the cardiovascular system. The development of model systems for the cardiac actions of adenosine has yielded important insights into its mechanism of action and have begun to elucidate the sequence of signalling events from receptor activation to the actual exertion of its cardioprotective effect. The present review will focus on the adenosine receptors that mediate the potent anti-ischemic effect of adenosine, new ligands at the receptors, potential molecular signalling mechanisms downstream of the receptor, mediators for cardioprotection, and possible clinical applications in cardiovascular disorders. PMID:10607860

  4. Biomarkers for ischemic preconditioning: finding the responders

    PubMed Central

    Koch, Sebastian; Della-Morte, David; Dave, Kunjan R; Sacco, Ralph L; Perez-Pinzon, Miguel A

    2014-01-01

    Ischemic preconditioning is emerging as an innovative and novel cytoprotective strategy to counter ischemic vascular disease. At the root of the preconditioning response is the upregulation of endogenous defense systems to achieve ischemic tolerance. Identifying suitable biomarkers to show that a preconditioning response has been induced remains a translational research priority. Preconditioning leads to a widespread genomic and proteonomic response with important effects on hemostatic, endothelial, and inflammatory systems. The present article summarizes the relevant preclinical studies defining the mechanisms of preconditioning, reviews how the human preconditioning response has been investigated, and which of these bioresponses could serve as a suitable biomarker. Human preconditioning studies have investigated the effects of preconditioning on coagulation, endothelial factors, and inflammatory mediators as well as on genetic expression and tissue blood flow imaging. A biomarker for preconditioning would significantly contribute to define the optimal preconditioning stimulus and the extent to which such a response can be elicited in humans and greatly aid in dose selection in the design of phase II trials. Given the manifold biologic effects of preconditioning a panel of multiple serum biomarkers or genomic assessments of upstream regulators may most accurately reflect the full spectrum of a preconditioning response. PMID:24643082

  5. Cerebral Ischemic Preconditioning: the Road So Far….

    PubMed

    Thushara Vijayakumar, N; Sangwan, Amit; Sharma, Bhargy; Majid, Arshad; Rajanikant, G K

    2016-05-01

    Cerebral preconditioning constitutes the brain's adaptation to lethal ischemia when first exposed to mild doses of a subtoxic stressor. The phenomenon of preconditioning has been largely studied in the heart, and data from in vivo and in vitro models from past 2-3 decades have provided sufficient evidence that similar machinery exists in the brain as well. Since preconditioning results in a transient protective phenotype labeled as ischemic tolerance, it can open many doors in the medical warfare against stroke, a debilitating cerebrovascular disorder that kills or cripples thousands of people worldwide every year. Preconditioning can be induced by a variety of stimuli from hypoxia to pharmacological anesthetics, and each, in turn, induces tolerance by activating a multitude of proteins, enzymes, receptors, transcription factors, and other biomolecules eventually leading to genomic reprogramming. The intracellular signaling pathways and molecular cascades behind preconditioning are extensively being investigated, and several first-rate papers have come out in the last few years centered on the topic of cerebral ischemic tolerance. However, translating the experimental knowledge into the clinical scaffold still evades practicality and faces several challenges. Of the various preconditioning strategies, remote ischemic preconditioning and pharmacological preconditioning appears to be more clinically relevant for the management of ischemic stroke. In this review, we discuss current developments in the field of cerebral preconditioning and then examine the potential of various preconditioning agents to confer neuroprotection in the brain. PMID:26081149

  6. Resveratrol and ischemic preconditioning in the brain.

    PubMed

    Raval, Ami P; Lin, Hung Wen; Dave, Kunjan R; Defazio, R Anthony; Della Morte, David; Kim, Eun Joo; Perez-Pinzon, Miguel A

    2008-01-01

    Cardiovascular pathologies in the French are not prevalent despite high dietary saturated fat consumption. This is commonly referred to as the "French Paradox" attributing its anti-lipidemic effects to moderate consumption of red wine. Resveratrol, a phytoalexin found in red wine, is currently the focus of intense research both in the cardiovascular system and the brain. Current research suggests resveratrol may enhance prognosis of neurological disorders such as, Parkinson's, Huntington's, Alzheimer's diseases and stroke. The beneficial effects of resveratrol include: antioxidation, free radical scavenger, and modulation of neuronal energy homeostasis and glutamatergic receptors/ion channels. Resveratrol directly increases sirtuin 1 (SIRT1) activity, a NAD(+) (oxidized form of nicotinamide adenine dinucleotide)-dependent histone deacetylase related to increased lifespan in various species similar to calorie restriction. We recently demonstrated that brief resveratrol pretreatment conferred neuroprotection against cerebral ischemia via SIRT1 activation. This neuroprotective effect produced by resveratrol was similar to ischemic preconditioning-induced neuroprotection, which protects against lethal ischemic insults in the brain and other organ systems. Inhibition of SIRT1 abolished ischemic preconditioning-induced neuroprotection in CA1 region of the hippocampus. Since resveratrol and ischemic preconditioning-induced neuroprotection require activation of SIRT1, this common signaling pathway may provide targeted therapeutic treatment modalities as it relates to stroke and other brain pathologies. In this review, we will examine common signaling pathways, cellular targets of resveratrol, and ischemic preconditioning-induced neuroprotection as it relates to the brain. PMID:18537630

  7. Intestinal ischemic preconditioning reduces liver ischemia reperfusion injury in rats

    PubMed Central

    XUE, TONG-MIN; TAO, LI-DE; ZHANG, JIE; ZHANG, PEI-JIAN; LIU, XIA; CHEN, GUO-FENG; ZHU, YI-JIA

    2016-01-01

    The aim of the current study was to investigate whether intestinal ischemic preconditioning (IP) reduces damage to the liver during hepatic ischemia reperfusion (IR). Sprague Dawley rats were used to model liver IR injury, and were divided into the sham operation group (SO), IR group and IP group. The results indicated that IR significantly increased Bax, caspase 3 and NF-κBp65 expression levels, with reduced expression of Bcl-2 compared with the IP group. Compared with the IR group, the levels of AST, ALT, MPO, MDA, TNF-α and IL-1 were significantly reduced in the IP group. Immunohistochemistry for Bcl-2 and Bax indicated that Bcl-2 expression in the IP group was significantly increased compared with the IR group. In addition, IP reduced Bax expression compared with the IR group. The average liver injury was worsened in the IR group and improved in the IP group, as indicated by the morphological evaluation of liver tissues. The present study suggested that IP may alleviates apoptosis, reduce the release of pro-inflammatory cytokines, ameloriate reductions in liver function and reduce liver tissue injury. To conclude, IP provided protection against hepatic IR injury. PMID:26821057

  8. Cardioprotection Acquired Through Exercise: The Role of Ischemic Preconditioning

    PubMed Central

    Marongiu, Elisabetta; Crisafulli, Antonio

    2014-01-01

    A great bulk of evidence supports the concept that regular exercise training can reduce the incidence of coronary events and increase survival chances after myocardial infarction. These exercise-induced beneficial effects on the myocardium are reached by means of the reduction of several risk factors relating to cardiovascular disease, such as high cholesterol, hypertension, obesity etc. Furthermore, it has been demonstrated that exercise can reproduce the “ischemic preconditioning” (IP), which refers to the capacity of short periods of ischemia to render the myocardium more resistant to subsequent ischemic insult and to limit infarct size during prolonged ischemia. However, IP is a complex phenomenon which, along with infarct size reduction, can also provide protection against arrhythmia and myocardial stunning due to ischemia-reperfusion. Several clues demonstrate that preconditioning may be directly induced by exercise, thus inducing a protective phenotype at the heart level without the necessity of causing ischemia. Exercise appears to act as a physiological stress that induces beneficial myocardial adaptive responses at cellular level. The purpose of the present paper is to review the latest data on the role played by exercise in triggering myocardial preconditioning. PMID:24720421

  9. Ischemic preconditioning reduces hemodynamic response during metaboreflex activation.

    PubMed

    Mulliri, Gabriele; Sainas, Gianmarco; Magnani, Sara; Palazzolo, Girolamo; Milia, Nicola; Orrù, Andrea; Roberto, Silvana; Marongiu, Elisabetta; Milia, Raffaele; Crisafulli, Antonio

    2016-05-01

    Ischemic preconditioning (IP) has been shown to improve exercise performance and to delay fatigue. However, the precise mechanisms through which IP operates remain elusive. It has been hypothesized that IP lowers the sensation of fatigue by reducing the discharge of group III and IV nerve endings, which also regulate hemodynamics during the metaboreflex. We hypothesized that IP reduces the blood pressure response during the metaboreflex. Fourteen healthy males (age between 25 and 48 yr) participated in this study. They underwent the following randomly assigned protocol: postexercise muscle ischemia (PEMI) test, during which the metaboreflex was elicited after dynamic handgrip; control exercise recovery session (CER) test; and PEMI after IP (IP-PEMI) test. IP was obtained by occluding forearm circulation for three cycles of 5 min spaced by 5 min of reperfusion. Hemodynamics were evaluated by echocardiography and impedance cardiography. The main results were that after IP the mean arterial pressure response was reduced compared with the PEMI test (means ± SD +3.37 ± 6.41 vs. +9.16 ± 7.09 mmHg, respectively). This was the consequence of an impaired venous return that impaired the stroke volume during the IP-PEMI more than during the PEMI test (-1.43 ± 15.35 vs. +10.28 ± 10.479 ml, respectively). It was concluded that during the metaboreflex, IP affects hemodynamics mainly because it impairs the capacity to augment venous return and to recruit the cardiac preload reserve. It was hypothesized that this is the consequence of an increased nitric oxide production, which reduces the possibility to constrict venous capacity vessels. PMID:26936782

  10. Ischemic preconditioning protects against gap junctional uncoupling in cardiac myofibroblasts.

    PubMed

    Sundset, Rune; Cooper, Marie; Mikalsen, Svein-Ole; Ytrehus, Kirsti

    2004-01-01

    Ischemic preconditioning increases the heart's tolerance to a subsequent longer ischemic period. The purpose of this study was to investigate the role of gap junction communication in simulated preconditioning in cultured neonatal rat cardiac myofibroblasts. Gap junctional intercellular communication was assessed by Lucifer yellow dye transfer. Preconditioning preserved intercellular coupling after prolonged ischemia. An initial reduction in coupling in response to the preconditioning stimulus was also observed. This may protect neighboring cells from damaging substances produced during subsequent regional ischemia in vivo, and may preserve gap junctional communication required for enhanced functional recovery during subsequent reperfusion. PMID:16247851

  11. Effects of Ischemic Preconditioning of Different Intraoperative Ischemic Times of Vascularized Bone Graft Rabbit Models

    PubMed Central

    Wan Ahmad Kamal, Wan Syazli Rodzaia; Noor, Norizal Mohd; Abdullah, Shafie

    2013-01-01

    Background Ischemic preconditioning has been shown to improve the outcomes of hypoxic tolerance of the heart, brain, lung, liver, jejunum, skin, and muscle tissues. However, to date, no report of ischemic preconditioning on vascularized bone grafts has been published. Methods Sixteen rabbits were divided into four groups with ischemic times of 2, 6, 14, and 18 hours. Half of the rabbits in each group underwent ischemic preconditioning. The osteomyocutaneous flaps consisted of the tibia bone, from which the overlying muscle and skin were raised. The technique of ischemic preconditioning involved applying a vascular clamp to the pedicle for 3 cycles of 10 minutes each. The rabbits then underwent serial plain radiography and computed tomography imaging on the first, second, fourth, and sixth postoperative weeks. Following this, all of the rabbits were sacrificed and histological examinations were performed. Results The results showed that for clinical analysis of the skin flaps and bone grafts, the preconditioned groups showed better survivability. In the plain radiographs, except for two non-preconditioned rabbits with intraoperative ischemic times of 6 hours, all began to show early callus formation at the fourth week. The computed tomography findings showed more callus formation in the preconditioned groups for all of the ischemic times except for the 18-hour group. The histological findings correlated with the radiological findings. There was no statistical significance in the difference between the two groups. Conclusions In conclusion, ischemic preconditioning improved the survivability of skin flaps and increased callus formation during the healing process of vascularized bone grafts. PMID:24286040

  12. Local and remote ischemic preconditioning protect against intestinal ischemic/reperfusion injury after supraceliac aortic clamping

    PubMed Central

    Erling, Nilon; de Souza Montero, Edna Frasson; Sannomiya, Paulina; Poli-de-Figueiredo (in memoriam), Luiz Francisco

    2013-01-01

    OBJECTIVES: This study tests the hypothesis that local or remote ischemic preconditioning may protect the intestinal mucosa against ischemia and reperfusion injuries resulting from temporary supraceliac aortic clamping. METHODS: Twenty-eight Wistar rats were divided into four groups: the sham surgery group, the supraceliac aortic occlusion group, the local ischemic preconditioning prior to supraceliac aortic occlusion group, and the remote ischemic preconditioning prior to supraceliac aortic occlusion group. Tissue samples from the small bowel were used for quantitative morphometric analysis of mucosal injury, and blood samples were collected for laboratory analyses. RESULTS: Supraceliac aortic occlusion decreased intestinal mucosal length by reducing villous height and elevated serum lactic dehydrogenase and lactate levels. Both local and remote ischemic preconditioning mitigated these histopathological and laboratory changes. CONCLUSIONS: Both local and remote ischemic preconditioning protect intestinal mucosa against ischemia and reperfusion injury following supraceliac aortic clamping. PMID:24473514

  13. A "second window of protection" occurs 24 h after ischemic preconditioning in the rat heart.

    PubMed

    Yamashita, N; Hoshida, S; Taniguchi, N; Kuzuya, T; Hori, M

    1998-06-01

    We and others found that cardioprotection is acquired not only soon after, but also 24 h after ischemic preconditioning in canine and rabbit myocardial infarction models (second window of protection). However, a second window phenomenon against myocardial infarction was dependent on species limitations and has not been observed in porcine hearts. In this study, we examined whether the "second window of protection" against myocardial infarction is observed in the rat heart. In the ischemic preconditioning (IP) group, the left main coronary artery (LCA) of rats was occluded four times for 3 min. each separated by reperfusion for 10 min. After 0, 3, and 24 h, the rats were subjected to a 20-min LCA occlusion followed by 48-h reperfusion. At 0 and 24 h after IP, infarct size and the incidence of ventricular fibrillation (VF) during ischemia were significantly reduced compared with corresponding sham-operated groups without preconditioning. After 3 h of IP, there were no differences either in the incidence of VF during ischemia or in infarct size. Manganese superoxide dismutase (Mn-SOD) content in ischemic (LCA) region of myocardium significantly increased as compared with that of sham-operated rats 24 h after IP. Treatment with N-2-mercaptopropionyl glycine, an antioxidant and a hydroxyl radical scavenger, during IP abolished the early-phase (0 h after IP) and late-phase (24 h after IP) cardioprotection and the corresponding late increase in Mn-SOD content. These results indicate that a "second window of protection" against myocardial infarction also exists in rat hearts and the induction of an intrinsic scavenger, Mn-SOD, via free radical production during IP may be important in the second window of protection. PMID:9689592

  14. Heat shock proteins, end effectors of myocardium ischemic preconditioning?

    PubMed Central

    Guisasola, María Concepcion; Desco, Maria del Mar; Gonzalez, Fernanda Silvana; Asensio, Fernando; Dulin, Elena; Suarez, Antonio; Garcia Barreno, Pedro

    2006-01-01

    The purpose of this study was to investigate (1) whether ischemia-reperfusion increased the content of heat shock protein 72 (Hsp72) transcripts and (2) whether myocardial content of Hsp72 is increased by ischemic preconditioning so that they can be considered as end effectors of preconditioning. Twelve male minipigs (8 protocol, 4 sham) were used, with the following ischemic preconditioning protocol: 3 ischemia and reperfusion 5-minute alternative cycles and last reperfusion cycle of 3 hours. Initial and final transmural biopsies (both in healthy and ischemic areas) were taken in all animals. Heat shock protein 72 messenger ribonucleic acid (mRNA) expression was measured by a semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method using complementary DNA normalized against the housekeeping gene cyclophilin. The identification of heat shock protein 72 was performed by immunoblot. In our “classic” preconditioning model, we found no changes in mRNA hsp72 levels or heat shock protein 72 content in the myocardium after 3 hours of reperfusion. Our experimental model is valid and the experimental techniques are appropriate, but the induction of heat shock proteins 72 as end effectors of cardioprotection in ischemic preconditioning does not occur in the first hours after ischemia, but probably at least 24 hours after it, in the so-called “second protection window.” PMID:17009598

  15. Ischemic Preconditioning in White Matter: Magnitude and Mechanism

    PubMed Central

    Hamner, Margaret A.; Ye, Zucheng; Lee, Richard V.; Colman, Jamie R.; Le, Thu; Gong, Davin C.; Weinstein, Jonathan R.

    2015-01-01

    Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon whereby brief ischemic exposure confers tolerance to a subsequent ischemic challenge. IPC has not been studied selectively in CNS white matter (WM), although stroke frequently involves WM. We determined whether IPC is present in WM and, if so, its mechanism. We delivered a brief in vivo preconditioning ischemic insult (unilateral common carotid artery ligation) to 12- to 14-week-old mice and determined WM ischemic vulnerability [oxygen–glucose deprivation (OGD)] 72 h later, using acutely isolated optic nerves (CNS WM tracts) from the preconditioned (ipsilateral) and control (contralateral) hemispheres. Functional and structural recovery was assessed by quantitative measurement of compound action potentials (CAPs) and immunofluorescent microscopy. Preconditioned mouse optic nerves (MONs) showed better functional recovery after OGD than the non-preconditioned MONs (31 ± 3 vs 17 ± 3% normalized CAP area, p < 0.01). Preconditioned MONs also showed improved axon integrity and reduced oligodendrocyte injury compared with non-preconditioned MONs. Toll-like receptor-4 (TLR4) and type 1 interferon receptor (IFNAR1), key receptors in innate immune response, are implicated in gray matter preconditioning. Strikingly, IPC-mediated WM protection was abolished in both TLR4−/− and IFNAR1−/− mice. In addition, IPC-mediated protection in WM was also abolished in IFNAR1fl/fl LysMcre, but not in IFNAR1fl/fl control, mice. These findings demonstrated for the first time that IPC was robust in WM, the phenomenon being intrinsic to WM itself. Furthermore, WM IPC was dependent on innate immune cell signaling pathways. Finally, these data demonstrated that microglial-specific expression of IFNAR1 plays an indispensable role in WM IPC. SIGNIFICANCE STATEMENT Ischemic preconditioning (IPC) has been studied predominantly in gray matter, but stroke in humans frequently involves white matter (WM) as well. Here we

  16. Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart.

    PubMed

    Abete, P; Testa, G; Galizia, G; Mazzella, F; Della Morte, D; de Santis, D; Calabrese, C; Cacciatore, F; Gargiulo, G; Ferrara, N; Rengo, G; Sica, V; Napoli, C; Rengo, F

    2005-01-01

    Ischemic preconditioning (IP) has been proposed as an endogenous form of protection against ischemia reperfusion injury. IP, however, does not prevent post-ischemic dysfunction in the aging heart but may be partially corrected by exercise training and food restriction. We investigated the role of exercise training combined with food restriction on restoring IP in the aging heart. Effects of IP against ischemia-reperfusion injury in isolated hearts from adult (A, 6 months old), sedentary 'ad libitum' fed (SL), trained ad libitum fed (TL), sedentary food-restricted (SR), trained- and food-restricted senescent rats (TR) (24 months old) were investigated. Norepinephrine release in coronary effluent was determined by high performance liquid cromatography. IP significantly improved final recovery of percent developed pressure in hearts from A (p<0.01) but not in those from SL (p=NS) vs unconditioned controls. Developed pressure recovery was partial in hearts from TL and SR (64.3 and 67.3%, respectively; p<0.05 vs controls) but it was total in those from TR (82.3%, p=NS vs A; p<0.05 vs hearts from TL and SR). Similarly, IP determined a similar increase of norepinephrine release in A (p<0.001) and in TR (p<0.001, p=NS vs adult). IP was abolished by depletion of myocardial norepinephrine stores by reserpine in all groups. Thus, IP reduces post-ischemic dysfunction in A but not in SL. Moreover, IP was preserved partially in TR and SR and totally in TR. Complete IP maybe due to full restoration of norepinephrine release in response to IP stimulus. PMID:15664731

  17. Role of Trimetazidine in Ischemic Preconditioning in Patients With Symptomatic Coronary Artery Disease.

    PubMed

    Costa, Leandro M A; Rezende, Paulo C; Garcia, Rosa M R; Uchida, Augusto H; Seguro, Luis Fernando B C; Scudeler, Thiago L; Bocchi, Edimar A; Krieger, Jose E; Hueb, Whady; Ramires, José Antonio F; Filho, Roberto Kalil

    2015-08-01

    Ischemic preconditioning (IP) is a powerful cardioprotective cellular mechanism that has been related to the "warm-up phenomenon" or "walk-through" angina, and has been documented through the use of sequential exercise tests (ETs). It is known that several drugs, for example, cromokalim, pinacidil, adenosine, and nicorandil, can interfere with the cellular pathways of IP. The purpose of this article is to report the effect of the anti-ischemic agent trimetazidine (TMZ) on IP in symptomatic coronary artery disease (CAD) patients.We conducted a prospective study evaluating IP by the analysis of ischemic parameters in 2 sequential ETs. In phase I, without TMZ, patients underwent ET1 and ET2 with a 30-minute interval between them. In phase II, after 1 week of TMZ 35 mg twice daily, all patients underwent 2 consecutive ETs (ET3 and ET4). IP was considered present when the time to 1.0-mm segment ST on electrocardiogram deviation (T-1.0 mm) and rate pressure product (RPP) were greater in the second of 2 tests. The improvement in T-1.0 mm and RPP were compared in the 2 phases: without TMZ and after 1-week TMZ to assess the action of such drug in myocardial protective mechanisms. ETs were analyzed by 2 independent cardiologists.From 135 CAD patients screened, 96 met inclusion criteria and 62 completed the study protocol. Forty patients manifested IP by demonstrating an improvement in T-1.0 mm in ET2 compared with ET1, without the use of any drugs (phase I). In phase II, after 1-week TMZ, 26 patients (65%) did not show any incremental result in ischemic parameters in ET4 compared with ET3. Furthermore, of these patients, 8 (20%) had IP blockage.In this study, TMZ did not add any benefit to IP in patients with stable symptomatic CAD. PMID:26287407

  18. Role of Trimetazidine in Ischemic Preconditioning in Patients With Symptomatic Coronary Artery Disease

    PubMed Central

    Costa, Leandro M.A.; Rezende, Paulo C.; Garcia, Rosa M.R.; Uchida, Augusto H.; Seguro, Luis Fernando B.C.; Scudeler, Thiago L.; Bocchi, Edimar A.; Krieger, Jose E.; Hueb, Whady; Ramires, José Antonio F.; Filho, Roberto Kalil

    2015-01-01

    Abstract Ischemic preconditioning (IP) is a powerful cardioprotective cellular mechanism that has been related to the “warm-up phenomenon” or “walk-through” angina, and has been documented through the use of sequential exercise tests (ETs). It is known that several drugs, for example, cromokalim, pinacidil, adenosine, and nicorandil, can interfere with the cellular pathways of IP. The purpose of this article is to report the effect of the anti-ischemic agent trimetazidine (TMZ) on IP in symptomatic coronary artery disease (CAD) patients. We conducted a prospective study evaluating IP by the analysis of ischemic parameters in 2 sequential ETs. In phase I, without TMZ, patients underwent ET1 and ET2 with a 30-minute interval between them. In phase II, after 1 week of TMZ 35 mg twice daily, all patients underwent 2 consecutive ETs (ET3 and ET4). IP was considered present when the time to 1.0-mm segment ST on electrocardiogram deviation (T-1.0 mm) and rate pressure product (RPP) were greater in the second of 2 tests. The improvement in T-1.0 mm and RPP were compared in the 2 phases: without TMZ and after 1-week TMZ to assess the action of such drug in myocardial protective mechanisms. ETs were analyzed by 2 independent cardiologists. From 135 CAD patients screened, 96 met inclusion criteria and 62 completed the study protocol. Forty patients manifested IP by demonstrating an improvement in T-1.0 mm in ET2 compared with ET1, without the use of any drugs (phase I). In phase II, after 1-week TMZ, 26 patients (65%) did not show any incremental result in ischemic parameters in ET4 compared with ET3. Furthermore, of these patients, 8 (20%) had IP blockage. In this study, TMZ did not add any benefit to IP in patients with stable symptomatic CAD. PMID:26287407

  19. Protective effects of remote ischemic preconditioning in rat hindlimb on ischemia- reperfusion injury★

    PubMed Central

    Zhang, Ying; Liu, Xiangrong; Yan, Feng; Min, Lianqiu; Ji, Xunming; Luo, Yumin

    2012-01-01

    Three cycles of remote ischemic pre-conditioning induced by temporarily occluding the bilateral femoral arteries (10 minutes) prior to 10 minutes of reperfusion were given once a day for 3 days before the animal received middle artery occlusion and reperfusion surgery. The results showed that brain infarct volume was significantly reduced after remote ischemic pre-conditioning. Scores in the forelimb placing test and the postural reflex test were significantly lower in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. Thus, neurological function was better in rats having undergone remote ischemic pre-conditioning compared with those who did not receive remote ischemic pre-conditioning. These results indicate that remote ischemic pre-conditioning in rat hindlimb exerts protective effects in ischemia-reperfusion injury. PMID:25745448

  20. Ischemic Preconditioning protects hepatocytes from ischemia-reperfusion injury via TGR5-mediated anti-apoptosis.

    PubMed

    Zhuang, Lin; Fan, Ye; Lu, Ling; Ding, Wenbin; Ni, Chuangye; Wang, Xuehao; Zhang, Feng; Rao, Jianhua

    2016-05-13

    Ischemic preconditioning (IP) has been shown to protect hepatic tissue from liver ischemia-reperfusion injury (IRI). TGR5, as a new-type bile acid receptor, has been shown protective roles in several liver diseases. However, the relationship between TGR5 and IP is still unknown. This study investigated effects of IP on TGR5 as well as the roles of TGR5 on hepatic tissue lesions and apoptosis in liver IRI. We showed that TGR5 was significantly upregulated in liver tissues after IP. To further analyzed effects of the TGR5 on liver IRI, wild type and TGR5 knockout mice were used to establish the liver IRI model. IP effectively alleviated liver IRI, but TGR5 deficiency significantly neutralized IP-related liver protection, as evidenced by serum alanine aminotransferase levels, histological liver damage, hepatocellular apoptosis and cytokines expressions. In addition, molecules related to apoptosis were detected by Western Blot, which showed that activation of TGR5 by IP increased expression of Bcl-2, and inhibited expressions of IRAK4 and cleaved caspase-3, but TGR5 deficiency abolished IP-induced expressions of anti-apoptosis molecule. In vitro, effects of TGR5 on hepatocytes were further analyzed by TGR5 agonist (INT-777) and hypoxia/reoxygenation (H/R), which displayed that INT-777 markedly attenuated H/R-induced hepatocellular apoptosis. In conclusion, our study indicates that IP alleviates hepatocellular apoptosis, and reduces liver IRI through TGR5-mediated anti-apoptosis functions. PMID:27045083

  1. Remote ischemic preconditioning improves post resuscitation cerebral function via overexpressing neuroglobin after cardiac arrest in rats.

    PubMed

    Fan, Ran; Yu, Tao; Lin, Jia-Li; Ren, Guang-Dong; Li, Yi; Liao, Xiao-Xing; Huang, Zi-Tong; Jiang, Chong-Hui

    2016-10-01

    In this study, we investigated the effects of remote ischemic preconditioning on post resuscitation cerebral function in a rat model of cardiac arrest and resuscitation. The animals were randomized into six groups: 1) sham operation, 2) lateral ventricle injection and sham operation, 3) cardiac arrest induced by ventricular fibrillation, 4) lateral ventricle injection and cardiac arrest, 5) remote ischemic preconditioning initiated 90min before induction of ventricular fibrillation, and 6) lateral ventricle injection and remote ischemic preconditioning before cardiac arrest. Reagent of Lateral ventricle injection is neuroglobin antisense oligodeoxynucleotides which initiated 24h before sham operation, cardiac arrest or remote ischemic preconditioning. Remote ischemic preconditioning was induced by four cycles of 5min of limb ischemia, followed by 5min of reperfusion. Ventricular fibrillation was induced by current and lasted for 6min. Defibrillation was attempted after 6min of cardiopulmonary resuscitation. The animals were then monitored for 2h and observed for an additionally maximum 70h. Post resuscitation cerebral function was evaluated by neurologic deficit score at 72h after return of spontaneous circulation. Results showed that remote ischemic preconditioning increased neurologic deficit scores. To investigate the neuroprotective effects of remote ischemic preconditioning, we observed neuronal injury at 48 and 72h after return of spontaneous circulation and found that remote ischemic preconditioning significantly decreased the occurrence of neuronal apoptosis and necrosis. To further comprehend mechanism of neuroprotection induced by remote ischemic preconditioning, we found expression of neuroglobin at 24h after return of spontaneous circulation was enhanced. Furthermore, administration of neuroglobin antisense oligodeoxynucleotides before induction of remote ischemic preconditioning showed that the level of neuroglobin was decreased then partly abrogated

  2. Investigation of Reperfusion Injury and Ischemic Preconditioning in Microsurgry

    PubMed Central

    Wang, Wei Zhong

    2008-01-01

    Ischemia/reperfusion (I/R) is inevitable in many vascular and musculoskeletal traumas, diseases, free tissue transfers, and during time-consuming reconstructive surgeries in the extremities. Salvage of a prolonged ischemic extremity or flap still remains a challenge for the microvascular surgeon. One of the common complications after microsurgery is I/R-induced tissue death or I/R injury. Twenty years after the discovery, ischemic preconditioning (IPC) has emerged as a powerful method for attenuating I/R injury in a variety of organs or tissues. However, its therapeutic expectations still need to be fulfilled. In this article, the author reviews some important experimental evidences of I/R injury as well as preconditioning-induced protection in the fields relevant to microsurgery. PMID:18946882

  3. Role of thioredoxin-1 in ischemic preconditioning, postconditioning and aged ischemic hearts.

    PubMed

    D'Annunzio, Veronica; Perez, Virginia; Boveris, Alberto; Gelpi, Ricardo J; Poderoso, Juan J

    2016-07-01

    Thioredoxin is one of the most important cellular antioxidant systems known to date, and is responsible of maintaining the reduced state of the intracellular space. Trx-1 is a small cytosolic protein whose transcription is induced by stress. Therefore it is possible that this antioxidant plays a protective role against the oxidative stress caused by an increase of reactive oxygen species concentration, as occurs during the reperfusion after an ischemic episode. However, in addition to its antioxidant properties, it is able to activate other cytoplasmic and nuclear mediators that confer cardioprotection. It is remarkable that Trx-1 also participates in myocardial protection mechanisms such as ischemic preconditioning and postconditioning, activating proteins related to cellular survival. In this sense, it has been shown that Trx-1 inhibition abolished the preconditioning cardioprotective effect, evidenced through apoptosis and infarct size. Furthermore, ischemic postconditioning preserves Trx-1 content at reperfusion, after ischemia. However, comorbidities such as aging can modify this powerful cellular defense leading to decrease cardioprotection. Even ischemic preconditioning and postconditioning protocols performed in aged animal models failed to decrease infarct size. Therefore, the lack of success of antioxidants therapies to treat ischemic heart disease could be solved, at least in part, avoiding the damage of Trx system. PMID:26987940

  4. Ischemic preconditioning attenuates functional, metabolic, and morphologic injury from ischemic acute renal failure in the rat.

    PubMed

    Cochrane, J; Williams, B T; Banerjee, A; Harken, A H; Burke, T J; Cairns, C B; Shapiro, J I

    1999-03-01

    Ischemic preconditioning has been shown to ameliorate injury due to subsequent ischemia in several organs. However, relatively little is known about preconditioning and the kidney. To address this, rats were randomized to control (C, N = 14), 2 min of ischemic preconditioning (P2 N = 10), 3 periods of 2 min of ischemia separated by 5 min periods of reflow (P2,3 N = 7), or three 5 min periods of ischemia separated by 5 min of reflow (P5,3 N = 6) prior to 45 min of bilateral renal ischemia followed by 24 hours of reperfusion. We observed a lower serum creatinine after 24 hours of reflow in P2, P2, 3 but not P5, 3 rats compared with C. Histology was examined in the C and P2, 3 groups and demonstrated less severe injury in the P2, 3 group. To gain insight into the mechanism by which preconditioning ameliorated ischemic injury, we performed near IR spectroscopy and 31P NMR spectroscopy. Based on near IR spectroscopy, the P2, 3 group had closer coupling of cytochrome aa3 redox state with that of hemoglobin during reflow. In the 31P NMR studies, the changes in ATP and pHi were similar during ischemia, but the P2, 3 group recovered ATP and pHi faster than C. These data suggest that ischemic preconditioning may ameliorate ischemic renal injury as assessed by functional, metabolic and morphological methods. The mechanism(s) by which this occurs requires additional study. PMID:10088174

  5. Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice.

    PubMed

    Eckle, Tobias; Grenz, Almut; Köhler, David; Redel, Andreas; Falk, Melanie; Rolauffs, Bernd; Osswald, Hartmut; Kehl, Franz; Eltzschig, Holger K

    2006-11-01

    Cardioprotection by ischemic preconditioning (IP) remains an area of intense investigation. To further elucidate its molecular basis, the use of transgenic mice seems critical. Due to technical difficulty associated with performing cardiac IP in mice, we developed an in situ model for cardiac IP using a hanging-weight system for coronary artery occlusion. This technique has the major advantage of eliminating the necessity of intermittently occluding the coronary artery with a knotted suture. To systematically evaluate this model, we first demonstrated correlation of ischemia times (10-60 min) with infarct sizes [3.5 +/- 1.3 to 42 +/- 5.2% area at risk (AAR), Evan's blue/triphenyltetrazolium chloride staining]. IP (4 x 5 min) and cold ischemia (27 degrees C) reduced infarct size by 69 +/- 6.7% and 84 +/- 4.2%, respectively (n = 6, P < 0.01). In contrast, lower numbers of IP cycles did not alter infarct size. However, infarct sizes were distinctively different in mice from different genetic backgrounds. In addition to infarct staining, we tested cardiac troponin I (cTnI) as marker of myocardial infarction in this model. In fact, plasma levels of cTnI were significantly lower in IP-treated mice and closely correlated with infarct sizes (R(2) = 0.8). To demonstrate transcriptional consequences of cardiac IP, we isolated total RNA from the AAR and showed repression of the equilibrative nucleoside transporters 1-4 by IP in this model. Taken together, this study demonstrates highly reproducible infarct sizes and cardiac protection by IP, thus minimizing the variability associated with knot-based coronary occlusion models. Further studies on cardiac IP using transgenic mice may consider this technique. PMID:16766632

  6. Muscle ischemic preconditioning does not improve performance during self-paced exercise.

    PubMed

    Tocco, F; Marongiu, E; Ghiani, G; Sanna, I; Palazzolo, G; Olla, S; Pusceddu, M; Sanna, P; Corona, F; Concu, A; Crisafulli, A

    2015-01-01

    Muscle ischemic preconditioning (IP) has been found to improve exercise performance in laboratory tests. This investigation aims at verifying whether performance is improved by IP during self-paced exercise (SPE) in the field. 11 well-trained male runners performed 3 randomly assigned 5 000 m self-paced running tests on an outdoor track. One was the reference (RT) test, while the others were performed following muscle IP (IPT) and a control sham test (ST). Average speeds were measured during each test. Mean values in oxygen uptake (VO2), aerobic energy cost (AEC) during race and post-race blood lactate (BLa) were gathered. Data showed that none of the studied variables were affected by IPT or ST with respect to the RT test. Average speeds were 4.63±0.31, 4.62±0.31 and 4.60±0.25 m·s(-1) for the RT, the ST and the IPT tests, respectively. Moreover, there was no difference among tests in speed reached during each lap. VO2 was 3.5±0.69, 3.74±0.85 and 3.62±1.19 l·min(-1). AEC was 1.04±0.15, 1.08±0.1 and 1.09±0.15 kcal·kg(-1)·km(-1). Finally, post-race BLa levels reached 12.85±3.54, 11.88±4.74 and 12.82±3.6 mmol·l(-1). These findings indicate that performance during SPE is not ameliorated by ischemic preconditioning, thereby indicating that IP is not suitable as an ergogenic aid. PMID:25264861

  7. Ischemic preconditioning enhances integrity of coronary endothelial tight junctions

    SciTech Connect

    Li, Zhao; Jin, Zhu-Qiu

    2012-08-31

    Highlights: Black-Right-Pointing-Pointer Cardiac tight junctions are present between coronary endothelial cells. Black-Right-Pointing-Pointer Ischemic preconditioning preserves the structural and functional integrity of tight junctions. Black-Right-Pointing-Pointer Myocardial edema is prevented in hearts subjected to ischemic preconditioning. Black-Right-Pointing-Pointer Ischemic preconditioning enhances translocation of ZO-2 from cytosol to cytoskeleton. -- Abstract: Ischemic preconditioning (IPC) is one of the most effective procedures known to protect hearts against ischemia/reperfusion (IR) injury. Tight junction (TJ) barriers occur between coronary endothelial cells. TJs provide barrier function to maintain the homeostasis of the inner environment of tissues. However, the effect of IPC on the structure and function of cardiac TJs remains unknown. We tested the hypothesis that myocardial IR injury ruptures the structure of TJs and impairs endothelial permeability whereas IPC preserves the structural and functional integrity of TJs in the blood-heart barrier. Langendorff hearts from C57BL/6J mice were prepared and perfused with Krebs-Henseleit buffer. Cardiac function, creatine kinase release, and myocardial edema were measured. Cardiac TJ function was evaluated by measuring Evans blue-conjugated albumin (EBA) content in the extravascular compartment of hearts. Expression and translocation of zonula occludens (ZO)-2 in IR and IPC hearts were detected with Western blot. A subset of hearts was processed for the observation of ultra-structure of cardiac TJs with transmission electron microscopy. There were clear TJs between coronary endothelial cells of mouse hearts. IR caused the collapse of TJs whereas IPC sustained the structure of TJs. IR increased extravascular EBA content in the heart and myocardial edema but decreased the expression of ZO-2 in the cytoskeleton. IPC maintained the structure of TJs. Cardiac EBA content and edema were reduced in IPC hearts. IPC

  8. Ischemic Preconditioning and Placebo Intervention Improves Resistance Exercise Performance.

    PubMed

    Marocolo, Moacir; Willardson, Jeffrey M; Marocolo, Isabela C; Ribeiro da Mota, Gustavo; Simão, Roberto; Maior, Alex S

    2016-05-01

    Marocolo, M, Willardson, JM, Marocolo, IC, da Mota, GR, Simão, R, and Maior, AS. Ischemic preconditioning and PLACEBO intervention improves resistance exercise performance. J Strength Cond Res 30(5): 1462-1469, 2016-This study evaluated the effect of ischemic preconditioning (IPC) on resistance exercise performance in the lower limbs. Thirteen men participated in a randomized crossover design that involved 3 separate sessions (IPC, PLACEBO, and control). A 12-repetition maximum (12RM) load for the leg extension exercise was assessed through test and retest sessions before the first experimental session. The IPC session consisted of 4 cycles of 5 minutes of occlusion at 220 mm Hg of pressure alternated with 5 minutes of reperfusion at 0 mm Hg for a total of 40 minutes. The PLACEBO session consisted of 4 cycles of 5 minutes of cuff administration at 20 mm Hg of pressure alternated with 5 minutes of pseudo-reperfusion at 0 mm Hg for a total of 40 minutes. The occlusion and reperfusion phases were conducted alternately between the thighs, with subjects remaining seated. No ischemic pressure was applied during the control (CON) session and subjects sat passively for 40 minutes. Eight minutes after IPC, PLACEBO, or CON, subjects performed 3 repetition maximum sets of the leg extension (2-minute rest between sets) with the predetermined 12RM load. Four minutes after the third set for each condition, blood lactate was assessed. The results showed that for the first set, the number of repetitions significantly increased for both the IPC (13.08 ± 2.11; p = 0.0036) and PLACEBO (13.15 ± 0.88; p = 0.0016) conditions, but not for the CON (11.88 ± 1.07; p > 0.99) condition. In addition, the IPC and PLACEBO conditions resulted insignificantly greater repetitions vs. the CON condition on the first set (p = 0.015; p = 0.007) and second set (p = 0.011; p = 0.019), but not on the third set (p = 0.68; p > 0.99). No difference (p = 0.465) was found in the fatigue index and lactate

  9. Ameliorative Effect of Recombinant Human Erythropoietin and Ischemic Preconditioning on Renal Ischemia Reperfusion Injury in Rats

    PubMed Central

    Elshiekh, Mohammed; Kadkhodaee, Mehri; Seifi, Behjat; Ranjbaran, Mina; Ahghari, Parisa

    2015-01-01

    Background: Ischemia-reperfusion (IR) injury is one of the most common causes of renal dysfunction. There is increasing evidence about the role of the reactive oxygen species (ROS) in these injuries and endogenous antioxidants seem to have an important role in decreasing the renal tissue injury. Objectives: The aim of this study was to compare the effect of recombinant human erythropoietin (EPO) and ischemic preconditioning (IPC) on renal IR injury. Materials and Methods: Twenty four male Wistar rats were allocated into four experimental groups: sham-operated, IR, EPO + IR, and IPC + IR. Rats were underwent 50 minutes bilateral ischemia followed by 24 hours reperfusion. Erythropoietin (5000 IU/kg, i.p) was administered 30 minutes before onset of ischemia. Ischemic preconditioning was performed by three cycles of 3 minutes ischemia followed by 3 minutes reperfusion. Plasma concentrations of urea and creatinine were measured. Kidney samples were taken for reactive oxidative species (ROS) measurement including superoxide dismutase (SOD) activity, glutathione (GSH) contents, and malondialdehyde (MDA) levels. Results: Compared to the sham group, IR led to renal dysfunction as evidenced by significantly higher plasma urea and creatinine. Treatment with EPO or IPC decreased urea, creatinine, and renal MDA levels and increased SOD activity and GSH contents in the kidney. Conclusions: Pretreatment with EPO and application of IPC significantly ameliorated the renal injury induced by bilateral renal IR. However, both treatments attenuated renal dysfunction and oxidative stress in kidney tissues. There were no significant differences between pretreatment with EPO or application of IPC. PMID:26866008

  10. Protective effects of remote ischemic preconditioning in isolated rat hearts

    PubMed Central

    Teng, Xiao; Yuan, Xin; Tang, Yue; Shi, Jingqian

    2015-01-01

    To use Langendorff model to investigate whether remote ischemic preconditioning (RIPC) attenuates post-ischemic mechanical dysfunction on isolated rat heart and to explore possible mechanisms. SD rats were randomly divided into RIPC group, RIPC + norepinephrine (NE) depletion group, RIPC + pertussis toxin (PTX) pretreatment group, ischemia/reperfusion group without treatment (ischemia group) and time control (TC) group. RIPC was achieved through interrupted occlusion of anterior mesenteric artery. Then, Langendorff model was established using routine methods. Heart function was tested; immunohistochemistry and ELISA methods were used to detect various indices related to myocardial injury. Compared with ischemia group in which the hemodynamic parameters deteriorated significantly, heart function recovered to a certain degree among the RIPC, RIPC + NE depletion, and RIPC + PTX groups (P<0.05). More apoptotic nuclei were observed in ischemia group than in the other three groups (P<0.05); more apoptotic nuclei were detected in NE depletion and PTX groups than in RIPC group (P<0.05). While, there was no significant difference between NE depletion and PTX groups. In conclusion, RIPC protection on I/R myocardium extends to the period after hearts are isolated. NE and PTX-sensitive inhibitory G protein might have a role in the protection process. PMID:26550168

  11. Remote Limb Ischemic Preconditioning: A Neuroprotective Technique in Rodents.

    PubMed

    Brandli, Alice

    2015-01-01

    Sublethal ischemia protects tissues against subsequent, more severe ischemia through the upregulation of endogenous mechanisms in the affected tissue. Sublethal ischemia has also been shown to upregulate protective mechanisms in remote tissues. A brief period of ischemia (5-10 min) in the hind limb of mammals induces self-protective responses in the brain, lung, heart and retina. The effect is known as remote ischemic preconditioning (RIP). It is a therapeutically promising way of protecting vital organs, and is already under clinical trials for heart and brain injuries. This publication demonstrates a controlled, minimally invasive method of making a limb - specifically the hind limb of a rat - ischemic. A blood pressure cuff developed for use in human neonates is connected to a manual sphygmomanometer and used to apply 160 mmHg pressure around the upper part of the hind limb. A probe designed to detect skin temperature is used to verify the ischemia, by recording the drop in skin temperature caused by pressure-induced occlusion of the leg arteries, and the rise in temperature which follows release of the cuff. This method of RIP affords protection to the rat retina against bright light-induced damage and degeneration. PMID:26065365

  12. Concepts of hypoxic NO signaling in remote ischemic preconditioning

    PubMed Central

    Totzeck, Matthias; Hendgen-Cotta, Ulrike; Rassaf, Tienush

    2015-01-01

    Acute coronary syndromes remain a leading single cause of death worldwide. Therapeutic strategies to treat cardiomyocyte threatening ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning (rIPC) applied by brief ischemic episodes to heart-distant organs has been tested in several clinical studies, and the major body of evidence points to beneficial effects of rIPC for patients. The underlying signaling, however, remains incompletely understood. This relates particularly to the mechanism by which the protective signal is transferred from the remote site to the target organ. Many pathways have been forwarded but none can explain the protective effects completely. In light of recent experimental studies, we here outline the current knowledge relating to the generation of the protective signal in the remote organ, the signal transfer to the target organ and the transduction of the transferred signal into cardioprotection. The majority of studies favors a humoral factor that activates cardiomyocyte downstream signaling - receptor-dependent and independently. Cellular targets include deleterious calcium (Ca2+) signaling, reactive oxygen species, mitochondrial function and structure, and cellular apoptosis and necrosis. Following an outline of the existing evidence, we will furthermore characterize the existing knowledge and discuss future perspectives with particular emphasis on the interaction between the recently discovered hypoxic nitrite-nitric oxide signaling in rIPC. This refers to the protective role of nitrite, which can be activated endogenously using rIPC and which then contributes to cardioprotection by rIPC. PMID:26516418

  13. Remote Ischemic Preconditioning (RIPC) Modifies Plasma Proteome in Humans

    PubMed Central

    Hepponstall, Michele; Ignjatovic, Vera; Binos, Steve; Monagle, Paul; Jones, Bryn; Cheung, Michael H. H.; d’Udekem, Yves; Konstantinov, Igor E.

    2012-01-01

    Remote Ischemic Preconditioning (RIPC) induced by brief episodes of ischemia of the limb protects against multi-organ damage by ischemia-reperfusion (IR). Although it has been demonstrated that RIPC affects gene expression, the proteomic response to RIPC has not been determined. This study aimed to examine RIPC induced changes in the plasma proteome. Five healthy adult volunteers had 4 cycles of 5 min ischemia alternating with 5 min reperfusion of the forearm. Blood samples were taken from the ipsilateral arm prior to first ischaemia, immediately after each episode of ischemia as well as, at 15 min and 24 h after the last episode of ischemia. Plasma samples from five individuals were analysed using two complementary techniques. Individual samples were analysed using 2Dimensional Difference in gel electrophoresis (2D DIGE) and mass spectrometry (MS). Pooled samples for each of the time-points underwent trypsin digestion and peptides generated were analysed in triplicate using Liquid Chromatography and MS (LC-MS). Six proteins changed in response to RIPC using 2D DIGE analysis, while 48 proteins were found to be differentially regulated using LC-MS. The proteins of interest were involved in acute phase response signalling, and physiological molecular and cellular functions. The RIPC stimulus modifies the plasma protein content in blood taken from the ischemic arm in a cumulative fashion and evokes a proteomic response in peripheral blood. PMID:23139772

  14. Effects of ischemic preconditioning on short-duration cycling performance.

    PubMed

    Cruz, Rogério Santos de Oliveira; de Aguiar, Rafael Alves; Turnes, Tiago; Salvador, Amadeo Félix; Caputo, Fabrizio

    2016-08-01

    It has been demonstrated that ischemic preconditioning (IPC) improves endurance performance. However, the potential benefits during anaerobic events and the mechanism(s) underlying these benefits remain unclear. Fifteen recreational cyclists were assessed to evaluate the effects of IPC of the upper thighs on anaerobic performance, skeletal muscle activation, and metabolic responses during a 60-s sprint performance. After an incremental test and a familiarization visit, subjects were randomly submitted in visits 3 and 4 to a performance protocol preceded by intermittent bilateral cuff inflation (4 × (5 min of blood flow restriction + 5 min reperfusion)) at either 220 mm Hg (IPC) or 20 mm Hg (control). To increase data reliability, each intervention was replicated, which was also in a random manner. In addition to the mean power output, the pulmonary oxygen uptake, blood lactate kinetics, and quadriceps electromyograms (EMGs) were analyzed during performance and throughout 45 min of passive recovery. After IPC, performance was improved by 2.1% compared with control (95% confidence intervals of 0.8% to 3.3%, P = 0.001), followed by increases in (i) the accumulated oxygen deficit, (ii) the amplitude of blood lactate kinetics, (iii) the total amount of oxygen consumed during recovery, and (iv) the overall EMG amplitude (P < 0.05). In addition, the ratio between EMG and power output was higher during the final third of performance after IPC (P < 0.05). These results suggest an increased skeletal muscle activation and a higher anaerobic contribution as the ultimate responses of IPC on short-term exercise performance. PMID:27404398

  15. The P2X4 receptor is required for neuroprotection via ischemic preconditioning

    PubMed Central

    Ozaki, Tomohiko; Muramatsu, Rieko; Sasai, Miwa; Yamamoto, Masahiro; Kubota, Yoshiaki; Fujinaka, Toshiyuki; Yoshimine, Toshiki; Yamashita, Toshihide

    2016-01-01

    Ischemic preconditioning (IPC), a procedure consisting of transient ischemia and subsequent reperfusion, provides ischemic tolerance against prolonged ischemia in the brain. Although the blood flow changes mediated by IPC are primarily perceived by vascular endothelial cells, the role of these cells in ischemic tolerance has not been fully clarified. In this study, we found that the P2X4 receptor, which is abundantly expressed in vascular endothelial cells, is required for ischemic tolerance following middle artery occlusion (MCAO) in mice. Mechanistically, the P2X4 receptor was stimulated by fluid shear stress, which mimics reperfusion, thus promoting the increased expression of osteopontin, a neuroprotective molecule. Furthermore, we found that the intracerebroventricular administration of osteopontin was sufficient to exert a neuroprotective effect mediated by preconditioning-stimulated P2X4 receptor activation. These results demonstrate a novel mechanism whereby vascular endothelial cells are involved in ischemic tolerance. PMID:27173846

  16. Remote ischemic preconditioning as treatment for non-ischemic gastrointestinal disorders: beyond ischemia-reperfusion injury.

    PubMed

    Camara-Lemarroy, Carlos Rodrigo

    2014-04-01

    Common gastrointestinal diseases such as radiation enteritis (RE), acute pancreatitis, inflammatory bowel diseases (IBD) and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level, mostly involving the activation of many pathways of the immune response, ultimately leading to tissue injury. Increased oxidative stress, inflammatory cytokine release, inflammatory cell infiltration and activation and the up-regulation of inflammatory transcription factors participate in the pathophysiology of these complex entities. Treatment varies in each specific disease, but at least in the cases of RE and IBD immunosuppressors are effective. However, full therapeutic responses are not always achieved. The pathophysiology of ischemia-reperfusion (IR) injury shares many of these mechanisms. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIP). This procedure has been shown to protect the gut, pancreas and liver by modulating many of the same inflammatory mechanisms. Since RIP is safe and tolerable, and has shown to be effective in some recent clinical trials, I suggest that RIP could be used as a physiologically relevant adjunct treatment for non-ischemic gastrointestinal inflammatory conditions. PMID:24707140

  17. Does nitric oxide generation contribute to the mechanism of remote ischemic preconditioning?

    PubMed

    Petrishchev, N N.; Vlasov, T D.; Sipovsky, V G.; Kurapeev, D I.; Galagudza, M M.

    2001-03-01

    The protective effect of local or remote ischemic preconditioning (IPC) on subsequent 40-min ischemic and 120-min reperfusion myocardial damage was investigated. Preconditioned rats underwent one cycle of myocardial ischemia/reperfusion consisting of 5-min ischemia produced as a left coronary artery (LCA) occlusion and 5 min of reperfusion. Remote IPC was produced as 15 min of small intestinal ischemia with 15 min of reperfusion as well as 30 min of limb ischemia with 15 min of reperfusion. A marked protective action was afforded by both IPC protocols with a more significant effect of local (classic) ischemic preconditioning. Since the protective effect of remote IPC was not abolished by nitric oxide (NO) synthase inhibition with Nomega-nitro-L-arginine (L-NNA) it is concluded that NO generation may not be involved in the mechanism of remote IPC. PMID:11228397

  18. Ischemic preconditioning affects long-term cell fate through DNA damage-related molecular signaling and altered proliferation.

    PubMed

    Kapoor, Sorabh; Berishvili, Ekaterine; Bandi, Sriram; Gupta, Sanjeev

    2014-10-01

    Despite the potential of ischemic preconditioning for organ protection, long-term effects in terms of molecular processes and cell fates are ill defined. We determined consequences of hepatic ischemic preconditioning in rats, including cell transplantation assays. Ischemic preconditioning induced persistent alterations; for example, after 5 days liver histology was normal, but γ-glutamyl transpeptidase expression was observed, with altered antioxidant enzyme content, lipid peroxidation, and oxidative DNA adducts. Nonetheless, ischemic preconditioning partially protected from toxic liver injury. Similarly, primary hepatocytes from donor livers preconditioned with ischemia exhibited undesirably altered antioxidant enzyme content and lipid peroxidation, but better withstood insults. However, donor hepatocytes from livers preconditioned with ischemia did not engraft better than hepatocytes from control livers. Moreover, proliferation of hepatocytes from donor livers preconditioned with ischemia decreased under liver repopulation conditions. Hepatocytes from donor livers preconditioned with ischemia showed oxidative DNA damage with expression of genes involved in MAPK signaling that impose G1/S and G2/M checkpoint restrictions, including p38 MAPK-regulated or ERK-1/2-regulated cell-cycle genes such as FOS, MAPK8, MYC, various cyclins, CDKN2A, CDKN2B, TP53, and RB1. Thus, although ischemic preconditioning allowed hepatocytes to better withstand secondary insults, accompanying DNA damage and molecular events simultaneously impaired their proliferation capacity over the long term. Mitigation of ischemic preconditioning-induced DNA damage and deleterious molecular perturbations holds promise for advancing clinical applications. PMID:25128377

  19. Remote Ischemic Preconditioning Reduces Cerebral Oxidative Stress Following Hypothermic Circulatory Arrest in a Porcine Model.

    PubMed

    Arvola, Oiva; Haapanen, Henri; Herajärvi, Johanna; Anttila, Tuomas; Puistola, Ulla; Karihtala, Peeter; Tuominen, Hannu; Anttila, Vesa; Juvonen, Tatu

    2016-01-01

    Remote ischemic precondition has become prominent as one of the most promising methods to mitigate neurological damage following ischemic insult. The purpose of this study was to investigate whether the effects of remote ischemic preconditioning can be seen in the markers of oxidative stress or in redox-regulating enzymes in a porcine model. A total of 12 female piglets were randomly assigned to 2 groups. The study group underwent an intervention of 4 cycles of 5-minute ischemic preconditioning on the right hind leg. All piglets underwent 60-minute hypothermic circulatory arrest. Oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG) was measured from blood samples with enzyme-linked immunosorbent assay. After 7 days of follow-up, samples from the brain, heart, kidney, and ovary were harvested for histopathologic examination. The immunohistochemical stainings of hypoxia marker hypoxia-inducible factor-1-α, oxidative stress marker 8-OHdG, DNA repair enzyme 8-oxoguanine glycosylase, and antioxidant response regulators nuclear factor erythroid 2-related factor 2 and protein deglycase were analyzed. The level of 8-OHdG referred to baseline was decreased in the sagittal sinus׳ blood samples in the study group after a prolonged deep hypothermic circulatory arrest at 360 minutes after reperfusion. Total histopathologic score was 3.8 (1.8-6.0) in the study group and was 4.4 (2.5-6.5) in the control group (P = 0.72), demonstrating no statistically significant difference in cerebral injury. Our findings demonstrate that the positive effects of remote ischemic preconditioning can be seen in cellular oxidative balance regulators in an animal model after 7 days of preconditioned ischemic insult. PMID:27568144

  20. Effects of ischemic preconditioning in a pig model of large-for-size liver transplantation

    PubMed Central

    Leal, Antonio José Gonçalves; Tannuri, Ana Cristina Aoun; Belon, Alessandro Rodrigo; Guimarães, Raimundo Renato Nunes; Coelho, Maria Cecília Mendonça; de Oliveira Gonçalves, Josiane; Serafini, Suellen; de Melo, Evandro Sobroza; Tannuri, Uenis

    2015-01-01

    OBJECTIVE: In most cases of pediatric liver transplantation, the clinical scenario of large-for-size transplants can lead to hepatic dysfunction and a decreased blood supply to the liver graft. The objective of the present experimental investigation was to evaluate the effects of ischemic preconditioning on this clinical entity. METHODS: Eighteen pigs were divided into three groups and underwent liver transplantation: a control group, in which the weights of the donors were similar to those of the recipients, a large-for-size group, and a large-for-size + ischemic preconditioning group. Blood samples were collected from the recipients to evaluate the pH and the sodium, potassium, aspartate aminotransferase and alanine aminotransferase levels. In addition, hepatic tissue was sampled from the recipients for histological evaluation, immunohistochemical analyses to detect hepatocyte apoptosis and proliferation and molecular analyses to evaluate the gene expression of Bax (pro-apoptotic), Bcl-XL (anti-apoptotic), c-Fos and c-Jun (immediate-early genes), ischemia-reperfusion-related inflammatory cytokines (IL-1, TNF-alpha and IL-6, which is also a stimulator of hepatocyte regeneration), intracellular adhesion molecule, endothelial nitric oxide synthase (a mediator of the protective effect of ischemic preconditioning) and TGF-beta (a pro-fibrogenic cytokine). RESULTS: All animals developed acidosis. At 1 hour and 3 hours after reperfusion, the animals in the large-for-size and large-for-size + ischemic preconditioning groups had decreased serum levels of Na and increased serum levels of K and aspartate aminotransferase compared with the control group. The molecular analysis revealed higher expression of the Bax, TNF-alpha, I-CAM and TGF-beta genes in the large-for-size group compared with the control and large-for-size + ischemic preconditioning groups. Ischemic preconditioning was responsible for an increase in c-Fos, IL-1, IL-6 and e-NOS gene expression. CONCLUSION

  1. Ischemic preconditioning and inflammatory response syndrome after reperfusion injury: an experimental model in diabetic rats.

    PubMed

    Grigorescu, Bianca Liana; Georgescu, Anca Meda; Cioc, Adrian-Dan; Fodor, Raluca-Ştefania; Cotoi, Ovidiu Simion; Fodor, Pal; Copotoiu, Sanda Maria; Azamfirei, Leonard

    2015-01-01

    Quantification of local ischemia and inflammatory response syndrome correlated with histological changes associated with ischemia-reperfusion injury (IRI) after revascularization techniques. We included 12 adult male Wistar rats, aged eight weeks that were randomly divided into two groups. The first group acted as the control and at the second group, we induced diabetes by intraperitoneal streptozotocin administration (60 mg/kg). After eight weeks, the rats were subject to ischemic preconditioning for 10 minutes at three regular intervals. Twenty-four hours post-preconditioning, both groups were subject to ischemia for 20 minutes, followed by 30 minutes of reperfusion. Oxygen extraction was higher in Group 1, the arterio-venous CO2 gradient was higher in the control group, but not significant. The lactate production was higher in Group 1. The second group had a higher Na+ and also a significant difference in K+ values. Receptor for Advanced Glycation End (RAGE) values were higher in the second group but with no significant difference (RAGE1=0.32 ng/mL versus RAGE2=0.40 ng/mL). The muscle samples from the control group displayed significant rhabdomyolysis, damage to the nucleus, while the preconditioned group showed almost normal morphological characteristics. The lungs and kidneys were most damaged in the control group, with damage expressed as thickened alveolar septa, neutrophil infiltrates, eosinophilic precipitates in the proximal convolute tubule. Ischemic preconditioning significantly attenuates the ischemic reperfusion injury. PMID:26743274

  2. Remote ischemic preconditioning for kidney protection: GSK3β-centric insights into the mechanism of action.

    PubMed

    Liu, Zhangsuo; Gong, Rujun

    2015-11-01

    Preventing acute kidney injury (AKI) in high-risk patients following medical interventions is a paramount challenge for clinical practice. Recent data from animal experiments and clinical trials indicate that remote ischemic preconditioning, represented by limb ischemic preconditioning, confers a protective action on the kidney. Ischemic preconditioning is effective in reducing the risk for AKI following cardiovascular interventions and the use of iodinated radiocontrast media. Nevertheless, the underlying mechanisms for this protective effect are elusive. A protective signal is conveyed from the remote site undergoing ischemic preconditioning, such as the limb, to target organs, such as the kidney, by multiple potential communication pathways, which may involve humoral, neuronal, and systemic mechanisms. Diverse transmitting pathways trigger a variety of signaling cascades, including the reperfusion injury salvage kinase and survivor activating factor enhancement pathways, all of which converge on glycogen synthase kinase 3β (GSK3β). Inhibition of GSK3β subsequent to ischemic preconditioning reinforces the Nrf2-mediated antioxidant defense, diminishes the nuclear factor-κB-dependent proinflammatory response, and exerts prosurvival effects ensuing from the desensitized mitochondria permeability transition. Thus, therapeutic targeting of GSK3β by ischemic preconditioning or by pharmacologic preconditioning with existing US Food and Drug Administration-approved drugs having GSK3β-inhibitory activities might represent a pragmatic and cost-effective adjuvant strategy for kidney protection and prophylaxis against AKI. PMID:26271146

  3. Effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart.

    PubMed

    Kansal, Sunil Kumar; Jyoti, Uma; Sharma, Samridhi; Kaura, Arun; Deshmukh, Rahul; Goyal, Sandeep

    2015-06-01

    Hyperlipidemia is regarded as independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia-/reperfusion (I/R)-induced injury. Hyperlipidemia attenuates the cardioprotective response of ischemic preconditioning (IPC). The present study investigated the effect of zinc supplements in the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat hearts. Hyperlipidemia was induced in rat by feeding high-fat diet (HFD) for 6 weeks then the serum lipid profile was observed. In experiment, the isolated Langendorff rat heart preparation was subjected to 4 cycles of ischemic preconditioning (IPC), then 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was elaborated morphologically by triphenyltetrazolium chloride (TTC) staining and biochemically by lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) release from coronary effluent and left ventricular collagen content. However, the effect of zinc supplement, i.e., zinc pyrithione (10 μM) perfused during reperfusion for 120 min, significantly abrogated the attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart whereas administration of chelator of this zinc ionophore, i.e., N,N,N',N'-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN; 10 μM), perfused during reperfusion 2 min before the perfusion of zinc pyrithione abrogated the cardioprotective effect of zinc supplement during experiment in hyperlipidemic rat heart. Thus, the administration of zinc supplements limits the infarct size, LDH, and CK-MB and enhanced the collagen level which suggests that the attenuated cardioprotective effect of IPC in hyperlipidemic rat is due to zinc loss during reperfusion caused by ischemia/reperfusion. PMID:25743572

  4. Advance in spinal cord ischemia reperfusion injury: Blood-spinal cord barrier and remote ischemic preconditioning.

    PubMed

    Yu, Qijing; Huang, Jinxiu; Hu, Ji; Zhu, Hongfei

    2016-06-01

    The blood-spinal cord barrier (BSCB) is the physiological and metabolic substance diffusion barrier between blood circulation and spinal cord tissues. This barrier plays a vital role in maintaining the microenvironment stability of the spinal cord. When the spinal cord is subjected to ischemia/reperfusion (I/R) injury, the structure and function of the BSCB is disrupted, further destroying the spinal cord homeostasis and ultimately leading to neurological deficit. Remote ischemic preconditioning (RIPC) is an approach in which interspersed cycles of preconditioning ischemia is followed by reperfusion to tissues/organs to protect the distant target tissues/organs against subsequent lethal ischemic injuries. RIPC is an innovation of the treatment strategies that protect the organ from I/R injury. In this study, we review the morphological structure and function of the BSCB, the injury mechanism of BSCB resulting from spinal cord I/R, and the effect of RIPC on it. PMID:27060223

  5. Progressive Evaluation of Apoptosis, Proliferation, and Angiogenesis in Fresh Rat Ovarian Autografts Under Remote Ischemic Preconditioning.

    PubMed

    Damous, Luciana Lamarão; Silva, Sônia Maria da; Carbonel, Adriana Aparecida Ferraz; Simões, Manuel de Jesus; Baracat, Edmund Chada; Montero, Edna Frasson de Souza

    2016-06-01

    This study evaluated the remote ischemic preconditioning (R-IPC) early and late repercussion on fresh ovarian transplants, aiming to assess a probable protective effect in ovarian follicular pool. Sixty Wistar EPM-1 rats were used, divided in 2 study groups: ovarian transplantation (Tx) and Tx + R-IPC, submitted to ovary transplant with or without R-IPC, respectively. These groups were subdivided according to the date for euthanasia: 4th, 7th, 14th, 21st, and 30th days of the postoperatory period. Morphology, morphometry, neoangiogenesis (vascular endothelial growth factor [VEGF]), proliferative activity (Ki-67), and apoptosis (cleaved caspase-3) were evaluated. Remote ischemic preconditioning was performed in the common iliac artery. Fresh autologous ovarian tissue was implanted integrally in the retroperitoneum. All animals showed resumption of estrous phase after ovary transplantation. Remote ischemic preconditioning attenuated the lesions progressively from the 7th day, with greater number of the immature follicles (14 days, P < .05), but didn't affect mature follicles and corpora lutea (P > .05). Immunohistochemical analyzes, taken as a whole, show that R-IPC benefic effect is more evident in the later periods of evaluation, when a greater proliferative activity (14, 21, and 30 days, P < .05) and lesser cell apoptotic activity (21 and 30 days, P < .05). The VEGF expression was similar in all times (P > .05). Remote ischemic preconditioning could have a benefic effect in the progressive evaluation of freshly grafted ovarian, especially on the latest phases of the posttransplant period. The 14th day was a landmark in the recuperation of the graft. Further investigations are necessary to determine the role of R-IPC in this scenario and its effect in frozen-thawed ovarian tissue. PMID:26674322

  6. Remote ischemic preconditioning for prevention of high-altitude diseases: fact or fiction?

    PubMed

    Berger, Marc Moritz; Macholz, Franziska; Mairbäurl, Heimo; Bärtsch, Peter

    2015-11-15

    Preconditioning refers to exposure to brief episodes of potentially adverse stimuli and protects against injury during subsequent exposures. This was first described in the heart, where episodes of ischemia/reperfusion render the myocardium resistant to subsequent ischemic injury, which is likely caused by reactive oxygen species (ROS) and proinflammatory processes. Protection of the heart was also found when preconditioning was performed in an organ different from the target, which is called remote ischemic preconditioning (RIPC). The mechanisms causing protection seem to include stimulation of nitric oxide (NO) synthase, increase in antioxidant enzymes, and downregulation of proinflammatory cytokines. These pathways are also thought to play a role in high-altitude diseases: high-altitude pulmonary edema (HAPE) is associated with decreased bioavailability of NO and increased generation of ROS, whereas mechanisms causing acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) seem to involve cytotoxic effects by ROS and inflammation. Based on these apparent similarities between ischemic damage and AMS, HACE, and HAPE, it is reasonable to assume that RIPC might be protective and improve altitude tolerance. In studies addressing high-altitude/hypoxia tolerance, RIPC has been shown to decrease pulmonary arterial systolic pressure in normobaric hypoxia (13% O2) and at high altitude (4,342 m). Our own results indicate that RIPC transiently decreases the severity of AMS at 12% O2. Thus preliminary studies show some benefit, but clearly, further experiments to establish the efficacy and potential mechanism of RIPC are needed. PMID:26089545

  7. Perfusion delay causes unintentional ischemic preconditioning in isolated heart preparation.

    PubMed

    Minhaz, U; Koide, S; Shohtsu, A; Fujishima, M; Nakazawa, H

    1995-01-01

    This study sought to show that unintentional preconditioning can be induced in the isolated perfused heart during the preparation procedure. The following four groups were compared: hearts were placed in ice cold saline and cooled for 15 s and then mounted to the Langendorff apparatus (n = 5; cool immediate group); hearts were cooled for 60 s and mounted (n = 5; cool delay group); hearts were mounted directly to the apparatus within 15 s after the isolation without cooling (n = 5; noncool immediate group); hearts were mounted without cooling, but the mounting was delayed for 60 s after the isolation (n = 5; noncool delay group). All hearts were paced at a fixed rate of 300 bpm, and an occlusion of left coronary (LCA) for 60 min was performed, which was followed by reperfusion for another 60 min. Coronary flow (CBF), left ventricular developed pressure (LVDP), and creatine phosphokinase (CPK) release did not change among the four groups during ischemia. At the end of reperfusion the LVDP values were 70 +/- 1%, 66 +/- 2%, 62 +/- 3%, and 73 +/- 2% of preischemic values in cool immediate, cool delay, noncool immediate, and noncool delay groups, respectively. CPK values were 116 +/- 4, 121 +/- 7, 138 +/- 6, and 29 +/- 1 x 10(3) U/g myocardium, and percentage necrosis/risk areas were 24 +/- 1.0%, 21 +/- 1.7%, 38 +/- 2.6%, and 13 +/- 0.5% in cool immediate, cool delay, noncool immediate, and noncool delay groups, respectively. The noncool delay group demonstrated high LVDP, least amount of CPK release, and smallest size of necrosis. These results indicate that an unintentional preconditioning effect can be induced when the cooling procedure is not applied and perfusion is delayed. PMID:8585864

  8. [Phytoadaptogens-induced phenomenon similar to ischemic preconditioning].

    PubMed

    Arbuzov, A G; Maslov, L N; Burkova, V N; Krylatov, A V; Konkovskaia, Iu N; Safronov, S M

    2009-04-01

    The course administration (16 mg/kg per os for 5 days) of extracts of Panax ginseng or Rhodiola rosea induced a decrease in the infarction size/the area at risk (IS AAR) ratio during a 45-min local ischemia and a 2-hr reperfusion in artificially ventilated chloralose-anaesthetized rats. Single administration of ginseng or Rhodiola 24 h before ischemia did not affect the IS/AAR ratio. Chronic administration of Extracts of Eleutherococcus senticosus, Leuzea carthamoides and Aralia mandshurica had no effect on the IS/AAR ratio. Pretreatment with extract ofAralia mandshurica prevented appearance of ventricular arrhythmias during first 10 min coronary artery occlusion. Pretreatment with extract of Rhodiola rosea decreased the incidence of ventricular fibrillation during ischemia. Single administration of extracts of Panax ginseng or Rhodiola rosea in a dose of 16 mg/kg had no effect on the IS/AAR ratio. The authors conclude that extracts of ginseng or Rhodiola exhibit a powerful cardioprotective effect. Extract of Aralia exhibit a strong antiarrhythmic effect. Extracts of ginseng and Rhodiola do not mimic phenomena of ischemia preconditioning. PMID:19505042

  9. Resveratrol preconditioning protects against cerebral ischemic injury via Nrf2

    PubMed Central

    Narayanan, Srinivasan V.; Dave, Kunjan R.; Saul, Isa; Perez-Pinzon, Miguel A.

    2015-01-01

    Background and Purpose Nuclear erythroid 2 related factor 2 (Nrf2) is an astrocyte-enriched transcription factor that has previously been shown to upregulate cellular antioxidant systems in response to ischemia. While resveratrol preconditioning (RPC) has emerged as a potential neuroprotective therapy, the involvement of Nrf2 in RPC-induced neuroprotection and mitochondrial reactive oxygen species (ROS) production following cerebral ischemia remains unclear. The goal of our study was to study the contribution of Nrf2 to RPC and its effects on mitochondrial function. Methods We used rodent astrocyte cultures and an in vivo stroke model with RPC. An Nrf2 DNA-binding ELISA and protein analysis via Western blotting of downstream Nrf2 targets were performed to determine RPC-induced activation of Nrf2 in rat and mouse astrocytes. Following RPC, mitochondrial function was determined by measuring ROS production and mitochondrial respiration in both wild-type (WT) and Nrf2−/− mice. Infarct volume was measured to determine neuroprotection, while protein levels were measured by immunoblotting. Results We report that Nrf2 is activated by RPC in rodent astrocyte cultures, and that loss of Nrf2 reduced RPC-mediated neuroprotection in a mouse model of focal cerebral ischemia. In addition, we observed that wild-type and Nrf2−/− cortical mitochondria exhibited increased uncoupling and ROS production following RPC treatments, Finally, Nrf2−/− astrocytes exhibited decreased mitochondrial antioxidant expression and were unable to upregulate cellular antioxidants following RPC treatment. Conclusion Nrf2 contributes to RPC-induced neuroprotection through maintaining mitochondrial coupling and antioxidant protein expression. PMID:25908459

  10. DNA Content in Extracellular Vesicles Isolated from Porcine Coronary Venous Blood Directly after Myocardial Ischemic Preconditioning

    PubMed Central

    Rodsand, Pouria; Hellman, Urban; Waldenström, Anders; Lundholm, Marie; Ahrén, Dag; Biber, Björn; Ronquist, Gunnar; Haney, Michael

    2016-01-01

    Background Extracellular vesicles (EV) are nano-sized membranous structures released from most cells. They have the capacity to carry bioactive molecules and gene expression signals between cells, thus mediating intercellular communication. It is believed that EV confer protection after ischemic preconditioning (IPC). We hypothesize that myocardial ischemic preconditioning will lead to rapid alteration of EV DNA content in EV collected from coronary venous effluent. Materials and Methods In a porcine myocardial ischemic preconditioning model, EV were isolated from coronary venous blood before and after IPC by differential centrifugation steps culminating in preparative ultracentrifugation combined with density gradient ultracentrifugation. The EV preparation was validated, the DNA was extracted and further characterized by DNA sequencing followed by bioinformatics analysis. Results Porcine genomic DNA fragments representing each chromosome, including mitochondrial DNA sequences, were detected in EV isolated before and after IPC. There was no difference detected in the number of sequenced gene fragments (reads) or in the genomic coverage of the sequenced DNA fragments in EV isolated before and after IPC. Gene ontology analysis showed an enrichment of genes coding for ion channels, enzymes and proteins for basal metabolism and vesicle biogenesis and specific cardiac proteins. Conclusions This study demonstrates that porcine EV isolated from coronary venous blood plasma contain fragments of DNA from the entire genome, including the mitochondria. In this model we did not find specific qualitative or quantitative changes of the DNA content in EV collected immediately after an in vivo myocardial IPC provocation. This does not rule out the possibility that EV DNA content changes in response to myocardial IPC which could occur in a later time frame. PMID:27434143

  11. Role of nitric oxide in the mechanism of preclamping and remote ischemic preconditioning of adipocutaneous flaps in a rat model.

    PubMed

    Küntscher, Markus V; Juran, Sebastian; Altmann, Jens; Menke, Henrik; Gebhard, Martha Maria; Germann, Günter

    2003-01-01

    The purpose of this study was to determine whether nitric oxide (NO) plays a role in the mechanism of acute ischemic preconditioning (IP). Fifty-eight male Wistar rats were divided into seven experimental groups. An extended epigastric flap was raised in one of the control groups (C, n = 8), and a 3-hr flap ischemia was induced. Another group served as a non-ischemic control (CO, n = 8). The animals of group S (n = 9) received 500 nmol/kg of Spermine/Nitric Oxide Complex (Sper/NO) intravenously 30 min prior to ischemia. The group N+P (L-NAME + preclamping, n = 8) received 10 mg/kg Nomega-Nitro-L-Arginine Methyl Ester (L-NAME) intravenously before preclamping of the flap pedicle (10-min cycle length, 30-min reperfusion). Ten mg/kg L-NAME were administered in group N+T (L-NAME + tourniquet, n = 9) before ischemia of the right hindlimb was induced using a tourniquet for 10 min after flap elevation. Flap ischemia was induced after 30 min of limb reperfusion. A similar protocol was used in the groups N+P+S (L-NAME + preclamping+Sper/NO, n = 8) and N+T+S (L-NAME + tourniquet + Sper/NO, n = 8). In both groups Sper/NO was administered 30 min prior to flap ischemia, additionally to the protocol of the groups N+P and N+T. Mean flap necrosis area was assessed on the fifth postoperative day using a planimetry software. Average flap necrosis area was 67 +/- 16 percent in the control group C, 28 +/- 13.3 percent in the non-ischemic controls (CO), 10 +/- 5.9 percent in group S, 77.5 +/- 10.2 percent in group N+P, 76 +/- 6.9 percent in group N+T, 71.5 +/- 9.4 percent in group N+P+S, and 78 +/- 9.9 percent in group N+T+S. The animals of group S and CO demonstrated a significantly lower area of flap necrosis than all other groups ( p < 0.001). No significant difference could be shown between the groups C, N+P, N+T, N+P+S and N+T+S. Group S showed a significantly lower flap necrosis area than group CO ( p < 0.01). The data showed, that NO plays an important role in the mechanism of

  12. TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis.

    PubMed

    Zhou, Jun-Hao; Zhang, Tong-Tong; Song, Dan-Dan; Xia, Yun-Fei; Qin, Zheng-Hong; Sheng, Rui

    2016-01-01

    Previous study showed that TIGAR (TP53-induced glycolysis and apoptosis regulator) protected ischemic brain injury via enhancing pentose phosphate pathway (PPP) flux and preserving mitochondria function. This study was aimed to study the role of TIGAR in cerebral preconditioning. The ischemic preconditioning (IPC) and isoflurane preconditioning (ISO) models were established in primary cultured cortical neurons and in mice. Both IPC and ISO increased TIGAR expression in cortical neurons. Preconditioning might upregulate TIGAR through SP1 transcription factor. Lentivirus mediated knockdown of TIGAR significantly abolished the ischemic tolerance induced by IPC and ISO. ISO also increased TIGAR in mouse cortex and hippocampus and alleviated subsequent brain ischemia-reperfusion injury, while the ischemic tolerance induced by ISO was eliminated with TIGAR knockdown in mouse brain. ISO increased the production of NADPH and glutathione (GSH), and scavenged reactive oxygen species (ROS), while TIGAR knockdown decreased GSH and NADPH production and increased the level of ROS. Supplementation of ROS scavenger NAC and PPP product NADPH effectively rescue the neuronal injury caused by TIGAR deficiency. Notably, TIGAR knockdown inhibited ISO-induced anti-apoptotic effects in cortical neurons. These results suggest that TIGAR participates in the cerebral preconditioning through reduction of ROS and subsequent cell apoptosis. PMID:27256465

  13. TIGAR contributes to ischemic tolerance induced by cerebral preconditioning through scavenging of reactive oxygen species and inhibition of apoptosis

    PubMed Central

    Zhou, Jun-Hao; Zhang, Tong-Tong; Song, Dan-Dan; Xia, Yun-Fei; Qin, Zheng-Hong; Sheng, Rui

    2016-01-01

    Previous study showed that TIGAR (TP53-induced glycolysis and apoptosis regulator) protected ischemic brain injury via enhancing pentose phosphate pathway (PPP) flux and preserving mitochondria function. This study was aimed to study the role of TIGAR in cerebral preconditioning. The ischemic preconditioning (IPC) and isoflurane preconditioning (ISO) models were established in primary cultured cortical neurons and in mice. Both IPC and ISO increased TIGAR expression in cortical neurons. Preconditioning might upregulate TIGAR through SP1 transcription factor. Lentivirus mediated knockdown of TIGAR significantly abolished the ischemic tolerance induced by IPC and ISO. ISO also increased TIGAR in mouse cortex and hippocampus and alleviated subsequent brain ischemia-reperfusion injury, while the ischemic tolerance induced by ISO was eliminated with TIGAR knockdown in mouse brain. ISO increased the production of NADPH and glutathione (GSH), and scavenged reactive oxygen species (ROS), while TIGAR knockdown decreased GSH and NADPH production and increased the level of ROS. Supplementation of ROS scavenger NAC and PPP product NADPH effectively rescue the neuronal injury caused by TIGAR deficiency. Notably, TIGAR knockdown inhibited ISO-induced anti-apoptotic effects in cortical neurons. These results suggest that TIGAR participates in the cerebral preconditioning through reduction of ROS and subsequent cell apoptosis. PMID:27256465

  14. Effects of IP3R2 Receptor Deletion in the Ischemic Mouse Retina.

    PubMed

    Wagner, Lysann; Pannicke, Thomas; Frommherz, Ina; Sauer, Katja; Chen, Ju; Grosche, Antje

    2016-04-01

    Glial cells in the diseased nervous system undergo a process known as reactive gliosis. Gliosis of retinal Müller glial cells is characterized by an upregulation of glial fibrillary acidic protein and frequently by a reduction of inward K(+) current amplitudes. Purinergic signaling is assumed to be involved in gliotic processes. As previously shown, lack of the nucleotide receptor P2Y1 leads to an altered regulation of K(+) currents in Müller cells of the ischemic retina. Here, we asked first whether this effect is mediated by the IP3 receptor subtype 2 (IP3R2) known as the major downstream signaling target of P2Y1 in Müller cells. The second question was whether lack of IP3R2 affects neuronal survival in the control and ischemic retina. Ischemia was induced in wild type and IP3R2-deficient (IP 3 R2 (-/-)) mice by transient elevation of the intraocular pressure. Immunostaining and TUNEL labelling were used to quantify neuronal cell loss. The downregulation of inward K(+) currents in Müller cells from ischemic IP 3 R2 (-/-) retinae was less strong than in wild type animals. The reduction of the number of cells in the ganglion cell layer and of calretinin- and calbindin-positive cells 7 days after ischemia was similar in wild type and IP 3 R2 (-/-) mice. However, IP3R2 deficiency led to an increased number of TUNEL-positive cells in the outer nuclear layer at 1 day and to an enhanced postischemic loss of photoreceptors 7 days after ischemia. This implies that IP3R2 is involved in some but not all aspects of signaling in Müller cells after an ischemic insult. PMID:26446037

  15. A Clinical Experimental Model to Evaluate Analgesic Effect of Remote Ischemic Preconditioning in Acute Postoperative Pain

    PubMed Central

    Pereira, Francisco Elano Carvalho; Mello, Irene Lopes; Pimenta, Fernando Heladio de Oliveira Medeiros; Costa, Debora Maia; Wong, Deysi Viviana Tenazoa; Fernandes, Claudia Regina; Lima Junior, Roberto César; Gomes, Josenília M. Alves

    2016-01-01

    This study aims to evaluate the viability of a clinical model of remote ischemic preconditioning (RIPC) and its analgesic effects. It is a prospective study with twenty (20) patients randomly divided into two groups: control group and RIPC group. The opioid analgesics consumption in the postoperative period, the presence of secondary mechanical hyperalgesia, the scores of postoperative pain by visual analog scale, and the plasma levels interleukins (IL-6) were evaluated. The tourniquet applying after spinal anesthetic block was safe, producing no pain for all patients in the tourniquet group. The total dose of morphine consumption in 24 hours was significantly lower in RIPC group than in the control group (p = 0.0156). The intensity analysis of rest pain, pain during coughing and pain in deep breathing, showed that visual analogue scale (VAS) scores were significantly lower in RIPC group compared to the control group: p = 0.0087, 0.0119, and 0.0015, respectively. There were no differences between groups in the analysis of presence or absence of mechanical hyperalgesia (p = 0.0704) and in the serum levels of IL-6 dosage over time (p < 0.0001). This clinical model of remote ischemic preconditioning promoted satisfactory analgesia in patients undergoing conventional cholecystectomy, without changing serum levels of IL-6. PMID:27446611

  16. A Clinical Experimental Model to Evaluate Analgesic Effect of Remote Ischemic Preconditioning in Acute Postoperative Pain.

    PubMed

    Pereira, Francisco Elano Carvalho; Mello, Irene Lopes; Pimenta, Fernando Heladio de Oliveira Medeiros; Costa, Debora Maia; Wong, Deysi Viviana Tenazoa; Fernandes, Claudia Regina; Lima Junior, Roberto César; Gomes, Josenília M Alves

    2016-01-01

    This study aims to evaluate the viability of a clinical model of remote ischemic preconditioning (RIPC) and its analgesic effects. It is a prospective study with twenty (20) patients randomly divided into two groups: control group and RIPC group. The opioid analgesics consumption in the postoperative period, the presence of secondary mechanical hyperalgesia, the scores of postoperative pain by visual analog scale, and the plasma levels interleukins (IL-6) were evaluated. The tourniquet applying after spinal anesthetic block was safe, producing no pain for all patients in the tourniquet group. The total dose of morphine consumption in 24 hours was significantly lower in RIPC group than in the control group (p = 0.0156). The intensity analysis of rest pain, pain during coughing and pain in deep breathing, showed that visual analogue scale (VAS) scores were significantly lower in RIPC group compared to the control group: p = 0.0087, 0.0119, and 0.0015, respectively. There were no differences between groups in the analysis of presence or absence of mechanical hyperalgesia (p = 0.0704) and in the serum levels of IL-6 dosage over time (p < 0.0001). This clinical model of remote ischemic preconditioning promoted satisfactory analgesia in patients undergoing conventional cholecystectomy, without changing serum levels of IL-6. PMID:27446611

  17. Plasticity of sarcolemmal KATP channel surface expression: relevance during ischemia and ischemic preconditioning.

    PubMed

    Yang, Hua-Qian; Foster, Monique N; Jana, Kundan; Ho, Joanne; Rindler, Michael J; Coetzee, William A

    2016-06-01

    Myocardial ischemia remains the primary cause of morbidity and mortality in the United States. Ischemic preconditioning (IPC) is a powerful form of endogenous protection against myocardial infarction. We studied alterations in KATP channels surface density as a potential mechanism of the protection of IPC. Using cardiac-specific knockout of Kir6.2 subunits, we demonstrated an essential role for sarcolemmal KATP channels in the infarct-limiting effect of IPC in the mouse heart. With biochemical membrane fractionation, we demonstrated that sarcolemmal KATP channel subunits are distributed both to the sarcolemma and intracellular endosomal compartments. Global ischemia causes a loss of sarcolemmal KATP channel subunit distribution and internalization to endosomal compartments. Ischemia-induced internalization of KATP channels was prevented by CaMKII inhibition. KATP channel subcellular redistribution was also observed with immunohistochemistry. Ischemic preconditioning before the index ischemia reduced not only the infarct size but also prevented KATP channel internalization. Furthermore, not only did adenosine mimic IPC by preventing infarct size, but it also prevented ischemia-induced KATP channel internalization via a PKC-mediated pathway. We show that preventing endocytosis with dynasore reduced both KATP channel internalization and strongly mitigated infarct development. Our data demonstrate that plasticity of KATP channel surface expression must be considered as a potentially important mechanism of the protective effects of IPC and adenosine. PMID:27037371

  18. Myths and Facts About the Effects of Ischemic Preconditioning on Performance.

    PubMed

    Marocolo, M; da Mota, G R; Simim, M A M; Appell Coriolano, H-J

    2016-02-01

    Although numerous studies have demonstrated the effect of ischemic preconditioning (IPC) in clinical application, the effectiveness of this procedure on performance and physiological variables is still debatable. Therefore a systematic review was performed, including a meta-analysis and evaluation of the quality of the papers that addressed this scope. The electronic databases of the National Library of Medicine (PubMed), Google Scholar (using [advanced search], [all fields]) and other online journals were searched, for the following descriptors: a) "ischemic preconditioning"; b) "blood flow" and "hyperemia"; c) "blood flow occlusion," combined with "exercise performance", "athletes", "exercise" and "performance". Relevant studies were included, if they conformed to strict pre-formulated criteria, excluding systematic review articles, meta-analyses and studies with only animals or non-healthy subjects. The 20 studies included had high quality scores (87%). The majority of the studies lacked statistical significance (P<0.05) for both performance and physiological variables when comparing IPC, placebo and control groups. Most studies showed that IPC has no significant influence on performance. The few studies with significant differences mainly described an improvement only in performance without altered physiological parameters. Therefore, the influence of IPC on performance is still unclear and physiologically highly debatable. PMID:26509376

  19. Hypoxia-Inducible Factor 1: Regulator of Mitochondrial Metabolism and Mediator of Ischemic Preconditioning

    PubMed Central

    Semenza, Gregg L.

    2010-01-01

    Hypoxia-inducible factor 1 (HIF-1) mediates adaptive responses to reduced oxygen availability by regulating gene expression. A critical cell-autonomous adaptive response to chronic hypoxia controlled by HIF-1 is reduced mitochondrial mass and/or metabolism. Exposure of HIF-1-deficient fibroblasts to chronic hypoxia results in cell death due to excessive levels of reactive oxygen species (ROS). HIF-1 reduces ROS production under hypoxic conditions by multiple mechanisms including: a subunit switch in cytochrome c oxidase from the COX4-1 to COX4-2 regulatory subunit that increases the efficiency of complex IV; induction of pyruvate dehydrogenase kinase 1, which shunts pyruvate away from the mitochondria; induction of BNIP3, which triggers mitochondrial selective autophagy; and induction of microRNA-210, which blocks assembly of Fe/S clusters that are required for oxidative phosphorylation. HIF-1 is also required for ischemic preconditioning and this effect may be due in part to its induction of CD73, the enzyme that produces adenosine. HIF-1-dependent regulation of mitochondrial metabolism may also contribute to the protective effects of ischemic preconditioning. PMID:20732359

  20. TARGETED DELETION OF INDUCIBLE HEAT SHOCK PROTEIN 70 ABROGATES THE LATE INFARCT-SPARING EFFECT OF MYOCARDIAL ISCHEMIC PRECONDITIONING

    EPA Science Inventory

    Abstract submitted for 82nd annual meeting of the American Association for Thoracic Surgery, May 4-8, 2002 in Washington D.C.

    Targeted Deletion of Inducible Heat Shock Protein 70 Abrogates the Late Infarct-Sparing Effect of Myocardial Ischemic Preconditioning

    Craig...

  1. Unraveling the role of adenosine in remote ischemic preconditioning-induced cardioprotection.

    PubMed

    Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2016-06-15

    Remote ischemic preconditioning (RIPC) induced by alternate cycles of preconditioning ischemia and reperfusion protects the heart against sustained ischemia-reperfusion-induced injury. This technique has been translated to clinical levels in patients undergoing various surgical interventions including coronary artery bypass graft surgery, abdominal aortic aneurysm repair, percutaneous coronary intervention and heart valve surgery. Adenosine is a master regulator of energy metabolism and reduces myocardial ischemia-reperfusion-induced injury. Furthermore, adenosine is a critical trigger as well as a mediator in RIPC-induced cardioprotection and scientists have demonstrated the role of adenosine by showing an increase in its levels in the systemic circulation during RIPC delivery. Furthermore, the blockade of cardioprotective effects of RIPC in the presence of specific adenosine receptor blockers and transgenic animals with targeted ablation of A1 receptors has also demonstrated its critical role in RIPC. The studies have shown that adenosine may elicit cardioprotection via activation of neurogenic pathway. The present review describes the possible role and mechanism of adenosine in mediating RIPC-induced cardioprotection. PMID:27157518

  2. Remote ischemic preconditioning to reduce contrast-induced nephropathy: study protocol for a randomized controlled trial

    PubMed Central

    2014-01-01

    Background Despite the increasing use of pre- and posthydration protocols and low-osmolar instead of high-osmolar iodine-containing contrast media, the incidence of contrast-induced nephropathy (CIN) is still significant. There is evidence that contrast media cause ischemia-reperfusion injury of the medulla. Remote ischemic preconditioning (RIPC) is a non-invasive, safe, and low-cost method to reduce ischemia-reperfusion injury. Methods The RIPCIN study is a multicenter, single-blinded, randomized controlled trial in which 76 patients at risk of CIN will receive standard hydration combined with RIPC or hydration with sham preconditioning. RIPC will be applied by four cycles of 5 min ischemia and 5 min reperfusion of the forearm by inflating a blood pressure cuff at 50 mmHg above the actual systolic pressure. The primary outcome measure will be the change in serum creatinine from baseline to 48 to 72 h after contrast administration. Discussion A recent pilot study reported that RIPC reduced the incidence of CIN after coronary angioplasty. The unusual high incidence of CIN in this study is of concern and limits its generalizability. Therefore, we propose a randomized controlled trial to study whether RIPC reduces contrast-induced kidney injury in patients at risk for CIN according to the Dutch guidelines. Trial registration Current Controlled Trials ISRCTN76496973 PMID:24721127

  3. Ischemia-induced mitochondrial apoptosis is significantly attenuated by ischemic preconditioning.

    PubMed

    Racay, Peter; Chomova, Maria; Tatarkova, Zuzana; Kaplan, Peter; Hatok, Jozef; Dobrota, Dusan

    2009-09-01

    Ischemic preconditioning (IPC) represents an important adaptation of CNS to sub-lethal ischemia, which results in increased tolerance of CNS to the lethal ischemia. Ischemia-induced mitochondrial apoptosis is considered to be an important event leading to neuronal cell death after cerebral blood flow arrest. In presented study, we have determined the effect of IPC on ischemia/reperfusion-induced mitochondrial apoptosis. Global brain ischemia was induced by permanent occlusion of vertebral arteries and temporal occlusion of carotid arteries for 15 min. Rats were preconditioned by 5 min of sub-lethal ischemia and 2 days later 15 min of lethal ischemia was induced. With respect to mitochondrial apoptosis initiation, translocation of p53 to mitochondria was observed in hippocampus but not in cerebral cortex. However, level of both apoptotic bax and anti-apoptotic bcl-xl in both hippocampal and cortical mitochondria was unchanged after global brain ischemia. Detection of genomic DNA fragmentation as well as Fluoro-Jade C staining showed that ischemia induces apoptosis in vulnerable CA1 layer of rat hippocampus. IPC abolished completely ischemia-induced translocation of p53 to mitochondria and had significant protective effect on ischemia-induced DNA fragmentation. In addition, significant decrease of Fluoro-Jade C positive cells was observed as well. Our results indicate that IPC abolished almost completely both initiation and execution of mitochondrial apoptosis induced by global brain ischemia. PMID:19283470

  4. Ischemic preconditioning of rat livers from non-heart-beating donors decreases parenchymal cell killing and increases graft survival after transplantation.

    PubMed

    Currin, Robert T; Peng, Xing-Xi; Lemasters, John J

    2012-01-01

    A critical shortage of donors exists for liver transplantation, which non-heart-beating cadaver donors could help ease. This study evaluated ischemic preconditioning to improve graft viability after non-heart-beating liver donation in rats. Ischemic preconditioning was performed by clamping the portal vein and hepatic artery for 10 min followed by unclamping for 5 min. Subsequently, the aorta was cross-clamped for up to 120 min. After 2 h of storage, livers were either transplanted or perfused with warm buffer containing trypan blue. Aortic clamping for 60 and 120 min prior to liver harvest markedly decreased 30-day graft survival from 100% without aortic clamping to 50% and 0%, respectively, which ischemic preconditioning restored to 100 and 50%. After 60 min of aortic clamping, loss of viability of parenchymal and nonparenchymal cells was 22.6 and 5.6%, respectively, which preconditioning decreased to 3.0 and 1.5%. Cold storage after aortic clamping further increased parenchymal and non-parenchymal cell killing to 40.4 and 10.1%, respectively, which ischemic preconditioning decreased to 12.4 and 1.8%. In conclusion, ischemic preconditioning markedly decreased cell killing after subsequent sustained warm ischemia. Most importantly, ischemic preconditioning restored 100% graft survival of livers harvested from non-heart-beating donors after 60 min of aortic clamping. PMID:22888183

  5. Accumulation of natural killer cells in ischemic brain tissues and the chemotactic effect of IP-10

    PubMed Central

    2014-01-01

    Background Stroke is accompanied by a distinguished inflammatory reaction that is initiated by the infiltration of immunocytes, expression of cytokines, and other inflammatory mediators. As natural killer cells (NK cells) are a type of cytotoxic lymphocyte critical to the innate immune system, we investigated the mechanism of NK cells-induced brain injuries after cerebral ischemia and the chemotactic effect of IP-10 simultaneously. Methods NK cells infiltration, interferon-gamma (IFN-γ) and IP-10 expression were detected by immunohistochemistry, immunofluorescence, PCR and flow cytometry in human and C57/BL6 wild type mouse ischemic brain tissues. The ischemia area was detected via 2,3,5-triphenyltetrazolium chloride staining. CXCR3 mean fluorescence intensity of isolated NK cells was measured by flow cytometry. The neuronal injury made by NK cells was examined via apoptosis experiment. The chemotactic of IP-10 was detected by migration and permeability assays. Results In human ischemic brain tissue, infiltrations of NK cells were observed and reached a peak at 2 to 5 days. In a permanent middle cerebral artery occlusion (pMCAO) model, infiltration of NK cells into the ischemic infarct region reached their highest levels 12 hours after ischemia. IFN-γ-positive NK cells and levels of the chemokine IP-10 were also detected within the ischemic region, from 6 hours up to 4 days after pMCAO was performed, and IFN-γ levels decreased after NK cells depletion in vivo. Co-culture experiments of neural cells with NK cells also showed that neural necrosis was induced via IFN-γ. In parallel experiments with IP-10, the presence of CXCR3 indicates that NK cells were affected by IP-10 via CXCR3, and the effect was dose-dependent. After IP-10 depletion in vivo, NK cells decreased. In migration assays and permeability experiments, disintegration of the blood–brain barrier (BBB) was observed following the addition of NK cells. Moreover, in the presence of IP-10 this injury

  6. Ischemic preconditioning protects the brain against injury via inhibiting CaMKII-nNOS signaling pathway.

    PubMed

    Wang, Mei; Qi, Da-Shi; Zhou, Cui; Han, Dong; Li, Pei-Pei; Zhang, Fang; Zhou, Xiao-Yan; Han, Meng; Di, Jie-Hui; Ye, Jun-Song; Yu, Hong-Min; Song, Yuan-Jian; Zhang, Guang-Yi

    2016-03-01

    Although studies have shown that cerebral ischemic preconditioning (IPC) can ameliorate ischemia/reperfusion (I/R) induced brain damage, but its precise mechanisms remain unknown. Therefore, the aim of this study was to investigate the neuroprotective mechanisms of IPC against ischemic brain damage induced by cerebral I/R and to explore whether the Calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated up-regulation of nNOS ser847-phosphorylation signaling pathway contributed to the protection provided by IPC. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with 3min of IPC alone or KN62 (selective antagonist of CaMKII) treatment before IPC, after reperfusion for 3 days, 6min ischemia was induced. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting was performed to measure the phosphorylation of CaMKII, nNOS, c-Jun and the expression of FasL. Immunoprecipitation was used to examine the binding between PSD95 and nNOS. The results showed that IPC could significantly protect neurons against cerebral I/R injury, furthermore, the combination of PSD95 and nNOS was increased, coinstantaneously the phosphorylation of CaMKII and nNOS (ser847) were up-regulated, however the activation of c-Jun and FasL were reduced. Conversely, KN62 treatment before IPC reversed all these effects of IPC. Taken together, the results suggest that IPC could diminish ischemic brain injury through CaMKII-mediated up-regulation of nNOS ser847-phosphorylation signaling pathway. PMID:26794251

  7. Exploring the Human Plasma Proteome for Humoral Mediators of Remote Ischemic Preconditioning - A Word of Caution

    PubMed Central

    Helgeland, Erik; Breivik, Lars Ertesvåg; Vaudel, Marc; Svendsen, Øyvind Sverre; Garberg, Hilde; Nordrehaug, Jan Erik; Berven, Frode Steingrimsen; Jonassen, Anne Kristine

    2014-01-01

    Despite major advances in early revascularization techniques, cardiovascular diseases are still the leading cause of death worldwide, and myocardial infarctions contribute heavily to this. Over the past decades, it has become apparent that reperfusion of blood to a previously ischemic area of the heart causes damage in and of itself, and that this ischemia reperfusion induced injury can be reduced by up to 50% by mechanical manipulation of the blood flow to the heart. The recent discovery of remote ischemic preconditioning (RIPC) provides a non-invasive approach of inducing this cardioprotection at a distance. Finding its endogenous mediators and their operative mode is an important step toward increasing the ischemic tolerance. The release of humoral factor(s) upon RIPC was recently demonstrated and several candidate proteins were published as possible mediators of the cardioprotection. Before clinical applicability, these potential biomarkers and their efficiency must be validated, a task made challenging by the large heterogeneity in reported data and results. Here, in an attempt to reproduce and provide more experimental data on these mediators, we conducted an unbiased in-depth analysis of the human plasma proteome before and after RIPC. From the 68 protein markers reported in the literature, only 28 could be mapped to manually reviewed (Swiss-Prot) protein sequences. 23 of them were monitored in our untargeted experiment. However, their significant regulation could not be reproducibly estimated. In fact, among the 394 plasma proteins we accurately quantified, no significant regulation could be confidently and reproducibly assessed. This indicates that it is difficult to both monitor and reproduce published data from experiments exploring for RIPC induced plasma proteomic regulations, and suggests that further work should be directed towards small humoral factors. To simplify this task, we made our proteomic dataset available via ProteomeXchange, where

  8. Enhanced nitric oxide-mediated autophagy contributes to the hepatoprotective effects of ischemic preconditioning during ischemia and reperfusion.

    PubMed

    Shin, Jun-Kyu; Kang, Jung-Woo; Lee, Sun-Mee

    2016-08-31

    Ischemic preconditioning (IPC) protects against liver ischemia/reperfusion (I/R) injury. Autophagy is an essential cytoprotective system that is rapidly activated by multiple stressors. Nitric oxide (NO) acts as an inducer of IPC. We examined the impact of autophagy in liver IPC and its regulation by NO. Male C57BL/6 mice were subjected to 60 min of hepatic ischemia followed by 6 h of reperfusion. IPC was achieved for 10 min of ischemia followed by 10 min of reperfusion prior to sustained ischemia. N(ω)-Nitro-l-arginine methyl ester (L-NAME, 15 mg/kg, i.v., all NOS inhibitor) and aminoguanidine (AG, 10 mg/kg, i.v., iNOS inhibitor) were injected 10 min before IPC. SB203580 (10 mg/kg, i.p., p38 inhibitor) was injected 30 min before IPC. I/R increased serum alanine aminotransferase activity. IPC attenuated this increase, which was abolished by L-NAME, but not AG. Microtubule-associated protein-1 light chain 3-II levels increased and p62 protein levels decreased after I/R; these changes were augmented by IPC and abolished by L-NAME. I/R increased liver protein expression of autophagy-related protein (Atg)12-Atg5 complex and lysosome-associated membrane protein-2. IPC augmented the expression of these proteins, which were abolished by L-NAME, but not AG. IPC also augmented the level of phosphorylated p38 MAPK induced by I/R and this phosphorylation was abolished by L-NAME. Our findings suggest that IPC-mediated NO protects against I/R-induced liver injury by enhancing autophagic flux. PMID:27246638

  9. Hypophosphorylation of ribosomal protein S6 is a molecular mechanism underlying ischemic tolerance induced by either hibernation or preconditioning.

    PubMed

    Miyake, Shin-ichi; Wakita, Hideaki; Bernstock, Joshua D; Castri, Paola; Ruetzler, Christl; Miyake, Junko; Lee, Yang-Ja; Hallenbeck, John M

    2015-12-01

    Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) have an extraordinary capacity to withstand prolonged and profound reductions in blood flow and oxygen delivery to the brain without incurring any cellular damage. As such, the hibernation torpor of I. tridecemlineatus provides a valuable model of tolerance to ischemic stress. Herein, we report that during hibernation torpor, a marked reduction in the phosphorylation of the ribosomal protein S6 (rpS6) occurs within the brains of I. tridecemlineatus. Of note, rpS6 phosphorylation was shown to increase in the brains of rats that underwent an occlusion of the middle cerebral artery. However, such an increase was attenuated after the implementation of an ischemic preconditioning paradigm. In addition, cultured cortical neurons treated with the rpS6 kinase (S6K) inhibitors, D-glucosamine or PF4708671, displayed a decrease in rpS6 phosphorylation and a subsequent increase in tolerance to oxygen/glucose deprivation, an in vitro model of ischemic stroke. Collectively, such evidence suggests that the down-regulation of rpS6 signal transduction may account for a substantial part of the observed increase in cellular tolerance to brain ischemia that occurs during hibernation torpor and after ischemic preconditioning. Further identification and characterization of the mechanisms used by hibernating species to increase ischemic tolerance may eventually clarify how the loss of homeostatic control that occurs during and after cerebral ischemia in the clinic can ultimately be minimized and/or prevented. Mammalian hibernation provides a valuable model of tolerance to ischemic stress. Herein, we demonstrate that marked reductions in the phosphorylation of ribosomal protein S6 (rpS6), extracellular signal-regulated kinase family of mitogen-activated protein (MAP) kinase p44/42 (p44/42MAPK) and ribosomal protein S6 kinase (S6K) occur within the brains of both hibernating squirrels and rats, which have undergone an ischemic

  10. Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles.

    PubMed

    Giricz, Zoltán; Varga, Zoltán V; Baranyai, Tamás; Sipos, Péter; Pálóczi, Krisztina; Kittel, Ágnes; Buzás, Edit I; Ferdinandy, Péter

    2014-03-01

    Remote ischemic preconditioning (RIPC) of the heart is exerted by brief ischemic insults affected on a remote organ or a remote area of the heart before a sustained cardiac ischemia. To date, little is known about the inter-organ transfer mechanisms of cardioprotection by RIPC. Exosomes and microvesicles/microparticles are vesicles of 30-100 nm and 100-1000 nm in diameter, respectively (collectively termed extracellular vesicles [EVs]). Their content of proteins, mRNAs and microRNAs, renders EV ideal conveyors of inter-organ communication. However, whether EVs are involved in RIPC, is unknown. Therefore, here we investigated whether (1) IPC induces release of EVs from the heart, and (2) EVs are necessary for cardioprotection by RIPC. Hearts of male Wistar rats were isolated and perfused in Langendorff mode. A group of donor hearts was exposed to 3 × 5-5 min global ischemia and reperfusion (IPC) or 30 min aerobic perfusion, while coronary perfusates were collected. Coronary perfusates of these hearts were given to another set of recipient isolated hearts. A group of recipient hearts received IPC effluent depleted of EVs by differential ultracentrifugation. Infarct size was determined after 30 min global ischemia and 120 min reperfusion. The presence or absence of EVs in perfusates was confirmed by dynamic light scattering, the EV marker HSP60 Western blot, and electron microscopy. IPC markedly increased EV release from the heart as assessed by HSP60. Administration of coronary perfusate from IPC donor hearts attenuated infarct size in non-preconditioned recipient hearts (12.9 ± 1.6% vs. 25.0 ± 2.7%), similarly to cardioprotection afforded by IPC (7.3 ± 2.7% vs. 22.1 ± 2.9%) on the donor hearts. Perfusates of IPC hearts depleted of EVs failed to exert cardioprotection in recipient hearts (22.0 ± 2.3%). This is the first demonstration that EVs released from the heart after IPC are necessary for cardioprotection by RIPC, evidencing the importance of vesicular

  11. Ischemic Preconditioning Increases the Tolerance of Fatty Liver to Hepatic Ischemia-Reperfusion Injury in the Rat

    PubMed Central

    Serafín, Anna; Roselló-Catafau, Joan; Prats, Neus; Xaus, Carme; Gelpí, Emilio; Peralta, Carmen

    2002-01-01

    Hepatic steatosis is a major risk factor in ischemia-reperfusion. The present study evaluates whether preconditioning, demonstrated to be effective in normal livers, could also confer protection in the presence of steatosis and investigates the potential underlying protective mechanisms. Fatty rats had increased hepatic injury and decreased survival after 60 minutes of ischemia compared with lean rats. Fatty livers showed a degree of neutrophil accumulation and microcirculatory alterations similar to that of normal livers. However, in presence of steatosis, an increased lipid peroxidation that could be reduced with glutathione-ester pretreatment was observed after hepatic reperfusion. Ischemic preconditioning reduced hepatic injury and increased animal survival. Both in normal and fatty livers, this endogenous protective mechanism was found to control lipid peroxidation, hepatic microcirculation failure, and neutrophil accumulation, reducing the subsequent hepatic injury. These beneficial effects could be mediated by nitric oxide, because the inhibition of nitric oxide synthesis and nitric oxide donor pretreatment abolished and simulated, respectively, the benefits of preconditioning. Thus, ischemic preconditioning could be an effective surgical strategy to reduce the hepatic ischemia-reperfusion injury in normal and fatty livers under normothermic conditions, including hepatic resections, and liver transplantation. PMID:12163383

  12. Sympathetic nervous response to ischemia-reperfusion injury in humans is altered with remote ischemic preconditioning.

    PubMed

    Lambert, Elisabeth A; Thomas, Colleen J; Hemmes, Robyn; Eikelis, Nina; Pathak, Atul; Schlaich, Markus P; Lambert, Gavin W

    2016-08-01

    Sympathetic neural activation may be detrimentally involved in tissue injury caused by ischemia-reperfusion (IR). We examined the effects of experimental IR in the forearm on sympathetic nerve response, finger reactive hyperemia, and oxidative stress, and the protection afforded by applying remote ischemic preconditioning (RIPC). Ischemia was induced in the forearm for 20 min in healthy volunteers. RIPC was induced by applying two cycles, 5 min each, of ischemia and reperfusion to the upper leg immediately before IR. We examined muscle sympathetic nerve activity (MSNA) in the contralateral leg using microneurography, finger reactive hyperemia [ischemic reactive hyperemia index (RHI)], erythrocyte production of reduced gluthathione (GSH), and plasma nitric oxide (NO) concentration. In controls (no RIPC; n = 15), IR increased MSNA in the early and late phase of ischemia (70% at 5 min; 101% at 15 min). In subjects who underwent RIPC (n = 15), the increase in MSNA was delayed to the late phase of ischemia and increased only by 40%. GSH increased during ischemia in the control group (P = 0.05), but not in those who underwent RIPC. Nitrate and nitrite concentration, taken as an index of NO availability, decreased during the reperfusion period in control individuals (P < 0.05), while no change was observed in those who underwent RIPC. Experimental IR did not affect RHI in the control condition, but a significant vasodilatory response occurred in the RIPC group (P < 0.05). RIPC attenuated ischemia-induced sympathetic activation, prevented the production of an erythrocyte marker of oxidative stress and the reduction of NO availability, and ameliorated RHI. PMID:27288436

  13. Increased BDNF protein expression after ischemic or PKC epsilon preconditioning promotes electrophysiologic changes that lead to neuroprotection

    PubMed Central

    Neumann, Jake T; Thompson, John W; Raval, Ami P; Cohan, Charles H; Koronowski, Kevin B; Perez-Pinzon, Miguel A

    2015-01-01

    Ischemic preconditioning (IPC) via protein kinase C epsilon (PKCɛ) activation induces neuroprotection against lethal ischemia. Brain-derived neurotrophic factor (BDNF) is a pro-survival signaling molecule that modulates synaptic plasticity and neurogenesis. Interestingly, BDNF mRNA expression increases after IPC. In this study, we investigated whether IPC or pharmacological preconditioning (PKCɛ activation) promoted BDNF-induced neuroprotection, if neuroprotection by IPC or PKCɛ activation altered neuronal excitability, and whether these changes were BDNF-mediated. We used both in vitro (hippocampal organotypic cultures and cortical neuronal-glial cocultures) and in vivo (acute hippocampal slices 48 hours after preconditioning) models of IPC or PKCɛ activation. BDNF protein expression increased 24 to 48 hours after preconditioning, where inhibition of the BDNF Trk receptors abolished neuroprotection against oxygen and glucose deprivation (OGD) in vitro. In addition, there was a significant decrease in neuronal firing frequency and increase in threshold potential 48 hours after preconditioning in vivo, where this threshold modulation was dependent on BDNF activation of Trk receptors in excitatory cortical neurons. In addition, 48 hours after PKCɛ activation in vivo, the onset of anoxic depolarization during OGD was significantly delayed in hippocampal slices. Overall, these results suggest that after IPC or PKCɛ activation, there are BDNF-dependent electrophysiologic modifications that lead to neuroprotection. PMID:25370861

  14. Effects of remote ischemic preconditioning in high-risk patients undergoing cardiac surgery (Remote IMPACT): a randomized controlled trial

    PubMed Central

    Walsh, Michael; Whitlock, Richard; Garg, Amit X.; Légaré, Jean-François; Duncan, Andra E.; Zimmerman, Robert; Miller, Scott; Fremes, Stephen; Kieser, Teresa; Karthikeyan, Ganesan; Chan, Matthew; Ho, Anthony; Nasr, Vivian; Vincent, Jessica; Ali, Imtiaz; Lavi, Ronit; Sessler, Daniel I.; Kramer, Robert; Gardner, Jeff; Syed, Summer; VanHelder, Tomas; Guyatt, Gordon; Rao-Melacini, Purnima; Thabane, Lehana; Devereaux, P.J.

    2016-01-01

    Background: Remote ischemic preconditioning is a simple therapy that may reduce cardiac and kidney injury. We undertook a randomized controlled trial to evaluate the effect of this therapy on markers of heart and kidney injury after cardiac surgery. Methods: Patients at high risk of death within 30 days after cardiac surgery were randomly assigned to undergo remote ischemic preconditioning or a sham procedure after induction of anesthesia. The preconditioning therapy was three 5-minute cycles of thigh ischemia, with 5 minutes of reperfusion between cycles. The sham procedure was identical except that ischemia was not induced. The primary outcome was peak creatine kinase–myocardial band (CK-MB) within 24 hours after surgery (expressed as multiples of the upper limit of normal, with log transformation). The secondary outcome was change in creatinine level within 4 days after surgery (expressed as log-transformed micromoles per litre). Patient-important outcomes were assessed up to 6 months after randomization. Results: We randomly assigned 128 patients to remote ischemic preconditioning and 130 to the sham therapy. There were no significant differences in postoperative CK-MB (absolute mean difference 0.15, 95% confidence interval [CI] −0.07 to 0.36) or creatinine (absolute mean difference 0.06, 95% CI −0.10 to 0.23). Other outcomes did not differ significantly for remote ischemic preconditioning relative to the sham therapy: for myocardial infarction, relative risk (RR) 1.35 (95% CI 0.85 to 2.17); for acute kidney injury, RR 1.10 (95% CI 0.68 to 1.78); for stroke, RR 1.02 (95% CI 0.34 to 3.07); and for death, RR 1.47 (95% CI 0.65 to 3.31). Interpretation: Remote ischemic precnditioning did not reduce myocardial or kidney injury during cardiac surgery. This type of therapy is unlikely to substantially improve patient-important outcomes in cardiac surgery. Trial registration: ClinicalTrials.gov, no. NCT01071265. PMID:26668200

  15. Unique Transcriptional Profile of Sustained Ligand-Activated Preconditioning in Pre- and Post-Ischemic Myocardium

    PubMed Central

    Ashton, Kevin J.; Tupicoff, Amanda; Williams-Pritchard, Grant; Kiessling, Can J.; See Hoe, Louise E.; Headrick, John P.; Peart, Jason N.

    2013-01-01

    Background Opioidergic SLP (sustained ligand-activated preconditioning) induced by 3–5 days of opioid receptor (OR) agonism induces persistent protection against ischemia-reperfusion (I-R) injury in young and aged hearts, and is mechanistically distinct from conventional preconditioning responses. We thus applied unbiased gene-array interrogation to identify molecular effects of SLP in pre- and post-ischemic myocardium. Methodology/Principal Findings Male C57Bl/6 mice were implanted with 75 mg morphine or placebo pellets for 5 days. Resultant SLP did not modify cardiac function, and markedly reduced dysfunction and injury in perfused hearts subjected to 25 min ischemia/45 min reperfusion. Microarray analysis identified 14 up- and 86 down-regulated genes in normoxic hearts from SLP mice (≥1.3-fold change, FDR≤5%). Induced genes encoded sarcomeric/contractile proteins (Myh7, Mybpc3,Myom2,Des), natriuretic peptides (Nppa,Nppb) and stress-signaling elements (Csda,Ptgds). Highly repressed genes primarily encoded chemokines (Ccl2,Ccl4,Ccl7,Ccl9,Ccl13,Ccl3l3,Cxcl3), cytokines (Il1b,Il6,Tnf) and other proteins involved in inflammation/immunity (C3,Cd74,Cd83, Cd86,Hla-dbq1,Hla-drb1,Saa1,Selp,Serpina3), together with endoplasmic stress proteins (known: Dnajb1,Herpud1,Socs3; putative: Il6, Gadd45g,Rcan1) and transcriptional controllers (Egr2,Egr3, Fos,Hmox1,Nfkbid). Biological themes modified thus related to inflammation/immunity, together with cellular/cardiovascular movement and development. SLP also modified the transcriptional response to I-R (46 genes uniquely altered post-ischemia), which may influence later infarction/remodeling. This included up-regulated determinants of cellular resistance to oxidant (Mgst3,Gstm1,Gstm2) and other forms of stress (Xirp1,Ankrd1,Clu), and repression of stress-response genes (Hspa1a,Hspd1,Hsp90aa,Hsph1,Serpinh1) and Txnip. Conclusions Protection via SLP is associated with transcriptional repression of inflammation/immunity, up

  16. The Impact of Remote Ischemic Preconditioning on Arterial Stiffness and Heart Rate Variability in Patients with Angina Pectoris

    PubMed Central

    Zagidullin, Naufal; Scherbakova, Elena; Safina, Yuliana; Zulkarneev, Rustem; Zagidullin, Shamil

    2016-01-01

    Remote ischemic preconditioning (RIPC) is the set of ischemia episodes that protects against subsequent periods of prolonged ischemia through the cascade of adaptive responses; however, the mechanisms of RIPC are not entirely clear. Here, we aimed to study the impact of RIPC in patients with stable angina pectoris and compare it with healthy individuals with respect to arterial stiffness and heart rate variability. In the randomized, sham-controlled, crossover blind design study, a group of 30 coronary heart disease (CHD) patients (63.9 ± 1.6 years) with stable angina pectoris NYHA II-III and a control group of 20 healthy individuals (58.2 ± 2.49) were both randomly allocated for remote RIPC or sham RIPC. Arterial stiffness, pulse wave velocity (Spygmacor, Australia), and heart rate variability (HRV) were recorded before and after the procedure followed by the crossover examination. In the group of healthy individuals, RIPC showed virtually no impact on the cardiovascular parameters, while, in the CHD group, the systolic and central systolic blood pressure, central pulse pressure, and augmentation decreased, and total power of HRV improved. We conclude that ischemic preconditioning reduces not only systolic blood pressure, but also reduces central systolic blood pressure and improves arterial compliance and heart rate modulation reserve, which may be associated with the antianginal effect of preconditioning. PMID:27348009

  17. The Impact of Remote Ischemic Preconditioning on Arterial Stiffness and Heart Rate Variability in Patients with Angina Pectoris.

    PubMed

    Zagidullin, Naufal; Scherbakova, Elena; Safina, Yuliana; Zulkarneev, Rustem; Zagidullin, Shamil

    2016-01-01

    Remote ischemic preconditioning (RIPC) is the set of ischemia episodes that protects against subsequent periods of prolonged ischemia through the cascade of adaptive responses; however, the mechanisms of RIPC are not entirely clear. Here, we aimed to study the impact of RIPC in patients with stable angina pectoris and compare it with healthy individuals with respect to arterial stiffness and heart rate variability. In the randomized, sham-controlled, crossover blind design study, a group of 30 coronary heart disease (CHD) patients (63.9 ± 1.6 years) with stable angina pectoris NYHA II-III and a control group of 20 healthy individuals (58.2 ± 2.49) were both randomly allocated for remote RIPC or sham RIPC. Arterial stiffness, pulse wave velocity (Spygmacor, Australia), and heart rate variability (HRV) were recorded before and after the procedure followed by the crossover examination. In the group of healthy individuals, RIPC showed virtually no impact on the cardiovascular parameters, while, in the CHD group, the systolic and central systolic blood pressure, central pulse pressure, and augmentation decreased, and total power of HRV improved. We conclude that ischemic preconditioning reduces not only systolic blood pressure, but also reduces central systolic blood pressure and improves arterial compliance and heart rate modulation reserve, which may be associated with the antianginal effect of preconditioning. PMID:27348009

  18. Protective effect of ischemic preconditioning on the jejunal graft mucosa injury during cold preservation.

    PubMed

    Jonecova, Zuzana; Toth, Stefan; Maretta, Milan; Ciccocioppo, Rachele; Varga, Jan; Rodrigo, Luis; Kruzliak, Peter

    2015-10-01

    Protection of intestinal graft mucosa during cold preservation is still an unmet need in clinical practice, thus affecting the success of transplantation. The present study investigates the ability of two ischemic preconditioning (IPC) procedures to limit cold preservation injury. Three groups of Sprague-Dawley rats were recruited (n=11 each) as follows: the short IPC (SIPC) performed through 4 cycles of mesenteric ischemia of 4 min each followed by 10 min of reperfusion, the long IPC (LIPC) obtained by 2 ischemic cycles of 12 min each followed by 10 min of reperfusion, and the control group (C) without IPC. Grafts were then stored in cold histidine-tryptophan-ketoglutarate solution and samples were taken at 0, 3, 6 and 9 h lasting preservation. Both IPC groups showed an advanced degree of preservation with delayed development of graft mucosa damage, mainly in the crypt region. At the beginning of preservation, the graft mucosa in both IPC groups showed lower degree of mucosal injury index (MII) by 50% in comparison with C group. Specifically, a significant improvement of MII was observed after 3h of preservation in the LIPC group (p<0.05) in comparison with untreated C grafts. Significant atrophy of the intestinal mucosa in C group was found after 3h of preservation (p<0.01), in SIPC group the progress of atrophy was delayed to 6 h (p<0.001), and in LIPC group only moderate decrease in that was found. A parallel increase of laminin expression with the MII rate after 6 and 9h of preservation in comparison with the level at time 0 was observed in all grafts (p<0.001 and p<0.01, respectively). In both IPC groups the apoptotic cell (AC) rate was significantly reduced at the beginning of cold preservation (p<0.05 both). Moreover, in both the SIPC and C groups, the progressive increase in MII rate connected with AC rate decrease was due to a predominance of necrosis. By contrast in the LIPC group, after an increase of nearly 50% in the AC rate at the 3rd hour, its level

  19. Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction.

    PubMed

    Addison, Patrick D; Neligan, Peter C; Ashrafpour, Homa; Khan, Asim; Zhong, Anguo; Moses, Michael; Forrest, Christopher R; Pang, Cho Y

    2003-10-01

    The aim of this study was to investigate the efficacy and mechanism of action of a noninvasive remote ischemic preconditioning (IPC) technique for the protection of multiple distant skeletal muscles against ischemic necrosis (infarction). It was observed in the pig that three cycles of 10-min occlusion and reperfusion in a hindlimb by tourniquet application reduced the infarction of latissimus dorsi (LD), gracilis (GC), and rectus abdominis (RA) muscle flaps by 55%, 60%, and 55%, respectively, compared with their corresponding control (n = 6, P < 0.01) when they were subsequently subjected to 4 h of ischemia and 48 h of reperfusion. This infarct-protective effect of remote IPC in LD muscle flaps was abolished by an intravenous bolus injection of the nonselective opioid receptor antagonist naloxone (3 mg/kg) 10 min before remote IPC and a continuous intravenous infusion (3 mg/kg) during remote IPC and by an intravenous bolus injection of the selective delta 1-opioid receptor antagonist 7-benzylidenealtrexone maleate (3 mg/kg). However, this infarct-protective effect of remote IPC was not affected by an intravenous bolus injection of the ganglionic blocker hexamethonium chloride (20 mg/kg) or the nonspecific adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (10 mg/kg) or by a local intra-arterial injection of the adenosine1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (3 mg/muscle flap) given 10 min before remote IPC. It was also observed that this remote IPC of skeletal muscle against infarction was associated with a slower rate of muscle ATP depletion during the 4 h of sustained ischemia and a reduced muscle neutrophilic myeloperoxidase activity after 1.5 h of reperfusion. These observations led us to speculate that noninvasive remote IPC by brief cycles of occlusion and reperfusion in a pig hindlimb is effective in global protection of skeletal muscle against infarction. This infarct-protective effect is most likely triggered by the activation

  20. Global gene expression profiles of ischemic preconditioning in deceased donor liver transplantation.

    PubMed

    Raza, Ali; Dikdan, George; Desai, Kunj K; Shareef, Asif; Fernandes, Helen; Aris, Virginie; de la Torre, Andrew N; Wilson, Dorian; Fisher, Adrian; Soteropoulos, Patricia; Koneru, Baburao

    2010-05-01

    The benefits of ischemic preconditioning (IPC) in reducing ischemia/reperfusion injury (IRI) remain indistinct in human liver transplantation (LT). To further understand mechanistic aspects of IPC, we performed microarray analyses as a nested substudy in a randomized trial of 10-minute IPC in 101 deceased donor LTs. Liver biopsies were performed after cold storage and at 90 minutes postreperfusion in 40 of 101 subjects. Global gene expression profiles in 6 biopsy pairs in IPC and work standard organ recovery groups at both time points were compared using the Affymetrix GeneChip Human Gene 1.0 ST array. Transcripts with >1.5-fold change and P < 0.05 were considered significant. IPC altered expression of 82 transcripts in antioxidant, immunological, lipid biosynthesis, cell development and growth, and other groups. Real-time polymerase chain reaction and immunoblotting validated our microarray data. IPC-induced overexpression of glutathione S-transferase mu transcripts (GSTM1, GSTM3, GSTM4, and GSTM5) was accompanied by increased protein expression and may contribute to a decrease in oxidative stress. However, the increased expression of fatty acid synthase may increase oxidative stress, and tumor necrosis factor ligand superfamily member 10 may promote apoptosis. These changes, in combination with decreased expression of heparin-binding epidermal growth factor-like growth factor and insulin-like growth factor binding protein-1, both of which inhibit apoptosis, may increase IRI. In our study of deceased donor LT, IPC induces changes in gene expression, some of which are potentially beneficial but some which are potentially injurious. Thus, our findings of changes in gene expression mirror the outcomes in our clinical trial. PMID:20440768

  1. Ischemia preconditioning protects astrocytes from ischemic injury through 14-3-3γ.

    PubMed

    Pang, Ying; Chai, Chao Rui; Gao, Kai; Jia, Xi Hua; Kong, Jin Ge; Chen, Xiao Qian; Vatcher, Greg; Chen, Jian Guo; Yu, Albert Cheung Hoi

    2015-10-01

    Stroke is a leading cause of death and disability, and new strategies are required to reduce neuronal injury and improve prognosis. Ischemia preconditioning (IPC) is an intrinsic phenomenon that protects cells from subsequent ischemic injury and might provide promising mechanisms for clinical treatment. In this study, primary astrocytes exhibited significantly less cell death than control when exposed to different durations of IPC (15, 30, 60, or 120 min). A 15-min duration was the most effective IPC to protect astrocytes from 8-hr-ischemia injury. The protective mechanisms of IPC involve the upregulation of protective proteins, including 14-3-3γ, and attenuation of malondialdehyde (MDA) content and ATP depletion. 14-3-3γ is an antiapoptotic intracellular protein that was significantly upregulated for up to 84 hr after IPC. In addition, IPC promoted activation of the c-Jun N-terminal kinase (JNK), extracellular signal-related kinase (ERK)-1/2, p38, and protein kinase B (Akt) signaling pathways. When JNK was specifically inhibited with SP600125, the upregulation of 14-3-3γ induced by IPC was almost completely abolished; however, there was no effect on ATP or MDA levels. This suggests that, even though both energy preservation and 14-3-3γ up-regulation were turned on by IPC, they were controlled by different pathways. The ERK1/2, p38, and Akt signaling pathways were not involved in the 14-3-3γ upregulation and energy preservation. These results indicate that IPC could protect astrocytes from ischemia injury by inducing 14-3-3γ and by alleviating energy depletion through different pathways, suggesting multiple protection of IPC and providing new insights into potential stroke therapies. PMID:25711139

  2. Long-term, regular remote ischemic preconditioning improves endothelial function in patients with coronary heart disease.

    PubMed

    Liang, Y; Li, Y P; He, F; Liu, X Q; Zhang, J Y

    2015-06-01

    Remote ischemic preconditioning (RIPre) can prevent myocardial injury. The purpose of this study was to assess the beneficial effects of long-term regular RIPre on human arteries. Forty patients scheduled for coronary artery bypass graft (CABG) surgery were assigned randomly to a RIPre group (n=20) or coronary heart disease (CHD) group (n=20). Twenty patients scheduled for mastectomy were enrolled as a control group. RIPre was achieved by occluding arterial blood flow 5 min with a mercury sphygmomanometer followed by a 5-min reperfusion period, and this was repeated 4 times. The RIPre procedure was repeated 3 times a day for 20 days. In all patients, arterial fragments discarded during surgery were collected to evaluate endothelial function by flow-mediated dilation (FMD), CD34(+) monocyte count, and endothelial nitric oxide synthase (eNOS expression). Phosphorylation levels of STAT-3 and Akt were also assayed to explore the underlying mechanisms. Compared with the CHD group, long-term regular RIPre significantly improved FMD after 20 days (8.5±2.4 vs 4.9±4.2%, P<0.05) and significantly reduced troponin after CABG surgery (0.72±0.31 and 1.64±0.19, P<0.05). RIPre activated STAT-3 and increased CD34(+) endothelial progenitor cell counts found in arteries. Long-term, regular RIPre improved endothelial function in patients with CHD, possibly due to STAT-3 activation, and this may have led to an increase in endothelial progenitor cells. PMID:25923462

  3. Ischemic preconditioning increases muscle perfusion, oxygen uptake, and force in strength-trained athletes.

    PubMed

    Paradis-Deschênes, Pénélope; Joanisse, Denis R; Billaut, François

    2016-09-01

    Muscle ischemia and reperfusion induced by ischemic preconditioning (IPC) can improve performance in various activities. However, the underlying mechanisms are still poorly understood. The purpose of this study was to examine the effects of IPC on muscle hemodynamics and oxygen (O2) uptake during repeated maximal contractions. In a cross-over, randomized, single-blind study, 10 strength-trained men performed 5 sets of 5 maximal voluntary knee extensions of the right leg on an isokinetic dynamometer, preceded by either IPC of the right lower limb (3×5-min compression/5-min reperfusion cycles at 200 mm Hg) or sham (20 mm Hg). Changes in deoxyhemoglobin, expressed as a percentage of arterial occlusion, and total hemoglobin ([THb]) concentrations of the vastus lateralis muscle were monitored continuously by near-infrared spectroscopy. Differences between IPC and sham were analyzed using Cohen's effect size (ES) ± 90% confidence limits, and magnitude-based inferences. Compared with sham, IPC likely increased muscle blood volume at rest (↑[THb], 46.5%; ES, 0.56; 90% confidence limits for ES, -0.21, 1.32). During exercise, peak force was almost certainly higher (11.8%; ES, 0.37; 0.27, 0.47), average force was very likely higher (12.6%; ES, 0.47; 0.29, 0.66), and average muscle O2 uptake was possibly increased (15.8%; ES, 0.36; -0.07, 0.79) after IPC. In the recovery periods between contractions, IPC also increased blood volume after sets 1 (23.6%; ES, 0.30; -0.05, 0.65) and 5 (25.1%; ES, 0.32; 0.09, 0.55). Three cycles of IPC immediately increased muscle perfusion and O2 uptake, conducive to higher repeated force capacity in strength-trained athletes. This maneuver therefore appears relevant to enhancing exercise training stimulus. PMID:27574913

  4. Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning.

    PubMed Central

    Heurteaux, C; Lauritzen, I; Widmann, C; Lazdunski, M

    1995-01-01

    Preconditioning with sublethal ischemia protects against neuronal damage after subsequent lethal ischemic insults in hippocampal neurons. A pharmacological approach using agonists and antagonists at the adenosine A1 receptor as well as openers and blockers of ATP-sensitive K+ channels has been combined with an analysis of neuronal death and gene expression of subunits of glutamate and gamma-aminobutyric acid receptors, HSP70, c-fos, c-jun, and growth factors. It indicates that the mechanism of ischemic tolerance involves a cascade of events including liberation of adenosine, stimulation of adenosine A1 receptors, and, via these receptors, opening of sulfonylurea-sensitive ATP-sensitive K+ channels. Images Fig. 2 Fig. 3 PMID:7753861

  5. Hypoxia/Reoxygenation-Preconditioned Human Bone Marrow-Derived Mesenchymal Stromal Cells Rescue Ischemic Rat Cortical Neurons by Enhancing Trophic Factor Release.

    PubMed

    Kim, Young Seo; Noh, Min Young; Cho, Kyung Ah; Kim, Hyemi; Kwon, Min-Soo; Kim, Kyung Suk; Kim, Juhan; Koh, Seong-Ho; Kim, Seung Hyun

    2015-08-01

    Bone marrow-derived mesenchymal stromal cells (BM-MSCs) represent a promising tool for stem cell-based therapies. However, the majority of MSCs fail to reach the injury site and have only minimal therapeutic effect. In this study, we assessed whether hypoxia/reoxygenation (H/R) preconditioning of human BM-MSCs could increase their functional capacity and beneficial effect on ischemic rat cortical neurons. Human BM-MSCs were cultured under hypoxia (1% O2) and with long-term reoxygenation for various times to identify the optimal conditions for increasing their viability and proliferation. The effects of H/R preconditioning on the BM-MSCs were assessed by analyzing the expression of prosurvival genes, trophic factors, and cell migration assays. The functionally improved BM-MSCs were cocultured with ischemic rat cortical neurons to compare with normoxic cultured BM-MSCs. Although the cell viability and proliferation of BM-MSCs were reduced after 1 day of hypoxic culture (1% O2), when this was followed by 5-day reoxygenation, the BM-MSCs recovered and multiplied extensively. The immunophenotype and trilineage differentiation of BM-MSCs were also maintained under this H/R preconditioning. In addition, the preconditioning enhanced the expression of prosurvival genes, the messenger RNA (mRNA) levels of various trophic factors and migration capacity. Finally, coculture with the H/R-preconditioned BM-MSCs promoted the survival of ischemic rat cortical neurons. H/R preconditioning of BM-MSCs increases prosurvival signals, trophic factor release, and cell migration and appears to increase their ability to rescue ischemic cortical neurons. This optimized H/R preconditioning procedure could provide the basis for a new strategy for stem cell therapy in ischemic stroke patients. PMID:25288154

  6. Ischemic preconditioning stimulates sodium and proton transport in isolated rat hearts.

    PubMed Central

    Ramasamy, R; Liu, H; Anderson, S; Lundmark, J; Schaefer, S

    1995-01-01

    One or more brief periods of ischemia, termed preconditioning, dramatically limits infarct size and reduces intracellular acidosis during subsequent ischemia, potentially via enhanced sarcolemmal proton efflux mechanisms. To test the hypothesis that preconditioning increases the functional activity of sodium-dependent proton efflux pathways, isolated rat hearts were subjected to 30 min of global ischemia with or without preconditioning. Intracellular sodium (Nai) was assessed using 23Na magnetic resonance spectroscopy, and the activity of the Na-H exchanger and Na-K-2Cl cotransporter was measured by transiently exposing the hearts to an acid load (NH4Cl washout). Creatine kinase release was reduced by greater than 60% in the preconditioned hearts (P < 0.05) and was associated with improved functional recovery on reperfusion. Preconditioning increased Nai by 6.24 +/- 2.04 U, resulting in a significantly higher level of Nai before ischemia than in the control hearts. Nai increased significantly at the onset of ischemia (8.48 +/- 1.21 vs. 2.57 +/- 0.81 U, preconditioned vs. control hearts; P < 0.01). Preconditioning did not reduce Nai accumulation during ischemia, but the decline in Nai during the first 5 min of reperfusion was significantly greater in the preconditioned than in the control hearts (13.48 +/- 1.73 vs. 2.54 +/- 0.41 U; P < 0.001). Exposure of preconditioned hearts to ethylisopropylamiloride or bumetanide in the last reperfusion period limited in the increase in Nai during ischemia and reduced the beneficial effects of preconditioning. After the NH4Cl prepulse, preconditioned hearts acidified significantly more than control hearts and had significantly more rapid recovery of pH (preconditioned, delta pH = 0.35 +/- 0.04 U over 5 min; control, delta pH = 0.15 +/- 0.02 U over 5 min). This rapid pH recovery was not affected by inhibition of the Na-K-2Cl cotransporter but was abolished by inhibition of the Na-H exchanger. These results demonstrate that

  7. Ischemic Preconditioning Preserves Mitochondrial Membrane Potential and Limits Reactive Oxygen Species Production

    PubMed Central

    Quarrie, Ricardo; Lee, Daniel S.; Steinbaugh, Gregory; Cramer, Brandon; Erdahl, Warren; Pfeiffer, Douglas R.; Zweier, Jay L.; Crestanello, Juan A.

    2012-01-01

    Background Mitochondrial superoxide radical (O2•−) production increases after cardiac ischemia-reperfusion (IR). Ischemic preconditioning (IPC) preserves mitochondrial function and attenuates O2•− production, but the mechanism is unknown. Mitochondrial membrane potential (mΔΨ) is known to affect O2•− production; mitochondrial depolarization decreases O2•− formation. We examined the relationship between O2•− production and mΔΨ during IR and IPC. Materials/Methods Rat hearts were subjected to Control or IPC. Mitochondria were isolated at end-equilibration (End EQ), end-ischemia (End I) and end-reperfusion (End RP). mΔΨ was measured using a tetraphenylphosphonium electrode. Mitochondrial O2•− production was measured by electron paramagnetic resonance (EPR) using DMPO spin trap. Cytochrome c levels were measured using high pressure liquid chromatography. Results IPC preserved mΔΨ at End I (−156±5 vs. −131±6 mV, p<0.001) and End RP (−168±2 vs. −155±2 mV, p<0.05). At End RP, IPC attenuated O2•− production (2527±221 vs. 3523±250 AU/mg protein, p<0.05). IPC preserved cytochrome c levels (351±14 vs. 269±16 picomoles/mg protein, p<0.05) at End RP, and decreased mitochondrial cristae disruption (10±4 vs. 33±7%, p<0.05) and amorphous density formation (18±4 vs. 28±1%, p<0.05). Conclusion We conclude that IPC preserves mΔΨ, possibly by limiting disruption of mitochondrial inner membrane. IPC also decreases mitochondrial O2•− production and preserves mitochondrial ultrastructure after IR. While it was previously held that slight decreases in mΔΨ decrease O2•− production, our results indicate that preservation of mΔΨ is associated with decreased O2•− and preservation of cardiac function in IPC. These findings indicate that the mechanism of IPC may not involve mΔΨ depolarization, but rather preservation of mitochondrial electrochemical potential. PMID:22763215

  8. Nrf2 activation in astrocytes contributes to spinal cord ischemic tolerance induced by hyperbaric oxygen preconditioning.

    PubMed

    Xu, Jiajun; Huang, Guoyang; Zhang, Kun; Sun, Jinchuan; Xu, Tao; Li, Runping; Tao, Hengyi; Xu, Weigang

    2014-08-01

    In this study, we investigated whether nuclear factor erythroid 2-related factor 2 (Nrf2) activation in astrocytes contributes to the neuroprotection induced by a single hyperbaric oxygen preconditioning (HBO-PC) against spinal cord ischemia/reperfusion (SCIR) injury. In vivo: At 24 h after a single HBO-PC at 2.5 atmospheres absolute for 90 min, the male ICR mice underwent SCIR injury by aortic cross-clamping surgery and observed for 48 h. HBO-PC significantly improved hindlimb motor function, reduced secondary spinal cord edema, ameliorated the reactivity of spinal motor-evoked potentials, and slowed down the process of apoptosis to exert neuroprotective effects against SCIR injury. At 12 h or 24 h after HBO-PC without aortic cross-clamping surgery, Western blot, enzyme-linked immunosorbent assay, realtime-polymerase chain reaction and double-immunofluorescence staining were used to detect the Nrf2 activity of spinal cord tissue, such as mRNA level, protein content, DNA binding activity, and the expression of downstream gene, such as glutamate-cysteine ligase, γ-glutamyltransferase, multidrug resistance protein 1, which are key proteins for intracellular glutathione synthesis and transit. The Nrf2 activity and downstream genes expression were all enhanced in normal spinal cord with HBO-PC. Glutathione content of spinal cord tissue with HBO-PC significantly increased at all time points after SCIR injury. Moreover, Nrf2 overexpression mainly occurs in astrocytes. In vitro: At 24 h after HBO-PC, the primary spinal astrocyte-neuron co-cultures from ICR mouse pups were subjected to oxygen-glucose deprivation (OGD) for 90 min to simulate the ischemia-reperfusion injury. HBO-PC significantly increased the survival rate of neurons and the glutathione content in culture medium, which was mainly released from asctrocytes. Moreover, the Nrf2 activity and downstream genes expression induced by HBO-PC were mainly enhanced in astrocytes, but not in neurons. In

  9. p-ERK involvement in the neuroprotection exerted by ischemic preconditioning in rat hippocampus subjected to four vessel occlusion.

    PubMed

    Kovalska, M; Kovalska, L; Mikuskova, K; Adamkov, M; Tatarkova, Z; Lehotsky, J

    2014-12-01

    Global brain ischemia-reperfusion causes delayed cell death in hippocampal CA1 (cornus ammonis 1) pyramidal neurons after reperfusion. Ischemic tolerance evoked by preconditioning (IPC) represents a phenomenon of CNS adaptation to any subsequent ischemia. This paper was designed to describe changes in the mitogen-activated protein kinases (MAPK) protein pathways of the hippocampal area following by IPC. Ischemia was induced by a 4-vessels occlusion (4VO) and the rats were preconditioned by a non-injurious ischemia. Apoptotic markers were used to follow the degeneration process. Western blot and immunohistochemistry identified p-ERK (phosphorylated extracellular signal-regulated protein kinase) and p38 proteins in injured hippocampal areas. P-ERK quantification increased after IPC and reached the highest level at 24 hours after ischemia. Interestingly, neuroprotection induced by IPC lead to the opposite effect on MAPK/p38, where the level was lowest at 24 hours after ischemia. Taken together, the present study clearly demonstrates that p-ERK takes part in complex cascades triggered by IPC in the selectively vulnerable hippocampal region. In addition, paper describes a crosstalk between p-ERK and p-p38 which occurs after preconditioning maneuver in 4VO model of global ischemia. PMID:25554980

  10. The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection.

    PubMed

    Johnsen, Jacob; Pryds, Kasper; Salman, Rasha; Løfgren, Bo; Kristiansen, Steen Buus; Bøtker, Hans Erik

    2016-03-01

    Remote ischemic preconditioning (rIPC), induced by cycles of transient limb ischemia and reperfusion (IR), is cardioprotective. The optimal rIPC-algorithm is not established. We investigated the effect of cycle numbers and ischemia duration within each rIPC-cycle and the influence of effector organ mass on the efficacy of cardioprotection. Furthermore, the duration of the early phase of protection by rIPC was investigated. Using a tourniquet tightened at the inguinal level, we subjected C57Bl/6NTac mice to intermittent hind-limb ischemia and reperfusion. The rIPC-protocols consisted of (I) two, four, six or eight cycles, (II) 2, 5 or 10 min of ischemia in each cycle, (III) single or two hind-limb occlusions and (IV) 0.5, 1.5, 2.0 or 2.5 h intervals from rIPC to index cardiac ischemia. All rIPC algorithms were followed by 5 min of reperfusion. The hearts were subsequently exposed to 25 min of global ischemia and 60 min of reperfusion in an ex vivo Langendorff model. Cardioprotection was evaluated by infarct size and post-ischemic hemodynamic recovery. Four to six rIPC cycles yielded significant cardioprotection with no further protection by eight cycles. Ischemic cycles lasting 2 min offered the same protection as cycles of 5 min ischemia, whereas prolonged cycles lasting 10 min abrogated protection. One and two hind-limb preconditioning were equally protective. In our mouse model, the duration of protection by rIPC was 1.5 h. These findings indicate that the number and duration of cycles rather than the tissue mass exposed to rIPC determines the efficacy of rIPC. PMID:26768477

  11. Zinc finger protein 667 expression is upregulated by cerebral ischemic preconditioning and protects cells from oxidative stress

    PubMed Central

    YUAN, DUN; HUANG, JUN; YUAN, XIANRUI; ZHAO, JIE; JIANG, WEIXI

    2013-01-01

    Brain ischemic injury is associated with clinical emergencies such as acute ischemic and hemorrhagic stroke, head trauma, prolonged severe hypotension and cardiac arrest. Ischemic preconditioning (IPC) is the most powerful endogenous mechanism against ischemic injury. However, the majority of IPC treatments are invasive and thus impractical in the clinical setting. Identifying the endogenous neuroprotective mechanism induced by IPC is important for developing new strategies to reduce stroke severity. Zinc finger protein 667 (ZNF667) is a novel zinc finger protein that is upregulated by myocardial IPC. However, its functional role in neuronal ischemia has not been elucidated. In this study, the changes of ZNF667 expression on cerebral IPC and its potential neuroprotective function were investigated. The cerebral ischemia model was established by ameliorated four-vessel occlusion in rats. The northern blot results demonstrated that ZNF667 expression was increased in the hippocampus and cortex at 12 and 24 h after cerebral ischemic pretreatment. To investigate the neuroprotective function of ZNF667, enhanced green fluorescent protein (EGFP)-ZNF667 fusion protein was expressed in C2C12 and brain astrocytoma cells and its subcellular localization was detected by confocal microscopy. EGFP-ZNF667 fusion proteins were localized in the nucleus of C2C12 and brain astrocytoma cells, indicating that ZNF667 may act as a transcription factor in neural cells. To mimic oxidative stress associated with ischemia/reperfusion injury, hydrogen peroxide (H2O2) was used to treat cells. Cell viability was measured by the lactate dehydrogenase (LDH) and WST-1 assays. A decrease in viability was detected in C2C12 and astrocytoma cells following H2O2 treatment, whereas ZNF667 gene overexpression significantly improved cell viability following H2O2 treatment. These results suggested that ZNF667 plays a neuroprotective role by acting as a transcription factor in cerebral IPC. PMID:24648981

  12. The Loss of Myocardial Benefit following Ischemic Preconditioning Is Associated with Dysregulation of Iron Homeostasis in Diet-Induced Diabetes

    PubMed Central

    Berenshtein, Eduard; Eliashar, Ron; Chevion, Mordechai

    2016-01-01

    Whether the diabetic heart benefits from ischemic preconditioning (IPC), similar to the non-diabetic heart, is a subject of controversy. We recently proposed new roles for iron and ferritin in IPC-protection in Type 1-like streptozotocin-induced diabetic rat heart. Here, we investigated iron homeostasis in Cohen diabetic sensitive rat (CDs) that develop hyperglycemia when fed on a high-sucrose/low-copper diet (HSD), but maintain normoglycemia on regular-diet (RD). Control Cohen-resistant rats (CDr) maintain normoglycemia on either diet. The IPC procedure improved the post-ischemic recovery of normoglycemic hearts (CDr-RD, CDr-HSD and CDs-RD). CDs-HSD hearts failed to show IPC-associated protection. The recovery of these CDs-HSD hearts following I/R (without prior IPC) was better than their RD controls. During IPC ferritin levels increased in normoglycemic hearts, and its level was maintained nearly constant during the subsequent prolonged ischemia, but decayed to its baseline level during the reperfusion phase. In CDs-HSD hearts the baseline levels of ferritin and ferritin-saturation with iron were notably higher than in the controls, and remained unchanged during the entire experiment. This unique and abnormal pattern of post-ischemic recovery of CDs-HSD hearts is associated with marked changes in myocardial iron homeostasis, and suggests that iron and iron-proteins play a causative role/s in the etiology of diabetes-associated cardiovascular disorders. PMID:27458721

  13. The Loss of Myocardial Benefit following Ischemic Preconditioning Is Associated with Dysregulation of Iron Homeostasis in Diet-Induced Diabetes.

    PubMed

    Vinokur, Vladimir; Weksler-Zangen, Sarah; Berenshtein, Eduard; Eliashar, Ron; Chevion, Mordechai

    2016-01-01

    Whether the diabetic heart benefits from ischemic preconditioning (IPC), similar to the non-diabetic heart, is a subject of controversy. We recently proposed new roles for iron and ferritin in IPC-protection in Type 1-like streptozotocin-induced diabetic rat heart. Here, we investigated iron homeostasis in Cohen diabetic sensitive rat (CDs) that develop hyperglycemia when fed on a high-sucrose/low-copper diet (HSD), but maintain normoglycemia on regular-diet (RD). Control Cohen-resistant rats (CDr) maintain normoglycemia on either diet. The IPC procedure improved the post-ischemic recovery of normoglycemic hearts (CDr-RD, CDr-HSD and CDs-RD). CDs-HSD hearts failed to show IPC-associated protection. The recovery of these CDs-HSD hearts following I/R (without prior IPC) was better than their RD controls. During IPC ferritin levels increased in normoglycemic hearts, and its level was maintained nearly constant during the subsequent prolonged ischemia, but decayed to its baseline level during the reperfusion phase. In CDs-HSD hearts the baseline levels of ferritin and ferritin-saturation with iron were notably higher than in the controls, and remained unchanged during the entire experiment. This unique and abnormal pattern of post-ischemic recovery of CDs-HSD hearts is associated with marked changes in myocardial iron homeostasis, and suggests that iron and iron-proteins play a causative role/s in the etiology of diabetes-associated cardiovascular disorders. PMID:27458721

  14. HSP70.1 AND -70.3 ARE REQUIRED FOR LATE-PHASE PROTECTION INDUCED BY ISCHEMIC PRECONDITIONING OF MOUSE HEARTS

    EPA Science Inventory

    Heat-Shock Proteins 70.1 and 70.3 Are Required for Late-phase Protection
    Induced by Ischemic Preconditioning of the Mouse Heart
    Craig R. Hampton 1 , Akira Shimamoto 1 , Christine L. Rothnie 1 , Jeaneatte Griscavage-Ennis 1 ,
    Albert Chong 1 , David J. Dix 2 , Edward D. Ve...

  15. Short-term remote ischemic preconditioning is not associated with improved blood pressure and exercise capacity in young adults.

    PubMed

    Banks, Laura; Wells, Greg D; Clarizia, Nadia A; Jean-St-Michel, Emilie; McKillop, Adam L; Redington, Andrew N; McCrindle, Brian W

    2016-08-01

    We sought to determine whether a 9-day remote ischemic preconditioning (IPC) causes improvements in exercise performance, energetics, and blood pressure. Ten participants (mean age 24 ± 4 years) had no changes in aerobic capacity (preintervention: 38 ± 10 mL/(kg·min)(-1) vs. postintervention: 38 ± 10 mL/(kg·min)(-1)), blood pressure (preintervention: 112 ± 7/66 ± 6 mm Hg vs. postintervention: 112 ± 10/62 ± 5 mm Hg), cardiac phosphocreatinine-to-adenosine-triphosphate ratio (preintervention: 2.1 ± 0.5 vs. postintervention: 2.3 ± 0.4), and postexercise skeletal muscle phosphocreatine recovery (preintervention: 34 ± 11 s vs. postintervention: 31 ± 11 s). Short-term remote IPC may be ineffective in improving these outcomes. PMID:27439445

  16. Isoflurane Preconditioning Induces Neuroprotection by Up-Regulation of TREK1 in a Rat Model of Spinal Cord Ischemic Injury

    PubMed Central

    Wang, Kun; Kong, Xiangang

    2016-01-01

    This study aimed to explore the neuroprotection and mechanism of isoflurane on rats with spinal cord ischemic injury. Total 40 adult male Sprague-Dawley rats were divided into the four groups (n=10). Group A was sham-operation group; group B was ischemia group; group C was isoflurane preconditioning group; group D was isoflurane preconditioning followed by ischemia treatment group. Then the expressions of TWIK-related K+ channel 1 (TREK1) in the four groups were detected by immunofluorescent assay, real time-polymerase chain reactions (RT-PCR) and western blot. The primary neurons of rats were isolated and cultured under normal and hypoxic conditions. Besides, the neurons under two conditions were transfected with green fluorescent protein (GFP)-TREK1 and lentivirual to overexpress and silence TREK1. Additionally, the neurons were treated with isoflurane or not. Then caspase-3 activity and cell cycle of neurons under normal and hypoxic conditions were detected. Furthermore, nicotinamide adenine dinucleotide hydrate (NADH) was detected using NAD+/NADH quantification colorimetric kit. Results showed that the mRNA and protein expressions of TREK1 increased significantly in group C and D. In neurons, when TREK1 silenced, isoflurane treatment improved the caspase-3 activity. In hypoxic condition, the caspase-3 activity and sub-G1 cell percentage significantly increased, however, when TREK1 overexpressed the caspase-3 activity and sub-G1 cell percentage decreased significantly. Furthermore, both isoflurane treatment and overexpression of TREK1 significantly decreased NADH. In conclusion, isoflurane-induced neuroprotection in spinal cord ischemic injury may be associated with the up-regulation of TREK1. PMID:27469140

  17. Generation of hypochlorite-modified proteins by neutrophils during ischemia-reperfusion injury in rat liver: attenuation by ischemic preconditioning.

    PubMed

    Hasegawa, Tadashi; Malle, Ernst; Farhood, Anwar; Jaeschke, Hartmut

    2005-10-01

    Although it is well documented that neutrophils are critical for the delayed phase of hepatic ischemia-reperfusion injury, there is no direct evidence for a specific neutrophil-derived oxidant stress in vivo. Therefore, we used a model of 60 min of partial hepatic ischemia and 0-24 h of reperfusion to investigate neutrophil accumulation and to analyze biomarkers for a general oxidant stress [glutathione disulfide (GSSG) and malondialdehyde (MDA)] and for a neutrophil-specific oxidant stress [hypochlorite (HOCl)-modified epitopes] in rats. Plasma alanine transaminase activities and histology showed progressively increasing liver injury during reperfusion, when hepatic GSSG and soluble MDA levels were elevated. At that time, few neutrophils were present in sinusoids. However, the number of hepatocytes positively stained for HOCl-modified epitopes increased from 6 to 24 h of reperfusion, which correlated with the bulk of hepatic neutrophil accumulation and extravasation into the parenchyma. Consistent with a higher oxidant stress at later times, hepatic GSSG and protein-bound MDA levels further increased. Treatment with the NADPH oxidase inhibitor diphenyleneiodonium chloride attenuated postischemic oxidant stress (GSSG, protein-bound MDA, and hepatocytes positively stained for HOCl-modified epitopes) and liver injury at 24 h of reperfusion. Ischemic preconditioning suppressed all oxidant stress biomarkers, liver injury, and extravasation of neutrophils. In conclusion, extravasated neutrophils generate HOCl, which diffuses into hepatocytes and causes oxidative modifications of intracellular proteins during the neutrophil-mediated reperfusion injury phase. Ischemic preconditioning is an effective intervention for reduction of the overall inflammatory response and, in particular, for limitation of the cytotoxic activity of neutrophils during the later reperfusion period. PMID:15994427

  18. Renoprotective Mechanism of Remote Ischemic Preconditioning Based on Transcriptomic Analysis in a Porcine Renal Ischemia Reperfusion Injury Model

    PubMed Central

    Kim, Sook Young; Cho, Young In; Lee, Kwang Suk; Kim, Kwang Hyun; Yang, Seung Choul; Han, Woong Kyu

    2015-01-01

    Ischemic preconditioning (IPC) is a well-known phenomenon in which tissues are exposed to a brief period of ischemia prior to a longer ischemic event. This technique produces tissue tolerance to ischemia reperfusion injury (IRI). Currently, IPC’s mechanism of action is poorly understood. Using a porcine single kidney model, we performed remote IPC with renal IRI and evaluated the IPC mechanism of action. Following left nephrectomy, 15 female Yorkshire pigs were divided into three groups: no IPC and 90 minutes of warm ischemia (control), remote IPC immediately followed by 90 minutes of warm ischemia (rIPCe), and remote IPC with 90 minutes of warm ischemia performed 24 hours later (rIPCl). Differential gene expression analysis was performed using a porcine-specific microarray. The microarray analysis of porcine renal tissues identified 1,053 differentially expressed probes in preconditioned pigs. Among these, 179 genes had altered expression in both the rIPCe and rIPCl groups. The genes were largely related to oxidation reduction, apoptosis, and inflammatory response. In the rIPCl group, an additional 848 genes had altered expression levels. These genes were primarily related to immune response and inflammation, including those coding for cytokines and cytokine receptors and those that play roles in the complement system and coagulation cascade. In the complement system, the membrane attack complex was determined to be sublytic, because it colocalized with phosphorylated extracellular signal-regulated kinase. Furthermore, alpha 2 macroglobulin, tissue plasminogen activator, uterine plasmin trypsin inhibitor, and arginase-1 mRNA levels were elevated in the rIPCl group. These findings indicate that remote IPC produces renoprotective effects through multiple mechanisms, and these effects develop over a long timeframe rather than immediately following IPC. PMID:26489007

  19. Remote ischemic precondition prevents radial artery endothelial dysfunction induced by ischemia and reperfusion based on a cyclooxygenase-2-dependent mechanism

    PubMed Central

    Liu, Zhen-Bing; Yang, Wen-Xia; Fu, Xiang-Hua; Zhao, Lin-Feng; Gao, Jun-Ling

    2015-01-01

    Ischemic preconditioning (IPC) and remote ischemic precondition (RIPC) are resistance to ischemia-reperfusion (IR) injury. They have common protective mechanism. Cyclooxygenase (COX)-2 participate in the mechanism of IPC. So, the purpose of this study was to determine whether RIPC protects endothelial function of radial artery in human against IR and whether COX-2 involves in this effect. Endothelial IR injury was induced by arm ischemia (20 min) and reperfusion. Flow-mediated dilation (FMD) of the radial artery was measured before and after IR. RIPC (three 5-min cycles of ischemia of the contralateral arm) was applied immediately and 24 h before IR. All volunteers received the COX-2 inhibitor celecoxib (200 mg orally twice daily) for 5 days. On day 6, all subjects experienced the same studies as described. FMD was reduced by IR without administration of RIPC (P<0.0001). RIPC prevent this impairment of FMD immediately (P=NS) and at 24 h (P=NS). Nevertheless, the COX-2 inhibiter abolished protective effect of RIPC at 24 h (P=NS), but not immediately (P=0.001). After administration of the COX-2 inhibiter, post-IR FMD after RIPC performed immediately had significant increase than after RIPC performed at 24 h (P=0.001) and without administration of RIPC (P=0.003). The COX-2 inhibiter made post-IR FMD evidently decrease after RIPC performed at 24 h (P=0.002). RIPC prevents radial artery endothelial dysfunction induced by IR. This protective effect of RIPC in the late phase is mediated by a COX-2-dependent mechanism. PMID:26885023

  20. Cardioprotective Effect of Extended Remote Ischemic Preconditioning in Patients Undergoing Coronary Artery Bypass Grafting : A Randomized Clinical Trial

    PubMed Central

    Karami, Ali; Khosravi, Mohamad Bagher; Shafa, Masih; Azemati, Simin; Khademi, Saeed; Akhlagh, Seyed Hedayatalla; Maghsodi, Behzad

    2016-01-01

    Background: The cardioprotective effect of ischemic preconditioning has been known for many years. Since the temporary ischemia in the heart may cause lethal cardiac effects, the idea of creating ischemia in organs far from the heart such as limbs was raised as remote ischemic preconditioning (RIPC). We hypothesized that the extension of RIPC has more cardioprotective effect in patients undergoing coronary artery bypass graft (CABG) surgeries. Methods: In this triple-blind randomized clinical trial study, 96 patients were randomly divided into 3 groups and two blood pressure cuffs were placed on both upper and lower extremities. In group A, only upper extremity cuff and in group B upper limb and lower limb cuff was inflated intermittently and group C was the control group. RIPC was induced with three 5-min cycles of cuff inflation about 100 mmHg over the initial systolic blood pressure before starting cardiopulmonary bypass. The primary endpoints were troponin I and creatine phosphokinase-myoglobin isoenzyme (CK-MB). Results: Six hours after the termination of CPB, there was a peak release of the troponin I level in all groups (group A=4.90 ng/ml, group B=4.40 ng/ml, and group C=4.50 ng/ml). There was a rise in plasma CK-MB in all groups postoperatively and there were not any significant differences in troponin I and CK-MB release between the three groups. Conclusion: RIPC induced by upper and lower limb ischemia does not reduce postoperative myocardial enzyme elevation in adult patients undergoing CABG. Trial Registration Number: IRCT2012071710311N1 PMID:27365547

  1. AdVEGF-All6A+ Preconditioning of Murine Ischemic Skin Flaps Is Comparable to Surgical Delay

    PubMed Central

    Gersch, Robert P.; Fourman, Mitchell S.; Phillips, Brett T.; Nasser, Ahmed; McClain, Steve A.; Khan, Sami U.; Dagum, Alexander B.

    2015-01-01

    Background: Surgical flap delay is commonly used in preconditioning reconstructive flaps to prevent necrosis. However, staged procedures are not ideal. Pharmacologic up-regulation of angiogenic and arteriogenic factors before flap elevation poses a nonsurgical approach to improve flap survival. Methods: Male Sprague Dawley rats were divided into control (n = 16), surgical delay (Delay), AdNull, AdEgr-1, and AdVEGF (n ≥ 9/group) groups. Delay rats had a 9 cm × 3 cm cranial based pedicle skin flap incised 10 days prior to elevation. Adenoviral groups received 28 intradermal injections (109 pu/animal total) throughout the distal two thirds of the flap 1 week prior to elevation. At postoperative day (POD) 0 flaps were elevated and silicone sheeting was placed between flap and wound bed. Perfusion analysis in arbitrary perfusion units of the ischemic middle third of the flap using laser Doppler imaging was conducted preoperatively and on POD 0, 3, and 7. Clinical and histopathologic assessments of the skin flaps were performed on POD 7. Results: AdVEGF (50.8 ± 10.9 APU) and AdEgr-1 (39.3 ± 10.6 APU) perfusion levels were significantly higher than controls (16.5 ± 4.2 APU) on POD 7. Delay models were equivalent to controls (25.9 ± 6.8 APU). AdVEGF and Delay animals showed significantly more viable surface area on POD 7 (14.4 ± 1.3 cm2, P < 0.01 and 12.4 ± 1.2 cm2, P < 0.05, respectively) compared with Controls (8.7 ± 0.7 cm2). Conclusions: AdVEGF preconditioning resulted in flap survival comparable to surgical delay. Adenoviral preconditioning maintained perfusion levels postoperatively while surgical delay did not. PMID:26495207

  2. Lost in translation: miRNAs and mRNAs in ischemic preconditioning and ischemia/reperfusion injury.

    PubMed

    Gottlieb, Roberta A; Pourpirali, Somayeh

    2016-06-01

    Ischemic stress involves nutrient deprivation, hypoxia, acidosis, and altered levels of various ions and metabolites. Reperfusion, which abruptly alters these parameters, is a second stress to already stressed cells. Ischemic preconditioning, in which brief ischemia alternates with reperfusion to elicit a protective response to ischemia/reperfusion (I/R) injury, revealed the existence of a highly conserved, cell-autonomous, and nearly ubiquitous program. While we often assume that evolutionary selection is irrelevant with respect to myocardial infarctions-which generally occur long after reproduction-the program of ischemia tolerance may date back much further, to hibernating squirrels, turtles, and estivating frogs and snails (extremophiles), which must survive by entering a hypometabolic state. This relationship is further strengthened by the presence of similar signaling pathways and regulatory mechanisms such as mRNA localization and miRNA regulation. These parallels may offer new insights into the myocardial response to I/R injury. This review will explore some of the recent advances in our understanding of autophagy and mitochondrial turnover in the setting of I/R injury, and related findings drawn from research on hibernating extremophiles. PMID:26582464

  3. Effect of ischemic preconditioning on antioxidant status in the gerbil hippocampal CA1 region after transient forebrain ischemia

    PubMed Central

    Park, Seung Min; Park, Chan Woo; Lee, Tae-Kyeong; Cho, Jeong Hwi; Park, Joon Ha; Lee, Jae-Chul; Chen, Bai Hui; Shin, Bich-Na; Ahn, Ji Hyeon; Tae, Hyun-Jin; Shin, Myoung Cheol; Ohk, Taek Geun; Cho, Jun Hwi; Won, Moo-Ho; Choi, Soo Young; Kim, In Hye

    2016-01-01

    Ischemic preconditioning (IPC) is a condition of sublethal transient global ischemia and exhibits neuroprotective effects against subsequent lethal ischemic insult. We, in this study, examined the neuroprotective effects of IPC and its effects on immunoreactive changes of antioxidant enzymes including superoxide dismutase (SOD) 1 and SOD2, catalase (CAT) and glutathione peroxidase (GPX) in the gerbil hippocampal CA1 region after transient forebrain ischemia. Pyramidal neurons of the stratum pyramidale (SP) in the hippocampal CA1 region of animals died 5 days after lethal transient ischemia without IPC (8.6% (ratio of remanent neurons) of the sham-operated group); however, IPC prevented the pyramidal neurons from subsequent lethal ischemic injury (92.3% (ratio of remanent neurons) of the sham-operated group). SOD1, SOD2, CAT and GPX immunoreactivities in the sham-operated animals were easily detected in pyramidal neurons in the stratum pyramidale (SP) of the hippocampal CA1 region, while all of these immunoreactivities were rarely detected in the stratum pyramidale at 5 days after lethal transient ischemia without IPC. Meanwhile, their immunoreactivities in the sham-operated animals with IPC were similar to (SOD1, SOD2 and CAT) or higher (GPX) than those in the sham-operated animals without IPC. Furthermore, their immunoreactivities in the stratum pyramidale of the ischemia-operated animals with IPC were steadily maintained after lethal ischemia/reperfusion. Results of western blot analysis for SOD1, SOD2, CAT and GPX were similar to immunohistochemical data. In conclusion, IPC maintained or increased the expression of antioxidant enzymes in the stratum pyramidale of the hippocampal CA1 region after subsequent lethal transient forebrain ischemia and IPC exhibited neuroprotective effects in the hippocampal CA1 region against transient forebrain ischemia.

  4. AMPK-Regulated and Akt-Dependent Enhancement of Glucose Uptake Is Essential in Ischemic Preconditioning-Alleviated Reperfusion Injury

    PubMed Central

    Liu, Wenchong; Huang, Qichao; Yang, Weidong; Fu, Feng; Ma, Heng; Su, Hui; Wang, Haichang; Wang, Jing; Zhang, Haifeng; Gao, Feng

    2013-01-01

    Aims Ischemic preconditioning (IPC) is a potent form of endogenous protection. However, IPC-induced cardioprotective effect is significantly blunted in insulin resistance-related diseases and the underlying mechanism is unclear. This study aimed to determine the role of glucose metabolism in IPC-reduced reperfusion injury. Methods Normal or streptozotocin (STZ)-treated diabetic rats subjected to 2 cycles of 5 min ischemia/5 min reperfusion prior to myocardial ischemia (30 min)/reperfusion (3 h). Myocardial glucose uptake was determined by 18F-fluorodeoxyglucose-positron emission tomography (PET) scan and gamma-counter biodistribution assay. Results IPC exerted significant cardioprotection and markedly improved myocardial glucose uptake 1 h after reperfusion (P<0.01) as evidenced by PET images and gamma-counter biodistribution assay in ischemia/reperfused rats. Meanwhile, myocardial translocation of glucose transporter 4 (GLUT4) to plasma membrane together with myocardial Akt and AMPK phosphorylation were significantly enhanced in preconditioned hearts. Intramyocardial injection of GLUT4 siRNA markedly decreased GLUT4 expression and blocked the cardioprotection of IPC as evidence by increased myocardial infarct size. Moreover, the PI3K inhibitor wortmannin significantly inhibited activation of Akt and AMPK, reduced GLUT4 translocation, glucose uptake and ultimately, depressed IPC-induced cardioprotection. Furthermore, IPC-afforded antiapoptotic effect was markedly blunted in STZ-treated diabetic rats. Exogenous insulin supplementation significantly improved glucose uptake via co-activation of myocardial AMPK and Akt and alleviated ischemia/reperfusion injury as evidenced by reduced myocardial apoptosis and infarction size in STZ-treated rats (P<0.05). Conclusions The present study firstly examined the role of myocardial glucose metabolism during reperfusion in IPC using direct genetic modulation in vivo. Augmented glucose uptake via co-activation of myocardial AMPK

  5. Preconditioning with recombinant high-mobility group box 1 induces ischemic tolerance in a rat model of focal cerebral ischemia-reperfusion.

    PubMed

    Wang, Chen; Liu, Xiao-Xi; Huang, Kai-Bin; Yin, Su-Bing; Wei, Jing-Jing; Hu, Ya-Fang; Gu, Yong; Zheng, Guo-Qing

    2016-05-01

    Preconditioning with ligands of toll-like receptors (TLRs) is a powerful neuroprotective approach whereby a low dose of stimulus confers significant protection against subsequent substantial brain damage by reprogramming the ischemia-activated TLRs signaling. Herein, we aim to explore whether preconditioning with recombinant high-mobility group box 1 (rHMGB1), one of the TLRs ligands, decreases cerebral ischemia-reperfusion injury (IRI). Rats were intracerebroventricularly pretreated with rHMGB1, 1 or 3 days before induction of middle cerebral artery occlusion. Results showed that preconditioning with rHMGB1 1 day, but not 3 days, prior to ischemia dramatically reduced neurological deficits, infarct size, brain swelling, cell apoptosis, and blood-brain barrier permeability. Interleukin-1R-associated kinase-M (IRAK-M), a critical negative regulator of TLRs signaling, was robustly increased in response to brain IRI and was further elevated by rHMGB1 pretreatment, indicating its role associated with the rHMGB1 preconditioning-mediated ischemic tolerance. In vitro and in vivo assays indicated that the induced IRAK-M expression was localized in microglia. In addition, TLR4 specific inhibitor TAK-242 abolished the neuroprotective effects and the induction of IRAK-M offered by rHMGB1 preconditioning. Collectively, our study demonstrates that rHMGB1 preconditioning is neuroprotective during cerebral IRI, which is associated with activated TLR4/IRAK-M signaling in microglia. We found that high-mobility group box 1 (HMGB1) pretreatment conditioned the brain against subsequent ischemia-reperfusion injury. We propose the following mechanism for HMGB1 preconditioning-mediated ischemic tolerance: through toll-like receptor TLR4, HMGB1 preconditioning magnifies the up-regulation of interleukin-1R-associated kinase-M (IRAK-M) induced by ischemia-reperfusion in microglia, resulting in the decreased phosphorylation of IRAK-1. These findings are helpful in understanding the

  6. Lithium microdialysis and its use for monitoring of stomach and colon submucosal blood perfusion--a pilot study using ischemic preconditioning in rats.

    PubMed

    Cibicek, Norbert; Micuda, Stanislav; Chládek, Jaroslav; Zivný, Pavel; Zadák, Zdenek; Cermáková, Eva; Palicka, Vladimír

    2006-01-01

    During shock, exposure of gut to ischemia determines patient's survival. Ischemic preconditioning (ISP) elevates nitric oxide and blood perfusion, whereby it protects organs against subsequent severe ischemia/reperfusion. Using appropriate flow marker, microdialysis may serve to monitor interstitial microcirculation. Hence, our aim was to test the reliability of lithium as a flow marker (lithium microdialysis, LM) on an ISP model. Rats were divided into three groups. Two (ischemic and preconditioned) groups underwent 30 min celiac artery occlusion (CAO) with 2.5 h reperfusion. 25 min before CAO, the latter experienced 5 min ischemia. Sham-operated animals served as controls. LM in stomach and colon submucosa, serum nitric oxide, hepatic and pancreatic enzymes were measured. In stomach, LM indicated a decrease in blood perfusion evoked by CAO (p < 0.01) in both experimental groups. During reperfusion, the ischemic animals showed a restoration of microcirculation, unlike the preconditioned ones, whose blood perfusion failed to regenerate (p < 0.001). For any group, LM showed no microcirculation modification in colon. Serum analytes remained unchanged. We conclude that LM appears to be a potentially suitable indicator of gastrointestinal interstitial microcirculation. However, we failed to demonstrate any beneficial effect of ISP on pancreas, systemic nitric oxide and local/remote microcirculation within studied organs. PMID:17438835

  7. Ischemic preconditioning does not improve peak exercise capacity at sea level or simulated high altitude in trained male cyclists.

    PubMed

    Hittinger, Elizabeth A; Maher, Jennifer L; Nash, Mark S; Perry, Arlette C; Signorile, Joseph F; Kressler, Jochen; Jacobs, Kevin A

    2015-01-01

    Ischemic preconditioning (IPC) may improve blood flow and oxygen delivery to tissues, including skeletal muscle, and has the potential to improve intense aerobic exercise performance, especially that which results in arterial hypoxemia. The aim of the study was to determine the effects of IPC of the legs on peak exercise capacity (W(peak)), submaximal and peak cardiovascular hemodynamics, and peripheral capillary oxygen saturation (SpO2) in trained males at sea level (SL) and simulated high altitude (HA; 13.3% FIO2, ∼ 3650 m). Fifteen highly trained male cyclists and triathletes completed 2 W(peak) tests (SL and HA) and 4 experimental exercise trials (10 min at 55% altitude-specific W(peak) then increasing by 30 W every 2 min until exhaustion) with and without IPC. HA resulted in significant arterial hypoxemia during exercise compared with SL (73% ± 6% vs. 93% ± 4% SpO2, p < 0.001) that was associated with 21% lower W(peak) values. IPC did not significantly improve W(peak) at SL or HA. Additionally, IPC failed to improve cardiovascular hemodynamics or SpO2 during submaximal exercise or at W(peak). In conclusion, IPC performed 45 min prior to exercise does not improve W(peak) or systemic oxygen delivery during submaximal or peak exercise at SL or HA. Future studies must examine the influence of IPC on local factors, such as working limb blood flow, oxygen delivery, and arteriovenous oxygen difference as well as whether the effectiveness of IPC is altered by the volume of muscle made ischemic, the timing prior to exercise, and high altitude acclimatization. PMID:25474566

  8. Hippocampal hypertrophy and sleep apnea: a role for the ischemic preconditioning?

    PubMed

    Rosenzweig, Ivana; Kempton, Matthew J; Crum, William R; Glasser, Martin; Milosevic, Milan; Beniczky, Sandor; Corfield, Douglas R; Williams, Steven C; Morrell, Mary J

    2013-01-01

    The full impact of multisystem disease such as obstructive sleep apnoea (OSA) on regions of the central nervous system is debated, as the subsequent neurocognitive sequelae are unclear. Several preclinical studies suggest that its purported major culprits, intermittent hypoxia and sleep fragmentation, can differentially affect adult hippocampal neurogenesis. Although the prospective biphasic nature of chronic intermittent hypoxia in animal models of OSA has been acknowledged, so far the evidence for increased 'compensatory' neurogenesis in humans is uncertain. In a cross-sectional study of 32 patients with mixed severity OSA and 32 non-apnoeic matched controls inferential analysis showed bilateral enlargement of hippocampi in the OSA group. Conversely, a trend for smaller thalami in the OSA group was noted. Furthermore, aberrant connectivity between the hippocampus and the cerebellum in the OSA group was also suggested by the correlation analysis. The role for the ischemia/hypoxia preconditioning in the neuropathology of OSA is herein indicated, with possible further reaching clinical implications. PMID:24349453

  9. The activation of p38alpha, and not p38beta, mitogen-activated protein kinase is required for ischemic preconditioning

    PubMed Central

    Sicard, Pierre; Clark, James E.; Jacquet, Sebastien; Mohammadi, Shahrooz; Arthur, J. Simon C.; O'Keefe, Stephen J.; Marber, Michael S.

    2010-01-01

    Numerous studies show that pharmacological inhibition of p38 mitogen-activated protein kinases (p38s) before lethal ischemia prevents conditioning. However, these inhibitors have off-target effects and do not discriminate between the alpha and beta isoforms; the activation of which is thought to have diverse and perhaps opposing actions with p38α aggravating, and p38β reducing, myocardial injury. We adopted a chemical genetic approach using mice in which either the p38α (DRα) or p38β (DRβ) alleles were targeted to substitute the “gatekeeper” threonine residue for methionine, thereby preventing the binding of a pharmacological inhibitor, SB203580. Isolated, perfused wild-type (WT), DRα and DRβ mouse hearts underwent ischemic preconditioning with 4 cycles of 4 min ischemia/6 min reperfusion, with or without SB203580 (10 µM), followed by 30 min of global ischemia and 120 min of reperfusion. In WT and DRβ hearts, SB203580 completely abolished the reduction in myocardial infarction seen with preconditioning and also the phosphorylation of downstream substrates of p38. These effects of SB203580 were not seen in DRα hearts. Furthermore ischemic preconditioning occurred unaltered in p38β null hearts. Contrary to expectation the activation of p38α, and not p38β, is necessary for ischemic preconditioning. Since p38α is also the isoform that leads to lethal myocardial injury, it is unlikely that targeted therapeutic strategies to achieve isoform-selective inhibition will only prevent the harmful consequences of activation. PMID:20188737

  10. Effects of ischemic preconditioning on VEGF and pFlk-1 immunoreactivities in the gerbil ischemic hippocampus after transient cerebral ischemia.

    PubMed

    Park, Yoo Seok; Cho, Jun Hwi; Kim, In Hye; Cho, Geum-Sil; Cho, Jeong-Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Shin, Myoung Cheol; Tae, Hyun-Jin; Cho, Young Shin; Lee, Yun Lyul; Kim, Young-Myeong; Won, Moo-Ho; Lee, Jae-Chul

    2014-12-15

    Ischemia preconditioning (IPC) displays an important adaptation of the CNS to sub-lethal ischemia. In the present study, we examined the effect of IPC on immunoreactivities of VEGF-, and phospho-Flk-1 (pFlk-1) following transient cerebral ischemia in gerbils. The animals were randomly assigned to four groups (sham-operated-group, ischemia-operated-group, IPC plus (+) sham-operated-group, and IPC+ischemia-operated-group). IPC was induced by subjecting gerbils to 2 min of ischemia followed by 1 day of recovery. In the ischemia-operated-group, a significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) alone 5 days after ischemia-reperfusion, however, in all the IPC+ischemia-operated-groups, pyramidal neurons in the SP were well protected. In immunohistochemical study, VEGF immunoreactivity in the ischemia-operated-group was increased in the SP at 1 day post-ischemia and decreased with time. Five days after ischemia-reperfusion, strong VEGF immunoreactivity was found in non-pyramidal cells, which were identified as pericytes, in the stratum oriens (SO) and radiatum (SR). In the IPC+sham-operated- and IPC+ischemia-operated-groups, VEGF immunoreactivity was significantly increased in the SP. pFlk-1 immunoreactivity in the sham-operated- and ischemia-operated-groups was hardly found in the SP, and, from 2 days post-ischemia, pFlk-1 immunoreactivity was strongly increased in non-pyramidal cells, which were identified as pericytes. In the IPC+sham-operated-group, pFlk-1 immunoreactivity was significantly increased in both pyramidal and non-pyramidal cells; in the IPC+ischemia-operated-groups, the similar pattern of VEGF immunoreactivity was found in the ischemic CA1, although the VEGF immunoreactivity was strong in non-pyramidal cells at 5 days post-ischemia. In brief, our findings show that IPC dramatically augmented the induction of VEGF and pFlk-1 immunoreactivity in the pyramidal cells of the CA1 after ischemia

  11. Postoperative Neurocognitive Dysfunction in Patients Undergoing Cardiac Surgery after Remote Ischemic Preconditioning: A Double-Blind Randomized Controlled Pilot Study

    PubMed Central

    Meybohm, Patrick; Renner, Jochen; Broch, Ole; Caliebe, Dorothee; Albrecht, Martin; Cremer, Jochen; Haake, Nils; Scholz, Jens; Zacharowski, Kai; Bein, Berthold

    2013-01-01

    Background Remote ischemic preconditioning (RIPC) has been shown to enhance the tolerance of remote organs to cope with a subsequent ischemic event. We hypothesized that RIPC reduces postoperative neurocognitive dysfunction (POCD) in patients undergoing complex cardiac surgery. Methods We conducted a prospective, randomized, double-blind, controlled trial including 180 adult patients undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomized either to RIPC or to control group. Primary endpoint was postoperative neurocognitive dysfunction 5–7 days after surgery assessed by a comprehensive test battery. Cognitive change was assumed if the preoperative to postoperative difference in 2 or more tasks assessing different cognitive domains exceeded more than one SD (1 SD criterion) or if the combined Z score was 1.96 or greater (Z score criterion). Results According to 1 SD criterion, 52% of control and 46% of RIPC patients had cognitive deterioration 5–7 days after surgery (p = 0.753). The summarized Z score showed a trend to more cognitive decline in the control group (2.16±5.30) compared to the RIPC group (1.14±4.02; p = 0.228). Three months after surgery, incidence and severity of neurocognitive dysfunction did not differ between control and RIPC. RIPC tended to decrease postoperative troponin T release at both 12 hours [0.60 (0.19–1.94) µg/L vs. 0.48 (0.07–1.84) µg/L] and 24 hours after surgery [0.36 (0.14–1.89) µg/L vs. 0.26 (0.07–0.90) µg/L]. Conclusions We failed to demonstrate efficacy of a RIPC protocol with respect to incidence and severity of POCD and secondary outcome variables in patients undergoing a wide range of cardiac surgery. Therefore, definitive large-scale multicenter trials are needed. Trial Registration ClinicalTrials.gov NCT00877305 PMID:23741380

  12. Effect of remote ischemic preconditioning on cognitive function after off-pump coronary artery bypass graft: a pilot study

    PubMed Central

    Joung, Kyoung-Woon; Rhim, Jin-Ho; Chin, Ji-Hyun; Kim, Wook-Jong; Choi, Dae-Kee; Lee, Eun-Ho; Hahm, Kyung-Don; Sim, Ji-Yeon

    2013-01-01

    Background Several studies have shown in animal models that remote ischemic preconditioning (rIPC) has a neuroprotective effect. However, a randomized controlled trial in human subjects to investigate the neuroprotective effect of rIPC after cardiac surgery has not yet been reported. Therefore, we performed this pilot study to determine whether rIPC reduced the occurrence of postoperative cognitive dysfunction in patients who underwent off-pump coronary artery bypass graft (OPCAB) surgery. Methods Seventy patients who underwent OPCAB surgery were assigned to either the control or the rIPC group using a computer-generated randomization table. The application of rIPC consisted of four cycles of 5 min ischemia and 5 min reperfusion on an upper limb using a blood pressure cuff inflating 200 mmHg before coronary artery anastomosis. The cognitive function tests were performed one day before surgery and again on postoperative day 7. We defined postoperative cognitive dysfunction as decreased postoperative test values more than 20% of the baseline values in more than two of the six cognitive function tests that were performed. Results In the cognitive function tests, there were no significant differences in the results obtained during the preoperative and postoperative periods for all tests and there were no mean differences observed in the preoperative and postoperative scores. The incidences of postoperative cognitive dysfunction in the control and rIPC groups were 28.6% (10 patients) and 31.4% (11 patients), respectively. Conclusions rIPC did not reduce the incidence of postoperative cognitive dysfunction after OPCAB surgery during the immediate postoperative period. PMID:24363844

  13. Characterization of acute ischemia‐related physiological responses associated with remote ischemic preconditioning: a randomized controlled, crossover human study

    PubMed Central

    Sharma, Vikram; Cunniffe, Brian; Verma, Amit P.; Cardinale, Marco; Yellon, Derek

    2014-01-01

    Abstract Remote Ischemic Preconditioning (RIPC) is emerging as a new noninvasive intervention that has the potential to protect a number of organs against ischemia–reperfusion (IR) injury. The standard protocols normally used to deliver RIPC involve a number of cycles of inflation of a blood pressure (BP) cuff on the arm and/or leg to an inflation pressure of 200 mmHg followed by cuff deflation for a short period of time. There is little evidence to support what limb (upper or lower) or cuff inflation pressures are most effective to deliver this intervention without causing undue discomfort/pain in nonanesthetized humans. In this preliminary study, a dose–response assessment was performed using a range of cuff inflation pressures (140, 160, and 180 mmHg) to induce limb ischemia in upper and lower limbs. Physiological changes in the occluded limb and any pain/discomfort associated with RIPC with each cuff inflation pressure were determined. Results showed that ischemia can be induced in the upper limb at much lower cuff inflation pressures compared with the standard 200 mmHg pressure generally used for RIPC, provided the cuff inflation pressure is ~30 mmHg higher than the resting systolic BP. In the lower limb, a higher inflation pressure, (~55 mmHg > resting systolic BP), is required to induce ischemia. Cyclical changes in capillary blood O2, CO2, and lactate levels during the RIPC stimulus were observed. RIPC at higher cuff inflation pressures of 160 and 180 mmHg was better tolerated in the upper limb. In summary, limb ischemia for RIPC can be more easily induced at lower pressures and is much better tolerated in the upper limb in young healthy individuals. However, whether benefits of RIPC can also be derived with protocols delivered to the upper limb using lower cuff inflation pressures and with lesser discomfort compared to the lower limb, remains to be investigated. PMID:25413320

  14. Monocarboxylate transporter 4 plays a significant role in the neuroprotective mechanism of ischemic preconditioning in transient cerebral ischemia.

    PubMed

    Hong, Seongkweon; Ahn, Ji Yun; Cho, Geum-Sil; Kim, In Hye; Cho, Jeong Hwi; Ahn, Ji Hyeon; Park, Joon Ha; Won, Moo-Ho; Chen, Bai Hui; Shin, Bich-Na; Tae, Hyun-Jin; Park, Seung Min; Cho, Jun Hwi; Choi, Soo Young; Lee, Jae-Chul

    2015-10-01

    Monocarboxylate transporters (MCTs), which carry monocarboxylates such as lactate across biological membranes, have been associated with cerebral ischemia/reperfusion process. In this study, we studied the effect of ischemic preconditioning (IPC) on MCT4 immunoreactivity after 5 minutes of transient cerebral ischemia in the gerbil. Animals were randomly designated to four groups (sham-operated group, ischemia only group, IPC + sham-operated group and IPC + ischemia group). A serious loss of neuron was found in the stratum pyramidale of the hippocampal CA1 region (CA1), not CA2/3, of the ischemia-only group at 5 days post-ischemia; however, in the IPC + ischemia groups, neurons in the stratum pyramidale of the CA1 were well protected. Weak MCT4 immunoreactivity was found in the stratum pyramidale of the CA1 in the sham-operated group. MCT4 immunoreactivity in the stratum pyramidale began to decrease at 2 days post-ischemia and was hardly detected at 5 days post-ischemia; at this time point, MCT4 immunoreactivity was newly expressed in astrocytes. In the IPC + sham-operated group, MCT4 immunoreactivity in the stratum pyramidale of the CA1 was increased compared with the sham-operated group, and, in the IPC + ischemia group, MCT4 immunoreactivity was also increased in the stratum pyramidale compared with the ischemia only group. Briefly, present findings show that IPC apparently protected CA1 pyramidal neurons and increased or maintained MCT4 expression in the stratum pyramidale of the CA1 after transient cerebral ischemia. Our findings suggest that MCT4 appears to play a significant role in the neuroprotective mechanism of IPC in the gerbil with transient cerebral ischemia. PMID:26692857

  15. Remote ischemic preconditioning confers late protection against myocardial ischemia-reperfusion injury in mice by upregulating interleukin-10

    PubMed Central

    Parajuli, Nirmal; Zheng, Xiaoxu; Becker, Lewis

    2013-01-01

    Remote ischemic preconditioning (RIPC) induces a prolonged late phase of multi-organ protection against ischemia-reperfusion (IR) injury. In the present study, we tested the hypothesis that RIPC confers late protection against myocardial IR injury by upregulating expression of interleukin (IL)-10. Mice were exposed to lower limb RIPC or sham ischemia. After 24 h, mice with RIPC demonstrated decreased myocardial infarct size and improved cardiac contractility following 30-min ischemia and 120-min reperfusion (I-30/R-120). These effects of RIPC were completely blocked by anti-IL-10 receptor antibodies. In IL-10 knockout mice, RIPC cardioprotection was lost, but it was mimicked by exogenous IL-10. Administration of IL-10 to isolated perfused hearts increased phosphory-lation of the protein kinase Akt and limited infarct size after I-30/R-120. In wild-type mice, RIPC increased plasma and cardiac IL-10 protein levels and caused activation of Akt and endothelial nitric oxide synthase in the heart at 24 h, which was also blocked by anti-IL-10 receptor antibodies. In the gastrocnemius muscle, RIPC resulted in immediate inactivation of the phosphatase PTEN and activation of Stat3, with increased IL-10 expression 24 h later. Myocyte-specific PTEN inactivation led to increased Stat3 phosphorylation and IL-10 protein expression in the gastrocnemius muscle. Taken together, these results suggest that RIPC induces late protection against myocardial IR injury by increasing expression of IL-10 in the remote muscle, followed by release of IL-10 into the circulation, and activation of protective signaling pathways in the heart. This study provides a scientific basis for the use of RIPC to confer systemic protection against IR injury. PMID:22752341

  16. Monocarboxylate transporter 4 plays a significant role in the neuroprotective mechanism of ischemic preconditioning in transient cerebral ischemia

    PubMed Central

    Hong, Seongkweon; Ahn, Ji Yun; Cho, Geum-Sil; Kim, In Hye; Cho, Jeong Hwi; Ahn, Ji Hyeon; Park, Joon Ha; Won, Moo-Ho; Chen, Bai Hui; Shin, Bich-Na; Tae, Hyun-Jin; Park, Seung Min; Cho, Jun Hwi; Choi, Soo Young; Lee, Jae-Chul

    2015-01-01

    Monocarboxylate transporters (MCTs), which carry monocarboxylates such as lactate across biological membranes, have been associated with cerebral ischemia/reperfusion process. In this study, we studied the effect of ischemic preconditioning (IPC) on MCT4 immunoreactivity after 5 minutes of transient cerebral ischemia in the gerbil. Animals were randomly designated to four groups (sham-operated group, ischemia only group, IPC + sham-operated group and IPC + ischemia group). A serious loss of neuron was found in the stratum pyramidale of the hippocampal CA1 region (CA1), not CA2/3, of the ischemia-only group at 5 days post-ischemia; however, in the IPC + ischemia groups, neurons in the stratum pyramidale of the CA1 were well protected. Weak MCT4 immunoreactivity was found in the stratum pyramidale of the CA1 in the sham-operated group. MCT4 immunoreactivity in the stratum pyramidale began to decrease at 2 days post-ischemia and was hardly detected at 5 days post-ischemia; at this time point, MCT4 immunoreactivity was newly expressed in astrocytes. In the IPC + sham-operated group, MCT4 immunoreactivity in the stratum pyramidale of the CA1 was increased compared with the sham-operated group, and, in the IPC + ischemia group, MCT4 immunoreactivity was also increased in the stratum pyramidale compared with the ischemia only group. Briefly, present findings show that IPC apparently protected CA1 pyramidal neurons and increased or maintained MCT4 expression in the stratum pyramidale of the CA1 after transient cerebral ischemia. Our findings suggest that MCT4 appears to play a significant role in the neuroprotective mechanism of IPC in the gerbil with transient cerebral ischemia. PMID:26692857

  17. Transcriptome Analysis of Renal Ischemia/Reperfusion Injury and Its Modulation by Ischemic Pre-Conditioning or Hemin Treatment

    PubMed Central

    Amano, Mariane Tami; Gonçalves, Giselle Martins; Hyane, Meire Ioshie; Cenedeze, Marcos Antonio; Renesto, Paulo Guilherme; Pacheco-Silva, Alvaro; Moreira-Filho, Carlos Alberto; Câmara, Niels Olsen Saraiva

    2012-01-01

    Ischemia/reperfusion injury (IRI) is a leading cause of acute renal failure. The definition of the molecular mechanisms involved in renal IRI and counter protection promoted by ischemic pre-conditioning (IPC) or Hemin treatment is an important milestone that needs to be accomplished in this research area. We examined, through an oligonucleotide microarray protocol, the renal differential transcriptome profiles of mice submitted to IRI, IPC and Hemin treatment. After identifying the profiles of differentially expressed genes observed for each comparison, we carried out functional enrichment analysis to reveal transcripts putatively involved in potential relevant biological processes and signaling pathways. The most relevant processes found in these comparisons were stress, apoptosis, cell differentiation, angiogenesis, focal adhesion, ECM-receptor interaction, ion transport, angiogenesis, mitosis and cell cycle, inflammatory response, olfactory transduction and regulation of actin cytoskeleton. In addition, the most important overrepresented pathways were MAPK, ErbB, JAK/STAT, Toll and Nod like receptors, Angiotensin II, Arachidonic acid metabolism, Wnt and coagulation cascade. Also, new insights were gained about the underlying protection mechanisms against renal IRI promoted by IPC and Hemin treatment. Venn diagram analysis allowed us to uncover common and exclusively differentially expressed genes between these two protective maneuvers, underscoring potential common and exclusive biological functions regulated in each case. In summary, IPC exclusively regulated the expression of genes belonging to stress, protein modification and apoptosis, highlighting the role of IPC in controlling exacerbated stress response. Treatment with the Hmox1 inducer Hemin, in turn, exclusively regulated the expression of genes associated with cell differentiation, metabolic pathways, cell cycle, mitosis, development, regulation of actin cytoskeleton and arachidonic acid metabolism

  18. Remote Ischemic Preconditioning (RIPC) Modifies the Plasma Proteome in Children Undergoing Repair of Tetralogy of Fallot: A Randomized Controlled Trial

    PubMed Central

    Hepponstall, Michele; Ignjatovic, Vera; Binos, Steve; Attard, Chantal; Karlaftis, Vasiliki; d’Udekem, Yves; Monagle, Paul; Konstantinov, Igor E.

    2015-01-01

    Background Remote ischemic preconditioning (RIPC) has been applied in paediatric cardiac surgery. We have demonstrated that RIPC induces a proteomic response in plasma of healthy volunteers. We tested the hypothesis that RIPC modifies the proteomic response in children undergoing Tetralogy of Fallot (TOF) repair. Methods and Results Children (n=40) were randomized to RIPC and control groups. Blood was sampled at baseline, after cardiopulmonary bypass (CPB) and 6, 12 and 24h post-CPB. Plasma was analysed by liquid chromatography mass spectrometry (LC-MS) in an untargeted approach. Peptides demonstrating differential expression (p<0.01) were subjected to tandem LC-MS/MS and protein identification. Corresponding proteins were identified using the NCBI protein database. There was no difference in age (7.3±3.5vs6.8±3.6 months)(p=0.89), weight (7.7±1.8vs7.5±1.9 kg)(p=0.71), CPB time (104±7vs94±7 min)(p=0.98) or aortic cross-clamp time (83±22vs75±20 min)(p=0.36). No peptides were differentially expressed at baseline or immediately after CPB. There were 48 peptides with higher expression in the RIPC group 6h post-CPB. This was no longer evident at 12 or 24h, with one peptide down-regulated in the RIPC group. The proteins identified were: inter-alpha globulin inhibitor (42.0±11.8 vs 820.8±181.1, p=0.006), fibrinogen preproprotein (59.3±11.2 vs 1192.6±278.3, p=0.007), complement-C3 precursor (391.2±160.9 vs 5385.1±689.4, p=0.0005), complement C4B (151.5±17.8 vs 4587.8±799.2, p=0.003), apolipoprotein B100 (53.4±8.3 vs 1364.5±278.2, p=0.005) and urinary proteinase inhibitor (358.6±74.9 vs 5758.1±1343.1, p=0.009). These proteins are involved in metabolism, haemostasis, immunity and inflammation. Conclusions We provided the first comprehensive analysis of RIPC-induced proteomic changes in children undergoing surgery. The proteomic changes peak 6h post-CPB and return to baseline within 24h of surgery. Trial Registration ACTR.org.au ACTRN12610000496011 PMID

  19. Remote ischemic preconditioning mitigates myocardial and neurological dysfunction via K(ATP) channel activation in a rat model of hemorrhagic shock.

    PubMed

    Hu, Xianwen; Yang, Zhengfei; Yang, Min; Qian, Jie; Cahoon, Jena; Xu, Jiefeng; Sun, Shijie; Tang, Wanchun

    2014-09-01

    Severe hemorrhagic shock and resuscitation is a state of global body ischemia and reperfusion that causes myocardial and cerebral dysfunction. We investigated whether remote ischemic preconditioning (RIPC) would reduce myocardial and cerebral ischemia and reperfusion injuries after hemorrhagic shock as the result of the K(ATP) channel activation. Twenty-one male rats were randomized into three groups: RIPC, RIPC with K(ATP) channel blocker, and control. Remote ischemic preconditioning was induced by four cycles of 5 min of limb ischemia followed by reperfusion for 5 min. Hemorrhagic shock was induced by removing 50% of the estimated total blood volume during an interval of 1 h. Thirty minutes after the completion of bleeding, the animals were reinfused with shed blood during the ensuing 30 min. The animals were monitored for 2 h and observed for an additional 72 h. Myocardial function was measured by echocardiography, and sublingual microcirculation was measured by a sidestream dark-field imaging device at baseline, 1 h after bleeding, 30 min after the completion of bleeding, 30 min after reinfusion, and hourly intervals thereafter. The survival and neurological function were evaluated at 12, 24, 48, and 72 h after reinfusion. At 2 h after reinfusion, ejection fraction and myocardial performance index were significantly better in the RIPC group than in the control group (P < 0.01). The sublingual microvascular flow index and perfused vessel density were significantly greater after reinfusion in the RIPC group than that in the control group (P < 0.01). The duration of survival was significantly longer, and neurological deficit score was significantly better in the RIPC group than the control animals (P < 0.01). Pretreatment with the K(ATP) channel blocker (glibenclamide) completely abolished the myocardial and cerebral protective effects of RIPC. We demonstrate, for the first time, that after severe hemorrhagic shock and resuscitation, RIPC mitigated myocardial and

  20. Protein SUMOylation is massively increased in hibernation torpor and is critical for the cytoprotection provided by ischemic preconditioning and hypothermia in SHSY5Y cells

    PubMed Central

    Lee, Yang-ja; Miyake, Shin-ichi; Wakita, Hideaki; McMullen, David C; Azuma, Yoshiaki; Auh, Sungyoung; Hallenbeck, John M

    2008-01-01

    Hibernation torpor provides an excellent natural model of tolerance to profound reductions in blood flow to the brain and other organs. Here, we report that during torpor of 13-lined ground squirrels, massive SUMOylation occurs in the brain, liver, and kidney. The level of small ubiquitin-related modifier (SUMO) conjugation coincides with the expression level of Ubc9, the SUMO specific E2-conjugating enzyme. Hypothermia alone also increased SUMO conjugation, but not as markedly as hibernation torpor. Increased SUMO conjugation (induced by Ubc9 overexpression, ischemic preconditioning (PC)±hypothermia) was necessary and sufficient for tolerance of SHSY5Y neuroblastoma cells to oxygen/glucose deprivation (OGD) (‘in vitro ischemia’); decreased SUMO conjugation (induced by a dominant-negative Ubc9) severely reduced tolerance to OGD in these cells. These data indicate that post-translational modification of proteins by SUMOylation is a prominent feature of hibernation torpor and is critical for cytoprotection by ischemic PC± hypothermia in SHSY5Y cells subjected to OGD. PMID:16955077

  1. Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation

    PubMed Central

    Sun, Meiyan; Deng, Bin; Zhao, Xiaoyong; Gao, Changjun; Yang, Lu; Zhao, Hui; Yu, Daihua; Zhang, Feng; Xu, Lixian; Chen, Lei; Sun, Xude

    2015-01-01

    Excessive microglial activation often contributes to inflammation-mediated neurotoxicity in the ischemic penumbra during the acute stage of ischemic stroke. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation via the NF-κB pathway. Isoflurane preconditioning (IP) can provide neuroprotection and inhibit microglial activation. In this study, we investigated the roles of the TLR4 signalling pathway in IP to exert neuroprotection following ischemic stroke in vivo and in vitro. The results showed that 2% IP alleviated neurological deficits, reduced the infarct volume, attenuated apoptosis and weakened microglial activation in the ischemic penumbra. Furthermore, IP down-regulated the expression of HSP 60, TLR4 and MyD88 and up-regulated inhibitor of IκB-α expression compared with I/R group in vivo. In vitro, 2% IP and a specific inhibitor of TLR4, CLI-095, down-regulated the expression of TLR4, MyD88, IL-1β, TNF-α and Bax, and up-regulated IκB-α and Bcl-2 expression compared with OGD group. Moreover, IP and CLI-095 attenuated microglial activation-induced neuronal apoptosis, and overexpression of the TLR4 gene reversed the neuroprotective effects of IP. In conclusion, IP provided neuroprotection by regulating TLR4 expression directly, alleviating microglial activation and neuroinflammation. Thus, inhibiting the activation of microglial activation via TLR4 may be a new avenue for stroke treatment. PMID:26086415

  2. Neuroprotection of Ischemic Preconditioning is Mediated by Anti-inflammatory, Not Pro-inflammatory, Cytokines in the Gerbil Hippocampus Induced by a Subsequent Lethal Transient Cerebral Ischemia.

    PubMed

    Kim, Dong Won; Lee, Jae-Chul; Cho, Jeong-Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Tae, Hyun-Jin; Seo, Jeong Yeol; Cho, Jun Hwi; Kang, Il Jun; Hong, Seongkweon; Kim, Young-Myeong; Won, Moo-Ho; Kim, In Hye

    2015-09-01

    Ischemic preconditioning (IPC) induced by sublethal transient cerebral ischemia could reduce neuronal damage/death following a subsequent lethal transient cerebral ischemia. We, in this study, compared expressions of interleukin (IL)-2 and tumor necrosis factor (TNF)-α as pro-inflammatory cytokines, and IL-4 and IL-13 as anti-inflammatory cytokines in the gerbil hippocampal CA1 region between animals with lethal ischemia and ones with IPC followed by lethal ischemia. In the animals with lethal ischemia, pyramidal neurons in the stratum pyramidale (SP) of the hippocampal CA1 region were dead at 5 days post-ischemia; however, IPC protected the CA1 pyramidal neurons from lethal ischemic injury. Expressions of all cytokines were significantly decreased in the SP after lethal ischemia and hardly detected in the SP at 5 days post-ischemia because the CA1 pyramidal neurons were dead. IPC increased expressions of anti-inflammatory cytokines (IL-4 and IL-13) in the stratum pyramidale of the CA1 region following no lethal ischemia (sham-operation), and the increased expressions of IL-4 and IL-13 by IPC were continuously maintained is the SP of the CA1 region after lethal ischemia. However, pro-inflammatory cytokines (IL-2 and TNF-α) in the SP of the CA1 region were similar those in the sham-operated animals with IPC, and the IL-4 and IL-13 expressions in the SP were maintained after lethal ischemia. In conclusion, this study shows that anti-inflammatory cytokines significantly increased and longer maintained by IPC and this might be closely associated with neuroprotection after lethal transient cerebral ischemia. PMID:26290267

  3. Effect of ischemic preconditioning on the expression of c-myb in the CA1 region of the gerbil hippocampus after ischemia/reperfusion injury

    PubMed Central

    Lee, Hui Young; Tae, Hyun-Jin; Cho, Geum-Sil; Kim, In Hye; Cho, Jeong Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Won, Moo-Ho; Park, Chan Woo; Cho, Jun Hwi; Seo, Jeong Yeol; Lee, Jae-Chul

    2016-01-01

    Objective(s): In the present study, we investigated the effect of ischemic preconditioning (IPC) on c-myb immunoreactivity as well as neuronal damage/death after a subsequent lethal transient ischemia in gerbils. Materials and Methods: IPC was subjected to a 2 min sublethal ischemia and a lethal transient ischemia was given 5 min transient ischemia. The animals in all of the groups were given recovery times of 1 day, 2 days and 5 days and we examined change in c-myb immunoreactivity as well as neuronal damage/death in the hippocampus induced by a lethal transient ischemia. Results: A lethal transient ischemia induced a significant loss of cells in the stratum pyramidale (SP) of the hippocampal CA1 region at 5 days post-ischemia, and this insult showed that c-myb immunoreactivity in cells of the SP of the CA1 region was significantly decreased at 2 days post-ischemia and disappeared at 5 days post-ischemia. However, IPC effectively prevented the neuronal loss in the SP and showed that c-myb immunoreactivity was constitutively maintained in the SP after a lethal transient ischemia. Conclusion: Our results show that a lethal transient ischemia significantly decreased c-myb immunoreactivity in the SP of the CA1 region and that IPC well preserved c-myb immunoreactivity in the SP of the CA1 region. We suggest that the maintenance of c-myb might be related with IPC-mediated neuroprotection after a lethal ischemic insult. PMID:27482343

  4. Molecular mechanism of preconditioning.

    PubMed

    Das, Manika; Das, Dipak K

    2008-04-01

    During the last 20 years, since the appearance of the first publication on ischemic preconditioning (PC), our knowledge of this phenomenon has increased exponentially. PC is defined as an increased tolerance to ischemia and reperfusion induced by previous sublethal period ischemia. This is the most powerful mechanism known to date for limiting the infract size. This adaptation occurs in a biphasic pattern (i) early preconditioning (lasts for 2-3 h) and (ii) late preconditioning (starting at 24 h lasting until 72-96 h after initial ischemia). Early preconditioning is more potent than delayed preconditioning in reducing infract size. Late preconditioning attenuates myocardial stunning and requires genomic activation with de novo protein synthesis. Early preconditioning depends on adenosine, opioids and to a lesser degree, on bradykinin and prostaglandins, released during ischemia. These molecules activate G-protein-coupled receptor, initiate activation of K(ATP) channel and generate oxygen-free radicals, and stimulate a series of protein kinases, which include protein kinase C, tyrosine kinase, and members of MAP kinase family. Late preconditioning is triggered by a similar sequence of events, but in addition essentially depends on newly synthesized proteins, which comprise iNOS, COX-2, manganese superoxide dismutase, and possibly heat shock proteins. The final mechanism of PC is still not very clear. The present review focuses on the possible role signaling molecules that regulate cardiomyocyte life and death during ischemia and reperfusion. PMID:18344203

  5. Using the Electroretinogram to Assess Function in the Rodent Retina and the Protective Effects of Remote Limb Ischemic Preconditioning.

    PubMed

    Brandli, Alice; Stone, Jonathan

    2015-01-01

    The ERG is the sum of all retinal activity. The ERG is usually recorded from the cornea, which acts as an antenna that collects and sums signals from the retina. The ERG is a sensitive measure of changes in retinal function that are pan-retinal, but is less effective for detecting damage confined to a small area of retina. In the present work we describe how to record the 'flash' ERG, which is the potential generated when the retina is exposed to a brief light flash. We describe methods of anaesthesia, mydriasis and corneal management during recording; how to keep the retina dark adapted; electrode materials and placement; the range and calibration of stimulus energy; recording parameters and the extraction of data. We also describe a method of inducing ischemia in one limb, and how to use the ERG to assess the effects of this remote-from-the-retina ischemia on retinal function after light damage. A two-flash protocol is described which allows isolation of the cone-driven component of the dark-adapted ERG, and thereby the separation of the rod and cone components. Because it can be recorded with techniques that are minimally invasive, the ERG has been widely used in studies of the physiology, pharmacology and toxicology of the retina. We describe one example of this usefulness, in which the ERG is used to assess the function of the light-damaged retina, with and without a neuroprotective intervention; preconditioning by remote ischemia. PMID:26131649

  6. No Evidence for Activated Autophagy in Left Ventricular Myocardium at Early Reperfusion with Protection by Remote Ischemic Preconditioning in Patients Undergoing Coronary Artery Bypass Grafting

    PubMed Central

    Gedik, Nilgün; Thielmann, Matthias; Kottenberg, Eva; Peters, Jürgen; Jakob, Heinz; Heusch, Gerd; Kleinbongard, Petra

    2014-01-01

    Objective Remote ischemic preconditioning (RIPC) by repeated brief limb ischemia/reperfusion reduces myocardial injury in patients undergoing coronary artery bypass grafting (CABG). Activation of signal transducer and activator of transcription 5 (STAT5) in left ventricular (LV) myocardium at early reperfusion is associated with such protection. Autophagy, i.e., removal of dysfunctional cellular components through lysosomes, has been proposed as one mechanism of cardioprotection. Therefore, we analyzed whether or not the protection by RIPC is associated with activated autophagy. Methods CABG patients were randomized to undergo RIPC (3×5 min blood pressure cuff inflation/5 min deflation) or placebo (cuff deflated) before skin incision (n = 10/10). Transmural myocardial biopsies were taken from the LV before cardioplegia (baseline) and at early (5–10 min) reperfusion. RIPC-induced protection was reflected by decreased serum troponin I concentration area under the curve (194±17 versus 709±129 ng/ml × 72 h, p = 0.002). Western blotting for beclin-1-phosphorylation and protein expression of autophagy-related gene 5–12 (ATG5-12) complex, light chain 3 (LC3), parkin, and p62 was performed. STAT3-, STAT5- and extracellular signal-regulated protein kinase 1/2 (ERK1/2)-phosphorylation was used as positive control to confirm signal activation by ischemia/reperfusion. Results Signals of all analyzed autophagy proteins did not differ between baseline and early reperfusion and not between RIPC and placebo. STAT5-phosphorylation was greater at early reperfusion only with RIPC (2.2-fold, p = 0.02). STAT3- and ERK1/2-phosphorylation were greater at early reperfusion with placebo and RIPC (≥2.7-fold versus baseline, p≤0.05). Conclusion Protection through RIPC in patients undergoing CABG surgery does not appear to be associated with enhanced autophagy in LV myocardium at early reperfusion. PMID:24797938

  7. Ischemic preconditioning maintains the immunoreactivities of glucokinase and glucokinase regulatory protein in neurons of the gerbil hippocampal CA1 region following transient cerebral ischemia.

    PubMed

    Cho, Young Shin; Cho, Jun Hwi; Shin, Bich-Na; Cho, Geum-Sil; Kim, In Hye; Park, Joon Ha; Ahn, Ji Hyeon; Ohk, Taek Geun; Cho, Byung-Ryul; Kim, Young-Myeong; Hong, Seongkweon; Won, Moo-Ho; Lee, Jae-Chul

    2015-10-01

    Glucokinase (GK) is involved in the control of blood glucose homeostasis. In the present study, the effect of ischemic preconditioning (IPC) on the immunoreactivities of GK and its regulatory protein (GKRP) following 5 min of transient cerebral ischemia was investigated in gerbils. The gerbils were randomly assigned to four groups (sham‑operated group, ischemia‑operated group, IPC + sham‑operated group and IPC + ischemia‑operated group). IPC was induced by subjecting the gerbils to 2 min of ischemia, followed by 1 day of recovery. In the ischemia‑operated group, a significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) at 5 days post‑ischemia; however, in the IPC+ischemia‑operated group, the neurons in the SP were well protected. Following immunohistochemical investigation, the immunoreactivities of GK and GKRP in the neurons of the SP were markedly decreased in the CA1, but not the CA2/3, from 2 days post‑ischemia, and were almost undetectable in the SP 5 days post‑ischemia. In the IPC + ischemia‑operated group, the immunoreactivities of GK and GKRP in the SP of the CA1 were similar to those in the sham‑group. In brief, the findings of the present study demonstrated that IPC notably maintained the immunoreactivities of GK and GKRP in the neurons of the SP of CA1 following ischemia‑reperfusion. This indicated that GK and GKRP may be necessary for neuron survival against transient cerebral ischemia. PMID:26134272

  8. Reappraisal of H2S/sulfide concentration in vertebrate blood and its potential significance in ischemic preconditioning and vascular signaling.

    PubMed

    Whitfield, Nathan L; Kreimier, Edward L; Verdial, Francys C; Skovgaard, Nini; Olson, Kenneth R

    2008-06-01

    Hydrogen sulfide (H(2)S) is rapidly emerging as a biologically significant signaling molecule. Studies published before 2000 report low or undetectable H(2)S (usually as total sulfide) levels in blood or plasma, whereas recent work has reported sulfide concentrations between 10 and 300 microM, suggesting it acts as a circulating signal. In the first series of experiments, we used a recently developed polarographic sensor to measure the baseline level of endogenous H(2)S gas and turnover of exogenous H(2)S gas in real time in blood from numerous animals, including lamprey, trout, mouse, rat, pig, and cow. We found that, contrary to recent reports, H(2)S gas was essentially undetectable (<100 nM total sulfide) in all animals. Furthermore, exogenous sulfide was rapidly removed from blood, plasma, or 5% bovine serum albumin in vitro and from intact trout in vivo. To determine if blood H(2)S could transiently increase, we measured oxygen-dependent H(2)S production by trout hearts in vitro and in vivo. H(2)S has been shown to mediate ischemic preconditioning (IPC) in mammals. IPC is present in trout and, unlike mammals, the trout myocardium obtains its oxygen from relatively hypoxic systemic venous blood. In vitro, myocardial H(2)S production was inversely related to Po(2), whereas we failed to detect H(2)S in ventral aortic blood from either normoxic or hypoxic fish in vivo. These results provide an autocrine or paracrine mechanism for myocardial coupling of hypoxia to H(2)S in IPC, i.e., oxygen sensing, but they fail to provide any evidence that H(2)S signaling is mediated by the circulation. PMID:18417642

  9. Ischemic preconditioning maintains the immunoreactivities of glucokinase and glucokinase regulatory protein in neurons of the gerbil hippocampal CA1 region following transient cerebral ischemia

    PubMed Central

    CHO, YOUNG SHIN; CHO, JUN HWI; SHIN, BICH-NA; CHO, GEUM-SIL; KIM, IN HYE; PARK, JOON HA; AHN, JI HYEON; OHK, TAEK GEUN; CHO, BYUNG-RYUL; KIM, YOUNG-MYEONG; HONG, SEONGKWEON; WON, MOO-HO; LEE, JAE-CHUL

    2015-01-01

    Glucokinase (GK) is involved in the control of blood glucose homeostasis. In the present study, the effect of ischemic preconditioning (IPC) on the immunoreactivities of GK and its regulatory protein (GKRP) following 5 min of transient cerebral ischemia was investigated in gerbils. The gerbils were randomly assigned to four groups (sham-operated group, ischemia-operated group, IPC + sham-operated group and IPC + ischemia-operated group). IPC was induced by subjecting the gerbils to 2 min of ischemia, followed by 1 day of recovery. In the ischemia-operated group, a significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) at 5 days post-ischemia; however, in the IPC+ischemia-operated group, the neurons in the SP were well protected. Following immunohistochemical investigation, the immunoreactivities of GK and GKRP in the neurons of the SP were markedly decreased in the CA1, but not the CA2/3, from 2 days post-ischemia, and were almost undetectable in the SP 5 days post-ischemia. In the IPC + ischemia-operated group, the immunoreactivities of GK and GKRP in the SP of the CA1 were similar to those in the sham-group. In brief, the findings of the present study demonstrated that IPC notably maintained the immunoreactivities of GK and GKRP in the neurons of the SP of CA1 following ischemia-reperfusion. This indicated that GK and GKRP may be necessary for neuron survival against transient cerebral ischemia. PMID:26134272

  10. Hyperthermic preconditioning severely accelerates neuronal damage in the gerbil ischemic hippocampal dentate gyrus via decreasing SODs expressions.

    PubMed

    Kim, Dong Won; Cho, Jeong-Hwi; Cho, Geum-Sil; Kim, In Hye; Park, Joon Ha; Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Tae, Hyun-Jin; Hong, Seongkweon; Cho, Jun Hwi; Kim, Young-Myeong; Won, Moo-Ho; Lee, Jae-Chul

    2015-11-15

    It is well known that neurons in the dentate gyrus (DG) of the hippocampus are resistant to short period of ischemia. Hyperthermia is a proven risk factor for cerebral ischemia and can produce more extensive brain damage related with mortality rates. The aim of this study was to examine the effect of hyperthermic conditioning (H) on neuronal death, gliosis and expressions of SODs as anti-oxidative enzymes in the gerbil DG following 5 min-transient cerebral ischemia. The animals were randomly assigned to 4 groups: 1) (N+sham)-group was given sham-operation with normothermia (N); 2) (N+ischemia)-group was given 5 min-transient ischemia with N; 3) (H+sham)-group was given sham-operation with H; and 4) (H+ischemia)-group was given 5 min-transient cerebral ischemia with H. H (39±0.5°C) was induced by subjecting the animals to a heating pad for 30 min before and during the operation. In the (N+ischemia)-groups, a significant neuronal death was observed in the polymorphic layer (PL) from 1 day after ischemia-reperfusion. In the (H+ischemia)-groups, neuronal death was also observed in the PL from 1day post-ischemia; the degree of the neuronal death was severer than that in the (N+ischemia)-groups. In addition, we examined the gliosis of astrocytes and microglia using anti-glial fibrillary acidic protein (GFAP) and anti- ionized calcium-binding adapter molecule 1 (Iba-1). GFAP(+) and Iba-1(+) glial cells were much more activated in the (H+ischemia)-groups than those in the (N+ischemia)-groups. On the other hand, immunoreactivities and levels of SOD1 rather than SOD2 were significantly lower in the (H+ischemia)-groups than those in the (N+ischemia)-groups. In brief, on the basis of our findings, we suggest that cerebral ischemic insult with hyperthermic conditioning brings up severer neuronal damage and gliosis in the polymorphic layer through reducing SOD1 expression rather than SOD2 expression in the DG. PMID:26365286

  11. The Impact of Remote Ischemic Pre-Conditioning on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography and Angioplasty: A Double-Blind Randomized Clinical Trial

    PubMed Central

    Gholoobi, Arash; Sajjadi, Seyyed Masoud; Shabestari, Mahmoud Mohammadzadeh; Eshraghi, Ali; Shamloo, Alireza Sepehri

    2015-01-01

    Background and objective Contrast-induced nephropathy (CIN) is an acute major complication following intravascular administration of iodinated contrast agents; however, the best approach for preventing CIN is not clear. Remote ischemic pre-conditioning (RIPC) is a new, non-pharmacological method that has been considered for the prevention of CIN following coronary angiography. This study assessed the effects of RIPC with four brief episodes of upper limb ischemia and reperfusion in the prevention of contrast-induced nephropathy (CIN) after coronary angiography and/or angioplasty. Methods In this double-blind randomized clinical trial, we enrolled 51 patients with chronic stable angina and non-ST elevation acute coronary syndrome (NSTE.ACS), and they underwent coronary angiography and/or angioplasty. Standard fluid therapy with normal saline was prescribed for all patients before and after the procedure. The patients were divided into two groups, i.e., a study group of patients who had undergone RIPC intervention and a control group of patients who had not undergone RIPC. One hour before the procedure, a sphygmomanometer cuff was placed around one arm and inflated up to 50 mmHg above the systolic pressure for five minutes; then, the cuff was deflated for another five minutes, and this cycle was repeated four times. The patients’ serum creatinine levels were measured at baseline and 48 hours after the procedure, and the incidence of CIN was calculated. Results Twenty-one males and 30 females were studied in two groups, i.e., an RIPC intervention group (n = 25) and a control group (n = 26) that were homogenous considering baseline characteristics. No significant difference was observed in the mean level of serum creatinine between the two groups at a post-intervention time of 48 hours (RICP: 1.74 ± 0.70 mg/dL vs. Control: 1.75 ± 0.87 mg/dL; P = 0.64). However, a lower incidence rate of CIN was observed 48 hours after the administration of the contrast medium in

  12. Preconditioning Strategy in Stem Cell Transplantation Therapy

    PubMed Central

    Yu, Shan Ping; Wei, Zheng; Wei, Ling

    2013-01-01

    Stem cell transplantation therapy has emerged as a promising regenerative medicine for ischemic stroke and other neurodegenerative disorders. However, many issues and problems remain to be resolved before successful clinical applications of the cell-based therapy. To this end, some recent investigations have sought to benefit from well-known mechanisms of ischemic/hypoxic preconditioning. Ischemic/hypoxic preconditioning activates endogenous defense mechanisms that show marked protective effects against multiple insults found in ischemic stroke and other acute attacks. As in many other cell types, a sub-lethal hypoxic exposure significantly increases the tolerance and regenerative properties of stem cells and progenitor cells. So far, a variety of preconditioning triggers have been tested on different stem cells and progenitor cells. Preconditioned stem cells and progenitors generally show much better cell survival, increased neuronal differentiation, enhanced paracrine effects leading to increased trophic support, and improved homing to the lesion site. Transplantation of preconditioned cells helps to suppress inflammatory factors and immune responses, and promote functional recovery. Although the preconditioning strategy in stem cell therapy is still an emerging research area, accumulating information from reports over the last few years already indicates it as an attractive, if not essential, prerequisite for transplanted cells. It is expected that stem cell preconditioning and its clinical applications will attract more attention in both the basic research field of preconditioning as well as in the field of stem cell translational research. This review summarizes the most important findings in this active research area, covering the preconditioning triggers, potential mechanisms, mediators, and functional benefits for stem cell transplant therapy. PMID:23914259

  13. Hyperbaric oxygen pretreatment and preconditioning.

    PubMed

    Camporesi, Enrico M; Bosco, Gerardo

    2014-01-01

    Exposure to hyperbaric oxygen (HBO2) before a crucial event, with the plan to create a preventing therapeutic situation, has been defined "preconditioning" and is emerging as a useful adjunct both in diving medicine as well before ischemic or inflammatory events. Oxygen pre-breathing before diving has been extensively documented in recreational, technical, commercial and military diving for tissue denitrogenation, resulting in reduced post-diving bubble loads, reduced decompression requirements and more rapid return to normal platelet function after a decompression. Preoxygenation at high atmospheric pressure has also been used in patients before exposure to clinical situations with beneficial effects, but the mechanisms of action have not yet been ascertained. During the reperfusion of ischemic tissue, oxygenated blood increases numbers and activities of oxidants generated in tissues. Previous reports showed that HBO2 preconditioning caused the activation of antioxidative enzymes and related genes in the central nervous system, including catalase (CAT), superoxide dismutase and heme oxygenase-1. Despite the increasing number of basic science publications on this issue, studies describing HBO2 preconditioning in the clinical practice remain scarce. To date, only a few studies have investigated the preconditioning effects of HBO2 in relation to the human brain and myocardium with robust and promising results. PMID:24984322

  14. Remote ischemic conditioning for acute ischemic stroke: dawn in the darkness.

    PubMed

    Pan, Jingrui; Li, Xiangpen; Peng, Ying

    2016-07-01

    Stroke is a leading cause of disability with high morbidity and mortality worldwide. Of all strokes, 87% are ischemic. The only approved treatments for acute ischemic stroke are intravenous thrombolysis with alteplase within 4.5 h and thrombectomy within 8 h after symptom onset, which can be applied to just a few patients. During the past decades, ischemic preconditioning has been widely studied to confirm its neuroprotection against subsequent ischemia/reperfusion injury in the brain, including preconditioning in situ or in a remote organ (such as a limb) before onset of brain ischemia, the latter of which is termed as remote ischemic preconditioning. Because acute stroke is unpredicted, ischemic preconditioning is actually not suitable for clinical application. So remote ischemic conditioning performed during or after the ischemic duration of the brain was then designed to study its neuroprotection alone or in combination with alteplase in animals and patients, which is named as remote ischemic perconditioning or remote ischemic postconditioning. As expected, animal experiments and clinical trials both showed exciting results, indicating that an evolution in the treatment for acute ischemic stroke may not be far away. However, some problems or disputes still exist. This review summarizes the research progress and unresolved issues of remote ischemic conditioning (pre-, per-, and post-conditioning) in treating acute ischemic stroke, with the hope of advancing our understanding of this promising neuroprotective strategy for ischemic stroke in the near future. PMID:26812782

  15. Remifentanil-induced preconditioning has cross-talk with A1 and A2B adenosine receptors in ischemic-reperfused rat heart

    PubMed Central

    Lee, Yong-Cheol; Jung, Jiyoon; Park, Sang-Jin

    2016-01-01

    The purpose of this study was to determine whether there is a cross-talk between opioid receptors (OPRs) and adenosine receptors (ADRs) in remifentanil preconditioning (R-Pre) and, if so, to investigate the types of ADRs involved in the cross-talk. Isolated rat hearts received 30 min of regional ischemia followed by 2 hr of reperfusion. OPR and ADR antagonists were perfused from 10 min before R-Pre until the end of R-Pre. The heart rate, left ventricular developed pressure (LVDP), velocity of contraction (+dP/dtmax), and coronary flow (CF) were recorded. The area at risk and area of necrosis were measured. After reperfusion, the LVDP, +dP/dtmax, and CF showed a significant increase in the R-Pre group compared with the control group (no intervention before or after regional ischemia). These increases in the R-Pre group were blocked by naloxone, a nonspecific ADR antagonist, an A1 ADR antagonist, and an A2B ADR antagonist. The infarct size was reduced significantly in the R-Pre group compared with the control group. The infarct-reducing effect in the R-Pre group was blocked by naloxone, the nonspecific ADR antagonist, the A1 ADR antagonist, and the A2B ADR antagonist. The results of this study demonstrate that there is cross-talk between ADRs and OPRs in R-Pre and that A1 ADR and A2B ADR appear to be involved in the cross-talk. PMID:26773185

  16. Remifentanil-induced preconditioning has cross-talk with A1 and A2B adenosine receptors in ischemic-reperfused rat heart.

    PubMed

    Lee, Yong-Cheol; Jung, Jiyoon; Park, Sang-Jin

    2016-01-01

    The purpose of this study was to determine whether there is a cross-talk between opioid receptors (OPRs) and adenosine receptors (ADRs) in remifentanil preconditioning (R-Pre) and, if so, to investigate the types of ADRs involved in the cross-talk. Isolated rat hearts received 30 min of regional ischemia followed by 2 hr of reperfusion. OPR and ADR antagonists were perfused from 10 min before R-Pre until the end of R-Pre. The heart rate, left ventricular developed pressure (LVDP),velocity of contraction (+dP/dtmax), and coronary flow (CF) were recorded. The area at risk and area of necrosis were measured. After reperfusion, the LVDP, +dP/dtmax,and CF showed a significant increase in the R-Pre group compared with the control group (no intervention before or after regional ischemia). These increases in the R-Pre group were blocked by naloxone, a nonspecific ADR antagonist, an A1 ADR antagonist, and an A2B ADR antagonist. The infarct size was reduced significantly in the R-Pre group compared with the control group. The infarct-reducing effect in the R-Pre group was blocked by naloxone, the nonspecific ADR antagonist, the A1 ADR antagonist, and the A2B ADR antagonist. The results of this study demonstrate that there is cross-talk between ADRs and OPRs in R-Pre and that A1 ADR and A2B ADR appear to be involved in the cross-talk. PMID:26773185

  17. Is longer sevoflurane preconditioning neuroprotective in permanent focal cerebral ischemia?

    PubMed

    Qiu, Caiwei; Sheng, Bo; Wang, Shurong; Liu, Jin

    2013-08-15

    Sevoflurane preconditioning has neuroprotective effects in the cerebral ischemia/reperfusion model. However, its influence on permanent cerebral ischemia remains unclear. In the present study, the rats were exposed to sevoflurane for 15, 30, 60, and 120 minutes, followed by induction of permanent cerebral ischemia. Results demonstrated that 30- and 60-minute sevoflurane preconditioning significantly reduced the infarct volume at 24 hours after cerebral ischemia, and 60-minute lurane preconditioning additionally reduced the number of TUNEL- and caspase-3-positive cells in the ischemic penumbra. However, 120-minute sevoflurane preconditioning did not show evident neuroprotective effects. Moreover, 60-minute sevoflurane preconditioning significantly attenuated neurological deficits and infarct volume in rats at 4 days after cerebral ischemia. These findings indicated that 60-minute sevoflurane preconditioning can induce the best neuroprotective effects in rats with permanent cerebral ischemia through the inhibition of apoptosis. PMID:25206521

  18. Cardiac sodium/calcium exchanger preconditioning promotes anti-arrhythmic and cardioprotective effects through mitochondrial calcium-activated potassium channel

    PubMed Central

    Zhang, Jian-Ying; Cheng, Kang; Lai, Dong; Kong, Ling-Heng; Shen, Min; Yi, Fu; Liu, Bing; Wu, Feng; Zhou, Jing-Jun

    2015-01-01

    Background: Reverse-mode of the Na+/Ca2+ exchanger (NCX) stimulation provides cardioprotective effects for the ischemic/reperfused heart during ischemic preconditioning (IP). This study was designed to test the hypothesis that pretreatment with an inhibitor of cardiac delayed-rectifying K+ channel (IKr), E4031, increases reverse-mode of NCX activity, and triggers preconditioning against infarct size (IS) and arrhythmias caused by ischemia/reperfusion injury through mitoKCa channels. Materials and methods: In the isolated perfused rat heart, myocardial ischemia/reperfusion injury was created by occlusion of the left anterior descending coronary artery for 30 min followed by 120 min reperfusion. Two cycles of coronary occlusion for 5 min and reperfusion were performed, or pretreatment with E4031 or sevoflurane (Sevo) before the 30 min occlusion with the reversed-mode of NCX inhibitor (KB-R7943) or not. Results: E4031 or Sevo preconditioning not only markedly decreased IS but also reduced arrhythmias, which was significantly blunted by KB-R7943. Furthermore, these effects of E4031 preconditioning on IS and arrhythmias were abolished by inhibition of the mitoKCa channels. Similarly, pretreatment with NS1619, an opener of the mitoKCa channels, for 10 min before occlusion reduced both the infarct size and arrhythmias caused by ischemia/reperfusion. However, these effects weren’t affected by blockade of the NCX with KB-R7943. Conclusion: Taken together, these preliminary results conclude that pretreatment with E4031 reduces infarct size and produces anti-arrhythmic effect via stimulating the reverse-mode NCX, and that the mitoKCa channels mediate the protective effects. PMID:26617732

  19. Bradykinin mediates cardiac preconditioning at a distance.

    PubMed

    Schoemaker, R G; van Heijningen, C L

    2000-05-01

    Preconditioning the heart by brief coronary (CAO) or mesenteric artery occlusion (MAO) can protect against damage during subsequent prolonged CAO and reperfusion. The role of bradykinin (BK) in remote cardiac preconditioning by MAO is investigated by antagonizing the BK B(2) receptor [Hoechst 140 (HOE-140)] or simulating local BK release by mesenteric intra-arterial infusion. Anesthetized male Wistar rats (n = 6-8) were treated with HOE-140 or saline before starting the preconditioning protocol, CAO, MAO, or non-preconditioned control. Infarct size related to risk area [ratio of infarct area to area at risk (IA/AR)] was determined after 3 h of reperfusion following a 60-min CAO. IA/AR was 62 +/- 5% in controls and not affected by HOE-140 (58 +/- 6%). CAO as well as MAO significantly protected the heart (IA/AR, 37 +/- 3 and 35 +/- 5%), which was prevented by HOE-140 (IA/AR, 71 +/- 6 and 65 +/- 7%, respectively). Brief intramesenteric BK infusion mimicked MAO (IA/AR, 26 +/- 3%). Pretreatment with hexamethonium could abolish this protection (IA/AR, 67 +/- 4%). These data indicate an important role for BK in remote preconditioning by MAO. Results support the hypothesis that remote preconditioning acts through sensory nerve stimulation in the ischemic organ. PMID:10775135

  20. Preconditioning for traumatic brain injury

    PubMed Central

    Yokobori, Shoji; Mazzeo, Anna T; Hosein, Khadil; Gajavelli, Shyam; Dietrich, W. Dalton; Bullock, M. Ross

    2016-01-01

    Traumatic brain injury (TBI) treatment is now focused on the prevention of primary injury and reduction of secondary injury. However, no single effective treatment is available as yet for the mitigation of traumatic brain damage in humans. Both chemical and environmental stresses applied before injury, have been shown to induce consequent protection against post-TBI neuronal death. This concept termed “preconditioning” is achieved by exposure to different pre-injury stressors, to achieve the induction of “tolerance” to the effect of the TBI. However, the precise mechanisms underlying this “tolerance” phenomenon are not fully understood in TBI, and therefore even less information is available about possible indications in clinical TBI patients. In this review we will summarize TBI pathophysiology, and discuss existing animal studies demonstrating the efficacy of preconditioning in diffuse and focal type of TBI. We will also review other non-TBI preconditionng studies, including ischemic, environmental, and chemical preconditioning, which maybe relevant to TBI. To date, no clinical studies exist in this field, and we speculate on possible futureclinical situation, in which pre-TBI preconditioning could be considered. PMID:24323189

  1. Ryanodine receptors contribute to the induction of ischemic tolerance.

    PubMed

    Nakamura-Maruyama, Emi; Miyamoto, Osamu; Okabe, Naohiko; Himi, Naoyuki; Feng, Lu; Narita, Kazuhiko; Keep, Richard F; Yamamoto, Tohru; Nakamura, Takehiro

    2016-04-01

    Ischemic tolerance (IT) is induced by a variety of insults to the brain (e.g., nonfatal ischemia, heat and hypoxia) and it provides a strong neuroprotective effect. Although the mechanisms are still not fully elucidated, Ca(2+) is regarded as a key mediator of IT. Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca(2+) from intracellular stores. In brain, neuronal RyRs are thought to play a role in various neuropathological conditions, including ischemia. The purpose of the present study was to investigate the involvement of RyRs in IT. Pretreatment with a RyR antagonist, dantrolene (25mg/kg, i.p), blocked IT in a gerbil global ischemia model, while a RyR agonist, caffeine (100mg/kg, i.p), stimulated the production of IT. In vitro, using rat hippocampal cells, short-term oxygen/glucose deprivation induced preconditioning and RyR antagonists, dantrolene (50 and 100μM) and ryanodine (100 and 200μM) prevented it. RyR protein and mRNA levels were transiently decreased after induction of IT. These results suggest that RyRs are involved in the induction of ischemic tolerance. PMID:26930163

  2. N-Acetylcysteine and Ceftriaxone as Preconditioning Strategies in Focal Brain Ischemia: Influence on Glutamate Transporters Expression.

    PubMed

    Krzyzanowska, Weronika; Pomierny, Bartosz; Budziszewska, Boguslawa; Filip, Malgorzata; Pera, Joanna

    2016-05-01

    Glutamate (Glu) plays a key role in excitotoxicity-related injury in cerebral ischemia. In the brain, Glu homeostasis depends on Glu transporters, including the excitatory amino acid transporters and the cysteine/Glu antiporter (xc-). We hypothesized that drugs acting on Glu transporters, such as ceftriaxone (CEF, 200 mg/kg, i.p.) and N-acetylcysteine (NAC, 150 mg/kg, i.p.), administered repeatedly for 5 days before focal cerebral ischemia in rats and induced by a 90-min middle cerebral artery occlusion (MCAO), may induce brain tolerance to ischemia. We compared the effects of these drugs on brain infarct volume, neurological deficits and the mRNA and protein expression of the Glu transporter-1 (GLT-1) and xc- with the effects of ischemic preconditioning and chemical preconditioning using 3-nitropropionic acid. Administration of CEF and NAC significantly reduced infarct size and neurological deficits caused by a 90-min MCAO. These beneficial effects were accompanied by changes in GLT-1 expression caused by a 90-min MCAO at both the mRNA and protein levels in the frontal cortex, hippocampus, and dorsal striatum. Thus, the results of this study suggest that the regulation of GLT-1 and xc- plays a role in the development of cerebral tolerance to ischemia and that this regulation may be a novel approach in the therapy of brain ischemia. PMID:26861954

  3. Myocardial ischemic protection in natural mammalian hibernation

    PubMed Central

    Yan, Lin; Kudej, Raymond K.; Vatner, Dorothy E.

    2015-01-01

    Hibernating myocardium is an important clinical syndrome protecting the heart with chronic myocardial ischemia, named for its assumed resemblance to hibernating mammals in winter. However, the effects of myocardial ischemic protection have never been studied in true mammalian hibernation, which is a unique strategy for surviving extreme winter environmental stress. The goal of this investigation was to test the hypothesis that ischemic stress may also be protected in woodchucks as they hibernate in winter. Myocardial infarction was induced by coronary occlusion followed by reperfusion in naturally hibernating woodchucks in winter with and without hibernation and in summer, when not hibernating. The ischemic area at risk was similar among groups. Myocardial infarction was significantly less in woodchucks in winter, whether hibernating or not, compared with summer, and was similar to that resulting after ischemic preconditioning. Whereas several genes were up or downregulated in both hibernating woodchuck and with ischemic preconditioning, one mechanism was unique to hibernation, i.e., activation of cAMP-response element binding protein (CREB). When CREB was upregulated in summer, it induced protection similar to that observed in the woodchuck heart in winter. The cardioprotection in hibernation was also mediated by endothelial nitric oxide synthase, rather than inducible nitric oxide synthase. Thus, the hibernating woodchuck heart is a novel model to study cardioprotection for two major reasons: (1) powerful cardioprotection occurs naturally in winter months in the absence of any preconditioning stimuli, and (2) it resembles ischemic preconditioning, but with novel mechanisms, making this model potentially useful for clinical translation. PMID:25613166

  4. Myocardial ischemic protection in natural mammalian hibernation.

    PubMed

    Yan, Lin; Kudej, Raymond K; Vatner, Dorothy E; Vatner, Stephen F

    2015-03-01

    Hibernating myocardium is an important clinical syndrome protecting the heart with chronic myocardial ischemia, named for its assumed resemblance to hibernating mammals in winter. However, the effects of myocardial ischemic protection have never been studied in true mammalian hibernation, which is a unique strategy for surviving extreme winter environmental stress. The goal of this investigation was to test the hypothesis that ischemic stress may also be protected in woodchucks as they hibernate in winter. Myocardial infarction was induced by coronary occlusion followed by reperfusion in naturally hibernating woodchucks in winter with and without hibernation and in summer, when not hibernating. The ischemic area at risk was similar among groups. Myocardial infarction was significantly less in woodchucks in winter, whether hibernating or not, compared with summer, and was similar to that resulting after ischemic preconditioning. Whereas several genes were up or downregulated in both hibernating woodchuck and with ischemic preconditioning, one mechanism was unique to hibernation, i.e., activation of cAMP-response element binding protein (CREB). When CREB was upregulated in summer, it induced protection similar to that observed in the woodchuck heart in winter. The cardioprotection in hibernation was also mediated by endothelial nitric oxide synthase, rather than inducible nitric oxide synthase. Thus, the hibernating woodchuck heart is a novel model to study cardioprotection for two major reasons: (1) powerful cardioprotection occurs naturally in winter months in the absence of any preconditioning stimuli, and (2) it resembles ischemic preconditioning, but with novel mechanisms, making this model potentially useful for clinical translation. PMID:25613166

  5. Beneficial effect of zinc chloride and zinc ionophore pyrithione on attenuated cardioprotective potential of preconditioning phenomenon in STZ-induced diabetic rat heart.

    PubMed

    Jamwal, Sumit; Kumar, Kushal; Reddy, B V Krishna

    2016-05-01

    Ischemic preconditioning (IPC) is well demonstrated to produce cardioprotection by phosphorylation and subsequent inactivation of glycogen synthase kinase-3β (GSk-3β) in the normal rat heart, but its effect is attenuated in the diabetic rat heart. This study was designed to investigate the effect of zinc chloride and zinc ionophore pyrithione (ZIP) on the attenuated cardioprotective potential of IPC in the diabetic rat heart. Diabetes mellitus (DM) was induced by a single intraperitoneal administration of streptozotocin (STZ) (50 mg/kg; i.p). The isolated perfused rat heart was subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining and cardiac injury was measured by estimating lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in the coronary effluent. Also, GSK-3β was measured and neutrophil accumulation was measured by estimating myeloperoxidase (MPO) levels. IPC significantly decreased the myocardial infarct size, the release of LDH and CK-MB, the GSK-3β levels and the MPO levels in the normal rat heart. Pre- and post-ischemic treatment with zinc chloride and zinc ionophore pyrithione (ZIP) in the normal and diabetic rat hearts significantly decreased the myocardial infarct size, the level of CK-MB and LDH in the coronary effluent and GSK-3β and MPO levels. Our results suggest that pharmacological preconditioning with zinc chloride and ZIP significantly restored the attenuated cardioprotective potential of IPC in the diabetic rat heart. PMID:26423303

  6. [Preconditioning impact on coronary perfusion during ischemia and reperfusion of heart].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Oeltgen, P; Peĭ, J-M; Krylatov, A V; Barzakh, E I; Portnichenko, A G; Meshoulam, R

    2012-04-01

    Recent studies have confirmed that ischemic preconditioning prevents appearance of reperfusion endothelial dysfunction. However, the issue of preconditioning impact on no-reflow phenomenon remains unresolved. The receptor mechanisms involved in the cardioprotective and vasoprotective effects of preconditioning are different. The ability of preconditioning in preventing reperfusion endothelial dysfunction is dependent upon bradykinin B2-receptor activation and not dependent upon adenosine receptor stimulation. The vasoprotective effect of preconditioning is mediated via mechanisms relying in part on activation of protein kinase C, NO-synthase, cyclooxygenase, mitochondrial K(ATP)-channel opening and an enhancement of antioxidative protection of the heart. The delayed preconditioning also exerts endothelium-protective effect. Peroxynitrite, NO* and O2* are the triggers of this effect but a possible end-effector involves endothelial NO-synthase. PMID:22834333

  7. Ischemic Stroke

    MedlinePlus

    A stroke is a medical emergency. There are two types - ischemic and hemorrhagic. Ischemic stroke is the most common type. It is usually ... are at risk for having a more serious stroke. Symptoms of stroke are Sudden numbness or weakness ...

  8. Ischemic perinatal stroke: challenge and opportunities.

    PubMed

    Raju, Tonse N K

    2008-08-01

    The second highest risk group for developing a cerebral stroke is the perinatal period, generally defined as 20 weeks of gestation through 28th postnatal day of age. In this commentary, a brief overview of ischemic perinatal strokes is presented. Ischemic perinatal stroke (IPS) occurs at a rate of 1 : 2300 to 1 : 5000 births, accounting for 30% of children with hemiplegic cerebral palsy (CP). Thus, IPS is the most common known cause for CP [1-3]. Although they occur frequently, much remains to be studied about perinatal strokes in general and the ischemic variety in particular. PMID:18705894

  9. Mesenchymal stem cells preconditioned with trimetazidine promote neovascularization of hearts under hypoxia/reoxygenation injury

    PubMed Central

    Hu, Xiaowu; Yang, Junjie; Wang, Ying; Zhang, You; Ii, Masaaki; Shen, Zhenya; Hui, Jie

    2015-01-01

    Background: Cell-based angiogenesis is a promising treatment for ischemic diseases; however, survival of implanted cells is impaired by the ischemic microenvironment. In this study, mesenchymal stem cells (MSCs) for cell transplantation were preconditioned with trimetazidine (TMZ). We hypothesized that TMZ enhances the survival rate of MSCs under hypoxic stimuli through up-regulation of HIF1-α. Methods and results: Bone marrow-derived rat mesenchymal stem cells were preconditioned with 10 μM TMZ for 6 h. TMZ preconditioning of MSCs remarkably increased cell viability and the expression of HIF1-α and Bcl-2, when cells were under hypoxia/reoxygenation (H/R) stimuli. But the protective effects of TMZ were abolished after knocking down of HIF-1α. Three days after implantation of the cells into the peri-ischemic zone of rat myocardial ischemia-reperfusion (I/R) injury model, survival of the TMZ-preconditioned MSCs was high. Furthermore, capillary density and cardiac function were significantly better in the rats implanted with TMZ-preconditioned MSCs 28 days after cell injection. Conclusions: TMZ preconditioning increased the survival rate of MSCs, through up-regulation of HIF1-α, thus contributing to neovascularization and improved cardiac function of rats subjected to myocardial I/R injury. PMID:26629255

  10. The evolving concept of physiological ischemia training vs. ischemia preconditioning.

    PubMed

    Ni, Jun; Lu, Hongjian; Lu, Xiao; Jiang, Minghui; Peng, Qingyun; Ren, Caili; Xiang, Jie; Mei, Chengyao; Li, Jianan

    2015-11-01

    Ischemic heart diseases are the leading cause of death with increasing numbers of patients worldwide. Despite advances in revascularization techniques, angiogenic therapies remain highly attractive. Physiological ischemia training, which is first proposed in our laboratory, refers to reversible ischemia training of normal skeletal muscles by using a tourniquet or isometric contraction to cause physiologic ischemia for about 4 weeks for the sake of triggering molecular and cellular mechanisms to promote angiogenesis and formation of collateral vessels and protect remote ischemia areas. Physiological ischemia training therapy augments angiogenesis in the ischemic myocardium by inducing differential expression of proteins involved in energy metabolism, cell migration, protein folding, and generation. It upregulates the expressions of vascular endothelial growth factor, and induces angiogenesis, protects the myocardium when infarction occurs by increasing circulating endothelial progenitor cells and enhancing their migration, which is in accordance with physical training in heart disease rehabilitation. These findings may lead to a new approach of therapeutic angiogenesis for patients with ischemic heart diseases. On the basis of the promising results in animal studies, studies were also conducted in patients with coronary artery disease without any adverse effect in vivo, indicating that physiological ischemia training therapy is a safe, effective and non-invasive angiogenic approach for cardiovascular rehabilitation. Preconditioning is considered to be the most protective intervention against myocardial ischemia-reperfusion injury to date. Physiological ischemia training is different from preconditioning. This review summarizes the preclinical and clinical data of physiological ischemia training and its difference from preconditioning. PMID:26664354

  11. Toll-Like Receptors and Ischemic Brain Injury

    PubMed Central

    Gesuete, Raffaella; Kohama, Steven G.; Stenzel-Poore, Mary

    2014-01-01

    Toll-like receptors (TLRs) are master regulators of innate immunity and play an integral role in the activation of the inflammatory response during infections. In addition, TLRs influence the body’s response to numerous forms of injury. Recent data have shown that TLRs play a modulating role in ischemic brain damage after stroke. Interestingly, their stimulation prior to ischemia induces a tolerant state that is neuroprotective. This phenomenon, referred to as TLR preconditioning, is the result of reprogramming of the TLR response to ischemic injury. This review addresses the role of TLRs in brain ischemia and the activation of endogenous neuroprotective pathways in the setting of preconditioning. We highlight the protective role of the interferon-related response and the potential site of action for TLR preconditioning involving the blood-brain-barrier. Pharmacological modulation of TLR activation to promote protection against stroke is a promising approach for the development of prophylactic and acute therapies targeting ischemic brain injury. PMID:24709682

  12. Preconditioned Iterative Solver

    Energy Science and Technology Software Center (ESTSC)

    2002-08-01

    AztecOO contains a collection of preconditioned iterative methods for the solution of sparse linear systems of equations. In addition to providing many of the common algebraic preconditioners and basic iterative methods, AztecOO can be easily extended to interact with user-provided preconditioners and matrix operators.

  13. Preconditioning ischemia time determines the degree of glycogen depletion and infarct size reduction in rat hearts.

    PubMed

    Barbosa, V; Sievers, R E; Zaugg, C E; Wolfe, C L

    1996-02-01

    The cardioprotective effect of preconditioning is associated with glycogen depletion and attenuation of intracellular acidosis during subsequent prolonged ischemia. This study determined the effects of increasing preconditioning ischemia time on myocardial glycogen depletion and on infarct size reduction. In addition, this study determined whether infarct size reduction by preconditioning correlates with glycogen depletion before prolonged ischemia. Anesthetized rats underwent a single episode of preconditioning lasting 1.25, 2.5, 5, or 10 minutes or multiple episodes cumulating in 10 (2 x 5 min) or 20 minutes (4 x 5 or 2 x 10 min) of preconditioning ischemia time, each followed by 5 minutes of reperfusion. Then both preconditioned and control rats underwent 45 minutes of ischemia induced by left coronary artery (LCA) occlusion and 120 minutes of reperfusion. After prolonged ischemia, infarct size was determined by dual staining with triphenyltetrazolium chloride and phthalocyanine blue dye. Glycogen levels were determined by an enzymatic assay in selected rats from each group before prolonged ischemia. We found that increasing preconditioning ischemia time resulted in glycogen depletion and infarct size reduction that could both be described by exponential functions. Furthermore, infarct size reduction correlated with glycogen depletion before prolonged ischemia (r = 0.98; p < 0.01). These findings suggest a role for glycogen depletion in reducing ischemic injury in the preconditioned heart. PMID:8579012

  14. Cardioprotection by remote ischemic conditioning: Mechanisms and clinical evidences.

    PubMed

    Aimo, Alberto; Borrelli, Chiara; Giannoni, Alberto; Pastormerlo, Luigi Emilio; Barison, Andrea; Mirizzi, Gianluca; Emdin, Michele; Passino, Claudio

    2015-10-26

    In remote ischemic conditioning (RIC), several cycles of ischemia and reperfusion render distant organ and tissues more resistant to the ischemia-reperfusion injury. The intermittent ischemia can be applied before the ischemic insult in the target site (remote ischemic preconditioning), during the ischemic insult (remote ischemic perconditioning) or at the onset of reperfusion (remote ischemic postconditioning). The mechanisms of RIC have not been completely defined yet; however, these mechanisms must be represented by the release of humoral mediators and/or the activation of a neural reflex. RIC has been discovered in the heart, and has been arising great enthusiasm in the cardiovascular field. Its efficacy has been evaluated in many clinical trials, which provided controversial results. Our incomplete comprehension of the mechanisms underlying the RIC could be impairing the design of clinical trials and the interpretation of their results. In the present review we summarize current knowledge about RIC pathophysiology and the data about its cardioprotective efficacy. PMID:26516416

  15. Microglia in ischemic brain injury

    PubMed Central

    Weinstein, Jonathan R; Koerner, Ines P; Möller, Thomas

    2010-01-01

    Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked changes in the gene-expression profile and phenotype of a variety of endogenous CNS cell types (astrocytes, neurons and microglia), as well as an influx of leukocytic cells (neutrophils, macrophages and T-cells) from the periphery. Many molecules and conditions can trigger a transformation of surveying microglia to microglia of an alerted or reactive state. Here we review recent developments in the literature that relate to microglial activation in the experimental setting of in vitro and in vivo ischemia. We also present new data from our own laboratory demonstrating the direct effects of in vitro ischemic conditions on the microglial phenotype and genomic profile. In particular, we focus on the role of specific molecular signaling systems, such as hypoxia inducible factor-1 and Toll-like receptor-4, in regulating the microglial response in this setting. We then review histological and novel radiological data that confirm a key role for microglial activation in the setting of ischemic stroke in humans. We also discuss recent progress in the pharmacologic and molecular targeting of microglia in acute ischemic stroke. Finally, we explore how recent studies on ischemic preconditioning have increased interest in pre-emptively targeting microglial activation in order to reduce stroke severity. PMID:20401171

  16. Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin

    SciTech Connect

    Chiueh, C.C. . E-mail: chiueh@tmu.edu.tw; Andoh, Tsugunobu; Chock, P. Boon

    2005-09-01

    Hormesis, a stress tolerance, can be induced by ischemic preconditioning stress. In addition to preconditioning, it may be induced by other means, such as gas anesthetics. Preconditioning mechanisms, which may be mediated by reprogramming survival genes and proteins, are obscure. A known neurotoxicant, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes less neurotoxicity in the mice that are preconditioned. Pharmacological evidences suggest that the signaling pathway of {center_dot}NO-cGMP-PKG (protein kinase G) may mediate preconditioning phenomenon. We developed a human SH-SY5Y cell model for investigating {sup {center_dot}}NO-mediated signaling pathway, gene regulation, and protein expression following a sublethal preconditioning stress caused by a brief 2-h serum deprivation. Preconditioned human SH-SY5Y cells are more resistant against severe oxidative stress and apoptosis caused by lethal serum deprivation and 1-mehtyl-4-phenylpyridinium (MPP{sup +}). Both sublethal and lethal oxidative stress caused by serum withdrawal increased neuronal nitric oxide synthase (nNOS/NOS1) expression and {sup {center_dot}}NO levels to a similar extent. In addition to free radical scavengers, inhibition of nNOS, guanylyl cyclase, and PKG blocks hormesis induced by preconditioning. S-nitrosothiols and 6-Br-cGMP produce a cytoprotection mimicking the action of preconditioning tolerance. There are two distinct cGMP-mediated survival pathways: (i) the up-regulation of a redox protein thioredoxin (Trx) for elevating mitochondrial levels of antioxidant protein Mn superoxide dismutase (MnSOD) and antiapoptotic protein Bcl-2, and (ii) the activation of mitochondrial ATP-sensitive potassium channels [K(ATP)]. Preconditioning induction of Trx increased tolerance against MPP{sup +}, which was blocked by Trx mRNA antisense oligonucleotide and Trx reductase inhibitor. It is concluded that Trx plays a pivotal role in {sup {center_dot}}NO-dependent preconditioning hormesis against

  17. Hyperbaric oxygen preconditioning induces tolerance against spinal cord ischemia by upregulation of antioxidant enzymes in rabbits.

    PubMed

    Nie, Huang; Xiong, Lize; Lao, Ning; Chen, Shaoyang; Xu, Ning; Zhu, Zhenghua

    2006-05-01

    The present study examined the hypothesis that spinal cord ischemic tolerance induced by hyperbaric oxygen (HBO) preconditioning is triggered by an initial oxidative stress and is associated with an increase of antioxidant enzyme activities as one effector of the neuroprotection. New Zealand White rabbits were subjected to HBO preconditioning, hyperbaric air (HBA) preconditioning, or sham pretreatment once daily for five consecutive days before spinal cord ischemia. Activities of catalase (CAT) and superoxide dismutase were increased in spinal cord tissue in the HBO group 24 h after the last pretreatment and reached a higher level after spinal cord ischemia for 20 mins followed by reperfusion for 24 or 48 h, in comparison with those in control and HBA groups. The spinal cord ischemic tolerance induced by HBO preconditioning was attenuated when a CAT inhibitor, 3-amino-1,2,4-triazole,1 g/kg, was administered intraperitoneally 1 h before ischemia. In addition, administration of a free radical scavenger, dimethylthiourea, 500 mg/kg, intravenous, 1 h before each day's preconditioning, reversed the increase of the activities of both enzymes in spinal cord tissue. The results indicate that an initial oxidative stress, as a trigger to upregulate the antioxidant enzyme activities, plays an important role in the formation of the tolerance against spinal cord ischemia by HBO preconditioning. PMID:16136055

  18. Immune mechanisms in cerebral ischemic tolerance

    PubMed Central

    Garcia-Bonilla, Lidia; Benakis, Corinne; Moore, Jamie; Iadecola, Costantino; Anrather, Josef

    2014-01-01

    Stressor-induced tolerance is a central mechanism in the response of bacteria, plants, and animals to potentially harmful environmental challenges. This response is characterized by immediate changes in cellular metabolism and by the delayed transcriptional activation or inhibition of genetic programs that are not generally stressor specific (cross-tolerance). These programs are aimed at countering the deleterious effects of the stressor. While induction of this response (preconditioning) can be established at the cellular level, activation of systemic networks is essential for the protection to occur throughout the organs of the body. This is best signified by the phenomenon of remote ischemic preconditioning, whereby application of ischemic stress to one tissue or organ induces ischemic tolerance (IT) in remote organs through humoral, cellular and neural signaling. The immune system is an essential component in cerebral IT acting simultaneously both as mediator and target. This dichotomy is based on the fact that activation of inflammatory pathways is necessary to establish IT and that IT can be, in part, attributed to a subdued immune activation after index ischemia. Here we describe the components of the immune system required for induction of IT and review the mechanisms by which a reprogrammed immune response contributes to the neuroprotection observed after preconditioning. Learning how local and systemic immune factors participate in endogenous neuroprotection could lead to the development of new stroke therapies. PMID:24624056

  19. PVM and IP multicast

    SciTech Connect

    Dunigan, T.H.; Hall, K.A.

    1996-12-01

    This report describes a 1994 demonstration implementation of PVM that uses IP multicast. PVM`s one-to-many unicast implementation of its pvm{_}mcast() function is replaced with reliable IP multicast. Performance of PVM using IP multicast over local and wide-area networks is measured and compared with the original unicast implementation. Current limitations of IP multicast are noted.

  20. Bradykinin in ischemic conditioning-induced tissue protection: Evidences and possible mechanisms.

    PubMed

    Sharma, Roohani; Randhawa, Puneet Kaur; Singh, Nirmal; Jaggi, Amteshwar Singh

    2015-12-01

    Ischemic conditioning is an intrinsic protective mechanism in which repeated short episodes of reversible ischemia protects the tissue and increases its tolerance against a subsequent longer period of ischemia (index ischemia). Bradykinin is a physiologically and pharmacologically active peptide of the kallikrein-kinin system. Besides the involvement of bradykinin in a variety of physiological and pathological responses such as pain, inflammation and in cardiovascular system as a potent vasodilator, it also acts as an endogenous cytoprotective mediator in the ischemic tissue. Pretreatment with various pharmacological modulators of bradykinin has confirmed the involvement of bradykinin in ischemic conditioning-induced protection. The protective actions of bradykinin in three major paradigms of ischemic conditioning i.e. ischemic preconditioning, ischemic postconditioning and remote ischemic preconditioning involves activation and regulation of various endogenous signaling cascades to render the heart resistant to infarction. In ischemic preconditioning, bradykinin exerts cardioprotective effect via activation of PI3K/Akt/eNOS signaling pathway and regulation of redox state via NO release. The role of bradykinin and its B2 receptors in ischemic-postconditioning induced neuroprotection has been described mainly due to its increased redox signaling cascade and activation of mitochondrial anti-apoptotic pathway. Furthermore, its cardioprotective role during remote ischemic preconditioning has been associated with activation of B2 receptors mediated neurogenic pathway and internalization of B2 receptors along with the formation of signalosomes that activates intracellular cytoprotective transduction pathways. The present review focuses on the potential role of bradykinin in mediating different forms of ischemic conditioning (pre/post/remote)-induced cardioprotection and neuroprotection along with the possible mechanisms. PMID:26499976

  1. Pre-ischemic exercise alleviates oxidative damage following ischemic stroke in rats.

    PubMed

    Feng, Rui; Zhang, Min; Wang, Xiao; Li, Wen-Bin; Ren, Shi-Qing; Zhang, Feng

    2014-10-01

    Physical exercise has been proved to be neuroprotective in clinical trials and animal experiments. However, the exact mechanism underlying this neuroprotective effect remains unclear. The aim of the present study was to explore whether pre-ischemic treadmill training could act as a form of ischemic preconditioning in a rat following ischemic stroke by reducing oxidative damage. Fifty-four rats were randomly divided into three groups (n=18 per group): Sham surgery, middle cerebral artery occlusion (MCAO) without exercise and MCAO with exercise. Subsequent to treadmill training, ischemic stroke was induced by occluding the MCA for 1.5 h, followed by reperfusion. Six rats in each group were evaluated for neurological deficits and then sacrificed by decapitation to calculate the infarct volume. The remaining rats in each group were sacrificed to detect the level of superoxide dismutase (SOD) activity (n=6) and malondialdehyde (MDA) concentration (n=6). The results indicated that pre-ischemic exercise training reduced brain infarct volume and neurological deficits, increased SOD activity and decreased the concentration of MDA following ischemic stroke. In conclusion, treadmill exercise training prior to MCAO/reperfusion increased the antioxidant ability and decreased the oxidative damage in the brain subsequent to ischemic stroke. PMID:25187848

  2. Preconditioning of heart by repeated stunning. Adaptive modification of antioxidative defense system.

    PubMed

    Das, D K; Prasad, M R; Lu, D; Jones, R M

    1992-11-01

    Previous studies demonstrated that preconditioning of a heart by repeated stunning can reduce the cellular injury to the heart from subsequent acute ischemic insult. To examine the possible biochemical mechanism for such myocardial preservation afforded by preconditioning, swine heart was subjected to four episodes of 5 min. stunning by occluding the left anterior descending coronary artery (LAD), followed by 10 min. of reperfusion after each stunning. Heart was then made regionally ischemic for 60 min. by LAD occlusion, followed by 6 hrs. reperfusion. Control heart was perfused for 60 min., followed by 60 min. ischemia and 6 hrs. reperfusion. The results of our studies indicated the stimulation of a number of antioxidative enzymes, including Mn-superoxide dismutase (Mn-SOD), catalase, glutathione peroxidase, and glutathione reductase, after repeated stunning and reperfusion. In addition, a number of new proteins were expressed after preconditioning the heart, including some oxidative-stress related proteins and 72 kDa heat-shock protein. These results suggest that preconditioning of a heart by repeated stunning may lead to strengthening of the oxidative defense system of the heart, which is likely to play a role in myocardial preservation during subsequent ischemic and reperfusion injury. PMID:1472901

  3. Ischemic Colitis

    PubMed Central

    FitzGerald, James F.; Hernandez III, Luis O.

    2015-01-01

    Most clinicians associate ischemic colitis with elderly patients who have underlying cardiovascular comorbidities. While the majority of cases probably occur in this population, the disease can present in younger patients as a result of different risk factors, making the diagnosis challenging. While a majority of patients respond to medical management, surgery is required in approximately 20% of the cases and is associated with high morbidity and mortality. PMID:26034405

  4. Preconditioning Provides Neuroprotection in Models of CNS Disease: Paradigms and Clinical Significance

    PubMed Central

    Stetler, R. Anne; Leak, Rehana K.; Gan, Yu; Li, Peiying; Hu, Xiaoming; Jing, Zheng; Chen, Jun; Zigmond, Michael J.; Gao, Yanqin

    2014-01-01

    Preconditioning is a phenomenon in which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. Preconditioning has been observed in multiple organisms and can occur in the brain as well as other tissues. Extensive animal studies suggest that the brain can be preconditioned to resist acute injuries, such as ischemic stroke, neonatal hypoxia/ischemia, trauma, and agents that are used in models of neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Effective preconditioning stimuli are numerous and diverse, ranging from transient ischemia, hypoxia, hyperbaric oxygen, hypothermia and hyperthermia, to exposure to neurotoxins and pharmacological agents. The phenomenon of “cross-tolerance,” in which a sublethal stress protects against a different type of injury, suggests that different preconditioning stimuli may confer protection against a wide range of injuries. Research conducted over the past few decades indicates that brain preconditioning is complex, involving multiple effectors such as metabolic inhibition, activation of extra- and intracellular defense mechanisms, a shift in the neuronal excitatory/inhibitory balance, and reduction in inflammatory sequelae. An improved understanding of brain preconditioning should help us identify innovative therapeutic strategies that prevent or at least reduce neuronal damage in susceptible patients. In this review, we focus on the experimental evidence of preconditioning in the brain and systematically survey the models used to develop paradigms for neuroprotection, and then discuss the clinical potential of brain preconditioning. In a subsequent components of this two-part series, we will discuss the cellular and molecular events that are likely to underlie these phenomena. PMID:24389580

  5. Hypoxia-induced preconditioning in adult stimulated cardiomyocytes is mediated by the opening and trafficking of sarcolemmal KATP channels

    PubMed Central

    Budas, Grant R.; Jovanovic, Sofija; Crawford, Russell M.; Jovanovic, Aleksandar

    2007-01-01

    The opening of sarcolemmal and mitochondrial ATP-sensitive K+ (KATP) channels in the heart is believed to mediate ischemic preconditioning, a phenomenon whereby brief periods of ischemia/reperfusion protect the heart against myocardial infarction. Here, we have applied digital epifluorescent microscopy, immunoprecipitation and Western blotting, perforated patch clamp electrophysiology, and immunofluorescence/laser confocal microscopy to examine the involvement of KATP channels in cardioprotection afforded by preconditioning. We have shown that adult, stimulated-to-beat, guinea-pig cardiomyocytes survived in sustained hypoxia for ∼17 min. An episode of 5-min-long hypoxia/5-min-long reoxygenation before sustained hypoxia dramatically increased the duration of cellular survival. Experiments with different antagonists of KATP channels, applied at different times during the experimental protocol, suggested that the opening of sarcolemmal KATP channels at the beginning of sustained hypoxia mediate preconditioning. This conclusion was supported by perforated patch clamp experiments that revealed activation of sarcolemmal KATP channels by preconditioning. Immunoprecipitation and Western blotting as well as immunofluorescence and laser confocal microscopy showed that the preconditioning is associated with the increase in KATP channel proteins in sarcolemma. Inhibition of trafficking of KATP channel subunits prevented preconditioning without affecting sensitivity of cardiomyocytes to hypoxia in the absence of preconditioning. We conclude that the preconditioning is mediated by the activation and trafficking of sarcolemmal KATP channels. PMID:15084521

  6. Systemic chemokine levels, coronary heart disease, and ischemic stroke events

    PubMed Central

    Canouï-Poitrine, F.; Luc, G.; Mallat, Z.; Machez, E.; Bingham, A.; Ferrieres, J.; Ruidavets, J.-B.; Montaye, M.; Yarnell, J.; Haas, B.; Arveiler, D.; Morange, P.; Kee, F.; Evans, A.; Amouyel, P.; Ducimetiere, P.

    2011-01-01

    Objectives: To quantify the association between systemic levels of the chemokine regulated on activation normal T-cell expressed and secreted (RANTES/CCL5), interferon-γ-inducible protein-10 (IP-10/CXCL10), monocyte chemoattractant protein-1 (MCP-1/CCL2), and eotaxin-1 (CCL11) with future coronary heart disease (CHD) and ischemic stroke events and to assess their usefulness for CHD and ischemic stroke risk prediction in the PRIME Study. Methods: After 10 years of follow-up of 9,771 men, 2 nested case-control studies were built including 621 first CHD events and 1,242 matched controls and 95 first ischemic stroke events and 190 matched controls. Standardized hazard ratios (HRs) for each log-transformed chemokine were estimated by conditional logistic regression. Results: None of the 4 chemokines were independent predictors of CHD, either with respect to stable angina or to acute coronary syndrome. Conversely, RANTES (HR = 1.70; 95% confidence interval [CI] 1.05–2.74), IP-10 (HR = 1.53; 95% CI 1.06–2.20), and eotaxin-1 (HR = 1.59; 95% CI 1.02–2.46), but not MCP-1 (HR = 0.99; 95% CI 0.68–1.46), were associated with ischemic stroke independently of traditional cardiovascular risk factors, hs-CRP, and fibrinogen. When the first 3 chemokines were included in the same multivariate model, RANTES and IP-10 remained predictive of ischemic stroke. Their addition to a traditional risk factor model predicting ischemic stroke substantially improved the C-statistic from 0.6756 to 0.7425 (p = 0.004). Conclusions: In asymptomatic men, higher systemic levels of RANTES and IP-10 are independent predictors of ischemic stroke but not of CHD events. RANTES and IP-10 may improve the accuracy of ischemic stroke risk prediction over traditional risk factors. PMID:21849651

  7. Angiopoietin-1 preconditioning enhances survival and functional recovery of mesenchymal stem cell transplantation*

    PubMed Central

    Liu, Xian-bao; Chen, Han; Chen, Hui-qiang; Zhu, Mei-fei; Hu, Xin-yang; Wang, Ya-ping; Jiang, Zhi; Xu, Yin-chuan; Xiang, Mei-xiang; Wang, Jian-an

    2012-01-01

    Objective: Mesenchymal stem cell (MSC) transplantation is a promising therapy for ischemic heart diseases. However, poor cell survival after transplantation greatly limits the therapeutic efficacy of MSCs. The purpose of this study was to investigate the protective effect of angiopoietin-1 (Ang1) preconditioning on MSC survival and subsequent heart function improvement after transplantation. Methods: MSCs were cultured with or without 50 ng/ml Ang1 in complete medium for 24 h prior to experiments on cell survival and transplantation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Hoechst staining were applied to evaluate MSC survival after serum deprivation in vitro, while cell survival in vivo was detected by terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling (TUNEL) assay 24 and 72 h after transplantation. Heart function and infarct size were measured four weeks later by small animal echocardiography and Masson’s trichrome staining, respectively. Results: Ang1 preconditioning induced Akt phosphorylation and increased expression of Bcl-2 and the ratio of Bcl-2/Bax. In comparison with non-preconditioned MSCs, Ang1-preconditioned cell survival was significantly increased while the apoptotic rate decreased in vitro. However, the PI3K/Akt pathway inhibitor, LY294002, abrogated the protective effect of Ang1 preconditioning. After transplantation, the Ang1-preconditioned-MSC group showed a lower death rate, smaller infarct size, and better heart functional recovery compared to the non-preconditioned-MSC group. Conclusions: Ang1 preconditioning enhances MSC survival, contributing to further improvement of heart function. PMID:22843181

  8. Application and Progress of Combined Mesenchymal Stem Cell Transplantation in the Treatment of Ischemic Cardiomyopathy

    PubMed Central

    Hua, Ping; Liu, Jian-Yang; Tao, Jun; Yang, Song-Ran

    2015-01-01

    Treatment of ischemic cardiomyopathy caused by myocardial infarction (MI) using mesenchymal stem cell (MSC) transplantation is a widely researched field, with promising clinical application. However, the low survival rate of transplanted cells has a severe impact on treatment outcome. Currently, research is focused on investigating the strategy of combining genetic engineering, tissue engineering materials, and drug/hypoxia preconditioning to improve ischemic cardiomyopathy treatment outcome using MSC transplantation treatment (MSCTT). This review discusses the application and progress of these techniques. PMID:26295041

  9. Orderings for conjugate gradient preconditionings

    NASA Technical Reports Server (NTRS)

    Ortega, James M.

    1991-01-01

    The effect of orderings on the rate of convergence of the conjugate gradient method with SSOR or incomplete Cholesky preconditioning is examined. Some results also are presented that help to explain why red/black ordering gives an inferior rate of convergence.

  10. [Hypoxic preconditioning is a phenomenon increasing tolerance of cardiomyocytes to hypoxia-reoxygenation].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Kolar, F; Portnichenko, A G; Podoksenov, Iu K; Khaliulin, I G; Wang, H; Pei, J M

    2010-12-01

    The work covers the problem of hypoxic preconditioning (HP) carried out in isolated cardiomyocytes. Papers on delayed HP in vivo are comparatively few, and only some single works are devoted to early preconditioning in vivo. It has been established that the HP limits necrosis and apoptosis of cardiomyocytes and improves contractility of the isolated heart after ischemia (hypoxia) and reperfusion (reoxygenation). It was found that adenosine was a trigger of iP in vitro. It was proved that NO* was a trigger of HP both in vitro and in vivo. It was shown that reactive oxygen species also were triggers of hypoxic preconditioning. It was shown that ERK1/2 and p38 kinase played important role in delayed HP in vitro. PMID:21473105

  11. Hypoxic preconditioning with cobalt ameliorates hypobaric hypoxia induced pulmonary edema in rat.

    PubMed

    Shukla, Dhananjay; Saxena, Saurabh; Purushothaman, Jayamurthy; Shrivastava, Kalpana; Singh, Mrinalini; Shukla, Shirish; Malhotra, Vineet Kumar; Mustoori, Sairam; Bansal, Anju

    2011-04-10

    Exposure to high altitude results in hypobaric hypoxia which is considered as an acute physiological stress and often leads to high altitude maladies such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). The best way to prevent high altitude injuries is hypoxic preconditioning which has potential clinical usefulness and can be mimicked by cobalt chloride. Preconditioning with cobalt has been reported to provide protection in various tissues against ischemic injury. However, the effect of preconditioning with cobalt against high altitude induced pulmonary edema has not been investigated in vivo. Therefore, in the present study, rats pretreated with saline or cobalt (12.5mg/kg body weight) for 7days were exposed to hypobaric hypoxia of 9142m for 5h at 24°C. Formation of pulmonary edema was assessed by measuring transvascular leakage of sodium fluorescein dye and lung water content. Total protein content, albumin content, vascular endothelial growth factor (VEGF) and cytokine levels were measured in bronchoalveolar lavage fluid. Expression of HO-1, MT, NF-κB DNA binding activity and lung tissue pathology were evaluated to determine the effect of preconditioning on HAPE. Hypobaric hypoxia induced increase in transvascular leakage of sodium fluorescein dye, lung water content, lavage total protein, albumin, VEGF levels, pro-inflammatory cytokine levels, tissue expression of cell adhesion molecules and NF-κB DNA binding activity were reduced significantly after hypoxic preconditioning with cobalt. Expression of anti-inflammatory protein HO-1, MT, TGF-β and IL-6 were increased after hypoxic preconditioning. These data suggest that hypoxic preconditioning with cobalt has protective effect against HAPE. PMID:21296072

  12. Preconditioning Operators on Unstructured Grids

    NASA Technical Reports Server (NTRS)

    Nepomnyaschikh, S. V.

    1996-01-01

    We consider systems of mesh equations that approximate elliptic boundary value problems on arbitrary (unstructured) quasi-uniform triangulations and propose a method for constructing optimal preconditioning operators. The method is based upon two approaches: (1) the fictitious space method, i.e., the reduction of the original problem to a problem in an auxiliary (fictitious) space, and (2) the multilevel decomposition method, i.e., the construction of preconditioners by decomposing functions on hierarchical meshes. The convergence rate of the corresponding iterative process with the preconditioner obtained is independent of the mesh step. The preconditioner has an optimal computational cost: the number of arithmetic operations required for its implementation is proportional to the number of unknowns in the problem. The construction of the preconditioning operators for three dimensional problems can be done in the same way.

  13. [Pharmacological preconditioning in carotid endarterectomy].

    PubMed

    Kuznetsov, M R; Karalkin, A V; Fedin, A I; Virganskii, A O; Kunitsyn, N V; Kholopova, E A; Yumin, S M

    2015-01-01

    The study was aimed at examining efficacy of preoperative preparation (pharmacological preconditioning) for carotid endarterectomy in patients with chronic cerebrovascular insufficiency. For this purpose, we analysed the outcomes of surgical treatment in a total of 80 patients presenting with haemodynamically significant unilateral and bilateral lesions of carotid arteries. Of these, 40 patients were operated on immediately and a further 40 patients underwent surgery after pharmacological preconditioning with Actovegin taken at a daily dose of 1,200 mg for 1.5 months. It was demonstrated that preoperative preparation prior to surgery increases cerebral perfusion which is determined by means of single-photon emission computed tomography, thus substantially improving the outcomes of surgical treatment. Statistically significant differences in cognitive function of these groups of patients were revealed 7 days and 6 months after the operation. Improvement of cognitive functions was associated with fewer symptom-free postoperative cerebral ischaemic foci in various regions of the brain. A conclusion was made on a positive role of pharmacological preconditioning with Actovegin in surgical management of cerebrovascular insufficiency, first of all in relation to more complete restoration of cognitive functions. PMID:26355920

  14. Ischemic Strokes (Clots)

    MedlinePlus

    ... Quiz 5 Things to Know About Stroke Ischemic Strokes (Clots) Updated:Jul 12,2016 Ischemic stroke accounts ... strokes. Read more about silent strokes . TIA and Stroke: Medical Emergencies When someone has shown symptoms of ...

  15. Dexmedetomidine preconditioning ameliorates kidney ischemia-reperfusion injury

    PubMed Central

    Lempiäinen, Juha; Finckenberg, Piet; Mervaala, Elina E; Storvik, Markus; Kaivola, Juha; Lindstedt, Ken; Levijoki, Jouko; Mervaala, Eero M

    2014-01-01

    Kidney ischemia-reperfusion (I/R) injury is a common cause of acute kidney injury. We tested whether dexmedetomidine (Dex), an alpha2 adrenoceptor (α2-AR) agonist, protects against kidney I/R injury. Sprague–Dawley rats were divided into four groups: (1) Sham-operated group; (2) I/R group (40 min ischemia followed by 24 h reperfusion); (3) I/R group + Dex (1 μg/kg i.v. 60 min before the surgery), (4) I/R group + Dex (10 μg/kg). The effects of Dex postconditiong (Dex 1 or 10 μg/kg i.v. after reperfusion) as well as the effects of peripheral α2-AR agonism with fadolmidine were also examined. Hemodynamic effects were monitored, renal function measured, and acute tubular damage along with monocyte/macrophage infiltration scored. Kidney protein kinase B, toll like receptor 4, light chain 3B, p38 mitogen-activated protein kinase (p38 MAPK), sirtuin 1, adenosine monophosphate kinase (AMPK), and endothelial nitric oxide synthase (eNOS) expressions were measured, and kidney transciptome profiles analyzed. Dex preconditioning, but not postconditioning, attenuated I/R injury-induced renal dysfunction, acute tubular necrosis and inflammatory response. Neither pre- nor postconditioning with fadolmidine protected kidneys. Dex decreased blood pressure more than fadolmidine, ameliorated I/R-induced impairment of autophagy and increased renal p38 and eNOS expressions. Dex downregulated 245 and upregulated 61 genes representing 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in particular, integrin pathway and CD44. Ingenuity analysis revealed inhibition of Rac and nuclear factor (erythroid-derived 2)-like 2 pathways, whereas aryl hydrocarbon receptor (AHR) pathway was activated. Dex preconditioning ameliorates kidney I/R injury and inflammatory response, at least in part, through p38-CD44-pathway and possibly also through ischemic preconditioning. PMID:25505591

  16. Preconditioned iterations to calculate extreme eigenvalues

    SciTech Connect

    Brand, C.W.; Petrova, S.

    1994-12-31

    Common iterative algorithms to calculate a few extreme eigenvalues of a large, sparse matrix are Lanczos methods or power iterations. They converge at a rate proportional to the separation of the extreme eigenvalues from the rest of the spectrum. Appropriate preconditioning improves the separation of the eigenvalues. Davidson`s method and its generalizations exploit this fact. The authors examine a preconditioned iteration that resembles a truncated version of Davidson`s method with a different preconditioning strategy.

  17. Management of Preconditioned Calves and Impacts of Preconditioning.

    PubMed

    Hilton, W Mark

    2015-07-01

    When studying the practice of preconditioning (PC) calves, many factors need to be examined to determine if cow-calf producers should make this investment. Factors such as average daily gain, feed efficiency, available labor, length of the PC period, genetics, and marketing options must be analyzed. The health sales price advantage is an additional benefit in producing and selling PC calves but not the sole determinant of PC's financially feasibility. Studies show that a substantial advantage of PC is the selling of additional pounds at a cost of gain well below the marginal return of producing those additional pounds. PMID:26139187

  18. Preconditioning for multidimensional TOMBO imaging.

    PubMed

    Horisaki, Ryoichi; Tanida, Jun

    2011-06-01

    In this Letter, we propose a preconditioning method to improve the convergence speed of iterative reconstruction algorithms in a compact, multidimensional, compound-eye imaging system called the thin observation module by bound optics. The condition number of the system matrix is improved by using a preconditioner matrix. To calculate the preconditioner matrix, the system model is expressed in the frequency domain. The proposed method is simulated by using a compressive sensing algorithm called the two-step iterative shrinkage/thresholding algorithm. The results showed improved reconstruction fidelity with a certain number of iterations for high signal-to-noise ratio measurements. PMID:21633452

  19. Failure and rescue of preconditioning-induced neuroprotection in severe stroke-like insults.

    PubMed

    Tauskela, Joseph S; Aylsworth, Amy; Hewitt, Melissa; Brunette, Eric; Blondeau, Nicolas

    2016-06-01

    Preconditioning is a well established neuroprotective modality. However, the mechanism and relative efficacy of neuroprotection between diverse preconditioners is poorly defined. Cultured neurons were preconditioned by 4-aminopyridine and bicuculline (4-AP/bic), rendering neurons tolerant to normally lethal (sufficient to kill most neurons) oxygen-glucose deprivation (OGD) or a chemical OGD-mimic, ouabain/TBOA, by suppression of extracellular glutamate (glutamateex) elevations. However, subjecting preconditioned neurons to longer-duration supra-lethal insults caused neurotoxic glutamateex elevations, thereby identifying a 'ceiling' to neuroprotection. Neuroprotective 'rescue' of neurons could be obtained by administration of an NMDA receptor antagonist, MK-801, just before glutamateex rose during these supra-lethal insults. Next, we evaluated if these concepts of glutamateex suppression during lethal OGD, and a neuroprotective ceiling requiring MK-801 rescue under supra-lethal OGD, extended to the preconditioning field. In screening a panel of 42 diverse putative preconditioners, neuroprotection against normally lethal OGD was observed in 12 cases, which correlated with glutamateex suppression, both of which could be reversed, either by the inclusion of a glutamate uptake inhibitor (TBOA, to increase glutamateex levels) during OGD or by exposure to supra-lethal OGD. Administrating MK-801 during the latter stages of supra-lethal OGD again rescued neurons, although to varying degrees dependent on the preconditioning agent. Thus, 'stress-testing' against the harshest ischemic-like insults yet tested identifies the most efficacious preconditioners, which dictates how early MK-801 needs to be administered during the insult in order to maintain neuroprotection. Preconditioning delays a neurotoxic rise in glutamateex levels, thereby 'buying time' for acute anti-excitotoxic pharmacologic rescue. PMID:26867506

  20. Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels.

    PubMed

    Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2016-08-01

    Remote ischemic preconditioning is a well reported therapeutic strategy that induces cardioprotective effects but the underlying intracellular mechanisms have not been widely explored. The current study was designed to investigate the involvement of TRP and especially TRPV channels in remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 alternate cycles of inflation and deflation of 5 min each) was delivered using a blood pressure cuff tied on the hind limb of the anesthetized rat. Using Langendorff's system, the heart was perfused and subjected to 30-min ischemia and 120-min reperfusion. The myocardial injury was assessed by measuring infarct size, lactate dehydrogenase (LDH), creatine kinase (CK), LVDP, +dp/dtmax, -dp/dtmin, heart rate, and coronary flow rate. Gadolinium, TRP blocker, and ruthenium red, TRPV channel blocker, were employed as pharmacological tools. Remote hind limb preconditioning significantly reduced the infarct size, LDH release, CK release and improved coronary flow rate, hemodynamic parameters including LVDP, +dp/dtmax, -dp/dtmin, and heart rate. However, gadolinium (7.5 and 15 mg kg(-1)) and ruthenium red (4 and 8 mg kg(-1)) significantly attenuated the cardioprotective effects suggesting the involvement of TRP especially TRPV channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus possibly activates TRPV channels on the heart or sensory nerve fibers innervating the heart to induce cardioprotective effects. Alternatively, remote hind limb preconditioning stimulus may also activate the mechanosensitive TRP and especially TRPV channels on the sensory nerve fibers innervating the skeletal muscles to trigger cardioprotective neurogenic signaling cascade. The cardioprotective effects of remote hind limb preconditioning may be mediated via activation of mechanosensitive TRP and especially TRPV channels. PMID:27118661

  1. Effects of Bordetella pertussis toxin pretreatment on the antiarrhythmic action of ischaemic preconditioning in anaesthetized rats.

    PubMed Central

    Piacentini, L; Wainwright, C L; Parratt, J R

    1995-01-01

    1. Bordetella pertussis toxin, which catalyses the ADP-ribosylation of certain guanine nucleotide binding proteins (G proteins), thus functionally uncoupling them from associated receptors, was examined to determine whether it modified the antiarrhythmic effect of ischaemic preconditioning in anaesthetized rats. 2. Pertussis toxin (25 micrograms kg-1, i.p., 48 h prior to heart isolation) attenuated the negative chronotropic effect of acetylcholine (ACh) in rat isolated Langendorff perfused hearts. ACh (10 microM) reduced heart rate by 4% in hearts taken from pertussis toxin-treated animals, compared to a reduction of 57% in hearts taken from animals treated only with vehicle. 3. In anaesthetized rats, ischaemic preconditioning (a single 3 min occlusion of the left main coronary artery followed by 10 min reperfusion) had a pronounced antiarrhythmic effect during a subsequent 30 min period of regional myocardial ischaemia. Compared to hearts receiving only a 30 min period of left coronary occlusion, there was a reduced mortality (67% and 0% for control and preconditioned groups, respectively; P < 0.01) and decreased incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF). Pretreatment with pertussis toxin (25 micrograms kg-1, i.p., 48 h previously) did not modify the arrhythmias associated with a 30 min period of regional myocardial ischaemia, neither did it modify the reduction in mortality (from 56% to 0%; P < 0.05) associated with preconditioning. Furthermore, the decrease in total ventricular premature beat count induced by preconditioning seen in controls (from 427 +/- 130 to 95 +/- 45) was also seen in pertussis toxin-treated rats (from 252 +/- 190 to 57 +/- 25).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7773535

  2. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... accordance with the “General vehicle handling requirements” per 40 CFR 86.132-96, up to and including the completion of the hot start exhaust test. (b) The preconditioning procedure prescribed at 40 CFR 86.132-96... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Vehicle preconditioning. 80.52...

  3. Opioid-induced preconditioning: recent advances and future perspectives.

    PubMed

    Peart, Jason N; Gross, Eric R; Gross, Garrett J

    2005-01-01

    Opioids, named by Acheson for compounds with morphine-like actions despite chemically distinct structures, have received much research interest, particularly for their central nervous system (CNS) actions involved in pain management, resulting in thousands of scientific papers focusing on their effects on the CNS and other organ systems. A more recent area which may have great clinical importance concerns the role of opioids, either endogenous or exogenous compounds, in limiting the pathogenesis of ischemia-reperfusion injury in heart and brain. The role of endogenous opioids in hibernation provides tantalizing evidence for the protective potential of opioids against ischemia or hypoxia. Mammalian hibernation, a distinct energy-conserving state, is associated with depletion of energy stores, intracellular acidosis and hypoxia, similar to those which occur during ischemia. However, despite the potentially detrimental cellular state induced with hibernation, the myocardium remains resilient for many months. What accounts for the hypoxia-tolerant state is of great interest. During hibernation, circulating levels of opioid peptides are increased dramatically, and indeed, are considered a "trigger" of hibernation. Furthermore, administration of opioid antagonists can effectively reverse hibernation in mammals. Therefore, it is not surprising that activation of opioid receptors has been demonstrated to preserve cellular status following a hypoxic insult, such as ischemia-reperfusion in many model systems including the intestine [Zhang, Y., Wu, Y.X., Hao, Y.B., Dun, Y. Yang, S.P., 2001. Role of endogenous opioid peptides in protection of ischemic preconditioning in rat small intestine. Life Sci. 68, 1013-1019], skeletal muscle [Addison, P.D., Neligan, P.C., Ashrafpour, H., Khan, A., Zhong, A., Moses, M., Forrest, C.R., Pang, C.Y., 2003. Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction. Am. J. Physiol. Heart Circ

  4. Autologous preconditioned mesenchymal stem cell sheets improve left ventricular function in a rabbit old myocardial infarction model

    PubMed Central

    Tanaka, Yuya; Shirasawa, Bungo; Takeuchi, Yuriko; Kawamura, Daichi; Nakamura, Tamami; Samura, Makoto; Nishimoto, Arata; Ueno, Koji; Morikage, Noriyasu; Hosoyama, Tohru; Hamano, Kimikazu

    2016-01-01

    Mesenchymal stem cells (MSCs) constitute one of the most powerful tools for therapeutic angiogenesis in infarcted hearts. However, conventional MSC transplantation approaches result in insufficient therapeutic effects due to poor retention of graft cells in severe ischemic diseases. Cell sheet technology has been developed as a new method to prolong graft cell retention even in ischemic tissue. Recently, we demonstrated that hypoxic pretreatment enhances the therapeutic efficacy of cell sheet implantation in infarcted mouse hearts. In this study, we investigated whether hypoxic pretreatment activates the therapeutic functions of bone marrow-derived MSC (BM-MSC) sheets and improves cardiac function in rabbit infarcted hearts following autologous transplantation. Production of vascular endothelial growth factor (VEGF) was increased in BM-MSC monolayer sheets and it peaked at 48 h under hypoxic culture conditions (2% O2). To examine in vivo effects, preconditioned autologous BM-MSC sheets were implanted into a rabbit old myocardial infarction model. Implantation of preconditioned BM-MSC sheets accelerated angiogenesis in the peri-infarcted area and decreased the infarcted area, leading to improvement of the left ventricular function of the infarcted heart. Importantly, the therapeutic efficacy of the preconditioned BM-MSC sheets was higher than that of standardly cultured sheets. Thus, implantation of autologous preconditioned BM-MSC sheets is a feasible approach for enhancing therapeutic angiogenesis in chronically infarcted hearts. PMID:27347329

  5. The involvement of cytokines in the second window of ischaemic preconditioning.

    PubMed

    Yamashita, N; Hoshida, S; Otsu, K; Taniguchi, N; Kuzuya, T; Hori, M

    2000-10-01

    We utilized a rat model of myocardial infarction to investigate whether manganese superoxide dismutase (Mn-SOD), an intrinsic radical scavenger, and tumour necrosis factor- alpha (TNF-alpha) and/or interleukin-1beta (IL-1beta) are involved in the late phase of ischaemic preconditioning (IP). IP was induced in anaesthetized rats by four 3-min left coronary artery (LCA) occlusions, each separated by 10 min of reperfusion. Twenty-four hours after the repetitive brief ischaemia, the LCA was occluded for 20 min followed by reperfusion for 48 h. IP reduced the infarct size by approximately 46% as determined after 48 h of reperfusion. Antisense oligodeoxynucleotides to Mn-SOD inhibited the increases in Mn-SOD content and activity, and abolished the expected decrease in myocardial infarct size. Sense or scrambled oligodeoxynucleotides did not abolish either Mn-SOD induction or tolerance to ischaemia/reperfusion. The simultaneous administration of the antibodies to TNF-alpha (0.5 ml) and IL-1beta (0.5 mg) prior to IP abolished the cardioprotection and the increase in Mn-SOD activity induced by IP. We conclude that the induction and activation of Mn-SOD, mediated by TNF-alpha and IL-1beta after IP, plays an important role in the acquisition of late-phase cardioprotection against ischaemia/reperfusion injury in rats. PMID:11015290

  6. IRE1-RACK1 axis orchestrates ER stress preconditioning-elicited cytoprotection from ischemia/reperfusion injury in liver.

    PubMed

    Liu, Dong; Liu, Xing; Zhou, Ti; Yao, William; Zhao, Jun; Zheng, Zhigang; Jiang, Wei; Wang, Fengsong; Aikhionbare, Felix O; Hill, Donald L; Emmett, Nerimah; Guo, Zhen; Wang, Dongmei; Yao, Xuebiao; Chen, Yong

    2016-04-01

    Endoplasmic reticulum (ER) stress is involved in ischemic preconditioning that protects various organs from ischemia/reperfusion (I/R) injury. We established an in vivo ER stress preconditioning model in which tunicamycin was injected into rats before hepatic I/R. The hepatic I/R injury, demonstrated by serum aminotransferase level and the ultra-structure of the liver, was alleviated by administration of tunicamycin, which induced ER stress in rat liver by activating inositol-requiring enzyme 1 (IRE1) and upregulating 78 kDa glucose-regulated protein (GRP78). The proteomic identification for IRE1 binders revealed interaction and cooperation among receptor for activated C kinase 1 (RACK1), phosphorylated AMPK, and IRE1 under ER stress conditions in a spatiotemporal manner. Furthermore, in vitro ER stress preconditioning was induced by thapsigargin and tunicamycin in L02 and HepG2 cells. Surprisingly, BCL2 was found to be phosphorylated by IRE1 under ER stress conditions to prevent apoptotic process by activation of autophagy. In conclusion, ER stress preconditioning protects against hepatic I/R injury, which is orchestrated by IRE1-RACK1 axis through the activation of BCL2. Our findings provide novel insights into the molecular pathways underlying ER stress preconditioning-elicited cytoprotective effect against hepatic I/R injury. PMID:26711306

  7. Preconditioning with hyperbaric oxygen induces tolerance against oxidative injury via increased expression of heme oxygenase-1 in primary cultured spinal cord neurons.

    PubMed

    Li, Qingbo; Li, Jinsheng; Zhang, Lifan; Wang, Bairen; Xiong, Lize

    2007-02-27

    Hyperbaric oxygen (HBO) preconditioning can induce ischemic tolerance in the spinal cord. The effect can be attenuated by the administration of an oxygen free radical scavenger or by inhibition of antioxidant enzymes. However, the mechanism underlying HBO preconditioning of neurons against ischemic injury remains enigmatic. Therefore, in the present study primary cultured spinal cord neurons were treated with HBO and then subjected to a hydrogen peroxide (H(2)O(2)) insult. The results show that H(2)O(2) stimulation of the cultured spinal neurons caused severe DNA damage and decreased cell viability, and that these neurons were well protected against damage after a single exposure to HBO preconditioning (0.35 MPa, 98% O(2), 37 degrees C, 2 h). The protective effect started 4 h after pretreatment and lasted for at least 24 h. The cultured neurons after HBO treatment also exhibited increased heme oxygenase-1 (HO-1) expression at both the protein and mRNA levels, which paralleled the protective effect of HBO. Treatment with tin-mesoporphyrin IX (SnMP), a specific HO-1 inhibitor, before HBO pretreatment abolished the HBO-induced adaptive protection noted in the cultured spinal neurons. In conclusion, HBO preconditioning can protect primary cultured spinal cord neurons against oxidative stress, and the upregulation of HO-1 expression plays an essential role in HBO induced preconditioning effect. PMID:17291539

  8. CANOPEN Controller IP Core

    NASA Astrophysics Data System (ADS)

    Caramia, Maurizio; Montagna, Mario; Furano, Gianluca; Winton, Alistair

    2010-08-01

    This paper will describe the activities performed by Thales Alenia Space Italia supported by the European Space Agency in the definition of a CAN bus interface to be used on Exomars. The final goal of this activity is the development of an IP core, to be used in a slave node, able to manage both the CAN bus Data Link and Application Layer totally in hardware. The activity has been focused on the needs of the EXOMARS mission where devices with different computational performances are all managed by the onboard computer through the CAN bus.

  9. Preconditioned Krylov subspace methods for eigenvalue problems

    SciTech Connect

    Wu, Kesheng; Saad, Y.; Stathopoulos, A.

    1996-12-31

    Lanczos algorithm is a commonly used method for finding a few extreme eigenvalues of symmetric matrices. It is effective if the wanted eigenvalues have large relative separations. If separations are small, several alternatives are often used, including the shift-invert Lanczos method, the preconditioned Lanczos method, and Davidson method. The shift-invert Lanczos method requires direct factorization of the matrix, which is often impractical if the matrix is large. In these cases preconditioned schemes are preferred. Many applications require solution of hundreds or thousands of eigenvalues of large sparse matrices, which pose serious challenges for both iterative eigenvalue solver and preconditioner. In this paper we will explore several preconditioned eigenvalue solvers and identify the ones suited for finding large number of eigenvalues. Methods discussed in this paper make up the core of a preconditioned eigenvalue toolkit under construction.

  10. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... accordance with the “General vehicle handling requirements” per 40 CFR 86.132-96, up to and including the completion of the hot start exhaust test. (b) The preconditioning procedure prescribed at 40 CFR...

  11. 40 CFR 80.52 - Vehicle preconditioning.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... accordance with the “General vehicle handling requirements” per 40 CFR 86.132-96, up to and including the completion of the hot start exhaust test. (b) The preconditioning procedure prescribed at 40 CFR...

  12. Laser thermal preconditioning enhances dermal wound repair

    NASA Astrophysics Data System (ADS)

    Wilmink, Gerald J.; Carter, Terry; Davidson, Jeffrey M.; Jansen, E. Duco

    2008-02-01

    Preconditioning tissues with an initial mild thermal stress, thereby eliciting a stress response, can serve to protect tissue from subsequent stresses. Patients at risk for impaired healing, such as diabetics, can benefit from therapeutic methods which enhance wound repair. We present a laser thermal preconditioning protocol that accelerates cutaneous wound repair in a murine model. A pulsed diode laser (λ = 1.86 μm, τ p = 2 ms, 50 Hz, H = 7.64 mJ/cm2) was used to precondition mouse skin before incisional wounds were made. The preconditioning protocol was optimized in vitro and in vivo using hsp70 expression, cell viability, and temperature measurements as benchmarks. Hsp70 expression was non-invasively monitored using a transgenic mouse strain with the hsp70 promoter driving luciferase expression. Tissue temperature recordings were acquired in real time using an infrared camera. Wound repair was assessed by measuring hsp70 expression, biomechanical properties, and wound histology for up to 24 d. Bioluminescence (BLI) was monitored with the IVIS 200 System (Xenogen) and tensile properties with a tensiometer (BTC-2000). The in vivo BLI studies indicated that the optimized laser preconditioning protocol increased hsp70 expression by 15-fold. The tensiometer data revealed that laser preconditioned wounds are ~40% stronger than control wounds at 10 days post surgery. Similar experiments in a diabetic mouse model also enhanced wound repair strength. These results indicate that 1) noninvasive imaging methods can aid in the optimization of novel laser preconditioning methods; 2) that optimized preconditioning with a 1.86 μm diode laser enhances early wound repair.

  13. Does remote ischemic conditioning salvage left ventricular function after successful primary PCI?

    PubMed

    Hoole, Stephen P; Dutka, David P

    2011-05-01

    The translation of ischemic preconditioning to a viable therapy that benefits patients has been slow. This has been largely due to the difficultly in preempting when ischemia will occur. Recent advances in the field have demonstrated that cardioprotection from brief episodes of ischemia is possible when applied immediately after reperfusion (ischemic postconditioning) or remotely in another tissue during myocardial ischemia, prior to reperfusion (remote ischemic conditioning). This has facilitated the therapeutic application to patients presenting with acute myocardial infarction. In this article, we will discuss the results of a recent study published by Munk et al., concerning the application of remote ischemic conditioning during primary percutaneous coronary intervention to salvage myocardial function following ST-elevation myocardial infarction. PMID:21615317

  14. REMOTE ISCHEMIC CONDITIONING INFLUENCES MITOCHONDRIAL DYNAMICS

    PubMed Central

    Cellier, Laura; Tamareille, Sophie; Kalakech, Hussein; Guillou, Sophie; Lenaers, Guy; Prunier, Fabrice; Mirebeau-Prunier, Delphine

    2016-01-01

    ABSTRACT Remote ischemic preconditioning (RIPC) has emerged as an attractive strategy to protect the heart against ischemia-reperfusion (I/R) injury. The mechanisms by which remote ischemic conditioning (RIC) is protective are to date unknown, yet a well-accepted theory holds that the mitochondria play a central role. Mitochondria are dynamic organelles that undergo fusion and fission. Interventions that decrease mitochondrial fission or increase mitochondrial fusion have been associated with reduced I/R injury. However, whether RIPC influences mitochondrial dynamics or not has yet to be ascertained. We sought to determine the role played by mitochondrial dynamics in RIPC-induced cardioprotection. Male adult rats exposed in vivo to myocardial I/R were assigned to one of two groups, either undergoing 40 min of myocardial ischemia followed by 120 min of reperfusion (MI group) or four 5-min cycles of limb ischemia interspersed by 5 min of limb reperfusion, immediately prior to myocardial ischemia and 120 min of reperfusion (MI+RIPC group). After reperfusion, infarct size was assessed and myocardial tissue was analyzed by Western blot and electron microscopy. RIPC induced smaller infarct size (−28%), increased mitochondrial fusion protein OPA1, and preserved mitochondrial morphology. These findings suggest that mitochondrial dynamics play a role in the mechanisms of RIPC-induced cardioprotection. PMID:26555744

  15. The hyperbaric oxygen preconditioning-induced brain protection is mediated by a reduction of early apoptosis after transient global cerebral ischemia

    PubMed Central

    Ostrowski, Robert P.; Graupner, Gerhart; Titova, Elena; Zhang, Jennifer; Chiu, Jeffrey; Dach, Neal; Corleone, Dalia; Tang, Jiping; Zhang, John H.

    2008-01-01

    We hypothesized that the brain-protective effect of hyperbaric oxygen (HBO) preconditioning in a transient global cerebral ischemia rat model is mediated by the inhibition of early apoptosis. One hundred ten male Sprague Dawley (SD) rats (300–350 g body weight) were allocated to the sham group and three other groups with 10 minutes of four-vessel occlusion, untreated or preconditioned with either 3 or 5 hyperbaric oxygenations. HBO preconditioning improved neurobehavioral scores and reduced mortality, decreased ischemic cell change, reduced the number of early apoptotic cells and hampered a conversion of early to late apoptotic alterations. HBO preconditioning reduced the immunoreactivity of phosphorylated p38 in vulnerable neurons and increased the expression of brain derived neurotrophic factor (BDNF) in early stage post-ischemia. However, preconditioning with 3 HBO treatments proved less beneficial than with 5 HBO treatments. We conclude that HBO preconditioning may be neuroprotective by reducing early apoptosis and inhibition of the conversion of early to late apoptosis, possibly through an increase in brain BDNF level and the suppression of p38 activation. PMID:17822911

  16. Role of MicroRNAs in innate neuroprotection mechanisms due to preconditioning of the brain

    PubMed Central

    Jimenez-Mateos, Eva M.

    2015-01-01

    Insults to the brain that are sub-threshold for damage activate endogenous protective pathways, which can temporarily protect the brain against a subsequent harmful episode. This mechanism has been named as tolerance and its protective effects have been shown in experimental models of ischemia and epilepsy. The preconditioning-stimulus can be a short period of ischemia or mild seizures induced by low doses of convulsant drugs. Gene-array profiling has shown that both ischemic and epileptic tolerance feature large-scale gene down-regulation but the mechanism are unknown. MicroRNAs are a class of small non-coding RNAs of ~20–22 nucleotides length which regulate gene expression at a post-transcriptional level via mRNA degradation or inhibition of protein translation. MicroRNAs have been shown to be regulated after non-harmful and harmful stimuli in the brain and to contribute to neuroprotective mechanisms. This review focuses on the role of microRNAs in the development of tolerance following ischemic or epileptic preconditioning. PMID:25954143

  17. Lubiprostone induced ischemic colitis.

    PubMed

    Sherid, Muhammed; Sifuentes, Humberto; Samo, Salih; Deepak, Parakkal; Sridhar, Subbaramiah

    2013-01-14

    Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding. It is often multifactorial and more commonly encountered in the elderly. Several medications have been implicated in the development of colonic ischemia. We report a case of a 54-year old woman who presented with a two-hour history of nausea, vomiting, abdominal pain, and bloody stool. The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding. The radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her condition improved without any serious complications after the cessation of lubiprostone. This is the first reported case of ischemic colitis with a clear relationship with lubiprostone (Naranjo score of 10). Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding. PMID:23345954

  18. Identification of a major IP5 kinase in Cryptococcus neoformans confirms that PP-IP5/IP7, not IP6, is essential for virulence

    PubMed Central

    Li, Cecilia; Lev, Sophie; Saiardi, Adolfo; Desmarini, Desmarini; Sorrell, Tania C.; Djordjevic, Julianne T.

    2016-01-01

    Fungal inositol polyphosphate (IP) kinases catalyse phosphorylation of IP3 to inositol pyrophosphate, PP-IP5/IP7, which is essential for virulence of Cryptococcus neoformans. Cryptococcal Kcs1 converts IP6 to PP-IP5/IP7, but the kinase converting IP5 to IP6 is unknown. Deletion of a putative IP5 kinase-encoding gene (IPK1) alone (ipk1Δ), and in combination with KCS1 (ipk1Δkcs1Δ), profoundly reduced virulence in mice. However, deletion of KCS1 and IPK1 had a greater impact on virulence attenuation than that of IPK1 alone. ipk1Δkcs1Δ and kcs1Δ lung burdens were also lower than those of ipk1Δ. Unlike ipk1Δ, ipk1Δkcs1Δ and kcs1Δ failed to disseminate to the brain. IP profiling confirmed Ipk1 as the major IP5 kinase in C. neoformans: ipk1Δ produced no IP6 or PP-IP5/IP7 and, in contrast to ipk1Δkcs1Δ, accumulated IP5 and its pyrophosphorylated PP-IP4 derivative. Kcs1 is therefore a dual specificity (IP5 and IP6) kinase producing PP-IP4 and PP-IP5/IP7. All mutants were similarly attenuated in virulence phenotypes including laccase, urease and growth under oxidative/nitrosative stress. Alternative carbon source utilisation was also reduced significantly in all mutants except ipk1Δ, suggesting that PP-IP4 partially compensates for absent PP-IP5/IP7 in ipk1Δ grown under this condition. In conclusion, PP-IP5/IP7, not IP6, is essential for fungal virulence. PMID:27033523

  19. Identification of a major IP5 kinase in Cryptococcus neoformans confirms that PP-IP5/IP7, not IP6, is essential for virulence.

    PubMed

    Li, Cecilia; Lev, Sophie; Saiardi, Adolfo; Desmarini, Desmarini; Sorrell, Tania C; Djordjevic, Julianne T

    2016-01-01

    Fungal inositol polyphosphate (IP) kinases catalyse phosphorylation of IP3 to inositol pyrophosphate, PP-IP5/IP7, which is essential for virulence of Cryptococcus neoformans. Cryptococcal Kcs1 converts IP6 to PP-IP5/IP7, but the kinase converting IP5 to IP6 is unknown. Deletion of a putative IP5 kinase-encoding gene (IPK1) alone (ipk1Δ), and in combination with KCS1 (ipk1Δkcs1Δ), profoundly reduced virulence in mice. However, deletion of KCS1 and IPK1 had a greater impact on virulence attenuation than that of IPK1 alone. ipk1Δkcs1Δ and kcs1Δ lung burdens were also lower than those of ipk1Δ. Unlike ipk1Δ, ipk1Δkcs1Δ and kcs1Δ failed to disseminate to the brain. IP profiling confirmed Ipk1 as the major IP5 kinase in C. neoformans: ipk1Δ produced no IP6 or PP-IP5/IP7 and, in contrast to ipk1Δkcs1Δ, accumulated IP5 and its pyrophosphorylated PP-IP4 derivative. Kcs1 is therefore a dual specificity (IP5 and IP6) kinase producing PP-IP4 and PP-IP5/IP7. All mutants were similarly attenuated in virulence phenotypes including laccase, urease and growth under oxidative/nitrosative stress. Alternative carbon source utilisation was also reduced significantly in all mutants except ipk1Δ, suggesting that PP-IP4 partially compensates for absent PP-IP5/IP7 in ipk1Δ grown under this condition. In conclusion, PP-IP5/IP7, not IP6, is essential for fungal virulence. PMID:27033523

  20. Polynomial preconditioning for conjugate gradient methods

    SciTech Connect

    Ashby, S.F.

    1987-12-01

    The solution of a linear system of equations, Ax = b, arises in many scientific applications. If A is large and sparse, an iterative method is required. When A is hermitian positive definite (hpd), the conjugate gradient method of Hestenes and Stiefel is popular. When A is hermitian indefinite (hid), the conjugate residual method may be used. If A is ill-conditioned, these methods may converge slowly, in which case a preconditioner is needed. In this thesis we examine the use of polynomial preconditioning in CG methods for both hermitian positive definite and indefinite matrices. Such preconditioners are easy to employ and well-suited to vector and/or parallel architectures. We first show that any CG method is characterized by three matrices: an hpd inner product matrix B, a preconditioning matrix C, and the hermitian matrix A. The resulting method, CG(B,C,A), minimizes the B-norm of the error over a Krylov subspace. We next exploit the versatility of polynomial preconditioners to design several new CG methods. To obtain an optimum preconditioner, we solve a constrained minimax approximation problem. The preconditioning polynomial, C(lambda), is optimum in that it minimizes a bound on the condition number of the preconditioned matrix, p/sub m/(A). An adaptive procedure for dynamically determining the optimum preconditioner is also discussed. Finally, in a variety of numerical experiments, conducted on a Cray X-MP/48, we demonstrate the effectiveness of polynomial preconditioning. 66 ref., 19 figs., 39 tabs.

  1. DAB2IP in cancer

    PubMed Central

    Hsieh, Jer-Tsong; Gong, Jianping; Xie, Daxing

    2016-01-01

    DOC-2/DAB2 is a member of the disable gene family that features tumor-inhibiting activity. The DOC-2/DAB2 interactive protein, DAB2IP, is a new member of the Ras GTPase-activating protein family. It interacts directly with DAB2 and has distinct cellular functions such as modulating different signal cascades associated with cell proliferation, survival, apoptosis and metastasis. Recently, DAB2IP has been found significantly down regulated in multiple types of cancer. The aberrant alteration of DAB2IP in cancer is caused by a variety of mechanisms, including the aberrant promoter methylation, histone deacetylation, and others. Reduced expression of DAB2IP in neoplasm may indicate a poor prognosis of many malignant cancers. Moreover, DAB2IP stands for a promising direction for developing targeted therapies due to its capacity to inhibit tumor cell growth in vitro and in vivo. Here, we summarize the present understanding of the tumor suppressive role of DAB2IP in cancer progression; the mechanisms underlying the dysregulation of DAB2IP; the gene functional mechanism and the prospects of DAB2IP in the future cancer research. PMID:26658103

  2. Combined iron sucrose and protoporphyrin treatment protects against ischemic and toxin-mediated acute renal failure.

    PubMed

    Zager, Richard A; Johnson, Ali C M; Frostad, Kirsten B

    2016-07-01

    Tissue preconditioning, whereby various short-term stressors initiate organ resistance to subsequent injury, is well recognized. However, clinical preconditioning of the kidney for protection against acute kidney injury (AKI) has not been established. Here we tested whether a pro-oxidant agent, iron sucrose, combined with a protoporphyrin (Sn protoporphyrin), can induce preconditioning and protect against acute renal failure. Mice were pretreated with iron sucrose, protoporphyrin, cyanocobalamin, iron sucrose and protoporphyrin, or iron sucrose and cyanocobalamin. Eighteen hours later, ischemic, maleate, or glycerol models of AKI were induced, and its severity was assessed the following day (blood urea nitrogen, plasma creatinine concentrations; post-ischemic histology). Agent impact on cytoprotective gene expression (heme oxygenase 1, hepcidin, haptoglobin, hemopexin, α1-antitrypsin, α1-microglobulin, IL-10) was assessed as renal mRNA and protein levels. AKI-associated myocardial injury was gauged by plasma troponin I levels. Combination agent administration upregulated multiple cytoprotective genes and, unlike single agent administration, conferred marked protection against each tested model of acute renal failure. Heme oxygenase was shown to be a marked contributor to this cytoprotective effect. Preconditioning also blunted AKI-induced cardiac troponin release. Thus, iron sucrose and protoporphyrin administration can upregulate diverse cytoprotective genes and protect against acute renal failure. Associated cardiac protection implies potential relevance to both AKI and its associated adverse downstream effects. PMID:27165818

  3. Pharmacological Preconditioning of Mesenchymal Stem Cells with Trimetazidine (1-[2,3,4-Trimethoxybenzyl]piperazine) Protects Hypoxic Cells against Oxidative Stress and Enhances Recovery of Myocardial Function in Infarcted Heart through Bcl-2 Expression

    PubMed Central

    Wisel, Sheik; Khan, Mahmood; Kuppusamy, M. Lakshmi; Mohan, I. Krishna; Chacko, Simi M.; Rivera, Brian K.; Sun, Benjamin C.; Hideg, Kálmán; Kuppusamy, Periannan

    2009-01-01

    Stem cell transplantation is a possible therapeutic option to repair ischemic damage to the heart. However, it is faced with a number of challenges including the survival of the transplanted cells in the ischemic region. The present study was designed to use stem cells preconditioned with trimetazidine (1-[2,3,4-trimethoxybenzyl]piperazine; TMZ), a widely used anti-ischemic drug for treating angina in cardiac patients, to increase the rate of their survival after transplantation. Bone marrow-derived rat mesenchymal stem cells (MSCs) were subjected to a simulated host tissue environment by culturing them under hypoxia (2% O2) and using hydrogen peroxide (H2O2) to induce oxidative stress. MSCs were preconditioned with 10 μM TMZ for 6 h followed by treatment with 100 μM H2O2 for 1 h and characterized for their cellular viability and metabolic activity. The preconditioned cells showed a significant protection against H2O2-induced loss of cellular viability, membrane damage, and oxygen metabolism accompanied by a significant increase in HIF-1α, survivin, phosphorylated Akt (pAkt), and Bcl-2 protein levels and Bcl-2 gene expression. The therapeutic efficacy of the TMZ-preconditioned MSCs was evaluated in an in vivo rat model of myocardial infarction induced by permanent ligation of left anterior descending coronary artery. A significant increase in the recovery of myocardial function and up-regulation of pAkt and Bcl-2 levels were observed in hearts transplanted with TMZ-preconditioned cells. This study clearly demonstrated the potential benefits of pharmacological preconditioning of MSCs with TMZ for stem cell therapy for repairing myocardial ischemic damage. PMID:19218529

  4. Chemical Conditioning as an Approach to Ischemic Stroke Tolerance: Mitochondria as the Target

    PubMed Central

    Jin, Zhen; Wu, Jinzi; Yan, Liang-Jun

    2016-01-01

    It is well established that the brain can be prepared to resist or tolerate ischemic stroke injury, and mitochondrion is a major target for this tolerance. The preparation of ischemic stroke tolerance can be achieved by three major approaches: ischemic conditioning, hypoxic conditioning and chemical conditioning. In each conditioning approach, there are often two strategies that can be used to achieve the conditioning effects, namely preconditioning (Pre-C) and postconditioning (Post-C). In this review, we focus on chemical conditioning of mitochondrial proteins as targets for neuroprotection against ischemic stroke injury. Mitochondrial targets covered include complexes I, II, IV, the ATP-sensitive potassium channel (mitoKATP), adenine dinucleotide translocase (ANT) and the mitochondrial permeability transition pore (mPTP). While numerous mitochondrial proteins have not been evaluated in the context of chemical conditioning and ischemic stroke tolerance, the paradigms and approaches reviewed in this article should provide general guidelines on testing those mitochondrial components that have not been investigated. A deep understanding of mitochondria as the target of chemical conditioning for ischemic stroke tolerance should provide valuable insights into strategies for fighting ischemic stroke, a leading cause of death in the world. PMID:27005615

  5. Combination of hyperhomocysteinemia and ischemic tolerance in experimental model of global ischemia in rats.

    PubMed

    Kovalska, M; Kovalska, L; Tothova, B; Mahmood, S; Adamkov, M; Lehotsky, J

    2015-12-01

    Epidemiological studies show positive relationship between mild-to-moderate hyperhomocysteinemia (hHcy) and the risk of cerebrovascular diseases. The study determines whether hyperhomocysteinemia (risk factor of brain ischemia) alone or in combination with the ischemic preconditioning (IPC) affects the ischemia-induced neurodegenerative changes and imbalance in MAPK/p-ERK1/2 and MAPK/p-p38 expression in the rat brains. hHcy was induced by subcutaneous administration of homocysteine (0.45 μmol/g body weight) twice a day at 8 h intervals for 14 days. Rats were preconditioned by 5 min ischemia and 2 days later, 15 min of global forebrain ischemia was induced by four vessel occlusion. We observed that hHcy alone significantly increased neurodegeneration by Fluoro-Jade C and TUNEL possitive cells in hippocampus as well as in cortex. We found elevated level of MAPK/p-ERK and decreased level of MAPK/p-p38 after pre-ischemic challenge by Western blot and fluorescent immunohistochemistry. In conclusion, preconditioning even if combined with hHcy could preserve the neuronal tissue from lethal ischemic effect. This study provides evidence for the interplay and tight integration between ERK and p38 MAPKs signalling mechanisms in response to the hHcy and also if in association with brain ischemia/IPC challenge in the rat brain. PMID:26769838

  6. Time to Give Up on Cardioprotection? A Critical Appraisal of Clinical Studies on Ischemic Pre-, Post-, and Remote Conditioning.

    PubMed

    Heusch, Gerd; Rassaf, Tienush

    2016-08-19

    The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of post-myocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin. Ischemic postconditioning reduces infarct size in most, but not all, studies in patients undergoing interventional reperfusion of AMI, but may require direct stenting and exclusion of patients with >6 hours of symptom onset to protect. Remote ischemic conditioning reduces infarct size in patients undergoing interventional reperfusion of AMI, elective percutaneous or surgical coronary revascularization, and other cardiovascular surgery in many, but not in all, studies. Adequate dose-finding phase II studies do not exist. There are only 2 phase III trials, both on remote ischemic conditioning in patients undergoing cardiovascular surgery, both with neutral results in terms of infarct size and clinical outcome, but also both with major problems in trial design. We discuss the difficulties in translation of cardioprotection from animal experiments and proof-of-concept trials to clinical practice. Given that most studies on ischemic postconditioning and all studies on remote ischemic preconditioning in patients with AMI reported reduced infarct size, it would be premature to give up on cardioprotection. PMID:27539973

  7. Minimal residual method stronger than polynomial preconditioning

    SciTech Connect

    Faber, V.; Joubert, W.; Knill, E.

    1994-12-31

    Two popular methods for solving symmetric and nonsymmetric systems of equations are the minimal residual method, implemented by algorithms such as GMRES, and polynomial preconditioning methods. In this study results are given on the convergence rates of these methods for various classes of matrices. It is shown that for some matrices, such as normal matrices, the convergence rates for GMRES and for the optimal polynomial preconditioning are the same, and for other matrices such as the upper triangular Toeplitz matrices, it is at least assured that if one method converges then the other must converge. On the other hand, it is shown that matrices exist for which restarted GMRES always converges but any polynomial preconditioning of corresponding degree makes no progress toward the solution for some initial error. The implications of these results for these and other iterative methods are discussed.

  8. Projection preconditioning for Lanczos-type methods

    SciTech Connect

    Bielawski, S.S.; Mulyarchik, S.G.; Popov, A.V.

    1996-12-31

    We show how auxiliary subspaces and related projectors may be used for preconditioning nonsymmetric system of linear equations. It is shown that preconditioned in such a way (or projected) system is better conditioned than original system (at least if the coefficient matrix of the system to be solved is symmetrizable). Two approaches for solving projected system are outlined. The first one implies straightforward computation of the projected matrix and consequent using some direct or iterative method. The second approach is the projection preconditioning of conjugate gradient-type solver. The latter approach is developed here in context with biconjugate gradient iteration and some related Lanczos-type algorithms. Some possible particular choices of auxiliary subspaces are discussed. It is shown that one of them is equivalent to using colorings. Some results of numerical experiments are reported.

  9. Late preconditioning against myocardial stunning. An endogenous protective mechanism that confers resistance to postischemic dysfunction 24 h after brief ischemia in conscious pigs.

    PubMed

    Sun, J Z; Tang, X L; Knowlton, A A; Park, S W; Qiu, Y; Bolli, R

    1995-01-01

    Conscious pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, for three consecutive days (days 1, 2, and 3 of stage I). The recovery of systolic wall thickening (WTh) after the 10th reperfusion was markedly improved on days 2 and 3 compared with day 1, indicating that the myocardium had become preconditioned against "stunning." 10 d after stage I, pigs underwent again a sequence of 10 2-min coronary occlusions for two consecutive days (days 1 and 2 of stage II). On day 1 of stage II, the recovery of WTh after the 10th reperfusion was similar to that noted on day 1 of stage I; on day 2 of stage II, however, the recovery of WTh was again markedly improved compared with day 1. Blockade of adenosine receptors with 8-p-sulfophenyl theophylline failed to prevent the development of preconditioning against stunning. Northern blot analysis demonstrated an increase in heat stress protein (HSP) 70 mRNA 2 h after the preconditioning ischemia; at this same time point, immunohistochemical analysis revealed a concentration of HSP70 in the nucleus and an overall increase in staining for HSP70. 24 h after the preconditioning ischemia, Western dot blot analysis demonstrated an increase in HSP70. This study indicates the existence of a new, previously unrecognized cardioprotective phenomenon. The results demonstrate that a brief ischemic stress induces a powerful, long-lasting (at least 48 h) adaptive response that renders the myocardium relatively resistant to stunning 24 h later (late preconditioning against stunning). This adaptive response disappears within 10 d after the last ischemic stress but can be reinduced by another ischemic stress. Unlike early and late preconditioning against infarction, late preconditioning against stunning is not blocked by adenosine receptor antagonists, and therefore appears to involve a mechanism different from that of other forms of preconditioning currently known. The increase in myocardial HSP70 is

  10. Preconditioning the Helmholtz Equation for Rigid Ducts

    NASA Technical Reports Server (NTRS)

    Baumeister, Kenneth J.; Kreider, Kevin L.

    1998-01-01

    An innovative hyperbolic preconditioning technique is developed for the numerical solution of the Helmholtz equation which governs acoustic propagation in ducts. Two pseudo-time parameters are used to produce an explicit iterative finite difference scheme. This scheme eliminates the large matrix storage requirements normally associated with numerical solutions to the Helmholtz equation. The solution procedure is very fast when compared to other transient and steady methods. Optimization and an error analysis of the preconditioning factors are present. For validation, the method is applied to sound propagation in a 2D semi-infinite hard wall duct.

  11. Increase of adenosine plasma levels after oral trimetazidine: a pharmacological preconditioning?

    PubMed

    Blardi, Patrizia; de Lalla, Arianna; Volpi, Luciana; Auteri, Alberto; Di Perri, Tullio

    2002-01-01

    Trimetazidine (1-[2,3,4-trimethoxybenzyl] piperazine) (TMZ) is a cellular anti-ischemic agent able to prevent intracellular ATP decrease, limit intracellular acidosis, protect against oxygen-free radical-induced toxicity and inhibit neutrophil infiltration. However, its definitive mechanism of action had not been identified. Recent studies showed the existence of an endogenous mechanism of cellular protection against ischemia, defined as 'ischemic preconditioning'. This mechanism was related mainly to cellular liberation of adenosine, a nucleoside with protective effects in myocardial ischemia. Since TMZ acts by increasing cell tolerance to ischemia and adenosine is the mediator of ischemic preconditioning, in this study we investigated a possible interaction between TMZ and adenosine. Two groups of patients affected by angina pectoris, were admitted to the study. They received a single oral dose of TMZ. One group was treated, during different sessions, with TMZ 10 and 20 mg, the other group with TMZ 40 and 80 mg. After a 3 day wash-out from drug administration, each group received a placebo. Blood samples were collected at baseline (time 0) and 1, 2, 3, 4, 6, 8 h after drug administration, in order to detect plasma levels of adenosine by a high-performance liquid chromatography method. We observed that the administration of TMZ at doses of 10, 20, 40 and 80 mg induced an increase of adenosine plasma levels of 19, 50, 62 and 62%, respectively. We hypothesized that the activity of TMZ could depend, at least in part, on adenosine mediation and this interaction opens a new interpretation of the drug antischemic effect. PMID:11820865

  12. TLR9 bone marrow chimeric mice define a role for cerebral TNF in neuroprotection induced by CpG preconditioning.

    PubMed

    Packard, Amy E B; Leung, Philberta Y; Vartanian, Keri B; Stevens, Susan L; Bahjat, Frances R; Stenzel-Poore, Mary P

    2012-12-01

    Systemic preconditioning with the TLR9 ligand CpG induces neuroprotection against brain ischemic injury through a tumor necrosis factor (TNF)-dependent mechanism. It is unclear how systemic administration of CpG engages the brain to induce the protective phenotype. To address this, we created TLR9-deficient reciprocal bone marrow chimeric mice lacking TLR9 on either hematopoietic cells or radiation-resistant cells of nonhematopoietic origin. We report that wild-type mice reconstituted with TLR9-deficient hematopoietic cells failed to show neuroprotection after systemic CpG preconditioning. Further, while hematopoietic expression of TLR9 is required for CpG-induced neuroprotection it is not sufficient to restore protection to TLR9-deficient mice that are reconstituted with hematopoietic cells bearing TLR9. To determine whether the absence of protection was associated with TNF, we examined TNF levels in the systemic circulation and the brain. We found that although TNF is required for CpG preconditioning, systemic TNF levels did not correlate with the protective phenotype. However, induction of cerebral TNF mRNA required expression of TLR9 on both hematopoietic and nonhematopoietic cells and correlated with neuroprotection. In accordance with these results, we show the therapeutic potential of intranasal CpG preconditioning, which induces brain TNF mRNA and robust neuroprotection with no concomitant increase in systemic levels of TNF. PMID:23010947

  13. Possible role of thromboxane A2 in remote hind limb preconditioning-induced cardioprotection.

    PubMed

    Sharma, Roohani; Randhawa, Puneet Kaur; Singh, Nirmal; Jaggi, Amteshwar Singh

    2016-01-01

    Remote hind limb preconditioning (RIPC) is a protective strategy in which short episodes of ischemia and reperfusion in a remote organ (hind limb) protects the target organ (heart) against sustained ischemic reperfusion injury. The present study was designed to investigate the possible role of thromboxane A2 in RIPC-induced cardioprotection in rats. Remote hind limb preconditioning was performed by four episodes of 5 min of inflation and 5 min of deflation of pressure cuff. Occlusion of the hind limb with blood pressure cuff is most feasible, non-invasive, clinically relevant, and safe method for inducing RIPC. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120-min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. The extent of myocardial infarct size along with the functional parameters including left ventricular developed pressure (LVDP), dp/dtmax, and dp/dtmin were also measured. Ozagrel (thromboxane synthase inhibitor) and seratrodast (thromboxane A2 receptor antagonist) were employed as pharmacological modulators of thromboxane A2. Remote hind limb preconditioning significantly attenuated ischemia/reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of ozagrel and seratrodast completely abolished the cardioprotective effects of RIPC suggesting the key role of thromboxane A2 in RIPC-induced cardioprotection. It may be concluded that brief episodes of preconditioning ischemia and reperfusion activates the thromboxane synthase enzyme that produces thromboxane A2, which may elicit cardioprotection either involving humoral or neurogenic pathway. PMID:26531833

  14. Health and Nutrition: Preconditions for Educational Achievement.

    ERIC Educational Resources Information Center

    Negussie, Birgit

    This paper discusses the importance of maternal and infant health for children's educational achievement. Education, health, and nutrition are so closely related that changes in one causes changes in the others. Improvement of maternal and preschooler health and nutrition is a precondition for improved educational achievement. Although parental…

  15. Preconditioning matrices for Chebyshev derivative operators

    NASA Technical Reports Server (NTRS)

    Rothman, Ernest E.

    1986-01-01

    The problem of preconditioning the matrices arising from pseudo-spectral Chebyshev approximations of first order operators is considered in both one and two dimensions. In one dimension a preconditioner represented by a full matrix which leads to preconditioned eigenvalues that are real, positive, and lie between 1 and pi/2, is already available. Since there are cases in which it is not computationally convenient to work with such a preconditioner, a large number of preconditioners were studied which were more sparse (in particular three and four diagonal matrices). The eigenvalues of such preconditioned matrices are compared. The results were applied to the problem of finding the steady state solution to an equation of the type u sub t = u sub x + f, where the Chebyshev collocation is used for the spatial variable and time discretization is performed by the Richardson method. In two dimensions different preconditioners are proposed for the matrix which arises from the pseudo-spectral discretization of the steady state problem. Results are given for the CPU time and the number of iterations using a Richardson iteration method for the unpreconditioned and preconditioned cases.

  16. Revealing Preconditions for Trustful Collaboration in CSCL

    ERIC Educational Resources Information Center

    Gerdes, Anne

    2010-01-01

    This paper analyses preconditions for trust in virtual learning environments. The concept of trust is discussed with reference to cases reporting trust in cyberspace and through a philosophical clarification holding that trust in the form of self-surrender is a common characteristic of all human co-existence. In virtual learning environments,…

  17. 40 CFR 1065.518 - Engine preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., such as with a diesel engine that relies on urea-based selective catalytic reduction. Note that § 1065... cycle specified in 40 CFR 1039.505(b)(1), the second half of the cycle consists of modes three through... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Engine preconditioning....

  18. Mitochondrial Dihydrolipoamide Dehydrogenase Is Upregulated in Response to Intermittent Hypoxic Preconditioning

    PubMed Central

    Li, Rongrong; Luo, Xiaoting; Wu, Jinzi; Thangthaeng, Nopporn; Jung, Marianna E.; Jing, Siqun; Li, Linya; Ellis, Dorette Z.; Liu, Li; Ding, Zhengnian; Forster, Michael J.; Yan, Liang-Jun

    2015-01-01

    Intermittent hypoxia preconditioning (IHP) has been shown to protect neurons against ischemic stroke injury. Studying how proteins respond to IHP may identify targets that can help fight stroke. The objective of the present study was to investigate whether mitochondrial dihydrolipoamide dehydrogenase (DLDH) would respond to IHP and if so, whether such a response could be linked to neuroprotection in ischemic stroke injury. To do this, we subjected male rats to IHP for 20 days and measured the content and activity of DLDH as well as the three α-keto acid dehydrogenase complexes that contain DLDH. We also measured mitochondrial electron transport chain enzyme activities. Results show that DLDH content was indeed upregulated by IHP and this upregulation did not alter the activities of the three α-keto acid dehydrogenase complexes. Results also show that the activities of the five mitochondrial complexes (I-V) were not altered either by IHP. To investigate whether IHP-induced DLDH upregulation is linked to neuroprotection against ischemic stroke injury, we subjected both DLDH deficient mouse and DLDH transgenic mouse to stroke surgery followed by measurement of brain infarction volume. Results indicate that while mouse deficient in DLDH had exacerbated brain injury after stroke, mouse overexpressing human DLDH also showed increased brain injury after stroke. Therefore, the physiological significance of IHP-induced DLDH upregulation remains to be further investigated. PMID:26078703

  19. Mitochondrial Dihydrolipoamide Dehydrogenase is Upregulated in Response to Intermittent Hypoxic Preconditioning.

    PubMed

    Li, Rongrong; Luo, Xiaoting; Wu, Jinzi; Thangthaeng, Nopporn; Jung, Marianna E; Jing, Siqun; Li, Linya; Ellis, Dorette Z; Liu, Li; Ding, Zhengnian; Forster, Michael J; Yan, Liang-Jun

    2015-01-01

    Intermittent hypoxia preconditioning (IHP) has been shown to protect neurons against ischemic stroke injury. Studying how proteins respond to IHP may identify targets that can help fight stroke. The objective of the present study was to investigate whether mitochondrial dihydrolipoamide dehydrogenase (DLDH) would respond to IHP and if so, whether such a response could be linked to neuroprotection in ischemic stroke injury. To do this, we subjected male rats to IHP for 20 days and measured the content and activity of DLDH as well as the three α-keto acid dehydrogenase complexes that contain DLDH. We also measured mitochondrial electron transport chain enzyme activities. Results show that DLDH content was indeed upregulated by IHP and this upregulation did not alter the activities of the three α-keto acid dehydrogenase complexes. Results also show that the activities of the five mitochondrial complexes (I-V) were not altered either by IHP. To investigate whether IHP-induced DLDH upregulation is linked to neuroprotection against ischemic stroke injury, we subjected both DLDH deficient mouse and DLDH transgenic mouse to stroke surgery followed by measurement of brain infarction volume. Results indicate that while mouse deficient in DLDH had exacerbated brain injury after stroke, mouse overexpressing human DLDH also showed increased brain injury after stroke. Therefore, the physiological significance of IHP-induced DLDH upregulation remains to be further investigated. PMID:26078703

  20. Beyond Preconditioning: Postconditioning as an Alternative Technique in the Prevention of Liver Ischemia-Reperfusion Injury

    PubMed Central

    Theodoraki, Kassiani; Karmaniolou, Iosifina; Tympa, Aliki; Tasoulis, Marios-Konstantinos; Nastos, Constantinos; Vassiliou, Ioannis; Arkadopoulos, Nikolaos; Smyrniotis, Vassilios

    2016-01-01

    Liver ischemia/reperfusion injury may significantly compromise hepatic postoperative function. Various hepatoprotective methods have been improvised, aiming at attenuating IR injury. With ischemic preconditioning (IPC), the liver is conditioned with a brief ischemic period followed by reperfusion, prior to sustained ischemia. Ischemic postconditioning (IPostC), consisting of intermittent sequential interruptions of blood flow in the early phase of reperfusion, seems to be a more feasible alternative than IPC, since the onset of reperfusion is more predictable. Regarding the potential mechanisms involved, it has been postulated that the slow intermittent oxygenation through controlled reperfusion decreases the burst production of oxygen free radicals, increases antioxidant activity, suppresses neutrophil accumulation, and modulates the apoptotic cascade. Additionally, favorable effects on mitochondrial ultrastructure and function, and upregulation of the cytoprotective properties of nitric oxide, leading to preservation of sinusoidal structure and maintenance of blood flow through the hepatic circulation could also underlie the protection afforded by postconditioning. Clinical studies are required to show whether biochemical and histological improvements afforded by the reperfusion/reocclusion cycles of postconditioning during early reperfusion can be translated to a substantial clinical benefit in liver resection and transplantation settings or to highlight more aspects of its molecular mechanisms. PMID:27340509

  1. Ischemic Colitis Revealing Polyarteritis Nodosa

    PubMed Central

    Hamzaoui, Amira; Litaiem, Noureddine; Smiti Khanfir, M.; Ayadi, Sofiene; Nfoussi, Haifa; Houman, M. H.

    2013-01-01

    Ischemic colitis is one of the most common intestinal ischemic injuries. It results from impaired perfusion of blood to the bowel and is rarely caused by vasculitis. We report a case of ischemic colitis revealing polyarteritis nodosa (PAN) in a 55-year-old man. Histological examination of the resected colon led to the diagnosis of PAN. PMID:24382967

  2. Ozone-Oxidative Preconditioning Prevents Doxorubicin-induced Cardiotoxicity in Sprague-Dawley Rats

    PubMed Central

    Delgado-Roche, Livan; Hernández-Matos, Yanet; Medina, Emilio A.; Morejón, Dalia Á.; González, Maité R.; Martínez-Sánchez, Gregorio

    2014-01-01

    Objectives: Induced dilated cardiomyopathy is the main limitation of the anti-cancer drug doxorubicin, which causes oxidative stress and cardiomyocyte death. As ozone therapy can activate the antioxidant systems, this study aimed to investigate the therapeutic efficacy of ozone-oxidative preconditioning against doxorubicin-induced cardiotoxicity. Methods: The study was carried out from September 2013 to January 2014. Sprague-Dawley rats were randomly distributed in the following treatment groups: Group 1 were treated with 2 mg/kg intraperitoneal (i.p.) of doxorubicin twice a week for 50 days; Group 2 were treated with 0.3 mg of ozone/oxygen mixture at 50 μg/mL of ozone per 6 mL of oxygen by rectal insufflation and then treated with doxorubicin; Group 3 were treated as Group 2 but only with the oxygen, and Group 4 were treated with oxygen first, and then with sodium chloride i.p. as the control group. Results: The results showed that ozone therapy preserved left ventricle morphology which was accompanied by a reduction of serum pro-brain natriuretic peptide levels. The cardioprotective effects of ozone-oxidative preconditioning were associated with a significant increase (P <0.05) of antioxidant enzymes activities and a reduction of lipid and protein oxidation (P <0.05). Conclusion: Ozone-oxidative preconditioning prevents doxorubicin-induced dilated cardiomyopathy through an increase of antioxidant enzymes and a reduction of oxidised macromolecules. This establishes the background for future studies to determine if ozone therapy can be used as a complementary treatment for attenuating doxorubicin-induced cardiotoxicity in cancer patients. PMID:25097769

  3. Condition number estimation of preconditioned matrices.

    PubMed

    Kushida, Noriyuki

    2015-01-01

    The present paper introduces a condition number estimation method for preconditioned matrices. The newly developed method provides reasonable results, while the conventional method which is based on the Lanczos connection gives meaningless results. The Lanczos connection based method provides the condition numbers of coefficient matrices of systems of linear equations with information obtained through the preconditioned conjugate gradient method. Estimating the condition number of preconditioned matrices is sometimes important when describing the effectiveness of new preconditionerers or selecting adequate preconditioners. Operating a preconditioner on a coefficient matrix is the simplest method of estimation. However, this is not possible for large-scale computing, especially if computation is performed on distributed memory parallel computers. This is because, the preconditioned matrices become dense, even if the original matrices are sparse. Although the Lanczos connection method can be used to calculate the condition number of preconditioned matrices, it is not considered to be applicable to large-scale problems because of its weakness with respect to numerical errors. Therefore, we have developed a robust and parallelizable method based on Hager's method. The feasibility studies are curried out for the diagonal scaling preconditioner and the SSOR preconditioner with a diagonal matrix, a tri-daigonal matrix and Pei's matrix. As a result, the Lanczos connection method contains around 10% error in the results even with a simple problem. On the other hand, the new method contains negligible errors. In addition, the newly developed method returns reasonable solutions when the Lanczos connection method fails with Pei's matrix, and matrices generated with the finite element method. PMID:25816331

  4. Condition Number Estimation of Preconditioned Matrices

    PubMed Central

    Kushida, Noriyuki

    2015-01-01

    The present paper introduces a condition number estimation method for preconditioned matrices. The newly developed method provides reasonable results, while the conventional method which is based on the Lanczos connection gives meaningless results. The Lanczos connection based method provides the condition numbers of coefficient matrices of systems of linear equations with information obtained through the preconditioned conjugate gradient method. Estimating the condition number of preconditioned matrices is sometimes important when describing the effectiveness of new preconditionerers or selecting adequate preconditioners. Operating a preconditioner on a coefficient matrix is the simplest method of estimation. However, this is not possible for large-scale computing, especially if computation is performed on distributed memory parallel computers. This is because, the preconditioned matrices become dense, even if the original matrices are sparse. Although the Lanczos connection method can be used to calculate the condition number of preconditioned matrices, it is not considered to be applicable to large-scale problems because of its weakness with respect to numerical errors. Therefore, we have developed a robust and parallelizable method based on Hager’s method. The feasibility studies are curried out for the diagonal scaling preconditioner and the SSOR preconditioner with a diagonal matrix, a tri-daigonal matrix and Pei’s matrix. As a result, the Lanczos connection method contains around 10% error in the results even with a simple problem. On the other hand, the new method contains negligible errors. In addition, the newly developed method returns reasonable solutions when the Lanczos connection method fails with Pei’s matrix, and matrices generated with the finite element method. PMID:25816331

  5. Ischemic Nerve Block.

    ERIC Educational Resources Information Center

    Williams, Ian D.

    This experiment investigated the capability for movement and muscle spindle function at successive stages during the development of ischemic nerve block (INB) by pressure cuff. Two male subjects were observed under six randomly ordered conditions. The duration of index finger oscillation to exhaustion, paced at 1.2Hz., was observed on separate…

  6. Simple Machine Perfusion Significantly Enhances Hepatocyte Yields of Ischemic and Fresh Rat Livers

    PubMed Central

    Izamis, Maria-Louisa; Calhoun, Candice; Uygun, Basak E.; Guzzardi, Maria Angela; Price, Gavrielle; Luitje, Martha; Saeidi, Nima; Yarmush, Martin L.; Uygun, Korkut

    2013-01-01

    The scarcity of viable hepatocytes is a significant bottleneck in cell transplantation, drug discovery, toxicology, tissue engineering, and bioartificial assist devices, where trillions of high-functioning hepatocytes are needed annually. We took the novel approach of using machine perfusion to maximize cell recovery, specifically from uncontrolled cardiac death donors, the largest source of disqualified donor organs. In a rat model, we developed a simple 3-h room temperature (20 ± 2°C) machine perfusion protocol to treat nonpremedicated livers exposed to 1 h of warm (34°C) ischemia. Treated ischemic livers were compared to fresh, fresh-treated, and untreated ischemic livers using viable hepatocyte yields and in vitro performance as quantitative endpoints. Perfusion treatment resulted in both a 25-fold increase in viable hepatocytes from ischemic livers and a 40% increase from fresh livers. While cell morphology and function in suspension and plate cultures of untreated warm ischemic cells was significantly impaired, treated warm ischemic cells were indistinguishable from fresh hepatocytes. Furthermore, a strong linear correlation between tissue ATP and cell yield enabled accurate evaluation of the extent of perfusion recovery. Maximal recovery of warm ischemic liver ATP content appears to be correlated with optimal flow through the microvasculature. These data demonstrate that the inclusion of a simple perfusion-preconditioning step can significantly increase the efficiency of functional hepatocyte yields and the number of donor livers that can be gainfully utilized. PMID:25431743

  7. Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing.

    PubMed

    Schaafsma, W; Zhang, X; van Zomeren, K C; Jacobs, S; Georgieva, P B; Wolf, S A; Kettenmann, H; Janova, H; Saiepour, N; Hanisch, U-K; Meerlo, P; van den Elsen, P J; Brouwer, N; Boddeke, H W G M; Eggen, B J L

    2015-08-01

    Microglia, the innate immune cells of the central nervous system (CNS), react to endotoxins like bacterial lipopolysaccharides (LPS) with a pronounced inflammatory response. To avoid excess damage to the CNS, the microglia inflammatory response needs to be tightly regulated. Here we report that a single LPS challenge results in a prolonged blunted pro-inflammatory response to a subsequent LPS stimulation, both in primary microglia cultures (100 ng/ml) and in vivo after intraperitoneal (0.25 and 1mg/kg) or intracerebroventricular (5 μg) LPS administration. Chromatin immunoprecipitation (ChIP) experiments with primary microglia and microglia acutely isolated from mice showed that LPS preconditioning was accompanied by a reduction in active histone modifications AcH3 and H3K4me3 in the promoters of the IL-1β and TNF-α genes. Furthermore, LPS preconditioning resulted in an increase in the amount of repressive histone modification H3K9me2 in the IL-1β promoter. ChIP and knock-down experiments showed that NF-κB subunit RelB was bound to the IL-1β promoter in preconditioned microglia and that RelB is required for the attenuated LPS response. In addition to a suppressed pro-inflammatory response, preconditioned primary microglia displayed enhanced phagocytic activity, increased outward potassium currents and nitric oxide production in response to a second LPS challenge. In vivo, a single i.p. LPS injection resulted in reduced performance in a spatial learning task 4 weeks later, indicating that a single inflammatory episode affected memory formation in these mice. Summarizing, we show that LPS-preconditioned microglia acquire an epigenetically regulated, immune-suppressed phenotype, possibly to prevent excessive damage to the central nervous system in case of recurrent (peripheral) inflammation. PMID:25843371

  8. Essential Role of the Redox Sensitive Kinase p66shc in Determining Energetic and Oxidative Status and Cell Fate in Neuronal Preconditioning

    PubMed Central

    Brown, Jacquelynn E.; Zeiger, Stephanie L.H.; Hettinger, Jane C.; Brooks, Joshua D.; Holt, Benjamin; Morrow, Jason D.; Musiek, Erik S.; Milne, Ginger; McLaughlin, BethAnn

    2010-01-01

    Ischemic preconditioning is a phenomenon in which low level stressful stimuli upregulate endogenous defensive programs resulting in subsequent resistance to otherwise lethal injuries. We previously observed that signal transduction systems typically associated with neurodegeneration such as caspase activation are requisite events for the expression of tolerance and induction of HSP70. In this work, we sought to determine the extent and duration of oxidative and energetic dysfunction as well as the role of effector kinases on metabolic function in preconditioned cells. Using an in vitro neuronal culture model, we observed a robust increase in Raf and p66Shc activation within 1h of preconditioning. Total ATP content decreased by 25% 3h after preconditioning but returned to baseline by 24h. Use of a free radical spin trap or p66shc inhibitor increased ATP content whereas a Raf inhibitor had no effect. Phosphorylated p66shc rapidly relocalized to the mitochondria and in the absence of activated p66shc, autophagic processing increased. The constitutively expressed chaperone HSC70 relocalized to autophagosomes. Preconditioned cells experience significant total oxidative stress measured by F2-isoprostanes and neuronal stress evaluated by F4-neuroprostane measurement. Neuroprostane levels were enhanced in the presence of Shc inhibitors. Finally, we found that inhibiting either p66shc or Raf blocked neuroprotection afforded by preconditioning as well as upregulation of HSP70 suggesting both kinases. This is the first work to demonstrate the essential role of p66shc in mediating requisite mitochondrial and energetic compensation following preconditioning and suggests a mechanism by which protein and organelle damage mediated by ROS can increase HSP70. PMID:20392947

  9. Running TCP/IP over ATM Networks.

    ERIC Educational Resources Information Center

    Witt, Michael

    1995-01-01

    Discusses Internet protocol (IP) and subnets and describes how IP may operate over asynchronous transfer mode (ATM). Topics include TCP (transmission control protocol), ATM cells and adaptation layers, a basic architectural model for IP over ATM, address resolution, mapping IP to a subnet technology, and connection management strategy. (LRW)

  10. Hypoxic-Ischemic Neonatal Encephalopathy: Animal Experiments for Neuroprotective Therapies

    PubMed Central

    Ikenoue, Tsuyomu

    2013-01-01

    Hypoxic-ischemic neonatal encephalopathy and ensuing brain damage is still an important problem in modern perinatal medicine. In this paper, we would like to share some of the results of our recent studies on neuroprotective therapies in animal experiments, as well as some literature reviews. From the basic animal studies, we have now obtained some possible candidates for therapeutic measures against hypoxic-ischemic neonatal encephalopathy. For example, they are hypothermia, rehabilitation, free radical scavenger, neurotrophic factors and growth factors, steroid, calcium channel blocker, vagal stimulation, some anti apoptotic agents, pre- and post conditioning, antioxidants, cell therapy with stem cells, modulators of K(+)-ATP channels, and so on. Whether combination of these therapies may be more beneficial than any single therapy needs to be clarified. Hypoxia-ischemia is a complicated condition, in which the cause, severity, and time-course are different in each case. Likewise, each fetus has its own inherent potentials such as adaptation, preconditioning-tolerance, and intolerance. Therefore, further extensive studies are required to establish an individualized strategy for neuroprotection against perinatal hypoxic-ischemic insult. PMID:23533962

  11. Preconditioning Stem Cells for In Vivo Delivery

    PubMed Central

    Sart, Sébastien; Ma, Teng

    2014-01-01

    Abstract Stem cells have emerged as promising tools for the treatment of incurable neural and heart diseases and tissue damage. However, the survival of transplanted stem cells is reported to be low, reducing their therapeutic effects. The major causes of poor survival of stem cells in vivo are linked to anoikis, potential immune rejection, and oxidative damage mediating apoptosis. This review investigates novel methods and potential molecular mechanisms for stem cell preconditioning in vitro to increase their retention after transplantation in damaged tissues. Microenvironmental preconditioning (e.g., hypoxia, heat shock, and exposure to oxidative stress), aggregate formation, and hydrogel encapsulation have been revealed as promising strategies to reduce cell apoptosis in vivo while maintaining biological functions of the cells. Moreover, this review seeks to identify methods of optimizing cell dose preparation to enhance stem cell survival and therapeutic function after transplantation. PMID:25126478

  12. A Hybrid Parallel Preconditioning Algorithm For CFD

    NASA Technical Reports Server (NTRS)

    Barth,Timothy J.; Tang, Wei-Pai; Kwak, Dochan (Technical Monitor)

    1995-01-01

    A new hybrid preconditioning algorithm will be presented which combines the favorable attributes of incomplete lower-upper (ILU) factorization with the favorable attributes of the approximate inverse method recently advocated by numerous researchers. The quality of the preconditioner is adjustable and can be increased at the cost of additional computation while at the same time the storage required is roughly constant and approximately equal to the storage required for the original matrix. In addition, the preconditioning algorithm suggests an efficient and natural parallel implementation with reduced communication. Sample calculations will be presented for the numerical solution of multi-dimensional advection-diffusion equations. The matrix solver has also been embedded into a Newton algorithm for solving the nonlinear Euler and Navier-Stokes equations governing compressible flow. The full paper will show numerous examples in CFD to demonstrate the efficiency and robustness of the method.

  13. Preserving Symmetry in Preconditioned Krylov Subspace Methods

    NASA Technical Reports Server (NTRS)

    Chan, Tony F.; Chow, E.; Saad, Y.; Yeung, M. C.

    1996-01-01

    We consider the problem of solving a linear system Ax = b when A is nearly symmetric and when the system is preconditioned by a symmetric positive definite matrix M. In the symmetric case, one can recover symmetry by using M-inner products in the conjugate gradient (CG) algorithm. This idea can also be used in the nonsymmetric case, and near symmetry can be preserved similarly. Like CG, the new algorithms are mathematically equivalent to split preconditioning, but do not require M to be factored. Better robustness in a specific sense can also be observed. When combined with truncated versions of iterative methods, tests show that this is more effective than the common practice of forfeiting near-symmetry altogether.

  14. Clustering of IP3 receptors by IP3 retunes their regulation by IP3 and Ca2+

    PubMed Central

    Taufiq-Ur-Rahman; Skupin, Alexander; Falcke, Martin; Taylor, Colin W.

    2009-01-01

    The versatility of Ca2+ signals derives from their spatio-temporal organization1,2. For Ca2+ signals initiated by inositol trisphosphate (IP3) this requires local interactions between IP3 receptors (IP3R)3,4 mediated by their rapid stimulation and slower inhibition4 by cytosolic Ca2+. This allows hierarchical recruitment of Ca2+ release events as the IP3 concentration increases5. Single IP3R respond first, then clustered IP3R open together giving a local Ca2+ puff, and as puffs become more frequent they ignite regenerative Ca2+ waves1,5-9. We demonstrate, using nuclear patch-clamp recording10, that IP3R are initially randomly distributed with an estimated separation of ~1 μm. Low concentrations of IP3 cause IP3R to aggregate rapidly and reversibly into small clusters of ~4 closely associated IP3R. At resting cytosolic [Ca2+], clustered IP3R open independently, but with lower open probability (Po), shorter open time, and lesser IP3 sensitivity than lone IP3R. Increasing cytosolic [Ca2+] reverses the inhibition caused by clustering, IP3R gating becomes coupled, and the duration of multiple openings is prolonged. Clustering both exposes IP3R to local Ca2+ rises and increases the effects of Ca2+. Dynamic regulation of clustering by IP3 tunes IP3R sensitivity to IP3 and Ca2+, facilitating hierarchical recruitment of the elementary events that underlie all IP3-evoked Ca2+ signals3,5. PMID:19348050

  15. M-step preconditioned conjugate gradient methods

    NASA Technical Reports Server (NTRS)

    Adams, L.

    1983-01-01

    Preconditioned conjugate gradient methods for solving sparse symmetric and positive finite systems of linear equations are described. Necessary and sufficient conditions are given for when these preconditioners can be used and an analysis of their effectiveness is given. Efficient computer implementations of these methods are discussed and results on the CYBER 203 and the Finite Element Machine under construction at NASA Langley Research Center are included.

  16. On polynomial preconditioning for indefinite Hermitian matrices

    NASA Technical Reports Server (NTRS)

    Freund, Roland W.

    1989-01-01

    The minimal residual method is studied combined with polynomial preconditioning for solving large linear systems (Ax = b) with indefinite Hermitian coefficient matrices (A). The standard approach for choosing the polynomial preconditioners leads to preconditioned systems which are positive definite. Here, a different strategy is studied which leaves the preconditioned coefficient matrix indefinite. More precisely, the polynomial preconditioner is designed to cluster the positive, resp. negative eigenvalues of A around 1, resp. around some negative constant. In particular, it is shown that such indefinite polynomial preconditioners can be obtained as the optimal solutions of a certain two parameter family of Chebyshev approximation problems. Some basic results are established for these approximation problems and a Remez type algorithm is sketched for their numerical solution. The problem of selecting the parameters such that the resulting indefinite polynomial preconditioners speeds up the convergence of minimal residual method optimally is also addressed. An approach is proposed based on the concept of asymptotic convergence factors. Finally, some numerical examples of indefinite polynomial preconditioners are given.

  17. Ischemic tissue injury.

    PubMed Central

    Jennings, R. B.; Ganote, C. E.; Reimer, K. A.

    1975-01-01

    The subendocardial to subepicardial gradient in the severity of ischemia following acute coronary occlusion is described. The effects of mild, moderate, and severe ischemia on cell structure and function are compared in summary form, and special attention is given to the effects of severe ischemia on myocardial cells. The characteristics of reversible and irreversible ischemic injury are defined in biologic terms. The failure of cell volume regulation in cells which have entered an irreversible state of ischemic injury is demonstrated by the use of free-hand slices in vitro. Irreversibility is associated with structural defects in the plasma membrane and is reflected in an increased slice inulin-diffusible space, increased slice H2O and Na+ content, and failure of the tissue to maintain the high K+ and Mg2+ levels characteristic of normal left ventricular myocardium. Defective cell membrane function is an early feature of irreversible ischemic injury and may be a primary event in the genesis of the irreversible state. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:1180331

  18. The Protective Effect of Remote Renal Preconditioning Against Hippocampal Ischemia Reperfusion Injury: Role of KATP Channels.

    PubMed

    Mehrjerdi, Fatemeh Zare; Aboutaleb, Nahid; Pazoki-Toroudi, Hamidreza; Soleimani, Mansoureh; Ajami, Marjan; Khaksari, Mehdi; Safari, Fatemeh; Habibey, Rouhollah

    2015-12-01

    Remote ischemic preconditioning (RIPC), which consists of several brief ischemia/reperfusion applied at the remote site of lethal ischemia reperfusion, can, through activating different mechanisms, increase the ability of the body's endogenous protection against prolonged ischemia/reperfusion. Recent studies have shown that RIPC has neuroprotective effects, but its mechanisms are not well elucidated. The present study aimed to determine whether activation of KATP channels in remote renal preconditioning decreases hippocampus damage induced by global cerebral ischemia. RIPC was induced by ischemia of the left renal artery (IPC); 24 h later, global cerebral ischemia reperfusion (IR) was induced by common carotid arteries occlusion. 5hydroxydecanoate (5HD) and glibenclamide (Gli) were injected before of IPC. The levels of malondialdehyde (MDA) and catalase (CAT) activity were assessed in hippocampus. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was assessed to detect apoptotic cells in hippocampus. RIPC inhibited apoptosis by decreasing positive TUNEL cells (P < 0.05). KATP channels blocking with 5HD and Gli markedly increased apoptosis in hippocampal cells in RIPC group (P < 0.001). RIPC decreased MDA level and increased CAT activity in ischemic hippocampus (P < 0.01). Also, 5HD and Gli inhibited the effect of RIPC on MDA level and CAT activity (P < 0.05). The present study shows that RIPC can effectively attenuate programmed cell death, increase activity of CAT, and reduce MDA levels. Blocking of KATP channels inhibited the protective effects of RIPC. PMID:26254913

  19. Hyperbaric oxygen preconditioning attenuates early apoptosis after spinal cord ischemia in rats.

    PubMed

    Wang, Liping; Li, Wenxian; Kang, Zhimin; Liu, Yun; Deng, Xiaoming; Tao, Hengyi; Xu, Weigang; Li, Runping; Sun, Xuejun; Zhang, John H

    2009-01-01

    This study tested the hypothesis that spinal cord ischemic tolerance induced by hyperbaric oxygen preconditioning (HBO-PC) is mediated by inhibition of early apoptosis. Male Sprague-Dawley rats were preconditioned with consecutive 4 cycles of 1-h HBO exposures (2.5 atmospheres absolute [ATA], 100% O(2)) at a 12-h interval. At 24 h after the last HBO pretreatment, rats underwent 9 min of spinal cord ischemia induced by occlusion of the descending thoracic aorta in combination with systemic hypotension (40 mmHg). Spinal cord ischemia produced marked neuronal death and neurological dysfunction in animals. HBO-PC enhanced activities of Mn-superoxide dismutase (Mn-SOD) and catalase, as well as the expression of Bcl-2 in the mitochondria in the normal spinal cord at 24 h after the last pretreatment (before spinal cord ischemia), and retained higher levels throughout the early reperfusion in the ischemic spinal cord. In parallel, superoxide and hydrogen peroxide levels in mitochondria were decreased, cytochrome c release into the cytosol was reduced at 1 h after reperfusion, and activation of caspase-3 and -9 was subsequently attenuated. HBO-PC improved neurobehavioral scores and reduced neuronal apoptosis in the anterior, intermediate, and dorsal gray matter of lumbar segment at 24 h after spinal cord ischemia. HBO-PC increased nitric oxide (NO) production. L-nitroarginine-methyl-ester (L-NAME; 10 mg/kg), a nonselective NO synthase (NOS) inhibitor, applied before each HBO-PC protocol abolished these beneficial effects of HBO-PC. We conclude that HBO-PC reduced spinal cord ischemia-reperfusion injury by increasing Mn-SOD, catalase, and Bcl-2, and by suppressing mitochondrial apoptosis pathway. NO may be involved in this neuroprotection. PMID:19196076

  20. Pre-ischemic treadmill training alleviates brain damage via GLT-1-mediated signal pathway after ischemic stroke in rats.

    PubMed

    Wang, X; Zhang, M; Yang, S-D; Li, W-B; Ren, S-Q; Zhang, J; Zhang, F

    2014-08-22

    Physical exercise could play a neuroprotective role in both human and animals. However, the involved signal pathways underlying the neuroprotective effect are still not well established. This study was to investigate the possible signal pathways involved in the neuroprotection of pre-ischemic treadmill training after ischemic stroke. Seventy-two SD rats were randomly assigned into three groups (n=24/group): sham surgery group, middle cerebral artery occlusion (MCAO) group and MCAO with exercise group. Following three weeks of treadmill training exercise, ischemic stroke was induced by occluding the middle cerebral artery (MCA) in rat for 2 h, followed by reperfusion. Twenty-four hours after MCAO/reperfusion, 12 rats in each group were evaluated for neurological deficit scores and then sacrificed to measure the infarct volume (n=6) and cerebral edema (n=6). Six rats in each group were sacrificed to measure the expression level of glutamate transporter-1 (GLT-1), protein kinase C-α (PKC-α), Akt, and phosphatidylinositol 3 kinase (PI3K) (n=6). Two hundred and eighty minutes (4.67 h) after occlusion, six rats in each group were decapitated to detect the mRNA expression level of metabotropic glutamate receptor 5 (mGluR5) and N-methyl-D-aspartate receptor subunit type 2B (NR2B) (n=6).The results demonstrated that pre-ischemic treadmill training exercise reduced brain infarct volume, cerebral edema and neurological deficits, also decreased the over expression of PKC-α and increased the expression level of GLT-1, Akt and PI3K after ischemic stroke (p<0.05). The over-expression of mGluR5 and NR2B mRNA was also inhibited by pre-ischemic exercise (p<0.05). In summary, exercise preconditioning ameliorated brain damage after ischemic stroke, which might be involved in two signal pathways: PKC-α-GLT-1-Glutamate and PI3K/Akt-GLT-1-Glutamate. PMID:24907601

  1. Continuously Connected With Mobile IP

    NASA Technical Reports Server (NTRS)

    2002-01-01

    Cisco Systems developed Cisco Mobile Networks, making IP devices mobile. With this innovation, a Cisco router and its connected IP devices can roam across network boundaries and connection types. Because a mobile user is able to keep the same IP address while roaming, a live IP connection can be maintained without interruption. Glenn Research Center jointly tested the technology with Cisco, and is working to use it on low-earth-orbiting research craft. With Cisco's Mobile Networks functionality now available in Cisco IOS Software release 12.2(4)T, the commercial advantages and benefits are numerous. The technology can be applied to public safety, military/homeland security, emergency management services, railroad and shipping systems, and the automotive industry. It will allow ambulances, police, firemen, and the U.S. Coast Guard to stay connected to their networks while on the move. In the wireless battlefield, the technology will provide rapid infrastructure deployment for U.S. national defense. Airline, train, and cruise passengers utilizing Cisco Mobile Networks can fly all around the world with a continuous Internet connection. Cisco IOS(R) Software is a registered trademark of Cisco Systems.

  2. Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts

    PubMed Central

    Pierre, Sandrine V.; Yang, Changjun; Yuan, Zhaokan; Seminerio, Jennifer; Mouas, Christian; Garlid, Keith D.; Dos-Santos, Pierre; Xie, Zijian

    2007-01-01

    Objective Because ouabain activates several pathways that are critical to cardioprotective mechanisms such as ischemic preconditioning, we tested if this digitalis compound could protect the heart against ischemia-reperfusion injury through activation of the Na+,K+-ATPase/c-Src receptor complex. Methods and Results In Langendorff-perfused rat hearts, a short (4 min) administration of ouabain 10 μM followed by an 8-minute washout before 30 minutes of global ischemia and reperfusion improved cardiac function, decreased lactate dehydrogenase release and reduced infarct size by 40%. Western blot analysis revealed that ouabain activated the cardioprotective phospholipase Cγ1/protein kinase Cε (PLC-γ1/PKCε) pathway. Pre-treatment of the hearts with the Src kinase family inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2) blocked not only ouabain-induced activation of PLC-γ1/PKCε pathway, but also cardiac protection. This protection was also blocked by a PKCε translocation inhibitor peptide (PKCε TIP). Conclusion Short exposure to a low concentration of ouabain protects the heart against ischemia/reperfusion injury. This effect of ouabain on the heart is most likely due to the activation of the Na+,K+-ATPase/c-Src receptor complex and subsequent stimulation of key mediators of preconditioning, namely PLC-γ1 and PKCε. PMID:17157283

  3. Implicit preconditioned WENO scheme for steady viscous flow computation

    NASA Astrophysics Data System (ADS)

    Huang, Juan-Chen; Lin, Herng; Yang, Jaw-Yen

    2009-02-01

    A class of lower-upper symmetric Gauss-Seidel implicit weighted essentially nonoscillatory (WENO) schemes is developed for solving the preconditioned Navier-Stokes equations of primitive variables with Spalart-Allmaras one-equation turbulence model. The numerical flux of the present preconditioned WENO schemes consists of a first-order part and high-order part. For first-order part, we adopt the preconditioned Roe scheme and for the high-order part, we employ preconditioned WENO methods. For comparison purpose, a preconditioned TVD scheme is also given and tested. A time-derivative preconditioning algorithm is devised and a discriminant is devised for adjusting the preconditioning parameters at low Mach numbers and turning off the preconditioning at intermediate or high Mach numbers. The computations are performed for the two-dimensional lid driven cavity flow, low subsonic viscous flow over S809 airfoil, three-dimensional low speed viscous flow over 6:1 prolate spheroid, transonic flow over ONERA-M6 wing and hypersonic flow over HB-2 model. The solutions of the present algorithms are in good agreement with the experimental data. The application of the preconditioned WENO schemes to viscous flows at all speeds not only enhances the accuracy and robustness of resolving shock and discontinuities for supersonic flows, but also improves the accuracy of low Mach number flow with complicated smooth solution structures.

  4. Preconditioning and the limit to the incompressible flow equations

    NASA Technical Reports Server (NTRS)

    Turkel, E.; Fiterman, A.; Vanleer, B.

    1993-01-01

    The use of preconditioning methods to accelerate the convergence to a steady state for both the incompressible and compressible fluid dynamic equations are considered. The relation between them for both the continuous problem and the finite difference approximation is also considered. The analysis relies on the inviscid equations. The preconditioning consists of a matrix multiplying the time derivatives. Hence, the steady state of the preconditioned system is the same as the steady state of the original system. For finite difference methods the preconditioning can change and improve the steady state solutions. An application to flow around an airfoil is presented.

  5. Transient expression of Nxf, a bHLH-PAS transactivator induced by neuronal preconditioning, confers neuroprotection in cultured cells.

    PubMed

    Hester, Ian; McKee, Sarah; Pelletier, Phillip; Thompson, Charles; Storbeck, Christopher; Mears, Alan; Schulz, Jörg B; Hakim, Antoine A; Sabourin, Luc A

    2007-03-01

    Cortical spreading depression (CSD) induces waves of neuronal depolarization that confer neuroprotection to subsequent ischemic events in the rat brain. To gain insights into the molecular mechanisms elicited by CSD, we used representational difference analysis (RDA) to identify mRNAs induced by potassium depolarization in vivo. Using this approach, we have isolated a cDNA encoding the SIM2-related bHLH-PAS protein Nxf. Our results confirm that Nxf mRNA and protein are rapidly and transiently expressed in cortical neurons following CSD. Reporter assays show that Nxf is a transcriptional activator that associates with the bHLH-PAS sub-class co-factor ARNT2. Adenovirus-mediated expression of epitope-tagged Nxf results in cell death and the direct activation of the Bax gene in cultured cells. However, RNA interference studies show that endogenous Nxf is required for optimal neuroprotection by preconditioning in cultured F-11 cells. Together, our data indicate that Nxf is a novel bHLH-PAS transactivator transiently induced by preconditioning and that its sustained expression is detrimental. The identification of Nxf may represent an important step in our understanding of the molecular mechanisms of brain preconditioning and injury. PMID:17214977

  6. Photodynamic impact induces ischemic tolerance in models in vivo and in vitro

    NASA Astrophysics Data System (ADS)

    Demyanenko, Svetlana; Sharifulina, Svetlana; Berezhnaya, Elena; Kovaleva, Vera; Neginskaya, Maria; Zhukovskaya, Ludmila

    2016-04-01

    Ischemic tolerance determines resistance to lethal ischemia gained by a prior sublethal stimulus (i.e., preconditioning). We reproduced this effect in two variants. In vitro the preliminary short (5 s) photodynamic treatment (PDT) (photosensitizer Photosens, 10 nM, 30 min preincubation; laser: 670 nm, 100 mW/cm2) significantly reduced the necrosis of neurons and glial cells in the isolated crayfish stretch receptor, which was caused by following 30-min PDT by 66% and 46%, respectively. In vivo PDT of the rat cerebral cortex with hydrophilic photosensitizer Rose Bengal (i.v. administration, laser irradiation: 532 nm, 60 mW/cm2, 3 mm beam diameter, 30 min) caused occlusion of small brain vessels and local photothrombotic infarct (PTI). It is a model of ischemic stroke. Cerebral tissue edema and global necrosis of neurons and glial cells occurred in the infarction core, which was surrounded by a 1.5 mm transition zone, penumbra. The maximal pericellular edema, hypo- and hyperchromia of neurons were observed in penumbra 24 h after PTI. The repeated laser irradiation of the contralateral cerebral cortex also caused PTI but lesser as compared with single PDT. Preliminary unilateral PTI provided ischemic tolerance: at 14 day after second exposure the PTI volume significantly decreased by 24% than in the case of a single exposure. Sensorimotor deficits in PDT-treated rats was registered using the behavioral tests. The preliminary PTI caused the preconditioning effect.

  7. Studies on cerebral protection of digoxin against hypoxic-ischemic brain damage in neonatal rats.

    PubMed

    Peng, Kaiwei; Tan, Danfeng; He, Miao; Guo, Dandan; Huang, Juan; Wang, Xia; Liu, Chentao; Zheng, Xiangrong

    2016-08-17

    Hypoxic-ischemic brain damage (HIBD) is a major cause of neonatal acute deaths and chronic nervous system damage. Our present study was designed to investigate the possible neuroprotective effect of digoxin-induced pharmacological preconditioning after hypoxia-ischemia and underlying mechanisms. Neonatal rats were assigned randomly to control, HIBD, or HIBD+digoxin groups. Pharmacological preconditioning was induced by administration of digoxin 72 h before inducing HIBD by carotid occlusion+hypoxia. Behavioral assays, and neuropathological and apoptotic assessments were performed to examine the effects; the expression of Na/K ATPase was also assessed. Rats in the HIBD group showed deficiencies on the T-maze, radial water maze, and postural reflex tests, whereas the HIBD+digoxin group showed significant improvements on all behavioral tests. The rats treated with digoxin showed recovery of pathological conditions, increased number of neural cells and proliferative cells, and decreased number of apoptotic cells. Meanwhile, an increased expression level of Na/K ATPase was observed after digoxin preconditioning treatment. The preconditioning treatment of digoxin contributed toward an improved functional recovery and exerted a marked neuroprotective effect including promotion of cell proliferation and reduction of apoptosis after HIBD, and the neuroprotective action was likely associated with increased expression of Na/K ATPase. PMID:27362436

  8. Effects of morphine and sufentanil preconditioning against myocardial ischemic-reperfusion injury in rabbits

    PubMed Central

    Wang, Xiu-Hong; Zeng, Jian-Feng; Lin, Chao; Chen, Shi-Biao

    2015-01-01

    Objective: This study aims to explore the treatment method of myocardial ischemia-reperfusion injury. Methods: Myocardial Ischemia-reperfusion rabbit model was established in this study. They were divided into four groups: sham operation (S) group, IRI control (I/R) group and IRI with morphine (MF) group and sufentanil (SF). Myocardial infarct size was compared with HE staining method. TUNEL assay was used to detect cell apoptosis. Results: Myocardial infarct size of control group and morphine and sufetanil group was 36.0±3.6, 23.0±1.2 and 27.1±2.3, respectively. There were significant differences between them (P < 0.01). Apoptotic index of I/R, MF and SF groups was 26.9±2.2, 12.5±2.3, 15.8±2.0, with statistical significance (P < 0.05). The concentration of CK-MB in serum: there were no significant differences of CK-MB between each group at baseline. The concentration of CK-MB after reperfusion were higher than that of baseline, except for group S (P < 0.05); Compared with group S, after reperfusion, the CK-MB of other three groups were higher (P < 0.05); The concentration of CK-MB in group MF and SF were lower than group I/R (P < 0.05); In contrast to group MF, the concentration of CK-MB after reperfusion was higher in group SF (P < 0.05). Conclusion: Morphine and sufentanil can specifically protect the myocardial function. PMID:26629064

  9. Parallel preconditioning techniques for sparse CG solvers

    SciTech Connect

    Basermann, A.; Reichel, B.; Schelthoff, C.

    1996-12-31

    Conjugate gradient (CG) methods to solve sparse systems of linear equations play an important role in numerical methods for solving discretized partial differential equations. The large size and the condition of many technical or physical applications in this area result in the need for efficient parallelization and preconditioning techniques of the CG method. In particular for very ill-conditioned matrices, sophisticated preconditioner are necessary to obtain both acceptable convergence and accuracy of CG. Here, we investigate variants of polynomial and incomplete Cholesky preconditioners that markedly reduce the iterations of the simply diagonally scaled CG and are shown to be well suited for massively parallel machines.

  10. Domain-decomposed preconditionings for transport operators

    NASA Technical Reports Server (NTRS)

    Chan, Tony F.; Gropp, William D.; Keyes, David E.

    1991-01-01

    The performance was tested of five different interface preconditionings for domain decomposed convection diffusion problems, including a novel one known as the spectral probe, while varying mesh parameters, Reynolds number, ratio of subdomain diffusion coefficients, and domain aspect ratio. The preconditioners are representative of the range of practically computable possibilities that have appeared in the domain decomposition literature for the treatment of nonoverlapping subdomains. It is shown that through a large number of numerical examples that no single preconditioner can be considered uniformly superior or uniformly inferior to the rest, but that knowledge of particulars, including the shape and strength of the convection, is important in selecting among them in a given problem.

  11. Extremely Intense Magnetospheric Substorms : External Triggering? Preconditioning?

    NASA Astrophysics Data System (ADS)

    Tsurutani, Bruce; Echer, Ezequiel; Hajra, Rajkumar

    2016-07-01

    We study particularly intense substorms using a variety of near-Earth spacecraft data and ground observations. We will relate the solar cycle dependences of events, determine whether the supersubstorms are externally or internally triggered, and their relationship to other factors such as magnetospheric preconditioning. If time permits, we will explore the details of the events and whether they are similar to regular (Akasofu, 1964) substorms or not. These intense substorms are an important feature of space weather since they may be responsible for power outages.

  12. H(curl) Auxiliary Mesh Preconditioning

    SciTech Connect

    Kolev, T V; Pasciak, J E; Vassilevski, P S

    2006-08-31

    This paper analyzes a two-level preconditioning scheme for H(curl) bilinear forms. The scheme utilizes an auxiliary problem on a related mesh that is more amenable for constructing optimal order multigrid methods. More specifically, we analyze the case when the auxiliary mesh only approximately covers the original domain. The latter assumption is important since it allows for easy construction of nested multilevel spaces on regular auxiliary meshes. Numerical experiments in both two and three space dimensions illustrate the optimal performance of the method.

  13. Towards bulk based preconditioning for quantum dotcomputations

    SciTech Connect

    Dongarra, Jack; Langou, Julien; Tomov, Stanimire; Channing,Andrew; Marques, Osni; Vomel, Christof; Wang, Lin-Wang

    2006-05-25

    This article describes how to accelerate the convergence of Preconditioned Conjugate Gradient (PCG) type eigensolvers for the computation of several states around the band gap of colloidal quantum dots. Our new approach uses the Hamiltonian from the bulk materials constituent for the quantum dot to design an efficient preconditioner for the folded spectrum PCG method. The technique described shows promising results when applied to CdSe quantum dot model problems. We show a decrease in the number of iteration steps by at least a factor of 4 compared to the previously used diagonal preconditioner.

  14. OSI and TCP/IP

    NASA Technical Reports Server (NTRS)

    Randolph, Lynwood P.

    1994-01-01

    The Open Systems Interconnection Transmission Control Protocol/Internet Protocol (OSI TCP/IP) and the Government Open Systems Interconnection Profile (GOSIP) are compared and described in terms of Federal internetworking. The organization and functions of the Federal Internetworking Requirements Panel (FIRP) are discussed and the panel's conclusions and recommendations with respect to the standards and implementation of the National Information Infrastructure (NII) are presented.

  15. Making the case for IPS supported employment.

    PubMed

    Bond, Gary R; Drake, Robert E

    2014-01-01

    Individual Placement and Support (IPS) is an evidence-based practice for helping people with severe mental illness (SMI) gain competitive employment, yet those who could benefit often find it difficult to obtain IPS services. We summarize the evidence supporting the effectiveness of IPS and the benefits of working, discuss the barriers to implementing IPS in the U.S., and suggest policy changes that could expand its access. PMID:23161326

  16. VoIP in a Campus Environment

    ERIC Educational Resources Information Center

    Young, Dan

    2005-01-01

    Internet Protocol (IP) Telephony, or voice-over IP (VoIP), has proved to be a wise decision for many organizations. This technology crosses the boundaries of public and private networks, enterprise and residential markets, voice and data technologies, as well as local and long-distance services. The convergence of voice and data into a single,…

  17. Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro.

    PubMed

    Landucci, Elisa; Lattanzi, Roberta; Gerace, Elisabetta; Scartabelli, Tania; Balboni, Gianfranco; Negri, Lucia; Pellegrini-Giampietro, Domenico E

    2016-09-01

    Bv8/prokineticin 2 (PK2) is a member of a bioactive family of peptides that regulate multiple functions in the CNS including hyperalgesia, neurogenesis, neuronal survival and inflammation. Recent studies have associated PK2 and prokineticin receptors (PKR) with human diseases, but because their role in neuropathology is still debated we examined whether prokineticins exert a protective or deleterious role in models of cerebral ischemia and ischemic tolerance in vitro. In order to mimic cerebral ischemia, we exposed primary murine cortical cell cultures or rat organotypic hippocampal slices to appropriate periods of oxygen-glucose deprivation (OGD), which leads to neuronal damage 24 h later. Ischemic tolerance was induced by exposing hippocampal slices to a preconditioning subtoxic pharmacological stimulus (3 μM NMDA for 1 h) 24 h before the exposure to OGD. Bv8 (10-100 nM) attenuated OGD injury in cortical cultures and hippocampal slices, and the effect was prevented by the PKR antagonist PC7. The development of OGD tolerance was associated with an increase in the expression of PK2, PKR1 and PKR2 mRNA and proteins and was prevented by addition of the antagonist PC7 into the medium during preconditioning. Both Bv8 at protective concentrations and the NMDA preconditioning stimulus promoted the phosphorylation of ERK1/2 and Akt. These findings indicate that the prokineticin system can be up-regulated by a defensive preconditioning subtoxic NMDA stimulus and that PK2 may act as an endogenous neuroprotective factor through the activation of the ERK1/2 and Akt transduction pathways. PMID:27140692

  18. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... tested for the SFTP supplemental tests of aggressive driving (US06) and air conditioning (SC03). Section...) Air Conditioning Test (SC03) Preconditioning. (1) If the SC03 test follows the exhaust emission FTP or... preconditioning cycles for the SC03 air conditioning test and the 10 minute soak are conducted at the same...

  19. 40 CFR 1066.407 - Vehicle preparation and preconditioning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) Prepare the vehicle for testing as described in 40 CFR 86.131. (b) If testing will include measurement of refueling emissions, perform the vehicle preconditioning steps as described in 40 CFR 86.153. Otherwise, perform the vehicle preconditioning steps as described in 40 CFR 86.132....

  20. 40 CFR 1066.407 - Vehicle preparation and preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) Prepare the vehicle for testing as described in 40 CFR 86.131. (b) If testing will include measurement of refueling emissions, perform the vehicle preconditioning steps as described in 40 CFR 86.153. Otherwise, perform the vehicle preconditioning steps as described in 40 CFR 86.132....

  1. [STRESS AND INFARCT LIMITING EFFECTS OF EARLY HYPOXIC PRECONDITIONING].

    PubMed

    Lishmanov, Yu B; Maslov, L N; Sementsov, A S; Naryzhnaya, N V; Tsibulnikov, S Yu

    2015-09-01

    It was established that early hypoxic preconditioning is an adaptive state different from eustress and distress. Hypoxic preconditioning has the cross effects, increasing the tolerance of the heart to ischemia-reperfusion and providing antiulcerogenic effect during immobilization stress. PMID:26672158

  2. 40 CFR 86.532-78 - Vehicle preconditioning.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 18 2011-07-01 2011-07-01 false Vehicle preconditioning. 86.532-78... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1978 and Later New Motorcycles; Test Procedures § 86.532-78 Vehicle preconditioning. (a) The...

  3. 40 CFR 86.532-78 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 19 2013-07-01 2013-07-01 false Vehicle preconditioning. 86.532-78... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1978 and Later New Motorcycles; Test Procedures § 86.532-78 Vehicle preconditioning. (a) The...

  4. 40 CFR 86.532-78 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Vehicle preconditioning. 86.532-78... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1978 and Later New Motorcycles; Test Procedures § 86.532-78 Vehicle preconditioning. (a) The...

  5. Parallel Preconditioning for CFD Problems on the CM-5

    NASA Technical Reports Server (NTRS)

    Simon, Horst D.; Kremenetsky, Mark D.; Richardson, John; Lasinski, T. A. (Technical Monitor)

    1994-01-01

    Up to today, preconditioning methods on massively parallel systems have faced a major difficulty. The most successful preconditioning methods in terms of accelerating the convergence of the iterative solver such as incomplete LU factorizations are notoriously difficult to implement on parallel machines for two reasons: (1) the actual computation of the preconditioner is not very floating-point intensive, but requires a large amount of unstructured communication, and (2) the application of the preconditioning matrix in the iteration phase (i.e. triangular solves) are difficult to parallelize because of the recursive nature of the computation. Here we present a new approach to preconditioning for very large, sparse, unsymmetric, linear systems, which avoids both difficulties. We explicitly compute an approximate inverse to our original matrix. This new preconditioning matrix can be applied most efficiently for iterative methods on massively parallel machines, since the preconditioning phase involves only a matrix-vector multiplication, with possibly a dense matrix. Furthermore the actual computation of the preconditioning matrix has natural parallelism. For a problem of size n, the preconditioning matrix can be computed by solving n independent small least squares problems. The algorithm and its implementation on the Connection Machine CM-5 are discussed in detail and supported by extensive timings obtained from real problem data.

  6. Imaging acute ischemic stroke.

    PubMed

    González, R Gilberto; Schwamm, Lee H

    2016-01-01

    Acute ischemic stroke is common and often treatable, but treatment requires reliable information on the state of the brain that may be provided by modern neuroimaging. Critical information includes: the presence of hemorrhage; the site of arterial occlusion; the size of the early infarct "core"; and the size of underperfused, potentially threatened brain parenchyma, commonly referred to as the "penumbra." In this chapter we review the major determinants of outcomes in ischemic stroke patients, and the clinical value of various advanced computed tomography and magnetic resonance imaging methods that may provide key physiologic information in these patients. The focus is on major strokes due to occlusions of large arteries of the anterior circulation, the most common cause of a severe stroke syndrome. The current evidence-based approach to imaging the acute stroke patient at the Massachusetts General Hospital is presented, which is applicable for all stroke types. We conclude with new information on time and stroke evolution that imaging has revealed, and how it may open the possibilities of treating many more patients. PMID:27432672

  7. Reduced-order preconditioning for bidomain simulations.

    PubMed

    Deo, Makarand; Bauer, Steffen; Plank, Gernot; Vigmond, Edward

    2007-05-01

    Simulations of the bidomain equations involve solving large, sparse, linear systems of the form Ax = b. Being an initial value problems, it is solved at every time step. Therefore, efficient solvers are essential to keep simulations tractable. Iterative solvers, especially the preconditioned conjugate gradient (PCG) method, are attractive since memory demands are minimized compared to direct methods, albeit at the cost of solution speed. However, a proper preconditioner can drastically speed up the solution process by reducing the number of iterations. In this paper, a novel preconditioner for the PCG method based on system order reduction using the Arnoldi method (A-PCG) is proposed. Large order systems, generated during cardiac bidomain simulations employing a finite element method formulation, are solved with the A-PCG method. Its performance is compared with incomplete LU (ILU) preconditioning. Results indicate that the A-PCG estimates an approximate solution considerably faster than the ILU, often within a single iteration. To reduce the computational demands in terms of memory and run time, the use of a cascaded preconditioner was suggested. The A-PCG was applied to quickly obtain an approximate solution, and subsequently a cheap iterative method such as successive overrelaxation (SOR) is applied to further refine the solution to arrive at a desired accuracy. The memory requirements are less than those of direct LU but more than ILU method. The proposed scheme is shown to yield significant speedups when solving time evolving systems. PMID:17518292

  8. The multigrid preconditioned conjugate gradient method

    NASA Technical Reports Server (NTRS)

    Tatebe, Osamu

    1993-01-01

    A multigrid preconditioned conjugate gradient method (MGCG method), which uses the multigrid method as a preconditioner of the PCG method, is proposed. The multigrid method has inherent high parallelism and improves convergence of long wavelength components, which is important in iterative methods. By using this method as a preconditioner of the PCG method, an efficient method with high parallelism and fast convergence is obtained. First, it is considered a necessary condition of the multigrid preconditioner in order to satisfy requirements of a preconditioner of the PCG method. Next numerical experiments show a behavior of the MGCG method and that the MGCG method is superior to both the ICCG method and the multigrid method in point of fast convergence and high parallelism. This fast convergence is understood in terms of the eigenvalue analysis of the preconditioned matrix. From this observation of the multigrid preconditioner, it is realized that the MGCG method converges in very few iterations and the multigrid preconditioner is a desirable preconditioner of the conjugate gradient method.

  9. Preconditioning cortical lesions reduce the incidence of peri-infarct depolarizations during focal ischemia in the Spontaneously Hypertensive Rat: interaction with prior anesthesia and the impact of hyperglycemia

    PubMed Central

    Zhao, Liang; Nowak Jr, Thaddeus S

    2015-01-01

    The relationship between peri-infarct depolarizations (PIDs) and infarction was investigated in a model of preconditioning by cortical freeze lesions (cryogenic lesions, CL) in the Spontaneously Hypertensive Rat. Small (< 5 mm3) lesions produced 24 hours before permanent focal ischemia were protective, without impacting baseline cerebral blood flow (CBF) and metabolism. Prior CL reduced infarct volume, associated with improved penumbral CBF as previously showed for ischemic preconditioning. The brief initial procedure avoided sham effects on infarct volume after subsequent occlusion under brief anesthesia. However, under prolonged isoflurane anesthesia for perfusion monitoring both sham and CL rats showed reduced PID incidence relative to naive animals. This anesthesia effect could be eliminated by using α-chloralose during perfusion imaging. As an additional methodological concern, blood glucose was frequently elevated at the time of the second surgery, reflecting buprenorphine-induced pica and other undefined mechanisms. Even modest hyperglycemia (>10 mmol/L) reduced PID incidence. In normoglycemic animals CL preconditioning reduced PID number by 50%, demonstrating associated effects on PID incidence, penumbral perfusion, and infarct progression. Hyperglycemia suppressed PIDs without affecting the relationship between CBF and infarction. This suggests that the primary effect of preconditioning is to improve penumbral perfusion, which in turn impacts PID incidence and infarct size. PMID:25757750

  10. Preconditioning cortical lesions reduce the incidence of peri-infarct depolarizations during focal ischemia in the Spontaneously Hypertensive Rat: interaction with prior anesthesia and the impact of hyperglycemia.

    PubMed

    Zhao, Liang; Nowak, Thaddeus S

    2015-07-01

    The relationship between peri-infarct depolarizations (PIDs) and infarction was investigated in a model of preconditioning by cortical freeze lesions (cryogenic lesions, CL) in the Spontaneously Hypertensive Rat. Small (< 5 mm(3)) lesions produced 24 hours before permanent focal ischemia were protective, without impacting baseline cerebral blood flow (CBF) and metabolism. Prior CL reduced infarct volume, associated with improved penumbral CBF as previously showed for ischemic preconditioning. The brief initial procedure avoided sham effects on infarct volume after subsequent occlusion under brief anesthesia. However, under prolonged isoflurane anesthesia for perfusion monitoring both sham and CL rats showed reduced PID incidence relative to naive animals. This anesthesia effect could be eliminated by using α-chloralose during perfusion imaging. As an additional methodological concern, blood glucose was frequently elevated at the time of the second surgery, reflecting buprenorphine-induced pica and other undefined mechanisms. Even modest hyperglycemia (>10 mmol/L) reduced PID incidence. In normoglycemic animals CL preconditioning reduced PID number by 50%, demonstrating associated effects on PID incidence, penumbral perfusion, and infarct progression. Hyperglycemia suppressed PIDs without affecting the relationship between CBF and infarction. This suggests that the primary effect of preconditioning is to improve penumbral perfusion, which in turn impacts PID incidence and infarct size. PMID:25757750

  11. Effect of atropine and gammahydroxybutyrate on ischemically induced changes in the level of radioactivity in (/sup 3/H)inositol phosphates in gerbil brain in vivo

    SciTech Connect

    Wikiel, H.; Halat, G.; Strosznajder, J.

    1988-05-01

    Brain ischemia in gerbils was induced by ligation of both common carotid arteries for 1 min or 10 min. Sham-operated animals served as controls. Intracerebral injection of (3H)inositol into gerbil brain 16 hr before ischemic insult resulted in equilibration of the label between inositol lipids and water-soluble inositol phosphate. A short ischemic period (1 min) resulted in a statistically significant increase in the radioactivity of inositol triphosphate (IP3) and inositol monophosphate (IP), by about 48% and 79%, respectively, with little change in that of the intermediate inositol biphosphate (IP2), which increased by about 16%. When the ischemic period was prolonged (10 min), an increase in the radioactivity of inositol monophosphate exclusively, by about 84%, was observed. The level of radioactivity in inositol phosphates IP2 and IP3 decreased by about 50%, probably as a consequence of phosphatase activation by the ischemic insult. The agonist of the cholinergic receptor, carbachol, injected intracerebrally (40 micrograms per animal) increased accumulation of radioactivity in all inositol phosphates. The level of radioactivity in IP3, IP2, and IP was elevated by about 40, 23, and 147%, respectively. The muscarinic cholinergic antagonist, atropine, injected intraperitoneally in doses of 100 mg/kg body wt. depressed phosphoinositide metabolism in control animals. The level of radioactivity in water-soluble inositol metabolites in the brain of animals pretreated with atropine was evidently about 32% lower than in untreated animals. Pretreatment with atropine decreased the radioactivity of all inositol phosphates in the brain of animals subjected to 1-min ischemia and the radioactivity of IP in the case of 10-min brain ischemia.

  12. Mobile-ip Aeronautical Network Simulation Study

    NASA Technical Reports Server (NTRS)

    Ivancic, William D.; Tran, Diepchi T.

    2001-01-01

    NASA is interested in applying mobile Internet protocol (mobile-ip) technologies to its space and aeronautics programs. In particular, mobile-ip will play a major role in the Advanced Aeronautic Transportation Technology (AATT), the Weather Information Communication (WINCOMM), and the Small Aircraft Transportation System (SATS) aeronautics programs. This report presents the results of a simulation study of mobile-ip for an aeronautical network. The study was performed to determine the performance of the transmission control protocol (TCP) in a mobile-ip environment and to gain an understanding of how long delays, handoffs, and noisy channels affect mobile-ip performance.

  13. IP Profiling via Service Cluster Membership Vectors

    SciTech Connect

    Bartoletti, A

    2009-02-23

    This study investigates the feasibility of establishing and maintaining a system of compact IP behavioral profiles as a robust means of computer anomaly definition and detection. These profiles are based upon the degree to which a system's (IP's) network traffic is distributed among stable characteristic clusters derived of the aggregate session traffic generated by each of the major network services. In short, an IP's profile represents its degree of membership in these derived service clusters. The goal is to quantify and rank behaviors that are outside of the statistical norm for the services in question, or present significant deviation from profile for individual client IPs. Herein, we establish stable clusters for accessible features of common session traffic, migrate these clusters over time, define IP behavior profiles with respect to these clusters, migrate individual IP profiles over time, and demonstrate the detection of IP behavioral changes in terms of deviation from profile.

  14. Hypoxic preconditioning: effect, mechanism and clinical implication (Part 1).

    PubMed

    Lu, Guo-wei; Shao, Guo

    2014-11-01

    Hypoxic preconditioning (HPC) refers to exposure of organisms, systems, organs, tissues or cells to moderate hypoxia/ischemia that is able to result in a resistance to subsequent severe hypoxia/ischemia in tissues and cells. The effects exerted by HPC are well documented. The original local in situ (LiHPC) is now broadened to remote ectopic organs-tissues (ReHPC) and extended crossly to cross pluripotential HPC(CpHPC) induced by a variety of stresses other than hypoxia/ischemia, including cancer, for example. We developed a unique animal model of repetitive autohypoxia in adult mice, and studied systematically on the effects and mechanisms of HPC on the model in our laboratory since the early 1960s. The tolerances to hypoxia and protection from injury increased significantly in this model. The adult mice behave like hypoxia-intolerant mammalian newborns and hypoxia-tolerant adult animals during their exposure to repetitive autohypoxia. The overall energy supply and demand decreased, the microorganization of the brain maintained and the spacial learning and memory ability improved but not impaired, the detrimental neurochemicals such as free radicals down-regulated and the beneficial neurochemicals such as adenosine(ADO) and antihypoxic gene(s)/factor(s) (AHGs/AHFs) up-regulated. Accordingly, we hypothesize that mechanisms for the tolerance/protective effects of HPC are fundamentally depending on energy saving and brain plasticity in particular. It is thought that these two major mechanisms are triggered by exposure to hypoxia/ischemia via oxygen sensing-transduction pathways and HIF-1 initiation cascades. We suggest that HPC is an intrinsic mechanism developed in biological evolution and is a novel potential strategy for fighting against hypoxia-ischemia and other stresses. Motivation of endogenous antihypoxic potential, activation of oxygen sensing--signal transduction systems and supplement of exogenous antihypoxic substances as well as development of HPC

  15. Acute Ischemic Stroke Intervention.

    PubMed

    Khandelwal, Priyank; Yavagal, Dileep R; Sacco, Ralph L

    2016-06-01

    Acute ischemic stroke (AIS) is the leading cause of disability worldwide and among the leading causes of mortality. Although intravenous tissue plasminogen activator (IV-rtPA) was approved nearly 2 decades ago for treatment of AIS, only a minority of patients receive it due to a narrow time window for administration and several contraindications to its use. Endovascular approaches to recanalization in AIS developed in the 1980s, and recently, 5 major randomized trials showed an overwhelming superior benefit of combining endovascular mechanical thrombectomy with IV-rtPA over IV-rtPA alone. In this paper, we discuss the evolution of catheter-based treatment from first-generation thrombectomy devices to the game-changing stent retrievers, results from recent trials, and the evolving stroke systems of care to provide timely access to acute stroke intervention to patients in the United States. PMID:27256835

  16. Remote Ischemic Conditioning

    PubMed Central

    Heusch, Gerd; Bøtker, Hans Erik; Przyklenk, Karin; Redington, Andrew; Yellon, Derek

    2014-01-01

    In remote ischemic conditioning (RIC) brief, reversible episodes of ischemia with reperfusion in one vascular bed, tissue or organ confer a global protective phenotype and render remote tissues and organs resistant to ischemia/reperfusion injury. The peripheral stimulus can be chemical, mechanical or electrical and involves activation of peripheral sensory nerves. The signal transfer to the heart or other organs is through neuronal and humoral communications. Protection can be transferred, even across species, with plasma-derived dialysate and involves nitric oxide, stromal derived factor-1α, microRNA-144, but also other, not yet identified factors. Intracardiac signal transduction involves: adenosine, bradykinin, cytokines, and chemokines, which activate specific receptors; intracellular kinases; and mitochondrial function. RIC by repeated brief inflation/deflation of a blood pressure cuff protects against endothelial dysfunction and myocardial injury in percutaneous coronary interventions, coronary artery bypass grafting and reperfused acute myocardial infarction. RIC is safe and effective, noninvasive, easily feasible and inexpensive. PMID:25593060

  17. [Cerebrolysin for acute ischemic stroke].

    PubMed

    iganshina, L E; Abakumova, T R

    2013-01-01

    The review discusses existing evidence of benefits and risks of cerebrolysin--a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue with proposed neuroprotective and neurotrophic properties, for acute ischemic stroke. The review presents results of systematic search and analysis of randomised clinical trials comparing cerebrolysin with placebo in patients with acute ischemic stroke. Only one trial was selected as meeting quality criteria. No difference in death and adverse events between cerebrolysin and placebo was established. The authors conclude about insufficiency of evidence to evaluate the effect of cerebrolysin on survival and dependency in people with acute ischemic stroke. PMID:23805635

  18. Ischemic Postconditioning and Subanesthetic S(+)-Ketamine Infusion: Effects on Renal Function and Histology in Rats

    PubMed Central

    de Resende, Marco A. C.; Pantoja, Alberto V.; Barcellos, Bruno M.; Reis, Eduardo P.; Consolo, Thays D.; Módolo, Renata P.; Domingues, Maria A. C.; Assad, Alexandra R.; Cavalcanti, Ismar L.; Castiglia, Yara M. M.; Módolo, Norma S. P.

    2015-01-01

    Background. Ischemic postconditioning (IP) in renal Ischemia reperfusion injury (IRI) models improves renal function after IRI. Ketamine affords significant benefits against IRI-induced acute kidney injury (AKI). The present study investigated the effects of IP and IP associated with subanesthetic S(+)-ketamine in ischemia-reperfusion-induced AKI. Methods. Forty-one Wistar rats were randomized into four groups: CG (10), control; KG (10), S(+)-ketamine infusion; IPG (10), IP; and KIPG (11), S(+)-ketamine infusion + IP. All rats underwent right nephrectomy. IRI and IP were induced only in IPG and KIPG by left kidney arterial occlusion for 30 min followed by reperfusion for 24 h. Complete reperfusion was preceded by three cycles of 2 min of reocclusion followed by 2 min of reperfusion. Renal function was assessed by measuring serum neutrophil gelatinase-associated lipocalin (NGAL), creatinine, and blood urea nitrogen (BUN). Tubular damage was evaluated by renal histology. Results. Creatinine and BUN were significantly increased. Severe tubular injury was only observed in the groups with IRI (IPG and KIPG), whereas no injury was observed in CG or KG. No significant differences were detected between IPG and KIPG. Conclusions. No synergic effect of the use of subanesthetic S(+)-ketamine and IP on AKI was observed in this rat model. PMID:26413552

  19. Involvement of SIRT1 in hypoxic down-regulation of c-Myc and β-catenin and hypoxic preconditioning effect of polyphenols

    SciTech Connect

    Hong, Kyung-Soo; Park, Jun-Ik; Kim, Mi-Ju; Kim, Hak-Bong; Lee, Jae-Won; Dao, Trong Tuan; Oh, Won Keun; Kang, Chi-Dug; Kim, Sun-Hee

    2012-03-01

    SIRT1 has been found to function as a Class III deacetylase that affects the acetylation status of histones and other important cellular nonhistone proteins involved in various cellular pathways including stress responses and apoptosis. In this study, we investigated the role of SIRT1 signaling in the hypoxic down-regulations of c-Myc and β-catenin and hypoxic preconditioning effect of the red wine polyphenols such as piceatannol, myricetin, quercetin and resveratrol. We found that the expression of SIRT1 was significantly increased in hypoxia-exposed or hypoxic preconditioned HepG2 cells, which was closely associated with the up-regulation of HIF-1α and down-regulation of c-Myc and β-catenin expression via deacetylation of these proteins. In addition, blockade of SIRT1 activation using siRNA or amurensin G, a new potent SIRT1 inhibitor, abolished hypoxia-induced HIF-1α expression but increased c-Myc and β-catenin expression. SIRT1 was also found to stabilize HIF-1α protein and destabilize c-Myc, β-catenin and PHD2 under hypoxia. We also found that myricetin, quercetin, piceatannol and resveratrol up-regulated HIF-1α and down-regulated c-Myc, PHD2 and β-catenin expressions via SIRT1 activation, in a manner that mimics hypoxic preconditioning. This study provides new insights of the molecular mechanisms of hypoxic preconditioning and suggests that polyphenolic SIRT1 activators could be used to mimic hypoxic/ischemic preconditioning. -- Graphical abstract: Polyphenols mimicked hypoxic preconditioning by up-regulating HIF-1α and SIRT1 and down-regulating c-Myc, PHD2, and β-catenin. HepG2 cells were pretreated with the indicated doses of myricetin (MYR; A), quercetin (QUR; B), or piceatannol (PIC; C) for 4 h and then exposed to hypoxia for 4 h. Levels of HIF-1α, SIRT1, c-Myc, β-catenin, and PHD2 were determined by western blot analysis. The data are representative of three individual experiments. Highlights: ► SIRT1 expression is increased in hypoxia

  20. A fast, preconditioned conjugate gradient Toeplitz solver

    NASA Technical Reports Server (NTRS)

    Pan, Victor; Schrieber, Robert

    1989-01-01

    A simple factorization is given of an arbitrary hermitian, positive definite matrix in which the factors are well-conditioned, hermitian, and positive definite. In fact, given knowledge of the extreme eigenvalues of the original matrix A, an optimal improvement can be achieved, making the condition numbers of each of the two factors equal to the square root of the condition number of A. This technique is to applied to the solution of hermitian, positive definite Toeplitz systems. Large linear systems with hermitian, positive definite Toeplitz matrices arise in some signal processing applications. A stable fast algorithm is given for solving these systems that is based on the preconditioned conjugate gradient method. The algorithm exploits Toeplitz structure to reduce the cost of an iteration to O(n log n) by applying the fast Fourier Transform to compute matrix-vector products. Matrix factorization is used as a preconditioner.

  1. Iterative image restoration using approximate inverse preconditioning.

    PubMed

    Nagy, J G; Plemmons, R J; Torgersen, T C

    1996-01-01

    Removing a linear shift-invariant blur from a signal or image can be accomplished by inverse or Wiener filtering, or by an iterative least-squares deblurring procedure. Because of the ill-posed characteristics of the deconvolution problem, in the presence of noise, filtering methods often yield poor results. On the other hand, iterative methods often suffer from slow convergence at high spatial frequencies. This paper concerns solving deconvolution problems for atmospherically blurred images by the preconditioned conjugate gradient algorithm, where a new approximate inverse preconditioner is used to increase the rate of convergence. Theoretical results are established to show that fast convergence can be expected, and test results are reported for a ground-based astronomical imaging problem. PMID:18285203

  2. Mitochondria: the missing link between preconditioning and neuroprotection.

    PubMed

    Correia, Sónia C; Santos, Renato X; Perry, George; Zhu, Xiongwei; Moreira, Paula I; Smith, Mark A

    2010-01-01

    The quote "what does not kill you makes you stronger" perfectly describes the preconditioning phenomenon - a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Over the last few decades, many attempts have been made to identify the molecular mechanisms involved in preconditioning-induced protective responses, and recent data suggests that many of these mechanisms converge on the mitochondria, positing mitochondria as master regulators of preconditioning-triggered endogenous neuroprotection. In this review, we critically discuss evidence for the involvement of mitochondria within the preconditioning paradigm. We will highlight the crucial targets and mediators by which mitochondria are integrated into neuroprotective signaling pathways that underlie preconditioning, putting focus on mitochondrial respiratory chain and mitochondrial reactive oxygen species, mitochondrial ATP-sensitive potassium channels, mitochondrial permeability transition pore, uncoupling proteins, and mitochondrial antioxidant enzyme manganese superoxide dismutase. We also discuss the role of mitochondria in the induction of hypoxia-inducible factor-1, a transcription factor engaged in preconditioning-mediated neuroprotective effects. The identification of intrinsic mitochondrial mechanisms involved in preconditioning will provide new insights which can be translated into potential pharmacological interventions aimed at counteracting neurodegeneration. PMID:20463394

  3. Applying a gaming approach to IP strategy.

    PubMed

    Gasnier, Arnaud; Vandamme, Luc

    2010-02-01

    Adopting an appropriate IP strategy is an important but complex area, particularly in the pharmaceutical and biotechnology sectors, in which aspects such as regulatory submissions, high competitive activity, and public health and safety information requirements limit the amount of information that can be protected effectively through secrecy. As a result, and considering the existing time limits for patent protection, decisions on how to approach IP in these sectors must be made with knowledge of the options and consequences of IP positioning. Because of the specialized nature of IP, it is necessary to impart knowledge regarding the options and impact of IP to decision-makers, whether at the level of inventors, marketers or strategic business managers. This feature review provides some insight on IP strategy, with a focus on the use of a new 'gaming' approach for transferring the skills and understanding needed to make informed IP-related decisions; the game Patentopolis is discussed as an example of such an approach. Patentopolis involves interactive activities with IP-related business decisions, including the exploitation and enforcement of IP rights, and can be used to gain knowledge on the impact of adopting different IP strategies. PMID:20127561

  4. Vaccines and IP Rights: A Multifaceted Relationship.

    PubMed

    Durell, Karen

    2016-01-01

    Just as there are many forms of vaccines and components to vaccines-particular compositions, delivery systems, components, and distribution networks-there are a variety of intellectual property (IP) protections applicable for vaccines. IP rights such as patent, copyright, trademarks, plant breeders' rights, and trade secrets may all be applicable to vaccines. Thus, discussion of IP rights and vaccines should not begin and end with the application of one IP right to a vaccine. The discussion should engage considerations of multiple IP rights applicable to a vaccine and how these can be utilized in an integrated manner in a strategy aimed at supporting the development and distribution of the vaccine. Such an approach to IP rights to vaccines allows for the integrated rights to be considered in light of the justifications for protecting vaccines with IP rights, as well as the issues relating to specific IP rights for vaccines, such as compulsory license regimes, available humanitarian purpose IP credits, etc. To view vaccines as the subject of multiple IP protections involves a refocusing, but the outcome can provide significant benefits for vaccine development and distribution. PMID:27076338

  5. Hyperbaric oxygen preconditioning protects rats against CNS oxygen toxicity.

    PubMed

    Arieli, Yehuda; Kotler, Doron; Eynan, Mirit; Hochman, Ayala

    2014-06-15

    We examined the hypothesis that repeated exposure to non-convulsive hyperbaric oxygen (HBO) as preconditioning provides protection against central nervous system oxygen toxicity (CNS-OT). Four groups of rats were used in the study. Rats in the control and the negative control (Ctl-) groups were kept in normobaric air. Two groups of rats were preconditioned to non-convulsive HBO at 202 kPa for 1h once every other day for a total of three sessions. Twenty-four hours after preconditioning, one of the preconditioned groups and the control rats were exposed to convulsive HBO at 608 kPa, and latency to CNS-OT was measured. Ctl- rats and the second preconditioned group (PrC-) were not subjected to convulsive HBO exposure. Tissues harvested from the hippocampus and frontal cortex were evaluated for enzymatic activity and nitrotyrosine levels. In the group exposed to convulsive oxygen at 608 kPa, latency to CNS-OT increased from 12.8 to 22.4 min following preconditioning. A significant decrease in the activity of glutathione reductase and glucose-6-phosphate dehydrogenase, and a significant increase in glutathione peroxidase activity, was observed in the hippocampus of preconditioned rats. Nitrotyrosine levels were significantly lower in the preconditioned animals, the highest level being observed in the control rats. In the cortex of the preconditioned rats, a significant increase was observed in glutathione S-transferase and glutathione peroxidase activity. Repeated exposure to non-convulsive HBO provides protection against CNS-OT. The protective mechanism involves alterations in the enzymatic activity of the antioxidant system and lower levels of peroxynitrite, mainly in the hippocampus. PMID:24675062

  6. Ischemic ulcers - self-care

    MedlinePlus

    ... restrict blood flow. Certain lifestyle changes can help prevent ischemic ulcers. If you have a wound, taking these steps can improve blood flow and aid healing. Quit smoking. Smoking can lead to clogged arteries. ...

  7. Analysis of Handoff Mechanisms in Mobile IP

    NASA Astrophysics Data System (ADS)

    Jayaraj, Maria Nadine Simonel; Issac, Biju; Haldar, Manas Kumar

    2011-06-01

    One of the most important challenges in mobile Internet Protocol (IP) is to provide service for a mobile node to maintain its connectivity to network when it moves from one domain to another. IP is responsible for routing packets across network. The first major version of IP is the Internet Protocol version 4 (IPv4). It is one of the dominant protocols relevant to wireless network. Later a newer version of IP called the IPv6 was proposed. Mobile IPv6 is mainly introduced for the purpose of mobility. Mobility management enables network to locate roaming nodes in order to deliver packets and maintain connections with them when moving into new domains. Handoff occurs when a mobile node moves from one network to another. It is a key factor of mobility because a mobile node can trigger several handoffs during a session. This paper briefly explains on mobile IP and its handoff issues, along with the drawbacks of mobile IP.

  8. Rational modulation of the innate immune system for neuroprotection in ischemic stroke

    PubMed Central

    Amantea, Diana; Micieli, Giuseppe; Tassorelli, Cristina; Cuartero, María I.; Ballesteros, Iván; Certo, Michelangelo; Moro, María A.; Lizasoain, Ignacio; Bagetta, Giacinto

    2015-01-01

    The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs) that contribute to blood–brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF)-β, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate toward several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13, or TGF-β. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction. PMID:25972779

  9. Piperidine derivatives as nonprostanoid IP receptor agonists.

    PubMed

    Hayashi, Ryoji; Sakagami, Hideki; Koiwa, Masakazu; Ito, Hiroaki; Miyamoto, Mitsuko; Isogaya, Masafumi

    2016-05-01

    The discovery of a new class of nonprostanoid prostaglandin I2 receptor (IP receptor) agonists is reported. Among them, the unique piperidine derivative 31b (2-((1-(2-(N-(4-tolyl)benzamido)ethyl)piperidin-4-yl)oxy)acetic acid) was a good IP receptor agonist and was 50-fold more selective for the human IP receptor than for other human prostanoid receptors. This compound showed good pharmacokinetic properties in dog. PMID:26996371

  10. Structure of mouse IP-10, a chemokine

    SciTech Connect

    Jabeen, Talat; Leonard, Philip; Jamaluddin, Haryati; Acharya, K. Ravi

    2008-06-01

    The structure of mouse IP-10 shows a novel tetrameric association. Interferon-γ-inducible protein (IP-10) belongs to the CXC class of chemokines and plays a significant role in the pathophysiology of various immune and inflammatory responses. It is also a potent angiostatic factor with antifibrotic properties. The biological activities of IP-10 are exerted by interactions with the G-protein-coupled receptor CXCR3 expressed on Th1 lymphocytes. IP-10 thus forms an attractive target for structure-based rational drug design of anti-inflammatory molecules. The crystal structure of mouse IP-10 has been determined and reveals a novel tetrameric association. In the tetramer, two conventional CXC chemokine dimers are associated through their N-terminal regions to form a 12-stranded elongated β-sheet of ∼90 Å in length. This association differs significantly from the previously studied tetramers of human IP-10, platelet factor 4 and neutrophil-activating peptide-2. In addition, heparin- and receptor-binding residues were mapped on the surface of IP-10 tetramer. Two heparin-binding sites were observed on the surface and were present at the interface of each of the two β-sheet dimers. The structure supports the formation of higher order oligomers of IP-10, as observed in recent in vivo studies with mouse IP-10, which will have functional relevance.

  11. Preconditioning methods for improved convergence rates in iterative reconstructions

    SciTech Connect

    Clinthorne, N.H.; Chiao, Pingchun; Rogers, W.L. . Div. of Nuclear Medicine); Pan, T.S. . Dept. of Nuclear Medicine); Stamos, J.A. . Dept. of Nuclear Engineering)

    1993-03-01

    Because of the characteristics of the tomographic inversion problem, iterative reconstruction techniques often suffer from poor convergence rates--especially at high spatial frequencies. By using preconditioning methods, the convergence properties of most iterative methods can be greatly enhanced without changing their ultimate solution. To increase reconstruction speed, the authors have applied spatially-invariant preconditioning filters that can be designed using the tomographic system response and implemented using 2-D frequency-domain filtering techniques. In a sample application, the authors performed reconstructions from noiseless, simulated projection data, using preconditioned and conventional steepest-descent algorithms. The preconditioned methods demonstrated residuals that were up to a factor of 30 lower than the unassisted algorithms at the same iteration. Applications of these methods to regularized reconstructions from projection data containing Poisson noise showed similar, although not as dramatic, behavior.

  12. The Galvanotactic Migration of Keratinocytes is Enhanced by Hypoxic Preconditioning

    PubMed Central

    Guo, Xiaowei; Jiang, Xupin; Ren, Xi; Sun, Huanbo; Zhang, Dongxia; Zhang, Qiong; Zhang, Jiaping; Huang, Yuesheng

    2015-01-01

    The endogenous electric field (EF)-directed migration of keratinocytes (galvanotaxis) into wounds is an essential step in wound re-epithelialization. Hypoxia, which occurs immediately after injury, acts as an early stimulus to initiate the healing process; however, the mechanisms for this effect, remain elusive. We show here that the galvanotactic migration of keratinocytes was enhanced by hypoxia preconditioning as a result of the increased directionality rather than the increased motility of keratinocytes. This enhancement was both oxygen tension- and preconditioning time-dependent, with the maximum effects achieved using 2% O2 preconditioning for 6 hours. Hypoxic preconditioning (2% O2, 6 hours) decreased the threshold voltage of galvanotaxis to < 25 mV/mm, whereas this value was between 25 and 50 mV/mm in the normal culture control. In a scratch-wound monolayer assay in which the applied EF was in the default healing direction, hypoxic preconditioning accelerated healing by 1.38-fold compared with the control conditions. Scavenging of the induced ROS by N-acetylcysteine (NAC) abolished the enhanced galvanotaxis and the accelerated healing by hypoxic preconditioning. Our data demonstrate a novel and unsuspected role of hypoxia in supporting keratinocyte galvanotaxis. Enhancing the galvanotactic response of cells might therefore be a clinically attractive approach to induce improved wound healing. PMID:25988491

  13. Role of protein kinase C in ischemic "conditioning": from first evidence to current perspectives.

    PubMed

    Simkhovich, Boris Z; Przyklenk, Karin; Kloner, Robert A

    2013-11-01

    Since the discovery of ischemic preconditioning (IPC) 26 years ago, numerous studies attempted to determine the mechanism of this powerful form of cardioprotection. One of the first proposed pathways of IPC suggested that the preconditioning stimulus activated phospholipase C via G-protein, and diacylglycerol released from phospholipid moieties activated protein kinase C (PKC) by translocating it from the cytosol to the sarcolemmal membranes. The major protective isoform of PKC was found to be the PKC-∈. Despite some contradictions and controversies, today even the most skeptical opponents acknowledge that PKC plays a significant role in the mechanism of IPC. During recent years, both the role and the place of PKC-∈ in the mechanism of IPC have been revised. The current review presents the evolution of the "PKC theory" and summarizes the most recent data regarding the role of PKC in IPC. In addition to classical IPC, PKC appears to play a role in the mechanisms of newer conditioning protocols, that is, remote IPC and ischemic postconditioning. PMID:23872508

  14. Ischemic penumbra in acute stroke: Demonstration by PET with fluorine-18 fluoromisonidazole

    SciTech Connect

    Yeh, S.H.; Liu, R.S.; Hu, H.H.

    1994-05-01

    Ischemic penumbra (IP) in acute stroke has gained clinical interest since tissue functions may be recovered if perfusion can be reestablished. However, such therapeutic intervention is {open_quotes}blind{close_quotes} since clinical examination can not distinguish IP from developing infarction. In vivo demonstration of IP may have significance for stroke patient management. This study was a preliminary evaluation of detecting IP in vivo by F-18 fluoromisonidazole ([F-18]-FMISO), a hypoxic imaging agent. Static PET imaging was performed after IV injection of 370 MBq of [F-18]-FMISO at 20 and 120 min. Tomograms were reconstructed and evaluated visually in correlation with CT or MR scans. In acute stroke, patients (pts) were called back for the second PET study one month after the initial study. CT was used for confirming infarction. In 6 pts with acute cerebral infarction, three of them had intense [F-18]-FMISO retention in the penumbra surrounding the central, eclipse-like zone of absent radio-activity (infarction) at 2 hr in the acute state, and the penumbra disappeared in association with increased area of infarction on CT in one case in the chronic state. In five pts with chronic infarction, all had no penumbra of [F-18]-FMISO retention. In summary, our preliminary results demonstrate the feasibility of using [F-18]-FMISO PET to detect ischemic penumbra in vivo.

  15. A Weakest Precondition Approach to Robustness

    NASA Astrophysics Data System (ADS)

    Balliu, Musard; Mastroeni, Isabella

    With the increasing complexity of information management computer systems, security becomes a real concern. E-government, web-based financial transactions or military and health care information systems are only a few examples where large amount of information can reside on different hosts distributed worldwide. It is clear that any disclosure or corruption of confidential information in these contexts can result fatal. Information flow controls constitute an appealing and promising technology to protect both data confidentiality and data integrity. The certification of the security degree of a program that runs in untrusted environments still remains an open problem in the area of language-based security. Robustness asserts that an active attacker, who can modify program code in some fixed points (holes), is unable to disclose more private information than a passive attacker, who merely observes unclassified data. In this paper, we extend a method recently proposed for checking declassified non-interference in presence of passive attackers only, in order to check robustness by means of weakest precondition semantics. In particular, this semantics simulates the kind of analysis that can be performed by an attacker, i.e., from public output towards private input. The choice of semantics allows us to distinguish between different attacks models and to characterize the security of applications in different scenarios.

  16. Responsive corneosurfametry following in vivo skin preconditioning.

    PubMed

    Uhoda, E; Goffin, V; Pierard, G E

    2003-12-01

    Skin is subjected to many environmental threats, some of which altering the structure and function of the stratum corneum. Among them, surfactants are recognized factors that may influence irritant contact dermatitis. The present study was conducted to compare the variations in skin capacitance and corneosurfametry (CSM) reactivity before and after skin exposure to repeated subclinical injuries by 2 hand dishwashing liquids. A forearm immersion test was performed on 30 healthy volunteers. 2 daily soak sessions were performed for 5 days. At inclusion and the day following the last soak session, skin capacitance was measured and cyanoacrylate skin-surface strippings were harvested. The latter specimens were used for the ex vivo microwave CSM. Both types of assessments clearly differentiated the 2 hand dishwashing liquids. The forearm immersion test allowed the discriminant sensitivity of CSM to increase. Intact skin capacitance did not predict CSM data. By contrast, a significant correlation was found between the post-test conductance and the corresponding CSM data. In conclusion, a forearm immersion test under realistic conditions can discriminate the irritation potential between surfactant-based products by measuring skin conductance and performing CSM. In vivo skin preconditioning by surfactants increases CSM sensitivity to the same surfactants. PMID:15025702

  17. Intravenous transplantation of mesenchymal stem cells preconditioned with early phase stroke serum: current evidence and study protocol for a randomized trial

    PubMed Central

    2013-01-01

    Background Recovery after a major stroke is usually limited, but cell therapy for patients with fixed neurologic deficits is emerging. Several recent clinical trials have investigated mesenchymal stem cell (MSC) therapy for patients with ischemic stroke. We previously reported the results of a controlled trial on the application of autologous MSCs in patients with ischemic stroke with a long-term follow-up of up to 5 years (the 'STem cell Application Researches and Trials In NeuroloGy’ (STARTING) study). The results from this pilot trial are challenging, but also raise important issues. In addition, there have been recent efforts to improve the safety and efficacy of MSC therapy for stroke. Methods and design The clinical and preclinical background and the STARTING-2 study protocol are provided. The trial is a prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial. Both acute and chronic stroke patients will be selected based on clinical and radiological features and followed for 3 months after MSC treatment. The subjects will be randomized into one of two groups: (A) a MSC group (n = 40) or (B) a control group (n = 20). Autologous MSCs will be intravenously administered after ex vivo culture expansion with autologous ischemic serum obtained as early as possible, to enhance the therapeutic efficacy (ischemic preconditioning). Objective outcome measurements will be performed using multimodal MRI and detailed functional assessments by blinded observers. Discussion This trial is the first to evaluate the efficacy of MSCs in patients with ischemic stroke. The results may provide better evidence for the effectiveness of MSC therapy in patients with ischemic stroke. Trial registration This trial was registered with ClinicalTrials.gov, number NCT01716481. PMID:24083670

  18. VoIP to the Rescue

    ERIC Educational Resources Information Center

    Milner, Jacob

    2005-01-01

    Voice over Internet Protocol (VoIP) is everywhere. The technology lets users make and receive phone calls over the Internet, transporting voice traffic alongside data traffic such as instant messages (IMs) and e-mail. While the number of consumer customers using VoIP increases every week, the technology is finding its way into K-12 education as…

  19. Approaches for Resolving Dynamic IP Addressing.

    ERIC Educational Resources Information Center

    Foo, Schubert; Hui, Siu Cheung; Yip, See Wai; He, Yulan

    1997-01-01

    A problem with dynamic Internet protocol (IP) addressing arises when the Internet connection is through an Internet provider since the IP address is allocated only at connection time. This article examines a number of online and offline methods for resolving the problem. Suggests dynamic domain name system (DNS) and directory service look-up are…

  20. Structure of mouse IP-10, a chemokine.

    PubMed

    Jabeen, Talat; Leonard, Philip; Jamaluddin, Haryati; Acharya, K Ravi

    2008-06-01

    Interferon-gamma-inducible protein (IP-10) belongs to the CXC class of chemokines and plays a significant role in the pathophysiology of various immune and inflammatory responses. It is also a potent angiostatic factor with antifibrotic properties. The biological activities of IP-10 are exerted by interactions with the G-protein-coupled receptor CXCR3 expressed on Th1 lymphocytes. IP-10 thus forms an attractive target for structure-based rational drug design of anti-inflammatory molecules. The crystal structure of mouse IP-10 has been determined and reveals a novel tetrameric association. In the tetramer, two conventional CXC chemokine dimers are associated through their N-terminal regions to form a 12-stranded elongated beta-sheet of approximately 90 A in length. This association differs significantly from the previously studied tetramers of human IP-10, platelet factor 4 and neutrophil-activating peptide-2. In addition, heparin- and receptor-binding residues were mapped on the surface of IP-10 tetramer. Two heparin-binding sites were observed on the surface and were present at the interface of each of the two beta-sheet dimers. The structure supports the formation of higher order oligomers of IP-10, as observed in recent in vivo studies with mouse IP-10, which will have functional relevance. PMID:18560148

  1. Instrument Pointing Subsystem /IPS/ design and performance

    NASA Astrophysics Data System (ADS)

    Hammesfahr, A. E.

    1981-01-01

    The Instrument Pointing Subsystem (IPS), currently under development at Dornier System, is a most versatile Spacelab subsystem providing precision pointing capabilities to any single or clustered group of scientific instruments observing inertially fixed or moving targets. The IPS comprises a three-axis gimbal system mounted to the payload aft end and a payload clamping assembly for support of the IPS mounted experiments during Orbiter launch and landing phases. The IPS control system is based on the inertial reference of a three-axis gyro package being updated by the payload mounted IPS star/sun trackers and operated in a gimbal mounted minicomputer. It enables inertial stabilization as well as slewing and target tracking operations. The functional and operational control is performed via the Spacelab S/S computer and its display and keyboard, thereby establishing a flexible and responsive operator interface in the Spacelab Module and the Orbiter AFD enabling optimized display and keyboard entries for any operational mode. The AFD accommodates in addition a hardwired panel serving for IPS emergency operations. Incorporated Experiment supporting services consist of several independent power sources, three Experiment Computer Remote Acquisition Units and direct data links to IPS and Spacelab which provide maximum flexibility for operation of independent experiment clusters and for an operational interlock between IPS and its payload.

  2. Ischemic Stroke after Heart Transplantation.

    PubMed

    Acampa, Maurizio; Lazzerini, Pietro Enea; Guideri, Francesca; Tassi, Rossana; Martini, Giuseppe

    2016-05-01

    Cerebrovascular complications after orthotopic heart transplantation (OHT) are more common in comparison with neurological sequelae subsequent to routine cardiac surgery. Ischemic stroke and transient ischemic attack (TIA) are more common (with an incidence of up to 13%) than intracranial hemorrhage (2.5%). Clinically, ischemic stroke is manifested by the appearance of focal neurologic deficits, although sometimes a stroke may be silent or manifests itself by the appearance of encephalopathy, reflecting a diffuse brain disorder. Ischemic stroke subtypes distribution in perioperative and postoperative period after OHT is very different from classical distribution, with different pathogenic mechanisms. Infact, ischemic stroke may be caused by less common and unusual mechanisms, linked to surgical procedures and to postoperative inflammation, peculiar to this group of patients. However, many strokes (40%) occur without a well-defined etiology (cryptogenic strokes). A silent atrial fibrillation (AF) may play a role in pathogenesis of these strokes and P wave dispersion may represent a predictor of AF. In OHT patients, P wave dispersion correlates with homocysteine plasma levels and hyperhomocysteinemia could play a role in the pathogenesis of these strokes with multiple mechanisms increasing the risk of AF. In conclusion, stroke after heart transplantation represents a complication with considerable impact not only on mortality but also on subsequent poor functional outcome. PMID:26915504

  3. Ischemic Stroke after Heart Transplantation

    PubMed Central

    Acampa, Maurizio; Lazzerini, Pietro Enea; Guideri, Francesca; Tassi, Rossana; Martini, Giuseppe

    2016-01-01

    Cerebrovascular complications after orthotopic heart transplantation (OHT) are more common in comparison with neurological sequelae subsequent to routine cardiac surgery. Ischemic stroke and transient ischemic attack (TIA) are more common (with an incidence of up to 13%) than intracranial hemorrhage (2.5%). Clinically, ischemic stroke is manifested by the appearance of focal neurologic deficits, although sometimes a stroke may be silent or manifests itself by the appearance of encephalopathy, reflecting a diffuse brain disorder. Ischemic stroke subtypes distribution in perioperative and postoperative period after OHT is very different from classical distribution, with different pathogenic mechanisms. Infact, ischemic stroke may be caused by less common and unusual mechanisms, linked to surgical procedures and to postoperative inflammation, peculiar to this group of patients. However, many strokes (40%) occur without a well-defined etiology (cryptogenic strokes). A silent atrial fibrillation (AF) may play a role in pathogenesis of these strokes and P wave dispersion may represent a predictor of AF. In OHT patients, P wave dispersion correlates with homocysteine plasma levels and hyperhomocysteinemia could play a role in the pathogenesis of these strokes with multiple mechanisms increasing the risk of AF. In conclusion, stroke after heart transplantation represents a complication with considerable impact not only on mortality but also on subsequent poor functional outcome. PMID:26915504

  4. Space Network IP Services (SNIS): An Architecture for Supporting Low Earth Orbiting IP Satellite Missions

    NASA Technical Reports Server (NTRS)

    Israel, David J.

    2005-01-01

    The NASA Space Network (SN) supports a variety of missions using the Tracking and Data Relay Satellite System (TDRSS), which includes ground stations in White Sands, New Mexico and Guam. A Space Network IP Services (SNIS) architecture is being developed to support future users with requirements for end-to-end Internet Protocol (IP) communications. This architecture will support all IP protocols, including Mobile IP, over TDRSS Single Access, Multiple Access, and Demand Access Radio Frequency (RF) links. This paper will describe this architecture and how it can enable Low Earth Orbiting IP satellite missions.

  5. Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia

    PubMed Central

    2014-01-01

    Background Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of brain preconditioning. Unraveling mechanisms of this endogenous neuroprotection, activated by preconditioning, is an important step towards new clinical strategies for treating asphyctic neonates. Therefore, we investigated whole-genome transcriptional changes in the brain of rats which underwent perinatal asphyxia (PA), and rats where PA was preceded by fetal asphyctic preconditioning (FAPA). Offspring were sacrificed 6 h and 96 h after birth, and whole-genome transcription was investigated using the Affymetrix Gene1.0ST chip. Microarray data were analyzed with the Bioconductor Limma package. In addition to univariate analysis, we performed Gene Set Enrichment Analysis (GSEA) in order to derive results with maximum biological relevance. Results We observed minimal, 25% or less, overlap of differentially regulated transcripts across different experimental groups which leads us to conclude that the transcriptional phenotype of these groups is largely unique. In both the PA and FAPA group we observe an upregulation of transcripts involved in cellular stress. Contrastingly, transcripts with a function in the cell nucleus were mostly downregulated in PA animals, while we see considerable upregulation in the FAPA group. Furthermore, we observed that histone deacetylases (HDACs) are exclusively regulated in FAPA animals. Conclusions This study is the first to investigate whole-genome transcription in the neonatal brain after PA alone, and after perinatal asphyxia preceded by preconditioning (FAPA). We describe several genes/pathways, such as ubiquitination and proteolysis, which were not previously linked to preconditioning-induced neuroprotection. Furthermore, we observed that the majority of upregulated genes in preconditioned animals have a function in the cell nucleus, including several epigenetic players such as HDACs, which suggests that epigenetic

  6. Reduction in postsystolic wall thickening during late preconditioning.

    PubMed

    Monnet, Xavier; Lucats, Laurence; Colin, Patrice; Derumeaux, Geneviève; Dubois-Rande, Jean-Luc; Hittinger, Luc; Ghaleh, Bijan; Berdeaux, Alain

    2007-01-01

    Brief coronary artery occlusion (CAO) and reperfusion induce myocardial stunning and late preconditioning. Postsystolic wall thickening (PSWT) also develops with CAO and reperfusion. However, the time course of PSWT during stunning and the regional function pattern of the preconditioned myocardium remain unknown. The goal of this study was to investigate the evolution of PSWT during myocardial stunning and its modifications during late preconditioning. Dogs were chronically instrumented to measure (sonomicrometry) systolic wall thickening (SWT), PSWT, total wall thickening (TWT = SWT + PSWT), and maximal rate of thickening (dWT/dt(max)). Two 10-min CAO (circumflex artery) were performed 24 h apart (day 0 and day 1, n = 7). At day 0, CAO decreased SWT and increased PSWT. During the first hours of the subsequent stunning, evolution of PSWT was symmetrical to that of SWT. At day 1, baseline SWT was similar to day 0, but PSWT was reduced (-66%), while dWT/dt(max) and SWT/TWT ratio increased (+48 and +14%, respectively). After CAO at day 1, stunning was reduced, indicating late preconditioning. Simultaneously vs. day 0, PSWT was significantly reduced, and dWT/dt(max) as well as SWT/TWT ratio were increased, i.e., a greater part of TWT was devoted to ejection. Similar decrease in PSWT was observed with a nonischemic preconditioning stimulus (rapid ventricular pacing, n = 4). In conclusion, a major contractile adaptation occurs during late preconditioning, i.e., the rate of wall thickening is enhanced and PWST is almost abolished. These phenotype adaptations represent potential approaches for characterizing stunning and late preconditioning with repetitive ischemia in humans. PMID:16920813

  7. HYPERTENSIVE-ISCHEMIC LEG ULCERS

    PubMed Central

    Farber, Eugene M.; Schmidt, Otto E. L.

    1950-01-01

    Ischemic ulcers of the leg having characteristics different from those of ordinary leg ulcers have been observed in a small number of hypertensive patients, mostly women, during the past few years. Such ulcers are usually located above the ankle. They begin with a small area of purplish discoloration at the site of slight trauma, and progress to acutely tender ulceration. In studies of tissue removed from the margin and the base of an ulcer of this kind, obliterative arteriolar sclerotic changes, ischemic-appearing connective tissue and inflammatory changes were noted. Two additional cases are reported. ImagesFigure 1.Figure 2.Figure 3.Figure 4. PMID:15398887

  8. MicroRNA-378 Alleviates Cerebral Ischemic Injury by Negatively Regulating Apoptosis Executioner Caspase-3.

    PubMed

    Zhang, Nan; Zhong, Jie; Han, Song; Li, Yun; Yin, Yanling; Li, Junfa

    2016-01-01

    miRNAs have been linked to many human diseases, including ischemic stroke, and are being pursued as clinical diagnostics and therapeutic targets. Among the aberrantly expressed miRNAs in our previous report using large-scale microarray screening, the downregulation of miR-378 in the peri-infarct region of middle cerebral artery occluded (MCAO) mice can be reversed by hypoxic preconditioning (HPC). In this study, the role of miR-378 in the ischemic injury was further explored. We found that miR-378 levels significantly decreased in N2A cells following oxygen-glucose deprivation (OGD) treatment. Overexpression of miR-378 significantly enhanced cell viability, decreased TUNEL-positive cells and the immunoreactivity of cleaved-caspase-3. Conversely, downregulation of miR-378 aggravated OGD-induced apoptosis and ischemic injury. By using bioinformatic algorithms, we discovered that miR-378 may directly bind to the predicted 3'-untranslated region (UTR) of Caspase-3 gene. The protein level of caspase-3 increased significantly upon OGD treatment, and can be downregulated by pri-miR-378 transfection. The luciferase reporter assay confirmed the binding of miR-378 to the 3'-UTR of Caspase-3 mRNA and repressed its translation. In addition, miR-378 agomir decreased cleaved-caspase-3 ratio, reduced infarct volume and neural cell death induced by MCAO. Furthermore, caspase-3 knockdown could reverse anti-miR-378 mediated neuronal injury. Taken together, our data demonstrated that miR-378 attenuated ischemic injury by negatively regulating the apoptosis executioner, caspase-3, providing a potential therapeutic target for ischemic stroke. PMID:27598143

  9. Implementation of Preconditioned Dual-Time Procedures in OVERFLOW

    NASA Technical Reports Server (NTRS)

    Pandya, Shishir A.; Venkateswaran, Sankaran; Pulliam, Thomas H.; Kwak, Dochan (Technical Monitor)

    2003-01-01

    Preconditioning methods have become the method of choice for the solution of flowfields involving the simultaneous presence of low Mach and transonic regions. It is well known that these methods are important for insuring accurate numerical discretization as well as convergence efficiency over various operating conditions such as low Mach number, low Reynolds number and high Strouhal numbers. For unsteady problems, the preconditioning is introduced within a dual-time framework wherein the physical time-derivatives are used to march the unsteady equations and the preconditioned time-derivatives are used for purposes of numerical discretization and iterative solution. In this paper, we describe the implementation of the preconditioned dual-time methodology in the OVERFLOW code. To demonstrate the performance of the method, we employ both simple and practical unsteady flowfields, including vortex propagation in a low Mach number flow, flowfield of an impulsively started plate (Stokes' first problem) arid a cylindrical jet in a low Mach number crossflow with ground effect. All the results demonstrate that the preconditioning algorithm is responsible for improvements to both numerical accuracy and convergence efficiency and, thereby, enables low Mach number unsteady computations to be performed at a fraction of the cost of traditional time-marching methods.

  10. Scalable architecture for VoIP privacy

    NASA Astrophysics Data System (ADS)

    Medvinsky, Alexander

    2001-07-01

    An access network for Voice over IP (VoIP) clients (e.g. DOCSIS-based HFC network) often provides a privacy service. However, such a privacy service is limited only to that access network. When VoIP packets are carried over an open IP network or over a network with some connections to the Internet, it is desirable to provide an end-to-end privacy service where each VoIP packet is encrypted at the source and decrypted at the terminating endpoint. Clearly, public key encryption cannot be applied to each voice packet; the performance would be unacceptable regardless of the choice of a public key algorithm. The only alternative is for the two VoIP endpoints to negotiate a shared symmetric key. Since VoIP connections are established only for duration of a phone call, the end-to-end key negotiation needs to occur during each call setup. And it should not noticeably delay the call setup phase. In order to provide end-to-end privacy, it is not sufficient to encrypt all messages between the two endpoints. It is important that the two endpoints authenticate each other - validate each other's identity. Without authentication an adversary might trick two VoIP clients to negotiate keys with her and then sit in the middle of their conversation and record each VoIP packet, before forwarding it to the intended destination. However, direct authentication of the two VoIP endpoints is not always possible in telephony networks - in particular when caller ID blocking services are enabled. To support such anonymity services, it may be sufficient to authenticate not the identity of the caller but the fact that it is a valid subscriber and that all subsequent signaling and voice traffic will be coming from the same source. The PacketCable specifications provide an example of a VoIP architecture with end-to-end privacy that meets the above stated criteria. This paper describes the PacketCable end-to-end privacy approach and suggests additional mechanisms that may be used to further

  11. Hyperbaric Oxygen Preconditioning Attenuates Hemorrhagic Transformation through Increasing PPARγ in Hyperglycemic MCAO Rats

    PubMed Central

    Bian, Hetao; Hu, Qin; Liang, Xiping; Chen, Di; Li, Bo; Tang, Jiping; Zhang, John H.

    2014-01-01

    Hyperbaric oxygen preconditioning (HBO-PC) has been demonstrated to attenuate hemorrhagic transformation (HT) after middle cerebral artery occlusion (MCAO) in hyperglycemic rats. However, the mechanisms remain to be illustrated. Recently, HBO-PC has been shown to activate peroxisome proliferator-activated receptor-gamma (PPARγ) by increasing 15d-PGJ2 in primary cultured neurons. We hypothesize that HBO-PC reduces HT by suppressing inflammation through increasing 15d-PGJ2 and activating PPARγ in hyperglycemic MCAO rats. HBO (2.5 ATA) was administrated for 1 hour daily for 5 consecutive days. The PPARγ inhibitor GW9662 was administrated intraperitoneally to designated animals. Infarction volume, hemorrhage volume, neurological scores and mortality were analyzed. The levels of 15d-PGJ2, PPARγ, TNF-α and IL-1β, tight junction proteins as well as the activity of MMP-2 and MMP-9 were evaluated 24 hours after MCAO. HBO-PC reduced HT, improved neurological function, down-regulated inflammatory molecules and inhibited the activation of MMP-9 by increasing 15d-PGJ2 and PPARγ at 24 hours after MCAO. The results suggested HBO-PC might be an alternative measure to decrease HT in ischemic stroke. PMID:25542160

  12. Preconditioning at a distance: Involvement of endothelial vasoactive substances in cardioprotection against ischemia-reperfusion injury.

    PubMed

    Aggarwal, Sapna; Randhawa, Puneet Kaur; Singh, Nirmal; Jaggi, Amteshwar Singh

    2016-04-15

    There is growing preclinical as well as clinical evidence supporting remote ischemic preconditioning (RIPC), in which short cycles of non-fatal ischemia followed by reperfusion to an organ or tissue distant from the heart elicits cardioprotection. It is the most practical, non-invasive, cost-free, and clinically compatible, secure procedure for reducing ischemia-reperfusion induced injury. The use of a conventional blood pressure cuff on the upper or lower limb in eliciting cardioprotection has expedited its clinical applicability. Endothelium has been documented to respond very quickly to blood flow and hypoxia by releasing different humoral factors such as endothelium derived releasing factor, endothelium derived contracting factor, endothelium derived hyperpolarizing factor. In recent years, there have been studies suggesting the key role of endothelial derived factors in RIPC induced cardioprotection. The signaling cascade involves nitric oxide, gap junctions, epoxyeicosatrienoic (EETs) acids, Ca-activated K(+) channels, angiotensin II, thromboxane A2, superoxide anions and prostacyclin. The present review describes the role of these endothelial derived factors in RIPC induced cardioprotection with possible mechanisms. PMID:26979771

  13. [Phenomenon of heart ischemic postconditioning].

    PubMed

    Maslov, L N; Mrochek, A G; Hanus, L; Pei, J -M; Zhang, Y; Wang, H; Naryzhnaia, N V

    2012-08-01

    Authors of review analyzed papers on problem of heart ischemic postconditioning. In the review, it was demonstrated that postconditioning decreased an infarct size, prevented cardiomyocytes apoptosis, improved cardiac contractility in reperfusion period, augmented cardiac tolerance to arrhythmogenic impact ofreperfusion, prevented neutrophil invasion into the reperfused heart, abolished reperfusion endothelial dysfunction and suppressed reperfusion oxidative stress in myocardium. PMID:23155619

  14. Myocardial ischemic reperfusion induces de novo Nrf2 protein translation

    PubMed Central

    Xu, Beibei; Zhang, Jack; Strom, Joshua; Lee, Sang; Chen, Qin M.

    2016-01-01

    Nrf2 is a bZIP transcription factor regulating the expression of antioxidant and detoxification genes. We have found that Nrf2 knockout mice have an increased infarction size in response to regional ischemic reperfusion and have a reduced degree of cardiac protection by means of ischemic preconditioning. With cycles of brief ischemia and reperfusion (5′I/5′R) that induce cardiac protection in wild type mice, an elevated Nrf2 protein was observed without prior increases of Nrf2 mRNA. When an mRNA species is being translated into a protein, it is occupied by multiple ribosomes. The level of ribosome-associated Nrf2 mRNA increased following cycles of 5′I/5′R, supporting de novo Nrf2 protein translation. A dicistronic reporter assay indicated a role of the 5′ untranslated region (5′ UTR) of Nrf2 mRNA in oxidative stress induced Nrf2 protein translation in isolated cardiomyocytes. Western blot analyses after isolation of proteins binding to biotinylated Nrf2 5′ UTR from the myocardium or cultured cardiomyocytes demonstrated that cycles of 5′I/5′R or oxidants caused an increased association of La protein with Nrf2 5′ UTR. Ribonucleoprotein complex immunoprecipitation assays confirmed such association indeed occurring in vivo. Knocking down La using siRNA was able to prevent Nrf2 protein elevation by oxidants in cultured cardiomyocytes and by cycles of 5′I/5′R in the myocardium. Our data point out a novel mechanism of cardiac protection by de novo Nrf2 protein translation involving interaction of La protein with 5′ UTR of Nrf2 mRNA in cardiomyocytes. PMID:24915518

  15. Gpu Implementation of Preconditioning Method for Low-Speed Flows

    NASA Astrophysics Data System (ADS)

    Zhang, Jiale; Chen, Hongquan

    2016-06-01

    An improved preconditioning method for low-Mach-number flows is implemented on a GPU platform. The improved preconditioning method employs the fluctuation of the fluid variables to weaken the influence of accuracy caused by the truncation error. The GPU parallel computing platform is implemented to accelerate the calculations. Both details concerning the improved preconditioning method and the GPU implementation technology are described in this paper. Then a set of typical low-speed flow cases are simulated for both validation and performance analysis of the resulting GPU solver. Numerical results show that dozens of times speedup relative to a serial CPU implementation can be achieved using a single GPU desktop platform, which demonstrates that the GPU desktop can serve as a cost-effective parallel computing platform to accelerate CFD simulations for low-Speed flows substantially.

  16. Operator-Based Preconditioning of Stiff Hyperbolic Systems

    SciTech Connect

    Reynolds, Daniel R.; Samtaney, Ravi; Woodward, Carol S.

    2009-02-09

    We introduce an operator-based scheme for preconditioning stiff components encoun- tered in implicit methods for hyperbolic systems of partial differential equations posed on regular grids. The method is based on a directional splitting of the implicit operator, followed by a char- acteristic decomposition of the resulting directional parts. This approach allows for solution to any number of characteristic components, from the entire system to only the fastest, stiffness-inducing waves. We apply the preconditioning method to stiff hyperbolic systems arising in magnetohydro- dynamics and gas dynamics. We then present numerical results showing that this preconditioning scheme works well on problems where the underlying stiffness results from the interaction of fast transient waves with slowly-evolving dynamics, scales well to large problem sizes and numbers of processors, and allows for additional customization based on the specific problems under study.

  17. Liquid hydrogen turbopump rapid start program. [thermal preconditioning using coatings

    NASA Technical Reports Server (NTRS)

    Wong, G. S.

    1973-01-01

    This program was to analyze, test, and evaluate methods of achieving rapid-start of a liquid hydrogen feed system (inlet duct and turbopump) using a minimum of thermal preconditioning time and propellant. The program was divided into four tasks. Task 1 includes analytical studies of the testing conducted in the other three tasks. Task 2 describes the results from laboratory testing of coating samples and the successful adherence of a KX-635 coating to the internal surfaces of the feed system tested in Task 4. Task 3 presents results of testing an uncoated feed system. Tank pressure was varied to determine the effect of flowrate on preconditioning. The discharge volume and the discharge pressure which initiates opening of the discharge valve were varied to determine the effect on deadhead (no through-flow) start transients. Task 4 describes results of testing a similar, internally coated feed system and illustrates the savings in preconditioning time and propellant resulting from the coatings.

  18. On adaptive weighted polynomial preconditioning for Hermitian positive definite matrices

    NASA Technical Reports Server (NTRS)

    Fischer, Bernd; Freund, Roland W.

    1992-01-01

    The conjugate gradient algorithm for solving Hermitian positive definite linear systems is usually combined with preconditioning in order to speed up convergence. In recent years, there has been a revival of polynomial preconditioning, motivated by the attractive features of the method on modern architectures. Standard techniques for choosing the preconditioning polynomial are based only on bounds for the extreme eigenvalues. Here a different approach is proposed, which aims at adapting the preconditioner to the eigenvalue distribution of the coefficient matrix. The technique is based on the observation that good estimates for the eigenvalue distribution can be derived after only a few steps of the Lanczos process. This information is then used to construct a weight function for a suitable Chebyshev approximation problem. The solution of this problem yields the polynomial preconditioner. In particular, we investigate the use of Bernstein-Szego weights.

  19. VoIP technology comes of age.

    PubMed

    2008-04-01

    Cabling specialist Connectix examines the growing potential for healthcare sector use of VoIP technology and highlights the importance of correct cabling infrastructure as a carrier of both voice and high-speed data traffic. PMID:18494421

  20. IP-1 Certification of Cargo Containers

    SciTech Connect

    Hagler, Lisle

    2010-10-05

    The purpose and scope of this engineering note is to demonstrate that the structural design of the cargo container complies with the IP-1 container requirements of 49 CFR 173.410 as required by CFR 173.411.

  1. Preconditioning boosts regenerative programmes in the adult zebrafish heart

    PubMed Central

    de Preux Charles, Anne-Sophie; Bise, Thomas; Baier, Felix; Sallin, Pauline; Jaźwińska, Anna

    2016-01-01

    During preconditioning, exposure to a non-lethal harmful stimulus triggers a body-wide increase of survival and pro-regenerative programmes that enable the organism to better withstand the deleterious effects of subsequent injuries. This phenomenon has first been described in the mammalian heart, where it leads to a reduction of infarct size and limits the dysfunction of the injured organ. Despite its important clinical outcome, the actual mechanisms underlying preconditioning-induced cardioprotection remain unclear. Here, we describe two independent models of cardiac preconditioning in the adult zebrafish. As noxious stimuli, we used either a thoracotomy procedure or an induction of sterile inflammation by intraperitoneal injection of immunogenic particles. Similar to mammalian preconditioning, the zebrafish heart displayed increased expression of cardioprotective genes in response to these stimuli. As zebrafish cardiomyocytes have an endogenous proliferative capacity, preconditioning further elevated the re-entry into the cell cycle in the intact heart. This enhanced cycling activity led to a long-term modification of the myocardium architecture. Importantly, the protected phenotype brought beneficial effects for heart regeneration within one week after cryoinjury, such as a more effective cell-cycle reentry, enhanced reactivation of embryonic gene expression at the injury border, and improved cell survival shortly after injury. This study reveals that exposure to antecedent stimuli induces adaptive responses that render the fish more efficient in the activation of the regenerative programmes following heart damage. Our results open a new field of research by providing the adult zebrafish as a model system to study remote cardiac preconditioning. PMID:27440423

  2. Using CisGenome to Analyze ChIP-chip and ChIP-seq Data

    PubMed Central

    Ji, Hongkai; Jiang, Hui; Ma, Wenxiu; Wong, Wing Hung

    2011-01-01

    Chromatin immunoprecipitation (ChIP) coupled with genome tiling array hybridization (ChIP-chip) and ChIP followed by massively parallel sequencing (ChIP-seq) are high throughput approaches to profile genome-wide protein-DNA interactions. Both technologies are increasingly used to study transcription factor binding sites and chromatin modifications. CisGenome is an integrated software system for analyzing ChIP-chip and ChIP-seq data. This unit describes basic functions of CisGenome and how to use them to find genomic regions with protein-DNA interactions, visualize binding signals, associate binding regions with nearby genes, search for novel transcription factor binding motifs, and map existing DNA sequence motifs to user-supplied genomic regions to define their exact locations. PMID:21400695

  3. Security labeling in TCP/IP networks

    SciTech Connect

    Brown, C.D.

    1989-01-30

    TCP/IP is the name commonly used to refer to a suite of networking protocols that was originally developed under the auspices of the Department of Defense for use on the Arpanet. These protocols are in wide use today on a large number of networks and have become accepted as a de facto industry standard. The Transmission Control Protocol (TCP) occupies the transport layer in the protocol suite, and the Internet Protocol (IP) occupies the network layer. In addition, there are a wide variety of other protocols in the DDN protocol suite. For example, the Unreliable Datagram Protocol (UDP) is alternative transport layer protocol that provides a simple unreliable datagram (packet) delivery service and uses the services of IP. The File Transport Protocol (FTP) and TELNET are application layer protocols that provide for file transfers and interactive logins, respectively, across a network using the services of TCP and IP. In this paper, we will discuss security labeling in a TCP/IP network with emphasis on the attempts to standardize labels at the IP layer; however, we will also discuss some of the issues relating to application protocols and privileged server processes in host computer systems. 4 refs., 1 fig.

  4. Comparative calibration of IP scanning equipment

    NASA Astrophysics Data System (ADS)

    Ingenito, F.; Andreoli, P.; Batani, D.; Boutoux, G.; Cipriani, M.; Consoli, F.; Cristofari, G.; Curcio, A.; De Angelis, R.; Di Giorgio, G.; Ducret, J.; Forestier-Colleoni, P.; Hulin, S.; Jakubowska, K.; Rabhi, N.

    2016-05-01

    Imaging Plates (IP) are diagnostic devices which contain a photostimulable phosphor layer that stores the incident radiation dose as a latent image. The image is read with a scanner which stimulates the decay of electrons, previously excited by the incident radiation, by exposition to a laser beam. This results in emitted light, which is detected by photomultiplier tubes; so the latent image is reconstructed. IPs have the interesting feature that can be reused many times, after erasing stored information. Algorithms to convert signals stored in the detector to Photostimulated luminescence (PSL) counts depend on the scanner and are not available on every model. A comparative cross-calibration of the IP scanner Dürr CR35 BIO, used in ABC laboratory, was performed, using the Fujifilm FLA 7000 scanner as a reference, to find the equivalence between grey-scale values given by the Dürr scanner to PSL counts. Using an IP and a 55Fe β-source, we produced pairs of samples with the same exposition times, which were analysed by both scanners, placing particular attention to fading times of the image stored on IPs. Data analysis led us to the determine a conversion formula which can be used to compare data of experiments obtained in different laboratories and to use IP calibrations available, till now, only for Fujifilm scanners.

  5. Incomplete block SSOR preconditionings for high order discretizations

    SciTech Connect

    Kolotilina, L.

    1994-12-31

    This paper considers the solution of linear algebraic systems Ax = b resulting from the p-version of the Finite Element Method (FEM) using PCG iterations. Contrary to the h-version, the p-version ensures the desired accuracy of a discretization not by refining an original finite element mesh but by introducing higher degree polynomials as additional basis functions which permits to reduce the size of the resulting linear system as compared with the h-version. The suggested preconditionings are the so-called Incomplete Block SSOR (IBSSOR) preconditionings.

  6. Choice of Variables and Preconditioning for Time Dependent Problems

    NASA Technical Reports Server (NTRS)

    Turkel, Eli; Vatsa, Verr N.

    2003-01-01

    We consider the use of low speed preconditioning for time dependent problems. These are solved using a dual time step approach. We consider the effect of this dual time step on the parameter of the low speed preconditioning. In addition, we compare the use of two sets of variables, conservation and primitive variables, to solve the system. We show the effect of these choices on both the convergence to a steady state and the accuracy of the numerical solutions for low Mach number steady state and time dependent flows.

  7. Fourier analysis of finite element preconditioned collocation schemes

    NASA Technical Reports Server (NTRS)

    Deville, Michel O.; Mund, Ernest H.

    1990-01-01

    The spectrum of the iteration operator of some finite element preconditioned Fourier collocation schemes is investigated. The first part of the paper analyses one-dimensional elliptic and hyperbolic model problems and the advection-diffusion equation. Analytical expressions of the eigenvalues are obtained with use of symbolic computation. The second part of the paper considers the set of one-dimensional differential equations resulting from Fourier analysis (in the tranverse direction) of the 2-D Stokes problem. All results agree with previous conclusions on the numerical efficiency of finite element preconditioning schemes.

  8. Preconditioning for multiplexed imaging with spatially coded PSFs.

    PubMed

    Horisaki, Ryoichi; Tanida, Jun

    2011-06-20

    We propose a preconditioning method to improve the convergence of iterative reconstruction algorithms in multiplexed imaging based on convolution-based compressive sensing with spatially coded point spread functions (PSFs). The system matrix is converted to improve the condition number with a preconditioner matrix. The preconditioner matrix is calculated by Tikhonov regularization in the frequency domain. The method was demonstrated with simulations and an experiment involving a range detection system with a grating based on the multiplexed imaging framework. The results of the demonstrations showed improved reconstruction fidelity by using the proposed preconditioning method. PMID:21716495

  9. A subspace preconditioning algorithm for eigenvector/eigenvalue computation

    SciTech Connect

    Bramble, J.H.; Knyazev, A.V.; Pasciak, J.E.

    1996-12-31

    We consider the problem of computing a modest number of the smallest eigenvalues along with orthogonal bases for the corresponding eigen-spaces of a symmetric positive definite matrix. In our applications, the dimension of a matrix is large and the cost of its inverting is prohibitive. In this paper, we shall develop an effective parallelizable technique for computing these eigenvalues and eigenvectors utilizing subspace iteration and preconditioning. Estimates will be provided which show that the preconditioned method converges linearly and uniformly in the matrix dimension when used with a uniform preconditioner under the assumption that the approximating subspace is close enough to the span of desired eigenvectors.

  10. Hypoxic Preconditioning Differentially Affects GABAergic and Glutamatergic Neuronal Cells in the Injured Cerebellum of the Neonatal Rat

    PubMed Central

    Patterson, Sean I.; Muñoz, Estela M.; Seltzer, Alicia M.

    2014-01-01

    In this study we examined cerebellar alterations in a neonatal rat model of hypoxic-ischemic brain injury with or without hypoxic preconditioning (Pc). Between postnatal days 7 and 15, the cerebellum is still undergoing intense cellular proliferation, differentiation and migration, dendritogenesis and synaptogenesis. The expression of glutamate decarboxylase 1 (GAD67) and the differentiation factor NeuroD1 were examined as markers of Purkinje and granule cells, respectively. We applied quantitative immunohistochemistry to sagittal cerebellar slices, and Western blot analysis of whole cerebella obtained from control (C) rats and rats submitted to Pc, hypoxia-ischemia (L) and a combination of both treatments (PcL). We found that either hypoxia-ischemia or Pc perturbed the granule cells in the posterior lobes, affecting their migration and final placement in the internal granular layer. These effects were partially attenuated when the Pc was delivered prior to the hypoxia-ischemia. Interestingly, whole nuclear NeuroD1 levels in Pc animals were comparable to those in the C rats. However, a subset of Purkinje cells that were severely affected by the hypoxic-ischemic insult—showing signs of neuronal distress at the levels of the nucleus, cytoplasm and dendritic arborization—were not protected by Pc. A monoclonal antibody specific for GAD67 revealed a three-band pattern in cytoplasmic extracts from whole P15 cerebella. A ∼110 kDa band, interpreted as a potential homodimer of a truncated form of GAD67, was reduced in Pc and L groups while its levels were close to the control animals in PcL rats. Additionally we demonstrated differential glial responses depending on the treatment, including astrogliosis in hypoxiated cerebella and a selective effect of hypoxia-ischemia on the vimentin-immunolabeled intermediate filaments of the Bergmann glia. Thus, while both glutamatergic and GABAergic cerebellar neurons are compromised by the hypoxic-ischemic insult, the former are

  11. The mechanistic target of rapamycin (mTOR) pathway and S6 Kinase mediate diazoxide preconditioning in primary rat cortical neurons.

    PubMed

    Dutta, Somhrita; Rutkai, Ibolya; Katakam, Prasad V G; Busija, David W

    2015-09-01

    We examined the role of the mechanistic target of rapamycin (mTOR) pathway in delayed diazoxide (DZ)-induced preconditioning of cultured rat primary cortical neurons. Neurons were treated for 3 days with 500 μM DZ or feeding medium and then exposed to 3 h of continuous normoxia in Dulbecco's modified eagle medium with glucose or with 3 h of oxygen-glucose deprivation (OGD) followed by normoxia and feeding medium. The OGD decreased viability by 50%, depolarized mitochondria, and reduced mitochondrial respiration, whereas DZ treatment improved viability and mitochondrial respiration, and suppressed reactive oxygen species production, but did not restore mitochondrial membrane potential after OGD. Neuroprotection by DZ was associated with increased phosphorylation of protein kinase B (Akt), mTOR, and the major mTOR downstream substrate, S6 Kinase (S6K). The mTOR inhibitors rapamycin and Torin-1, as well as S6K-targeted siRNA abolished the protective effects of DZ. The effects of DZ on mitochondrial membrane potential and reactive oxygen species production were not affected by rapamycin. Preconditioning with DZ also changed mitochondrial and non-mitochondrial oxygen consumption rates. We conclude that in addition to reducing reactive oxygen species (ROS) production and mitochondrial membrane depolarization, DZ protects against OGD by activation of the Akt-mTOR-S6K pathway and by changes in mitochondrial respiration. Ischemic strokes have limited therapeutic options. Diazoxide (DZ) preconditioning can reduce neuronal damage. Using oxygen-glucose deprivation (OGD), we studied Akt/mTOR/S6K signaling and mitochondrial respiration in neuronal preconditioning. We found DZ protects neurons against OGD via the Akt/mTOR/S6K pathway and alters the mitochondrial and non-mitochondrial oxygen consumption rate. This suggests that the Akt/mTOR/S6k pathway and mitochondria are novel stroke targets. PMID:26016889

  12. Hypobaric Preconditioning Modifies Group I mGluRs Signaling in Brain Cortex.

    PubMed

    Semenov, Dmitry G; Belyakov, Alexandr V; Glushchenko, Tatjana S; Samoilov, Mikhail O; Salinska, Elzbieta; Lazarewicz, Jerzy W

    2015-11-01

    The study assessed involvement of Ca(2+) signaling mediated by the metabotropic glutamate receptors mGluR1/5 in brain tolerance induced by hypoxic preconditioning. Acute slices of rat piriform cortex were tested 1 day after exposure of adult rats to mild hypobaric hypoxia for 2 h at a pressure of 480 hPa once a day for three consecutive days. We detected 44.1 ± 11.6 % suppression of in vitro anoxia-induced increases of intracellular Ca(2+) levels and a fivefold increase in Ca(2+) transients evoked by selective mGluR1/5 agonist, DHPG. Western blot analysis of cortical homogenates demonstrated a 11 ± 4 % decrease in mGluR1 immunoreactivity (IR), and in the nuclei-enriched fraction a 12 ± 3 % increase in IR of phospholipase Cβ1 (PLCβ1), which is a major mediator of mGluR1/5 signaling. Immunocytochemical analysis of the cortex revealed increase in the mGluR1/5 and PLCβ1 IR in perikarya, and a decrease in IR of the neuronal inositol trisphosphate receptors (IP3Rs). We suggest that enhanced expression of mGluR5 and PLCβ1 and potentiation of Ca(2+) signaling may represent pro-survival upregulation of Ca(2+)-dependent genomic processes, while decrease in mGluR1 and IP3R IR may be attributed to a feedback mechanism preventing excessive intracellular Ca(2+) release. PMID:26318863

  13. Arterial ischemic stroke in HIV

    PubMed Central

    Bryer, Alan; Lucas, Sebastian; Stanley, Alan; Allain, Theresa J.; Joekes, Elizabeth; Emsley, Hedley; Turnbull, Ian; Downey, Colin; Toh, Cheng-Hock; Brown, Kevin; Brown, David; Ison, Catherine; Smith, Colin; Corbett, Elizabeth L.; Nath, Avindra; Heyderman, Robert S.; Connor, Myles D.; Solomon, Tom

    2016-01-01

    HIV infection, and potentially its treatment, increases the risk of an arterial ischemic stroke. Multiple etiologies and lack of clear case definitions inhibit progress in this field. Several etiologies, many treatable, are relevant to HIV-related stroke. To fully understand the mechanisms and the terminology used, a robust classification algorithm to help ascribe the various etiologies is needed. This consensus paper considers the strengths and limitations of current case definitions in the context of HIV infection. The case definitions for the major etiologies in HIV-related strokes were refined (e.g., varicella zoster vasculopathy and antiphospholipid syndrome) and in some instances new case definitions were described (e.g., HIV-associated vasculopathy). These case definitions provided a framework for an algorithm to help assign a final diagnosis, and help classify the subtypes of HIV etiology in ischemic stroke. PMID:27386505

  14. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 19 2014-07-01 2014-07-01 false Vehicle preconditioning. 86.132-00 Section 86.132-00 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1977 and Later Model Year New...

  15. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 19 2013-07-01 2013-07-01 false Vehicle preconditioning. 86.132-00 Section 86.132-00 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1977 and Later Model Year New...

  16. 40 CFR 1066.405 - Vehicle preparation and preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Vehicle preparation and preconditioning. 1066.405 Section 1066.405 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS VEHICLE-TESTING PROCEDURES Preparing Vehicles and Running an Exhaust...

  17. 40 CFR 86.132-00 - Vehicle preconditioning.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 19 2012-07-01 2012-07-01 false Vehicle preconditioning. 86.132-00 Section 86.132-00 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1977 and Later Model Year New...

  18. 33 CFR 183.220 - Preconditioning for tests.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Preconditioning for tests. 183.220 Section 183.220 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of More Than 2 Horsepower General...

  19. 33 CFR 183.320 - Preconditioning for tests.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Preconditioning for tests. 183.320 Section 183.320 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) BOATING SAFETY BOATS AND ASSOCIATED EQUIPMENT Flotation Requirements for Outboard Boats Rated for Engines of 2 Horsepower or Less General §...

  20. 40 CFR 1065.516 - Sample system decontamination and preconditioning.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 33 2014-07-01 2014-07-01 false Sample system decontamination and preconditioning. 1065.516 Section 1065.516 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Performing an Emission Test Over Specified Duty Cycles § 1065.516 Sample...

  1. Combustion of coal/water mixtures with thermal preconditioning

    SciTech Connect

    Novack, M.; Roffe, G.; Miller, G.

    1987-01-01

    Thermal preconditioning is a process in which coal/water mixtures are vaporized to produce coal/steam suspensions, and then superheated to allow the coal to devolitalize producing suspensions of char particles in hydrocarbon gases and steam. This final product of the process can be injected without atomization, and burned directly in a gas turbine combustor. This paper reports on the results of an experimental program in which thermally preconditioned coal/water mixture was successfully burned with a stable flame in a gas turbine combustor test rig. Tests were performed at a mixture flowrate of 300 1b/hr and combustor pressure of 8 atmospheres. The coal/water mixture was thermally preconditioned and injected into the combustor over a temperature range from 350/sup 0/F to 600/sup 0/F, and combustion air was supplied at between 600/sup 0/F to 725/sup 0/F. Test durations varied between 10 to 20 minutes. The original mean coal particle size for these tests, prior to preconditioning was 25 microns. Results of additional tests showed that one-third of the sulfur contained in the solids of a coal/water mixture with 3 percent sulfur were evolved in gaseous form (under mild thermolized conditions) mainly as H/sub 2/S with the remainder as light mercaptans.

  2. Improvement in computational fluid dynamics through boundary verification and preconditioning

    NASA Astrophysics Data System (ADS)

    Folkner, David E.

    This thesis provides improvements to computational fluid dynamics accuracy and efficiency through two main methods: a new boundary condition verification procedure and preconditioning techniques. First, a new verification approach that addresses boundary conditions was developed. In order to apply the verification approach to a large range of arbitrary boundary conditions, it was necessary to develop unifying mathematical formulation. A framework was developed that allows for the application of Dirichlet, Neumann, and extrapolation boundary condition, or in some cases the equations of motion directly. Verification of boundary condition techniques was performed using exact solutions from canonical fluid dynamic test cases. Second, to reduce computation time and improve accuracy, preconditioning algorithms were applied via artificial dissipation schemes. A new convective upwind and split pressure (CUSP) scheme was devised and was shown to be more effective than traditional preconditioning schemes in certain scenarios. The new scheme was compared with traditional schemes for unsteady flows for which both convective and acoustic effects dominated. Both boundary conditions and preconditioning algorithms were implemented in the context of a "strand grid" solver. While not the focus of this thesis, strand grids provide automatic viscous quality meshing and are suitable for moving mesh overset problems.

  3. 40 CFR 86.132-96 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Vehicle preconditioning. 86.132-96 Section 86.132-96 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES Emission Regulations for 1977 and Later Model Year New...

  4. 40 CFR 86.1774-99 - Vehicle preconditioning.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 19 2011-07-01 2011-07-01 false Vehicle preconditioning. 86.1774-99... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES (CONTINUED) General Provisions for the Voluntary National Low Emission Vehicle Program for Light-Duty Vehicles and...

  5. 40 CFR 86.1774-99 - Vehicle preconditioning.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 19 2010-07-01 2010-07-01 false Vehicle preconditioning. 86.1774-99... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES (CONTINUED) General Provisions for the Voluntary National Low Emission Vehicle Program for Light-Duty Vehicles and...

  6. 40 CFR 86.1774-99 - Vehicle preconditioning.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 20 2013-07-01 2013-07-01 false Vehicle preconditioning. 86.1774-99... (CONTINUED) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES (CONTINUED) General Provisions for the Voluntary National Low Emission Vehicle Program for Light-Duty Vehicles and...

  7. [Ischemic cerebrovascular accidents in childhood].

    PubMed

    Pascual Pascual, S I; Pascual Castroviejo, I; Vélez, A

    1988-04-01

    Authors review 53 children, aged 0 to 14 years, affected with cerebrovascular ischemic strokes. Largest aetiological groups were: a) congenital heart disease, 16 patients; b) arteritis of unknown cause, 11; c) idiopathic arterial occlusion without arteritis images on angiography, 7; d) moyamoya disease, 6; and d) local or systemic infections, 5. The mode of onset was as completed stroke in 72% and stroke in evolution in 24%. After acute stage 17.6% of patients presented other definitive strokes, 11.7% suffered only transient ischemic strokes (TIA), and 4% reversible ischemic neurologic deficits (RIND). Mean follow-up was 4.36 years, 9.8% of patients died, 11.8% recovered completely and 52.9% improved after initial stroke. Poor global evolution was associated with heart disease (p less than 0.05) and with onset of strokes before age 2 (p less than 0.05). Most important sequelae, besides motor impairment, were epilepsy (49%) and mental retardation (50% got less than IQ 80). Late epilepsy was associated with seizures at onset (p less than 0.05). Clinical factors of adverse mental development were: a) seizures at onset, b) late epilepsy and c) stroke before age 2. 66% of cases had two or more arterial lesions in the same or in different arterial trees. Therefore, embolic and arteritic factors probably play an important role in infancy and childhood stroke. PMID:3400936

  8. Intravenous thrombolytics for ischemic stroke.

    PubMed

    Barreto, Andrew D

    2011-07-01

    For many decades, intravenous (IV) thrombolytics have been delivered to treat acute thrombosis. Although these medications were originally effective for coronary thrombosis, their mechanisms have proven beneficial for many other disease processes, including ischemic stroke. Treatment paradigms for acute ischemic stroke have largely followed those of cardiology. Specifically, the aim has been to recanalize the occluded artery and to restore perfusion to the brain that remains salvageable. To that end, rapid clot lysis was sought using thrombolytic medicines already proven effective in the coronary arteries. IV-thrombolysis for ischemic stroke began its widespread adoption in the late 1990s after the publication of the National Institute of Neurological Disorders and Stroke study. Since that time, other promising IV-thrombolytics have been developed and tested in human trials, but as of yet, none have been proven better than a placebo. Adjunctive treatments are also being evaluated. The challenge remains balancing reperfusion and salvaging brain tissue with the potential risks of brain hemorrhage. PMID:21638138

  9. The Role of Preconditioning on Thermosphere Mass Density (Invited)

    NASA Astrophysics Data System (ADS)

    Thayer, J. P.; Liu, X.

    2013-12-01

    The ability to determine the amount of change expected in thermosphere mass density at a specific altitude in response to solar and geomagnetic disturbances is of major importance in predicting how low-earth orbiting satellites will be affected by atmospheric drag. It is also of importance in understanding how energy deposited in the thermosphere results in a certain change in thermosphere mass density. The response at a particular altitude will depend on the type of energy input, the altitude distribution of energy input, the internal processing of the energy input, and the state properties of the thermosphere gas (i.e. density, temperature, composition, winds) prior to the energy input - that is, the preconditioned state. As an example of preconditioning, the mass density at an altitude a few scale heights above the altitude where a fixed amount of energy is deposited will have a greater relative change when the initial state of the thermosphere exospheric temperature is cold. Thus, the preconditioned state of the thermosphere must be described properly in order to adequately predict the mass density response to a given energy input. Furthermore, the preconditioned composition structure will be important and can also cause the level of response in mass density to vary with altitude. The solar EUV flux is the major contributor in establishing the preconditioned state of thermosphere and the recent solar cycle with its extreme solar minimum EUV flux has resulted in an unprecedented cold and contracted thermosphere. High-resolution mass density observations inferred from accelerometer measurements on the CHAMP and GRACE satellites are used to demonstrate the role of preconditioning in mass density response to geomagnetic disturbances. Temperature and composition conditions are evaluated to explain observed changes in mass density. In particular, the dynamic action of the oxygen to helium transition region in both latitude and altitude is used to explain complex

  10. Toward future IP optical backbone networks

    NASA Astrophysics Data System (ADS)

    Urushidani, Shigeo

    2005-11-01

    The rapid and aggressive penetration of broadband access services such as fiber to the home (FTTH) has been accelerating the increase in IP traffic volume and new networking technologies are required in order to accommodate future traffic in a cost-effective manner. This paper overviews the advanced IP optical network architecture and technologies for very-large-scale IP backbone networks. These technologies are the key to accommodate the huge volumes of IP traffic expected and control network resources in an effective and dynamic manner. We describe advanced IP optical networking technologies which accommodate multiple service networks using multi-instance technologies, and enable multi-layer traffic engineering using virtual network topology technologies. The migration scenario is described from the existing networks to GMPLS networks; reference is made to the advanced Path Computation Element (PCE) which enables multi-layer traffic engineering and MPLS/GMPLS migration. New network concepts such as Layer 1 Virtual Private Network (L1VPN) and GMPLS interoperability issues, which are being discussed in IETF, are also described.

  11. Regulation of IP 3 Receptors by IP 3 and Ca 2+

    NASA Astrophysics Data System (ADS)

    Taylor, Colin W.; Swatton, Jane E.

    Inositol 1,4,5-trisphosphate ( IP 3) receptors are intracellular Ca 2+ channels that mediate release of Ca 2+ from intracellular stores. The channels are oligomeric assemblies of four subunits, each of which has an N-terminal IP 3-binding domain and each of which contributes to formation of the Ca 2+ channel. In mammals, three different genes encode IP 3 receptors subunits and the type 1 receptor (and perhaps the type 2 receptor) is also expressed as splice variants. Further diversity arises from assembly of the receptor in hetero- and homo-tetrameric channels. The subtypes differ in their expression and regulation, but they share the key property of being regulated by both IP3 and cytosolic Ca 2+. All three mammalian IP 3 subtypes, and probably also the IP 3 receptors expressed in invertebrates, are biphasically regulated by cytosolic Ca2+, although the underlying mechanisms appear to differ between subtypes. The interactions between IP 3 and Ca 2+ in controlling IP 3 receptor gating, and the physiological significance of such regulation will be reviewed.

  12. Thermal preconditioning of coal/water mixtures. Final report

    SciTech Connect

    Roffe, G.; Miller, G.

    1984-10-01

    Thermal preconditioning of coal/water mixtures is a process proposed for use with stationary gas turbine engines in which the CWM is heated before delivery to the combustor in order to accomplish the water vaporization and coal pyrolysis/devolatilization steps prior to injection. The process offers a number of potential advantages such as the ability to start the engine without the use of an auxiliary fuel system, the elimination of atomizing nozzles, increased flame stability for proper turndown, compatibility with NO/sub x/-control techniques such as rich-burn-quick quench combustors, and potentially faster char burnout. The objective of the program was to obtain information which will allow the feasibility of thermal preconditioning to be evaluated. The economics of the process and its impact on a combined cycle system have been addressed. The slurry heating and boiling processes have been studied and the relationships between fuel properties, temperature and residence time in the processing apparatus and the evolution of combustible gases have been measured. A special apparatus was designed and constructed for the experimental portion of the program. Results indicate that at temperatures above 900/sup 0/F significant devolatilization can be accomplished in residence times on the order of one second. A preliminary economic and performance analysis has been completed for the thermal preconditioning process. Four gas turbine power plant concepts incorporating thermal preconditioning of CWS have been investigated. These concepts differ from one another in the source of heat used for the preconditioning process. Heat paths have been defined and the relationships between the efficiencies and operating conditions of the various components on heat rate and plant output have been determined. The analysis indicates that increases in heat rate of less than 5% can be expected. 4 refs., 10 figs., 2 tabs.

  13. Combustion of coal/water mixtures with thermal preconditioning

    SciTech Connect

    Novack, M.; Roffe, G.; Miller, G.

    1987-07-01

    Thermal preconditioning is a process in which coal/water mixtures are vaporized to produce coal/steam suspensions, and then superheated to allow the coal to devolatilize producing suspensions of char particles in hydrocarbon gases and steam. This final product of the process can be injected without atomization, and burned directly in a gas turbine combustor. This paper reports on the results of an experimental program in which thermally preconditioned coal/water mixture was successfully burned with a stable flame in a gas turbine combustor test rig. Tests were performed at a mixture flowrate of 300 lb/hr and combustor pressure of 8 atm. The coal/water mixture was thermally preconditioned and injected into the combustor over a temperature range from 340/sup 0/F to 600/sup 0/F, and combustion air was supplied at between 600/sup 0/F to 725/sup 0/F. Test durations varied between 10 and 20 min. Major results of the combustion testing were that: A stable flame was maintained over a wide equivalence ratio range, between phi = 2.2 (rich) and 0.2 (lean); and combustion efficiency of over 99 percent was achieved when the mixture was preconditioned to 600/sup 0/F and the combustion air preheated to 725/sup 0/F. Measurements of ash particulates, captured in the exhaust sampling probe located 20 in. from the injector face, show typical sizes collected to be about 1 ..mu..m, with agglomerates of these particulates to be not more than 8 ..mu..m. The original mean coal particle size for these tests, prior to preconditioning, was 25 ..mu..m. Results of additional tests showed that one third of the sulfur contained in the solids of a coal/water mixture with 3 percent sulfur was evolved in gaseous form (under mild thermolized conditions) mainly as H/sub 2/S with the remainder as light mercaptans.

  14. A survey of IP over ATM architectures

    SciTech Connect

    Chen, H.; Tsang, R.; Brandt, J.; Hutchins, J.

    1997-07-01

    Over the past decade, the Internet has burgeoned into a worldwide information highway consisting of approximately 5 million hosts on over 45,000 interconnected networks. This unprecedented growth, together with the introduction of multimedia workstations, has spurred the development of innovative applications that require high speed, low latency, and real-time transport. Today`s Internet can neither scale in its bandwidth nor guarantee the Quality of Services (QoS) necessary to meet these performance requirements. Many network researchers propose to use the Asynchronous Transfer Mode (ATM) technology as the underlying infrastructure for the next generation of workgroup, campus, and enterprise IP networks. Since ATM is significantly different from today`s legacy network technologies, efficient implementation of IP over ATM is especially challenging. This tutorial paper covers several existing proposals that integrate IP over ATM.

  15. 76 FR 81955 - Assessment Questionnaire-IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-29

    ... submissions of responses. Analysis Agency: Department of Homeland Security, National Protection and Programs... SECURITY Assessment Questionnaire--IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT) AGENCY...: Assessment Questionnaire--IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT). OMB Number:...

  16. 77 FR 33227 - Assessment Questionnaire-IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-05

    ...). Analysis Agency: Department of Homeland Security, National Protection and Programs Directorate, Office of... SECURITY Assessment Questionnaire--IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT) AGENCY...--Assessment Questionnaire--IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT). DHS...

  17. Space-Based Voice over IP Networks

    NASA Technical Reports Server (NTRS)

    Nguyen, Sam P.; Okino, Clayton; Walsh, William; Clare, Loren

    2007-01-01

    In human space exploration missions (e.g. a return to the Moon and for future missions to Mars), there will be a need to provide voice communications services. In this work we focus on the performance of Voice over IP (VoIP) techniques applied to space networks, where long range latencies, simplex links, and significant bit error rates occur. Link layer and network layer overhead issues are examined. Finally, we provide some discussion on issues related to voice conferencing in the space network environment.

  18. Management of ischemic optic neuropathies

    PubMed Central

    Hayreh, Sohan Singh

    2011-01-01

    Ischemic optic neuropathies (IONs) consist primarily of two types: anterior ischemic optic neuropathy (AION) and posterior ischemic optic neuropathy (PION). AION comprises arteritic AION (A-AION: due to giant cell arteritis) and non-arteritic AION (NA-AION: due to other causes). PION consists of arteritic PION (A-PION: due to giant cell arteritis), non-arteritic PION (NA-PION: due to other causes), and surgical PION (a complication of several systemic surgical procedures). These five types of ION are distinct clinical entities etiologically, pathogenetically, clinically and from the management point of view. In the management of AION, the first crucial step with patients aged 50 and over is to identify immediately whether it is arteritic or not because A-AION is an ophthalmic emergency and requires urgent treatment with high-dose steroid therapy to prevent any further visual loss in one or both eyes. Patients with NA-AION, when treated with systemic corticosteroid therapy within first 2 weeks of onset, had significantly better visual outcome than untreated ones. Systemic risk factors, particularly nocturnal arterial hypotension, play major roles in the development of NA-AION; management of them is essential in its prevention and management. NA-PION patients, when treated with high-dose systemic steroid therapy during the very early stages of the disease, showed significant improvement in visual acuity and visual fields, compared to untreated eyes. A-PION, like A-AION, requires urgent treatment with high-dose steroid therapy to prevent any further visual loss in one or both eyes. There is no satisfactory treatment for surgical PION, except to take prophylactic measures to prevent its development. PMID:21350282

  19. Is VoIP Worth It?

    ERIC Educational Resources Information Center

    Schaffhauser, Dian

    2008-01-01

    School districts have by and large had great results implementing VoIP, which has become the conduit for delivering expanded functionality, achieving greater internal control, and gaining freedom from onerous monthly phone bills. But demonstrating a financial return on what is a substantial investment can be an elusive effort. The goal of…

  20. IP validation in remote microelectronics testing

    NASA Astrophysics Data System (ADS)

    Osseiran, Adam; Eshraghian, Kamran; Lachowicz, Stefan; Zhao, Xiaoli; Jeffery, Roger; Robins, Michael

    2004-03-01

    This paper presents the test and validation of FPGA based IP using the concept of remote testing. It demonstrates how a virtual tester environment based on a powerful, networked Integrated Circuit testing facility, aimed to complement the emerging Australian microelectronics based research and development, can be employed to perform the tasks beyond the standard IC test. IC testing in production consists in verifying the tested products and eliminating defective parts. Defects could have a number of different causes, including process defects, process migration and IP design and implementation errors. One of the challenges in semiconductor testing is that while current fault models are used to represent likely faults (stuck-at, delay, etc.) in a global context, they do not account for all possible defects. Research in this field keeps growing but the high cost of ATE is preventing a large community from accessing test and verification equipment to validate innovative IP designs. For these reasons a world class networked IC teletest facility has been established in Australia under the support of the Commonwealth government. The facility is based on a state-of-the-art semiconductor tester operating as a virtual centre spanning Australia and accessible internationally. Through a novel approach the teletest network provides virtual access to the tester on which the DUT has previously been placed. The tester software is then accessible as if the designer is sitting next to the tester. This paper presents the approach used to test and validate FPGA based IPs using this remote test approach.

  1. Operational Space Weather Products at IPS

    NASA Astrophysics Data System (ADS)

    Neudegg, D.; Steward, G.; Marshall, R.; Terkildsen, M.; Kennewell, J.; Patterson, G.; Panwar, R.

    2008-12-01

    IPS Radio and Space Services operates an extensive network (IPSNET) of monitoring stations and observatories within the Australasian and Antarctic regions to gather information on the space environment. This includes ionosondes, magnetometers, GPS-ISM, oblique HF sounding, riometers, and solar radio and optical telescopes. IPS exchanges this information with similar organisations world-wide. The Regional Warning Centre (RWC) is the Australian Space Forecast Centre (ASFC) and it utilizes this data to provide products and services to support customer operations. A wide range of customers use IPS services including; defence force and emergency services using HF radio communications and surveillance systems, organisations involved in geophysical exploration and pipeline cathodic protection, GPS users in aviation. Subscriptions to the alerts, warnings, forecasts and reports regarding the solar, geophysical and ionospheric conditions are distributed by email and Special Message Service (SMS). IPS also develops and markets widely used PC software prediction tools for HF radio skywave and surface wave (ASAPS/GWPS) and provides consultancy services for system planning.

  2. EQuIP-ped for Success

    ERIC Educational Resources Information Center

    Ewing, Molly

    2015-01-01

    The Educators Evaluating the Quality of Instructional Products (EQuIP) Rubric for science is a new tool for science educators that provides criteria by which to examine the alignment and overall quality of lessons and units with respect to the "Next Generation Science Standards" ("NGSS"). The rubric criteria are divided into…

  3. 75 FR 13235 - IP-Enabled Services

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-19

    ... 47 CFR 63.60(a) and (f), published on August 7, 2009 (74 FR 39551), were approved by the Office of... published a document in the Federal Register, 74 FR 39551, August 7, 2009, that sets forth an effective date... COMMISSION 47 CFR Part 63 IP-Enabled Services AGENCY: Federal Communications Commission ACTION: Final...

  4. How To: Be VoIP-Savvy

    ERIC Educational Resources Information Center

    Branzburg, Jeffrey

    2005-01-01

    Cablevision, Comcast, Verizon, and many other high-speed broadband Internet providers are now also offering telephone services through "Voice over Internet Protocol" (VoIP). This technology sends ordinary telephone calls over the Internet rather than over telephone lines. While impractical without the use of a broadband Internet connection, with…

  5. Call progress time measurement in IP telephony

    NASA Astrophysics Data System (ADS)

    Khasnabish, Bhumip

    1999-11-01

    Usually a voice call is established through multiple stages in IP telephony. In the first stage, a phone number is dialed to reach a near-end or call-originating IP-telephony gateway. The next stages involve user identification through delivering an m-digit user-id to the authentication and/or billing server, and then user authentication by using an n- digit PIN. After that, the caller is allowed (last stage dial tone is provided) to dial a destination phone number provided that authentication is successful. In this paper, we present a very flexible method for measuring call progress time in IP telephony. The proposed technique can be used to measure the system response time at every stage. It is flexible, so that it can be easily modified to include new `tone' or a set of tones, or `voice begin' can be used in every stage to detect the system's response. The proposed method has been implemented using scripts written in Hammer visual basic language for testing with a few commercially available IP telephony gateways.

  6. Repetitive hypoxic preconditioning induces an immunosuppressed B cell phenotype during endogenous protection from stroke

    PubMed Central

    2014-01-01

    Background Repetitive hypoxic preconditioning (RHP) creates an anti-inflammatory phenotype that protects from stroke-induced injury for months after a 2-week treatment. The mechanisms underlying long-term tolerance are unknown, though one exposure to hypoxia significantly increased peripheral B cell representation. For this study, we sought to determine if RHP specifically recruited B cells into the protected ischemic hemisphere, and whether RHP could phenotypically alter B cells prior to stroke onset. Methods Adult, male SW/ND4 mice received RHP (nine exposures over 2 weeks; 8 to 11 % O2; 2 to 4 hours) or identical exposures to 21 % O2 as control. Two weeks following RHP, a 60-minute transient middle cerebral artery occlusion was induced. Standard techniques quantified CXCL13 mRNA and protein expression. Two days after stroke, leukocytes were isolated from brain tissue (70:30 discontinuous Percoll gradient) and profiled on a BD-FACS Aria flow cytometer. In a separate cohort without stroke, sorted splenic CD19+ B cells were isolated 2 weeks after RHP and analyzed on an Illumina MouseWG-6 V2 Bead Chip. Final gene pathways were determined using Ingenuity Pathway Analysis. Student’s t-test or one-way analysis of variance determined significance (P < 0.05). Results CXCL13, a B cell-specific chemokine, was upregulated in post-stroke cortical vessels of both groups. In the ischemic hemisphere, RHP increased B cell representation by attenuating the diapedesis of monocyte, macrophage, neutrophil and T cells, to quantities indistinguishable from the uninjured, contralateral hemisphere. Pre-stroke splenic B cells isolated from RHP-treated mice had >1,900 genes differentially expressed by microarray analysis. Genes related to B-T cell interactions, including antigen presentation, B cell differentiation and antibody production, were profoundly downregulated. Maturation and activation were arrested in a cohort of B cells from pre-stroke RHP-treated mice while

  7. Isoflurane Preconditioning Elicits Competent Endogenous Mechanisms of Protection from Oxidative Stress in Cardiomyocytes Derived from Human Embryonic Stem Cells

    PubMed Central

    Sepac, Ana; Sedlic, Filip; Si-Tayeb, Karim; Lough, John; Duncan, Stephen A.; Bienengraeber, Martin; Park, Frank; Kim, Jinhee; Bosnjak, Zeljko J.

    2010-01-01

    Background Human embryonic stem cell (hESC)-derived cardiomyocytes potentially represent a powerful experimental model complementary to myocardium obtained from patients, relatively inaccessible for research purposes. We tested whether anesthetic-induced preconditioning (APC) with isoflurane elicits competent protective mechanisms in hESC-derived cardiomyocytes against oxidative stress to be used as a model of human cardiomyocytes for studying preconditioning. Methods H1 hESC cell line was differentiated into cardiomyocytes using growth factors activin A and bone morphogenetic protein-4. Living ventricular hESC-derived cardiomyocytes were identified using lentiviral vector expressing a reporter gene (enhanced green fluorescent protein) driven by a cardiac-specific human myosin light chain 2v promoter. Mitochondrial membrane potential, reactive oxygen species production, opening of mitochondrial permeability transition pore, and survival of hESC-derived cardiomyocytes were assessed using confocal microscopy. Oxygen consumption was measured in contracting cell clusters. Results Differentiation yielded a high percentage (∼85%) of cardiomyocytes in beating clusters that were positive for cardiac-specific markers and exhibited action potentials resembling mature cardiomyocytes. Isoflurane depolarized mitochondria, attenuated oxygen consumption, and stimulated generation of reactive oxygen species. APC protected these cells from oxidative stress-induced death and delayed mitochondrial permeability transition pore opening. Conclusions APC elicits competent protective mechanisms against oxidative stress in hESC-derived cardiomyocytes, suggesting the feasibility to use these cells as a model of human cardiomyocytes for studying APC and potentially other treatments/diseases. Our differentiation protocol is very efficient and yields a high percentage of cardiomyocytes. These results also suggest a promising ability of APC to protect and improve engraftment of h

  8. Using VoIP to compete.

    PubMed

    Werbach, Kevin

    2005-09-01

    Internet telephony, or VoIP, is rapidly replacing the conventional kind. This year, for the first time, U.S. companies bought more new Internet-phone connections than standard lines. The major driver behind this change is cost. But VoIP isn't just a new technology for making old-fashioned calls cheaper, says consultant Kevin Werbach. It is fundamentally changing how companies use voice communications. What makes VoIP so powerful is that it turns voice into digital data packets that can be stored, copied, combined with other data, and distributed to virtually any device that connects to the Internet. And it makes it simple to provide all the functionality of a corporate phone-call features, directories, security-to anyone anywhere there's broadband access. That fosters new kinds of businesses such as virtual call centers, where widely dispersed agents work at all hours from their homes. The most successful early adopters, says Werbach, will focus more on achieving business objectives than on saving money. They will also consider how to push VoIP capabilities out to the extended organization, making use of everyone as a resource. Deployment may be incremental, but companies should be thinking about where VoIP could take them. Executives should ask what they could do if, on demand, they could bring all their employees, customers, suppliers, and partners together in a virtual room, with shared access to every modern communications and computing channel. They should take a fresh look at their business processes to find points at which richer and more customizable communications could eliminate bottlenecks and enhance quality. The important dividing line won't be between those who deploy Vol P and those who don't, or even between early adopters and laggards. It will be between those who see Vol P as just a new way to do the same old things and those who use itto rethink their entire businesses. PMID:16171218

  9. Shape reanalysis and sensitivities utilizing preconditioned iterative boundary solvers

    NASA Technical Reports Server (NTRS)

    Guru Prasad, K.; Kane, J. H.

    1992-01-01

    The computational advantages associated with the utilization of preconditined iterative equation solvers are quantified for the reanalysis of perturbed shapes using continuum structural boundary element analysis (BEA). Both single- and multi-zone three-dimensional problems are examined. Significant reductions in computer time are obtained by making use of previously computed solution vectors and preconditioners in subsequent analyses. The effectiveness of this technique is demonstrated for the computation of shape response sensitivities required in shape optimization. Computer times and accuracies achieved using the preconditioned iterative solvers are compared with those obtained via direct solvers and implicit differentiation of the boundary integral equations. It is concluded that this approach employing preconditioned iterative equation solvers in reanalysis and sensitivity analysis can be competitive with if not superior to those involving direct solvers.

  10. Combined incomplete LU and strongly implicit procedure preconditioning

    SciTech Connect

    Meese, E.A.

    1996-12-31

    For the solution of large sparse linear systems of equations, the Krylov-subspace methods have gained great merit. Their efficiency are, however, largely dependent upon preconditioning of the equation-system. A family of matrix factorisations often used for preconditioning, is obtained from a truncated Gaussian elimination, ILU(p). Less common, supposedly due to it`s restriction to certain sparsity patterns, is factorisations generated by the strongly implicit procedure (SIP). The ideas from ILU(p) and SIP are used in this paper to construct a generalized strongly implicit procedure, applicable to matrices with any sparsity pattern. The new algorithm has been run on some test equations, and efficiency improvements over ILU(p) was found.

  11. Finding Chemical Reaction Paths with a Multilevel Preconditioning Protocol

    PubMed Central

    2015-01-01

    Finding transition paths for chemical reactions can be computationally costly owing to the level of quantum-chemical theory needed for accuracy. Here, we show that a multilevel preconditioning scheme that was recently introduced (Tempkin et al. J. Chem. Phys.2014, 140, 184114) can be used to accelerate quantum-chemical string calculations. We demonstrate the method by finding minimum-energy paths for two well-characterized reactions: tautomerization of malonaldehyde and Claissen rearrangement of chorismate to prephanate. For these reactions, we show that preconditioning density functional theory (DFT) with a semiempirical method reduces the computational cost for reaching a converged path that is an optimum under DFT by several fold. The approach also shows promise for free energy calculations when thermal noise can be controlled. PMID:25516726

  12. Finding Chemical Reaction Paths with a Multilevel Preconditioning Protocol

    DOE PAGESBeta

    Kale, Seyit; Sode, Olaseni; Weare, Jonathan; Dinner, Aaron R.

    2014-11-07

    Finding transition paths for chemical reactions can be computationally costly owing to the level of quantum-chemical theory needed for accuracy. Here, we show that a multilevel preconditioning scheme that was recently introduced (Tempkin et al. J. Chem. Phys. 2014, 140, 184114) can be used to accelerate quantum-chemical string calculations. We demonstrate the method by finding minimum-energy paths for two well-characterized reactions: tautomerization of malonaldehyde and Claissen rearrangement of chorismate to prephanate. For these reactions, we show that preconditioning density functional theory (DFT) with a semiempirical method reduces the computational cost for reaching a converged path that is an optimum undermore » DFT by several fold. In conclusion, the approach also shows promise for free energy calculations when thermal noise can be controlled.« less

  13. Reconstructing Clusters for Preconditioned Short-term Load Forecasting

    NASA Astrophysics Data System (ADS)

    Itagaki, Tadahiro; Mori, Hiroyuki

    This paper presents a new preconditioned method for short-term load forecasting that focuses on more accurate predicted value. In recent years, the deregulated and competitive power market increases the degree of uncertainty. As a result, more sophisticated short-term load forecasting techniques are required to deal with more complicated load behavior. To alleviate the complexity of load behavior, this paper presents a new preconditioned model. In this paper, clustering results are reconstructed to equalize the number of learning data after clustering with the Kohonen-based neural network. That enhances a short-term load forecasting model at each reconstructed cluster. The proposed method is successfully applied to real data of one-step ahead daily maximum load forecasting.

  14. Finding Chemical Reaction Paths with a Multilevel Preconditioning Protocol

    SciTech Connect

    Kale, Seyit; Sode, Olaseni; Weare, Jonathan; Dinner, Aaron R.

    2014-11-07

    Finding transition paths for chemical reactions can be computationally costly owing to the level of quantum-chemical theory needed for accuracy. Here, we show that a multilevel preconditioning scheme that was recently introduced (Tempkin et al. J. Chem. Phys. 2014, 140, 184114) can be used to accelerate quantum-chemical string calculations. We demonstrate the method by finding minimum-energy paths for two well-characterized reactions: tautomerization of malonaldehyde and Claissen rearrangement of chorismate to prephanate. For these reactions, we show that preconditioning density functional theory (DFT) with a semiempirical method reduces the computational cost for reaching a converged path that is an optimum under DFT by several fold. In conclusion, the approach also shows promise for free energy calculations when thermal noise can be controlled.

  15. Parallel Domain Decomposition Preconditioning for Computational Fluid Dynamics

    NASA Technical Reports Server (NTRS)

    Barth, Timothy J.; Chan, Tony F.; Tang, Wei-Pai; Kutler, Paul (Technical Monitor)

    1998-01-01

    This viewgraph presentation gives an overview of the parallel domain decomposition preconditioning for computational fluid dynamics. Details are given on some difficult fluid flow problems, stabilized spatial discretizations, and Newton's method for solving the discretized flow equations. Schur complement domain decomposition is described through basic formulation, simplifying strategies (including iterative subdomain and Schur complement solves, matrix element dropping, localized Schur complement computation, and supersparse computations), and performance evaluation.

  16. Object-oriented design of preconditioned iterative methods

    SciTech Connect

    Bruaset, A.M.

    1994-12-31

    In this talk the author discusses how object-oriented programming techniques can be used to develop a flexible software package for preconditioned iterative methods. The ideas described have been used to implement the linear algebra part of Diffpack, which is a collection of C++ class libraries that provides high-level tools for the solution of partial differential equations. In particular, this software package is aimed at rapid development of PDE-based numerical simulators, primarily using finite element methods.

  17. Preconditioned Alternating Projection Algorithms for Maximum a Posteriori ECT Reconstruction.

    PubMed

    Krol, Andrzej; Li, Si; Shen, Lixin; Xu, Yuesheng

    2012-11-01

    We propose a preconditioned alternating projection algorithm (PAPA) for solving the maximum a posteriori (MAP) emission computed tomography (ECT) reconstruction problem. Specifically, we formulate the reconstruction problem as a constrained convex optimization problem with the total variation (TV) regularization. We then characterize the solution of the constrained convex optimization problem and show that it satisfies a system of fixed-point equations defined in terms of two proximity operators raised from the convex functions that define the TV-norm and the constrain involved in the problem. The characterization (of the solution) via the proximity operators that define two projection operators naturally leads to an alternating projection algorithm for finding the solution. For efficient numerical computation, we introduce to the alternating projection algorithm a preconditioning matrix (the EM-preconditioner) for the dense system matrix involved in the optimization problem. We prove theoretically convergence of the preconditioned alternating projection algorithm. In numerical experiments, performance of our algorithms, with an appropriately selected preconditioning matrix, is compared with performance of the conventional MAP expectation-maximization (MAP-EM) algorithm with TV regularizer (EM-TV) and that of the recently developed nested EM-TV algorithm for ECT reconstruction. Based on the numerical experiments performed in this work, we observe that the alternating projection algorithm with the EM-preconditioner outperforms significantly the EM-TV in all aspects including the convergence speed, the noise in the reconstructed images and the image quality. It also outperforms the nested EM-TV in the convergence speed while providing comparable image quality. PMID:23271835

  18. Preconditioned Alternating Projection Algorithms for Maximum a Posteriori ECT Reconstruction

    PubMed Central

    Krol, Andrzej; Li, Si; Shen, Lixin; Xu, Yuesheng

    2012-01-01

    We propose a preconditioned alternating projection algorithm (PAPA) for solving the maximum a posteriori (MAP) emission computed tomography (ECT) reconstruction problem. Specifically, we formulate the reconstruction problem as a constrained convex optimization problem with the total variation (TV) regularization. We then characterize the solution of the constrained convex optimization problem and show that it satisfies a system of fixed-point equations defined in terms of two proximity operators raised from the convex functions that define the TV-norm and the constrain involved in the problem. The characterization (of the solution) via the proximity operators that define two projection operators naturally leads to an alternating projection algorithm for finding the solution. For efficient numerical computation, we introduce to the alternating projection algorithm a preconditioning matrix (the EM-preconditioner) for the dense system matrix involved in the optimization problem. We prove theoretically convergence of the preconditioned alternating projection algorithm. In numerical experiments, performance of our algorithms, with an appropriately selected preconditioning matrix, is compared with performance of the conventional MAP expectation-maximization (MAP-EM) algorithm with TV regularizer (EM-TV) and that of the recently developed nested EM-TV algorithm for ECT reconstruction. Based on the numerical experiments performed in this work, we observe that the alternating projection algorithm with the EM-preconditioner outperforms significantly the EM-TV in all aspects including the convergence speed, the noise in the reconstructed images and the image quality. It also outperforms the nested EM-TV in the convergence speed while providing comparable image quality. PMID:23271835

  19. Peroxisomal Biogenesis in Ischemic Brain

    PubMed Central

    Young, Jennifer M.; Nelson, Jonathan W.; Cheng, Jian; Zhang, Wenri; Mader, Sarah; Davis, Catherine M.; Morrison, Richard S.

    2015-01-01

    Abstract Aims: Peroxisomes are highly adaptable and dynamic organelles, adjusting their size, number, and enzyme composition to changing environmental and metabolic demands. We determined whether peroxisomes respond to ischemia, and whether peroxisomal biogenesis is an adaptive response to cerebral ischemia. Results: Focal cerebral ischemia induced peroxisomal biogenesis in peri-infarct neurons, which was associated with a corresponding increase in peroxisomal antioxidant enzyme catalase. Peroxisomal biogenesis was also observed in primary cultured cortical neurons subjected to ischemic insult induced by oxygen-glucose deprivation (OGD). A catalase inhibitor increased OGD-induced neuronal death. Moreover, preventing peroxisomal proliferation by knocking down dynamin-related protein 1 (Drp1) exacerbated neuronal death induced by OGD, whereas enhancing peroxisomal biogenesis pharmacologically using a peroxisome proliferator-activated receptor-alpha agonist protected against neuronal death induced by OGD. Innovation: This is the first documentation of ischemia-induced peroxisomal biogenesis in mammalian brain using a combined in vivo and in vitro approach, electron microscopy, high-resolution laser-scanning confocal microscopy, and super-resolution structured illumination microscopy. Conclusion: Our findings suggest that neurons respond to ischemic injury by increasing peroxisome biogenesis, which serves a protective function, likely mediated by enhanced antioxidant capacity of neurons. Antioxid. Redox Signal. 22, 109–120. PMID:25226217

  20. Symptoms of transient ischemic attack.

    PubMed

    Kim, Jong S

    2014-01-01

    Transient ischemic attack (TIA) is a cerebrovascular disease with temporary (<24 h) neurological symptoms. The symptoms of TIA patients are largely similar to those of ischemic stroke patients and include unilateral limb weakness, speech disturbances, sensory symptoms, visual disturbances, and gait difficulties. As these symptoms are transient, they are frequently evaluated based on patients' subjective reports, which are less precise than those of patients with stroke whose longer-lasting symptoms and signs can be reliably assessed by physicians. Some symptoms, such as monocular blindness, are much more common in TIA than in stroke, and limb shaking occurs almost exclusively in TIA patients. On the other hand, symptoms like hemivisual field defects or limb ataxia are underappreciated in TIA patients. These transient neurological symptoms are not necessarily caused by cerebrovascular diseases, but can be produced by a variety of non-vascular diseases. Careful history taking, examination, and appropriate imaging tests are needed to differentiate these TIA mimics from TIA. Each TIA symptom has a different specificity and sensitivity, and there has been an effort to assess the outcome of the patients through the use of specific clinical features. On top of this, recent developments in imaging techniques have greatly enhanced our ability to predict the outcomes of TIA patients. Perception or recognition of TIA symptoms may differ according to the race, sex, education, and specialty of physicians. Appropriate education of both the general population and physicians with regard to TIA symptoms is important as TIAs need emergent evaluation and treatment. PMID:24157558

  1. Preconditioned conjugate gradient methods for the Navier-Stokes equations

    SciTech Connect

    Ajmani, K.; Ng, Wing Fai ); Liou, Meng Sing )

    1994-01-01

    A preconditioned Krylov subspace method (GMRES) is used to solve the linear systems of equations formed at each time-integration step of the unsteady, two-dimensional, compressible Navier-Stokes equations of fluid flow. The Navier-Stokes equations are cast in an implicit, upwind finite-volume, flux-split formulations. Several preconditioning techniques are investigated to enhance the efficiency and convergence rate of the implicit solver based on the GMRES algorithm. The superiority of the new solver is established by comparisons with a (LGSR). Computational test results for low-speed (incompressible flow over a backward-facing step at Mach 0.1), transonic flow (trailing edge flow in a transonic turbine cascade), and hypersonic flow (shock-on-shock interactions on a cylindrical leading edge at Mach 6.0) are presented. For the Mach 0.1 case, overall speedup factors of up to 17 (in terms of time-steps) and 15 (in terms of CPU times on a CRAY-YMP/8) are found in favor of the preconditioned GMRES solver, when compared with the LGSR solver. The corresponding speedup factors for the transonic flow cases are 17 and 23, respectively. The hypersonic flow case shows slightly lower speedup factors of 9 and 13, respectively. The study of preconditioners conducted in this research reveals that a new LUSGS-type preconditioner is much more efficient than a conventional incomplete LU-type preconditioner. 34 refs., 15 figs.

  2. Preconditioning the bidomain model with almost linear complexity

    NASA Astrophysics Data System (ADS)

    Pierre, Charles

    2012-01-01

    The bidomain model is widely used in electro-cardiology to simulate spreading of excitation in the myocardium and electrocardiograms. It consists of a system of two parabolic reaction diffusion equations coupled with an ODE system. Its discretisation displays an ill-conditioned system matrix to be inverted at each time step: simulations based on the bidomain model therefore are associated with high computational costs. In this paper we propose a preconditioning for the bidomain model either for an isolated heart or in an extended framework including a coupling with the surrounding tissues (the torso). The preconditioning is based on a formulation of the discrete problem that is shown to be symmetric positive semi-definite. A block LU decomposition of the system together with a heuristic approximation (referred to as the monodomain approximation) are the key ingredients for the preconditioning definition. Numerical results are provided for two test cases: a 2D test case on a realistic slice of the thorax based on a segmented heart medical image geometry, a 3D test case involving a small cubic slab of tissue with orthotropic anisotropy. The analysis of the resulting computational cost (both in terms of CPU time and of iteration number) shows an almost linear complexity with the problem size, i.e. of type nlog α( n) (for some constant α) which is optimal complexity for such problems.

  3. Preconditioned conjugate gradient methods for the Navier-Stokes equations

    NASA Technical Reports Server (NTRS)

    Ajmani, Kumud; Ng, Wing-Fai; Liou, Meng-Sing

    1994-01-01

    A preconditioned Krylov subspace method (GMRES) is used to solve the linear systems of equations formed at each time-integration step of the unsteady, two-dimensional, compressible Navier-Stokes equations of fluid flow. The Navier-Stokes equations are cast in an implicit, upwind finite-volume, flux-split formulation. Several preconditioning techniques are investigated to enhance the efficiency and convergence rate of the implicit solver based on the GMRES algorithm. The superiority of the new solver is established by comparisons with a conventional implicit solver, namely line Gauss-Seidel relaxation (LGSR). Computational test results for low-speed (incompressible flow over a backward-facing step at Mach 0.1), transonic flow (trailing edge flow in a transonic turbine cascade), and hypersonic flow (shock-on-shock interactions on a cylindrical leading edge at Mach 6.0) are presented. For the Mach 0.1 case, overall speedup factors of up to 17 (in terms of time-steps) and 15 (in terms of CPU time on a CRAY-YMP/8) are found in favor of the preconditioned GMRES solver, when compared with the LGSR solver. The corresponding speedup factors for the transonic flow case are 17 and 23, respectively. The hypersonic flow case shows slightly lower speedup factors of 9 and 13, respectively. The study of preconditioners conducted in this research reveals that a new LUSGS-type preconditioner is much more efficient than a conventional incomplete LU-type preconditioner.

  4. Preconditioning for edge-preserving image super resolution.

    PubMed

    Pelletier, Stéphane; Cooperstock, Jeremy R

    2012-01-01

    We propose a simple preconditioning method for accelerating the solution of edge-preserving image super-resolution (SR) problems in which a linear shift-invariant point spread function is employed. Our technique involves reordering the high-resolution (HR) pixels in a similar manner to what is done in preconditioning methods for quadratic SR formulations. However, due to the edge preserving requirements, the Hessian matrix of the cost function varies during the minimization process. We develop an efficient update scheme for the preconditioner in order to cope with this situation. Unlike some other acceleration strategies that round the displacement values between the low-resolution (LR) images on the HR grid, the proposed method does not sacrifice the optimality of the observation model. In addition, we describe a technique for preconditioning SR problems involving rational magnification factors. The use of such factors is motivated in part by the fact that, under certain circumstances, optimal SR zooms are nonintegers. We show that, by reordering the pixels of the LR images, the structure of the problem to solve is modified in such a way that preconditioners based on circulant operators can be used. PMID:21693419

  5. Integrated IP telephony gateway and its stochastic petri net model

    NASA Astrophysics Data System (ADS)

    Huang, Yongfeng; Li, Xing

    2001-10-01

    With rapid development of computer network and a wide application of Internet, IP telephony has been realized. Currently, one of the most important research areas of IP telephony system is to develop the IP telephony gateway. In this paper, a new idea of design on an Integrated IP Telephony Gateway is proposed, and the hardware of Integrated IP Telephony is discussed in detail. The software architecture of the Integrated IP telephone gateway is studied, and this paper focus on the voice compression module and SPOX schedule module. In addition, Stochastic Petri Net Model of an Integrated IP Telephony Gateway is set up, and its performance analyzed through the Stochastic Petri Net model. Array of Petri Net Model is computed, and educes the mathematical relationship of CPU efficiency and structure parameters of the IP telephony gateway.

  6. Hyperbaric oxygen preconditioning attenuates hyperglycemia-enhanced hemorrhagic transformation by inhibiting matrix metalloproteinases in focal cerebral ischemia in rats

    PubMed Central

    Soejima, Yoshiteru; Hu, Qin; Krafft, Paul R.; Fujii, Mutsumi; Tang, Jiping; Zhang, John H.

    2013-01-01

    Hyperglycemia dramatically aggravates brain infarct and hemorrhagic transformation (HT) after ischemic stroke. Oxidative stress and matrix metalloproteinases (MMPs) play an important role in the pathophysiology of HT. Hyperbaric oxygen preconditioning (HBO-PC) has been proved to decrease oxidative stress and be neuroprotective in experimental stroke models. The present study determined whether HBO-PC would ameliorate HT by a pre-ischemic increase of reactive oxygen species (ROS) generation, and a suppression of MMP-2 and MMP-9 in hyperglycemic middle cerebral artery occlusion (MCAO) rats. Rats were pretreated with HBO (100% O2, 2.5 atmospheres absolute) 1 h daily for 5 days before MCAO. Acute hyperglycemia was induced by an injection of 50% dextrose. Neurological deficits, infarction volume and hemorrhagic volume were assessed 24 h and 7 days after ischemia. ROS scavenger n-acetyl cysteine (NAC), hypoxia-inducible factor-1α (HIF-1α) inhibitor 2-methoxyestradiol (2ME2) and activator cobalt chloride (CoCl2), and MMPs inhibitor SB-3CT were administrated for mechanism study. The activity of MMP-2 and MMP-9, and the expression HIF-1α were measured. HBO-PC improved neurological deficits, and reduced hemorrhagic volume; the expression of HIF-1α was significantly decreased, and the activity of MMP-2 and MMP-9 was reduced by HBO-PC compared with vehicle group. Our results suggested that HBO-PC attenuated HT via decreasing HIF-1α and its downstream MMP-2 and MMP-9 in hyperglycemic MCAO rats. PMID:23537951

  7. Stem cell therapy in ischemic stroke

    PubMed Central

    Misra, Vivek; Ritchie, Michael M.; Stone, Laura L.; Low, Walter C.

    2012-01-01

    Objective: Cell-based therapies are being investigated as an adjunct to IV thrombolysis or mechanical thrombectomy in ischemic stroke. This review summarizes the potential applications as well as challenges of intravascular cell delivery in ischemic stroke. Method: We conducted a search of Medline as well as the clinicaltrials.gov Web site for all ongoing human clinical studies using stem cells in ischemic stroke patients. Result: The pros and cons of the various donor cell types and routes of cell delivery, including intravascular delivery, in ischemic stroke are discussed. In addition, the potential challenges in translation from bench to bedside, the optimal techniques for intravascular cell delivery, and an updated comprehensive list of ongoing clinical trials in ischemic stroke are highlighted. Conclusions: Stem cells have shown a promising role in ischemic stroke, in preclinical studies as well as initial pilot studies. Further studies are needed to assess intravascular cell therapy as a potential adjunct to thrombolysis or mechanical thrombectomy in ischemic stroke. PMID:23008400

  8. IP- -: A Reduced Internet Protocol for Optical Packet Networking

    NASA Astrophysics Data System (ADS)

    Ohta, Masataka; Fujikawa, Kenji

    IP- - is proposed as an Internet Protocol suitable for optical packet networking. As optical routers require much faster control than electric ones and lack of optical buffers other than those by fiber delay lines requires fixed time control, Internet Protocols must be at least as simple as IPv4 and much simpler than IPv6. IP- - also addresses issues of IP address space exhaustion and IP routing table explosion.

  9. Characteristics of Misclassified CT Perfusion Ischemic Core in Patients with Acute Ischemic Stroke

    PubMed Central

    Geuskens, Ralph R. E. G.; Borst, Jordi; Lucas, Marit; Boers, A. M. Merel; Berkhemer, Olvert A.; Roos, Yvo B. W. E. M.; van Walderveen, Marianne A. A.; Jenniskens, Sjoerd F. M.; van Zwam, Wim H.; Dippel, Diederik W. J.; Majoie, Charles B. L. M.; Marquering, Henk A.

    2015-01-01

    Background CT perfusion (CTP) is used to estimate the extent of ischemic core and penumbra in patients with acute ischemic stroke. CTP reliability, however, is limited. This study aims to identify regions misclassified as ischemic core on CTP, using infarct on follow-up noncontrast CT. We aim to assess differences in volumetric and perfusion characteristics in these regions compared to areas that ended up as infarct on follow-up. Materials and Methods This study included 35 patients with >100 mm brain coverage CTP. CTP processing was performed using Philips software (IntelliSpace 7.0). Final infarct was automatically segmented on follow-up noncontrast CT and used as reference. CTP and follow-up noncontrast CT image data were registered. This allowed classification of ischemic lesion agreement (core on CTP: rMTT≥145%, aCBV<2.0 ml/100g and infarct on follow-up noncontrast CT) and misclassified ischemic core (core on CTP, not identified on follow-up noncontrast CT) regions. False discovery ratio (FDR), defined as misclassified ischemic core volume divided by total CTP ischemic core volume, was calculated. Absolute and relative CTP parameters (CBV, CBF, and MTT) were calculated for both misclassified CTP ischemic core and ischemic lesion agreement regions and compared using paired rank-sum tests. Results Median total CTP ischemic core volume was 49.7ml (IQR:29.9ml-132ml); median misclassified ischemic core volume was 30.4ml (IQR:20.9ml-77.0ml). Median FDR between patients was 62% (IQR:49%-80%). Median relative mean transit time was 243% (IQR:198%-289%) and 342% (IQR:249%-432%) for misclassified and ischemic lesion agreement regions, respectively. Median absolute cerebral blood volume was 1.59 (IQR:1.43–1.79) ml/100g (P<0.01) and 1.38 (IQR:1.15–1.49) ml/100g (P<0.01) for misclassified ischemic core and ischemic lesion agreement, respectively. All CTP parameter values differed significantly. Conclusion For all patients a considerable region of the CTP ischemic core

  10. A native IP satellite communications system

    NASA Astrophysics Data System (ADS)

    Koudelka, O.; Schmidt, M.; Ebert, J.; Schlemmer, H.; Kastner-Puschl, S.; Riedler, W.

    2004-08-01

    ≪ In the framework of ESA's ARTES-5 program the Institute of Applied Systems Technology (Joanneum Research) in cooperation with the Department of Communications and Wave Propagation has developed a novel meshed satellite communications system which is optimised for Internet traffic and applications (L*IP—Local Network Interconnection via Satellite Systems Using the IP Protocol Suite). Both symmetrical and asymmetrical connections are supported. Bandwidth on demand and guaranteed quality of service are key features of the system. A novel multi-frequency TDMA access scheme utilises efficient methods of IP encapsulation. In contrast to other solutions it avoids legacy transport network techniques. While the DVB-RCS standard is based on ATM or MPEG transport cells, the solution of the L*IP system uses variable-length cells which reduces the overhead significantly. A flexible and programmable platform based on Linux machines was chosen to allow the easy implementation and adaptation to different standards. This offers the possibility to apply the system not only to satellite communications, but provides seamless integration with terrestrial fixed broadcast wireless access systems. The platform is also an ideal test-bed for a variety of interactive broadband communications systems. The paper describes the system architecture and the key features of the system.

  11. Ischemic post-conditioning to counteract intestinal ischemia/reperfusion injury

    PubMed Central

    Guan, Yan-Fang; Pritts, Timothy A; Montrose, Marshall H

    2010-01-01

    Intestinal ischemia is a severe disorder with a variety of causes. Reperfusion is a common occurrence during treatment of acute intestinal ischemia but the injury resulting from ischemia/reperfusion (IR) may lead to even more serious complications from intestinal atrophy to multiple organ failure and death. The susceptibility of the intestine to IR-induced injury (IRI) appears from various experimental studies and clinical settings such as cardiac and major vascular surgery and organ transplantation. Whereas oxygen free radicals, activation of leukocytes, failure of microvascular perfusion, cellular acidosis and disturbance of intracellular homeostasis have been implicated as important factors in the pathogenesis of intestinal IRI, the mechanisms underlying this disorder are not well known. To date, increasing attention is being paid in animal studies to potential pre- and post-ischemia treatments that protect against intestinal IRI such as drug interference with IR-induced apoptosis and inflammation processes and ischemic pre-conditioning. However, better insight is needed into the molecular and cellular events associated with reperfusion-induced damage to develop effective clinical protection protocols to combat this disorder. In this respect, the use of ischemic post-conditioning in combination with experimentally prolonged acidosis blocking deleterious reperfusion actions may turn out to have particular clinical relevance. PMID:21607154

  12. DETERMINATION OF AN EMPIRICALLY DERIVED IP/TSP RELATIONSHIP

    EPA Science Inventory

    The primary objective of this study was to provide researchers with statistical methodology for comparing data on inhalable particulate (IP) and on the IP/TSP ratios from various sites, predicting IP concentration as a function of total suspended particulate (TSP) concentration, ...

  13. A Conjoint Analysis of Voice Over IP Attributes.

    ERIC Educational Resources Information Center

    Zubey, Michael L.; Wagner, William; Otto, James R.

    2002-01-01

    Managers need to understand the tradeoffs associated with voice over Internet protocol (VoIP) networks as compared to the Public Switched Telephone Network (PSTN). This article measures the preference structures between IP telephony and PSTN services using conjoint analysis. The purpose is to suggest VoIP technology attributes that best meet…

  14. A Survey of Voice over IP Security Research

    NASA Astrophysics Data System (ADS)

    Keromytis, Angelos D.

    We present a survey of Voice over IP security research. Our goal is to provide a roadmap for researchers seeking to understand existing capabilities and, and to identify gaps in addressing the numerous threats and vulnerabilities present in VoIP systems. We also briefly discuss the implications of our findings with respect to actual vulnerabilities reported in a variety VoIP products.

  15. Covert Channels in SIP for VoIP Signalling

    NASA Astrophysics Data System (ADS)

    Mazurczyk, Wojciech; Szczypiorski, Krzysztof

    In this paper, we evaluate available steganographic techniques for SIP (Session Initiation Protocol) that can be used for creating covert channels during signaling phase of VoIP (Voice over IP) call. Apart from characterizing existing steganographic methods we provide new insights by introducing new techniques. We also estimate amount of data that can be transferred in signalling messages for typical IP telephony call.

  16. Prevention of experimental stroke by hypercapnic-hypoxic preconditioning.

    PubMed

    Yakushev, N N; Bespalov, A G; Kulikov, V P

    2008-09-01

    The effectiveness of hypercapnic hypoxic training in the prevention of acute disturbances in cerebral circulation was studied under experimental conditions. Hypercapnic hypoxic training was followed by a significant decrease in the severity of neurological deficit and locomotor and coordination disorders after cerebral ischemic injury. PMID:19240841

  17. Efficiency of tazobactam/piperacillin in lethal peritonitis is enhanced after preconditioning of rats with O3/O2-pneumoperitoneum.

    PubMed

    Bette, Michael; Nüsing, Rolf M; Mutters, Reinier; Zamora, Zullyt B; Menendez, Silvia; Schulz, Siegfried

    2006-01-01

    Insufflation of ozonized oxygen into the peritoneum (O3/O2-pneumoperitoneum [O3/O2-PP]) of rats reduced the lethality of peritonitis. We evaluated the prophylactic effect of O3/O2-PP combined with tazobactam/piperacillin (TZP) in polymicrobial lethal peritonitis. Wistar rats were conditioned by daily repeated insufflation of ozone for 5 days, and hematologic parameters were determined. Sepsis was induced by i.p. injection of cecal material derived from donor rats. Simultaneously, TZP was applied at a single dosage of 65 mg/kg or at two dosage schedules of 65 mg/kg each at an interval of 1 h. The conditioning effect of O3/O2-PP on the number of blood cells was measured before inoculation of bacteria. The mRNA levels of proinflammatory cytokine IL-lbeta and TNF-alpha were determined at 4 h post infection in spleen and liver by semiquantitative in situ hybridization analysis. Preconditioning of rats by O3/O2-PP enhanced the number of blood leukocytes and granulocytes and increased the survival rate of septic rats up to 33%. The combination of O3/O2-PP and TZP further enhanced the survival rate up to 93%. This effect was accompanied by a reduced amount of IL-1beta and TNF-alpha mRNA in spleen and liver. In contrast, in non-infected animals the combination of O3/O2-PP and TZP enhanced IL-1beta and TNF-alpha mRNA in the spleen and IL-1beta mRNA in liver when compared with TZP- and sham-treated controls. The preconditioning effect of O3/O2-PP seems to support the biological effectiveness of TZP by altering the immune status before and during the onset of sepsis. The combined therapy could be a simple, preoperative intervention for abdominal surgery to reduce postoperative morbidity and mortality. PMID:16369182

  18. Growth factors in ischemic stroke

    PubMed Central

    Lanfranconi, S; Locatelli, F; Corti, S; Candelise, L; Comi, G P; Baron, P L; Strazzer, S; Bresolin, N; Bersano, A

    2011-01-01

    Abstract Data from pre-clinical and clinical studies provide evidence that colony-stimulating factors (CSFs) and other growth factors (GFs) can improve stroke outcome by reducing stroke damage through their anti-apoptotic and anti-inflammatory effects, and by promoting angiogenesis and neurogenesis. This review provides a critical and up-to-date literature review on CSF use in stroke. We searched for experimental and clinical studies on haemopoietic GFs such as granulocyte CSF, erythropoietin, granulocyte-macrophage colony-stimulating factor, stem cell factor (SCF), vascular endothelial GF, stromal cell-derived factor-1α and SCF in ischemic stroke. We also considered studies on insulin-like growth factor-1 and neurotrophins. Despite promising results from animal models, the lack of data in human beings hampers efficacy assessments of GFs on stroke outcome. We provide a comprehensive and critical view of the present knowledge about GFs and stroke, and an overview of ongoing and future prospects. PMID:20015202

  19. In-Hospital Ischemic Stroke

    PubMed Central

    2015-01-01

    Between 2.2% and 17% of all strokes have symptom onset during hospitalization in a patient originally admitted for another diagnosis or procedure. These in-hospital strokes represent a unique population with different risk factors, more mimics, and substantially worsened outcomes compared to community-onset strokes. The fact that these strokes manifest during the acute care hospitalization, in patients with higher rates of thrombolytic contraindications, creates distinct challenges for treatment. However, the best evidence suggests benefit to treating appropriately selected in-hospital ischemic strokes with thrombolysis. Evidence points toward a “quality gap” for in-hospital stroke with longer in-hospital delays to evaluation and treatment, lower rates of evaluation for etiology, and decreased adherence to consensus quality process measures of care. This quality gap for in-hospital stroke represents a focused opportunity for quality improvement. PMID:26288675

  20. Preconditioned iterative methods for space-time fractional advection-diffusion equations

    NASA Astrophysics Data System (ADS)

    Zhao, Zhi; Jin, Xiao-Qing; Lin, Matthew M.

    2016-08-01

    In this paper, we propose practical numerical methods for solving a class of initial-boundary value problems of space-time fractional advection-diffusion equations. First, we propose an implicit method based on two-sided Grünwald formulae and discuss its stability and consistency. Then, we develop the preconditioned generalized minimal residual (preconditioned GMRES) method and preconditioned conjugate gradient normal residual (preconditioned CGNR) method with easily constructed preconditioners. Importantly, because resulting systems are Toeplitz-like, fast Fourier transform can be applied to significantly reduce the computational cost. We perform numerical experiments to demonstrate the efficiency of our preconditioners, even in cases with variable coefficients.

  1. Post-ischemic diastolic dysfunction.

    PubMed

    Marsch, S C; Dalmas, S; Philbin, D M; Wanigasekera, V A; Ryder, W A; Wong, L S; Foëx, P

    1994-12-01

    Though a sustained post-ischemic decrease in contractile function has been clearly established, post-ischemic diastolic function has not been thoroughly investigated. Accordingly, 11 anesthetized (isoflurane 1%) open-chest beagles were instrumented to measure left ventricular pressure and dimensions (circumferential length and wall thickness) in an apicoanterior area supplied by the left anterior descending coronary artery (LAD). Pressure-dimension relations were modified by stepwise infusion and withdrawal of 200 mL of the animals' own blood during baseline, 45 minutes partial occlusion of the LAD (systolic bulging), and 60 minutes after the onset of reperfusion. Stiffness constants were derived from the end-diastolic pressure-length and stress-strain relations, respectively. Myocardial ischemia was associated with significant (P < 0.05) alterations of the following parameters of diastolic function: (1) 47% increase in end-diastolic pressure; (2) 22% decrease in peak negative dP/dt; (3) 9% increase in the time constant of isovolumic relaxation (tau); (4) postcystolic contraction; (5) 6% increase in end-diastolic length and 10% decrease in end-diastolic thickness; (6) 12% increase in unstressed length (creep) and 13% decrease in unstressed thickness; (7) 51% increase in chamber stiffness and a 63% increase in myocardial stiffness; and (8) 40% decrease in the peak lengthening rate. After 60 minutes of reperfusion, only end-diastolic pressure and tau had returned to baseline values whereas systolic shortening fraction, postsystolic contraction, and end-diastolic and unstressed dimensions had only partially recovered. No recovery occurred in peak negative dP/dt, chamber stiffness, myocardial stiffness, and peak lengthening rate. Thus, both myocardial ischemia and reperfusion are associated with complex changes in global and regional left ventricular diastolic function. PMID:7880987

  2. Research and Simulation on Application of the Mobile IP Network

    NASA Astrophysics Data System (ADS)

    Yibing, Deng; Wei, Hu; Minghui, Li; Feng, Gao; Junyi, Shen

    The paper analysed the mobile node, home agent, and foreign agent of mobile IP network firstly, some key technique, such as mobile IP network basical principle, protocol work principle, agent discovery, registration, and IP packet transmission, were discussed. Then a network simulation model was designed, validating the characteristic of mobile IP network, and some advantages, which were brought by mobile network, were testified. Finally, the conclusion is gained: mobile IP network could realize the expectation of consumer that they can communicate with others anywhere.

  3. Neuroprotective Mechanisms of Taurine against Ischemic Stroke

    PubMed Central

    Menzie, Janet; Prentice, Howard; Wu, Jang-Yen

    2013-01-01

    Ischemic stroke exhibits a multiplicity of pathophysiological mechanisms. To address the diverse pathophysiological mechanisms observed in ischemic stroke investigators seek to find therapeutic strategies that are multifaceted in their action by either investigating multipotential compounds or by using a combination of compounds. Taurine, an endogenous amino acid, exhibits a plethora of physiological functions. It exhibits antioxidative properties, stabilizes membrane, functions as an osmoregulator, modulates ionic movements, reduces the level of pro-inflammators, regulates intracellular calcium concentration; all of which contributes to its neuroprotective effect. Data are accumulating that show the neuroprotective mechanisms of taurine against stroke pathophysiology. In this review, we describe the neuroprotective mechanisms employed by taurine against ischemic stroke and its use in clinical trial for ischemic stroke. PMID:24961429

  4. Molecular Mechanisms of Renal Ischemic Conditioning Strategies.

    PubMed

    Kierulf-Lassen, Casper; Nieuwenhuijs-Moeke, Gertrude J; Krogstrup, Nicoline V; Oltean, Mihai; Jespersen, Bente; Dor, Frank J M F

    2015-01-01

    Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized. PMID:26330099

  5. Neuroimaging in Neonatal Hypoxic Ischemic Encephalopathy.

    PubMed

    Krishnan, Pradeep; Shroff, Manohar

    2016-09-01

    Magnetic resonance (MR) imaging is emerging as one of the most important tools in identifying the etiology of neonatal encephalopathy as well as in predicting long-term outcomes. This makes it imperative to have a broader understanding of normal myelination of the neonatal brain on MR imaging and to be familiar with the spectrum of imaging features in ischemic and non-ischemic neonatal encephalopathy. Hypoxic ischemic injury (HIE) is one of the most common causes of neonatal encephalopathy and imaging appearances are influenced by factors such as the stage of maturation of the neonatal brain and severity as well as duration of ischemic insult. Other common causes of neonatal encephalopathy include infectious diseases, congenital disorders and inborn errors of metabolism. PMID:26909496

  6. Steps to translate preconditioning from basic research to the clinic

    PubMed Central

    Bahjat, Frances R; Gesuete, Raffaella; Stenzel-Poore, Mary P

    2012-01-01

    Efforts to treat cardiovascular and cerebrovascular diseases often focus on the mitigation of ischemia-reperfusion (I/R) injury. Many treatments or “preconditioners” are known to provide substantial protection against the I/R injury when administered prior to the event. Brief periods of ischemia itself have been validated as a means to achieve neuroprotection in many experimental disease settings, in multiple organ systems, and in multiple species suggesting a common pathway leading to tolerance. In addition, pharmacological agents that act as potent preconditioners have been described. Experimental induction of neuroprotection using these various preconditioning paradigms has provided a unique window into the brain’s endogenous protective mechanisms. Moreover, preconditioning agents themselves hold significant promise as clinical-stage therapies for prevention of I/R injury. The aim of this article is to explore several key steps involved in the preclinical validation of preconditioning agents prior to the conduct of clinical studies in humans. Drug development is difficult, expensive and relies on multi-factorial analysis of data from diverse disciplines. Importantly, there is no single path for the preclinical development of a novel therapeutic and no proven strategy to ensure success in clinical translation. Rather, the conduct of a diverse array of robust preclinical studies reduces the risk of clinical failure by varying degrees depending upon the relevance of preclinical models and drug pharmacology to humans. A strong sense of urgency and high tolerance of failure are often required to achieve success in the development of novel treatment paradigms for complex human conditions. PMID:23504609

  7. Calcium preconditioning triggers neuroprotection in retinal ganglion cells

    PubMed Central

    Brandt, Sean K.; Weatherly, Monique E.; Ware, Lillian; Linn, David M.; Linn, Cindy L.

    2010-01-01

    In the mammalian retina, excitotoxicity has been shown to be involved in apoptotic retinal ganglion cell (RGC) death and is associated with certain retinal disease states including glaucoma, diabetic retinopathy and retinal ischemia. Previous studies from this lab (Wehrwein et al., 2004) have demonstrated that acetylcholine (ACh) and nicotine protects against glutamate-induced excitotoxicity in isolated adult pig RGCs through nicotinic acetylcholine receptors (nAChRs). Activation of nAChRs in these RGCs triggers cell survival signaling pathways and inhibits apoptotic enzymes (Asomugha et al., 2010). However, the link between binding of nAChRs and activation of neuroprotective pathways is unknown. In this study, we examine the hypothesis that calcium permeation through nAChR channels is required for ACh-induced neuroprotection against glutamate-induced excitotoxicity in isolated pig RGCs. RGCs were isolated from other retinal tissue using a two step panning technique and cultured for 3 days under different conditions. In some studies, calcium imaging experiments were performed using the fluorescent calcium indicator, fluo-4, and demonstrated that calcium permeates the nAChR channels located on pig RGCs. In other studies, the extracellular calcium concentration was altered to determine the effect on nicotine-induced neuroprotection. Results support the hypothesis that calcium is required for nicotine-induced neuroprotection in isolated pig RGCs. Lastly, studies were performed to analyze the effects of preconditioning on glutamate-induced excitotoxicity and neuroprotection. In these studies, a preconditioning dose of calcium was introduced to cells using a variety of mechanisms before a large glutamate insult was applied to cells. Results from these studies support the hypothesis that preconditioning cells with a relatively low level of calcium before an excitotoxic insult leads to neuroprotection. In the future, these results could provide important information

  8. Preconditioned Conjugate Gradient methods for low speed flow calculations

    NASA Technical Reports Server (NTRS)

    Ajmani, Kumud; Ng, Wing-Fai; Liou, Meng-Sing

    1993-01-01

    An investigation is conducted into the viability of using a generalized Conjugate Gradient-like method as an iterative solver to obtain steady-state solutions of very low-speed fluid flow problems. Low-speed flow at Mach 0.1 over a backward-facing step is chosen as a representative test problem. The unsteady form of the two dimensional, compressible Navier-Stokes equations are integrated in time using discrete time-steps. The Navier-Stokes equations are cast in an implicit, upwind finite-volume, flux split formulation. The new iterative solver is used to solve a linear system of equations at each step of the time-integration. Preconditioning techniques are used with the new solver to enhance the stability and the convergence rate of the solver and are found to be critical to the overall success of the solver. A study of various preconditioners reveals that a preconditioner based on the lower-upper (L-U)-successive symmetric over-relaxation iterative scheme is more efficient than a preconditioner based on incomplete L-U factorizations of the iteration matrix. The performance of the new preconditioned solver is compared with a conventional line Gauss-Seidel relaxation (LGSR) solver. Overall speed-up factors of 28 (in terms of global time-steps required to converge to a steady-state solution) and 20 (in terms of total CPU time on one processor of a CRAY-YMP) are found in favor of the new preconditioned solver, when compared with the LGSR solver.

  9. Insight on stem cell preconditioning and instructive biomaterials to enhance cell adhesion, retention, and engraftment for tissue repair.

    PubMed

    Shafiq, Muhammad; Jung, Youngmee; Kim, Soo Hyun

    2016-06-01

    Stem cells are a promising solution for the treatment of a variety of diseases. However, the limited survival and engraftment of transplanted cells due to a hostile ischemic environment is a bottleneck for effective utilization and commercialization. Within this environment, the majority of transplanted cells undergo apoptosis prior to participating in lineage differentiation and cellular integration. Therefore, in order to maximize the clinical utility of stem/progenitor cells, strategies must be employed to increase their adhesion, retention, and engraftment in vivo. Here, we reviewed key strategies that are being adopted to enhance the survival, retention, and engraftment of transplanted stem cells through the manipulation of both the stem cells and the surrounding environment. We describe how preconditioning of cells or cell manipulations strategies can enhance stem cell survival and engraftment after transplantation. We also discuss how biomaterials can enhance the function of stem cells for effective tissue regeneration. Biomaterials can incorporate or mimic extracellular function (ECM) function and enhance survival or differentiation of transplanted cells in vivo. Biomaterials can also promote angiogenesis, enhance engraftment and differentiation, and accelerate electromechanical integration of transplanted stem cells. Insight gained from this review may direct the development of future investigations and clinical trials. PMID:27016619

  10. Hepatocellular protein profiles after hepatic ischemia/reperfusion injury with or without octreotide preconditioning in a rabbit model.

    PubMed

    Yang, J; Sun, H; Guan, R; Liu, W; Xia, Y; Zhao, J; Liu, J

    2014-12-01

    Hepatic ischemic/reperfusion injury (HIRI) is a major complication of liver resection and transplantation. Octreotide, a somatostatin analogue, has been used to treat hepatic fibrosis and portal hypertension; however, its function against HIRI remains unclear. To elucidate the effect of octreotide in HIRI, we investigated the hepatocellular protein profiles in response to octreotide preconditioning in a rabbit model by using proteomic analysis. Twenty-four rabbits were divided into 3 groups: the sham operative group (control), the ischemia/reperfusion group (IR), and the ischemia/reperfusion + octreotide group (IR+Oct). They were subjected to 30 minutes of normothermic ischemia followed by 120 minutes of reperfusion by using Pringle's maneuver method. Proteomic studies were then performed to compare the protein profiles of their left liver lobe. A total of 16 differential proteins were successfully identified. These findings suggest that octreotide might exert an effect against HIRI through up-regulating the expression of the anti-injury substances, such as heat-shock proteins 70 and 27 (confirmed by using Western blot analysis); significantly raising the phosphatidylethanolamine-binding protein that alleviates IR-related apoptosis; and down-regulating mitochondrial metabolic enzymes such as NADH2 dehydrogenase and triosephosphate isomerase. PMID:25498038

  11. Ischemic Conditioning: Implications for Emergency Medicine.

    PubMed

    Frumkin, Kenneth; Bloom, Adam S

    2016-09-01

    Ischemic conditioning refers to the ability of brief episodes of controlled hypoperfusion around the time of an acute ischemic event to protect the target organ from reperfusion injury. A considerable body of literature suggests that interventions as simple and safe as repetitively inflating a blood pressure cuff could reduce the size and long-term morbidity of myocardial and cerebral infarction. This review introduces and summarizes the body of evidence contributing to these impressions. PMID:26973174

  12. Transient central diabetes insipidus following ischemic stroke.

    PubMed

    Jayaraman, Muthukrishnan; Kumar, Sandeep; Ahmad, F M H

    2013-10-01

    Central Diabetes Insipidus (CDI) following ischemic infarction of the brain has been described as a rare presentation. Posterior pituitary ischemia has also been postulated as a possible cause of idiopathic CDI. We encountered a young male with bilateral extensive ischemic infarction sustained at high altitude, who had transient polyuria due to central diabetes insipidus, requiring desmopressin therapy. DI completely resolved during the course of his neurological recovery. PMID:24251140

  13. Chinese Herbal Products for Ischemic Stroke.

    PubMed

    Hung, I-Ling; Hung, Yu-Chiang; Wang, Lin-Yi; Hsu, Sheng-Feng; Chen, Hsuan-Ju; Tseng, Ying-Jung; Kuo, Chun-En; Hu, Wen-Long; Li, Tsai-Chung

    2015-01-01

    Traditional Chinese herbal products (CHPs) have been described in ancient medicine systems as treatments for various stroke-associated ailments. This study is aimed to investigate the prescription patterns and combinations of CHPs for ischemic stroke in Taiwan. Prescriptions of CHPs for ischemic stroke were obtained from the National Health Insurance Research Database (NHIRD) of Taiwan. Every prescription with a leading diagnosis of ischemic stroke made during 2000-2010 was analyzed. Descriptive statistics were applied to the pattern of co-prescriptions. Multiple logistic regression models were used to assess demographic and risk factors that are correlated with CHP use. The dataset of inpatient claims data contained information on 15,896 subjects who experienced ischemic stroke from 2000 to 2010. There was an average of 5.82 CHPs in a single prescription for subjects with ischemic stroke. Bu-yang-huan-wu-tang (BYHWT) (40.32%) was by far the most frequently prescribed formula CHP for ischemic stroke, and the most commonly used combination of two-formula-CHP was BYHWT with Shu-jin-huo-xue-tang (SJHXT) (4.40%). Dan Shen (16.50%) was the most commonly used single CHP for ischemic stroke, and the most commonly used combination of two single CHPs was Shi Chang Pua with Yuan Zhi (4.79%). We found that BYHWT and Dan Shen were the most frequently prescribed formula and single CHP for ischemic stroke, respectively. These results provide information about individualized therapy and may contribute to further pharmacologic experiments and clinical trials. PMID:26477801

  14. Incomplete block factorization preconditioning for indefinite elliptic problems

    SciTech Connect

    Guo, Chun-Hua

    1996-12-31

    The application of the finite difference method to approximate the solution of an indefinite elliptic problem produces a linear system whose coefficient matrix is block tridiagonal and symmetric indefinite. Such a linear system can be solved efficiently by a conjugate residual method, particularly when combined with a good preconditioner. We show that specific incomplete block factorization exists for the indefinite matrix if the mesh size is reasonably small. And this factorization can serve as an efficient preconditioner. Some efforts are made to estimate the eigenvalues of the preconditioned matrix. Numerical results are also given.

  15. Preconditioning a product of matrices arising in trust region subproblems

    SciTech Connect

    Hribar, M.E.; Plantenga, T.D.

    1996-03-01

    In solving large scale optimization problems, we find it advantageous to use iterative methods to solve the sparse linear systems that arise. In the ETR software for solving equality constrained optimization problems, we use a conjugate gradient method to approximately solve the trust region subproblems. To speed up the convergence of the conjugate gradient routine, we need to precondition matrices of the form Z{sup T} W Z, which are not explicitly stored. Four preconditioners were implemented and the results for each are given.

  16. Preconditioning methods for ideal and multiphase fluid flows

    NASA Astrophysics Data System (ADS)

    Gupta, Ashish

    The objective of this study is to develop a preconditioning method for ideal and multiphase multispecies compressible fluid flow solver using homogeneous equilibrium mixture model. The mathematical model for fluid flow going through phase change uses density and temperature in the formulation, where the density represents the multiphase mixture density. The change of phase of the fluid is then explicitly determined using the equation of state of the fluid, which only requires temperature and mixture density. The method developed is based on a finite-volume framework in which the numerical fluxes are computed using Roe's approximate Riemann solver and the modified Harten, Lax and Van-leer scheme (HLLC). All speed Roe and HLLC flux based schemes have been developed either by using preconditioning or by directly modifying dissipation to reduce the effect of acoustic speed in its numerical dissipation when Mach number decreases. Preconditioning proposed by Briley, Taylor and Whitfield, Eriksson and Turkel are studied in this research, where as low dissipation schemes proposed by Rieper and Thornber, Mosedale, Drikakis, Youngs and Williams are also considered. Various preconditioners are evaluated in terms of development, performance, accuracy and limitations in simulations at various Mach numbers. A generalized preconditioner is derived which possesses well conditioned eigensystem for multiphase multispecies flow simulations. Validation and verification of the solution procedure are carried out on several small model problems with comparison to experimental, theoretical, and other numerical results. Preconditioning methods are evaluated using three basic geometries; 1) bump in a channel 2) flow over a NACA0012 airfoil and 3) flow over a cylinder, which are then compared with theoretical and numerical results. Multiphase capabilities of the solver are evaluated in cryogenic and non-cryogenic conditions. For cryogenic conditions the solver is evaluated by predicting

  17. Weighted graph based ordering techniques for preconditioned conjugate gradient methods

    NASA Technical Reports Server (NTRS)

    Clift, Simon S.; Tang, Wei-Pai

    1994-01-01

    We describe the basis of a matrix ordering heuristic for improving the incomplete factorization used in preconditioned conjugate gradient techniques applied to anisotropic PDE's. Several new matrix ordering techniques, derived from well-known algorithms in combinatorial graph theory, which attempt to implement this heuristic, are described. These ordering techniques are tested against a number of matrices arising from linear anisotropic PDE's, and compared with other matrix ordering techniques. A variation of RCM is shown to generally improve the quality of incomplete factorization preconditioners.

  18. Interface preconditionings for domain-decomposed convection-diffusion operators

    NASA Technical Reports Server (NTRS)

    Chan, Tony F.; Keyes, David E.

    1990-01-01

    The performance of five different interface preconditionings for domain-decomposed convection-diffusion problems, including a novel one known as the spectral probe is tested in a three-dimensional parameter space consisting of mesh parameters, Reynolds number, and domain aspect ratio. The preconditioners are representative of the range of practically computable possibilities that have appeared in the literature for the treatment of nonoverlapping subdomains. Numerical examples show that no single preconditioner can be considered uniformly superior or uniformly inferior to the rest, but that knowledge of the particulars of the shape and strength of the convection is important in selecting among them in a given problem.

  19. IP address management : augmenting Sandia's capabilities through open source tools.

    SciTech Connect

    Nayar, R. Daniel

    2005-08-01

    Internet Protocol (IP) address management is an increasingly growing concern at Sandia National Laboratories (SNL) and the networking community as a whole. The current state of the available IP addresses indicates that they are nearly exhausted. Currently SNL doesn't have the justification to obtain more IP address space from Internet Assigned Numbers Authority (IANA). There must exist a local entity to manage and allocate IP assignments efficiently. Ongoing efforts at Sandia have been in the form of a multifunctional database application notably known as Network Information System (NWIS). NWIS is a database responsible for a multitude of network administrative services including IP address management. This study will explore the feasibility of augmenting NWIS's IP management capabilities utilizing open source tools. Modifications of existing capabilities to better allocate available IP address space are studied.

  20. Cell Reprogramming, IPS Limitations, and Overcoming Strategies in Dental Bioengineering

    PubMed Central

    Ibarretxe, Gaskon; Alvarez, Antonia; Cañavate, Maria-Luz; Hilario, Enrique; Aurrekoetxea, Maitane; Unda, Fernando

    2012-01-01

    The procurement of induced pluripotent stem cells, or IPS cells, from adult differentiated animal cells has the potential to revolutionize future medicine, where reprogrammed IPS cells may be used to repair disease-affected tissues on demand. The potential of IPS cell technology is tremendous, but it will be essential to improve the methodologies for IPS cell generation and to precisely evaluate each clone and subclone of IPS cells for their safety and efficacy. Additionally, the current state of knowledge on IPS cells advises that research on their regenerative properties is carried out in appropriate tissue and organ systems that permit a safe assessment of the long-term behavior of these reprogrammed cells. In the present paper, we discuss the mechanisms of cell reprogramming, current technical limitations of IPS cells for their use in human tissue engineering, and possibilities to overcome them in the particular case of dental regeneration. PMID:22690226

  1. Therapeutic hypothermia for acute ischemic stroke.

    PubMed

    Froehler, Michael T; Ovbiagele, Bruce

    2010-04-01

    Intravenous recombinant tissue plasminogen activator remains the only US FDA-approved treatment for acute ischemic stroke. However, the very limited time window for its administration restricts its usefulness. Furthermore, it is becoming increasingly clear that, given the numerous pathways via which cerebral ischemia causes cell death, the capacity to inhibit multiple mechanisms simultaneously may provide additive or synergistic beneficial clinical effects for stroke patients. Although no clinical trials have yet investigated the efficacy of therapeutic hypothermia in focal cerebral ischemia, its pleiotropic neuroprotective actions, positive results in preclinical studies, as well as proven enhancement of neurologic outcomes in survivors of cardiac arrest and newborns with hypoxic-ischemic encephalopathy, make this neuroprotective strategy highly promising. This review presents an overview of the potential role of hypothermia in the treatment of acute ischemic stroke and discusses ischemic cell death pathophysiology, neuroprotective mechanisms of hypothermia, methodologies employed for the induction of hypothermia, results from animal models of cerebral ischemia, and finally, currently available clinical trial data. Two valuable lessons learned thus far are that first, rapid induction of hypothermia is key and is best accomplished with a combination of ice-cold saline infusion and the use of endovascular cooling devices, and second, that shivering can be overcome with aggressive anti-shivering protocols including meperidine, buspirone and surface warming. We await the results of clinical trials to determine the utility of therapeutic hypothermia in acute ischemic stroke. If proven efficacious, hypothermia would be a welcome complement to established reperfusion therapies for ischemic stroke patients. PMID:20397832

  2. The Ischemic Stroke Genetics Study (ISGS) Protocol

    PubMed Central

    Meschia, James F; Brott, Thomas G; Brown, Robert D; Crook, Richard JP; Frankel, Michael; Hardy, John; Merino, José G; Rich, Stephen S; Silliman, Scott; Worrall, Bradford Burke

    2003-01-01

    Background The molecular basis for the genetic risk of ischemic stroke is likely to be multigenic and influenced by environmental factors. Several small case-control studies have suggested associations between ischemic stroke and polymorphisms of genes that code for coagulation cascade proteins and platelet receptors. Our aim is to investigate potential associations between hemostatic gene polymorphisms and ischemic stroke, with particular emphasis on detailed characterization of the phenotype. Methods/Design The Ischemic Stroke Genetic Study is a prospective, multicenter genetic association study in adults with recent first-ever ischemic stroke confirmed with computed tomography or magnetic resonance imaging. Patients are evaluated at academic medical centers in the United States and compared with sex- and age-matched controls. Stroke subtypes are determined by central blinded adjudication using standardized, validated mechanistic and syndromic classification systems. The panel of genes to be tested for polymorphisms includes β-fibrinogen and platelet glycoprotein Ia, Iba, and IIb/IIIa. Immortalized cell lines are created to allow for time- and cost-efficient testing of additional candidate genes in the future. Discussion The study is designed to minimize survival bias and to allow for exploring associations between specific polymorphisms and individual subtypes of ischemic stroke. The data set will also permit the study of genetic determinants of stroke outcome. Having cell lines will permit testing of future candidate risk factor genes. PMID:12848902

  3. Angiotensinogen polymorphism and ischemic stroke risk

    PubMed Central

    Bao, Huan; Hao, Jun-Jie; Yang, Yu-Mei; Xu, Xia-Hong; Wang, Yue; Zuo, Lian; Lu, Jing; Zhang, Jing; Zhang, Yue; Xu, Si-Yi; Wang, Xuan; Li, Ying; Li, Gang

    2015-01-01

    The angiotensinogen M235T polymorphism was associated with ischemic stroke risk. However, the results were controversial. Thus, a meta-analysis was conducted. NCBI, Medline, Web of Science and Embase databases were systematically searched. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models. There was a significant association between angiotensinogen M235T polymorphism and ischemic stroke risk (OR = 1.69; 95% CI, 1.35-2.11; P < 0.001). In the stratified analysis by ethnicity, we found that this polymorphism was significantly associated with ischemic stroke in Asian (OR = 1.85; 95% CI, 1.45-2.35; P < 0.001). In the age subgroup, we found that angiotensinogen M235T polymorphism could increase both early-onset ischemic stroke risk (OR = 1.88; 95% CI, 1.33-2.43; P < 0.001) and late-onset ischemic stroke risk (OR = 1.20; 95% CI, 1.01-1.39; P = 0.04). This meta-analysis suggested that angiotensinogen M235T polymorphism was associated with ischemic stroke. PMID:26550208

  4. Demonstrating a Realistic IP Mission Prototype

    NASA Technical Reports Server (NTRS)

    Rash, James; Ferrer, Arturo B.; Goodman, Nancy; Ghazi-Tehrani, Samira; Polk, Joe; Johnson, Lorin; Menke, Greg; Miller, Bill; Criscuolo, Ed; Hogie, Keith

    2003-01-01

    Flight software and hardware and realistic space communications environments were elements of recent demonstrations of the Internet Protocol (IP) mission concept in the lab. The Operating Missions as Nodes on the Internet (OMNI) Project and the Flight Software Branch at NASA/GSFC collaborated to build the prototype of a representative space mission that employed unmodified off-the-shelf Internet protocols and technologies for end-to-end communications between the spacecraft/instruments and the ground system/users. The realistic elements used in the prototype included an RF communications link simulator and components of the TRIANA mission flight software and ground support system. A web-enabled camera connected to the spacecraft computer via an Ethernet LAN represented an on-board instrument creating image data. In addition to the protocols at the link layer (HDLC), transport layer (UDP, TCP), and network (IP) layer, a reliable file delivery protocol (MDP) at the application layer enabled reliable data delivery both to and from the spacecraft. The standard Network Time Protocol (NTP) performed on-board clock synchronization with a ground time standard. The demonstrations of the prototype mission illustrated some of the advantages of using Internet standards and technologies for space missions, but also helped identify issues that must be addressed. These issues include applicability to embedded real-time systems on flight-qualified hardware, range of applicability of TCP, and liability for and maintenance of commercial off-the-shelf (COTS) products. The NASA Earth Science Technology Office (ESTO) funded the collaboration to build and demonstrate the prototype IP mission.

  5. Expression of Monocarboxylate Transporter Isoforms in Rat Skeletal Muscle Under Hypoxic Preconditioning and Endurance Training.

    PubMed

    Saxena, Saurabh; Shukla, Dhananjay; Bansal, Anju

    2016-03-01

    Previously, we have reported the regulation of monocarboxylate transporters (MCT)1 and MCT4 by physiological stimuli such as hypoxia and exercise. In the present study, we have evaluated the effect of hypoxic preconditioning and training on expression of different MCT isoforms in muscles. We found the increased mRNA expression of MCT1, MCT11, and MCT12 after hypoxic preconditioning with cobalt chloride and training. However, the expression of other MCT isoforms increased marginally or even reduced after hypoxic preconditioning. Only the protein expression of MCT1 increased after hypoxia preconditioning. MCT2 protein expression increased after training only and MCT4 protein expression decreased both in preconditioning and hypoxic training. Furthermore, we found decreased plasma lactate level during hypoxia preconditioning (0.74-fold), exercise (0.78-fold), and hypoxia preconditioning along with exercise (0.67-fold), which indicates increased lactate uptake by skeletal muscle. The protein-protein interactions with hypoxia inducible factor-1 and MCT isoforms were also evaluated, but no interaction was found. In conclusion, we say that almost all MCTs are expressed in red gastrocnemius muscle at the mRNA level and their expression is regulated differently under hypoxia preconditioning and exercise condition. PMID:26716978

  6. Sensory Preconditioning in Newborn Rabbits: From Common to Distinct Odor Memories

    ERIC Educational Resources Information Center

    Coureaud, Gerard; Tourat, Audrey; Ferreira, Guillaume

    2013-01-01

    This study evaluated whether olfactory preconditioning is functional in newborn rabbits and based on joined or independent memory of odorants. First, after exposure to odorants A+B, the conditioning of A led to high responsiveness to odorant B. Second, responsiveness to B persisted after amnesia of A. Third, preconditioning was also functional…

  7. 40 CFR 85.2220 - Preconditioned two speed idle test-EPA 91.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 19 2013-07-01 2013-07-01 false Preconditioned two speed idle test-EPA... Warranty Short Tests § 85.2220 Preconditioned two speed idle test—EPA 91. (a) General requirements—(1...-speed mode followed immediately by a first-chance idle mode. (ii) The second-chance test as...

  8. 40 CFR 85.2220 - Preconditioned two speed idle test-EPA 91.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 19 2012-07-01 2012-07-01 false Preconditioned two speed idle test-EPA... Warranty Short Tests § 85.2220 Preconditioned two speed idle test—EPA 91. (a) General requirements—(1...-speed mode followed immediately by a first-chance idle mode. (ii) The second-chance test as...

  9. 40 CFR 85.2220 - Preconditioned two speed idle test-EPA 91.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 18 2010-07-01 2010-07-01 false Preconditioned two speed idle test-EPA... Warranty Short Tests § 85.2220 Preconditioned two speed idle test—EPA 91. (a) General requirements—(1... between 2200 and 2800 rpm. If the engine speed falls below 2200 rpm or exceeds 2800 rpm for more than...

  10. 40 CFR 85.2220 - Preconditioned two speed idle test-EPA 91.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 18 2011-07-01 2011-07-01 false Preconditioned two speed idle test-EPA... Warranty Short Tests § 85.2220 Preconditioned two speed idle test—EPA 91. (a) General requirements—(1...-speed mode followed immediately by a first-chance idle mode. (ii) The second-chance test as...

  11. In vitro synthesis and purification of PhIP-deoxyguanosine and PhIP-DNA oligomer covalent complexes

    SciTech Connect

    Freeman, J.

    1994-12-01

    2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine compound formed when meats are cooked at high temperatures. PhIP damages DNA by forming covalent complexes with DNA carcinogen. In an effort to understand how the binding of PhIP to DNA may cause cancer, it is important to characterize the structures of PhIP-damaged DNA molecules. Our HPLC data support fluorescence and {sup 32}P Post-labeling studies which indicate the formation of several species of 2{prime}deoxyguanosine-(dG) or oligodeoxynucleotide-PhIP adducts. The reaction of PhIP with dG resulted in a reddish precipitate that was likely the major adduct, N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP) adduct, with a more polar adduct fraction remaining in the supernatant. Reversed-phase HPLC analysis of the adducts in the supernatant revealed the existence of species of much shorter retention times than the dG-C8-PhIP adduct, confirming that these species are more polar than dG-C8-PhIP. At least four adducts were formed in the reaction of PhIP with DNA oligomer. HPLC analysis of the PhIP-DNA oligomer supernatant after butanol extractions revealed four unresolved peaks which spectra had maximum wavelengths between 340 and 360 nm. Though adduct peaks were not completely resolved, there was {approximately}3 minutes interval between the DNA oligomer peak and the adduct peaks. Furthermore, fluorescence emission data of the DNA oligomer-PhIP adduct solution show heterogeneous binding. The more polar PhIP adducts were fraction-collected and their structures will be solved by nuclear magnetic resonance or x-ray crystallography.

  12. Preconditioning 2D Integer Data for Fast Convex Hull Computations.

    PubMed

    Cadenas, José Oswaldo; Megson, Graham M; Luengo Hendriks, Cris L

    2016-01-01

    In order to accelerate computing the convex hull on a set of n points, a heuristic procedure is often applied to reduce the number of points to a set of s points, s ≤ n, which also contains the same hull. We present an algorithm to precondition 2D data with integer coordinates bounded by a box of size p × q before building a 2D convex hull, with three distinct advantages. First, we prove that under the condition min(p, q) ≤ n the algorithm executes in time within O(n); second, no explicit sorting of data is required; and third, the reduced set of s points forms a simple polygonal chain and thus can be directly pipelined into an O(n) time convex hull algorithm. This paper empirically evaluates and quantifies the speed up gained by preconditioning a set of points by a method based on the proposed algorithm before using common convex hull algorithms to build the final hull. A speedup factor of at least four is consistently found from experiments on various datasets when the condition min(p, q) ≤ n holds; the smaller the ratio min(p, q)/n is in the dataset, the greater the speedup factor achieved. PMID:26938221

  13. Stress Preconditioning of Spreading Depression in the Locust CNS

    PubMed Central

    Rodgers, Corinne I.; Armstrong, Gary A. B.; Shoemaker, Kelly L.; LaBrie, John D.; Moyes, Christopher D.; Robertson, R. Meldrum

    2007-01-01

    Cortical spreading depression (CSD) is closely associated with important pathologies including stroke, seizures and migraine. The mechanisms underlying SD in its various forms are still incompletely understood. Here we describe SD-like events in an invertebrate model, the ventilatory central pattern generator (CPG) of locusts. Using K+ -sensitive microelectrodes, we measured extracellular K+ concentration ([K+]o) in the metathoracic neuropile of the CPG while monitoring CPG output electromyographically from muscle 161 in the second abdominal segment to investigate the role K+ in failure of neural circuit operation induced by various stressors. Failure of ventilation in response to different stressors (hyperthermia, anoxia, ATP depletion, Na+/K+ ATPase impairment, K+ injection) was associated with a disturbance of CNS ion homeostasis that shares the characteristics of CSD and SD-like events in vertebrates. Hyperthermic failure was preconditioned by prior heat shock (3 h, 45°C) and induced-thermotolerance was associated with an increase in the rate of clearance of extracellular K+ that was not linked to changes in ATP levels or total Na+/K+ ATPase activity. Our findings suggest that SD-like events in locusts are adaptive to terminate neural network operation and conserve energy during stress and that they can be preconditioned by experience. We propose that they share mechanisms with CSD in mammals suggesting a common evolutionary origin. PMID:18159249

  14. Parallelizable approximate solvers for recursions arising in preconditioning

    SciTech Connect

    Shapira, Y.

    1996-12-31

    For the recursions used in the Modified Incomplete LU (MILU) preconditioner, namely, the incomplete decomposition, forward elimination and back substitution processes, a parallelizable approximate solver is presented. The present analysis shows that the solutions of the recursions depend only weakly on their initial conditions and may be interpreted to indicate that the inexact solution is close, in some sense, to the exact one. The method is based on a domain decomposition approach, suitable for parallel implementations with message passing architectures. It requires a fixed number of communication steps per preconditioned iteration, independently of the number of subdomains or the size of the problem. The overlapping subdomains are either cubes (suitable for mesh-connected arrays of processors) or constructed by the data-flow rule of the recursions (suitable for line-connected arrays with possibly SIMD or vector processors). Numerical examples show that, in both cases, the overhead in the number of iterations required for convergence of the preconditioned iteration is small relatively to the speed-up gained.

  15. Preconditioning 2D Integer Data for Fast Convex Hull Computations

    PubMed Central

    2016-01-01

    In order to accelerate computing the convex hull on a set of n points, a heuristic procedure is often applied to reduce the number of points to a set of s points, s ≤ n, which also contains the same hull. We present an algorithm to precondition 2D data with integer coordinates bounded by a box of size p × q before building a 2D convex hull, with three distinct advantages. First, we prove that under the condition min(p, q) ≤ n the algorithm executes in time within O(n); second, no explicit sorting of data is required; and third, the reduced set of s points forms a simple polygonal chain and thus can be directly pipelined into an O(n) time convex hull algorithm. This paper empirically evaluates and quantifies the speed up gained by preconditioning a set of points by a method based on the proposed algorithm before using common convex hull algorithms to build the final hull. A speedup factor of at least four is consistently found from experiments on various datasets when the condition min(p, q) ≤ n holds; the smaller the ratio min(p, q)/n is in the dataset, the greater the speedup factor achieved. PMID:26938221

  16. Preconditioning techniques for constrained vector potential integral equations, with application to 3-D magnetoquasistatic analysis of electronic packages

    SciTech Connect

    Kamon, M.; Phillips, J.R.

    1994-12-31

    In this paper techniques are presented for preconditioning equations generated by discretizing constrained vector integral equations associated with magnetoquasistatic analysis. Standard preconditioning approaches often fail on these problems. The authors present a specialized preconditioning technique and prove convergence bounds independent of the constraint equations and electromagnetic excitation frequency. Computational results from analyzing several electronic packaging examples are given to demonstrate that the new preconditioning approach can sometimes reduce the number of GMRES iterations by more than an order of magnitude.

  17. COMPARING MULTIPLE ChIP-SEQUENCING EXPERIMENTS

    PubMed Central

    OZER, HATICE GULCIN; HUANG, YI-WEN; WU, JIEJUN; PARVIN, JEFFREY D.; HUANG, TIM HUI-MING; HUANG, KUN

    2015-01-01

    New high-throughput sequencing technologies can generate millions of short sequences in a single experiment. As the size of the data increases, comparison of multiple experiments on different cell lines under different experimental conditions becomes a big challenge. In this paper, we investigate ways to compare multiple ChIP-sequencing experiments. We specifically studied epigenetic regulation of breast cancer and the effect of estrogen using 50 ChIP-sequencing data from Illumina Genome Analyzer II. First, we evaluate the correlation among different experiments focusing on the total number of reads in transcribed and promoter regions of the genome. Then, we adopt the method that is used to identify the most stable genes in RT-PCR experiments to understand background signal across all of the experiments and to identify the most variable transcribed and promoter regions of the genome. We observed that the most variable genes for transcribed regions and promoter regions are very distinct. Gene ontology and function enrichment analysis on these most variable genes demonstrate the biological relevance of the results. In this study, we present a method that can effectively select differential regions of the genome based on protein-binding profiles over multiple experiments using real data points without any normalization among the samples. PMID:21523932

  18. Live Video and IP-TV

    NASA Astrophysics Data System (ADS)

    Merani, Maria Luisa; Saladino, Daniela

    This Chapter aims at providing a comprehensive insight into the most recent advances in the field of P2P architectures for video broadcasting, focusing on live video streaming P2P live video streaming . After introducing a classification of P2P video solutions, the first part of the Chapter provides an overview of the most interesting P2P IP-TV P2P IP-TV systems currently available over the Internet. It also concentrates on the process of data diffusion within the P2P overlay and complements this view with some measurements that highlight the most salient features of P2P architectures. The second part of the Chapter completes the view, bringing up the modeling efforts to capture the main characteristics and limits of P2P streaming systems, both analytically and numerically. The Chapter is closed by a pristine look at some challenging, open questions, with a specific emphasis on the adoption of network coding in P2P streaming solutions.

  19. IP-Based Video Modem Extender Requirements

    SciTech Connect

    Pierson, L G; Boorman, T M; Howe, R E

    2003-12-16

    Visualization is one of the keys to understanding large complex data sets such as those generated by the large computing resources purchased and developed by the Advanced Simulation and Computing program (aka ASCI). In order to be convenient to researchers, visualization data must be distributed to offices and large complex visualization theaters. Currently, local distribution of the visual data is accomplished by distance limited modems and RGB switches that simply do not scale to hundreds of users across the local, metropolitan, and WAN distances without incurring large costs in fiber plant installation and maintenance. Wide Area application over the DOE Complex is infeasible using these limited distance RGB extenders. On the other hand, Internet Protocols (IP) over Ethernet is a scalable well-proven technology that can distribute large volumes of data over these distances. Visual data has been distributed at lower resolutions over IP in industrial applications. This document describes requirements of the ASCI program in visual signal distribution for the purpose of identifying industrial partners willing to develop products to meet ASCI's needs.

  20. Contribution of the maritime continent convection during the preconditioning stage of the Madden-Julian Oscillation

    NASA Astrophysics Data System (ADS)

    Kubota, H.; Yoneyama, K.; Nasuno, T.; Hamada, J.

    2013-12-01

    During the international field experiment 'Cooperative Indian Ocean experiment on intraseasonal variability in the Year 2011 (CINDY2011)', the preconditioning process of the MJO was observed. In this study, the contribution of the maritime continent convection was focused on the preconditioning process of the third MJO. During the preconditioning stage of the MJO, westward propagating disturbances were observed from Sumatera Island to the central Indian Ocean and moistened the atmosphere. Convections over the Sumatera Island were activated around December 15th when the moist air mass reached from South China Sea. The origin of the moist air mass was tropical cyclone which was formed in South China Sea in December 10th. The high moisture associated with tropical cyclone activated the convection over Sumatera Island, promoted westward propagating disturbances, and acted a favorable environment for the preconditioning of the MJO. This preconditioning stage of the MJO is simulated by Nonhydrostatic ICosahedral Atmospheric Model (NICAM) and investigated the moistening process.

  1. Candesartan and glycyrrhizin ameliorate ischemic brain damage through downregulation of the TLR signaling cascade.

    PubMed

    Barakat, Waleed; Safwet, Nancy; El-Maraghy, Nabila N; Zakaria, Mohamed N M

    2014-02-01

    Stroke is the second leading cause of death in industrialized countries and the most frequent cause of permanent disability in adults worldwide. The final outcome of stroke is determined not only by the volume of the ischemic core, but also by the extent of secondary brain damage inflicted to penumbral tissues by brain swelling, impaired microcirculation, and inflammation. The only drug approved for the treatment ischemic stroke is recombinant tissue plasminogen activator (rt-PA). The current study was designed to investigate the protective effects of candesartan (0.15 mg/kg, orally) and glycyrrhizin (30 mg/kg, orally) experimentally-induced ischemic brain damage in C57BL/6 mice (middle cerebral artery occlusion, MCAO) in comparison to the effects of a standard neuroprotective drug (cerebrolysin, 7.5 mg/kg, IP). All drugs were administered 30 min before and 24h after MCAO. Both candesartan and glycyrrhizin ameliorated the deleterious effects of MCAO as indicated by the improvement in the performance of the animals in behaviour tests, reduction in brain infarction, neuronal degeneration, and leukocyte infiltration. In addition, MCAO induced a significant upregulation in the different elements of the TLR pathway including TLR-2 and TLR-4, Myd88, TRIF and IRF-3 and the downstream effectors TNF-α, IL-1β, IL-6 and NF-kB. All these changes were significantly ameliorated by treatment with candesartan and glycyrrhizin. The results of the current study represent a new indication for both candesartan and glycyrrhizin in the management of ischemic stroke with effects comparable to those of the standard neuroprotective drug cerebrolysin. PMID:24378346

  2. Citalopram Enhances Neurovascular Regeneration and Sensorimotor Functional Recovery after Ischemic Stroke in Mice

    PubMed Central

    Espinera, Alyssa R.; Ogle, Molly E.; Gu, Xiaohuan; Wei, Ling

    2013-01-01

    Recent clinical trials have demonstrated that treatment with selective serotonin reuptake inhibitors (SSRIs) after stroke enhances motor functional recovery; however, the underlying mechanisms remain to be further elucidated. We hypothesized that daily administration of the clinical drug citalopram would produce these functional benefits via enhancing neurovascular repair in the ischemic peri-infarct region. To test this hypothesis, focal ischemic stroke was induced in male C57/B6 mice by permanent ligation of distal branches of the middle cerebral artery to the barrel cortex and 7-min occlusion of the bilateral common carotid arteries. Citalopram (10 mg/kg, i.p.) was injected 24 hrs after stroke and daily thereafter. To label proliferating cells, bromo-deoxyuridine was injected daily beginning 3 days after stroke. Immunohistochemical and functional assays were performed to elucidate citalopram-mediated cellular and sensorimotor changes after stroke. Citalopram treatment had no significant effect on infarct formation or edema 3 days after stroke; however, citalopram-treated mice had better functional recovery than saline-treated controls 3 and 14 days after stroke in the adhesive removal test. Increased expression of brain derived neurotrophic factor was detected in the peri-infarct region 7 days after stroke in citalopram-treated animals. The number of proliferating neural progenitor cells and the distance of neuroblast migration from the sub-ventricular zone towards the ischemic cortex were significantly greater in citalopram-treated mice at 7 days after stroke. Immunohistochemical staining and co-localization analysis showed that citalopram-treated animals generated more new neurons and microvessels in the peri-infarct region 21 and 28 days after stroke. Taken together, these results suggest that citalopram promotes post-stroke sensorimotor recovery likely via enhancing neurogenesis, neural cell migration and the microvessel support in the peri-infarct region of

  3. Argon Induces Protective Effects in Cardiomyocytes during the Second Window of Preconditioning

    PubMed Central

    Mayer, Britta; Soppert, Josefin; Kraemer, Sandra; Schemmel, Sabrina; Beckers, Christian; Bleilevens, Christian; Rossaint, Rolf; Coburn, Mark; Goetzenich, Andreas; Stoppe, Christian

    2016-01-01

    Increasing evidence indicates that argon has organoprotective properties. So far, the underlying mechanisms remain poorly understood. Therefore, we investigated the effect of argon preconditioning in cardiomyocytes within the first and second window of preconditioning. Primary isolated cardiomyocytes from neonatal rats were subjected to 50% argon for 1 h, and subsequently exposed to a sublethal dosage of hypoxia (<1% O2) for 5 h either within the first (0–3 h) or second window (24–48 h) of preconditioning. Subsequently, the cell viability and proliferation was measured. The argon-induced effects were assessed by evaluation of mRNA and protein expression after preconditioning. Argon preconditioning did not show any cardioprotective effects in the early window of preconditioning, whereas it leads to a significant increase of cell viability 24 h after preconditioning compared to untreated cells (p = 0.015) independent of proliferation. Argon-preconditioning significantly increased the mRNA expression of heat shock protein (HSP) B1 (HSP27) (p = 0.048), superoxide dismutase 2 (SOD2) (p = 0.001), vascular endothelial growth factor (VEGF) (p < 0.001) and inducible nitric oxide synthase (iNOS) (p = 0.001). No difference was found with respect to activation of pro-survival kinases in the early and late window of preconditioning. The findings provide the first evidence of argon-induced effects on the survival of cardiomyocytes during the second window of preconditioning, which may be mediated through the induction of HSP27, SOD2, VEGF and iNOS. PMID:27447611

  4. Argon Induces Protective Effects in Cardiomyocytes during the Second Window of Preconditioning.

    PubMed

    Mayer, Britta; Soppert, Josefin; Kraemer, Sandra; Schemmel, Sabrina; Beckers, Christian; Bleilevens, Christian; Rossaint, Rolf; Coburn, Mark; Goetzenich, Andreas; Stoppe, Christian

    2016-01-01

    Increasing evidence indicates that argon has organoprotective properties. So far, the underlying mechanisms remain poorly understood. Therefore, we investigated the effect of argon preconditioning in cardiomyocytes within the first and second window of preconditioning. Primary isolated cardiomyocytes from neonatal rats were subjected to 50% argon for 1 h, and subsequently exposed to a sublethal dosage of hypoxia (<1% O₂) for 5 h either within the first (0-3 h) or second window (24-48 h) of preconditioning. Subsequently, the cell viability and proliferation was measured. The argon-induced effects were assessed by evaluation of mRNA and protein expression after preconditioning. Argon preconditioning did not show any cardioprotective effects in the early window of preconditioning, whereas it leads to a significant increase of cell viability 24 h after preconditioning compared to untreated cells (p = 0.015) independent of proliferation. Argon-preconditioning significantly increased the mRNA expression of heat shock protein (HSP) B1 (HSP27) (p = 0.048), superoxide dismutase 2 (SOD2) (p = 0.001), vascular endothelial growth factor (VEGF) (p < 0.001) and inducible nitric oxide synthase (iNOS) (p = 0.001). No difference was found with respect to activation of pro-survival kinases in the early and late window of preconditioning. The findings provide the first evidence of argon-induced effects on the survival of cardiomyocytes during the second window of preconditioning, which may be mediated through the induction of HSP27, SOD2, VEGF and iNOS. PMID:27447611

  5. Study of retinal vessel oxygen saturation in ischemic and non-ischemic branch retinal vein occlusion

    PubMed Central

    Lin, Lei-Lei; Dong, Yan-Min; Zong, Yao; Zheng, Qi-Shan; Fu, Yue; Yuan, Yong-Guang; Huang, Xia; Qian, Garrett; Gao, Qian-Ying

    2016-01-01

    AIM To explore how oxygen saturation in retinal blood vessels is altered in ischemic and non-ischemic branch retinal vein occlusion (BRVO). METHODS Fifty BRVO eyes were divided into ischemic (n=26) and non-ischemic (n=24) groups, based on fundus fluorescein angiography. Healthy individuals (n=52 and n=48, respectively) were also recruited as controls for the two groups. The mean oxygen saturations of the occluded vessels and central vessels were measured by oximetry in the BRVO and control groups. RESULTS In the ischemic BRVO group, the occluded arterioles oxygen saturation (SaO2-A, 106.0%±14.3%), instead of the occluded venule oxygen saturation (SaO2-V, 60.8%±9.4%), showed increases when compared with those in the same quadrant vessels (SaO2-A, 86.1%±16.5%) in the contralateral eyes (P<0.05). The oxygen saturations of the central vessels showed similar trends with those of the occluded vessels. In the non-ischemic BRVO group, the occluded and central SaO2-V and SaO2-A showed no significant changes. In both the ischemic and non-ischemic BRVOs, the central SaO2-A was significantly increased when compared to healthy individuals. CONCLUSION Obvious changes in the occluded and central SaO2-A were found in the ischemic BRVO group, indicating that disorders of oxygen metabolism in the arterioles may participate in the pathogenesis of ischemic BRVO. PMID:26949618

  6. Brain protection against ischemic stroke using choline as a new molecular bypass treatment

    PubMed Central

    Jin, Xin; Wang, Ru-huan; Wang, Hui; Long, Chao-liang; Wang, Hai

    2015-01-01

    Aim: To determine whether administration of choline could attenuate brain injury in a rat model of ischemic stroke and the underlying mechanisms. Methods: A rat model of ischemic stroke was established through permanent middle cerebral artery occlusion (pMCAO). After the surgery, the rats were treated with choline or choline plus the specific α7 nAChR antagonist methyllycaconitine (MLA), or with the control drug nimodipine for 10 days. The neurological deficits, brain-infarct volume, pial vessel density and the number of microvessels in the cortex were assessed. Rat brain microvascular endothelial cells (rBMECs) cultured under hypoxic conditions were used in in vitro experiments. Results: Oral administration of choline (100 or 200 mg·kg−1·d−1) or nimodipine (20 mg·kg−1·d−1) significantly improved neurological deficits, and reduced infarct volume and nerve cell loss in the ischemic cerebral cortices in pMCAO rats. Furthermore, oral administration of choline, but not nimodipine, promoted the pial arteriogenesis and cerebral-cortical capillary angiogenesis in the ischemic regions. Moreover, oral administration of choline significantly augmented pMCAO-induced increases in the expression levels of α7 nAChR, HIF-1α and VEGF in the ischemic cerebral cortices as well as in the serum levels of VEGF. Choline-induced protective effects were prevented by co-treatment with MLA (1 mg·kg−1·d−1, ip). Treatment of rBMECs cultured under hypoxic conditions in vitro with choline (1, 10 and 100 μmol/L) dose-dependently promoted the endothelial-cell proliferation, migration and tube formation, as well as VEGF secretion, which were prevented by co-treatment with MLA (1 μmol/L) or by transfection with HIF-1α siRNA. Conclusion: Choline effectively attenuates brain ischemic injury in pMCAO rats, possibly by facilitating pial arteriogenesis and cerebral-cortical capillary angiogenesis via upregulating α7 nAChR levels and inducing the expression of HIF-1α and VEGF

  7. [Experimental model of ocular ischemic diseases].

    PubMed

    Kiseleva, T N; Chudin, A V

    2014-01-01

    The review presents the most common methods of modeling of retinal ischemia in vitro (chemical ischemia with iodoacetic acid, incubation of the retinal pigment epithelium cells with oligomycin, deprivation of oxygen and glucose) and in vivo (a model with increased intraocular pressure, cerebral artery occlusion, chronic ligation of the carotid arteries, photocoagulation of the retinal vessels, occlusion of the central retinal artery, endothelin-1 administration). Modeling ischemic injury in rats is the most frequently used method in studies, because the blood supply of their eyes is similar to blood flow in the human eyes. Each method has its own advantages and disadvantages. Application of methods depends on the purpose of the experimental study. Currently model of ocular ischemic disease can be obtained easily by injecting vasoconstrictive drug endothelin-1. It is the most widely used method of high intraocular pressure induced ocular ischemic damage similar to glaucoma, occlusion of central retinal artery or ophthalmic artery in human. The development of experimental models of ocular ischemic diseases and detailed investigation of mechanisms of impairment of microcirculation are useful for improve the efficiency of diagnostic and treatment of ischemic diseases of retina and optic nerve. PMID:25971134

  8. Small vessel hematocrit in ischemic myocardium

    SciTech Connect

    Gumm, D.C.; Cooper, S.M.; Marcus, M.L.; Chilian, W.M.; Harrison, D.G.

    1986-03-01

    As blood enters the microvasculature of normally perfused myocardium, there is a progressive decrease in small vessel hematocrit (SV Hct) due to RBC streaming in smaller branching vessels and the Fahraeus-Lindqvist effect. We hypothesized that if the coronary collateral circulation was composed of very small vessels branching from large parent vessels, plasma streaming would result in a further decrease of SV Hct in ischemic myocardium. Six open chest anesthetized dogs were studied. Plasma was labelled with /sup 59/FeCl siderophilin and RBC's with /sup 99/mTc to estimate SV Hct from myocardial biopsies. The LAD was occluded and cannulated for measurement of retrograde flow (arising presumably from proximal collaterals). The ischemic region was identified using the microsphere shadow technique. Collateral flow after LAD occlusion was 30 +- 12 ml/min 100g (x +- SE). Systemic Hct was 40 +- 1%. The Hct of blood from retrograde flow was 39 +- 1% (p = NS). Activity of /sup 59/FeCl and /sup 99/mTc in known quantities of blood were compared to myocardial biopsies to estimate SV Hct. Ischemic SV Hct was 23 +- 2% and non-ischemic SV Hct was 21 +- 1% (p = NS). We conclude that the size and branching pattern of coronary collaterals is such that plasma streaming in collaterals does not result in an additional decrease in SV Hct in ischemic myocardium.

  9. Calcium preconditioning triggers neuroprotection in retinal ganglion cells.

    PubMed

    Brandt, S K; Weatherly, M E; Ware, L; Linn, D M; Linn, C L

    2011-01-13

    In the mammalian retina, excitotoxicity has been shown to be involved in apoptotic retinal ganglion cell (RGC) death and is associated with certain retinal disease states including glaucoma, diabetic retinopathy and retinal ischemia. Previous studies from this lab [Wehrwein E, Thompson SA, Coulibaly SF, Linn DM, Linn CL (2004) Invest Ophthalmol Vis Sci 45:1531-1543] have demonstrated that acetylcholine (ACh) and nicotine protects against glutamate-induced excitotoxicity in isolated adult pig RGCs through nicotinic acetylcholine receptors (nAChRs). Activation of nAChRs in these RGCs triggers cell survival signaling pathways and inhibits apoptotic enzymes [Asomugha CO, Linn DM, Linn CL (2010) J Neurochem 112:214-226]. However, the link between binding of nAChRs and activation of neuroprotective pathways is unknown. In this study, we examine the hypothesis that calcium permeation through nAChR channels is required for ACh-induced neuroprotection against glutamate-induced excitotoxicity in isolated pig RGCs. RGCs were isolated from other retinal tissue using a two step panning technique and cultured for 3 days under different conditions. In some studies, calcium imaging experiments were performed using the fluorescent calcium indicator, fluo-4, and demonstrated that calcium permeates the nAChR channels located on pig RGCs. In other studies, the extracellular calcium concentration was altered to determine the effect on nicotine-induced neuroprotection. Results support the hypothesis that calcium is required for nicotine-induced neuroprotection in isolated pig RGCs. Lastly, studies were performed to analyze the effects of preconditioning on glutamate-induced excitotoxicity and neuroprotection. In these studies, a preconditioning dose of calcium was introduced to cells using a variety of mechanisms before a large glutamate insult was applied to cells. Results from these studies support the hypothesis that preconditioning cells with a relatively low level of calcium before

  10. Telemetry and Communication IP Video Player

    NASA Technical Reports Server (NTRS)

    OFarrell, Zachary L.

    2011-01-01

    Aegis Video Player is the name of the video over IP system for the Telemetry and Communications group of the Launch Services Program. Aegis' purpose is to display video streamed over a network connection to be viewed during launches. To accomplish this task, a VLC ActiveX plug-in was used in C# to provide the basic capabilities of video streaming. The program was then customized to be used during launches. The VLC plug-in can be configured programmatically to display a single stream, but for this project multiple streams needed to be accessed. To accomplish this, an easy to use, informative menu system was added to the program to enable users to quickly switch between videos. Other features were added to make the player more useful, such as watching multiple videos and watching a video in full screen.

  11. An IP Traceback Model for Network Forensics

    NASA Astrophysics Data System (ADS)

    Pilli, Emmanuel S.; Joshi, R. C.; Niyogi, Rajdeep

    Network forensics deals with capture, recording, analysis and investigation of network traffic to traceback the attackers. Its ultimate goal is to provide sufficient evidence to allow the perpetrator to be prosecuted. IP traceback is an important aspect in the investigation process where the real attacker is identified by tracking source address of the attack packets. In this paper we classify the various approaches to network forensics to list the requirements of the traceback. We propose a novel model for traceback based on autonomous systems (AS) and deterministic packet marking (DPM) to enable traceback even with a single packet. The model is analyzed against various evaluation metrics. The traceback solution will be a major step in the direction of attack attribution and investigation.

  12. Security Research on VoIP with Watermarking

    NASA Astrophysics Data System (ADS)

    Hu, Dong; Lee, Ping

    2008-11-01

    With the wide application of VoIP, many problems have occurred. One of the problems is security. The problems with securing VoIP systems, insufficient standardization and lack of security mechanisms emerged the need for new approaches and solutions. In this paper, we propose a new security architecture for VoIP which is based on digital watermarking which is a new, flexible and powerful technology that is increasingly gaining more and more attentions. Besides known applications e.g. to solve copyright protection problems, we propose to use digital watermarking to secure not only transmitted audio but also signaling protocol that VoIP is based on.

  13. A Scalable and Practical Authentication Protocol in Mobile IP

    NASA Astrophysics Data System (ADS)

    Lee, Yong; Lee, Goo-Yeon; Kim, Hwa-Long

    Due to the proliferation of mobile devices connected to the Internet, implementing a secure and practical Mobile IP has become an important goal. A mobile IP can not work properly without authentication between the mobile node (MN), the home agent (HA) and the foreign agent (FA). In this paper, we propose a practical Mobile IP authentication protocol that uses public key cryptography only during the initial authentication. The proposed scheme is compatible with the conventional Mobile IP protocol and provides scalability against the number of MN's. We also show that the proposed protocol offers secure operation.

  14. Chromosome and genetic testing using ChIP assay.

    PubMed

    Kohzaki, Hidetsugu; Asano, Maki

    2016-01-01

    Chromatin immunoprecipitation (ChIP) assay can be used to easily visualize information about proteins, DNA, and RNA on chromosomes and is widely used for analysis of genomes, epigenomes, mRNAs, and non-coding RNAs. The ChIP assay can detect, not only DNA-binding proteins of various organisms, but also the temporal and spatial regulating mechanisms of RNA-binding proteins. Because of these features, demand for ChIP assay is expected to grow. Here, by using yeast and Drosophila as examples, we describe the superiority of the improved ChIP assay that we have developed. PMID:27100707

  15. Machinability of IPS Empress 2 framework ceramic.

    PubMed

    Schmidt, C; Weigl, P

    2000-01-01

    Using ceramic materials for an automatic production of ceramic dentures by CAD/CAM is a challenge, because many technological, medical, and optical demands must be considered. The IPS Empress 2 framework ceramic meets most of them. This study shows the possibilities for machining this ceramic with economical parameters. The long life-time requirement for ceramic dentures requires a ductile machined surface to avoid the well-known subsurface damages of brittle materials caused by machining. Slow and rapid damage propagation begins at break outs and cracks, and limits life-time significantly. Therefore, ductile machined surfaces are an important demand for machine dental ceramics. The machining tests were performed with various parameters such as tool grain size and feed speed. Denture ceramics were machined by jig grinding on a 5-axis CNC milling machine (Maho HGF 500) with a high-speed spindle up to 120,000 rpm. The results of the wear test indicate low tool wear. With one tool, you can machine eight occlusal surfaces including roughing and finishing. One occlusal surface takes about 60 min machining time. Recommended parameters for roughing are middle diamond grain size (D107), cutting speed v(c) = 4.7 m/s, feed speed v(ft) = 1000 mm/min, depth of cut a(e) = 0.06 mm, width of contact a(p) = 0.8 mm, and for finishing ultra fine diamond grain size (D46), cutting speed v(c) = 4.7 m/s, feed speed v(ft) = 100 mm/min, depth of cut a(e) = 0.02 mm, width of contact a(p) = 0.8 mm. The results of the machining tests give a reference for using IPS Empress(R) 2 framework ceramic in CAD/CAM systems. PMID:10898875

  16. Lessons Learned in the Design and Use of IP1 / IP2 Flexible Packaging - 13621

    SciTech Connect

    Sanchez, Mike; Reeves, Wendall; Smart, Bill

    2013-07-01

    For many years in the USA, Low Level Radioactive Waste (LLW), contaminated soils and construction debris, have been transported, interim stored, and disposed of, using IP1 / IP2 metal containers. The performance of these containers has been more than adequate, with few safety occurrences. The containers are used under the regulatory oversight of the US Department of Transportation (DOT), 49 Code of Federal Regulations (CFR). In the late 90's the introduction of flexible packaging for the transport, storage, and disposal of low level contaminated soils and construction debris was introduced. The development of flexible packaging came out of a need for a more cost effective package, for the large volumes of waste generated by the decommissioning of many of the US Department of Energy (DOE) legacy sites across the US. Flexible packaging had to be designed to handle a wide array of waste streams, including soil, gravel, construction debris, and fine particulate dust migration. The design also had to meet all of the IP1 requirements under 49CFR 173.410, and be robust enough to pass the IP2 testing 49 CFR 173.465 required for many LLW shipments. Tens of thousands of flexible packages have been safely deployed and used across the US nuclear industry as well as for hazardous non-radioactive applications, with no recorded release of radioactive materials. To ensure that flexible packages are designed properly, the manufacturer must use lessons learned over the years, and the tests performed to provide evidence that these packages are suitable for transporting low level radioactive wastes. The design and testing of flexible packaging for LLW, VLLW and other hazardous waste streams must be as strict and stringent as the design and testing of metal containers. The design should take into consideration the materials being loaded into the package, and should incorporate the right materials, and manufacturing methods, to provide a quality, safe product. Flexible packaging can be

  17. Magnetic Resonance Characterization of Ischemic Tissue Metabolism

    PubMed Central

    Cheung, Jerry S; Wang, Xiaoying; Zhe Sun, Phillip

    2011-01-01

    Magnetic resonance imaging (MRI) and spectroscopy (MRS) are versatile diagnostic techniques capable of characterizing the complex stroke pathophysiology, and hold great promise for guiding stroke treatment. Particularly, tissue viability and salvageability are closely associated with its metabolic status. Upon ischemia, ischemic tissue metabolism is disrupted including altered metabolism of glucose and oxygen, elevated lactate production/accumulation, tissue acidification and eventually, adenosine triphosphate (ATP) depletion and energy failure. Whereas metabolism impairment during ischemic stroke is complex, it may be monitored non-invasively with magnetic resonance (MR)-based techniques. Our current article provides a concise overview of stroke pathology, conventional and emerging imaging and spectroscopy techniques, and data analysis tools for characterizing ischemic tissue damage. PMID:22216079

  18. Spectroscopic Monitoring of Kidney Tissue Ischemic Injury

    SciTech Connect

    Demos, S G; Fitzgerald, J T; Michalopoulou, A P; Troppmann, C

    2004-03-11

    Noninvasive evaluation of tissue viability of donor kidneys used for transplantation is an issue that current technology is not able to address. In this work, we explore optical spectroscopy for its potential to assess the degree of ischemic damage in kidney tissue. We hypothesized that ischemic damage to kidney tissue will give rise to changes in its optical properties which in turn may be used to asses the degree of tissue injury. The experimental results demonstrate that the autofluorescence intensity of the injured kidney is decreasing as a function of time exposed to ischemic injury. Changes were also observed in the NIR light scattering intensities most probably arising from changes due to injury and death of the tissue.

  19. Resilience in Patients with Ischemic Heart Disease

    PubMed Central

    de Lemos, Conceição Maria Martins; Moraes, David William; Pellanda, Lucia Campos

    2016-01-01

    Background Resilience is a psychosocial factor associated with clinical outcomes in chronic diseases. The relationship between this protective factor and certain diseases, such heart diseases, is still under-explored. Objective The present study sought to investigate the frequency of resilience in individuals with ischemic heart disease. Method This was a cross-sectional study with 133 patients of both genders, aged between 35 and 65 years, treated at Rio Grande do Sul Cardiology Institute - Cardiology University Foundation, with a diagnosis of ischemic heart disease during the study period. Sixty-seven patients had a history of acute myocardial infarction. The individuals were interviewed and evaluated by the Wagnild & Young resilience scale and a sociodemographic questionnaire. Results Eighty-one percent of patients were classified as resilient according to the scale. Conclusion In the sample studied, resilience was identified in high proportion among patients with ischemic heart disease. PMID:26815312

  20. Parallel preconditioning for the solution of nonsymmetric banded linear systems

    SciTech Connect

    Amodio, P.; Mazzia, F.

    1994-12-31

    Many computational techniques require the solution of banded linear systems. Common examples derive from the solution of partial differential equations and of boundary value problems. In particular the authors are interested in the parallel solution of block Hessemberg linear systems Gx = f, arising from the solution of ordinary differential equations by means of boundary value methods (BVMs), even if the considered preconditioning may be applied to any block banded linear system. BVMs have been extensively investigated in the last few years and their stability properties give promising results. A new class of BVMs called Reverse Adams, which are BV-A-stable for orders up to 6, and BV-A{sub 0}-stable for orders up to 9, have been studied.

  1. Preconditioned Mixed Spectral Element Methods for Elasticity and Stokes Problems

    NASA Technical Reports Server (NTRS)

    Pavarino, Luca F.

    1996-01-01

    Preconditioned iterative methods for the indefinite systems obtained by discretizing the linear elasticity and Stokes problems with mixed spectral elements in three dimensions are introduced and analyzed. The resulting stiffness matrices have the structure of saddle point problems with a penalty term, which is associated with the Poisson ratio for elasticity problems or with stabilization techniques for Stokes problems. The main results of this paper show that the convergence rate of the resulting algorithms is independent of the penalty parameter, the number of spectral elements Nu and mildly dependent on the spectral degree eta via the inf-sup constant. The preconditioners proposed for the whole indefinite system are block-diagonal and block-triangular. Numerical experiments presented in the final section show that these algorithms are a practical and efficient strategy for the iterative solution of the indefinite problems arising from mixed spectral element discretizations of elliptic systems.

  2. Institutionalized ignorance as a precondition for rational risk expertise.

    PubMed

    Merkelsen, Henrik

    2011-07-01

    The present case study seeks to explain the conditions for experts' rational risk perception by analyzing the institutional contexts that constitute a field of food safety expertise in Denmark. The study highlights the role of risk reporting and how contextual factors affect risk reporting from the lowest organizational level, where concrete risks occur, to the highest organizational level, where the body of professional risk expertise is situated. The article emphasizes the role of knowledge, responsibility, loyalty, and trust as risk-attenuation factors and concludes by suggesting that the preconditions for the expert's rationality may rather be a lack of risk-specific knowledge due to poor risk reporting than a superior level of risk knowledge. PMID:21284683

  3. A frequency dependent preconditioned wavelet method for atmospheric tomography

    NASA Astrophysics Data System (ADS)

    Yudytskiy, Mykhaylo; Helin, Tapio; Ramlau, Ronny

    2013-12-01

    Atmospheric tomography, i.e. the reconstruction of the turbulence in the atmosphere, is a main task for the adaptive optics systems of the next generation telescopes. For extremely large telescopes, such as the European Extremely Large Telescope, this problem becomes overly complex and an efficient algorithm is needed to reduce numerical costs. Recently, a conjugate gradient method based on wavelet parametrization of turbulence layers was introduced [5]. An iterative algorithm can only be numerically efficient when the number of iterations required for a sufficient reconstruction is low. A way to achieve this is to design an efficient preconditioner. In this paper we propose a new frequency-dependent preconditioner for the wavelet method. In the context of a multi conjugate adaptive optics (MCAO) system simulated on the official end-to-end simulation tool OCTOPUS of the European Southern Observatory we demonstrate robustness and speed of the preconditioned algorithm. We show that three iterations are sufficient for a good reconstruction.

  4. Rural water-supply and sanitation planning: The use of socioeconomic preconditions in project identification

    NASA Astrophysics Data System (ADS)

    Warner, Dennis B.

    1984-02-01

    Recognition of the socioeconomic preconditions for successful rural water-supply and sanitation projects in developing countries is the key to identifying a new project. Preconditions are the social, economic and technical characteristics defining the project environment. There are two basic types of preconditions: those existing at the time of the initial investigation and those induced by subsequent project activities. Successful project identification is dependent upon an accurate recognition of existing constraints and a carefully tailored package of complementary investments intended to overcome the constraints. This paper discusses the socioeconomic aspects of preconditions in the context of a five-step procedure for project identification. The procedure includes: (1) problem identification; (2) determination of socioeconomic status; (3) technology selection; (4) utilization of support conditions; and (5) benefit estimation. Although the establishment of specific preconditions should be based upon the types of projects likely to be implemented, the paper outlines a number of general relationships regarding favourable preconditions in water and sanitation planning. These relationships are used within the above five-step procedure to develop a set of general guidelines for the application of preconditions in the identification of rural water-supply and sanitation projects.

  5. The Effect of Hypoxic Preconditioning on Induced Schwann Cells under Hypoxic Conditions

    PubMed Central

    Chen, Ou; Wu, Miaomiao; Jiang, Liangfu

    2015-01-01

    Object Our objective was to explore the protective effects of hypoxic preconditioning on induced Schwann cells exposed to an environment with low concentrations of oxygen. It has been observed that hypoxic preconditioning of induced Schwann cells can promote axonal regeneration under low oxygen conditions. Method Rat bone marrow mesenchymal stem cells (MSCs) were differentiated into Schwann cells and divided into a normal oxygen control group, a hypoxia-preconditioning group and a hypoxia group. The ultrastructure of each of these groups of cells was observed by electron microscopy. In addition, flow cytometry was used to measure changes in mitochondrial membrane potential. Annexin V-FITC/PI staining was used to detect apoptosis, and Western blots were used to detect the expression of Bcl-2/Bax. Fluorescence microscopic observations of axonal growth in NG-108 cells under hypoxic conditions were also performed. Results The hypoxia-preconditioning group maintained mitochondrial cell membrane and crista integrity, and these cells exhibited less edema than the hypoxia group. In addition, the cells in the hypoxia-preconditioning group were found to be in early stages of apoptosis, whereas cells from the hypoxia group were in the later stages of apoptosis. The hypoxia-preconditioning group also had higher levels of Bcl-2/Bax expression and longer NG-108 cell axons than were observed in the hypoxia group. Conclusion Hypoxic preconditioning can improve the physiological state of Schwann cells in a severe hypoxia environment and improve the ability to promote neurite outgrowth. PMID:26509259

  6. Drug Delivery to the Ischemic Brain

    PubMed Central

    Thompson, Brandon J.; Ronaldson, Patrick T.

    2014-01-01

    Cerebral ischemia occurs when blood flow to the brain is insufficient to meet metabolic demand. This can result from cerebral artery occlusion that interrupts blood flow, limits CNS supply of oxygen and glucose, and causes an infarction/ischemic stroke. Ischemia initiates a cascade of molecular events inneurons and cerebrovascular endothelial cells including energy depletion, dissipation of ion gradients, calcium overload, excitotoxicity, oxidative stress, and accumulation of ions and fluid. Blood-brain barrier (BBB) disruption is associated with cerebral ischemia and leads to vasogenic edema, a primary cause of stroke-associated mortality. To date, only a single drug has received US Food and Drug Administration (FDA) approval for acute ischemic stroke treatment, recombinant tissue plasminogen activator (rt-PA). While rt-PA therapy restores perfusion to ischemic brain, considerable tissue damage occurs when cerebral blood flow is re-established. Therefore, there is a critical need for novel therapeutic approaches that can “rescue” salvageable brain tissue and/or protect BBB integrity during ischemic stroke. One class of drugs that may enable neural cell rescue following cerebral ischemia/reperfusion injury is the HMG-CoA reductase inhibitors (i.e., statins). Understanding potential CNS drug delivery pathways for statins is critical to their utility in ischemic stroke. Here, we review molecular pathways associated with cerebral ischemia and novel approaches for delivering drugs to treat ischemic disease. Specifically, we discuss utility of endogenous BBB drug uptake transporters such as organic anion transporting polypeptides (OATPs/Oatps) and nanotechnology-based carriers for optimization of CNS drug delivery. Overall, this chapter highlights state-of-the-art technologies that may improve pharmacotherapy of cerebral ischemia. PMID:25307217

  7. Flow Augmentation in Acute Ischemic Stroke.

    PubMed

    Yadollahikhales, Golnaz; Borhani-Haghighi, Afshin; Torabi-Nami, Mohammad; Edgell, Randall; Cruz-Flores, Salvador

    2016-01-01

    There is an urgent need for additional therapeutic options for acute ischemic stroke considering the major pitfalls of the options available. Herein, we briefly review the role of cerebral blood flow, collaterals, vasoreactivity, and reperfusion injury in acute ischemic stroke. Then, we reviewed pharmacological and interventional measures such as volume expansion and induced hypertension, intra-aortic balloon counterpulsation, partial aortic occlusion, extracranial-intracranial carotid bypass surgery, sphenopalatine ganglion stimulation, and transcranial laser therapy with regard to their effects on flow augmentation and neuroprotection. PMID:25475112

  8. Ischemic Gastropathic Ulcer Mimics Gastric Cancer

    PubMed Central

    Daher, Saleh; Lahav, Ziv; Rmeileh, Ayman Abu; Mizrahi, Meir

    2016-01-01

    Gastric ulcer due to mesenteric ischemia is a rare clinical finding. As a result, few reports of ischemic gastric ulcers have been reported in the literature. The diagnosis of ischemic gastropathy is seldom considered in patients presenting with abdominal pain and gastric ulcers. In this case report, we describe a patient with increasing abdominal pain, weight loss, and gastric ulcers, who underwent extensive medical evaluation and whose symptoms were resistant to medical interventions. Finally he was diagnosed with chronic mesenteric ischemia, and his clinical and endoscopic abnormalities resolved after surgical revascularization of both the superior mesenteric artery and the celiac trunk. PMID:27579191

  9. [Reactive oxygen species are triggers and mediators of an increase in cardiac tolerance to impact of ischemia-reperfusion].

    PubMed

    Maslov, L N; Naryzhnaia, N V; Podoksenov, Iu K; Prokudina, E S; Gorbunov, A S; Zhang, I; Peĭ, Zh-M

    2015-01-01

    Reactive oxygen species (ROS) are triggers of ischemic preconditioning (IP). On the role of intracellular messengers of such cardioprotective effect of preconditioning claim: O2*, H2O2, OH*. However, we cannot exclude the possibility that other reactive oxygen metabolites also involved in the IP. Presented data suggest that IP enhances the production of ROS. The source of ROS may be mitochondrial respiratory chain and NADPH oxidase. Exogenous reactive oxygen species (O2*, H2O2) mimic the cardioprotective effect of preconditioning. Preconditioning prevents free radical damage of the heart during ischemia-reperfusion. The protective effect of IP is the consequence of reducing the production of ROS or the result of increased formation of endogenous antioxidants. Antioxidant enzymes are not involved in the protective effect of IP. Cardioprotective effect of many compounds (bradykinin, opioids, acetylcholine, phenylephrine, tumor necrosis factor-α, volatile anesthetics, protonophores, diazoxide, angiotensin II) depends on the increased production of ROS. PMID:25868322

  10. Sonographic and Endoscopic Findings in Cocaine-Induced Ischemic Colitis

    PubMed Central

    Leth, Thomas; Wilkens, Rune; Bonderup, Ole K.

    2015-01-01

    Cocaine-induced ischemic colitis is a recognized entity. The diagnosis is based on clinical and endoscopic findings. However, diagnostic imaging is helpful in the evaluation of abdominal symptoms and prior studies have suggested specific sonographic findings in ischemic colitis. We report sonographic and endoscopic images along with abdominal computed tomography in a case of cocaine-induced ischemic colitis. PMID:26798523

  11. Eigenmode Analysis of Boundary Conditions for One-Dimensional Preconditioned Euler Equations

    NASA Technical Reports Server (NTRS)

    Darmofal, David L.

    1998-01-01

    An analysis of the effect of local preconditioning on boundary conditions for the subsonic, one-dimensional Euler equations is presented. Decay rates for the eigenmodes of the initial boundary value problem are determined for different boundary conditions. Riemann invariant boundary conditions based on the unpreconditioned Euler equations are shown to be reflective with preconditioning, and, at low Mach numbers, disturbances do not decay. Other boundary conditions are investigated which are non-reflective with preconditioning and numerical results are presented confirming the analysis.

  12. Safeguarding Nonhuman Primate iPS Cells With Suicide Genes

    PubMed Central

    Zhong, Bonan; Watts, Korashon L; Gori, Jennifer L; Wohlfahrt, Martin E; Enssle, Joerg; Adair, Jennifer E; Kiem, Hans-Peter

    2011-01-01

    The development of technology to generate induced pluripotent stem (iPS) cells constitutes one of the most exciting scientific breakthroughs because of the enormous potential for regenerative medicine. However, the safety of iPS cell-related products is a major concern for clinical translation. Insertional mutagenesis, possible oncogenic transformation of iPS cells or their derivatives, or the contamination of differentiated iPS cells with undifferentiated cells, resulting in the formation of teratomas, have remained considerable obstacles. Here, we demonstrate the utility of suicide genes to safeguard iPS cells and their derivatives. We found suicide genes can control the cell fate of iPS cells in vitro and in vivo without interfering with their pluripotency and self-renewal capacity. This study will be useful to evaluate the safety of iPS cell technology in a clinically highly relevant, large animal model and further benefit the clinical use of human iPS cells. PMID:21587213

  13. Fair Scheduling for Delay-Sensitive VoIP Traffic

    NASA Astrophysics Data System (ADS)

    Ahmed, Shawish; Jiang, Xiaohong; Horiguchi, Susumu

    With the wide expansion of voice services over the IP networks (VoIP), the volume of this delay sensitive traffic is steadily growing. The current packet schedulers for IP networks meet the delay constraint of VoIP traffic by simply assigning its packets the highest priority. This technique is acceptable as long as the amount of VoIP traffic is relatively very small compared to other non-voice traffic. With the notable expansion of VoIP applications, however, the current packet schedulers will significantly sacrifice the fairness deserved by the non-voice traffic. In this paper, we extend the conventional Deficit Round-Robin (DRR) scheduler by including a packet classifier, a Token Bucket and a resource reservation scheme and propose an integrated packet scheduler architecture for the growing VoIP traffic. We demonstrate through both theoretical analysis and extensive simulation that the new architecture makes it possible for us to significantly improve the fairness to non-voice traffic while still meeting the tight delay requirement of VoIP applications.

  14. Computational methodology for ChIP-seq analysis

    PubMed Central

    Shin, Hyunjin; Liu, Tao; Duan, Xikun; Zhang, Yong; Liu, X. Shirley

    2015-01-01

    Chromatin immunoprecipitation coupled with massive parallel sequencing (ChIP-seq) is a powerful technology to identify the genome-wide locations of DNA binding proteins such as transcription factors or modified histones. As more and more experimental laboratories are adopting ChIP-seq to unravel the transcriptional and epigenetic regulatory mechanisms, computational analyses of ChIP-seq also become increasingly comprehensive and sophisticated. In this article, we review current computational methodology for ChIP-seq analysis, recommend useful algorithms and workflows, and introduce quality control measures at different analytical steps. We also discuss how ChIP-seq could be integrated with other types of genomic assays, such as gene expression profiling and genome-wide association studies, to provide a more comprehensive view of gene regulatory mechanisms in important physiological and pathological processes. PMID:25741452

  15. Scalable Network Emulator Architecture for IP Optical Network Management

    NASA Astrophysics Data System (ADS)

    Oki, Eiji; Kitsuwan, Nattapong; Tsunoda, Shunichi; Miyamura, Takashi; Masuda, Akeo; Shiomoto, Kohei

    This letter proposes a scalable network emulator architecture to support IP optical network management. The network emulator uses the same router interfaces to communicate with the IP optical TE server as the actual IP optical network, and behaves as an actual IP optical network between the interfaces. The network emulator mainly consists of databases and three modules: interface module, resource simulator module, and traffic generator module. To make the network emulator scalable in terms of network size, we employ TCP/IP socket communications between the modules. The proposed network emulator has the benefit that its implementation is not strongly dependent on hardware limitations. We develop a prototype of the network emulator based on the proposed architecture. Our design and experiments show that the proposed architecture is effective.

  16. Research on implementation of proxy Arp in IP DSLAM

    NASA Astrophysics Data System (ADS)

    Cheng, Chuanqing; Wang, Li; Huang, Qiugen

    2005-02-01

    While the ethernet is applied more and more in public network environment and xdsl service become the most common access mode ,IP kenel DSLAM undertakes some functions such as service distribution and convergence ,security management and customer management.Facing the contradiction of the need of port isolation and the shortage of ip address,VLAN aggregation technology is applied in DSLAM.How to implement the communicatio between the two vlan but share the same ip subnet,proxy arp does this. This paper introduces how to implement proxy arp in the DSLAM. TCP/IP communication detail procedure betweent two host ,the relation of VLAN and network segment are discussed. The proxy arp model and its implementation in IP DSLAM is also expatiated in this paper and a conformance tesing is given.

  17. Audio CAPTCHA for SIP-Based VoIP

    NASA Astrophysics Data System (ADS)

    Soupionis, Yannis; Tountas, George; Gritzalis, Dimitris

    Voice over IP (VoIP) introduces new ways of communication, while utilizing existing data networks to provide inexpensive voice communications worldwide as a promising alternative to the traditional PSTN telephony. SPam over Internet Telephony (SPIT) is one potential source of future annoyance in VoIP. A common way to launch a SPIT attack is the use of an automated procedure (bot), which generates calls and produces audio advertisements. In this paper, our goal is to design appropriate CAPTCHA to fight such bots. We focus on and develop audio CAPTCHA, as the audio format is more suitable for VoIP environments and we implement it in a SIP-based VoIP environment. Furthermore, we suggest and evaluate the specific attributes that audio CAPTCHA should incorporate in order to be effective, and test it against an open source bot implementation.

  18. Obesity Exacerbates Rat Cerebral Ischemic Injury through Enhancing Ischemic Adiponectin-Containing Neuronal Apoptosis.

    PubMed

    Wu, Ming-Hsiu; Chio, Chung-Ching; Tsai, Kuen-Jer; Chang, Ching-Ping; Lin, Nan-Kai; Huang, Chao-Ching; Lin, Mao-Tsun

    2016-08-01

    A diet consisting of high levels of saturated fat has been linked to a dramatic rise in obesity. Long-term exposure to high fat, "Western diet" (WD), is detrimental to ischemic brain injury. Adiponectin receptor 1 (ADR-1) activation is also shown to exacerbate ischemic neuronal death. However, it is not known whether increasing percentages of adiponectin (APN)-containing neurons attenuates ischemic neuronal apoptosis by modulating ADRS. To explore the role of APN and its ADRs in the development of acute cerebral injury, we subjected WD and control diet (CD) rats to 1 h of middle cerebral artery occlusion followed by 23 h of reperfusion. Compared with CD rats, WD rats exhibited higher levels of brain infarct, neurologic deficits, brain edema, and apoptosis of APN-containing neurons; upregulation of both ADR-1 and P38 mitogen-activated protein kinase (P38MAPK); and downregulation of ADR-2 in ischemic brain tissues including frontal cortex, striatum, and hippocampus. Increasing percentages of APN-containing neurons by baculovirus-mediated administration of APN, in addition to reducing apoptosis of APN-containing neurons in ischemic brain tissues, significantly attenuated brain infarct and edema, neurologic deficits, and altered expression of ADR-1, P38MAPK, and ADR-2 in both WD and CD group rats. These data suggest a negative correlation between percentages of APN-containing neurons and cerebral ischemic injury. Obesity could exacerbate rat cerebral ischemic injury by enhancing apoptosis of APN-containing neurons in ischemic brain tissues probably via modulating ADRs and P38MAPK. PMID:26126515

  19. An overview of antithrombotics in ischemic stroke.

    PubMed

    Schweickert, Patricia A; Gaughen, John R; Kreitel, Elizabeth M; Shephard, Timothy J; Solenski, Nina J; Jensen, Mary E

    2016-06-19

    The use of antithrombotic medications is an important component of ischemic stroke treatment and prevention. This article reviews the evidence for best practices for antithrombotic use in stroke with focused discussion on the specific agents used to treat and prevent stroke. PMID:27153001

  20. Ischemic Stroke during Pregnancy and Puerperium

    PubMed Central

    Del Zotto, Elisabetta; Giossi, Alessia; Volonghi, Irene; Costa, Paolo; Padovani, Alessandro; Pezzini, Alessandro

    2011-01-01

    Ischemic stroke during pregnancy and puerperium represents a rare occurrence but it could be a serious and stressful event for mothers, infants, and also families. Whenever it does occur, many concerns arise about the safety of the mother and the fetus in relation to common diagnostic tests and therapies leading to a more conservative approach. The physiological adaptations in the cardiovascular system and in the coagulability that accompany the pregnant state, which are more significant around delivery and in the postpartum period, likely contribute to increasing the risk of an ischemic stroke. Most of the causes of an ischemic stroke in the young may also occur in pregnant patients. Despite this, there are specific conditions related to pregnancy which may be considered when assessing this particular group of patients such as pre-eclampsia-eclampsia, choriocarcinoma, peripartum cardiomiopathy, amniotic fluid embolization, and postpartum cerebral angiopathy. This article will consider several questions related to pregnancy-associated ischemic stroke, dwelling on epidemiological and specific etiological aspects, diagnostic issue concerning the use of neuroimaging, and the related potential risks to the embryo and fetus. Therapeutic issues surrounding the use of anticoagulant and antiplatelets agents will be discussed along with the few available reports regarding the use of thrombolytic therapy during pregnancy. PMID:21331336

  1. Cerebrovascular ischemic events in wind instrument players.

    PubMed

    Evers, S; Altenmüller, E; Ringelstein, E B

    2000-09-26

    Two cases of ischemic stroke due to carotid artery dissection occurring during wind instrument playing, probably caused by increased intrathoracic and subsequent intrapharyngeal pressure, are presented. A review of the literature revealed three similar patients with other types of cerebrovascular events, such as paradoxical cerebral embolism due to a patent foramen ovale and spinal epidural hematoma during trumpet playing. PMID:10994010

  2. Hyperglycemia Increases Susceptibility to Ischemic Necrosis

    PubMed Central

    Lévigne, D.; Tobalem, M.; Modarressi, A.; Pittet-Cuénod, B.

    2013-01-01

    Diabetic patients are at risk for spontaneous foot ulcers, chronic wounds, infections, and tissue necrosis. Current theories suggest that the development and progression of diabetic foot ulcers are mainly caused by arteriosclerosis and peripheral neuropathy. Tissue necrosis plays a primordial role in the progression of diabetic foot ulcers but the underlying mechanisms are poorly understood. The aim of the present study was to investigate the effects of hyperglycemia per se on the susceptibility of ischemic tissue to necrosis, using a critical ischemic hind limb animal model. We inflicted the same degree of ischemia in both euglycemic and streptozotocin-induced hyperglycemic rats by resecting the external iliac, the femoral, and the saphenous arteries. Postoperative laser Doppler flowmetry of the ischemic feet showed the same degree of reduction in skin perfusion in both hyperglycemic and euglycemic animals. Nevertheless, we found a significantly higher rate of limb necrosis in hyperglycemic rats compared to euglycemic rats (71% versus 29%, resp.). In this study, we revealed that hyperglycemia per se increases the susceptibility to limb necrosis in ischemic conditions. Our results may help to better understand the physiopathology of progressive diabetic wounds and underline the importance of strict glycemic control in patients with critical limb ischemia. PMID:23509730

  3. Systemic corticosteroids in nonarteritic ischemic optic neuropathy

    PubMed Central

    Al-Zubidi, Nagham; Zhang, Jason; Spitze, Arielle; Lee, Andrew G

    2014-01-01

    Nonarteritic ischemic optic neuropathy (NAION) is one of the most prevalent optic nerve disorders seen in ophthalmic practice. The role of corticosteroid therapy in NAION remains a highly controversial area of debate in ophthalmology. This brief review will provide an overview of the current clinical evidence on this topic as well as some comment on the medical debate. PMID:25449939

  4. Ischemic tolerance: the mechanisms of neuroprotective strategy.

    PubMed

    Lehotský, Jan; Burda, Jozef; Danielisová, Viera; Gottlieb, Miroslav; Kaplán, Peter; Saniová, Beata

    2009-12-01

    The phenomenon of ischemic tolerance perfectly describes this quote "What does not kill you makes you stronger." Ischemic pre- or postconditioning is actually the strongest known procedure to prevent or reverse neurodegeneration. It works specifically in sensitive vulnerable neuronal populations, which are represented by pyramidal neurons in the hippocampal CA1 region. However, tolerance is effective in other brain cell populations as well. Although, its nomenclature is "ischemic" tolerance, the tolerant phenotype can also be induced by other stimuli that lead to delayed neuronal death (intoxication). Moreover, the recent data have proven that this phenomenon is not limited to application of sublethal stimuli before the lethal stress but reversed arrangement of events, sublethal stress after lethal insult, is rather equally effective. A very important term is called "cross conditioning." Cross conditioning is the capability of one stressor to induce tolerance against another. So, since pre- or post-conditioners can be used plenty of harmful stimuli, hypo- or hyperthermia and some physiological compounds, such as norepinephrine, bradykinin. Delayed neuronal death is the slow development of postischemic neurodegeneration. This allows an opportunity for a great therapeutic window of 2-3 days to reverse the cellular death process. Moreover, it seems that the mechanisms of ischemic tolerance-delayed postconditioning could be used not only after ischemia but also in some other processes leading to apoptosis. PMID:19943353

  5. Gene Therapy For Ischemic Heart Disease

    PubMed Central

    Lavu, Madhav; Gundewar, Susheel; Lefer, David J.

    2010-01-01

    Current pharmacologic therapy for ischemic heart disease suffers multiple limitations such as compliance issues and side effects of medications. Revascularization procedures often end with need for repeat procedures. Patients remain symptomatic despite maximal medical therapy. Gene therapy offers an attractive alternative to current pharmacologic therapies and may be beneficial in refractory disease. Gene therapy with isoforms of growth factors such as VEGF, FGF and HGF induces angiogenesis, decreases apoptosis and leads to protection in the ischemic heart. Stem cell therapy augmented with gene therapy used for myogenesis has proven to be beneficial in numerous animal models of myocardial ischemia. Gene therapy coding for antioxidants, eNOS, HSP, mitogen-activated protein kinase and numerous other anti apoptotic proteins have demonstrated significant cardioprotection in animal models. Clinical trials have demonstrated safety in humans apart from symptomatic and objective improvements in cardiac function. Current research efforts are aimed at refining various gene transfection techniques and regulation of gene expression in vivo in the heart and circulation to improve clinical outcomes in patients that suffer from ischemic heart disease. In this review article we will attempt to summarize the current state of both preclinical and clinical studies of gene therapy to combat myocardial ischemic disease. PMID:20600100

  6. Probabilistic Route Selection Algorithm for IP Traceback

    NASA Astrophysics Data System (ADS)

    Yim, Hong-Bin; Jung, Jae-Il

    DoS(Denial of Service) or DDoS(Distributed DoS) attack is a major threaten and the most difficult problem to solve among many attacks. Moreover, it is very difficult to find a real origin of attackers because DoS/DDoS attacker uses spoofed IP addresses. To solve this problem, we propose a probabilistic route selection traceback algorithm, namely PRST, to trace the attacker's real origin. This algorithm uses two types of packets such as an agent packet and a reply agent packet. The agent packet is in use to find the attacker's real origin and the reply agent packet is in use to notify to a victim that the agent packet is reached the edge router of the attacker. After attacks occur, the victim generates the agent packet and sends it to a victim's edge router. The attacker's edge router received the agent packet generates the reply agent packet and send it to the victim. The agent packet and the reply agent packet is forwarded refer to probabilistic packet forwarding table (PPFT) by routers. The PRST algorithm runs on the distributed routers and PPFT is stored and managed by routers. We validate PRST algorithm by using mathematical approach based on Poisson distribution.

  7. I.P. Pavlov as a youth.

    PubMed

    Windholz, G

    1991-01-01

    Ivan P. Pavlov's youthful relations with parents and siblings, formal education, and social activities in Riazan' are described. The Pavlovs, a highly achievement-oriented family descending from a lowly serf, improved their social status by serving the Russian Orthodox Church. Pavlov, the son of a priest, studied in the 1860s at the Riazan' Ecclesiastic Seminary for priesthood. The turbulent 1860s' decade was a period of social and political reforms. Western ideas and science were introduced to Russia. The ambitious and idealistic I.P. Pavlov was influenced by popular essays written by the journalist D.I. Pisarev, the works of the German physiologist J. Moleschott, the English writer G.H. Lewes, the German zoologist C. Vogt and the physiologist M.I. Sechenov. Losing his religious faith, Pavlov abandoned the traditional goal of becoming a priest, and, convinced that science was a road to truth and progress, left Riazan' to study natural science at the University of St. Petersburg. PMID:2054299

  8. Preconditioning for Numerical Simulation of Low Mach Number Three-Dimensional Viscous Turbomachinery Flows

    NASA Technical Reports Server (NTRS)

    Tweedt, Daniel L.; Chima, Rodrick V.; Turkel, Eli

    1997-01-01

    A preconditioning scheme has been implemented into a three-dimensional viscous computational fluid dynamics code for turbomachine blade rows. The preconditioning allows the code, originally developed for simulating compressible flow fields, to be applied to nearly-incompressible, low Mach number flows. A brief description is given of the compressible Navier-Stokes equations for a rotating coordinate system, along with the preconditioning method employed. Details about the conservative formulation of artificial dissipation are provided, and different artificial dissipation schemes are discussed and compared. The preconditioned code was applied to a well-documented case involving the NASA large low-speed centrifugal compressor for which detailed experimental data are available for comparison. Performance and flow field data are compared for the near-design operating point of the compressor, with generally good agreement between computation and experiment. Further, significant differences between computational results for the different numerical implementations, revealing different levels of solution accuracy, are discussed.

  9. Analysis of a Lipid/Polymer Membrane for Bitterness Sensing with a Preconditioning Process.

    PubMed

    Yatabe, Rui; Noda, Junpei; Tahara, Yusuke; Naito, Yoshinobu; Ikezaki, Hidekazu; Toko, Kiyoshi

    2015-01-01

    It is possible to evaluate the taste of foods or medicines using a taste sensor. The taste sensor converts information on taste into an electrical signal using several lipid/polymer membranes. A lipid/polymer membrane for bitterness sensing can evaluate aftertaste after immersion in monosodium glutamate (MSG), which is called "preconditioning". However, we have not yet analyzed the change in the surface structure of the membrane as a result of preconditioning. Thus, we analyzed the change in the surface by performing contact angle and surface zeta potential measurements, Fourier transform infrared spectroscopy (FTIR), X-ray photon spectroscopy (XPS) and gas cluster ion beam time-of-flight secondary ion mass spectrometry (GCIB-TOF-SIMS). After preconditioning, the concentrations of MSG and tetradodecylammonium bromide (TDAB), contained in the lipid membrane were found to be higher in the surface region than in the bulk region. The effect of preconditioning was revealed by the above analysis methods. PMID:26404301

  10. Hybrid preconditioning for iterative diagonalization of ill-conditioned generalized eigenvalue problems in electronic structure calculations

    SciTech Connect

    Cai, Yunfeng; Bai, Zhaojun; Pask, John E.; Sukumar, N.

    2013-12-15

    The iterative diagonalization of a sequence of large ill-conditioned generalized eigenvalue problems is a computational bottleneck in quantum mechanical methods employing a nonorthogonal basis for ab initio electronic structure calculations. We propose a hybrid preconditioning scheme to effectively combine global and locally accelerated preconditioners for rapid iterative diagonalization of such eigenvalue problems. In partition-of-unity finite-element (PUFE) pseudopotential density-functional calculations, employing a nonorthogonal basis, we show that the hybrid preconditioned block steepest descent method is a cost-effective eigensolver, outperforming current state-of-the-art global preconditioning schemes, and comparably efficient for the ill-conditioned generalized eigenvalue problems produced by PUFE as the locally optimal block preconditioned conjugate-gradient method for the well-conditioned standard eigenvalue problems produced by planewave methods.

  11. Some Dilemmas of Institutional Evaluation and Their Relationship to Preconditions and Procedures.

    ERIC Educational Resources Information Center

    Adelman, Clem

    1980-01-01

    Using "A Study of Student Choice in Context of Institutional Change (SCIC)" is an example of an evaluation using social anthropological methods. The problems of confidentiality, rapport, evaluator autonomy, and unclear preconditions are discussed and illustrated. (BW)

  12. A highly efficient and effective motif discovery method for ChIP-seq/ChIP-chip data using positional information.

    PubMed

    Ma, Xiaotu; Kulkarni, Ashwinikumar; Zhang, Zhihua; Xuan, Zhenyu; Serfling, Robert; Zhang, Michael Q

    2012-04-01

    Identification of DNA motifs from ChIP-seq/ChIP-chip [chromatin immunoprecipitation (ChIP)] data is a powerful method for understanding the transcriptional regulatory network. However, most established methods are designed for small sample sizes and are inefficient for ChIP data. Here we propose a new k-mer occurrence model to reflect the fact that functional DNA k-mers often cluster around ChIP peak summits. With this model, we introduced a new measure to discover functional k-mers. Using simulation, we demonstrated that our method is more robust against noises in ChIP data than available methods. A novel word clustering method is also implemented to group similar k-mers into position weight matrices (PWMs). Our method was applied to a diverse set of ChIP experiments to demonstrate its high sensitivity and specificity. Importantly, our method is much faster than several other methods for large sample sizes. Thus, we have developed an efficient and effective motif discovery method for ChIP experiments. PMID:22228832

  13. Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function.

    PubMed

    Scherer, Paul C; Ding, Yan; Liu, Zhiqing; Xu, Jing; Mao, Haibin; Barrow, James C; Wei, Ning; Zheng, Ning; Snyder, Solomon H; Rao, Feng

    2016-03-29

    The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. Inositol polyphosphates are highly conserved signaling molecules implicated in diverse cellular processes. We now report that inositol hexakisphosphate (IP6) is a major physiologic determinant of the CRL-CSN interface, which includes a hitherto unidentified electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins. IP6, with an EC50 of 20 nM, acts as an intermolecular "glue," increasing cullin-CSN2 binding affinity by 30-fold, thereby promoting assembly of the inactive CRL-CSN complexes. The IP6 synthase, Ins(1,3,4,5,6)P5 2-kinase (IPPK/IP5K) binds to cullins. Depleting IP5K increases the percentage of neddylated, active Cul1 and Cul4A, and decreases levels of the Cul1/4A substrates p27 and p21. Besides dysregulating CRL-mediated cell proliferation and UV-induced apoptosis, IP5K depletion potentiates by 28-fold the cytotoxic effect of the neddylation inhibitor MLN4924. Thus, IP5K and IP6 are evolutionarily conserved components of the CRL-CSN system and are potential targets for cancer therapy in conjunction with MLN4924. PMID:26976604

  14. The noble gas xenon induces pharmacological preconditioning in the rat heart in vivo via induction of PKC-ɛ and p38 MAPK

    PubMed Central

    Weber, Nina C; Toma, Octavian; Wolter, Jessica I; Obal, Detlef; Müllenheim, Jost; Preckel, Benedikt; Schlack, Wolfgang

    2004-01-01

    Xenon is an anesthetic with minimal hemodynamic side effects, making it an ideal agent for cardiocompromised patients. We investigated if xenon induces pharmacological preconditioning (PC) of the rat heart and elucidated the underlying molecular mechanisms. For infarct size measurements, anesthetized rats were subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion. Rats received either the anesthetic gas xenon, the volatile anesthetic isoflurane or as positive control ischemic preconditioning (IPC) during three 5-min periods before 25-min ischemia. Control animals remained untreated for 45 min. To investigate the involvement of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK), rats were pretreated with the PKC inhibitor calphostin C (0.1 mg kg−1) or the p38 MAPK inhibitor SB203580 (1 mg kg−1). Additional hearts were excised for Western blot and immunohistochemistry. Infarct size was reduced from 50.9±16.7% in controls to 28.1±10.3% in xenon, 28.6±9.9% in isoflurane and to 28.5±5.4% in IPC hearts. Both, calphostin C and SB203580, abolished the observed cardioprotection after xenon and isoflurane administration but not after IPC. Immunofluorescence staining and Western blot assay revealed an increased phosphorylation and translocation of PKC-ɛ in xenon treated hearts. This effect could be blocked by calphostin C but not by SB203580. Moreover, the phosphorylation of p38 MAPK was induced by xenon and this effect was blocked by calphostin C. In summary, we demonstrate that xenon induces cardioprotection by PC and that activation of PKC-ɛ and its downstream target p38 MAPK are central molecular mechanisms involved. Thus, the results of the present study may contribute to elucidate the beneficial cardioprotective effects of this anesthetic gas. PMID:15644876

  15. ERK5/KLF4 signaling as a common mediator of the neuroprotective effects of both nerve growth factor and hydrogen peroxide preconditioning.

    PubMed

    Su, Chang; Sun, Fen; Cunningham, Rebecca L; Rybalchenko, Nataliya; Singh, Meharvan

    2014-01-01

    Oxidative stress has long been implicated in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease and stroke. While high levels of oxidative stress are generally associated with cell death, a slight rise of reactive oxygen species (ROS) levels can be protective by "preconditioning" cells to develop a resistance against subsequent challenges. However, the mechanisms underlying such preconditioning (PC)-induced protection are still poorly understood. Previous studies have supported a role of ERK5 (mitogen-activated protein [MAP] kinase 5) in neuroprotection and ischemic tolerance in the hippocampus. In agreement with these findings, our data suggest that ERK5 mediates both hydrogen peroxide (H2O2)-induced PC as well as nerve growth factor (NGF)-induced neuroprotection. Activation of ERK5 partially rescued pheochromocytoma PC12 cells as well as primary hippocampal neurons from H2O2-caused death, while inhibition of ERK5 abolished NGF or PC-induced protection. These results implicate ERK5 signaling as a common downstream pathway for NGF and PC. Furthermore, both NGF and PC increased the expression of the transcription factor, KLF4, which can initiate an anti-apoptotic response in various cell types. Induction of KLF4 by NGF or PC was blocked by siERK5, suggesting that ERK5 is required in this process. siKLF4 can also attenuate NGF- or PC-induced neuroprotection. Overexpression of active MEK5 or KLF4 in H2O2-stressed cells increased Bcl-2/Bax ratio and the expression of NAIP (neuronal apoptosis inhibitory protein). Taken together, our data suggest that ERK5/KLF4 cascade is a common signaling pathway shared by at least two important mechanisms by which neurons can be protected from cell death. PMID:25015774

  16. Remote ischemic perconditioning attenuates ischemia/reperfusion-induced downregulation of AQP2 in rat kidney.

    PubMed

    Kristensen, Marie Louise V; Kierulf-Lassen, Casper; Nielsen, Per Mose; Krag, Søren; Birn, Henrik; Nejsum, Lene N; Nørregaard, Rikke

    2016-07-01

    Renal ischemia/reperfusion (I/R) can lead to impaired urine concentration ability and increased fractional excretion of sodium (FeNa). Local ischemic preconditioning improves renal water and sodium handling after I/R injury. Here, we investigate whether remote ischemic perconditioning (rIPeC) prevents dysregulation of renal water and salt handling in response to I/R injury and mechanisms that may be involved. Rats were subjected to right nephrectomy and randomized into a sham group or an I/R group. In the I/R group, rats were subjected to 37 min of renal ischemia and 3 days of reperfusion. rIPeC was applied to the abdominal aorta. Blood and urine were collected on day 3 postoperatively for clearance studies. The expression of aquaporins (AQPs) and the sodium transporter Na-K-ATPase were analyzed using immunoblotting and immunohistochemistry. I/R injury resulted in polyuria, increased FeNa, and decreased urine osmolality compared to sham rats. rIPeC attenuated the increase in FeNa and the decrease in urine osmolality. Expression of AQP1, AQP2, phosphorylated AQP2 (pAQP2), and Na-K-ATPase was downregulated in I/R rats. rIPeC attenuated the reductions in AQP2 and pAQP2 expression. Immunohistochemistry revealed decreased labeling of Na-K-ATPase in the outer medulla in I/R kidneys compared to kidneys from sham and I/R + rIPeC rats. After renal ischemia, the expression of Na-K-ATPase was substantially reduced in the outer medullary thick ascending limb. In conclusion, our data suggest that rIPeC might prevent dysregulation of renal water and salt handling via regulation of AQP2 expression and phosphorylation as well as via regulation of Na-K-ATPase expression in I/R rat kidneys. PMID:27405971

  17. Preconditioned domain decomposition scheme for three-dimensional aerodynamic sensitivity analysis

    NASA Technical Reports Server (NTRS)

    Eleshaky, Mohammed E.; Baysal, Oktay

    1993-01-01

    A preconditioned domain decomposition scheme is introduced for the solution of the 3D aerodynamic sensitivity equation. This scheme uses the iterative GMRES procedure to solve the effective sensitivity equation of the boundary-interface cells in the sensitivity analysis domain-decomposition scheme. Excluding the dense matrices and the effect of cross terms between boundary-interfaces is found to produce an efficient preconditioning matrix.

  18. Monophasic action potentials and Ca2+ transients in ischaemically preconditioned rabbit ventricular muscle

    PubMed Central

    Dekker, L.R.C.; van Bavel, E.; Opthof, T.; Coronel, R.; Janse, M.J.

    2003-01-01

    Background ATP-sensitive K+ (KATP) channels play an important role in the protective mechanism underlying ischaemic preconditioning. Ample evidence indicates, however, that action potential shortening is not a prerequisite for the cardioprotective effect of preconditioning. Methods Monophasic action potential duration (MAPD), tissue resistance, intracellular Ca2+ (Indo-1) and mechanical activity were simultaneously assessed in arterially perfused rabbit papillary muscles. We studied four experimental protocols preceding sustained ischaemia: 1. control perfusion (n=6), 2. ischaemic preconditioning (PC; n=4), 3. pretreatment with a KATP channel blocker, glibenclamide (15 μmol/1), prior to ischaemic preconditioning (PC+glib; n=3), 4. glibenclamide pretreatment only (Glib; n=2). Results In the PC group an increase in the diastolic Ca2+ level and a prolongation of the Ca2+ transient just prior to the induction of sustained ischaemia correlate to the postponement of the onset of irreversible ischaemic damage, as established by a rise in [Ca2+]i, electrical uncoupling and contracture. Glibenclamide antagonised these changes in the Ca2+ transient and the cardioprotection induced by preconditioning. MAPD was equal in all experimental groups. Conclusions Prolongation of the Ca2+ transient and increase of diastolic [Ca2+]i just prior to the induction of sustained ischaemia and not action potential shortening are involved in the cardioprotective effect of ischaemic preconditioning. Therefore, a glibenclamide-sensitive mechanism, other than the sarcolemmal KATP channels, is involved in the protective effect of ischaemic preconditioning. Changes in Ca2+ metabolism may play a crucial role in ischaemic preconditioning. ImagesFigure 1 PMID:25696182

  19. Valsartan preconditioning protects against myocardial ischemia-reperfusion injury through TLR4/NF-kappaB signaling pathway.

    PubMed

    Yang, Jian; Jiang, Hong; Yang, Jun; Ding, Jia-Wang; Chen, Li-Hua; Li, Song; Zhang, Xiao-Dong

    2009-10-01

    Toll-like receptor 4 (TLR4) activation has been implicated in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. The activated TLR4 is capable of activating a variety of proinflammatory mediators, such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6). Valsartan as a kind of Angiotensin II type 1 receptor blockers is gradually used for the treatment of ischemic heart disease depending on its anti-inflammation function. Therefore, we hypothesized that valsartan protects against myocardial I/R injury by suppressing TLR4 activation. We constructed the rat model of myocardial I/R injury. The rats were pretreated with valsartan for 2 weeks, and then subjected to 30 min ischemia and 2 h reperfusion. TLR4 and Nuclear factor kappa-B (NF-kappaB) levels were detected by quantitative real-time PCR and western blot. In order to evaluate myocardial damage, the myocardial infarct size, histopathologic changes, and the release of myocardial enzymes, proinflammation cytokines and Angiotensin II were analyzed by triphenyl tetrazolium chloride (TTC) staining, light microscopy, and enzyme-linked immunosorbent assay (ELISA), respectively. Valsartan preconditioning inhibited TLR4 and NF-kappaB expressions concomitant with an improvement in myocardial injury, such as smaller infarct size, fewer release of myocardial enzymes, and proinflammation mediators. These findings suggest that valsartan plays a pivotal role in the protective effects on myocardial I/R injury. This protection mechanism is possibly due to its anti-inflammation function via TLR4/NF-kappaB signaling pathway. PMID:19370315

  20. Enhanced nucleotide excision repair capacity in lung cancer cells by preconditioning with DNA-damaging agents

    PubMed Central

    Choi, Ji Ye; Park, Jeong-Min; Yi, Joo Mi; Leem, Sun-Hee; Kang, Tae-Hong

    2015-01-01

    The capacity of tumor cells for nucleotide excision repair (NER) is a major determinant of the efficacy of and re