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Biomarkers for ischemic preconditioning: finding the responders.
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
Koch, Sebastian; Della-Morte, David; Dave, Kunjan R; Sacco, Ralph L; Perez-Pinzon, Miguel A
Ischemic preconditioning-induced neuroprotection is associated with differential expression of IL1? and IL1 receptor antagonist in the ischemic cortex
Ischemic preconditioning (IP) is a phenomenon that organs develop a tolerance toward subsequent lethal ischemic insults. Among the factors that are involved in IP, IL-1? and its endogenous receptor antagonist IL-1ra have been identified as important players in the induction of IP. The present study investigated whether IP affects the levels of these two antagonistic proteins during tolerance and reperfusion
Jin A. Shin; Eun-Mi Park; Ji-Seung Choi; Sun-Mi Seo; Jihee Lee Kang; Kyung-Eun Lee; Sunghee Cho
Sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia.
Brain ischemic tolerance is an endogenous protective mechanism activated by a preconditioning stimulus that is closely related to N-methyl-d-aspartate receptor (NMDAR). Glycine transporter type 1 (GlyT-1) inhibitors potentiate NMDAR and suggest an alternative strategy for brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by sarcosine, a GlyT-1 inhibitor, against global cerebral ischemia and its relation to NMDAR. Sarcosine was administered over 7days (300 or 500mg/kg/day, ip) before the induction of a global cerebral ischemia model in Wistar rats (male, 8-week-old). It was observed that sarcosine preconditioning reduced cell death in rat hippocampi submitted to cerebral ischemia. Hippocampal levels of glycine were decreased in sarcosine-treated animals, which was associated with a reduction of [(3)H] glycine uptake and a decrease in glycine transporter expression (GlyT-1 and GlyT-2). The expression of glycine receptors and the NR1 and NR2A subunits of NMDAR were not affected by sarcosine preconditioning. However, sarcosine preconditioning reduced the expression of the NR2B subunits of NMDAR. In conclusion, these data demonstrate that sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia and this neuroprotective state is associated with changes in glycine transport and reduction of NR2B-containing NMDAR expression. PMID:24797328
Pinto, M C X; Sim�o, F; da Costa, F L P; Rosa, D V; de Paiva, M J N; Resende, R R; Romano-Silva, M A; Gomez, M V; Gomez, R S
Neuronal plasticity after ischemic preconditioning and TIA-like preconditioning ischemic periods
Transient ischemic attacks (TIAs) have recently become the center of attention since they are thought to share some characteristics\\u000a with experimental ischemic preconditioning (IPC). This phenomenon describes the situation that a brief, per se harmless, cerebral\\u000a ischemic period renders the brain resistant to a subsequent severe and normally damaging ischemia. Preconditioning (PC) is\\u000a not restricted to the brain but also
Clemens Sommer
Resveratrol and ischemic preconditioning in the brain.
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
Raval, Ami P; Lin, Hung Wen; Dave, Kunjan R; Defazio, R Anthony; Della Morte, David; Kim, Eun Joo; Perez-Pinzon, Miguel A
An electrocardiographic sign of ischemic preconditioning.
Ischemic preconditioning is a form of intrinsic cardioprotection where an episode of sublethal ischemia protects against subsequent episodes of ischemia. Identifying a clinical biomarker of preconditioning could have important clinical implications, and prior work has focused on the electrocardiographic ST segment. However, the electrophysiology biomarker of preconditioning is increased action potential duration (APD) shortening with subsequent ischemic episodes, and APD shortening should primarily alter the T wave, not the ST segment. We translated findings from simulations to canine to patient models of preconditioning to test the hypothesis that the combination of increased [delta (?)] T wave amplitude with decreased ST segment elevation characterizes preconditioning. In simulations, decreased APD caused increased T wave amplitude with minimal ST segment elevation. In contrast, decreased action potential amplitude increased ST segment elevation significantly. In a canine model of preconditioning (9 mongrel dogs undergoing 4 ischemia-reperfusion episodes), ST segment amplitude increased more than T wave amplitude during the first ischemic episode [?T/?ST slope = 0.81, 95% confidence interval (CI) 0.46-1.15]; however, during subsequent ischemic episodes the T wave increased significantly more than the ST segment (?T/?ST slope = 2.43, CI 2.07-2.80) (P < 0.001 for interaction of occlusions 2 vs. 1). A similar result was observed in patients (9 patients undergoing 2 consecutive prolonged occlusions during elective percutaneous coronary intervention), with an increase in slope of ?T/?ST of 0.13 (CI -0.15 to 0.42) in the first occlusion to 1.02 (CI 0.31-1.73) in the second occlusion (P = 0.02). This integrated analysis of the T wave and ST segment goes beyond the standard approach to only analyze ST elevation, and detects cellular electrophysiology changes of preconditioning. PMID:24778173
Meijs, Loek P B; Galeotti, Loriano; Pueyo, Esther P; Romero, Daniel; Jennings, Robert B; Ringborn, Michael; Warren, Stafford G; Wagner, Galen S; Strauss, David G
Antiarrhythmic Effect of Ischemic Preconditioning in Recent Unstable Angina Patients Undergoing Coronary Artery Bypass Grafting
Coronary artery bypass grafting (CABG) for unstable angina pectoris patients results in a higher incidence of arrhythmia and higher arrhythmic cardiac mortality. Ischemic preconditioning (IP) has proved effective in suppressing ischemia reperfusion arrhythmias in animals and in humans. The purpose of the present study was to investigate whether IP protects against postoperative arrhythmias in recent unstable angina patients undergoing urgent
Zhong-Kai Wu; Tiina Iivainen; Erkki Pehkonen; Jari Laurikka; Matti R. Tarkka
Mechanism of Cardioprotection by Early Ischemic Preconditioning
A series of brief ischemia\\/reperfusion cycles (termed ischemic preconditioning, IPC) limits myocardial injury produced by\\u000a a subsequent prolonged period of coronary artery occlusion and reperfusion. Over the last 2 decades our understanding of IPC�s\\u000a mechanism has increased exponentially. Hearts exposed to IPC have a better metabolic and ionic status during prolonged ischemia\\u000a compared to na�ve hearts. However, this difference is
Xiulan Yang; Michael V. Cohen; James M. Downey
Influence of fasting on the effects of ischemic preconditioning in the ischemic-reperfused rat heart.
The effects of fasting and ischemic preconditioning (IP) on heart function of Langendorff-perfused rat hearts exposed to 25 min global ischemia plus 30 min reperfusion (RP), were correlated with lactate release and tissue-levels of long-chain acyl carnitine (LCCa) and CoA (LCCoA). IP was achieved by a 3 min ischemia plus a 5 min reperfusion cycle. Creatine kinase leakage was measured to assess the extent of cardiac injury. Fasting reduced the ischemic-induced contracture, improved RP recovery of mechanical function, reduced lactate release and increased the end-ischemia LCCoA and LCCa levels. Both in the fed and the fasted rat hearts IP delayed the pacemaker depression, reduced the amplitude of ischemic contracture and improved the RP recovery of contraction. However, IP reduced creatine kinase and lactate release only in the fed rat hearts. IP had no effects on tissue LCCa and LCCoA in both groups. These data suggest that: 1) beneficial effects of fasting may be ascribed, at least in part, to a reduced lactate production which may attenuate ischemic myocyte acidification and to the accumulation of fatty acyl esters which would favour citric acid cycle replenishment during RP. 2) beneficial effects of IP could be in part explained by the reduction of lactate production in the fed group although data obtained with the fasted rat heart indicate that another mechanisms must also be involved in the effects of IP. 3) accumulation of LCCoA and LCCa is not involved in the noxious effects of ischemia as well as in the protection effected by IP. PMID:12221519
Varela, A; Marina Prendes, M G; Testoni, G; V�zquez, N; Astudilla, C; Cerruti, S; Savino, E A
Ischemic Preconditioning in the Younger and Aged Heart
Ischemic preconditioning is the effect of brief ischemic episodes which protect the heart from the following more prolonged ischemic episode. This mechanism is effective in younger but not in aged heart. The age-related reduction of ischemic preconditioning has been demonstrated in experimental models and in elderly patients. Preinfarction angina, a clinical equivalent of ischemic preconditioning, reduces mortality in adult but not in elderly patients with acute myocardial infarction. Physical activity or caloric restriction is partially capable to preserve the cardioprotective effect of ischemic preconditioning in the aging heart. More importantly, physical activity and caloric restriction in tandem action completely preserve the protective mechanism of ischemic preconditioning. Accordingly, the protective mechanism of preinfarction angina is preserved in elderly patients with a high grade of physical activity or a low body-mass index. Thus, both physical activity and caloric restriction are confirmed as powerful anti-aging interventions capable to restore age-dependent reduction of a critical endogenous protective mechanism such as ischemic preconditioning.
Abete, Pasquale; Testa, Gianluca; Cacciatore, Francesco; Della-Morte, David; Galizia, Gianluigi; Langellotto, Assunta; Rengo, Franco
Limb ischemic preconditioning attenuates cerebral ischemic injury in rat model.
Ischemic brain injury is not uncommon after open-heart surgery with cardiopulmonary bypass and seriously undermines the patients' life quality. Therefore, potential protective effects of limb ischemic preconditioning (LIP) on subsequent ischemic injury of the brain were investigated by evaluating anti-inflammatory effects and apoptosis of pyramidal neurons in the CA1 hippocampus. One hundred and eight Sprague-Dawley rats were divided into the middle cerebral artery occlusion (MCAO) group (n=54) and the LIP group (n=54). A thread was used to occlude the middle cerebral artery in the MCAO group and the LIP group animals were pretreated with LIP followed by MCAO. In the two groups, nine samples were collected at each time-point of 0, 6, 12, 24, 48 and 72 h after MCAO to detect IL-6 and IL-17 and their mRNA levels. Neurological severity scores (NSS) were examined before the animals were sacrificed. Compared with the LIP group, cerebral histopathological changes in the MCAO group were most distinct and significantly more infiltrated inflammatory and apoptotic neuronal cells were observed at 24, 48 and 72 h post-surgery. IL-17 and IL-6 mRNA levels analyzed by quantitative real-time polymerase chain reaction (PCR) (qRT-PCR) were significantly reduced in the LIP group compared with the MCAO group at the 12, 24 and 48 h time-points. A significant reduction in IL-17 expression level was determined by enzyme-linked immunosorbent assay (ELISA) in the LIP group at 12, 24 and 48 h, while IL-6 was significantly reduced at the 24 and 48 h time-points. The NSSs were not significantly different between the groups. Therefore, in a MCAO rat model, we have proved that LIP pretreatment can protect the brain from infarction after ischemic injury and induce ischemic tolerance, potentially, by reducing IL-17 to provide anti-inflammatory effects and attenuate apoptosis of hippocampal neuronal cells. PMID:24002779
Wang, W; Yu, X D; Mo, X; Zhang, H B; Zhu, D M
Protective effect of ischemic preconditioning on hepatic ischemia-reperfusion injury by advancing the expressive phase of survivin in rats
BACKGROUND: Survivin is a new and important gene in the regulation of apoptosis. It is very important to explore the effect of the expression of survivin protein caused by ischemia-reperfusion (IR) injury. The effect of IR injury caused by ischemic preconditioning (IP) on the liver in rats and the relation between the protective effect of IP and the expression of
Jian-Yi Li; Xi Gu; Hong-Zhuan Yin; Yong Zhou; Wen-Hai Zhang; Yi-Min Qin
Effects of Ischemic Preconditioning of Different Intraoperative Ischemic Times of Vascularized Bone Graft Rabbit Models
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.
Wan Ahmad Kamal, Wan Syazli Rodzaia; Noor, Norizal Mohd; Abdullah, Shafie
The protective roles of autophagy in ischemic preconditioning.
Autophagy, a process for the degradation of protein aggregates and dysfunctional organelles, is required for cellular homeostasis and cell survival in response to stress and is implicated in endogenous protection. Ischemic preconditioning is a brief and nonlethal episode of ischemia, confers protection against subsequent ischemia-reperfusion through the up-regulation of endogenous protective mechanisms. Emerging evidence shows that autophagy is associated with the protective effect of ischemic preconditioning. This review summarizes recent progress in research on the functions and regulations of the autophagy pathway in preconditioning-induced protection and cellular survival. PMID:23603984
Yan, Wen-jun; Dong, Hai-long; Xiong, Li-ze
Ischemic Preconditioning: A Novel Target for Neuroprotective Therapy
Ischemic preconditioning involves a brief exposure to ischemia in order to develop a tolerance to injurious effects of prolonged ischemia. The molecular mechanisms of neuroprotection that lead to ischemic tolerance are not yet completely understood. However, it seems that two distinct phases are involved. Firstly, a cellular defense function against ischemia may be developed by the mechanisms inherent to neurons
Miguel Blanco; Ignacio Lizasoain; Tom�s Sobrino; Jos� Vivancos; Jos� Castillo
Protection of the Liver by Ischemic Preconditioning: A Review of Mechanisms and Clinical Applications
Ischemic preconditioning refers to the endogenous mechanism of protection against a sustained ischemic insult following an initial, brief ischemic stimulus. Ischemia-reperfusion injury of the liver is a major cause of morbidity and mortality in liver surgery and transplantation and ischemic preconditioning is a promising strategy for improving the outcome of liver surgery. The preconditioning phenomenon was first described in a
Rahul S. Koti; Alexander M. Seifalian; Brian R. Davidson
Impact of hypoglycemic agents on myocardial ischemic preconditioning
Murry et al in 1986 discovered the intrinsic mechanism of profound protection called ischemic preconditioning. The complex cellular signaling cascades underlying this phenomenon remain controversial and are only partially understood. However, evidence suggests that adenosine, released during the initial ischemic insult, activates a variety of G protein-coupled agonists, such as opioids, bradykinin, and catecholamines, resulting in the activation of protein kinases, especially protein kinase C (PKC). This leads to the translocation of PKC from the cytoplasm to the sarcolemma, where it stimulates the opening of the ATP-sensitive K+ channel, which confers resistance to ischemia. It is known that a range of different hypoglycemic agents that activate the same signaling cascades at various cellular levels can interfere with protection from ischemic preconditioning. This review examines the effects of several hypoglycemic agents on myocardial ischemic preconditioning in animal studies and clinical trials.
Rahmi Garcia, Rosa Maria; Rezende, Paulo Cury; Hueb, Whady
Redox Signaling Pathways Involved in Neuronal Ischemic Preconditioning
There is extensive evidence that the restoration of blood flow following cerebral ischemia contributes greatly to the pathophysiology of ischemia mediated brain injury. The initiating stimulus of reperfusion injury is believed to be the excessive production of reactive oxygen (ROS) and nitrogen (RNS) species by the mitochondria. ROS and RNS generation leads to mitochondrial protein, lipid and DNA oxidation which impedes normal mitochondrial physiology and initiates cellular death pathways. However not all ROS and RNS production is detrimental. It has been demonstrated that low levels of ROS production are protective and may serve as a trigger for activation of ischemic preconditioning. Ischemic preconditioning is a neuroprotective mechanism which is activated upon a brief sublethal ischemic exposure and is sufficient to provide protection against a subsequent lethal ischemic insult. Numerous proteins and signaling pathways have been implicated in the ischemic preconditioning neuroprotective response. In this review we examine the origin and mechanisms of ROS and RNS production following ischemic/reperfusion and the role of free radicals in modulating proteins associated with ischemic preconditioning neuroprotection.
Thompson, John W; Narayanan, Srinivasan V; Perez-Pinzon, Miguel A
Myocardial remote ischemic preconditioning: from pathophysiology to clinical application.
Short periods of myocardial ischemia followed by reperfusion induce a cardioprotective mechanism when the myocardium is subsequently subjected to a prolonged period of ischemia, a phenomenon known as ischemic preconditioning. As well as its application in the myocardium, ischemic preconditioning can also be induced by brief interruptions of blood flow to other organs, particularly skeletal muscle. Transient ischemia induced noninvasively by inflating a cuff on a limb, followed by reperfusion, helps reduce the damage caused to the myocardium by interruption of the coronary circulation. Remote ischemic preconditioning involves activation of humoral and/or neural pathways that open mitochondrial ATP-sensitive potassium channels in the myocardium and close mitochondrial permeability transition pores, making cardiomyocytes less vulnerable to ischemia-induced cell death. This cardioprotective mechanism is now being translated into clinical practice, with positive results in several clinical trials in coronary artery bypass surgery, surgical repair of abdominal aortic aneurysms, valve replacement surgery and percutaneous coronary intervention. However, certain factors weaken the subcellular mechanisms of preconditioning - age, comorbidities, medication, anesthetic protocol - and appear to explain the heterogeneity of results in some studies. Detailed understanding of the pathways involved in cardioprotection induced by ischemic preconditioning is expected to lead to the development of new drugs to reduce the consequences of prolonged ischemia. PMID:24120469
Costa, Jos� F; Fontes-Carvalho, Ricardo; Leite-Moreira, Adelino F
Heat shock proteins, end effectors of myocardium ischemic preconditioning?
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.�
Guisasola, Maria Concepcion; Desco, Maria del Mar; Gonzalez, Fernanda Silvana; Asensio, Fernando; Dulin, Elena; Suarez, Antonio; Garcia Barreno, Pedro
Ischemic preconditioning for cell-based therapy and tissue engineering.
Cell- and tissue-based therapies are innovative strategies to repair and regenerate injured hearts. Despite major advances achieved in optimizing these strategies in terms of cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. The non-genetic approach of ischemic/hypoxic preconditioning to enhance cell- and tissue-based therapies has received much attention in recent years due to its non-invasive drug-free application. Here we discuss the current development of hypoxic/ischemic preconditioning to enhance stem cell-based cardiac repair and regeneration. PMID:24321597
Hsiao, Sarah T; Dilley, Rodney J; Dusting, Gregory J; Lim, Shiang Y
Protein kinase C isoform�dependent myocardial protection by ischemic preconditioning and potassium cardioplegia
Objective: Ischemic preconditioning combined with potassium cardioplegia does not always confer additive myocardial protection. This study tested the hypothesis that the efficacy of ischemic preconditioning under potassium cardioplegia is dependent on protein kinase C isoform. Methods: Isolated and crystalloid-perfused rat hearts underwent 5 cycles of 1 minute of ischemia and 5 minutes of reperfusion (low-grade ischemic preconditioning) or 3 cycles
Kejie Lu; Hajime Otani; Tadashi Yamamura; Yoshihisa Nakao; Reiji Hattori; Hideki Ninomiya; Motohiko Osako; Hiroji Imamura
Tandem action of exercise training and food restriction completely preserves ischemic preconditioning in the aging heart.
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
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
Autophagy Induced by Ischemic Preconditioning is Essential for Cardioprotection
Based on growing evidence linking autophagy to preconditioning, we tested the hypothesis that autophagy is necessary for cardioprotection conferred by ischemic preconditioning (IPC). We induced IPC with three cycles of 5�min regional ischemia alternating with 5�min reperfusion and assessed the induction of autophagy in mCherry-LC3 transgenic mice by imaging of fluorescent autophagosomes in cryosections. We found a rapid and significant increase in the number of autophagosomes in the risk zone of the preconditioned hearts. In Langendorff-perfused hearts subjected to an IPC protocol of 3?�?5�min ischemia, we also observed an increase in autophagy within 10�min, as assessed by Western blotting for p62 and cadaverine dye binding. To establish the role of autophagy in IPC cardioprotection, we inhibited autophagy with Tat-ATG5K130R, a dominant negative mutation of the autophagy protein Atg5. Cardioprotection by IPC was reduced in rat hearts perfused with recombinant Tat-ATG5K130R. To extend the potential significance of autophagy in cardioprotection, we also assessed three structurally unrelated cardioprotective agents�UTP, diazoxide, and ranolazine�for their ability to induce autophagy in HL-1 cells. We found that all three agents induced autophagy; inhibition of autophagy abolished their protective effect. Taken together, these findings establish autophagy as an end-effector in ischemic and pharmacologic preconditioning.
Huang, Chengqun; Yitzhaki, Smadar; Perry, Cynthia N.; Liu, Wayne; Giricz, Zoltan; Mentzer, Robert M.
Conditional Knockout of Myocyte Focal Adhesion Kinase Abrogates Ischemic Preconditioning in Adult Murine Hearts
Background Our laboratory has previously demonstrated the importance of a cytoskeletal?based survival signaling pathway using in vitro models of ischemia/reperfusion (IR). However, the importance of this pathway in mediating stress?elicited survival signaling in vivo is unknown. Methods and Results The essential cytoskeletal signaling pathway member focal adhesion kinase (FAK) was selectively deleted in adult cardiac myocytes using a tamoxifen?inducible Cre?Lox system (??MHC?MerCreMer). Polymerase chain reaction (PCR) and Western blot were performed to confirm FAK knockout (KO). All mice were subjected to a 40?minute coronary occlusion followed by 24 hours of reperfusion. Ischemic preconditioning (IP) was performed using a standard protocol. Control groups included wild?type (WT) and tamoxifen?treated ??MHC?MerCreMer+/?/FAKWT/WT (experimental control) mice. Infarct size was expressed as a percentage of the risk region. In WT mice IP significantly enhanced the expression of activated/phosphorylated FAK by 36.3% compared to WT mice subjected to a sham experimental protocol (P?0.05; n=6 hearts [sham], n=4 hearts [IP]). IP significantly reduced infarct size in both WT and experimental control mice (43.7% versus 19.8%; P?0.001; 44.7% versus 17.5%; P?0.001, respectively). No difference in infarct size was observed between preconditioned FAK KO and nonpreconditioned controls (37.1% versus 43.7% versus 44.7%; FAK KO versus WT versus experimental control; P=NS). IP elicited a 67.2%/88.8% increase in activated phosphatidylinositol?3?kinase (PI3K) p85/activated Akt expression in WT mice, but failed to enhance the expression of either in preconditioned FAK KO mice. Conclusions Our results indicate that FAK is an essential mediator of IP?elicited cardioprotection and provide further support for the hypothesis that cytoskeletal?based signaling is an important component of stress?elicited survival signaling.
Perricone, Adam J.; Bivona, Benjamin J.; Jackson, Fannie R.; Vander Heide, Richard S.
Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance.
Preconditioning to ischemic tolerance is a phenomenon in which brief episodes of a subtoxic insult induce a robust protection against the deleterious effects of subsequent, prolonged, lethal ischemia. The subtoxic stimuli that constitute the preconditioning event are quite diverse, ranging from brief ischemic episodes, spreading depression or potassium depolarization, chemical inhibition of oxidative phosphorylation, exposure to excitotoxins and cytokines. The beneficial effects of preconditioning were first demonstrated in the heart; it is now clear that preconditioning can induce ischemic tolerance in a variety of organ systems including brain, heart, liver, small intestine, skeletal muscle, kidney, and lung. There are two temporally and mechanistically distinct types of protection afforded by preconditioning stimuli, acute and delayed preconditioning. The signaling cascades that initiate the acute and delayed preconditioning responses may have similar biochemical components. However, the protective effects of acute preconditioning are protein synthesis-independent, mediated by post-translational protein modifications, and are short-lived. The effects of delayed preconditioning require new protein synthesis and are sustained for days to weeks. Elucidation of the molecular mechanisms that are involved in preconditioning and ischemic tolerance and identification of drugs that mimic this protective response have the potential to improve the prognosis of patients at risk for ischemic injury. This article focuses on recent findings on the effects of ischemic preconditioning in the cardiac and nervous systems and discusses potential targets for a successful therapeutic approach to limit ischemia-reperfusion injury. PMID:11303032
Nandagopal, K; Dawson, T M; Dawson, V L
Age-related reduction of cerebral ischemic preconditioning: myth or reality?
Stroke is one of the leading causes of death in industrialized countries for people older than 65 years of age. The reasons are still unclear. A reduction of endogenous mechanisms against ischemic insults has been proposed to explain this phenomenon. The �cerebral� ischemic preconditioning mechanism is characterized by a brief episode of ischemia that renders the brain more resistant against subsequent longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. This protective mechanism seems to be reduced with aging both in experimental and clinical studies. Alterations of mediators released and/or intracellular pathways may be responsible for age-related ischemic preconditioning reduction. Agents able to mimic the �cerebral� preconditioning effect may represent a new powerful tool for the treatment of acute ischemic stroke in the elderly. In this article, animal and human cerebral ischemic preconditioning, its age-related difference, and its potential therapeutical applications are discussed.
Della-Morte, David; Cacciatore, Francesco; Salsano, Elisa; Pirozzi, Gilda; Genio, Maria Teresa Del; D'Antonio, Iole; Gargiulo, Gaetano; Palmirotta, Raffaele; Guadagni, Fiorella; Rundek, Tatjana; Abete, Pasquale
Ischemic preconditioning attenuates lipid peroxidation and apoptosis in the cecal ligation and puncture model of sepsis
Sepsis and septic shock are are among the major causes of mortality in intensive care units. The lung and kidney are the organs most affected by sepsis. Evidence exists that lipid peroxidation and apoptosis may be responsible for the high mortality due to sepsis. Ischemic preconditioning (IP) is a method for the protection of tissues and organs against ischemia/reperfusion injury by reducing reactive oxygen species levels, lipid peroxidation and apoptosis. In the present study, the effects of IP were investigated in cecal ligation and puncture (CLP)-induced sepsis in rats. The three groups of animals used in the present controlled study were the sham-operated group (sham, n=7), which only underwent a laparotomy; the sepsis group (sepsis, n=7), which underwent cecal ligation and perforation; and the IP + sepsis group (IP+sepsis, n=7), which underwent CLP immediately prior to the application of three cycles of IP to the hind limb. The study was terminated at 6 h after the induction of CLP. Blood, kidney and lung tissue samples were collected for the determination of serum creatinine, blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL) and lung tissue malondialdehyde (MDA) levels, as well as histological examination. The serum creatinine, plasma NGAL and lung tissue MDA levels in the sepsis group were significantly increased compared with those in the sham and the IP+sepsis groups (P<0.05). Alveolar macrophage counts, histological kidney and lung injury scores, kidney (caspase 3) and lung tissue immuonreactivity (M30) scores in the sepsis group were also significantly increased compared with those in the sham and IP+sepsis groups (P<0.05). The alveolar macrophage count in the IP+sepsis group was increased compared with that in the sham group (P<0.05). In conclusion, IP inhibits lipid peroxidation and attenuates histological injury and apoptosis in the lung and kidney during sepsis.
Ischemic preconditioning-induced hyperperfusion correlates with hepatoprotection after liver resection
AIM: To characterize the impact of the Pringle maneuver (PM) and ischemic preconditioning (IP) on total blood supply to the liver following hepatectomies. METHODS: Sixty one consecutive patients who underwent hepatic resection under inflow occlusion were randomized either to receive PM alone (n = 31) or IP (10 min of ischemia followed by 10 min of reperfusion) prior to PM (n = 30). Quantification of liver perfusion was measured by Doppler probes at the hepatic artery and portal vein at various time points after reperfusion of remnant livers. RESULTS: Occlusion times of 33 � 12 min (mean � SD) and 34 � 14 min and the extent of resected liver tissue (2.7 segments) were similar in both groups. In controls (PM), on reperfusion of liver remnants for 15 min, portal perfusion markedly decreased by 29% while there was a slight increase of 8% in the arterial blood flow. In contrast, following IP + PM the portal vein flow remained unchanged during reperfusion and a significantly increased arterial blood flow (+56% vs baseline) was observed. In accordance with a better postischemic blood supply of the liver, hepatocellular injury, as measured by alanine aminotransferase (ALT) levels on day 1 was considerably lower in group B compared to group A (247 � 210 U/I vs 550 � 650 U/I, P < 0.05). Additionally, ALT levels were significantly correlated to the hepatic artery inflow. CONCLUSION: IP prevents postischemic flow reduction of the portal vein and simultaneously increases arterial perfusion, suggesting that improved hepatic macrocirculation is a protective mechanism following hepatectomy.
Heizmann, Oleg; Meimarakis, Georgios; Volk, Andreas; Matz, Daniel; Oertli, Daniel; Schauer, Rolf J
Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes
Whether ischemic preconditioning (IP) reduces ischemia/reperfusion (I/R) injury in human normal and fatty livers remains controversial. We compared two independent groups of liver donor transplants with versus without steatosis to evaluate IP consequences. Liver donors with (n=22) or without (n=28) steatosis either did or did not undergo IP before graft retrieval. Clinical data from the recipients, as well as histological and immunohistological characteristics of post-reperfusion biopsies were analyzed. Incidence of post-reperfusion necrosis was increased (10/10 versus 9/14, respectively; P<0.05) and the clinical outcome of recipients was worse for non-IP steatotic liver grafts compared with non-IP non-steatotic grafts. IP significantly lowered the transaminase values only in patients receiving a non-steatotic liver. An increased expression of beclin-1 and LC3, two pro-autophagic proteins, tended to decrease the incidence of necrosis (P=0.067) in IP steatotic livers compared with non-IP steatotic group. IP decreased the incidence of acute and chronic rejection episodes in steatotic livers (2/12 versus 6/10; P=0.07 and 2/12 versus 7/10; P<0.05, respectively), but not in non-steatotic livers. Thus, IP may induce autophagy in human steatotic liver grafts and reduce rejection in their recipients.
Degli Esposti, D; Sebagh, M; Pham, P; Reffas, M; Pous, C; Brenner, C; Azoulay, D; Lemoine, A
Remote Ischemic Preconditioning (RIPC) Modifies Plasma Proteome in Humans
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.
Hepponstall, Michele; Ignjatovic, Vera; Binos, Steve; Monagle, Paul; Jones, Bryn; Cheung, Michael H. H.; d'Udekem, Yves; Konstantinov, Igor E.
Beneficial effects of ischemic preconditioning on pancreas cold preservation.
Ischemic preconditioning (IPC) confers tissue resistance to subsequent ischemia in several organs. The protective effects are obtained by applying short periods of warm ischemia followed by reperfusion prior to extended ischemic insults to the organs. In the present study, we evaluated whether IPC can reduce pancreatic tissue injury following cold ischemic preservation. Rat pancreata were exposed to IPC (10 min of warm ischemia followed by 10 min of reperfusion) prior to ~18 h of cold preservation before assessment of organ injury or islet isolation. Pancreas IPC improved islet yields (964 � 336 vs. 711 � 204 IEQ/pancreas; p = 0.004) and lowered islet loss after culture (33 � 10% vs. 51 � 14%; p = 0.0005). Islet potency in vivo was well preserved with diabetes reversal and improved glucose clearance. Pancreas IPC reduced levels of NADPH-dependent oxidase, a source of reactive oxygen species, in pancreas homogenates versus controls (78.4 � 45.9 vs. 216.2 � 53.8 RLU/?g; p = 0.002). Microarray genomic analysis of pancreata revealed upregulation of 81 genes and downregulation of 454 genes (greater than twofold change) when comparing IPC-treated glands to controls, respectively, and showing a decrease in markers of apoptosis and oxidative stress. Collectively, our study demonstrates beneficial effects of IPC of the pancreas prior to cold organ preservation and provides evidence of the key role of IPC-mediated modulation of oxidative stress pathways. The use of IPC of the pancreas may contribute to increasing the quality of donor pancreas for transplantation and to improving organ utilization. PMID:22305457
Hogan, Anthony R; Doni, Marco; Molano, R Damaris; Ribeiro, Melina M; Szeto, Angela; Cobianchi, Lorenzo; Zahr-Akrawi, Elsie; Molina, Judith; Fornoni, Alessia; Mendez, Armando J; Ricordi, Camillo; Pastori, Ricardo L; Pileggi, Antonello
Pathways for ischemic cytoprotection: Role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning
Caloric restriction (CR), resveratrol, and ischemic preconditioning (IPC) have been shown to promote protection against ischemic injury in the heart and brain, as well as in other tissues. The activity of sirtuins, which are enzymes that modulate diverse biologic processes, seems to be vital in the ability of these therapeutic modalities to prevent against cellular dysfunction and death. The protective mechanisms of the yeast Sir2 and the mammalian homolog sirtuin 1 have been extensively studied, but the involvement of other sirtuins in ischemic protection is not yet clear. We examine the roles of mammalian sirtuins in modulating protective pathways against oxidative stress, energy depletion, excitotoxicity, inflammation, DNA damage, and apoptosis. Although many of these sirtuins have not been directly implicated in ischemic protection, they may have unique roles in enhancing function and preventing against stress-mediated cellular damage and death. This review will include in-depth analyses of the roles of CR, resveratrol, and IPC in activating sirtuins and in mediating protection against ischemic damage in the heart and brain.
Morris, Kahlilia C; Lin, Hung Wen; Thompson, John W; Perez-Pinzon, Miguel A
Effects of sevoflurane preconditioning and postconditioning on rat myocardial stunning in ischemic reperfusion injury
Ischemic preconditioning and postconditioning distinctly attenuate ventricular arrhythmia after ischemia without affecting\\u000a the severity of myocardial stunning. Therefore, we report the effects of sevoflurane preconditioning and postconditioning\\u000a on stunned myocardium in isolated rat hearts. Isolated rat hearts were underwent 20 min of global ischemia and 40 min of reperfusion.\\u000a After an equilibration period (20 min), the hearts in the preconditioning
An-lu Dai; Li-hua Fan; Feng-jiang Zhang; Mei-juan Yang; Jing Yu; Jun-kuan Wang; Tao Fang; Gang Chen; Li-na Yu; Min Yan
Late ischemic preconditioning of the myocardium alters the expression of genes involved in inflammatory response
Myocardial ischemic preconditioning (IPC) is a potent endogenous mechanism of cardioprotection against ischemia�reperfusion injury. In this study we focused on the second phase of IPC as the most interesting in terms of therapeutic implementations. We aimed at the detection of genes, which are differentially expressed at 16 h after reperfusion. Preconditioning of canine myocardium was initiated by 5 min occlusion
Dmitrij Zubakov; J�rg D Hoheisel; Franz-Werner Kluxen; Marian Br�ndle; Thomas Ehring; Bernd Hentsch; Marcus Frohme
Critical Role for Nitric Oxide Signaling in Cardiac and Neuronal Ischemic Preconditioning and Tolerance
Preconditioning to ischemic tolerance is a phenomenon in which brief episodes of a subtoxic insult induce a robust pro- tection against the deleterious effects of subsequent, pro- longed, lethal ischemia. The subtoxic stimuli that constitute the preconditioning event are quite diverse, ranging from brief isch- emic episodes, spreading depression or potassium depolariza- tion, chemical inhibition of oxidative phosphorylation, exposure to
Toll-like receptor 9: a new target of ischemic preconditioning in the brain.
Preconditioning with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, provides neuroprotection against subsequent cerebral ischemic brain injury, through a tumor necrosis factor (TNF)alpha-dependent process. Here, we report the first evidence that another TLR, TLR9, can induce neuroprotection. We show that the TLR9 ligand CpG oligodeoxynucleotide (ODN) can serve as a potent preconditioning stimulus and provide protection against ischemic brain injury. Our studies show that systemic administration of CpG ODN 1826 in advance of brain ischemia (middle cerebral artery occlusion (MCAO)) reduces ischemic damage up to 60% in a dose- and time-dependent manner. We also offer evidence that CpG ODN preconditioning can provide direct protection to cells of the central nervous system, as we have found marked neuroprotection in modeled ischemia in vitro. Finally, we show that CpG preconditioning significantly increases serum TNFalpha levels before MCAO and that TNFalpha is required for subsequent reduction in damage, as mice lacking TNFalpha are not protected against ischemic injury by CpG preconditioning. Our studies show that preconditioning with a TLR9 ligand induces neuroprotection against ischemic injury through a mechanism that shares common elements with LPS preconditioning via TLR4. PMID:18183029
Stevens, Susan L; Ciesielski, Thomas M P; Marsh, Brenda J; Yang, Tao; Homen, Delfina S; Boule, Jo-Lynn; Lessov, Nikola S; Simon, Roger P; Stenzel-Poore, Mary P
Remote ischemic preconditioning in patients with intermittent claudication
OBJECTIVE: Remote ischemic preconditioning (RIPC) is a phenomenon in which a short period of sub-lethal ischemia in one organ protects against subsequent bouts of ischemia in another organ. We hypothesized that RIPC in patients with intermittent claudication would increase muscle tissue resistance to ischemia, thereby resulting in an increased ability to walk. METHODS: In a claudication clinic, 52 ambulatory patients who presented with complaints of intermittent claudication in the lower limbs associated with an absent or reduced arterial pulse in the symptomatic limb and/or an ankle-brachial index <0.90 were recruited for this study. The patients were randomly divided into three groups (A, B and C). All of the patients underwent two tests on a treadmill according to the Gardener protocol. Group A was tested first without RIPC. Group A was subjected to RIPC prior to the second treadmill test. Group B was subjected to RIPC prior to the first treadmill test and then was subjected to a treadmill test without RIPC. In Group C (control group), both treadmill tests were performed without RIPC. The first and second tests were conducted seven days apart. Brazilian Clinical Trials: RBR-7TF6TM. RESULTS: Group A showed a significant increase in the initial claudication distance in the second test compared to the first test. CONCLUSION: RIPC increased the initial claudication distance in patients with intermittent claudication; however, RIPC did not affect the total walking distance of the patients.
Saes, Glauco Fernandes; Zerati, Antonio Eduardo; Wolosker, Nelson; Ragazzo, Luciana; Rosoky, Ruben Miguel Ayzin; Ritti-Dias, Raphael Mendes; Cucato, Gabriel Grizzo; Chehuen, Marcelo; Farah, Breno Quintella; Puech-Leao, Pedro
Remote ischemic preconditioning as treatment for non-ischemic gastrointestinal disorders: beyond ischemia-reperfusion injury.
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
Camara-Lemarroy, Carlos Rodrigo
Remote ischemic preconditioning as treatment for non-ischemic gastrointestinal disorders: Beyond ischemia-reperfusion injury
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.
Camara-Lemarroy, Carlos Rodrigo
Ischemic preconditioning of the liver in rats: Implications of heat shock protein induction to increase tolerance of ischemia-reperfusion injury
It has been reported that ischemic preconditioning of the heart or brain has a possible relevance to heat shock protein (HSP). It is still unknown, however, whether HSP induced by means of ischemic preconditioning of the liver is a direct factor in the acquisition of tolerance to succeeding ischemia-reperfusion injury. In the present study we used ischemic preconditioning of the
Makoto Kume; Yuzo Yamamoto; Stefano Saad; Takashi Gomi; Syuji Kimoto; Takashi Shimabukuro; Toshikazu Yagi; Mikio Nakagami; Yasutsugu Takada; Taisuke Morimoto; Yoshio Yamaoka
Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart
Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1?. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1? into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1? or HIF-1?. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.
Cai, Zheqing; Luo, Weibo; Zhan, Huiwang; Semenza, Gregg L.
Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart.
Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1?. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1? into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1? or HIF-1?. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning. PMID:24101519
Cai, Zheqing; Luo, Weibo; Zhan, Huiwang; Semenza, Gregg L
Ischemic preconditioning-induced neuroprotection against transient cerebral ischemic damage via attenuating ubiquitin aggregation.
Ubiquitin binds to short-lived proteins, and denatured proteins are produced by various forms of injuries. In the present study, we investigated the effect of ischemic preconditioning (IPC) on free ubiquitin and its mutant form (ubiquitin(+1)) in the gerbil hippocampus induced by transient cerebral ischemia. The animals were randomly assigned to 4 groups (sham-operated-group, ischemia-operated-group, IPC plus (+)-sham-operated-group, and IPC+ischemia-operated-group). IPC was induced by subjecting gerbils to a 2 min of ischemia followed by 1 day of recovery. A significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) in the ischemia-operated-groups 5 days after ischemia-reperfusion (I-R). In all the IPC+ischemia-operated-groups, neurons in the SP were well protected. We found that strong ubiquitin immunoreactivity was detected in the SP in the sham-operated-group and the immunoreactivity was decreased with time after I-R. In all the IPC+ischemia-operated-groups, ubiquitin immunoreactivity in the SP was similar to that in the sham-operated group. Moderate ubiquitin(+1) immunoreactivity was detected in the SP of the sham-operated-group, and the immunoreactivity was markedly increased 2 days after I-R. Five days after I-R, ubiquitin(+1) immunoreactivity was very weak in the SP. In all the IPC+ischemia-operated-groups, ubiquitin(+1) immunoreactivity in the SP was slightly decreased with time after I-R. Western blot analysis showed that, in all the IPC+ischemia-ischemia-groups, the levels of ubiquitin and ubiquitin(+1) proteins were well maintained after I-R. In brief, our findings suggest that the inhibition of the depletion of free ubiquitin and the formation of ubiquitin(+1) may have an essential role in inducing cerebral ischemic tolerance by IPC. PMID:24268923
Lee, Jae-Chul; Kim, In Hye; Cho, Geum-Sil; Park, Joon Ha; Ahn, Ji Hyeon; Yan, Bing Chun; Kwon, Hyuk Min; Kim, Young-Myeong; Cheon, Seung Hwan; Cho, Jun Hwi; Lee, Hui Young; Won, Moo-Ho; Seo, Jeong Yeol
Ischemic preconditioning by brief extremity ischemia before flap ischemia in a rat model.
Ischemic preconditioning is a protective endogenous mechanism to reduce ischemia/reperfusion injury and is defined as a brief period of ischemia the authors term "preclamping." This is followed by tissue reperfusion and is believed to increase the ischemic tolerance. The objective of this study was to determine whether acute remote ischemic preconditioning, which has been reported to be successful for other organs, such as the heart, kidney, intestine, and liver, will also result in an enhancement of survival in flaps, and whether remote ischemic preconditioning is as effective as preclamping. Forty male Wistar rats were divided into four experimental groups. An extended epigastric adipocutaneous flap (6 x 10 cm) was raised, based on the left superficial epigastric artery and vein. In the control group, a 3-hour flap ischemia was induced. In the preclamping group, a brief ischemia of 10 minutes was induced by clamping the flap pedicle, followed by 30 minutes of reperfusion. Ischemia of the right hind limb was induced in the femoral ischemia group by clamping the femoral artery and vein for 10 minutes after flap elevation. The limb was then reperfused for 30 minutes. Thereafter, flap ischemia was induced as in the control group. A similar protocol was used in the tourniquet group. A tourniquet was used to induce hind-limb ischemia. The experiment was then performed as in the femoral ischemia group. Mean flap necrosis area was assessed for all groups on the fifth postoperative day using planimetry software. Average flap necrosis area was 68.2 +/- 18.1 percent in the control group, 11 +/- 8.38 percent in the preclamping group, 12.5 +/- 5.83 percent in the femoral ischemia group, and 24 +/- 11.75 percent in the tourniquet group. All preconditioned animals demonstrated a significantly lower area of flap necrosis than the control group (p < 0.001, one-way analysis of variance, post hoc Tukey's test). The data show that ischemic preconditioning and enhancement of flap survival can be achieved not only by preclamping of the flap pedicle but also by induction of an ischemia/reperfusion event in a body area distant from the flap before harvest. These findings indicate that remote ischemic preconditioning is a systemic phenomenon, leading to an enhancement of flap survival. The exact mechanism is not yet completely understood. The data suggest that remote ischemic preconditioning could be performed simultaneously with flap harvest in the clinical setting, resulting in an improved flap survival without prolongation of the operation. This may decrease the rate of partial flap loss or fat necrosis, especially in high-risk groups such as smokers, those with irradiated tissues, and obese patients. PMID:12045567
K�ntscher, Markus V; Schirmbeck, Eva U; Menke, Henrik; Klar, Ernst; Gebhard, Martha Maria; Germann, G�nter
Visual Evidence of Ischemic Preconditioning During PCI Using 80 Lead ECG Body Surface Mapping
Ischemic preconditioning (IPC) is a well-documented phenomenon. Short episodes of sublethal ischemia provide cardioprotective effects for subsequent longer duration ischemic events. Although the exact mechanism of IPC is not yet known, the chemical basis of IPC seems to involve preservation of ATP or collateral vascularization recruitment. In this case report, we present visual evidence of ischemic preconditioning using Heartscape Technologies 80 Lead ECG device. The 80 Lead ECG is described as a body surface mapping modality, converting its inputted 80 lead ECG data into a 3-Dimensional color coded map. The 80 lead ECG device can detect instantaneous ischemic changes. Different studies have been performed to show different clinical and biochemical aspects of IPC. However data regarding direct visual evidence of this phenomenon is lacking. The secondary objective of this study is to show the ability of 80 lead ECG to identify ST-segment elevation and depression during ischemic events. The utility of 80 Lead ECG body surface mapping is enormous when evaluating ischemic events.
Dadkhah, Shahriar; Dowlatshahi, Samaneh; Sharain, Korosh; Sharain, Roza
Intracoronary administration of the cx ,-receptor agonist, methoxamine, does not reproduce the infarct-limiting effect of ischemic preconditioning in dogs
Background: The cardioprotective effect of ischemic preconditioning has been hypothesized to occur through one or more signalling mechanisms which activate protein kinase C. Stimulation of Q ,-adrenergic receptors by catecholamines released during the precondition- ing episodes of ischemia is one of these putative signalling mechanisms. Methods: To determine whether stimulation of cr,-adrenergic receptors before an ischemic challenge can mimic preconditioning,
Laurent Sebbag; Masayuki Katsuragawa; Steven Verbinski; Robert B. Jennings; Keith A. Reimer
Effects of ischemic preconditioning and iloprost on myocardial ischemia-reperfusion damage in rats.
This study investigates the effects of cardiac ischemic preconditioning and iloprost on reperfusion damage in rats with myocardial ischemia/reperfusion. 38 male Wistar Albino rats used in this study were divided into 5 groups. The control group (Group 1) (n=6), ischemia/reperfusion (IR) group (Group 2) (n=8), cardiac ischemic preconditioning (CIP) group (Group 3) (n=8), iloprost (ILO) group (Group 4) (n=8), and cardiac ischemic preconditioning + iloprost (CIP+ILO) group (Group 5) (n=8). Pre-ischemia, 15 minutes post-ischemia, 45 minutes post-reperfusion, mean blood pressure (MBP), and heart rates (HR) were recorded. The rate-pressure product (RPP) was calculated. Post-reperfusion plasma creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin (cTn) vlaues, and infarct size/area at risk (IS/AAR) were calculated from myocardial tissue samples. Arrhythmia and ST segment elevations were evaluated during the ischemia and reperfusion stages. Although the MBP, HR, RPP values, biochemical parameters of CK-MB and LDH levels, IS/AAR rates, ST segment elevation values were found to be similar in CIP and CIP+ILO groups and the IR and ILO groups (p>0.05), CIP-containing group values had a positively meaningful difference (p<0.05) compared with the IR and ILO group. While mild-moderate findings of damage were observed in Group 3 and Group 5, severely findings of damage were releaved in Group 2 and Group 4. The arrhythmia score of the ILO group was meaningfully lower (F: 41.4, p<0.001) than the IR group. We can conclude that the effects of myocardial reperfusion damage can be reduced by cardiac ischemic preconditioning, intravenous iloprost reduced the incidence of ventricular arrhythmia associated with reperfusion, and its use with CIP caused no additional changes. PMID:23936589
Ay, Yasin; Kara, Ibrahim; Aydin, Cemalettin; Ay, Nuray Kahraman; Teker, Melike Elif; Senol, Serkan; Inan, Bekir; Basel, Halil; Uysal, Omer; Zeybek, Rahmi
Ischemic preconditioning and nicotinamide in spinal cord protection in an experimental model of transient aortic occlusion
Objectives: Spinal cord injury is a devastating complication after aortic surgery. The aim of the present study is to examine the effects of ischemic preconditioning (IPC) and nicotinamide containing perfusate in transient aortic occlusion in the rat. Methods: Thirty-two male Spraque�Dawley rats under general anesthesia were randomly assigned to four groups (n=8 in each group). The infrarenal aortas were clamped
C. Selim Isbir; Koray Aka; Ozlem Kurtkaya; �mit Zeybek; Serdar Akg�n; Bernd W. Scheitauer; Aydin Sav; Adnan Cobanoglu
Effects of ischemic preconditioning and iloprost on myocardial ischemia-reperfusion damage in rats
This study investigates the effects of cardiac ischemic preconditioning and iloprost on reperfusion damage in rats with myocardial ischemia/reperfusion. 38 male Wistar Albino rats used in this study were divided into 5 groups. The control group (Group 1) (n=6), ischemia/reperfusion (IR) group (Group 2) (n=8), cardiac ischemic preconditioning (CIP) group (Group 3) (n=8), iloprost (ILO) group (Group 4) (n=8), and cardiac ischemic preconditioning + iloprost (CIP+ILO) group (Group 5) (n=8). Pre-ischemia, 15 minutes post-ischemia, 45 minutes post-reperfusion, mean blood pressure (MBP), and heart rates (HR) were recorded. The rate-pressure product (RPP) was calculated. Post-reperfusion plasma creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin (cTn) vlaues, and infarct size/area at risk (IS/AAR) were calculated from myocardial tissue samples. Arrhythmia and ST segment elevations were evaluated during the ischemia and reperfusion stages. Although the MBP, HR, RPP values, biochemical parameters of CK-MB and LDH levels, IS/AAR rates, ST segment elevation values were found to be similar in CIP and CIP+ILO groups and the IR and ILO groups (p>0.05), CIP-containing group values had a positively meaningful difference (p<0.05) compared with the IR and ILO group. While mild-moderate findings of damage were observed in Group 3 and Group 5, severely findings of damage were releaved in Group 2 and Group 4. The arrhythmia score of the ILO group was meaningfully lower (F: 41.4, p<0.001) than the IR group. We can conclude that the effects of myocardial reperfusion damage can be reduced by cardiac ischemic preconditioning, intravenous iloprost reduced the incidence of ventricular arrhythmia associated with reperfusion, and its use with CIP caused no additional changes.
Ay, Yasin; Kara, Ibrahim; Aydin, Cemalettin; Ay, Nuray Kahraman; Teker, Melike Elif; Senol, Serkan; Inan, Bekir; Basel, Halil; Uysal, Omer; Zeybek, Rahmi
The COX-2/PGI2 Receptor Axis Plays an Obligatory Role in Mediating the Cardioprotection Conferred by the Late Phase of Ischemic Preconditioning
Background Pharmacologic studies with cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by COX-2. However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only relative. Furthermore, the specific prostaglandin (PG) receptors responsible for the salubrious actions of COX-2-derived prostanoids remain unclear. Objective To determine the role of COX-2 and prostacyclin receptor (IP) in late PC by gene deletion. Methods COX-2 knockout (KO) mice (COX-2?/?), prostacyclin receptor KO (IP?/?) mice, and respective wildtype (WT, COX-2+/+ and IP+/+) mice underwent sham surgery or PC with six 4-min coronary occlusion (O)/4-min R cycles 24 h before a 30-min O/24 h R. Results There were no significant differences in infarct size (IS) between non-preconditioned (non-PC) COX-2+/+, COX-2?/?, IP+/+, and IP?/? mice, indicating that neither COX-2 nor IP modulates IS in the absence of PC. When COX-2?/? or IP?/? mice were preconditioned, IS was not reduced, indicating that the protection of late PC was completely abrogated by deletion of either the COX-2 or the IP gene. Administration of the IP selective antagonist, RO3244794 to C57BL6/J (B6) mice 30 min prior to the 30-min O had no effect on IS. When B6 mice were preconditioned 24 h prior to the 30-min O, IS was markedly reduced; however, the protection of late PC was completely abrogated by pretreatment of RO3244794. Conclusions This is the first study to demonstrate that targeted disruption of the COX-2 gene completely abrogates the infarct-sparing effect of late PC, and that the IP, downstream of the COX-2/prostanoid pathway, is a key mediator of the late PC. These results provide unequivocal molecular genetic evidence for an essential role of the COX-2/PGI2 receptor axis in the cardioprotection afforded by the late PC.
Guo, Yiru; Tukaye, Deepali Nivas; Wu, Wen-Jian; Zhu, Xiaoping; Book, Michael; Tan, Wei; Jones, Steven P.; Rokosh, Gregg; Narumiya, Shuh; Li, Qianhong; Bolli, Roberto
Ischemic preconditioning regulates expression of microRNAs and a predicted target, MeCP2, in mouse cortex
Preconditioning describes the ischemic stimulus that triggers an endogenous, neuroprotective response that protects the brain during a subsequent severe ischemic injury, a phenomenon known as �tolerance�. Ischemic tolerance requires new protein synthesis, leads to genomic reprogramming of the brain's response to subsequent ischemia, and is transient. MicroRNAs (miRNAs) regulate posttranscriptional gene expression by exerting direct effects on messenger RNA (mRNA)
Theresa A Lusardi; Carol D Farr; Craig L Faulkner; Giuseppe Pignataro; Tao Yang; Jingquan Lan; Roger P Simon; Julie A Saugstad
The Effects of Remote Ischemic Preconditioning and N-Acetylcysteine with Remote Ischemic Preconditioning in Rat Hepatic Ischemia Reperfusion Injury Model
Background. Remote ischemic preconditioning (RIP) and pharmacological preconditioning are the effective methods that can be used to prevent ischemia reperfusion (IR) injury. The aim of this study was to evaluate the effects of RIP and N-Acetylcysteine (NAC) with RIP in the rat hepatic IR injury model. Materials and Methods. 28 rats were divided into 4 groups. Group I (sham): only laparotomy was performed. Group II (IR): following 30 minutes of hepatic pedicle occlusion, 4 hours of reperfusion was performed. Group III (RIP + IR): following 3 cycles of RIP, hepatic IR was performed. Group IV (RIP + NAC + IR): following RIP and intraperitoneal administration of NAC (150?mg/kg), hepatic IR was performed. All the rats were sacrificed after blood samples were taken for the measurements of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver was processed for conventional histopathology. Results. The hepatic histopathological injury scores of RIP + IR and RIP + NAC + IR groups were significantly lower than IR group (P = 0.006, P = 0.003, resp.). There were no significant differences in AST and ALT values between the IR, RIP + IR, and RIP + NAC + IR groups. Conclusions. In the present study, it was demonstrated histopathologically that RIP and RIP + NAC decreased hepatic IR injury significantly.
Uysal, Ali Ihsan; Ozkardesler, Sevda; Ergur, Bekir Ugur; Guneli, Ensari; Kume, Tuncay; Unal Togrul, Belgin
Effect of ischemic preconditioning on the expression of putative neuroprotective genes in the rat brain.
Previous studies have demonstrated that sublethal ischemic insults protect from subsequent ischemia in the intact brain. There are two windows for the induction of tolerance by ischemic preconditioning (IPC). One occurs within 1 h following IPC, and the other one develops from 1 to 3 days after IPC. The goal of this study was to determine whether IPC neuroprotection may be mediated by expression of known neuroprotective genes and to characterize the temporal and spatial expression patterns of these genes. IPC was produced by bilateral carotid artery occlusions and hypotension (50 mmHg) for 2 min. After various survival times, the expression of MAP-2, brain-derived neurotrophic factor (BDNF), c-jun, c-fos, nerve growth factor (NGF) and HSP70 was assessed by in situ hybridization of coronal brain sections with 35S labeled probes. BDNF, NGF, and c-jun were significantly upregulated in the hippocampus. c-fos was detected in the hippocampus, cortex and striatum. HSP70 mRNA was induced in the cortex, hippocampus, striatum, and thalamus. MAP-2 showed no change in expression, confirming previous studies that no cell death occurs following IPC. The increase in expression of these stress-related, neurotrophic and immediate early genes in response to a mild preconditioning insult may help mediate the protection of vulnerable neurons to subsequent lethal ischemic insults. PMID:12106696
Truettner, Jessie; Busto, Raul; Zhao, Weizhao; Ginsberg, Myron D; P�rez-Pinz�n, Miguel A
Ischemic Preconditioning Protects against Spinal Cord Ischemia-Reperfusion Injury in Rabbits by Attenuating Blood Spinal Cord Barrier Disruption.
Ischemic preconditioning has been reported to protect against spinal cord ischemia-reperfusion (I-R) injury, but the underlying mechanisms are not fully understood. To investigate this, Japanese white rabbits underwent I-R (30 min aortic occlusion followed by reperfusion), ischemic preconditioning (three cycles of 5 min aortic occlusion plus 5 min reperfusion) followed by I-R, or sham surgery. At 4 and 24 h following reperfusion, neurological function was assessed using Tarlov scores, blood spinal cord barrier permeability was measured by Evan's Blue extravasation, spinal cord edema was evaluated using the wet-dry method, and spinal cord expression of zonula occluden-1 (ZO-1), matrix metalloproteinase-9 (MMP-9), and tumor necrosis factor-? (TNF-?) were measured by Western blot and a real-time polymerase chain reaction. ZO-1 was also assessed using immunofluorescence. Spinal cord I-R injury reduced neurologic scores, and ischemic preconditioning treatment ameliorated this effect. Ischemic preconditioning inhibited I-R-induced increases in blood spinal cord barrier permeability and water content, increased ZO-1 mRNA and protein expression, and reduced MMP-9 and TNF-? mRNA and protein expression. These findings suggest that ischemic preconditioning attenuates the increase in blood spinal cord barrier permeability due to spinal cord I-R injury by preservation of tight junction protein ZO-1 and reducing MMP-9 and TNF-? expression. PMID:23685868
Fang, Bo; Li, Xiao-Man; Sun, Xi-Jia; Bao, Na-Ren; Ren, Xiao-Yan; Lv, Huang-Wei; Ma, Hong
Both ischemic preconditioning and ghrelin administration protect hippocampus from ischemia/reperfusion and upregulate uncoupling protein-2
Background A major endogenous protective mechanism in many organs against ischemia/reperfusion (I/R) injury is ischemic preconditioning (IPC). By moderately uncoupling the mitochondrial respiratory chain and decreasing production of reactive oxygen species (ROS), IPC reduces apoptosis induced by I/R by reducing cytochrome c release from the mitochondria. One element believed to contribute to reduce ROS production is the uncoupling protein UCP2 (and UCP3 in the heart). Although its implication in IPC in the brain has been shown in vitro, no in vivo study of protein has shown its upregulation. Our first goal was to determine in rat hippocampus whether UCP2 protein upregulation was associated with IPC-induced protection and increased ROS production. The second goal was to determine whether the peptide ghrelin, which possesses anti-oxidant and protective properties, alters UCP2 mRNA levels in the same way as IPC during protection. Results After global forebrain ischemia (15 min) with 72 h reperfusion (I/R group), we found important neuronal lesion in the rat hippocampal CA1 region, which was reduced by a preceding 3-min preconditioning ischemia (IPC+I/R group), whereas the preconditioning stimulus alone (IPC group) had no effect. Compared to control, UCP2 protein labelling increased moderately in the I/R (+39%, NS) and IPC+I/R (+28%, NS) groups, and substantially in the IPC group (+339%, P < 0.05). Treatment with superoxide dismutase (10000 U/kg ip) at the time of a preconditioning ischemia greatly attenuated (-73%, P < 0.001) the increase in UCP2 staining at 72 h, implying a role of oxygen radicals in UCP2 induction. Hippocampal UCP2 mRNA showed a moderate increase in I/R (+33%, P < 0.05) and IPC+I/R (+40%, P < 0.05) groups versus control, and a large increase in the IPC group (+333%, P < 0.001). In ghrelin experiments, the I/R+ghrelin group (3 daily administrations) showed considerable protection of CA1 neurons versus I/R animals, and increased hippocampal UCP2 mRNA (+151%, P < 0.001). Conclusion We confirm that IPC causes increased expression of UCP2 protein in vivo, at a moment appropriate for protection against I/R in the hippocampus. The two dissimilar protective strategies, IPC and ghrelin administration, were both associated with upregulated UCP2, suggesting that UCP2 may often represent a final common pathway in protection from I/R.
Liu, Yajun; Chen, Lianbi; Xu, Xiaoqun; Vicaut, Eric; Sercombe, Richard
Involvement of adenosine and standardization of aqueous extract of garlic (Allium sativum Linn.) on cardioprotective and cardiodepressant properties in ischemic preconditioning and myocardial ischemia-reperfusion induced cardiac injury
The present study investigated the effect of garlic (Allium sativum Linn.) aqueous extracts on ischemic preconditioning and ischemia-reperfusion induced cardiac injury, as well as adenosine involvement in ischemic preconditioning and garlic extract induced cardioprotection. A model of ischemia-reperfusion injury was established using Langendorff apparatus. Aqueous extract of garlic dose was standardized (0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.07%, 0.05%, 0.03%, 0.01%), and the 0.05% dose was found to be the most effective. Higher doses (more than 0.05%) were highly toxic, causing arrhythmia and cardiodepression, whereas the lower doses were ineffective. Garlic exaggerated the cardioprotective effect of ischemic preconditioning. The cardioprotective effect of ischemic preconditioning and garlic cardioprotection was significantly attenuated by theophylline (1,000 �mol/L) and 8-SPT (10 mg/kg, i.p.) and expressed by increased myocardial infarct size, increased LDH level, and reduced nitrite and adenosine levels. These findings suggest that adenosine is involved in the pharmacological and molecular mechanism of garlic induced cardioprotection and mediated by the modulation of nitric oxide.
Sharma, Ashish Kumar; Munajjam, Arshee; Vaishnav, Bhawna; Sharma, Richa; Sharma, Ashok; Kishore, Kunal; Sharma, Akash; Sharma, Divya; Kumari, Rita; Tiwari, Ashish; Singh, Santosh Kumar; Gaur, Samir; Jatav, Vijay Singh; Srinivasan, Barthu Parthi; Agarwal, Shyam Sunder
Involvement of adenosine and standardization of aqueous extract of garlic (Allium sativum Linn.) on cardioprotective and cardiodepressant properties in ischemic preconditioning and myocardial ischemia-reperfusion induced cardiac injury.
The present study investigated the effect of garlic (Allium sativum Linn.) aqueous extracts on ischemic preconditioning and ischemia-reperfusion induced cardiac injury, as well as adenosine involvement in ischemic preconditioning and garlic extract induced cardioprotection. A model of ischemia-reperfusion injury was established using Langendorff apparatus. Aqueous extract of garlic dose was standardized (0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.07%, 0.05%, 0.03%, 0.01%), and the 0.05% dose was found to be the most effective. Higher doses (more than 0.05%) were highly toxic, causing arrhythmia and cardiodepression, whereas the lower doses were ineffective. Garlic exaggerated the cardioprotective effect of ischemic preconditioning. The cardioprotective effect of ischemic preconditioning and garlic cardioprotection was significantly attenuated by theophylline (1,000 �mol/L) and 8-SPT (10 mg/kg, i.p.) and expressed by increased myocardial infarct size, increased LDH level, and reduced nitrite and adenosine levels. These findings suggest that adenosine is involved in the pharmacological and molecular mechanism of garlic induced cardioprotection and mediated by the modulation of nitric oxide. PMID:23554727
Sharma, Ashish Kumar; Munajjam, Arshee; Vaishnav, Bhawna; Sharma, Richa; Sharma, Ashok; Kishore, Kunal; Sharma, Akash; Sharma, Divya; Kumari, Rita; Tiwari, Ashish; Singh, Santosh Kumar; Gaur, Samir; Jatav, Vijay Singh; Srinivasan, Barthu Parthi; Agarwal, Shyam Sunder
Epigenetics and the Environment: In Search of the "Toleroasome" Vital to Execution of Ischemic Preconditioning
Activation and repression of gene expression are key features of ischemic tolerance. Converging lines of inquiry from several groups suggests that epigenetic proteins may transduce sublethal stresses, including bio-energetic or oxidative stress into durable (2�3 days) changes in gene expression that mediate ischemic tolerance. Here we discuss the potential mechanisms by which changes in cell state (e.g., ATP, NAD+, and oxygen) can modify specific targets including polycomb complexes, jumonji domain histone demethylases, and zinc and NAD-dependent histone decetylases and thus trigger an adaptive program. A major unanswered question is whether these proteins work in parallel or convergently as part of a �tolerosome� (tolero is the Latin word for tolerance), a multiprotein complex recruited to promoters or enhancers of specific genes, to mediate preconditioning. Whatever the case may be, epigenetic proteins are fertile targets for the treatment of stroke.
Brand, David
miR-15b Suppression of Bcl-2 Contributes to Cerebral Ischemic Injury and is Reversed by Sevoflurane Preconditioning
Ischemic neuroprotection afforded by sevoflurane preconditioning has been previously demonstrated, yet the underlying mechanism is poorly understood and likely affects a wide range of cellular activities. Several individual microRNAs have been implicated in both the pathogenesis of cerebral ischemia and cellular survival, and are capable of affecting a range of target mRNA. Conceivably, sevoflurane preconditioning may lead to alterations in ischemia-induced microRNA expression that may subsequently exert neuroprotective effects. We first examined the microRNA expression profile following transient cerebral ischemia in rats and the impact of sevoflurane preconditioning. Microarray analysis revealed that 3 microRNAs were up-regulated (>2.0 fold) and 9 were down-regulated (< 0.5 fold) following middle cerebral artery occlusion (MCAO) compared to sham controls. In particular, miR-15b was expressed at significantly high levels after MCAO. Preconditioning with sevoflurane significantly attenuated the upregulation of miR-15b at 72h after reperfusion. Bcl-2, an anti-apoptotic gene involved in the pathogenesis of cerebral ischemia, has been identified as a direct target of miR-15b. Consistent with the observed downregulation of miR-15b in sevoflurane-preconditioned brain, post-ischemic Bcl-2 expression was significantly increased by sevoflurane preconditioning. We identified the 3�-UTR of Bcl-2 as the target for miR-15b. Molecular inhibition of miR-15b was capable of mimicking the neuroprotective effect of sevoflurane preconditioning, suggesting that the suppression of miR-15b due to sevoflurane contributes to its ischemic neuroprotection. Thus, sevoflurane preconditioning may exert its anti-apoptotic effects by reducing the elevated expression of miR-15b following ischemic injury, allowing its target proteins, including Bcl-2, to be translated and expressed at the protein level.
Shi, Hong; Sun, Bao-liang; Zhang, Jia; Lu, Shiduo; Zhang, Pengyue; Wang, Hailian; Yu, Qiong; Stetler, R Anne; Vosler, Peter S.; Chen, Jun; Gao, Yanqin
Ischemic Preconditioning Increases iNOS Transcript Levels in Conscious Rabbits via a Nitric Oxide-dependent Mechanism
Recent studies implicate iNOS as the mediator of the late phase of ischemic preconditioning (PC). However, it is unknown whether induction of iNOS activity is mediated by transcriptional, post-transcriptional, translational, or post-translational mechanisms. To address this issue, we isolated and sequenced a partial iNOS cDNA expressed in preconditioned rabbit myocardium. Using a rabbit-specific probe generated from this sequence, we measured
W. Keith Jones; Michael P. Flaherty; Xian-Liang Tang; Hitoshi Takano; Yumin Qiu; Supratim Banerjee; Traci Smith; Roberto Bolli
Hypoxia-Inducible Factor 1: Regulator of Mitochondrial Metabolism and Mediator of Ischemic Preconditioning
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.
Semenza, Gregg L.
Global and Ocular Hypothermic Preconditioning Protect the Rat Retina from Ischemic Damage
Retinal ischemia could provoke blindness. At present, there is no effective treatment against retinal ischemic damage. Strong evidence supports that glutamate is implicated in retinal ischemic damage. We investigated whether a brief period of global or ocular hypothermia applied 24 h before ischemia (i.e. hypothermic preconditioning, HPC) protects the retina from ischemia/reperfusion damage, and the involvement of glutamate in the retinal protection induced by HPC. For this purpose, ischemia was induced by increasing intraocular pressure to 120 mm Hg for 40 min. One day before ischemia, animals were submitted to global or ocular hypothermia (33�C and 32�C for 20 min, respectively) and fourteen days after ischemia, animals were subjected to electroretinography and histological analysis. Global or ocular HPC afforded significant functional (electroretinographic) protection in eyes exposed to ischemia/reperfusion injury. A marked alteration of the retinal structure and a decrease in retinal ganglion cell number were observed in ischemic retinas, whereas global or ocular HPC significantly preserved retinal structure and ganglion cell count. Three days after ischemia, a significant decrease in retinal glutamate uptake and glutamine synthetase activity was observed, whereas ocular HPC prevented the effect of ischemia on these parameters. The intravitreal injection of supraphysiological levels of glutamate induced alterations in retinal function and histology which were significantly prevented by ocular HPC. These results support that global or ocular HPC significantly protected retinal function and histology from ischemia/reperfusion injury, probably through a glutamate-dependent mechanism.
Salido, Ezequiel M.; Dorfman, Damian; Bordone, Melina; Chianelli, Monica; Gonzalez Fleitas, Maria Florencia; Rosenstein, Ruth E.
The role of neuroglobin in the neuroprotection of limb ischemic preconditioning in rats.
Recent evidence suggests that limb ischemic preconditioning (LIP) protects neurons against cerebral ischemia-reperfusion injury. However, the mechanisms of LIP are not well understood. Neuroglobin (Ngb) is a recently discovered globin that affords protection against hypoxic/ischemic brain injury. This study was performed to investigate the role of Ngb in the neuroprotection of LIP against brain ischemia and the involvements of mitochondria in the process. The rat global brain ischemic model was used, and the CA1 hippocampus was selected as the observational target. Ngb expression was investigated by RT-PCR and Western blot. Neuropathological evaluation was performed by thionin staining. Mitochondrial membrane potential (??m), Na(+)-K(+)-ATPase activity, and ultrastructure were examined by flow cytometry, spectrophotometry, and transmission electron microscopy, respectively. We also used Ngb antisense oligodeoxynucleotides (AS-ODNs) and Ngb inducer hemin to inhibit or mimic the effect of LIP. We found that LIP significantly up-regulated Ngb expression and protected neurons against ischemia. Furthermore, LIP effectively improved deterioration in the ??m, mitochondrial Na(+)-K(+)-ATPase activity, and ultrastructure induced by cerebral ischemia. These effects of LIP were inhibited partly by Ngb AS-ODNs and mimicked by hemin. It could be concluded that up-regulation of Ngb expression played an important role in the neuroprotection induced by LIP, and the Ngb-mediated neuroprotection of LIP was, at least partly, associated with mitochondria. PMID:23180278
Li, Shu-Qin; Li, Wen-Bin; Zhang, Min; Wu, Yu-Zhou; Hu, Yu-Yan
Notch signaling activation contributes to cardioprotection provided by ischemic preconditioning and postconditioning
Background Notch signaling is known to be activated following myocardial ischemia, but its role in cardioprotection provided by ischemic preconditioning (IPC) and ischemic postconditioning (IPost) remains unclear. Methods Lentiviral vectors were constructed to overexpress or knockdown N1ICD in H9c2 cardiomyocyte and rat heart exposed to ischemia reperfusion injury (IRI), IPC or IPost. Results Notch1 signaling was activated during myocardial IPC and IPost, and could enhance cell viability and inhibit apoptosis. Furthermore, activated Notch1 signaling stabilized mitochondrial membrane potential and reduced reactive oxygen species induced by IRI. The cardioprotection provided by activated Notch1 signaling resembled that of IPC and IPost, which was related to Stat3 activation and regulation of apoptosis related proteins. Furthermore, in langendorff heart perfusion model, activated Notch1 signaling restored cardiac function, decreased lactate dehydrogenase release and limited infarct size after myocardial ischemia. Conclusions: Notch1 signaling is activated and mediates cardioprotection provided by IPC and Ipost. Notch1 signaling may represent a potential new pharmacologic mimic for cardioprotection of ischemic heart disease.
Using hormetic strategies to improve ischemic preconditioning and postconditioning against stroke
Both ischemic preconditioning (IPreC) and ischemic postconditioning (IPostC) trigger endogenous neuroprotective mechanisms in cerebral ischemia. IPreC is defined as a brief ischemia that protects against a subsequent severe ischemia, while IPostC refers to a series of brief cerebral blood vessel occlusions performed at reperfusion following an ischemic event. Hormesis describes a biphasic dose-response relationship in toxicology, where a low dose of toxicant stimulates and a high dose inhibits biological responses. In general, any minor stress will stimulate a biological system to generate an adaptive response; in most cases, if not all, such an adaptive response to a minor stress is beneficial to the biological system. Proponents of hormesis suggest that this effect is independent of any models, either in vivo or in vitro, from animal, plant, fungi, yeast, to bacteria, by any measurement of end points, survival ratio or time, growth, tissue repair, life span, cognition, learning and memory. In this review, we examine whether IPreC and IPostC are actually sub-forms of hormesis and whether quantitative hormetic strategies can be used to study IPreC and IPostC. By integrating the concepts of IPreC and IPostC with hormesis, we aim to broaden the avenues leading to clinical translation of IPreC and IPostC in stroke treatment.
Zhao, Heng; Joo, Sungpil; Xie, Weiying; Ji, Xunming
Effects of neutral endopeptidase 24.11 inhibition on myocardial infarct size and ischemic preconditioning in rabbits
This study was designed to determine whether inhibition of neutral endopeptidase 24.11 (NEP) reduces infarct size and enhances protection afforded by ischemic preconditioning (PC) by elevation of the tissue bradykinin (BK) level in the heart in situ. In experiments to determine a dose of thiorphan (Thio) that inhibits NEP activity in the rabbit, infusion of Thio at a rate of
Atsushi Nakano; Tetsuji Miura; Takayuki Miki; Yukinaga Nozawa; Yoshihiko Ichikawa; Nobuyuki Ura; Kazuaki Shimamoto
Modification of the Hepatic Mitochondrial Proteome in Response to Ischemic Preconditioning following Ischemia-Reperfusion Injury of the Rat Liver
Background\\/Aim: Ischemic preconditioning (IPC) may reduce hepatic ischemia-reperfusion (IR) injury, but efficacy of IPC on mitochondrial proteome is not demonstrated. We investigated how IPC modifies the mitochondrial proteome after IR injury. Methods: Rats were subjected to 25 min of portal triad crossclamping (IR group, n = 8). In the IPC group (n = 8), 10 min of temporal portal triad
R. Oshima; H. Nakano; M. Katayama; J. Sakurai; W. Wu; S. Koizumi; T. Asano; T. Watanabe; T. Asakura; T. Ohta; T. Otsubo
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...
Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion
AIM: To study the effects of preconditioning on inducible nitric oxide synthase (iNOS) and interleukin 1 (IL-1) receptor transcription in rat liver ischemia/reperfusion injury (IRI). METHODS: Seventy-two male rats were randomized into 3 groups: the one-hour segmental ischemia (IRI, n = 24) group, the ischemic preconditioning (IPC, n = 24) group or the remote ischemic preconditioning (R-IPC, n = 24) group. The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion. The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR. The total Nitrite and Nitrate (NOx) in continuously sampled microdialysate (MD) from the liver was analyzed. In addition, the NOx levels in the serum were analyzed. RESULTS: After 4 h of reperfusion, the iNOS mRNA was significantly higher in the R-IPC (?Ct: 3.44 � 0.57) group than in the IPC (?Ct: 5.86 � 0.82) group (P = 0.025). The IL-1 receptor transcription activity was reduced in the IPC group (?Ct: 1.88 � 0.53 to 4.81 � 0.21), but not in the R-IPC group, during reperfusion (P = 0.027). In the MD, a significant drop in the NOx levels was noted in the R-IPC group (12.3 � 2.2 to 4.7 � 1.2 ?mol/L) at the end of ischemia compared with the levels in early ischemia (P = 0.008). A similar trend was observed in the IPC group (11.8 � 2.1 to 6.4 � 1.5 ?mol/L), although this difference was not statistically significant. The levels of NOx rose quickly during reperfusion in both groups. CONCLUSION: IPC, but not R-IPC, reduces iNOS and IL-1 receptor transcription during early reperfusion, indicating a lower inflammatory reaction. NOx is consumed in the ischemic liver lobe.
Bjornsson, Bergthor; Winbladh, Anders; Bojmar, Linda; Sundqvist, Tommy; Gullstrand, Per; Sandstrom, Per
Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injury in vitro through type I interferon signaling
Preconditioning with a low dose of harmful stimulus prior to injury induces tolerance to a subsequent ischemic challenge resulting in neuroprotection against stroke. Experimental models of preconditioning primarily focus on neurons as the cellular target of cerebral protection while less attention has been paid to the cerebrovascular compartment whose role in the pathogenesis of ischemic brain injury is crucial. We have shown that preconditioning with polyinosinic polycytidylic acid (poly-ICLC) protects against cerebral ischemic damage. To delineate the mechanism of poly-ICLC protection, we investigated whether poly-ICLC preconditioning preserves the function of the blood-brain-barrier (BBB) in response to ischemic injury. Using an in vitro BBB model, we found that poly-ICLC treatment prior to exposure to oxygen-glucose deprivation maintained the paracellular and transcellular transport across the endothelium and attenuated the drop in transendothelial electric resistance. We found that poly-ICLC treatment induced interferon (IFN) ? mRNA expression in astrocytes and microglia and that type I IFN signaling in brain microvascular endothelial cells was required for protection. Importantly, this implicates a potential mechanism underlying neuroprotection in our in vivo experimental stroke model where type I IFN signaling is required for poly-ICLC-induced neuroprotection against ischemic injury. In conclusion, we are the first to show that preconditioning with poly-ICLC attenuates ischemia-induced BBB dysfunction. This mechanism is likely an important feature of poly-ICLC-mediated neuroprotection and highlights the therapeutic potential of targeting BBB signaling pathways to protect the brain against stroke.
Gesuete, Raffaella; Packard, Amy E. B.; Vartanian, Keri B.; Conrad, Valerie K.; Stevens, Susan L.; Bahjat, Frances R.; Yang, Tao; Stenzel-Poore, Mary P.
Dystrophin proteolysis: a potential target for MMP-2 and its prevention by ischemic preconditioning.
Dystrophin is responsible for the mechanical stabilization of the sarcolemma, and it has been shown that it is one of the most sensitive proteins to ischemic injury. However, the enzyme responsible for this proteolysis is still unknown. Isolated rabbit hearts were subjected to 30 min of global ischemia with and without reperfusion (180 min) to determine whether dystrophin is cleaved by matrix metalloproteinase (MMP)-2 during acute ischemia and whether ischemic preconditioning (PC) prevents dystrophin breakdown through MMP-2 inhibition. The activity of MMP-2 was evaluated by zymography and using doxycycline as an inhibitor. Also, to stimulate MMP-2 activity without ischemia, SIN-1 was administered in the absence and presence of doxycycline. Finally, we considered the PC effect on MMP-2 activity and dystrophin expression. The dystrophin level decreased during ischemia, reaching 21% of control values (P < 0.05), but the spectrin level remained unchanged. MMP-2 activity increased 71% during ischemia compared with control values (P < 0.05). Doxycycline administration before ischemia prevented dystrophin breakdown. In normoxic hearts, SIN-1 increased thiobarbituric acid-reactive substances by 33% (P < 0.05) and MMP-2 activity by 36% (P < 0.05) and significantly reduced the dystrophin level to 23% of control values (P < 0.05). PC significantly prevented dystrophin breakdown by inhibiting MMP-2 activity, and the dystrophin level reached 89% of control values (P < 0.05). In conclusion, MMP-2 could be responsible for the proteolysis of dystrophin. Thus, dystrophin emerges as a possible novel substrate for MMP-2 in the context of ischemic injury. Furthermore, our results demonstrate that ischemic PC prevents dystrophin breakdown most likely by inhibiting MMP-2 activity. PMID:24791785
Buchholz, Bruno; Perez, Virginia; Siachoque, Nadezda; Miksztowicz, Ver�nica; Berg, Gabriela; Rodr�guez, Manuel; Donato, Mart�n; Gelpi, Ricardo J
Ischemic Preconditioning and Brain Tolerance Temporal Histological and Functional Outcomes, Protein Synthesis Requirement, and Interleukin1 Receptor Antagonist and Early Gene Expression
Background and Purpose�A short duration of ischemia (ie, ischemic preconditioning (PC)) can provide significant brain protection to subsequent ischemic events (ie, ischemic tolerance (IT)). The present series of studies was conducted to characterize the temporal pattern of a PC paradigm, to systematically evaluate the importance of protein synthesis in PC-induced IT, and to explore candidate gene expression changes associated with
Frank C. Barone; Raymond F. White; Patricia A. Spera; Julie Ellison; R. William Currie; Xinkang Wang; Giora Z. Feuerstein
Remote ischemic preconditioning to reduce contrast-induced nephropathy: study protocol for a randomized controlled trial
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
Late ischemic preconditioning of the myocardium alters the expression of genes involved in inflammatory response.
Myocardial ischemic preconditioning (IPC) is a potent endogenous mechanism of cardioprotection against ischemia-reperfusion injury. In this study we focused on the second phase of IPC as the most interesting in terms of therapeutic implementations. We aimed at the detection of genes, which are differentially expressed at 16 h after reperfusion. Preconditioning of canine myocardium was initiated by 5 min occlusion of the left anterior descending coronary artery with subsequent reperfusion. cDNA representational difference analysis in combination with microarray hybridization and reverse transcription polymerase chain reaction were used to reveal the changes in gene expression in canine hearts. We found that functionally related genes for tristetraproline (TTP), selectin E, matrix metalloproteinase 9, and tumor necrosis factor-alpha were highly upregulated at the late phase of IPC. The upregulation of TTP gene at the late phase of IPC, reported here for the first time, may represent a cardioprotective mechanism, which could be a promising perspective in clinical interventions against ischemia-reperfusion injuries of the heart. PMID:12860385
Zubakov, Dmitrij; Hoheisel, J�rg D; Kluxen, Franz-Werner; Br�ndle, Marian; Ehring, Thomas; Hentsch, Bernd; Frohme, Marcus
Somatostatin analogue mimics acute ischemic preconditioning in a rat model of myocardial infarction.
We tested the hypothesis that octreotide, a somatostatin analogue, can mimic ischemic preconditioning (PC) to provide cardioprotection against myocardial infarction. An ischemia-reperfusion model of adult Wistar rats was used. Infarct size was expressed as a percentage of the area at risk under different treatment protocols. Octreotide PC (35 microg/Kg 20 minutes before ischemia-reperfusion) significantly decreased infarct size (18 +/- 4%) versus control (60 +/- 7%). The somatostatin receptor antagonist cyclo-somatostatin (0.5 mg/Kg) could blunt the above cardioprotection. Administration of either chelerythrine (a protein kinase C inhibitor, 2 mg/Kg) or genistein (a tyrosine kinase inhibitor, 5 mg/Kg) could also block octreotide PC (54 +/- 7% and 58 +/- 6%, respectively). Pretreatment with the mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoic acid (5-HD) and the sarcolemmal ATP-sensitive potassium channel antagonist glibenclamide could abolish the effects of octreotide PC (54 +/- 6% and 52 +/- 6%). Chelerythrine, however, had no effect on octreotide PC. In conclusion, the present study demonstrates that octreotide can mimic ischemic PC to reduce infarct size. Acute effects of octreotide PC involve the activation of protein kinase C, tyrosine kinase C, and mitochondrial ATP-sensitive potassium channels, but not systemic IGF-I activation. PMID:15772521
Wang, Tzong-Luen; Huang, Yu-Hui; Chang, Hang
Ginkgolides mimic the effects of hypoxic preconditioning to protect C6 cells against ischemic injury by up-regulation of hypoxia-inducible factor-1 alpha and erythropoietin
Hypoxic preconditioning can play a significant neuroprotective role. However, it has not been employed clinically because of safety concerns. To find a safer preconditioning stimulus that is both practical and effective, we investigated whether ginkgolides are capable of preconditioning as hypoxia to protect C6 cells against ischemic injury. We demonstrated that both ginkgolides (37.5?g\\/mL) and hypoxia (1% O2 for 16h)
Wei He; Ming Qian Zhong; Li Zhu; Qian Christopher; Fang Du; Wing Ho Yung; Ya Ke
Remote Ischemic Preconditioning Protects against Liver Ischemia-Reperfusion Injury via Heme Oxygenase-1-Induced Autophagy
Background Growing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR). Heme oxygenase-1 (HO-1) is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC). The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy. Methods RIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II). The HO-1/extracellular signal-related kinase (ERK)/p38/mitogen-activated protein kinase (MAPK) pathway was detected in an autophagy model and mineral oil-induced IR in vitro. Results In liver IR, the expression of LC3-II peaked 12�24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI) in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA. Conclusions RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.
Xiong, Xuanxuan; Xu, Yonghua; Zhang, Hai; Huang, Changjun; Tian, Yuan; Jiao, Chengyu; Wang, Xuehao; Li, Xiangcheng
The role of 17-beta estradiol in ischemic preconditioning protection of the heart
BACKGROUND: The protective effects of 17-beta estradiol (E2) on cardiac tissue during ischemia/reperfusion (I/R) injury have not yet been fully elucidated. OBJECTIVE: To assess the protective effects of short- and long-term E2 treatments on cardiac tissue exposed to I/R, and to assess the effects of these treatments in combination with ischemic preconditioning (IPC) on cardiac protection from I/R injury. METHODS: Sprague Dawley rats were assigned to the following treatment protocols: control (no preconditioning); IPC (isolated hearts were subjected to two cycles of 5 min global ischemia followed by 10 min of reperfusion); E2 preconditioning (E2PC; isolated hearts were subjected to E2 pharmacological perfusion for 15 min); short-term in vivo E2 pretreatment for 3 h; long-term in vivo E2 pretreatment or withdrawal (ovariectomy followed by a six-week treatment with E2 or a placebo); combined IPC and E2PC; combined IPC and short- or long-term E2 pretreatments or withdrawal. All hearts were isolated and stabilized for at least 30 min before being subjected to 40 min of global ischemia followed by 30 min of reperfusion; left ventricular function and vascular hemodynamics were then assessed. RESULTS: IPC, E2PC and short-term E2 pretreatment led to the recovery of left ventricle function and vascular hemodynamics. Long-term E2 and placebo treatments did not result in any protection compared with untreated controls. The combination of E2PC or short-term E2 treatments with IPC did not block the IPC protection or result in any additional protection to the heart. Long-term E2 treatment blocked IPC protection; however, placebo treatment did not. CONCLUSIONS: Short-term treatment with E2 protected the heart against I/R injury through a pathway involving the regulation of tumour necrosis factor-alpha. The combination of short-term E2 treatment with IPC did not provide additional protection to the heart. Short-term E2 treatment may be a suitable alternative for classical estrogen replacement therapy.
Babiker, Fawzi A; Hoteit, Lamia J; Joseph, Shaji; Mustafa, Abu Salim; Juggi, Jasbir S
Ischemic preconditioning prevents in vivo hyperoxygenation in postischemic myocardium with preservation of mitochondrial oxygen consumption.
Ischemic preconditioning (IPC) strongly protects against ischemia-reperfusion injury; however, its effect on subsequent myocardial oxygenation is unknown. Therefore, we determine in an in vivo mouse model of regional ischemia and reperfusion (I/R) if IPC attenuates postischemic myocardial hyperoxygenation and decreases formation of reactive oxygen/nitrogen species (ROS/RNS), with preservation of mitochondrial function. The following five groups of mice were studied: sham, control (I/R), ischemic preconditioning (IPC + I/R, 3 cycles of 5 min coronary occlusion/5 min reperfusion) and IPC + I/R N(G)-nitro-L-arginine methyl ester treated, and IPC + I/R eNOS knockout mice. I/R and IPC + I/R mice were subjected to 30 min regional ischemia followed by 60 min reperfusion. Myocardial Po(2) and redox state were monitored by electron paramagnetic resonance spectroscopy. In the IPC + I/R, but not the I/R group, regional blood flow was increased after reperfusion. Po(2) upon reperfusion increased significantly above preischemic values in I/R but not in IPC + I/R mice. Tissue redox state was measured from the reduction rate of a spin probe, and this rate was 60% higher in IPC than in non-IPC hearts. Activities of NADH dehydrogenase (NADH-DH) and cytochrome c oxidase (CcO) were reduced in I/R mice after 60 min reperfusion but conserved in IPC + I/R mice compared with sham. There were no differences in NADH-DH and CcO expression in I/R and IPC + I/R groups compared with sham. After 60 min reperfusion, strong nitrotyrosine formation was observed in I/R mice, but only weak staining was observed in IPC + I/R mice. Thus IPC markedly attenuates postischemic myocardial hyperoxygenation with less ROS/RNS generation and preservation of mitochondrial O(2) metabolism because of conserved NADH-DH and CcO activities. PMID:17513495
Zhu, Xuehai; Liu, Bin; Zhou, Shaotang; Chen, Yeong-Renn; Deng, Yuanmu; Zweier, Jay L; He, Guanglong
The sulfonylurea glipizide does not inhibit ischemic preconditioning in anesthetized rabbits.
The K(ATP) channel blocker glibenclamide inhibits cardioprotection afforded by ischemic preconditioning (IPC), raising concern about sulfonylurea use by patients with cardiovascular disease. We examined the effects of the widely prescribed sulfonylurea glipizide (Glucotrol XL(R) ) on IPC in anesthetized rabbits. Initially, in parallel studies in pentobarbital-anesthetized rabbits, we identified doses of glipizide (GLIP, 0.17 mg/kg + 0.12 mg/kg/h, IV) and glibenclamide (GLIB, 0.05 mg/kg + 0.03 mg/kg/h, IV) that produced steady-state, clinically relevant plasma levels of both drugs; these doses also significantly increased plasma insulin by 51 +/- 17% (GLIP) and by 57 +/- 17% (GLIB, both p < 0.05 vs. their respective baseline levels). Subsequent parallel studies in ketamine-xylazine-anesthetized rabbits examined the effects of these doses of GLIP and GLIB on IPC. Myocardial injury (30 min coronary occlusion/120 min reperfusion), either with or without IPC (5 min occlusion/10 min reperfusion) was induced midway during a 2 h infusion of vehicle (VEH), GLIP or GLIB (n = 10-11 each). Infarct area (IA) normalized to area-at-risk (%IA/AAR) was 62 +/- 3% in the VEH group, and was significantly reduced to 39 +/- 5% by IPC (p < 0.05 vs. VEH). Neither GLIP nor GLIB treatment had any effect on %IA/AAR in the absence of IPC (p > 0.05). IPC-induced cardioprotection was preserved in the GLIP + IPC treatment group (45 +/- 4%) when compared to VEH alone (p < 0.05), but was attenuated in the presence of GLIB (GLIB+IPC: 53 +/- 4% IA/AAR, p > 0.05 vs. VEH). Thus, at a clinically relevant plasma concentration, glipizide did not limit the cardioprotective effects of IPC, and is unlikely to increase the severity of cardiac ischemic injury. PMID:16382296
Flynn, David M; Smith, Andrew H; Treadway, Judith L; Levy, Carolyn B; Soeller, Walter C; Boettner, Wayne A; Wisniecki, Peter; Plowchalk, David R; Gernhardt, Steve S; Tracey, W Ross; Knight, Delvin R
Cardiac Phosphoproteomics during Remote Ischemic Preconditioning: A Role for the Sarcomeric Z-Disk Proteins
Remote ischemic preconditioning (RIPC) induced by brief ischemia/reperfusion cycles of remote organ (e.g., limb) is cardioprotective. The myocardial cellular changes during RIPC responsible for this phenomenon are not currently known. The aim of this work was to identify the activation by phosphorylation of cardiac proteins following RIPC. To achieve our aim we used isobaric tandem mass tagging (TMT) and reverse phase nanoliquid chromatography tandem spectrometry using a Linear Trap Quadropole (LTQ) Orbitrap Velos mass spectrometer. Male C57/Bl6 mice were anesthetized by an intraperitoneal injection of Tribromoethanol. A cuff was placed around the hind limb and inflated at 200?mmHg to prevent blood flow as confirmed by Laser Doppler Flowmetry. RIPC was induced by 4 cycles of 5?min of limb ischemia followed by 5?min of reperfusion. Hearts were extracted for phosphoproteomics. We identified approximately 30 phosphoproteins that were differentially expressed in response to RIPC protocol. The levels of several phosphoproteins in the Z-disk of the sarcomere including phospho-myozenin-2 were significantly higher than control. This study describes and validates a novel approach to monitor the changes in the cardiac phosphoproteome following the cardioprotective intervention of RIPC and prior to index ischemia. The increased level of phosphorylated sarcomeric proteins suggests they may have a role in cardiac signaling during RIPC.
Abdul-Ghani, Safa; Heesom, Kate J.; Angelini, Gianni D.; Suleiman, M-Saadeh
Ischemic preconditioning and tacrolimus pretreatment as strategies to attenuate intestinal ischemia-reperfusion injury in mice.
The intestine is highly sensitive to ischemia-reperfusion injury (IRI), a phenomenon occurring in different intestinal diseases. Several strategies to mitigate IRI are in experimental stages; unfortunately, no consensus has been reached about the most appropriate one. We report a protocol to study ischemic preconditioning (IPC) evaluation in mice and to combine IPC and tacrolimus (TAC) pretreatment in a warm ischemia model. Mice were divided into treated (IPC, TAC, and IPC�+ TAC) and untreated groups before intestinal ischemia. IPC, TAC, and IPC�+ TAC groups were able to decrease postreperfusion nitrites levels (P�< .05). IPC-containing groups had a major beneficial effect by preserving the integrity of the intestinal histology (P�< .05) and improving animal survival (P�< .002) compared with TAC alone or the untreated group. The IPC�+ TAC group was the only one that showed significant improvement in lung histological analysis (P�< .05). The TAC and IPC�+ TAC groups down-regulated intestinal expression of interleukin (II)-6 and IL1b more than 10-fold compared with the control group. Although IPC and TAC alone reduced intestinal IRI, the used of a combined therapy produced the most significant results in all the local and distant evaluated parameters. PMID:23953566
Stringa, P; Romanin, D; Lausada, N; Machuca, M; Raimondi, J C; Cabanne, A; Rumbo, M; Gondolesi, G
Astrocytic Toll-Like Receptor 3 Is Associated with Ischemic Preconditioning- Induced Protection against Brain Ischemia in Rodents
Background Cerebral ischemic preconditioning (IPC) protects brain against ischemic injury. Activation of Toll-like receptor 3 (TLR3) signaling can induce neuroprotective mediators, but whether astrocytic TLR3 signaling is involved in IPC-induced ischemic tolerance is not known. Methods IPC was modeled in mice with three brief episodes of bilateral carotid occlusion. In vitro, IPC was modeled in astrocytes by 1-h oxygen-glucose deprivation (OGD). Injury and components of the TLR3 signaling pathway were measured after a subsequent protracted ischemic event. A neutralizing antibody against TLR3 was used to evaluate the role of TLR3 signaling in ischemic tolerance. Results IPC in vivo reduced brain damage from permanent middle cerebral artery occlusion in mice and increased expression of TLR3 in cortical astrocytes. IPC also reduced damage in isolated astrocytes after 12-h OGD. In astrocytes, IPC or 12-h OGD alone increased TLR3 expression, and 12-h OGD alone increased expression of phosphorylated NF?B (pNF?B). However, IPC or 12-h OGD alone did not alter the expression of Toll/interleukin receptor domain-containing adaptor-inducing IFN? (TRIF) or phosphorylated interferon regulatory factor 3 (pIRF3). Exposure to IPC before OGD increased TRIF and pIRF3 expression but decreased pNF?B expression. Analysis of cytokines showed that 12-h OGD alone increased IFN? and IL-6 secretion; 12-h OGD preceded by IPC further increased IFN? secretion but decreased IL-6 secretion. Preconditioning with TLR3 ligand Poly I:C increased pIRF3 expression and protected astrocytes against ischemic injury; however, cells treated with a neutralizing antibody against TLR3 lacked the IPC- and Poly I:C-induced ischemic protection and augmentation of IFN?. Conclusions The results suggest that IPC-induced ischemic tolerance is mediated by astrocytic TLR3 signaling. This reprogramming of TLR3 signaling by IPC in astrocytes may play an important role in suppression of the post-ischemic inflammatory response and thereby protect against ischemic damage. The mechanism may be via activation of the TLR3/TRIF/IRF3 signaling pathway.
Li, Yang; Xu, Xu-lin; Guo, Lian-jun; Lu, Qing; Wang, Jian
Accumulation of natural killer cells in ischemic brain tissues and the chemotactic effect of IP-10
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-?) 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-?-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-? 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-?. 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 was aggravated. Conclusions All findings support the hypothesis that NK cells participate in cerebral ischemia and promote neural cells necrosis via IFN-?. Moreover, IP-10 intensifies injury to the BBB by NK cells via CXCR3.
Fenofibrate attenuates impaired ischemic preconditioning-mediated cardioprotection in the fructose-fed hypertriglyceridemic rat heart.
We investigated in this study whether or not the ischemic preconditioning (IPC)-mediated cardioprotective effect against ischemia-reperfusion (I/R) injury exists in the fructose-fed hypertriglyceridemic (HTG) rat heart. Langendorff-perfused normal and fructose-fed (10�%?w/v in drinking water, 8�weeks) HTG rat hearts were subjected to 30-min global ischemia and 120-min reperfusion. IPC protocol included four brief episodes (5�min each) of ischemia and reperfusion. Myocardial infarct size using triphenyltetrazolium chloride staining, markers of cardiac injury such as lactate dehydrogenase (LDH) and creatine kinase (CK-MB) release, coronary flow rate (CFR), and myocardial oxidative stress were assessed. High degree of myocardial I/R injury, by means of significant myocardial infarct size, elevated coronary LDH and CK-MB release, reduced CFR, and high oxidative stress, was noted in the HTG rat heart as compared to the normal rat heart. The IPC-mediated cardioprotection against I/R injury was markedly impaired in the HTG rat heart as compared to the normal rat heart. Interestingly, pharmacological reduction of triglycerides using 8-week treatment protocol with fenofibrate (80�mg/kg/day, p.o.) restored the IPC effect in the HTG rat heart that was blunted by coinfusion, during the IPC reperfusion protocol, of a specific inhibitor of phosphoinositide-3-kinase (PI3-K), wortmannin (100 nM). The IPC failed to protect the HTG rat heart against I/R injury. Fenofibrate treatment reduced high triglycerides in the fructose-fed HTG rat and subsequently restored the cardioprotective effect of IPC. PMID:23325365
Babbar, Lalita; Mahadevan, Nanjaian; Balakumar, Pitchai
Effect of one-cycle remote ischemic preconditioning to reduce myocardial injury during percutaneous coronary intervention.
Up to 1/3 of percutaneous coronary interventions (PCIs) are complicated by troponin release. Remote ischemic preconditioning (IPC) confers effective cardioprotection; however, a 30-minute remote IPC protocol may be difficult to implement during ad hoc PCI. This study was performed to assess the ability of a brief remote IPC protocol to attenuate cardiac troponin I (cTnI) release after ad hoc PCI. Ninety-four patients undergoing ad hoc PCI for stable coronary artery disease, with undetectable preprocedural cTnI, were recruited and randomized to receive remote IPC (induced by one 5-minute inflation of a blood pressure cuff to 200�mm Hg around the upper arm) or control after the decision for PCI was made. The primary outcome was the difference between cTnI levels 24�hours after PCI and cTnI levels before coronary angiography (?cTnI). ?cTnI in the remote IPC group was significantly lower compared with the control group (0.04�ng/ml [interquartile range 0.01 to 0.14] vs 0.19�ng/ml [interquartile range 0.18 to 0.59], p <0.001). The incidence of PCI-related myocardial infarction (MI) was greater in the control group (42.6% vs 19.1%, p�= 0.014). In multivariate analysis, remote IPC was independently associated with ?cTnI and PCI-related MI. In conclusion, our results suggest that even 1 cycle of remote IPC immediately before ad hoc PCI�attenuates periprocedural cTnI release and reduces the incidence of type 4a MI. PMID:24793669
Zografos, Theodoros A; Katritsis, George D; Tsiafoutis, Ioannis; Bourboulis, Nikolaos; Katsivas, Apostolos; Katritsis, Demosthenes G
Ischemic Preconditioning Preserves Mitochondrial Membrane Potential and Limits Reactive Oxygen Species Production
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 (m??) is known to affect O2�? production; mitochondrial depolarization decreases O2�? formation. We examined the relationship between O2�? production and m?? 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). m?? 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 m?? 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 m??, 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 m?? decrease O2�? production, our results indicate that preservation of m?? is associated with decreased O2�? and preservation of cardiac function in IPC. These findings indicate that the mechanism of IPC may not involve m?? depolarization, but rather preservation of mitochondrial electrochemical potential.
Quarrie, Ricardo; Lee, Daniel S.; Steinbaugh, Gregory; Cramer, Brandon; Erdahl, Warren; Pfeiffer, Douglas R.; Zweier, Jay L.; Crestanello, Juan A.
Apolipoprotein A-I Is a Potential Mediator of Remote Ischemic Preconditioning
Background Remote ischemic preconditioning (RIPC) has emerged as an attractive strategy in clinical settings. Despite convincing evidence of the critical role played by circulating humoral mediators, their actual identities remain unknown. In this study, we aimed to identify RIPC-induced humoral mediators using a proteomic approach. Methods and Results Rats were exposed to 10-min limb ischemia followed by 5- (RIPC 5?) or 10-min (RIPC 10?) reperfusion prior to blood sampling. The control group only underwent blood sampling. Plasma samples were analyzed using surface-enhanced laser desorption and ionization - time of flight - mass spectrometry (SELDI-TOF-MS). Three protein peaks were selected for their significant increase in RIPC 10?. They were identified and confirmed as apolipoprotein A-I (ApoA-I). Additional rats were exposed to myocardial ischemia-reperfusion (I/R) and assigned to one of the following groups RIPC+myocardial infarction (MI) (10-min limb ischemia followed by 10-min reperfusion initiated 20 minutes prior to myocardial I/R), ApoA-I+MI (10 mg/kg ApoA-I injection 10 minutes before myocardial I/R), and MI (no further intervention). In comparison with untreated MI rats, RIPC reduced infarct size (52.2�3.7% in RIPC+MI vs. 64.9�2.6% in MI; p<0.05). Similarly, ApoA-I injection decreased infarct size (50.9�3.8%; p<0.05 vs. MI). Conclusions RIPC was associated with a plasmatic increase in ApoA-I. Furthermore, ApoA-I injection before myocardial I/R recapitulated the cardioprotection offered by RIPC in rats. This data suggests that ApoA-I may be a protective blood-borne factor involved in the RIPC mechanism.
Hibert, Pierre; Prunier-Mirebeau, Delphine; Beseme, Olivia; Chwastyniak, Maggy; Tamareille, Sophie; Lamon, Delphine; Furber, Alain; Pinet, Florence; Prunier, Fabrice
MicroRNA-144 is a circulating effector of remote ischemic preconditioning.
Remote ischemic preconditioning (rIPC) induced by cycles of transient limb ischemia and reperfusion is a powerful cardioprotective strategy with additional pleiotropic effects. However, our understanding of its underlying mediators and mechanisms remains incomplete. We examined the role of miR-144 in the cardioprotection induced by rIPC. Microarray studies first established that rIPC increases, and IR injury decreases miR-144 levels in mouse myocardium, the latter being rescued by both rIPC and intravenous administration of miR-144. Going along with this systemic treatment with miR-144 increased P-Akt, P-GSK3? and P-p44/42 MAPK, decreased p-mTOR level and induced autophagy signaling, and induced early and delayed cardioprotection with improved functional recovery and reduction in infarct size similar to that achieved by rIPC. Conversely, systemic administration of a specific antisense oligonucleotide reduced myocardial levels of miR-144 and abrogated cardioprotection by rIPC. We then showed that rIPC increases plasma miR-144 levels in mice and humans, but there was no change in plasma microparticle (50-400�nM) numbers or their miR-144 content. However, there was an almost fourfold increase in miR-144 precursor in the exosome pellet, and a significant increase in miR-144 levels in exosome-poor serum which, in turn, was associated with increased levels of the miR carriage protein Argonaute-2. Systemic release of microRNA 144 plays a pivotal role in the cardioprotection induced by rIPC. Future studies should assess the potential for plasma miR-144 as a biomarker of the effectiveness of rIPC induced by limb ischemia, and whether miR-144 itself may represent a novel therapy to reduce clinical ischemia-reperfusion injury. PMID:25060662
Li, Jing; Rohailla, Sagar; Gelber, Nitai; Rutka, James; Sabah, Nesrin; Gladstone, Rachel A; Wei, Can; Hu, Pingzhao; Kharbanda, Rajesh K; Redington, Andrew N
Cerebral ischemic preconditioning reduces glutamate excitotoxicity by up-regulating the uptake activity of GLT-1 in rats.
Our previous study has shown that cerebral ischemic preconditioning (CIP) can up-regulate the expression of glial glutamate transporter-1 (GLT-1) during the induction of brain ischemic tolerance in rats. The present study was undertaken to further explore the uptake activity of GLT-1 in the process by observing the changes in the concentration of extracellular glutamate with cerebral microdialysis and high-performance liquid chromatography. The results showed that a significant pulse of glutamate concentration reached the peak value of sevenfold of the basal level after lethal ischemic insult, which was associated with delayed neuronal death in the CA1 hippocampus. When the rats were pretreated 2�days before the lethal ischemic insult with CIP which protected the pyramidal neurons against delayed neuronal death, the peak value of glutamate concentration decreased to 3.9 fold of the basal level. Furthermore, pre-administration of dihydrokainate, an inhibitor of GLT-1, prevented the protective effect of CIP on ischemia-induced CA1 cell death. At the same time, compared with the CIP�+�Ischemia group, the peak value of glutamate concentration significantly increased and reached sixfold of the basal level. These results indicate that CIP induced brain ischemic tolerance via up-regulating GLT-1 uptake activity for glutamate and then decreasing the excitotoxicity of glutamate. PMID:24643365
Gong, Jianxue; Gong, Shujuan; Zhang, Min; Zhang, Lianwei; Hu, Yuyan; Liu, Yixian; Li, Wenbin
Inhibition of phosphatase activity enhances preconditioning and limits cell death in the ischemic/reperfused aged rat heart.
Brief, nonlethal episodes of ischemia in the mammalian heart provide cardioprotection against the detrimental effects of a longer duration ischemia. The manifestation of this preconditioning (PC) phenomenon is initiated by the enhanced phosphorylation state of signal transduction proteins. We reported previously that PC is decreased in the aged rat myocardium. Although the mechanism responsible for this loss is not understood, a reduction in the phosphorylation of critical proteins associated with PC may be postulated. Experiments were conducted to investigate whether PC in the aged heart can be restored with the inhibition of endogenous protein phosphatases thereby enhancing phosphorylation of signaling proteins. Levels of phosphatase activities were also assessed with adult heart aging. Hearts from young adult (3-4 mo.) and aged (21-22 mo.) Fischer-344 rats were perfused in the presence or absence of okadaic acid (OKA; 0.1 microM). Aged adult hearts were either not preconditioned or were preconditioned with two PC cycles (5 min ischemia/5 min reperfusion). Myocardial cellular death that developed with a subsequent ischemia was determined with triphenyltetrazolium. With PC, 55% of the aged heart after ischemia was no longer viable. OKA administered before or after ischemia reduced this ischemia-induced cellular death by 29%. Without PC, OKA reduced viability 18% only when present before and after the ischemic episode. OKA in the ischemic young heart during reperfusion reduced the loss of viability 31%. The Protein Phosphatase 2A (PP2A) activity was found to be up to 82% greater in ventricular myocardium of aged rats. In conclusion, aging-induced changes in protein dephosphorylation may be one mechanism reducing the manifestation of preconditioning in the aged heart. PMID:16098993
Fenton, Richard A; Dickson, Eric W; Dobson, James G
Protein kinase C epsilon regulates mitochondrial pools of Nampt and NAD following resveratrol and ischemic preconditioning in the rat cortex.
Preserving mitochondrial pools of nicotinamide adenine dinucleotide (NAD) or nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in NAD production, maintains mitochondrial function and confers neuroprotection after ischemic stress. However, the mechanisms involved in regulating mitochondrial-localized Nampt or NAD have not been defined. In this study, we investigated the roles of protein kinase C epsilon (PKC?) and AMP-activated protein kinase (AMPK) in regulating mitochondrial pools of Nampt and NAD after resveratrol or ischemic preconditioning (IPC) in the cortex and in primary neuronal-glial cortical cultures. Using the specific PKC? agonist ??RACK, we found that PKC? induced robust activation of AMPK in vitro and in vivo and that AMPK was required for PKC?-mediated ischemic neuroprotection. In purified mitochondrial fractions, PKC? enhanced Nampt levels in an AMPK-dependent manner and was required for increased mitochondrial Nampt after IPC or resveratrol treatment. Analysis of intrinsic NAD autofluorescence using two-photon microscopy revealed that PKC? modulated NAD in the mitochondrial fraction. Further assessments of mitochondrial NAD concentrations showed that PKC? has a key role in regulating the mitochondrial NAD(+)/nicotinamide adenine dinucleotide reduced (NADH) ratio after IPC and resveratrol treatment in an AMPK- and Nampt-dependent manner. These findings indicate that PKC? is critical to increase or maintain mitochondrial Nampt and NAD after pathways of ischemic neuroprotection in the brain. PMID:24667915
Morris-Blanco, Kahlilia C; Cohan, Charles H; Neumann, Jake T; Sick, Thomas J; Perez-Pinzon, Miguel A
Coronary microembolization does not induce acute preconditioning against infarction in pigs�the role of adenosine
Objective: After coronary microembolization (ME) adenosine is released from ischemic areas of the microembolized myocardium. This adenosine dilates vessels in adjacent nonembolized myocardium and increases coronary blood flow. For ischemic preconditioning (IP) to protect the myocardium against infarction, an increase in the interstitial adenosine concentration (iADO) prior to the subsequent ischemia\\/reperfusion is necessary. We hypothesized that the adenosine release after
Andreas Skyschally; Rainer Schulz; Petra Gres; Ina Konietzka; Claus Martin; Michael Haude; Raimund Erbel; Gerd Heusch
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...
Endoplasmic reticulum refilling and mitochondrial calcium extrusion promoted in neurons by NCX1 and NCX3 in ischemic preconditioning are determinant for neuroprotection.
Ischemic preconditioning (IPC), an important endogenous adaptive mechanism of the CNS, renders the brain more tolerant to lethal cerebral ischemia. The molecular mechanisms responsible for the induction and maintenance of ischemic tolerance in the brain are complex and still remain undefined. Considering the increased expression of the two sodium calcium exchanger (NCX) isoforms, NCX1 and NCX3, during cerebral ischemia and the relevance of nitric oxide (NO) in IPC modulation, we investigated whether the activation of the NO/PI3K/Akt pathway induced by IPC could regulate calcium homeostasis through changes in NCX1 and NCX3 expression and activity, thus contributing to ischemic tolerance. To this aim, we set up an in vitro model of IPC by exposing cortical neurons to a 30-min oxygen and glucose deprivation (OGD) followed by 3-h OGD plus reoxygenation. IPC was able to stimulate NCX activity, as revealed by Fura-2AM single-cell microfluorimetry. This effect was mediated by the NO/PI3K/Akt pathway since it was blocked by the following: (a) the NOS inhibitors L-NAME and 7-Nitroindazole, (b) the IP3K/Akt inhibitors LY294002, wortmannin and the Akt-negative dominant, (c) the NCX1 and NCX3 siRNA. Intriguingly, this IPC-mediated upregulation of NCX1 and NCX3 activity may control calcium level within endoplasimc reticulum (ER) and mitochondria, respectively. In fact, IPC-induced NCX1 upregulation produced an increase in ER calcium refilling since this increase was prevented by siNCX1. Moreover, by increasing NCX3 activity, IPC reduced mitochondrial calcium concentration. Accordingly, the inhibition of NCX by CGP37157 reverted this effect, thus suggesting that IPC-induced NCX3-increased activity may improve mitochondrial function during OGD/reoxygenation. Collectively, these results indicate that IPC-induced neuroprotection may occur through the modulation of calcium homeostasis in ER and mitochondria through NO/PI3K/Akt-mediated NCX1 and NCX3 upregulation. PMID:24632945
Sisalli, M J; Secondo, A; Esposito, A; Valsecchi, V; Savoia, C; Di Renzo, G F; Annunziato, L; Scorziello, A
In vivo hypoxic preconditioning protects from warm liver ischemic/reperfusion injury through the adenosine A2B receptor
BACKGROUND Liver ischemia(I)/reperfusion(R) injury(I) is a known risk factor for the postoperative outcome of patients undergoing liver surgery/transplantation. Attempts to protect from organ damage require multidisciplinary strategies and are of emerging interest in view of patients with higher age and ASA-status. Ischemic preconditioning has been successfully applied to prevent from IRI during liver resections/transplantation. Since even short periods of ischemia during preconditioning inevitably lead to hypoxia and formation of anti-inflammatory/ cytoprotective acting adenosine, we reasoned that short non-ischemic hypoxia also protects against hepatic IRI. METHODS Mice underwent hypoxic preconditioning(HPC) by breathing 10%-oxygen for 10 minutes, followed by 10 minutes of 21%-oxygen prior to left-liver-lobe-ischemia(45 min) and reperfusion(4 hrs). The interactions of hypoxia->adenosine->adenosine-receptors were tested by pharmacologic antagonism at adenosine receptor(AR) sites in wild type mice and in mice with genetic deletions at the A1-;A2A-;A2B- and A3-ARs. Hepatocellular damage, inflammation and metabolic effects were quantified by enzyme activities, cytokines, liver-myeloperoxidase(MPO), blood adenosine and tissue-adenosinemonophosphate(AMP), respectively. RESULTS Hepatoprotection by HPC was significant in wild type and A1-, A2A-and A3 AR-knock-out mice as quantified by lower ALT serum activities, cytokine levels, histological damage-scores, tissue-myeloperoxidase-concentrations and as well as preserved AMP-concentrations. Protection by HPC was blunted in mice pretreated with the A2B-AR-antagonist MRS1754 or in A2B-AR�knock-outs�. CONCLUSION Because liver protective effects of HPC are negated when the A2B receptor is non-functional, the "hypoxia->adenosine->A2B receptor" pathway plays a critical role in the prevention of warm ischemia reperfusion injury in vivo. Hypoxic activation of this pathway warrants use of selective A2B-AR-agonists or even intermittent hypoxia (e.g. in deceased organ donors) to protect from liver ischemia/reperfusion injury.
Chouker, Alexander; Ohta, Akio; Martignoni, Andre; Lukashev, Dmitriy; Zacharia, Lefteris C; Jackson, Edwin K; Schnermann, Jurgen; Ward, Jerrold M; Kaufmann, Ines; Klaunberg, Brenda; Sitkovsky, Michail V; Thiel, Manfred
Lipopolysaccharide-induced preconditioning against ischemic injury is associated with changes in toll-like receptor 4 expression in the rat developing brain.
Lipopolysaccharide (LPS) preconditioning reduces ischemic injury in adult brain by activating Toll-like receptor 4 (TLR-4). We sought to investigate the effect of brain maturity on the efficacy of LPS preconditioning against hypoxic-ischemic (HI) injury in the developing rat brain. Rat pups at the specified age were randomly assigned to LPS-treated (0.1 mg/kg) or saline-treated groups. HI injury was induced 48 h later by occluding the right common carotid artery followed by transient hypoxia. Brains were removed 1 wk after HI injury, and infarct volumes were compared between the two groups. TLR-4 expression was also compared among different ages. We found that LPS treated P7, P9, and P14 rat pups had significantly smaller infarct volume compared with saline-treated pups (p = 0.006, 0.03, and 0.01, respectively). This significant reduction in infarct volume was not observed in P3 and P5 rats. TLR-4 expression was significantly higher in older rats compared with P3 and P5 rats (p < 0.01). These findings indicate that LPS-induced preconditioning is a robust neuroprotective phenomenon in the ischemic developing brain that is age dependent. Pattern of TLR-4 expression is also affected by brain maturity and likely to be responsible for differences in the efficacy of LPS preconditioning. PMID:21659958
Hickey, Edward; Shi, Hui; Van Arsdell, Glen; Askalan, Rand
Targeted deletion of the A3 adenosine receptor confers resistance to myocardial ischemic injury and does not prevent early preconditioning.
We used mice with genetic disruption of the A3 adenosine receptor (AR) gene (A3AR(-/-)mice) to assess the in vivo role of the A3AR in modulating myocardial ischemia/reperfusion injury and preconditioning (PC). Surprisingly, infarct size induced by 30 min of coronary artery occlusion and 24 h of reperfusion was 35% smaller in A3AR(-/-)compared to wild-type mice (A3AR(+/+)). The reduction in infarct size was not the result of differences in heart rate, body temperature or increased cardiac expression of A1ARs. However, neutrophil infiltration within infarcted regions was less in A3AR(-/-)mice. Furthermore, ischemic PC induced by either a single episode (one 5 min occlusion) or multiple episodes (six 4 min occlusions) of ischemia produced equivalent reductions in infarct size in A3AR(-/-)and A3AR(+/+)mice. These results indicate that, in the mouse, (i) A3ARs play an injurious role during acute myocardial ischemia/reperfusion injury, possibly by exacerbating the inflammatory response, and (ii) A3ARs are not necessary for the development of the early phase of ischemic PC. PMID:11273734
Guo, Y; Bolli, R; Bao, W; Wu, W J; Black, R G; Murphree, S S; Salvatore, C A; Jacobson, M A; Auchampach, J A
Targeted Deletion of the A3 Adenosine Receptor Confers Resistance to Myocardial Ischemic Injury and does not Prevent Early Preconditioning
We used mice with genetic disruption of the A3 adenosine receptor (AR) gene (A3AR?/? mice) to assess the in vivo role of the A3AR in modulating myocardial ischemia/reperfusion injury and preconditioning (PC). Surprisingly, infarct size induced by 30 min of coronary artery occlusion and 24 h of reperfusion was 35% smaller in A3AR?/? compared to wild-type mice (A3AR+/+). The reduction in infarct size was not the result of differences in heart rate, body temperature or increased cardiac expression of A1ARs. However, neutrophil infiltration within infarcted regions was less in A3AR?/? mice. Furthermore, ischemic PC induced by either a single episode (one 5 min occlusion) or multiple episodes (six 4 min occlusions) of ischemia produced equivalent reductions in infarct size in A3AR?/? and A3AR+/+ mice. These results indicate that, in the mouse, (i) A3ARs play an injurious role during acute myocardial ischemia/reperfusion injury, possibly by exacerbating the inflammatory response, and (ii) A3ARs are not necessary for the development of the early phase of ischemic PC.
Guo, Yiru; Bolli, Roberto; Bao, Weike; Wu, Wen-Jian; Black, Richard G.; Murphree, Sidney S.; Salvatore, Christopher A.; Jacobson, Marlene A.; Auchampach, John A.
AMPK-Regulated and Akt-Dependent Enhancement of Glucose Uptake Is Essential in Ischemic Preconditioning-Alleviated Reperfusion Injury
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 and Akt in reperfused myocardium is essential to IPC-alleviated reperfusion injury. This intrinsic metabolic modulation and cardioprotective capacity are present in STZ-treated hearts and can be triggered by insulin.
Liu, Wenchong; Huang, Qichao; Yang, Weidong; Fu, Feng; Ma, Heng; Su, Hui; Wang, Haichang; Wang, Jing; Zhang, Haifeng; Gao, Feng
Comparison of three different A1 adenosine receptor antagonists on infarct size and multiple cycle ischemic preconditioning in anesthetized dogs.
A(1) adenosine receptor (AR) antagonists are effective diuretic agents that may be useful for treating fluid retention disorders including congestive heart failure. However, antagonism of A(1)ARs is potentially a concern when using these agents in patients with ischemic heart disease. To address this concern, the present study was designed to compare the actions of the A(1)AR antagonists CPX (1,3-dipropyl-8-cyclopentylxanthine), BG 9719 (1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)]xanthine), and BG 9928 (1,3-dipropyl-8-[1-(4-propionate)-bicyclo-[2,2,2]octyl]xanthine) on acute myocardial ischemia/reperfusion injury and ischemic preconditioning (IPC) in an in vivo dog model of infarction. Barbital-anesthetized dogs were subjected to 60 min of left anterior descending coronary artery occlusion followed by 3 h of reperfusion, after which infarct size was assessed by staining with triphenyltetrazolium chloride. IPC was elicited by four 5-min occlusion/5-min reperfusion cycles produced 10 min before the 60-min occlusion. Multiple-cycle IPC produced a robust reduction ( approximately 65%) in infarct size; this effect of IPC on infarct size was not abrogated in dogs pretreated with any of the three AR antagonists. Surprisingly, in the absence of IPC, pretreatment with CPX or BG 9928 before occlusion or immediately before reperfusion resulted in significant reductions ( approximately 40-50%) in myocardial infarct size. However, treatment with an equivalent dose of BG 9719 had no similar effect. We conclude that the A(1)AR antagonists BG 9719, BG 9928, and CPX do not exacerbate cardiac injury and do not interfere with IPC induced by multiple ischemia/reperfusion cycles. We discuss the possibility that the cardioprotective actions of CPX and BG 9928 may be related to antagonism of A(2B)ARs. PMID:14634049
Auchampach, John A; Jin, Xiaowei; Moore, Jeannine; Wan, Tina C; Kreckler, Laura M; Ge, Zhi-Dong; Narayanan, Jayashree; Whalley, Eric; Kiesman, William; Ticho, Barry; Smits, Glenn; Gross, Garrett J
Effect of Hypoglycemic Agents on Ischemic Preconditioning in Patients With Type 2 Diabetes and Symptomatic Coronary Artery Disease
OBJECTIVE To assess the effect of two hypoglycemic drugs on ischemic preconditioning (IPC) patients with type 2 diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS We performed a prospective study of 96 consecutive patients allocated into two groups: 42 to group repaglinide (R) and 54 to group vildagliptin (V). All patients underwent two consecutive exercise tests (ET1 and ET2) in phase 1 without drugs. In phase 2, 1 day after ET1 and -2, 2 mg repaglinide three times daily or 50 mg vildagliptin twice daily was given orally to patients in the respective group for 6 days. On the seventh day, 60 min after 6 mg repaglinide or 100 mg vildagliptin, all patients underwent two consecutive exercise tests (ET3 and ET4). RESULTS In phase 1, IPC was demonstrated by improvement in the time to 1.0 mm ST-segment depression and rate pressure product (RPP). All patients developed ischemia in ET3; however, 83.3% of patients in group R experienced ischemia earlier in ET4, without significant improvement in RPP, indicating the cessation of IPC (P < 0.0001). In group V, only 28% of patients demonstrated IPC cessation, with 72% still having the protective effect (P < 0.0069). CONCLUSIONS Repaglinide eliminated myocardial IPC, probably by its effect on the KATP channel. Vildagliptin did not damage this protective mechanism in a relevant way in patients with type 2 diabetes and CAD, suggesting a good alternative treatment in this population.
Rahmi, Rosa Maria; Uchida, Augusto Hiroshi; Rezende, Paulo Cury; Lima, Eduardo Gomes; Garzillo, Cibele Larrosa; Favarato, Desiderio; Strunz, Celia M.C.; Takiuti, Myrthes; Girardi, Priscyla; Hueb, Whady; Kalil Filho, Roberto; Ramires, Jose A.F.
Temperature preconditioning is optimal at 26?C and confers additional protection to hypothermic cardioplegic ischemic arrest
We have recently shown that brief episodes of hypothermic perfusion interspersed with periods of normothermic perfusion, referred to as temperature preconditioning (TP), are cardioprotective and can be mimicked by consecutive isoproterenol/adenosine treatment. Here we investigate the optimal temperature for TP and whether TP further enhances protection provided by hypothermic ischemia with or without polarized cardioplegic arrest. Three experimental groups of Langendorff-perfused rat hearts were used. In the first group, hearts were subjected to three episodes of hypothermic perfusion at 7, 17, 26 and 32�C during the TP protocol, followed by 30 min normothermic index ischemia and 60 min reperfusion (37�C). Protein kinase A (PKA) activity and cyclic AMP (cAMP) concentrations were measured prior to index ischemia. In the second group, TP (26�C) hearts were subjected to two hours hypothermic index ischemia at 26�C and two hours normothermic reperfusion. In the third group, TP (26�C) hearts or hearts treated with isoproterenol/adenosine (pharmacological simulation of TP) were subjected to four hours hypothermic index ischemia with procaine-induced polarized cardioplegia at 26�C followed by two hours normothermic reperfusion. Hemodynamic function recovery, lactate dehydrogenase release and infarct size were used to assess cardioprotection. TP at 26�C resulted in highest cardioprotection, increased cAMP concentration and PKA activity, while TP at 7�C exacerbated ischemia/reperfusion damage, and had no effect on cAMP concentration or PKA activity. TP at 26�C also protected hearts during hypothermic ischemia with or without polarized cardioplegia. Isoproterenol/adenosine treatment conferred additional protection similar to TP. In conclusion, the study shows that TP-induced cardioprotection is temperature dependent and is optimal at 26�C; TP confers additional protection to hypothermia and polarized cardioplegia; and that the pharmacological treatment based on the mechanism of TP (consecutive isoproterenol/adenosine treatment) is a potential cardioprotective strategy that can be used during heart surgery and transplantation.
Halestrap, Andrew P; Suleiman, M-Saadeh
Hypotheses, rationale, design, and methods for evaluation of ischemic preconditioning assessed by sequential exercise tests in diabetic and non-diabetic patients with stable coronary artery disease - a prospective study
Background Ischemic preconditioning is a powerful mechanism of myocardial protection and in humans it can be evaluated by sequential exercise tests. Coronary Artery Disease in the presence of diabetes mellitus may be associated with worse outcomes. In addition, some studies have shown that diabetes interferes negatively with the development of ischemic preconditioning. However, it is still unknown whether diabetes may influence the expression of ischemic preconditioning in patients with stable multivessel coronary artery disease. Methods/Design This study will include 140 diabetic and non-diabetic patients with chronic, stable coronary artery disease and preserved left ventricular systolic function. The patients will be submitted to two sequential exercise tests with 30-minutes interval between them. Ischemic parameters will be compared between diabetic and non-diabetic patients. Ischemic preconditioning will be considered present when time to 1.0�mm ST-segment deviation is greater in the second of two sequential exercise tests. Exercise tests will be analyzed by two independent cardiologists. Discussion Ischemic preconditioning was first demonstrated by Murry et al. in dog�s hearts. Its work was reproduced by other authors, clearly demonstrating that brief periods of myocardial ischemia followed by reperfusion triggers cardioprotective mechanisms against subsequent and severe ischemia. On the other hand, the demonstration of ischemic preconditioning in humans requires the presence of clinical symptoms or physiological changes difficult to be measured. One methodology largely accepted are the sequential exercise tests, in which, the improvement in the time to 1.0�mm ST depression in the second of two sequential tests is considered manifestation of ischemic preconditioning. Diabetes is an important and independent determinant of clinical prognosis. It's a major risk factor for coronary artery disease. Furthermore, the association of diabetes with stable coronary artery disease imposes worse prognosis, irrespective of treatment strategy. It�s still not clearly known the mechanisms responsible by these worse outcomes. Impairment in the mechanisms of ischemic preconditioning may be one major cause of this worse prognosis, but, in the clinical setting, this is not known. The present study aims to evaluate how diabetes mellitus interferes with ischemic preconditioning in patients with stable, multivessel coronary artery disease and preserved systolic ventricular function.
Neuroprotection of preconditioning against ischemic brain injury in rat hippocampus through inhibition of the assembly of GluR6�PSD95�mixed lineage kinase 3 signaling module via nuclear and non-nuclear pathways
Our previous studies showed that the assembly of the GluR6�PSD95�mixed lineage kinase 3 (MLK3) signaling module played an important role in rat ischemic brain injury. In this study, we aimed to elucidate whether ischemic preconditioning could downregulate the assembly of the GluR6�PSD95�MLK3 signaling module and suppress the activation of MLK3, MKK4\\/7, and c-Jun N-terminal kinase (JNK). As a result, ischemic
Y. Du; C. Li; W.-W. Hu; Y.-J. Song; G.-Y. Zhang
Remote ischemic preconditioning confers late protection against myocardial ischemia-reperfusion injury in mice by upregulating interleukin-10
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.
Parajuli, Nirmal; Zheng, Xiaoxu; Becker, Lewis
Kir6.2 is not the mitochondrial KATP channel but is required for cardioprotection by ischemic preconditioning
ATP-sensitive K+ (KATP) channels that contain K+ inward rectifier subunits of the 6.2 isotype (Kir6.2) are important regulators of the cardiac response to ischemia-reperfusion (I/R) injury. Opening of these channels is implicated in the cardioprotective mechanism of ischemic preconditioning (IPC), but debate surrounds the contribution of surface KATP (sKATP) versus mitochondrial KATP (mKATP) channels. While responses to I/R injury and IPC have been examined in Kir6.2?/? mice before, breeding methods and other technical obstacles may have confounded interpretations. The aim of this study was to elucidate the role of Kir6.2 in cardioprotection and mKATP activity, using conventionally bred Kir6.2?/? mice with wild-type littermates as controls. We found that perfused hearts from Kir6.2?/? mice exhibited a normal baseline response to I/R injury, were not protected by IPC, and showed a blunted response to the IPC mimetic drug diazoxide. These data suggest that the loss of IPC in Kir6.2?/? hearts is not due to an underlying difference in I/R sensitivity. Furthermore, mKATP channel activity was identical in cardiac mitochondria isolated from wild-type versus Kir6.2?/? mice, suggesting no role for Kir6.2 in the mKATP. Collectively, these data indicate that Kir6.2 is required for the full response to IPC or diazoxide but is not involved in mKATP formation.
Wojtovich, Andrew P.; Urciuoli, William R.; Chatterjee, Shampa; Fisher, Aron B.; Nehrke, Keith
Hyperlipidemia attenuates the infarct size-limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition.
Hyperlipidemia attenuates the cardioprotective effect of preconditioning via unknown mechanisms. We have reported previously that in normolipidemic rats, preconditioning decreased ischemia-induced activation and release of myocardial matrix metalloproteinase (MMP)-2 into the coronary perfusate. Here, we investigated whether hyperlipidemia interferes with the cardioprotective effect of preconditioning through modulation of MMP-2. Hearts isolated from male Wistar rats fed 2% cholesterol-enriched or control chow for 9 weeks were subjected to a preconditioning protocol (three intermittent periods of ischemia/reperfusion of 5-min duration each) or a time-matched nonpreconditioning protocol. This was followed by a test ischemia/reperfusion (30-min ischemia and 120-min reperfusion) in both groups. Preconditioning decreased infarct size in the control but not the cholesterol-fed group. Cardioprotection in the preconditioned control group but not in the cholesterol-fed group was associated with an 18 +/- 3% (p < 0.05) inhibition of test ischemia/reperfusion-induced activation and release of myocardial MMP-2 into the perfusate. Myocardial protein levels of tissue inhibitors of MMPs [tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4] were not changed in either group. A reduction of infarct size in nonpreconditioned hearts from both control and cholesterol-fed group was produced by the MMP inhibitor ilomastat at 0.25 microM, a concentration producing MMP-2 inhibition comparable with that of preconditioning in the control group. We conclude that hyperlipidemia blocks preconditioning-induced cardioprotection, hyperlipidemia abolishes preconditioning-induced inhibition of myocardial MMP-2 activation and release, preconditioning-induced inhibition of MMP-2 activation and release is not mediated by TIMPs, and pharmacological inhibition of MMPs produces cardioprotection in both normal and hyperlipidemic rats. PMID:16166272
Giricz, Zolt�n; Lalu, Manoj M; Csonka, Csaba; Bencsik, P�ter; Schulz, Richard; Ferdinandy, P�ter
Effects of neutral endopeptidase 24.11 inhibition on myocardial infarct size and ischemic preconditioning in rabbits.
This study was designed to determine whether inhibition of neutral endopeptidase 24.11 (NEP) reduces infarct size and enhances protection afforded by ischemic preconditioning (PC) by elevation of the tissue bradykinin (BK) level in the heart in situ. In experiments to determine a dose of thiorphan (Thio) that inhibits NEP activity in the rabbit, infusion of Thio at a rate of 15 micro g/kg per min was found to be NEP-selective, since it increased the extent and duration of hypotension after BK injection (50 ng/kg and 100 ng/kg, i.v.) but did not inhibit pressor response to angiotensin I (100 ng/kg and 500 ng/kg, i.v.). Infusion of Thio at a rate of 25 micro g/kg per min blunted pressor response to angiotensin I by 30%, suggesting this dose partially inhibits angiotensin-converting enzyme activity. In the second series of experiments, myocardial infarction was induced by 30-min coronary occlusion and 3-h reperfusion in rabbits. In untreated controls, infarct size as a percentage of area at risk (%IS/AR) was 50.1+/-4.1%, and infusion of Thio at 15 micro g/kg per min and 25 micro g/kg per min failed to limit infarct size (54.3+/-4.0% and 50.1+/-2.8%, respectively). However, these doses of Thio significantly reduced %IS/AR when combined with PC with 2-min ischemia to 25.7+/-3.3% and 19.7+/-3.1%, respectively, although this submaximal PC protocol alone did not achieve significant cardioprotection (%IS/AR=35.6+/-4.0%). This effect of Thio on PC was abolished by pretreatment with icatibant (2 micro g/kg), a BK B(2) receptor blocker. The results of the present study suggest that NEP inhibition does not increase anti-infarct tolerance of the myocardium but significantly enhances cardioprotection of PC via a B(2) receptor-mediated mechanism. PMID:12237747
Nakano, Atsushi; Miura, Tetsuji; Miki, Takayuki; Nozawa, Yukinaga; Ichikawa, Yoshihiko; Ura, Nobuyuki; Shimamoto, Kazuaki
Decreased tetrahydrobiopterin and disrupted association of Hsp90 with eNOS by hyperglycemia impair myocardial ischemic preconditioning
Cardioprotection by ischemic preconditioning (IPC) is impaired during hyperglycemia, but the mechanisms underlying this phenomenon are poorly understood. This study investigated the role of hyperglycemia to adversely modulate tetrahydrobiopterin (BH4) and heat shock protein 90 (Hsp90) during cardioprotection by IPC. Rabbits or mice underwent 30 min of coronary occlusion followed by reperfusion with or without IPC in the presence or absence of hyperglycemia. IPC significantly (P < 0.05) decreased myocardial infarct size (46 � 1 to 19 � 2% of the area at risk in control and IPC rabbits, respectively) and increased BH4 concentrations (HPLC; 7.6 � 0.2 to 10.2 � 0.3 pmol/mg protein, respectively), Hsp90-endothelial nitric oxide synthase (eNOS) association (coimmunoprecipitation and Western blotting in mice; 4.0 � 0.3 to 5.4 � 0.1, respectively), and the ratio of phosphorylated eNOS/total eNOS. These beneficial actions of IPC on infarct size, BH4, Hsp90/eNOS, and phosphorylated eNOS were eliminated by hyperglycemia. Pretreatment of animals with the Hsp90 inhibitor geldanamycin (0.6 mg/kg) or the BH4 synthesis inhibitor diamino-6-hydroxypyrimidine (1.0 g/kg) also eliminated cardioprotection produced by IPC. In contrast, the BH4 precursor sepiapterin (2 mg/kg iv) restored the beneficial effects of IPC on myocardial BH4 concentrations, eNOS dimerization, and infarct size during hyperglycemia. A-23871 increased Hsp90-eNOS association (0.33 � 0.06 to 0.59 � 0.3) and nitric oxide production (184 � 17%) in human coronary artery endothelial cells cultured in normal (5.5 mM) but not high (20 mM) glucose media. These data indicate that hyperglycemia eliminates protection by IPC via decreases in myocardial BH4 concentration and disruption of the association of Hsp90 with eNOS. The results suggest that eNOS dysregulation may be a central mechanism of impaired cardioprotection during hyperglycemia.
Vladic, Nikolina; Leucker, Thorsten; Brzezinska, Anna K.; Du, Jian-Hai; Shi, Yang; Warltier, David C.; Pratt, Phillip F.; Kersten, Judy R.
Decreased tetrahydrobiopterin and disrupted association of Hsp90 with eNOS by hyperglycemia impair myocardial ischemic preconditioning.
Cardioprotection by ischemic preconditioning (IPC) is impaired during hyperglycemia, but the mechanisms underlying this phenomenon are poorly understood. This study investigated the role of hyperglycemia to adversely modulate tetrahydrobiopterin (BH(4)) and heat shock protein 90 (Hsp90) during cardioprotection by IPC. Rabbits or mice underwent 30 min of coronary occlusion followed by reperfusion with or without IPC in the presence or absence of hyperglycemia. IPC significantly (P < 0.05) decreased myocardial infarct size (46 � 1 to 19 � 2% of the area at risk in control and IPC rabbits, respectively) and increased BH(4) concentrations (HPLC; 7.6 � 0.2 to 10.2 � 0.3 pmol/mg protein, respectively), Hsp90-endothelial nitric oxide synthase (eNOS) association (coimmunoprecipitation and Western blotting in mice; 4.0 � 0.3 to 5.4 � 0.1, respectively), and the ratio of phosphorylated eNOS/total eNOS. These beneficial actions of IPC on infarct size, BH(4), Hsp90/eNOS, and phosphorylated eNOS were eliminated by hyperglycemia. Pretreatment of animals with the Hsp90 inhibitor geldanamycin (0.6 mg/kg) or the BH(4) synthesis inhibitor diamino-6-hydroxypyrimidine (1.0 g/kg) also eliminated cardioprotection produced by IPC. In contrast, the BH(4) precursor sepiapterin (2 mg/kg iv) restored the beneficial effects of IPC on myocardial BH(4) concentrations, eNOS dimerization, and infarct size during hyperglycemia. A-23871 increased Hsp90-eNOS association (0.33 � 0.06 to 0.59 � 0.3) and nitric oxide production (184 � 17%) in human coronary artery endothelial cells cultured in normal (5.5 mM) but not high (20 mM) glucose media. These data indicate that hyperglycemia eliminates protection by IPC via decreases in myocardial BH(4) concentration and disruption of the association of Hsp90 with eNOS. The results suggest that eNOS dysregulation may be a central mechanism of impaired cardioprotection during hyperglycemia. PMID:21908789
Vladic, Nikolina; Ge, Zhi-Dong; Leucker, Thorsten; Brzezinska, Anna K; Du, Jian-Hai; Shi, Yang; Warltier, David C; Pratt, Phillip F; Kersten, Judy R
Hypoxic preconditioning with cobalt of bone marrow mesenchymal stem cells improves cell migration and enhances therapy for treatment of ischemic acute kidney injury.
Mesenchymal stem cell (MSC) administration is known to enhance the recovery of the kidney following injury. Here we tested the potential of hypoxic-preconditioned-MSC transplantation to enhance the efficacy of cell therapy on acute kidney injury (AKI) by improving MSC migration to the injured kidney. Cobalt was used as hypoxia mimetic preconditioning (HMP). MSC were subjected to HMP through 24 h culture in 200 �mol/L cobalt. Compared to normoxia cultured MSC (NP-MSC), HMP significantly increased the expression of HIF-1? and CXCR4 in MSC and enhanced the migration of MSC in vitro. This effect was lost when MSC were treated with siRNA targeting HIF-1? or CXCR4 antagonist. SPIO labeled MSC were administered to rats with I/R injury followed immediately by magnetic resonance imaging. Imaging clearly showed that HMP-MSC exhibited greater migration and a longer retention time in the ischemic kidney than NP-MSC. Histological evaluation showed more HMP-MSC in the glomerular capillaries of ischemic kidneys than in the kidneys receiving NP-MSC. Occasional tubules showed iron labeling in the HMP group, while no tubules had iron labeling in NP group, indicating the possibility of tubular transdifferentiation after HMP. These results were also confirmed by fluorescence microscopy study using CM-DiI labeling. The increased recruitment of HMP-MSC was associated with reduced kidney injury and enhanced functional recovery. This effect was also related to the increased paracrine action by HMP-MSC. Thus we suggest that by enhancing MSC migration and prolonging kidney retention, hypoxic preconditioning of MSC may be a useful approach for developing AKI cell therapy. PMID:23671625
Yu, Xiaofang; Lu, Chunlai; Liu, Hong; Rao, Shengxiang; Cai, Jieru; Liu, Shaopeng; Kriegel, Alison J; Greene, Andrew S; Liang, Minyu; Ding, Xiaoqiang
Ischemic preconditioning negatively regulates plenty of SH3s�mixed lineage kinase 3�Rac1 complex and c-Jun N-terminal kinase 3 signaling via activation of Akt
Activation of Akt\\/protein kinase B has been recently reported to play an important role in ischemic tolerance. We here demonstrate that the decreased protein expression and phosphorylation of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) underlie the increased Akt-Ser-473 phosphorylation in the hippocampal CA1 subfield in ischemic preconditioning (IPC). Co-immunoprecipitation analysis reveals that Akt physically interacts with Rac1,
Q.-G. Zhang; D. Han; J. Xu; Q. Lv; R. Wang; X.-H. Yin; T.-L. Xu; G.-Y. Zhang
Brief anoxia preconditioning and HIF prolyl-hydroxylase inhibition enhances neuronal resistance in organotypic hippocampal slices on model of ischemic damage.
It is well known that a brief anoxia or hypoxia episodes can render brain resistant to a subsequent ischemia. Recent investigations indicate that mechanisms of such stimulated endogenous neuroprotection are related to the family of hypoxia-inducible factors (HIF), however there are still little data available on the role of HIF family members in hippocampus-a brain structure, highly sensitive to oxygen deficiency. We have used the model of cultured hippocampal slices and single-cell quantitative RT-PCR to study HIF-1? and HIF-3? mRNA expression following triple 5-min mild anoxia, 30-min oxygen-glucose deprivation and their combination. We also tested the effects of HIF prolyl-hydroxylase inhibition with 2,4-pyridinedicarboxylic acid diethyl ester pre-treatment followed by a 30-min oxygen-glucose deprivation. It was found that neuronal damage induced by oxygen-glucose deprivation was accompanied by a significant decrease in both HIF-1? and HIF-3? mRNA levels in CA1 but not CA3 neurons. Anoxia preconditioning did not affect cell viability and HIF mRNA levels but applied before oxygen-glucose deprivation prevented neuronal damage and suppression of HIF-1? and HIF-3? mRNA expression. It was also found that effects of the prolyl-hydroxylase inhibitor were similar to anoxia preconditioning. These results suggest that anoxia preconditioning increases anti-ischemic neuronal resistance which to a certain extent correlates with the changes of HIF-1? and HIF-3? expression. PMID:21338581
Lushnikova, Iryna; Orlovsky, Maxim; Dosenko, Victor; Maistrenko, Anastasiia; Skibo, Galina
Akt and Erk1/2 activate the ornithine decarboxylase/polyamine system in cardioprotective ischemic preconditioning in rats: the role of mitochondrial permeability transition pores.
Ornithine decarboxylase (ODC) is the first rate-limiting enzyme in polyamine biosynthesis, which is essential for cell survival. We hypothesized that the ODC/polyamine system is involved in ischemic preconditioning (IPC)-mediated cardioprotection through the activation of Erk1/2 and Akt and through the inhibition of the mitochondrial permeability transition (mPT). Isolated rat hearts were subjected to 40 min of ischemia either with or without IPC (3 cycles of 5-min global ischemia), and ODC protein expression, polyamine content, and Akt and Erk1/2 phosphorylation were evaluated after 30 min of reperfusion. IPC significantly upregulated the ODC/polyamine pathway, promoted Erk1/2 and Akt phosphorylation, and reduced the infarct size and heart dysfunction after reperfusion. An inhibitor of ODC, ?-difluoromethylornithine (DFMO), abolished the IPC-induced cardioprotection. Moreover, the inhibition of the IPC-induced activation of Erk1/2 and Akt using PD98059 or wortmannin downregulated the ODC/polyamine system. In separate studies, the Ca(2+) load required to open the mPT pore was significantly lower in DFMO-treated cardiac mitochondria than in mitochondria from IPC hearts. Furthermore, spermine or spermidine significantly inhibited the mPT induced by CaCl2. These results suggest that IPC upregulates the ODC/polyamine system and mediates preconditioning cardioprotection, which may depend on the phosphorylation/activation of Erk1/2 and Akt and on the inhibition of the mPT during reperfusion. PMID:24464033
Zhang, Hao; Xue, Guo; Zhang, Weihua; Wang, Lina; Li, Hong; Zhang, Li; Lu, Fanghao; Bai, Shuzhi; Lin, Yan; Lou, Yu; Xu, Changqing; Zhao, Yajun
Nuclear Factor-kB Plays an Essential Role in the Late Phase of Ischemic Preconditioning in Conscious Rabbits
Although it is recognized that late preconditioning (PC) results from upregulation of cardioprotective genes, the specific transcription factor(s) that govern this genetic adaptation remains unknown. The aim of this study was to test the hypothesis that the development of late PC is mediated by nuclear factor-kB (NF-kB) and to elucidate the mechanisms that control the activation of NF-kB after an
Yu-Ting Xuan; Xian-Liang Tang; Supratim Banerjee; Hitoshi Takano; Richard C. X. Li; Hui Han; Yumin Qiu; Jian-Jun Li; Roberto Bolli
Neuroprotection of preconditioning against ischemic brain injury in rat hippocampus through inhibition of the assembly of GluR6-PSD95-mixed lineage kinase 3 signaling module via nuclear and non-nuclear pathways.
Our previous studies showed that the assembly of the GluR6-PSD95-mixed lineage kinase 3 (MLK3) signaling module played an important role in rat ischemic brain injury. In this study, we aimed to elucidate whether ischemic preconditioning could downregulate the assembly of the GluR6-PSD95-MLK3 signaling module and suppress the activation of MLK3, MKK4/7, and c-Jun N-terminal kinase (JNK). As a result, ischemic preconditioning could not only inhibit the assembly of the GluR6-PSD95-MLK3 signaling module, diminish the phosphorylation of the transcription factor c-Jun, downregulate Fas ligand expression, attenuate the phosphorylation of 14-3-3 and Bcl-2 and the translocation of Bax to mitochondria, but also increase the release of cytochrome c and the activation of caspase-3. In contrast, both GluR6 antisense ODNs (oligodeoxynucleotides) and 6,7,8,9-tetrahydro-5-nitro-1 H-benz[g]indole-2,3-dione-3-oxime (NS102), an antagonist of GluR6 receptor, prevented the above effects of preconditioning, which shows that suppressing the expression of GluR6 or inhibiting GluR6 activity contributes negatively to preconditioning-induced ischemia tolerance. Taken together, our results indicate that preconditioning can inhibit the over-assembly of the GluR6-PSD95-MLK3 signaling module and the JNK3 activation. GluR6 subunit-containing kainite receptors play an important role in the preconditioning-induced neuronal survival and provide new insight into stroke therapy. PMID:19328223
Du, Y; Li, C; Hu, W-W; Song, Y-J; Zhang, G-Y
Preconditioning: from experimental findings to novel therapies in acute kidney injury.
Improving the ability of the kidney to tolerate injury through preconditioning is likely to have important clinical implications. Although a number of preconditioning strategies have been studied, ischemic preconditioning (IP) has been studied the most experimentally. The information gathered has helped us shed more light into the mechanisms responsible for this tissue adaptation that confers to tissues a more resistant status. IP is effective within minutes, suggesting that preformed mediators are involved. This is followed by delayed preconditioning, a phenomenon that is less potent but longer acting. Remote preconditioning occurs also in non-affected tissues and can be transferable. A number of mediators and transcription factors have been implicated including kinases, heat shock proteins, nitric oxide and neurogenic pathways, all of which help change the cell into a more resistant phenotype. There is evidence that IP also occurs in the human environment with lessons learned from myocardial ischemia, hepatic resection and cerebral ischemia. Because of the ethical impediment with intentionally applying organ ischemia, there has been an interest in pharmacological preconditioning lately. Exogenously administered erythropoietin was shown to benefit kidneys subjected to different insults. In addition, mesenchymal stem cells-based approaches for the prevention and treatment of acute kidney injury (AKI) are being studied. Calcineurin inhibitors may represent a viable way to reduce ischemia reperfusion injury in transplantation. Translating the experimental findings to the clinical arena remains a challenge. The discovery of new biomarkers for AKI should help initiate therapy early, when therapy could make a difference. PMID:19773719
Shihab, F S
Cardiac genomic response following preconditioning stimulus
This review focuses on the genomic response following a preconditioning stimulus. Initial studies demonstrated that classical ischemic preconditioning mediated by cyclic episodes of short durations of reversible ischemia and reperfusion could result in the reprogramming of gene expression. Some of these genes are translated into proteins during the late preconditioning or so-called ''second window of protection''. Subsequent studies determined a
Dipak K. Das; Nilanjana Maulik
Transient Limb Ischemia Alters Serum Protein Expression in Healthy Volunteers: Complement C3 and Vitronectin May Be Involved in Organ Protection Induced by Remote Ischemic Preconditioning
The protective mechanism underlying remote ischemic preconditioning (RIPC) is unclear. This study aims to verify whether the protein expression profile in the serum could be altered by RIPC and to detect potential protein mediators. Transient limb ischemia consisting of three cycles of 5-min ischemia followed by 5-min reperfusion was performed on sixty healthy volunteers. Serum samples were collected at 30?min before transient limb ischemia and at 1 hour (h), 3?h, 8?h, 24?h, and 48?h after completion of three cycles. Changes in the serum protein profile were analyzed by two-dimensional gel electrophoresis and proteins were identified by MALDI-TOF/TOF mass spectrometry. Fourteen differentially expressed proteins were identified and, respectively, involved in immune system, lipid binding and metabolism, apoptosis, and blood coagulation. Complement C3, vitronectin, and apolipoprotein A-I were further confirmed by western blotting, and the results showed that their contents decreased significantly after transient limb ischemia. It is concluded that transient limb ischemia alters the serum protein expression profile in human being, and that reduction of serum contents of complement C3 and vitronectin may represent an important part of the mechanism whereby RIPC confers its protection.
Pang, Ting; Zhang, Nan-Rong; Jin, San-Qing; Pan, San-Qiang
The 'silence' of silent brain infarctions may be related to chronic ischemic preconditioning and nonstrategic locations rather than to a small infarction size
OBJECTIVE: Silent brain infarctions are the silent cerebrovascular events that are distinguished from symptomatic lacunar infarctions by their �silence'; the origin of these infarctions is still unclear. This study analyzed the characteristics of silent and symptomatic lacunar infarctions and sought to explore the mechanism of this �silence'. METHODS: In total, 156 patients with only silent brain infarctions, 90 with only symptomatic lacunar infarctions, 160 with both silent and symptomatic lacunar infarctions, and 115 without any infarctions were recruited. Vascular risk factors, leukoaraiosis, and vascular assessment results were compared. The National Institutes of Health Stroke Scale scores were compared between patients with only symptomatic lacunar infarctions and patients with two types of infarctions. The locations of all of the infarctions were evaluated. The evolution of the two types of infarctions was retrospectively studied by comparing the infarcts on the magnetic resonance images of 63 patients obtained at different times. RESULTS: The main risk factors for silent brain infarctions were hypertension, age, and advanced leukoaraiosis; the main factors for symptomatic lacunar infarctions were hypertension, atrial fibrillation, and atherosclerosis of relevant arteries. The neurological deficits of patients with only symptomatic lacunar infarctions were more severe than those of patients with both types of infarctions. More silent brain infarctions were located in the corona radiata and basal ganglia; these locations were different from those of the symptomatic lacunar infarctions. The initial sizes of the symptomatic lacunar infarctions were larger than the silent brain infarctions, whereas the final sizes were almost equal between the two groups. CONCLUSIONS: Chronic ischemic preconditioning and nonstrategic locations may be the main reasons for the �silence' of silent brain infarctions.
Feng, Chao; Bai, Xue; Xu, Yu; Hua, Ting; Liu, Xue-Yuan
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
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.
Gedik, Nilgun; Thielmann, Matthias; Kottenberg, Eva; Peters, Jurgen; Jakob, Heinz; Heusch, Gerd; Kleinbongard, Petra
Liver Ischemic Preconditioning (IPC) Improves Intestinal Microbiota Following Liver Transplantation in Rats through 16s rDNA-Based Analysis of Microbial Structure Shift
Background Ischemia-reperfusion (I/R) injury is associated with intestinal microbial dysbiosis. The �gut-liver axis� closely links gut function and liver function in health and disease. Ischemic preconditioning (IPC) has been proven to reduce I/R injury in the surgery. This study aims to explore the effect of IPC on intestinal�microbiota and to analyze characteristics of microbial structure shift following liver transplantation (LT). Methods The LT animal models of liver and gut IPC were established. Hepatic graft function was assessed by histology and serum ALT/AST. Intestinal barrier function was evaluated by mucosal ultrastructure, serum endotoxin, bacterial translocation, fecal sIgA content and serum TNF-?. Intestinal bacterial populations were determined by quantitative PCR. Microbial composition was characterized by DGGE and specific bacterial species were determined by sequence analysis. Principal Findings Liver IPC improved hepatic graft function expressed as ameliorated graft structure and reduced ALT/AST levels. After administration of liver IPC, intestinal mucosal ultrastructure improved, serum endotoxin and bacterial translocation mildly decreased, fecal sIgA content increased, and serum TNF-? decreased. Moreover, liver IPC promoted microbial restorations mainly through restoring Bifidobacterium spp., Clostridium clusters XI and Clostridium cluster XIVab on bacterial genus level. DGGE profiles indicated that liver IPC increased microbial diversity and species richness, and cluster analysis demonstrated that microbial structures were similar and clustered together between the NC group and Liver-IPC group. Furthermore, the phylogenetic tree of band sequences showed key bacteria corresponding to 10 key band classes of microbial structure shift induced by liver IPC, most of which were assigned to Bacteroidetes phylum. Conclusion Liver IPC cannot only improve hepatic graft function and intestinal barrier function, but also promote restorations of intestinal microbiota following LT, which may further benefit hepatic graft by positive feedback of the �gut-liver axis�.
Lu, Haifeng; Chen, Xinhua; Jiang, Jianwen; Liu, Hui; He, Yong; Ding, Songming; Hu, Zhenhua; Wang, Weilin; Zheng, Shusen
Interruption of signal transduction between G protein and PKC-epsilon underlies the impaired myocardial response to ischemic preconditioning in postinfarct remodeled hearts.
We have recently shown that the protective mechanism of ischemic preconditioning (PC) is impaired in the myocardium that survived infarction and underwent postinfarct ventricular remodeling. In this study, we examined the hypothesis that failure of PC to activate PKC-epsilon underlies the refractoriness of the remodeling heart to PC. Circumflex coronary arteries were ligated in rabbits to induce infarction and subsequent ventricular remodeling, and only sham operations were performed in controls. Hearts were isolated before (i.e. 4 days later) or after (i.e. 2 weeks later) remodeling of the left ventricle and used for isolated buffer-perfused heart experiments. Myocardial infarction was induced in isolated hearts by 30 min global ischemia/2 h reperfusion, and its size was measured by tetrazolium staining. Using separate groups of hearts, tissue biopsies were taken before and after PC, and PKC translocation was assessed by Western blotting. Areas infarcted in vivo by coronary ligation (CL) were excluded from subsequent infarct size/PKC analyses. In the hearts 4 days after CL, PC with 2 cycles of 5 min ischemia/5 min reperfusion induced PKC-epsilon translocation from cytosol to particulate fractions and limited infarct size to 40% of control value. In the hearts remodeled 2 weeks after CL, PC failed to induce PKC-epsilon translocation and infarct size limitation. In this group, PKC activity and hemodynamic responses to adenosine were similar to those in sham-operated controls. When remodeling after CL was prevented by valsartan infusion (10 mg/kg/day), an angiotensin II type 1 (AT1) receptor blocker, PC could induce both infarct limitation and PKC-epsilon translocation. The present results suggest that persistent activation of AT1 receptors during remodeling disturbed the PC signaling between G proteins and PKC-epsilon, which underlies the refractoriness of the remodeled myocardium to PC. PMID:12841647
Miki, Takayuki; Miura, Tetsuji; Tanno, Masaya; Sakamoto, Jun; Kuno, Atsushi; Genda, Satoshi; Matsumoto, Tomoaki; Ichikawa, Yoshihiko; Shimamoto, Kazuaki
Neuronal Preconditioning by Inhalational Anesthetics
Background Ischemic preconditioning is an important intrinsic mechanism for neuroprotection. Preconditioning can also be achieved by exposure of neurons to K+ channel�opening drugs that act on adenosine triphosphate�sensitive K+ (KATP) channels. However, these agents do not readily cross the blood�brain barrier. Inhalational anesthetics which easily partition into brain have been shown to precondition various tissues. Here, the authors explore the neuronal preconditioning effect of modern inhalational anesthetics and investigate their effects on KATP channels. Methods Neuronal�glial cocultures were exposed to inhalational anesthetics in a preconditioning paradigm, followed by oxygen�glucose deprivation. Increased cell survival due to preconditioning was quantified with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide reduction test. Recombinant plasmalemmal KATP channels of the main neuronal type (Kir6.2/SUR1) were expressed in HEK293 cells, and the effects of anesthetics were evaluated in whole cell patch clamp recordings. Results Both sevoflurane and the noble gas xenon preconditioned neurons at clinically used concentrations. The effect of sevoflurane was independent of KATP channel activation, whereas the effect of xenon required the opening of plasmalemmal KATP channels. Recombinant KATP channels were activated by xenon but inhibited by halogenated volatiles. Modulation of mitochondrial K-ATP channels did not affect the activity of KATP channels, thus ruling out an indirect effect of volatiles via mitochondrial channels. Conclusions The preconditioning properties of halogenated volatiles cannot be explained by their effect on KATP channels, whereas xenon preconditioning clearly involves the activation of these channels. Therefore, xenon might mimic the intrinsic mechanism of ischemic preconditioning most closely. This, together with its good safety profile, might suggest xenon as a viable neuroprotective agent in the clinical setting.
Bantel, Carsten; Maze, Mervyn; Trapp, Stefan
A pilot study investigating the effects of remote ischemic preconditioning in high-risk cardiac surgery using a randomised controlled double-blind protocol.
The efficacy of remote ischemic preconditioning (RIPC) in high-risk cardiac surgery is uncertain. In this study, 96 adults undergoing high-risk cardiac surgery were randomised to RIPC (3 cycles of 5 min of upper-limb ischemia induced by inflating a blood pressure cuff to 200 mmHg with 5 min of reperfusion) or control. Main endpoints were plasma high-sensitivity troponin T (hsTNT) levels at 6 and 12 h, worst post-operative acute kidney injury (AKI) based on RIFLE criteria, and noradrenaline duration. hsTNT levels were log-normally distributed and higher with RIPC than control at 6-h post cross-clamp removal [810 ng/ml (IQR 527-1,724) vs. 634 ng/ml (429-1,012); ratio of means 1.41 (99.17% CI 0.92-2.17); P=0.04] and 12 h [742 ng/ml (IQR 427-1,700) vs. 514 ng/ml (IQR 356-833); ratio of means 1.56 (99.17% CI 0.97-2.53); P=0.01]. After adjustment for baseline confounders, the ratio of means of hsTNT at 6 h was 1.23 (99.17% CI 0.88-1.72; P=0.10) and at 12 h was 1.30 (99.17% CI 0.92-1.84; P=0.05). In the RIPC group, 35/48 (72.9%) had no AKI, 5/48 (10.4%) had AKI risk, and 8/48 (16.7%) had either renal injury or failure compared to the control group where 34/48 (70.8%) had no AKI, 7/48 (14.6%) had AKI risk, and 7/48 (14.6%) had renal injury or failure (Chi-squared 0.41; two degrees of freedom; P = 0.82). RIPC increased post-operative duration of noradrenaline support [21 h (IQR 7-45) vs. 9 h (IQR 3-19); ratio of means 1.70 (99.17% CI 0.86-3.34); P=0.04]. RIPC does not reduce hsTNT, AKI, or ICU-support requirements in high-risk cardiac surgery. PMID:22406977
Young, Paul Jeffrey; Dalley, Paul; Garden, Alexander; Horrocks, Christopher; La Flamme, Anne; Mahon, Barry; Miller, John; Pilcher, Janine; Weatherall, Mark; Williams, Jenni; Young, William; Beasley, Richard
Vector-Free and Transgene-Free Human iPS Cells Differentiate into Functional Neurons and Enhance Functional Recovery after Ischemic Stroke in Mice
Stroke is a leading cause of human death and disability in the adult population in the United States and around the world. While stroke treatment is limited, stem cell transplantation has emerged as a promising regenerative therapy to replace or repair damaged tissues and enhance functional recovery after stroke. Recently, the creation of induced pluripotent stem (iPS) cells through reprogramming of somatic cells has revolutionized cell therapy by providing an unlimited source of autologous cells for transplantation. In addition, the creation of vector-free and transgene-free human iPS (hiPS) cells provides a new generation of stem cells with a reduced risk of tumor formation that was associated with the random integration of viral vectors seen with previous techniques. However, the potential use of these cells in the treatment of ischemic stroke has not been explored. In the present investigation, we examined the neuronal differentiation of vector-free and transgene-free hiPS cells and the transplantation of hiPS cell-derived neural progenitor cells (hiPS-NPCs) in an ischemic stroke model in mice. Vector-free hiPS cells were maintained in feeder-free and serum-free conditions and differentiated into functional neurons in vitro using a newly developed differentiation protocol. Twenty eight days after transplantation in stroke mice, hiPS-NPCs showed mature neuronal markers in vivo. No tumor formation was seen up to 12 months after transplantation. Transplantation of hiPS-NPCs restored neurovascular coupling, increased trophic support and promoted behavioral recovery after stroke. These data suggest that using vector-free and transgene-free hiPS cells in stem cell therapy are safe and efficacious in enhancing recovery after focal ischemic stroke in mice.
Mohamad, Osama; Faulkner, Ben; Chen, Dongdong; Yu, Shan Ping; Wei, Ling
Ligand triggers of classical preconditioning and postconditioning
The cardioprotection afforded by ischemic preconditioning (IPC) and ischemic postconditioning (PC) are receptor mediated. In this review, we will focus on the major ligand classes and receptors that contribute to IPC and PC-induced cardioprotection. Ligand classes discussed include adenosine, bradykinin, opioids, erythropoietin, adrenergics and muscarinics. The cardioprotective therapeutic window of each ligand class will also be summarized, with particular focus
Eric R. Gross; Garrett J. Gross
Suppression of reperfusion arrhythmia by ischemic preconditioning in the rat: Is it mediated by the adenosine receptor, prostaglandin, or bradykinin receptor?
The mechanism for the suppression of reperfusion arrhythmia by preconditioning (PC) remains unknown. This study aimed to examine the roles of the adenosine receptor, prostaglandin (PG), and bradykinin (BK) receptor in PC. Under pentobarbital anesthesia, the coronary artery of the rat was occluded for 5 min and then reperfused. In untreated controls, this protocol induced ventricular tachycardia (VT) in 100%
T. Miura; R. Ishimoto; J. Sakamoto; A. Tsuchida; K. Suzuki; T. Ogawa; K. Shimamoto; O. Iimura
Preconditioning Strategy in Stem Cell Transplantation Therapy
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.
Yu, Shan Ping; Wei, Zheng; Wei, Ling
Hyperbaric oxygen pretreatment and preconditioning.
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
Camporesi, Enrico M; Bosco, Gerardo
A murine model of inducible, cardiac-specific deletion of STAT3: its use to determine the role of STAT3 in the upregulation of cardioprotective proteins by ischemic preconditioning.
Pharmacological studies have shown that signal transducers and activators of transcription (STATs) are necessary for the delayed cardioprotection of ischemic preconditioning (PC). However, pharmacologic STAT inhibitors are not specific; furthermore, the individual role of STAT3 in late PC remains unknown. The objectives of the study were (i) to create an inducible, cardiac-specific STAT3 knockout mouse; (ii) to verify whether STAT3 deletion has any adverse effects in the short term (~1 month); and (iii) to use this novel tool to evaluate the role of STAT3 in the PC-induced upregulation of cardioprotective and anti-apoptotic proteins. We created an inducible, cardiomyocyte-restricted STAT3 deficient mouse (MCM TG:STAT3(flox/flox)) by interbreeding STAT3(flox/flox) mice and tamoxifen-inducible MCM TG mice. Treatment of MCM TG:STAT3(flox/flox) mice with tamoxifen resulted in deletion of STAT3 specifically in cardiac myocytes, concomitant with abrogation of ischemic PC-induced Tyr-705 and Ser-727 phosphorylation of STAT3 and increased STAT3 DNA-binding activity. In vehicle-treated MCM TG:STAT3(flox/flox) mice, ischemic PC increased the expression of cardioprotective (COX-2 and HO-1) and anti-apoptotic (e.g., Mcl-1, Bcl-x(L), c-FLIP(L), c-FLIP(S)) proteins 24h later; in contrast, in tamoxifen-treated MCM TG:STAT3(flox/flox) mice this increase was completely absent. Deletion of STAT3 had no apparent adverse effects on LV structure or function after 35 days. We have developed a novel inducible, cardiomyocyte-restricted STAT3 deficient mouse that can be used to specifically interrogate the role of this transcription factor in cardiovascular pathophysiology in vivo. Our data demonstrate, for the first time, that recruitment of STAT3 plays an obligatory role in the upregulation of cardioprotective and anti-apoptotic proteins and suggest that STAT3 activation is important in inhibiting both the death receptor pathway (which is modulated by c-FLIP(L) and c-FLIP(S)) and the mitochondrial pathway (which is mediated by Mcl-1 and Bcl-x(L)). PMID:21223971
Bolli, Roberto; Stein, Adam B; Guo, Yiru; Wang, Ou-Li; Rokosh, Gregg; Dawn, Buddhadeb; Molkentin, Jeffery D; Sanganalmath, Santosh K; Zhu, Yanqing; Xuan, Yu-Ting
Preconditioning of swine heart with monophosphoryl lipid A improves myocardial preservation
Background. Ischemic preconditioning has been proven to be a powerful tool for myocardial protection in the setting of ischemia and reperfusion. A new drug to provide pharmacologic preconditioning, monophosphoryl lipid A (MLA), was administered 24 hours before an acute coronary occlusion in pigs to determine the effect on pharmacologic preconditioning.Methods. Two studies were completed. In the first, swine were distributed
Tetsuya Yoshida; Richard M Engelman; Daniel T Engelman; John A Rousou; Nilanjana Maulik; Motoaki Sato; Gary T Elliott; Dipak K Das
Mitochondrial Preconditioning: A Potential Neuroprotective Strategy
Mitochondria have long been known as the powerhouse of the cell. However, these organelles are also pivotal players in neuronal cell death. Mitochondrial dysfunction is a prominent feature of chronic brain disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), and cerebral ischemic stroke. Data derived from morphologic, biochemical, and molecular genetic studies indicate that mitochondria constitute a convergence point for neurodegeneration. Conversely, mitochondria have also been implicated in the neuroprotective signaling processes of preconditioning. Despite the precise molecular mechanisms underlying preconditioning-induced brain tolerance are still unclear, mitochondrial reactive oxygen species generation and mitochondrial ATP-sensitive potassium channels activation have been shown to be involved in the preconditioning phenomenon. This review intends to discuss how mitochondrial malfunction contributes to the onset and progression of cerebral ischemic stroke and AD and PD, two major neurodegenerative disorders. The role of mitochondrial mechanisms involved in the preconditioning-mediated neuroprotective events will be also discussed. Mitochondrial targeted preconditioning may represent a promising therapeutic weapon to fight neurodegeneration.
Correia, Sonia C.; Carvalho, Cristina; Cardoso, Susana; Santos, Renato X.; Santos, Maria S.; Oliveira, Catarina R.; Perry, George; Zhu, Xiongwei; Smith, Mark A.; Moreira, Paula I.
Stunning, preconditioning, and functional recovery after global myocardial ischemia.
Stunning (reversible myocardial ischemia without necrosis) occurs with induced global ischemia during cardiac operations and depresses the ability of the heart to utilize oxygen efficiently because less contractile work is developed per unit of oxygen utilized. Interestingly, regional studies have demonstrated dramatic infarct size reduction with stunning episodes before prolonged ischemia, a phenomenon known as myocardial preconditioning. It is postulated that the postischemic contractile dysfunction noted after stunning causes reduced energy demands, which "preconditions" myocardium to withstand a subsequent longer ischemic episode. Some evidence from regional studies suggests that preconditioning may improve functional recovery after ischemia. This study examined the complex relationship between stunning and preconditioning to functional recovery in a surgical setting of global ischemia. To study the effect of stunning, myocardial oxygen consumption, oxygen extraction, and functional indices of contractility were measured before and after isolated rabbit hearts were subjected to 10, 20, or 45 minutes of normothermic 37 degrees C global ischemic stun intervals. This demonstrated that while oxygen consumption and extraction quickly recover to prestun levels, contractility remains depressed well beyond the stun interval. To study the effect of preconditioning using stunning, isolated hearts were then subjected to 120 minutes of 34 degrees C cardioplegic-induced ischemia after preconditioning. Hearts received either modified St. Thomas cardioplegic solution as a control or cardioplegia administered after preconditioning with 37 degrees C ischemic stunning for 5, 10, 15, 20, or 45 minutes or multiple 5- or 10-minute stuns, with reperfusion before cardioplegic-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7944710
Bolling, S F; Olszanski, D A; Childs, K F; Gallagher, K P; Ning, X H
NCX1 and NCX3: two new effectors of delayed preconditioning in brain ischemia.
Substantial evidence has established that a short sub-lethal brain ischemia applied before a prolonged harmful ischemic episode confers ischemic neuroprotection, a phenomenon named ischemic preconditioning. Na(+)/Ca(2+) exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are plasmamembrane ionic transporters widely distributed in the brain, where they are involved in the control of Na(+) and Ca(2+) homeostasis and in the progression of stroke damage. The objective of this study was to evaluate the role of these three proteins in the preconditioning-induced neuroprotection. NCX protein expression was evaluated at different time points in the ischemic temporoparietal cortex of rats subjected to ischemia alone, to ischemic preconditioning alone, or to ischemic preconditioning plus ischemia. NCX1 and NCX3 were up-regulated in those brain regions protected by preconditioning treatment. These changes were mediated by p-AKT, since the p-AKT inhibition prevented the up-regulation of both isoforms. The relevant role of NCX1 and NCX3 during preconditioning was further confirmed when NCX1 and NCX3 silencing, induced by icv infusion of siRNA, partially reverted the preconditioning-induced neuroprotection. The enhancement of NCX1 and NCX3 expression and activity might represent a reasonable strategy to reduce the infarct extension after stroke. PMID:22036625
Pignataro, Giuseppe; Boscia, Francesca; Esposito, Elga; Sirabella, Rossana; Cuomo, Ornella; Vinciguerra, Antonio; Di Renzo, Gianfranco; Annunziato, Lucio
The therapeutic potential of ischemic conditioning: an update
Novel approaches are required to improve clinical outcomes in patients with coronary heart disease (CHD). Ischemic conditioning�the practice of applying brief episodes of nonlethal ischemia and reperfusion to confer protection against a sustained episode of lethal ischemia and reperfusion injury�is one potential therapeutic strategy. Importantly, the protective stimulus can be applied before (ischemic preconditioning) or after (ischemic perconditioning) onset of
Derek J. Hausenloy; Derek M. Yellon
Hyperthermic preconditioning protects astrocytes from ischemia\\/reperfusion injury by up-regulation of HIF-1 alpha expression and binding activity
It has been demonstrated that hypoxia-inducible factor-1 alpha (HIF-1 alpha) mediates ischemic tolerance induced by hypoxia\\/ischemia or pharmacological preconditioning. In addition, preconditioning stimuli can be cross-tolerant, safeguarding against other types of injury. We therefore hypothesized HIF-1 alpha might also be associated with ischemic tolerance induced by hyperthermic preconditioning. In the present study, we demonstrated for the first time that 6h
Fang Du; Li Zhu; Zhong-Ming Qian; Xiao-Mei Wu; Wing-Ho Yung; Ya Ke
Isoflurane preconditioning neuroprotection in experimental stroke is male-specific. The role of androgens in the ischemic sensitivity of isoflurane preconditioned male brain and whether androgen effects are androgen receptor dependent were assessed. Male C57BL/6 mice were implanted with flutamide (androgen receptor antagonist), or castrated and implanted with testosterone, dihydrotestosterone, flutamide, letrozole (aromatase inhibitor), or vehicle 7�13 days before preconditioning. P450 estrogen aromatase wild-type and knockout mice were also evaluated. All mice were preconditioned for 4 h with 0% (sham preconditioning) or 1% isoflurane (isoflurane preconditioning) and recovered for 24 h. Mice then underwent 2 h of middle cerebral artery occlusion and were evaluated 22 h later for infarct volume. For neurobehavioral outcomes, sham and isoflurane preconditioned castrated male�dihydrotestosterone groups underwent 1 h of middle cerebral artery occlusion followed by 9 days of reperfusion. Isoflurane preconditioning neuroprotection relative to infarct volume outcomes were testosterone and dihydrotestosterone dose-specific and androgen receptor-dependent. Relative to long-term neurobehavioral outcomes, front paw sensorimotor function improved in isoflurane preconditioned mice regardless of androgen status while androgen replacement independently improved sensorimotor function. In contrast, isoflurane preconditioning improved cognitive function in castrates lacking endogenous androgens, but this improvement was absent in androgen replaced mice. Our findings suggest that androgen availability during isoflurane preconditioning may influence infarct volume and neurobehavioral outcomes in male mice following experimental stroke.
Preconditioned resistance to oxygen�glucose deprivation-induced cortical neuronal death: alterations in vesicular GABA and glutamate release
Central neurons exposed to several types of sublethal stress, including ischemia, acquire resistance to injury induced by subsequent ischemic insults, a phenomenon called ischemic preconditioning. We modeled this phenomenon in vitro, utilizing exposure to 45 mM KCl to reduce the vulnerability of cultured murine cortical neurons to subsequent oxygen�glucose deprivation. Twenty-four hours after preconditioning, cultures exhibited enhanced depolarization-induced, tetanus toxin-sensitive
M. C Grabb; D Lobner; D. M Turetsky; D. W Choi
Pharmacological preconditioning with diazoxide slows energy metabolism during sustained ischemia.
Ischemic preconditioning (PC) is associated with slower destruction of the adenine nucleotide pool ( summation operatorAd) and slower rate of anaerobic glycolysis during ischemic stress. These changes are concordant with the preconditioned state, supporting an essential role of lowered energy demand in the cardioprotective mechanism of PC. Although pharmacological PC induced by the activation of mitochondrial K(ATP) channels also limits infarct size, its effect on energy metabolism during sustained ischemia is unknown. Using metabolite levels found at baseline and after a 15 min test episode of regional ischemia, the effect of a cardioprotective dose of diazoxide on metabolic features associated with PC was tested in barbital-anesthetized, open-chest dogs. Diazoxide (3.5 mg/kg at an intravenous rate of 1 mL/min) infused before a test episode of ischemia had no effect on baseline metabolic indices. However, during ischemic stress, treated hearts exhibited less destruction of ATP, less degradation of the summation operatorAd into nucleosides and bases, as well as less lactate production than control hearts subjected only to ischemic stress. Thus, diazoxide mimics the metabolic alterations observed in PC tissue. This supports the hypothesis that a reduction in energy demand, which is now equated with an increased ATP to ADP ratio in the sarcoplasm, is a critical component of the mechanism of cardioprotection in preconditioned myocardium. It is hypothesized that during PC or diazoxide treatment, the passage of the summation operatorAd into and out of the mitochondria is slowed, limiting the level of ATP available to the mitochondrial ATPase and preserving ATP and the total summation operatorAd. Altered ischemic mitochondrial metabolism plays an important role in establishing and maintaining the preconditioned state. PMID:18650995
Schwartz, Lisa M; Reimer, Keith A; Crago, Mark S; Jennings, Robert B
Angiogenic signal triggered by ischemic stress induces myocardial repair in rat during chronic infarction.
In the present study, we examined a novel method of stimulating myocardial angiogenesis through ischemic preconditioning (IP) in the form of in vivo four repetitive cycles of coronary artery occlusion each followed by reperfusion. Rats divided into 4 groups: Control+Sham surgery (CS), Control+ Left anterior descending coronary artery (LAD) occlusion (CMI), IP+ Sham surgery (IPS) and IP+LAD occlusion (IPMI). For cardiac function, rats were subjected to stress testing with dobutamine after 2, 4, 7, 14 and 21 operative days. Capillary density (CD) and arteriolar density (AD) were evaluated by immunohistochemistry. Western blot was performed to examine the expression pattern for VEGF and anti-death candidates, Bcl-2 and survivin. Blood flow and the extent of endothelial and cardiomyocyte cell death were examined. The protein/DNA array was performed to determine the status of various transcription factor related to stress signal. Left ventricular functional reserve was better preserved in IPMI compared to the CMI group. The infarct size and apoptotic cell death were reduced in IPMI group significantly. Left ventricular regional blood flow, perfused capillary density and AD increased significantly in the IPMI group. VEGF, Bcl-2 and survivin expression were increased in IPMI compared to CMI. VEGF mediated vascular permeability was controlled in the IPMI due to suppression of c-Src in the infarcted myocardium. Our study documented first time the ability of IP to induce angiogenesis in the infarcted myocardium along with the activation of several transcription factors such as Stat3, Pax-5, NF kappa B, TFIID, SP1 and reduction of VEGF mediated vascular permeability by inhibition of c-Src in IPMI group thereby reducing ischemic injury in rat MI model. PMID:15081314
Fukuda, Shoji; Kaga, Shigeaki; Sasaki, Hiroaki; Zhan, Lijun; Zhu, Li; Otani, Hajime; Kalfin, Reni; Das, Dipak K; Maulik, Nilanjana
Preconditioning during warm blood cardioplegia
Objective: Preconditioning describes the cardioprotective effects of multiple brief episodes of warm ischemia. The purpose of the study was to determine whether warm ischemia, during the intermittent delivery of warm blood cardioplegia, would induce preconditioning during cardioplegia arrest. Methods: Dogs, 15, were randomized to a preconditioning protocol or to serve as controls. The control group received 60 min of continuous
Roderick Landymore; John You; Thomas Murphy; John Fris
Preconditioning during warm blood cardioplegia
Objective: Preconditioning describes the cardioprotective effects of multiple brief episodes of warm ischemia. The purpose of the study was to determine whether warm ischemia, during the intermittent delivery of warm blood cardioplegia, would induce preconditioning during cardioplegia arrest. Methods: Dogs, 15, were randomized to a preconditioning protocol or to serve as controls. The control group received 60 min of continuous
Roderick Landymore; John You; Thomas Murphy; John Fris
The Internet is growing exponentially, both in the amount of traffic carried, and in the amount of hosts connected. IP technology is becoming more and more important, in company networks (Intranets), and also in the core networks for the next generation mobile networks. Further, wireless access to IP networks is becoming mature (e.g., IEEE 802.11 networks, Irda, Bluetooth). At the
Geert Heijenk; S. Sallent; A. Pras
Metabolomic Analysis of Two Different Models of Delayed Preconditioning
Recently we described an ischemic preconditioning induced by repetitive coronary stenosis, which is induced by 6 episodes of non-lethal ischemia over 3 days, and which also resembles the hibernating myocardium phenotype. When compared with traditional second window of ischemic preconditioning using DNA microarrays, many genes which differed in the repetitive coronary stenosis appeared targeted to metabolism. Accordingly, the goal of this study was to provide a more in depth analysis of changes in metabolism in the different models of delayed preconditioning, i.e., second window and repetitive coronary stenosis. This was accomplished using a metabolomic approach based on liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques. Myocardial samples from the ischemic section of porcine hearts subjected to both models of late preconditioning were compared against sham controls. Interestingly, although both models involve delayed preconditioning, their metabolic signatures were radically different; of the total number of metabolites that changed in both models (135 metabolites) only 7 changed in both models, and significantly more, p<0.01, were altered in the repetitive coronary stenosis (40%) than in the second window (8.1%). The most significant changes observed were in energy metabolism, e.g., phosphocreatine was increased 4 fold and creatine kinase activity increased by 27.2%, a pattern opposite from heart failure, suggesting that the repetitive coronary stenosis and potentially hibernating myocardium have enhanced stress resistance capabilities. The improved energy metabolism could also be a key mechanism contributing to the cardioprotection observed in the repetitive coronary stenosis and in hibernating myocardium.
Bravo, Claudio; Kudej, Raymond K.; Yuan, Chujun; Yoon, Seonghun; Ge, Hui; Park, Ji Yeon; Tian, Bin; Stanley, William C.; Vatner, Stephen F.; Vatner, Dorothy E.; Yan, Lin
Pathway and gene ontology based analysis of gene expression in a rat model of cerebral ischemic tolerance
Ischemic tolerance is a phenomenon whereby a sublethal ischemic insult [ischemic preconditioning (IPC)] provides robust protection against subsequent lethal ischemia. Activation of N-methyl-d-aspartate (NMDA) receptors and subsequent new gene transcription are required for tolerance. We utilized the NMDA antagonist, MK801, prior to the IPC stimulus to separate candidate genes from epiphenomenona. Rats were divided into four groups: vehicle\\/IPC (preconditioned), MK801\\/IPC
Zheng Feng; Daniel P. Davis; Roman ��ik; Hemal H. Patel; John C. Drummond; Piyush M. Patel
Hyperbaric oxygen preconditioning protects against traumatic brain injury at high altitude
\\u000a \\u000a Background��Recent studies have shown that preconditioning with hyperbaric oxygen (HBO) can reduce ischemic and hemorrhagic brain injury.\\u000a We investigated effects of HBO preconditioning on traumatic brain injury (TBI) at high altitude and examined the role of matrix\\u000a metalloproteinase-9 (MMP-9) in such protection.\\u000a \\u000a \\u000a \\u000a Methods��Rats were randomly divided into 3 groups: HBO preconditioning group (HBOP; n=13), high-altitude group (HA; n=13), and high-altitude
S. L. Hu; R. Hu; F. Li; Z. Liu; Y. Z. Xia; G. Y. Cui; H. Feng
Role of Inducible Nitric Oxide Synthase in Pharmacological �Preconditioning� with Monophosphoryl Lipid A
Pretreatment with monophosphoryl lipid A (MLA) can pharmacologically mimic the second window of ischemic preconditioning (SWOP) to protect the heart from prolonged ischemia and reperfusion injury. Based on the delayed time course for development of MLA associated cardioprotection, this study was designed to test if MLA's cardioprotective effect is mediated by signalling through production of inducible nitric oxide synthase (iNOS),
Lin Zhao; Patricia A. Weber; Jerry R. Smith; Malissa L. Comerford; Gary T. Elliott
The ischemic dermatopathies are a group of vasculopathic diseases that share clinical and histologic features but result from variable causes. Generalized ischemic dermatopathies are typically characterized by atrophic lesions with erythema, scale/crust, erosions/ulcerations, and pigmentary changes. Lesions may affect the toes, tail tip, pinnal margins, bony prominences, or any combination of these areas. Familial dermatomyositis (FDM) most commonly occurs in juvenile collies and Shetland sheepdogs. Ischemic reactions to rabies vaccines may mimic FDM and can occur in any breed. The most reliable symptomatic therapy for any form of ischemic dermatopathy is the combination of pentoxifylline and vitamin E. PMID:23182327
Morris, Daniel O
Bihemispheric ischemic tolerance induced by a unilateral focal cortical lesion.
The purpose of the present study was to determine whether a unilateral photothrombotic brain lesion induces bilateral ischemic tolerance towards a subsequent severe ischemia performed 5 days later. Severe ischemia was induced by transient (1h; t) or permanent (p) occlusion of the middle cerebral artery (MCAO). Rats were sacrificed 24h later. Preconditioning reduced the size of subsequent infarcts in both hemispheres. This effect was most prominent with tMCAO, and ipsilateral preconditioning was more effective than contralateral preconditioning (% of hemispheric volume, mean�SD: 31.9�3.7 to 19.0�10.3 with ipsilateral tMCAO; 31.9�3.7 to 22.9�4.9 with contralateral tMCAO; 64.7�4.3% to 47.2�12.5% with ipsilateral pMCAO; 64.7�4.3% to 53.1�8.9% with contralateral pMCAO). Ischemic preconditioning was associated with a successive bilateral up-regulation of superoxide dismutases which may be involved in the development of ischemic tolerance. Our data suggest that a focal ischemic brain lesion induces neuroprotective mechanisms in extensive brain areas and thus cause bilateral ischemic tolerance within a certain time window. PMID:24835408
Schumacher, Lena; Urbach, Anja; Lutzenburg, Michael; Bidmon, Hans-J; Witte, Otto W
Preconditioning: a paradigm shift in the biology of myocardial ischemia
The discovery of preconditioning (PC) has arguably been the single most important development in the field of ischemic biology in the past 20 years. The significance of this phenomenon transcends cardiovascular medicine, since it is ubiquitously observed in virtually every tissue of the body. This article reviews the pathophysiology and molecular basis of myocardial PC, with particular emphasis on the late phase of this cardioprotective adaptation. The article also discusses the exploitation of late PC for the development of novel gene therapy strategies aimed at inducing a permanently preconditioned cardiac phenotype (prophylactic cardioprotection). Besides its conceptual interest, deciphering the mechanism of late PC has considerable therapeutic reverberations, since transfer of the genes that underlie late PC would be expected to emulate the salubrious effects of this response of the heart to stress.
Bolli, Roberto
Nitric Oxide Synthase (NOS) Does Not Contribute to Simulated Ischaemic Preconditioning in an Isolated Rat Cardiomyocyte Model
It is widely accepted that nitric oxide (NO) is a trigger and mediator of late ischaemic preconditioning (IP), however its\\u000a role in classic (protection observed within 2�4 hours after the IP stimulus) IP is less certain. In addition, the contribution\\u000a of cardiomyocyte nitric oxide synthase (NOS) activation to NO production in ischaemia is unknown. The aim of this study was
Hans Strijdom; Sonia Genade; Amanda Lochner
Mild Stress in the Aging Heart: Role of Ischemic Preconditioning
Hormetic effects have been documented in diverse combinations of stressors and recipient organism. Such sublethal stress pre-treatments\\u000a have been shown to increase stress resistance and life expectancy in several animal organisms. Stressors reported to increase\\u000a subsequent stress resistance include heat, cold, hypergravity, and pesticides. Increased life span has been reported after\\u000a a similarly diverse number of hormetic treatments including heat,
Pasquale Abete; Franco Rengo
Short-term hypoxic preconditioning improved survival following cardiac arrest and resuscitation in rats.
Cardiac arrest and resuscitation produces delayed mortality and hippocampal neuronal death in rats. Hypoxic preconditioning has been to shown to protect the brain from ischemic insults. We have previously reported that with chronic hypobaric hypoxia, the accumulation of hypoxic-inducible factor-1 alpha (HIF-1?) and its target genes was increased for the first several days of hypoxic exposure, and returned to baseline level by 3 weeks when angiogenesis is completed. In this study, we investigated the effect of short-term (3 days) and long-term (21 days) hypoxic preconditioning on recovery from cardiac arrest and resuscitation in rats. Our data showed that the overall survival rate was considerably improved in the short-term hypoxic preconditioning group compared to the non-preconditioned controls (86 %, 6/7 vs. 54 %, 7/13); however, the survival rate in the long-term hypoxic preconditioning group was decreased. Our data suggest that hypoxic preconditioning provides protection after cardiac arrest and resuscitation more likely through increased accumulation of HIF-1? and its target genes rather than through successful vascular adaptation as a result of hypoxia-induced angiogenesis. PMID:24729248
Xu, Kui; Lamanna, Joseph C
Cardioprotection by multiple preconditioning cycles does not require mitochondrial K(ATP) channels in pigs.
To test whether cardioprotection induced by ischemic preconditioning depends on the opening of mitochondrial ATP-sensitive K(+) (K(ATP)) channels, the effect of channel blockade was studied in barbital-anesthetized open-chest pigs subjected to 30 min of complete occlusion of the left anterior descending coronary artery and 3 h of reflow. Preconditioning was elicited by two cycles of 5-min occlusion plus 10-min reperfusion before the 30-min occlusion period. 5-Hydroxydecanoate (5 mg/kg iv) was injected 15 min before preconditioning or pharmacological preconditioning induced by diazoxide (3.5 mg/kg, 1 ml/min iv). Infarct size (percentage of the area at risk) after 30 min of ischemia was 35.1 +/- 9.9% (n = 7). Preconditioning markedly limited myocardial infarct size (2.7 +/- 1.6%, n = 7), and 5-hydroxydecanoate did not abolish protection (2.4 +/- 0.9%, n = 8). Diazoxide infusion also significantly limited infarct size (14.6 +/- 7.4%, n = 7), and 5-hydroxydecanoate blocked this effect (30.8 +/- 8.0%, n = 7). Thus the opening of mitochondrial K(ATP) channels is cardioprotective in pigs, but these data do not support the hypothesis that opening of mitochondrial K(ATP) channels is required for the endogenous protection afforded by preconditioning. PMID:12234807
Schwartz, Lisa M; Welch, Timothy S; Crago, Mark S
The late phase of preconditioning and its natural clinical application--gene therapy
There is little doubt that the discovery of ischemic preconditioning (PC) has been one of the fundamental milestones in the field of ischemic biology in the past 20 years. The purpose of this article is to review the pathophysiology and molecular basis of the late phase of myocardial PC. The exploitation of late PC for the development of novel gene therapy strategies aimed at inducing a permanently preconditioned cardiac phenotype (prophylactic cardioprotection) will also be discussed. Deciphering the mechanism of late PC has not only conceptual interest but also a considerable therapeutic implications, since transfer of the genes that underlie late PC would be expected to replicate the salubrious effects of this response of the heart to stress.
Li, Qian-Hong; Tang, Xian-Liang; Guo, Yiru; Xuan, Yu-Ting; Rokosh, Gregg; Dawn, Buddhadeb
Delayed Preconditioning-Mimetic Action of Nitroglycerin in Patients Undergoing Coronary Angioplasty
Background�Experimental studies suggest that the cardioprotective effects of the late phase of ischemic preconditioning (PC) can be mimicked pharmacologically. However, to date, no drug has been tested with respect to its ability to elicit a late PC effect in humans. As a consequence, clinical exploitation of the powerful anti-stunning and anti-infarct actions of late PC has been elusive thus far.
Massoud A. Leesar; Marcus F. Stoddard; Buddhadeb Dawn; Venu G. Jasti; Ronald Masden; Roberto Bolli
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.
Dunigan, T.H.; Hall, K.A.
Preconditioning rabbit cardiomyocytes: role of pH, vacuolar proton ATPase, and apoptosis.
Ischemic preconditioning signals through protein kinase C (PKC) to protect against myocardial infarction. This protection is characterized by diminished intracellular acidification. Acidification is also a feature of apoptosis, and several agents act to prevent apoptosis by preventing acidification through activation of ion channels and pumps to promote cytoplasmic alkalinization. We characterized metabolic inhibition, recovery, and preconditioning through a PKC-dependent pathway in cardiomyocytes isolated from adult rabbit hearts. Preconditioning reduced loss of viability assessed by morphology and reduced DNA nicking. Blockade of the vacuolar proton ATPase (VPATPase) prevented the effect of preconditioning to reduce metabolic inhibition-induced acidosis, loss of viability, and DNA nicking. The beneficial effect of Na+/H+ exchange inhibition, which is thought to be effective through reduced intracellular Na+ and Ca++, was also abrogated by VPATPase blockade, suggesting that acidification even in the absence of Na+/H+ exchange may lead to cell death. We conclude that a target of PKC in mediating preconditioning is activation of the VPATPase with resultant attenuation of intracellular acidification during metabolic inhibition. Inhibition of the "death protease," interleukin-1-beta converting enzyme or related enzymes, also protected against the injury that followed metabolic inhibition. This observation, coupled with the detection of DNA nicking in cells subjected to metabolic inhibition, suggests that apoptotic cell death may be preventable in this model of ischemia/reperfusion injury.
Gottlieb, R A; Gruol, D L; Zhu, J Y; Engler, R L
Preconditioning Operators on Unstructured Grids
NASA Technical Reports Server (NTRS)
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.
Nepomnyaschikh, S. V.
LPS-Induced Delayed Preconditioning Is Mediated by Hsp90 and Involves the Heat Shock Response in Mouse Kidney
Introduction We and others demonstrated previously that preconditioning with endotoxin (LPS) protected from a subsequent lethal LPS challenge or from renal ischemia-reperfusion injury (IRI). LPS is effective in evoking the heat shock response, an ancient and essential cellular defense mechanism, which plays a role in resistance to, and recovery from diseases. Here, by using the pharmacological Hsp90 inhibitor novobiocin (NB), we investigated the role of Hsp90 and the heat shock response in LPS-induced delayed renal preconditioning. Methods Male C57BL/6 mice were treated with preconditioning (P: 2 mg/kg, ip.) and subsequent lethal (L: 10 mg/kg, ip.) doses of LPS alone or in combination with NB (100 mg/kg, ip.). Controls received saline (C) or NB. Results Preconditioning LPS conferred protection from a subsequent lethal LPS treatment. Importantly, the protective effect of LPS preconditioning was completely abolished by a concomitant treatment with NB. LPS induced a marked heat shock protein increase as demonstrated by Western blots of Hsp70 and Hsp90. NB alone also stimulated Hsp70 and Hsp90 mRNA but not protein expression. However, Hsp70 and Hsp90 protein induction in LPS-treated mice was abolished by a concomitant NB treatment, demonstrating a NB-induced impairment of the heat shock response to LPS preconditioning. Conclusion LPS-induced heat shock protein induction and tolerance to a subsequent lethal LPS treatment was prevented by the Hsp90 inhibitor, novobiocin. Our findings demonstrate a critical role of Hsp90 in LPS signaling, and a potential involvement of the heat shock response in LPS-induced preconditioning.
Kaucsar, Tamas; Bodor, Csaba; Godo, Maria; Szalay, Csaba; Revesz, Csaba; Nemeth, Zalan; Mozes, Miklos; Szenasi, Gabor; Rosivall, Laszlo; Soti, Csaba; Hamar, Peter
IP traffic on the Internet and private enterprise networks has been growing exponentially for some time. This growth is beginning to stress the traditional, processor based design of current day routers. Switching technology offers much higher aggregate bandwidth but presently only offers a layer-2 bridging solution. Various proposals are under way to support IP routing over an ATM network. However,
Peter Newman; Greg Minshall; Thomas L. Lyon
Bradykinin preconditioning affects the number of degenerated neurons and the level of antioxidant enzymes in spinal cord ischemia in rabbits.
Bradykinin preconditioning has been used for acquisition of tolerance after spinal cord ischemia. Rabbits were preconditioned intraperitoneally with bradykinin 48 h prior to 20 min of abdominal aorta ligation followed by 24 and 48 h of reperfusion. The activities of SOD and catalase were measured and Fluoro Jade B (FJB)-positive degenerated neurons were evaluated. The outcomes of Tarlov scoring system used to assess neurological functions showed significant improvement in bradykinin groups compared to the ischemic group. The number of FJB-positive degenerated neurons was decreased in ventral horns of both bradykinin groups. Significantly decreased activities of total SOD and mitochondrial Mn-SOD were also detected in both bradykinin groups versus ischemic group while CuZn-SOD and catalase activities were significantly decreased only in the bradykinin group after 24h of reperfusion versus ischemic group. These findings suggest that one of the possibilities of the neuroprotective effect of delayed bradykinin preconditioning against spinal cord ischemic injury could be realized by mitochondrial protection and decreased synthesis of Mn-SOD as well as by promotion of neuronal survival. PMID:23981244
Mech�rov�, Eva; Danielisov�, Viera; Domor�kov�, Iveta; Dankov�, Marianna; Stebnick�, Milan; Mi?kov�, Helena; Burda, Jozef
Preconditioning to mild oxidative stress mediates astroglial neuroprotection in an IL-10-dependent manner.
Oxidative stress plays an important role in the pathogenesis of various brain insults, including stroke. Astroglia are the main glial cells that play a fundamental role in maintaining the homeostasis of the CNS. They are important for protection from injury and aid the brain in functional recovery after injuries. It has been shown that the brain can be prepared to withstand an oxidative stress insult by a process known as preconditioning. We used primary astroglial cell culture to investigate whether preconditioning to mild oxidative stress and glucose deprivation (OSGD) can increase both astroglia survival and neuroprotective features. We found that preconditioning astroglia to mild OSGD increases astroglial survival of a second insult through activation of the NF-E2-related factor-2 (Nrf-2) pathway. Moreover, we found that Nrf-2 is highly expressed in adult brain astroglia and that preconditioning to OSGD in vivo, such as in a murine model of ischemic stroke, leads to a significant increase in astroglial Nrf-2 expression. Furthermore, we discovered an increase in neuroprotection, as measured by increased neuronal cell survival, following OSGD in the presence of medium from astroglia exposed to a mild OSGD condition. Interestingly, we discovered a significant increase in astroglial secretion of the anti-inflammatory cytokine IL-10 vs. the pro-inflammatory cytokine IL-1? in mild vs. severe oxidative stress, respectively. We demonstrated that preconditioning astroglia to mild oxidative stress increases neuroprotection in an IL-10-dependent manner. By using tert-butylhydroquinone (tBHQ), a known specific activator of Nrf-2, we found that Nrf-2 can enhance IL-10 expression. Further studies of Nrf-2-mediated cellular pathways in astroglia through IL-10 may provide useful insights into the development of therapeutic interventions following oxidative stress insults such as ischemic stroke. PMID:23313057
Segev-Amzaleg, Niva; Trudler, Dorit; Frenkel, Dan
Effects of diabetes on myocardial infarct size and cardioprotection by preconditioning and postconditioning
In spite of the current optimal therapy, the mortality of patients with ischemic heart disease (IHD) remains high, particularly in cases with diabetes mellitus (DM) as a co-morbidity. Myocardial infarct size is a major determinant of prognosis in IHD patients, and development of a novel strategy to limit infarction is of great clinical importance. Ischemic preconditioning (PC), postconditioning (PostC) and their mimetic agents have been shown to reduce infarct size in experiments using healthy animals. However, a variety of pharmacological agents have failed to demonstrate infarct size limitation in clinical trials. One of the possible reasons for the discrepancy between the results of animal experiments and clinical trials is that co-morbidities, including DM, modified myocardial responses to ischemia/reperfusion and to cardioprotective agents. Here we summarize observations of the effects of DM on myocardial infarct size and ischemic PC and PostC and discuss perspectives for protection of DM hearts.
Preconditioning Techniques in Computational Fluid Dynamics
An overview of preconditioning for the steady-state compressible inviscid fluid dynamic equations is presented. Extensions to the Navier-Stokes equations are also considered. These preconditioners are necessary for many algorithms in order to have the correct behavior at low speeds and to converge to the solution of the incompressible equations as the Mach number goes to zero. In addition, the preconditioning
E. Turkel
Mutually Protective Actions of Kainic Acid Epileptic Preconditioning and Sublethal Global Ischemia on Hippocampal Neuronal Death: Involvement of Adenosine A1 Receptors and KATP Channels
Preconditioning with sublethal ischemia attenuates the detrimental effects of subsequent prolonged ischemic insults. This research elucidates potential in vivo cross-tolerance between different neuronal death-generating treatments such as kainate administration, which induces seizures and global ischemia. This study also investigates the effects of a mild epileptic insult on neuronal death in rat hippocampus after a subsequent, lethal epileptic stress using kainic
Nicolas Blondeau; Catherine Heurteaux; Michel Lazdunski
Methods for studying redox cycling of thioredoxin in mediating preconditioning-induced survival genes and proteins.
Recent advances in molecular biology provide methods and tools for studying cell signaling pathways underlying hormetic mechanisms produced by radiation hormesis, ischemic, remote ischemic, and chemical preconditioning as well as withholding of nutrients and/or trophic factors. Most of the proposed key signaling pathways of hormetic mechanisms remain to be elucidated. For the investigation of possible role of thiol redox signaling systems in hormesis, a serum deprivation preconditioned human cell model, free radical assays, and molecular biological methods are employed for studying whether free radicals, the NO-cGMP-PKG cell signaling pathway, and the redox protein thioredoxin (Trx) play any roles in the hormetic mechanism against cytotoxicity caused by serum deprivation and also neurotoxin 1-methyl-4-phenyltetrahydropyridinium ion (MPP(+)). This NO-dependent cell signaling pathway of the redox protein Trx may play a key role in the cellular protective mechanism of several potential neuroprotective agents such as S-nitrosoglutathione (GSNO), 17beta-estradiol, selegiline as well as ebeselen, sildenafil, and rasagiline. Consistently, exogenously administrated Trx (<1 microM) provides a concentration-dependent protection for human neuroblasts against MPP(+)-induced oxidative injury. This newly discovered role of the redox protein of Trx in preconditioning-induced cell signaling and protection could lead to the development of new lead compounds for upregulation of Trx and related thiol redox proteins for cell survival, repair, proliferation, and neuronal plasticity. PMID:20609912
Chiueh, Chuang C
Remote renal preconditioning-induced cardioprotection: a key role of hypoxia inducible factor-prolyl 4-hydroxylases.
Remote preconditioning is a unique phenomenon in which brief episodes of ischemia and reperfusion to remote organ protect the target organ against sustained ischemia-reperfusion (I/R)-induced injury. Protective effects of remote renal preconditioning (RRPC) are well established in heart, but their mechanisms still remain to be elucidated. So, the present study was designed to investigate the possible role of oxygen-sensing hypoxia inducible factor-prolyl 4-hydroxylases (HIF-P4Hs) in RRPC-induced cardioprotection in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion and reperfusion. 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. Extent of myocardial infarct size and coronary flow rate was also measured. Ethyl 3,4-dihydroxybenzoate (EDHB) and alpha-ketoglutarate (alpha-KG) were employed as HIF-P4Hs inhibitor and activator, respectively. Diethyldithiocarbamic acid (DDCA) was employed as NFkB inhibitor. Remote renal preconditioning prevented I/R-induced myocardial injury and produced cardioprotective effects. Pharmacological preconditioning with EDHB (100 mg kg(-1) i.p.) mimicked the cardioprotective effects of RRPC. However, alpha-KG (200 mg kg(-1) i.p.) and DDCA (150 mg kg(-1) i.p.) abolished cardioprotective effects of RRPC and EDHB. So, it may be concluded that inhibition of HIF-P4H has a key role in RRPC-induced cardioprotection. Further, remote preconditioning-induced HIF-P4H inhibition may have triggered a transduction pathway involving activation of NFkB. PMID:18273560
Kant, Ravi; Diwan, Vishal; Jaggi, Amteshwar Singh; Singh, Nirmal; Singh, Dhandeep
ATP-sensitive potassium channels (K ATP) in retina: a key role for delayed ischemic tolerance
The objectives of the present study were to determine the localization of KATP channels in normal retina and to evaluate their potential roles in ischemic preconditioning (IPC) in a rat model of ischemia induced by increased intraocular pressure (IOP). Brown Norway rats were subjected to sublethal 3-, lethal 20- and 40-min ischemia and the functional recovery was evaluated using electroretinography.
Mohamed Ettaiche; Catherine Heurteaux; Nicolas Blondeau; Marc Borsotto; Norbert Tinel; Michel Lazdunski
Omapatrilat Limits Infarct Size and Lowers the Threshold for Induction of Myocardial Preconditioning Through a Bradykinin Receptor-Mediated Mechanism
Bradykinin is an important endogenous trigger of myocardial ischemic preconditioning (IPC). Through simultaneous inhibition\\u000a of neutral endopeptidase and angiotensin converting enzyme, omapatrilat prevents enzymatic degradation of bradykinin. The\\u000a aim of this study was to investigate if omapatrilat, through its ability to augment bradykinin levels, can augment a subthreshold\\u000a IPC stimulus (Sub-IPC) and to compare the action of omapatrilat with the
Z. Ebrahim; G. F. Baxter; D. M. Yellon
Toll-like receptors in cerebral ischemic inflammatory injury
Cerebral ischemia triggers acute inflammation, which has been associated with an increase in brain damage. The mechanisms that regulate the inflammatory response after cerebral ischemia are multifaceted. An important component of this response is the activation of the innate immune system. However, details of the role of the innate immune system within the complex array of mechanisms in cerebral ischemia remain unclear. There have been recent great strides in our understanding of the innate immune system, particularly in regard to the signaling mechanisms of Toll-like receptors (TLRs), whose primary role is the initial activation of immune cell responses. So far, few studies have examined the role of TLRs in cerebral ischemia. However, work with experimental models of ischemia suggests that TLRs are involved in the enhancement of cell damage following ischemia, and their absence is associated with lower infarct volumes. It may be possible that therapeutic targets could be designed to modulate activities of the innate immune system that would attenuate cerebral brain damage. Ischemic tolerance is a protective mechanism induced by a variety of preconditioning stimuli. Interpreting the molecular mechanism of ischemic tolerance will open investigative avenues into the treatment of cerebral ischemia. In this review, we discuss the critical role of TLRs in mediating cerebral ischemic injury. We also summarize evidence demonstrating that cerebral preconditioning downregulates pro-inflammatory TLR signaling, thus reducing the inflammation that exacerbates ischemic brain injury.
Investigating the role of the actin regulating complex ARP2/3 in rapid ischemic tolerance induced neuro-protection
Neuronal morphology is highly sensitive to ischemia, although some re-organization may promote neuroprotection. In this study we investigate the role of actin regulating proteins (ARP2, ARP3 and WAVE-1) and their role in rapid ischemic tolerance. Using an established in vitro model of rapid ischemic tolerance, we show that WAVE-1 protein levels are stabilized following brief tolerance inducing ischemia (preconditioning). The stabilization appears to be due to a reduction in the ubiquitination of WAVE-1. Levels of ARP2, ARP3 and N-WASP were not affected by ischemic preconditioning. Immunocytochemical studies show a relocalization of ARP2 and ARP3 proteins in neurons following preconditioning ischemia, as well as a re-organization of actin. Blocking the protein kinase CK2 using emodin blocks ischemic tolerance, and our data suggests CK2 binds to WAVE-1 in neurons. We observe an increase in binding of the ARP2 subunit with WAVE-1. The neuroprotection observed following preconditioning is inhibited when cells are transduced with an N-WASP CA domain that blocks the activation of ARP2/3. Together these data show that ischemia affects actin regulating enzymes, and that the ARP2/3 pathway plays a role in rapid ischemic tolerance induced neuroprotection.
Jessick, Veronica J; Xie, Mian; Pearson, Andrea N; Torrey, Dan J; Ashley, Michelle D; Thompson, Simon; Meller, Robert
(S)-ZJM-289 Preconditioning Induces a Late Phase Protection Against Nervous Injury Induced by Transient Cerebral Ischemia and Oxygen-Glucose Deprivation.
(S)-ZJM-289, a novel nitric oxide (NO)-releasing derivative of 3-n-butylphthalide, induces the neuroprotection in a rat model of focal cerebral ischemia/reperfusion (I/R). However, much is unknown about the late phase effect in the neuroprotection of (S)-ZJM-289 preconditioning. The purpose of this study is to explore the late phase neuroprotection of (S)-ZJM-289 preconditioning, as well as underlying mechanisms involved. Preconditioning with 40-160�mg/kg, (S)-ZJM-289 significantly reduces brain damage after I/R. (S)-ZJM-289 preconditioning is effective when applied 1-3�days before I/R. Moreover, the degrees of neuroprotection offered by (S)-ZJM-289 preconditioning and ischemic preconditioning are virtually identical. (S)-ZJM-289 preconditioning also protects primary cultured cortical neurons against oxygen-glucose deprivation and recovery-induced cytotoxicity in vitro. (S)-ZJM-289 preconditioning significantly increases the generation of NO, but has no effect on the nitric oxide synthase activities. Additionally, (S)-ZJM-289 preconditioning promotes the dissociation between nuclear-factor-E2-related factor (Nrf2) and kelch-like ECH-associated protein 1, and induces Nrf2 nuclear localization. The neuroprotection of (S)-ZJM-289 preconditioning is blocked by Nrf2-siRNA in vitro. (S)-ZJM-289 preconditioning up-regulates antioxidant enzymes against nervous injury. (S)-ZJM-289 preconditioning significantly activates extracellular regulated protein kinases (ERK) and inhibits c-Jun N-terminal kinases signaling cascade. The neuroprotection is abolished by the ERK inhibitor PD98059 in vitro. Subsequently, (S)-ZJM-289 preconditioning increases the levels of anti-apoptotic protein B cell lymphoma 2 (Bcl-2) and inhibited the translocation of Bcl-2 associated X to the mitochondria, thus attenuating the release of cytochrome c from the mitochondria and the activation of downstream caspase. These results suggest that (S)-ZJM-289 preconditioning exerts the late phase protection against nervous injury induced by transient cerebral ischemia and oxygen-glucose deprivation. PMID:24277159
Zhang, Chao; Zhang, Zhenzhen; Zhao, Qian; Wang, Xuliang; Ji, Hui; Zhang, Yihua
Preconditioned characteristic boundary conditions for solution of the preconditioned Euler equations at low Mach number flows
NASA Astrophysics Data System (ADS)
Preconditioned characteristic boundary conditions (BCs) are implemented at artificial boundaries for the solution of the two- and three-dimensional preconditioned Euler equations at low Mach number flows. The preconditioned compatibility equations and the corresponding characteristic variables (or the Riemann invariants) based on the characteristic forms of preconditioned Euler equations are mathematically derived for three preconditioners proposed by Eriksson, Choi and Merkle, and Turkel. A cell-centered finite volume Roe's method is used for the discretization of the preconditioned system of equations on unstructured meshes. The accuracy and performance of the preconditioned characteristic BCs applied at artificial boundaries are evaluated in comparison with the non-preconditioned characteristic BCs and the simplified BCs in computing steady low Mach number flows. The two-dimensional flow over the NACA0012 airfoil and three-dimensional flow over the hemispherical headform are computed and the results are obtained for different conditions and compared with the available numerical and experimental data. The sensitivity of the solution to the size of computational domain and the variation of the angle of attack for each type of BCs is also examined. Indications are that the preconditioned characteristic BCs implemented in the preconditioned system of Euler equations greatly enhance the convergence rate of the solution of low Mach number flows compared to the other two types of BCs.
Hejranfar, Kazem; Kamali-Moghadam, Ramin
The Protective Effects of Ischemic Postconditioning against Stroke: From Rapid to Delayed and Remote Postconditioning
The author reviews the protective effects of ischemic postconditioning, a recently emerging strategy with broad implications in the search for new treatments in stroke and myocardial ischemic injury. Ischemic postconditioning, which refers to a series of brief ischemia and reperfusion cycles applied immediately at the site of the ischemic organ after reperfusion, results in reduced infarction in both cerebral and myocardial ischemia. Conventional postconditioning induced within a few minutes after reperfusion is arbitrarily defined as rapid postconditioning. In contrast, postconditioning performed hours to days after stroke is defined as delayed postconditioning. In addition, postconditioning can be mimicked using anesthetics or other pharmacological agents as stimuli to protect against ischemia/reperfusion injury or performed in a distant organ, which is known as remote postconditioning. In this article, the author discusses the conceptual origin of classical rapid ischemic postconditioning and its evolution into a term that represents a broad range of stimuli or triggers, including delayed postconditioning, pharmacological postconditioning, and remote postconditioning. Thereafter, various in vivo and in vitro models of postconditioning and its potential protective mechanisms are discussed. Since the concept of postconditioning is so closely associated with that of preconditioning and both share some common protective mechanisms, whether a combination of preconditioning and postconditioning offers greater protection than preconditioning or postconditioning alone is also discussed.
Zhao, Heng
Fetal brain genomic reprogramming following asphyctic preconditioning
Background Fetal asphyctic (FA) preconditioning is effective in attenuating brain damage incurred by a subsequent perinatal asphyctic insult. Unraveling mechanisms of this endogenous neuroprotection, activated by FA preconditioning, is an important step towards new clinical strategies for asphyctic neonates. Genomic reprogramming is thought to be, at least in part, responsible for the protective effect of preconditioning. Therefore we investigated whole genome differential gene expression in the preconditioned rat brain. FA preconditioning was induced on embryonic day 17 by reversibly clamping uterine circulation. Male control and FA offspring were sacrificed 96�h after FA preconditioning. Whole genome transcription was investigated with Affymetrix Gene1.0ST chip. Results Data were analyzed with the Bioconductor Limma package, which showed 53 down-regulated and 35 up-regulated transcripts in the FA-group. We validated these findings with RT-qPCR for adh1, edn1, leptin, rdh2, and smad6. Moreover, we investigated differences in gene expression across different brain regions. In addition, we performed Gene Set Enrichment Analysis (GSEA) which revealed 19 significantly down-regulated gene sets, mainly involved in neurotransmission and ion transport. 10 Gene sets were significantly up-regulated, these are mainly involved in nucleosomal structure and transcription, including genes such as mecp2. Conclusions Here we identify for the first time differential gene expression after asphyctic preconditioning in fetal brain tissue, with the majority of differentially expressed transcripts being down-regulated. The observed down-regulation of cellular processes such as neurotransmission and ion transport could represent a restriction in energy turnover which could prevent energy failure and subsequent neuronal damage in an asphyctic event. Up-regulated transcripts seem to exert their function mainly within the cell nucleus, and subsequent Gene Set Enrichment Analysis suggests that epigenetic mechanisms play an important role in preconditioning induced neuroprotection.
Laser thermal preconditioning enhances dermal wound repair
NASA Astrophysics Data System (ADS)
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 (? = 1.86 ?m, ? 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 ?m diode laser enhances early wound repair.
Wilmink, Gerald J.; Carter, Terry; Davidson, Jeffrey M.; Jansen, E. Duco
Hypoxic preconditioning reinforces cellular functions of autologous peripheral blood-derived cells in rabbit hindlimb ischemia model.
Peripheral blood mononuclear cell (PBMNC) is one of powerful tools for therapeutic angiogenesis in hindlimb ischemia. However, traditional approaches with transplanted PBMNCs show poor therapeutic effects in severe ischemia patients. In this study, we used autograft models to determine whether hypoxic pretreatment effectively enhances the cellular functions of PBMNCs and improves hindlimb ischemia. Rabbit PBMNCs were cultured in the hypoxic condition. After pretreatment, cell adhesion, stress resistance, and expression of angiogenic factor were evaluated in vitro. To examine in vivo effects, we autografted preconditioned PBMNCs into a rabbit hindlimb ischemia model on postoperative day (POD) 7. Preconditioned PBMNCs displayed significantly enhanced functional capacities in resistance to oxidative stress, cell viability, and production of vascular endothelial growth factor. In addition, autologous transplantation of preconditioned PBMNCs significantly induced new vessels and improved limb blood flow. Importantly, preconditioned PBMNCs can accelerate vessel formation despite transplantation on POD 7, whereas untreated PBMNCs showed poor vascularization. Our study demonstrated that hypoxic preconditioning of PBMNCs is a feasible approach for increasing the retention of transplanted cells and enhancing therapeutic angiogenesis in ischemic tissue. PMID:24463101
Kudo, Tomoaki; Hosoyama, Tohru; Samura, Makoto; Katsura, Shunsaku; Nishimoto, Arata; Kugimiya, Naruji; Fujii, Yasuhiko; Li, Tao-Sheng; Hamano, Kimikazu
Myocardial ischemic conditioning: Physiological aspects and clinical applications in cardiac surgery
Ischemia�reperfusion is a major determinant of myocardial impairment in patients undergoing cardiac surgery. The main goal of research in cardioprotection is to develop effective techniques to avoid ischemia�reperfusion lesions. Myocardial ischemic conditioning is a powerful endogenous cardioprotective phenomenon. First described in animals in 1986, myocardial ischemic conditioning consists of applying increased tolerance of the myocardium to sustained ischemia by exposing it to brief episodes of ischemia�reperfusion. Several studies have sought to demonstrate its effective cardioprotective action in humans and to understand its underlying mechanisms. Myocardial ischemic conditioning has two forms: ischemic preconditioning (IPC) when the conditioning stimulus is applied before the index ischemia and ischemic postconditioning when the conditioning stimulus is applied after it. The cardioprotective action of ischemic conditioning was reproduced by applying the ischemia�reperfusion stimulus to organs remote from the heart. This non-invasive manner of applying ischemic conditioning has led to its application in clinical settings. Clinical trials for the different forms of ischemic conditioning were mainly developed in cardiac surgery. Many studies suggest that this phenomenon can represent an interesting adjuvant to classical cardioprotection during on-pump cardiac surgery. Ischemic conditioning was also tested in interventional cardiology with interesting results. Finally, advances made in the understanding of mechanisms that underlie the cardioprotective action of ischemic conditioning have paved the way to a new form of myocardial conditioning which is pharmacological conditioning.
Bousselmi, Radhouane; Lebbi, Mohamed Anis; Ferjani, Mustapha
Remote ischemic postconditioning promotes the survival of retinal ganglion cells after optic nerve injury.
Ischemic conditioning, the application of a mild ischemic stimulus to an ischemia-sensitive structure like the heart or brain either before (preconditioning) or after (postconditioning) its exposure to a lethal ischemic insult, is known to switch on endogenous protective mechanisms. However, most studies of its neuroprotective effect in the central nervous system (CNS) have focused on ischemic damage or related conditions like hypoxia, while its potential in treating other neural diseases remains uncertain. In particular, the recent discovery of remote ischemic postconditioning whereby mild ischemia applied to a region remote from the target after the main ischemic insult also confers protection offers an attractive paradigm to study its potential in other types of neural injury. Retinal ganglion cells damaged by optic nerve transection undergo extensive cell death. However, application of a series of mild ischemic/reperfusion cycles to the hind limb (limb remote ischemic postconditioning) at 10 min or 6 h after optic nerve cut was found to promote ganglion cell survival at 7 days post-injury, with the 10 min postconditioning still exerting protection at 14 days post-injury. Concomitant with the increased ganglion cell survival, 51 % more ganglion cells expressed the small heat shock protein HSP27, when remote ischemic postconditioning was performed at 10 min post-injury, as compared to the sham conditioning group. Our results highlight the potential of using remote ischemic postconditioning as a noninvasive neuroprotective strategy in different CNS disorders like spinal cord and traumatic brain injury. PMID:23733254
Liu, Xia; Sha, Ou; Cho, Eric Y P
Osteopontin protects against cardiac ischemia-reperfusion injury through late preconditioning.
Osteopontin (OPN) has been considered as a proinflammatory cytokine. A protective role for OPN in ischemic injury was demonstrated recently. Because proinflammatory cytokines play an important role in induction of late preconditioning, we deduce that OPN may induce late preconditioning in myocardium. Fifty consecutive patients scheduled for mitral valve replacement (MVR) were investigated. Osteopontin and high-sensitivity C-reactive protein levels in plasma before surgery were determined. Nuclear factor kappa B and signal transducer and activator of transcription 3 (STAT3), two main transcription factors involved in late preconditioning, were investigated by electrophoretic mobility shift assay. The effector proteins in late preconditioning, including inducible nitric oxide synthase and cyclooxygenase-2, were evaluated by immunoblotting. Cardioprotective effects were assessed by creatine kinase MB (CK-MB) and cardiac troponin T (cTnT) leakage postoperatively. The protective effects of OPN on neonatal cardiomyocytes against anoxia-reoxygenation-induced injury were also tested. The protein synthesis inhibitor cycloheximide (CH) was used in this model to test if new protein synthesis was necessary for its cardioprotective effects. There was no perioperative death in the groups. We found that patients with higher plasma OPN levels (167 +/- 35 ng/ml vs 63 +/- 13 ng/ml) had more activated extent of transcription factors, higher expression of effector proteins, and better cardioprotective effects, assessed by CK-MB and cTnT. An in vitro experiment also revealed that OPN had a cardioprotective effect 24 h after pretreatment. However, the protective effect was blocked by the protein synthesis inhibitor CH. Osteopontin can protect against cardiac ischemia-reperfusion injury through late preconditioning. PMID:19337795
Wang, Yongyi; Chen, Baofu; Shen, Dafu; Xue, Song
Mild activation of poly(ADP-ribose) polymerase (PARP) is neuroprotective in rat hippocampal slice models of ischemic tolerance.
Ischemic tolerance is a phenomenon in which exposure to a mild preconditioning stress results in resistance to a subsequent lethal ischemic insult. Here we investigated the role of poly(ADP-ribose) polymerase (PARP) in the development of ischemic tolerance by using organotypic rat hippocampal slices exposed to 30 min oxygen-glucose deprivation (OGD), which leads to selective injury of the CA1 subregion 24 h later. We developed models of pharmacological preconditioning by exposing slices to subtoxic concentrations of either N-methyl-D-aspartate (NMDA) or (S)-3,5-dihydroxyphenylglycine (DHPG) and then, 24 h later, to 30 min OGD. Under these conditions, we observed a significant reduction in OGD-induced CA1 damage. Exposure of slices to the PARP-1 and -2 inhibitors TIQ-A, PJ-34 and UPF 1069 during preconditioning prevented the development of OGD tolerance in a concentration-dependent manner. NMDA and DHPG preconditioning increased the activity of PARP, as detected by immunoblots using antibodies against the poly(ADP-ribose) polymer product, but was not associated with consumption of cellular NAD(+) or ATP. Neuroprotection induced by preconditioning was also prevented by the caspase inhibitor Z-VAD-FMK. The modest but significant increase in caspase-3/7 induced by preconditioning, however, was not associated with PARP-1 cleavage, as occurred with staurosporine. Finally, TIQ-A prevented the activation of ERK1/2 and Akt induced by NMDA preconditioning, suggesting that the protective mechanism evoked by PARP requires activation of these prosurvival mediators. Our results suggest that preconditioning with appropriate pharmacological stimuli may promote neuroprotective mechanisms triggered by the sublethal activation of two otherwise deleterious executioners such as PARP and caspase-3/7. PMID:22639866
Gerace, Elisabetta; Scartabelli, Tania; Formentini, Laura; Landucci, Elisa; Moroni, Flavio; Chiarugi, Alberto; Pellegrini-Giampietro, Domenico E
Lipopolysaccharide preconditioning attenuates apoptotic processes and improves neuropathologic changes after spinal cord injury in rats.
We have shown earlier that administration of low-dose lipopolysaccharide (LPS) significantly contributed to recovery of motor function after traumatic spinal cord injury in the adult female rat. Using the same standardized animal model, we have now designed a set of experiments to test the hypothesis that LPS preconditioning attenuates stress-related apoptotic processes early after spinal cord trauma. The lower thoracic spinal cord injury in adult female Sprague-Dawley rats was caused by a 10�g weight rod drop from 25�mm on the dural surface of the exposed spinal cord at T10. The rats were randomly assigned to three groups: Sham injury, control (received normal saline alone), and LPS preconditioning (0.2�mg/kg, ip; 72�h prior to the injury). The animals were euthanized at 72�h postinjury. Neuropathologic changes were assessed using hematoxylin and eosin staining. SCI-induced apoptosis were observed by transmission electron microscopy. Caspase-3, cleaved caspase-3, Bax, and Bcl-2 were examined with immunohistochemistry or Western blotting. Compared with the control group, LPS preconditioning group showed significant improvement in the SCI-induced morphology changes. Furthermore, LPS preconditioning reduced the expressions of apoptotic markers caspase-3, cleaved caspase-3, and Bax, upregulated the expression of antiapoptotic marker Bcl-2 in the samples of spinal cord. Low-dose LPS attenuated the recruitment of inflammatory cells and the proliferation of glial cells in the site of injury. LPS preconditioning has neuroprotective effects against TSCI in rats due to its antiapoptosis properties as shown by the inhibition of caspase pathway and the upregulation of antiapoptotic protein. PMID:24205811
Li, Wei-Chao; Jiang, Rong; Jiang, Dian-Ming; Zhu, Feng-Chen; Su, Bao; Qiao, Bo; Qi, Xiao-Tong
IP switching and gigabit routers
To cope with the growth in the Internet and corporate IP networks, we require IP routers capable of much higher performance than is possible with existing architectures. This article examines two approaches to the design of a high-performance router, the gigabit router and the IP switch, and then provides some detail on the implementation of an IP switch and the
P. Newman; G. Minshall; T. Lyon; L. Huston
Erythropoietin Is a Paracrine Mediator of Ischemic Tolerance in the Brain: Evidence from an In Vitro Model
In an in vitro model of cerebral ischemia (oxygen glucose deprivation, OGD) we investigated whether erythropoietin (EPO) plays a critical role in ischemic preconditioning. We found that EPO time and dose-dependently induced protection against OGD in rat primary cortical neurons. Protection was significant at 5 min and reached a maximum at 48 hr after EPO application. Protection was blocked by
Karsten Ruscher; Dorette Freyer; Maria Karsch; Nikolai Isaev; Dirk Megow; Birgit Sawitzki; Josef Priller; Ulrich Dirnagl; Andreas Meisel
Histone Acetylation and CREB Binding Protein Are Required for Neuronal Resistance against Ischemic Injury.
Epigenetic transcriptional regulation by histone acetylation depends on the balance between histone acetyltransferase (HAT) and deacetylase activities (HDAC). Inhibition of HDAC activity provides neuroprotection, indicating that the outcome of cerebral ischemia depends crucially on the acetylation status of histones. In the present study, we characterized the changes in histone acetylation levels in ischemia models of focal cerebral ischemia and identified cAMP-response element binding protein (CREB)-binding protein (CBP) as a crucial factor in the susceptibility of neurons to ischemic stress. Both neuron-specific RNA interference and neurons derived from CBP heterozygous knockout mice showed increased damage after oxygen-glucose deprivation (OGD) in vitro. Furthermore, we demonstrated that ischemic preconditioning by a short (5 min) subthreshold occlusion of the middle cerebral artery (MCA), followed 24 h afterwards by a 30 min occlusion of the MCA, increased histone acetylation levels in vivo. Ischemic preconditioning enhanced CBP recruitment and histone acetylation at the promoter of the neuroprotective gene gelsolin leading to increased gelsolin expression in neurons. Inhibition of CBP's HAT activity attenuated neuronal ischemic preconditioning. Taken together, our findings suggest that the levels of CBP and histone acetylation determine stroke outcome and are crucially associated with the induction of an ischemia-resistant state in neurons. PMID:24748101
Yildirim, Ferah; Ji, Shengbo; Kronenberg, Golo; Barco, Angel; Olivares, Roman; Benito, Eva; Dirnagl, Ulrich; Gertz, Karen; Endres, Matthias; Harms, Christoph; Meisel, Andreas
Dynamic clustering of IP3 receptors by IP3.
The versatility of Ca2+ as an intracellular messenger stems largely from the impressive, but complex, spatiotemporal organization of the Ca2+ signals. For example, the latter when initiated by IP3 (inositol 1,4,5-trisphosphate) in many cells manifest hierarchical recruitment of elementary Ca2+ release events ('blips' and then 'puffs') en route to global regenerative Ca2+ waves as the cellular IP3 concentration rises. The spacing of IP3Rs (IP3 receptors) and their regulation by Ca2+ are key determinants of these spatially organized Ca2+ signals, but neither is adequately understood. IP3Rs have been proposed to be pre-assembled into clusters, but their composition, geometry and whether clustering affects IP3R behaviour are unknown. Using patch-clamp recording from the outer nuclear envelope of DT40 cells expressing rat IP3R1 or IP3R3, we have recently shown that low concentrations of IP3 cause IP3Rs to aggregate rapidly and reversibly into small clusters of approximately four IP3Rs. At resting cytosolic Ca2+ concentrations, clustered IP3Rs open independently, but with lower open probability, shorter open duration and lesser IP3-sensitivity than lone IP3Rs. This inhibitory influence of clustering on IP3R is reversed when the [Ca2+]i (cytosolic free Ca2+ concentration) increases. The gating of clustered IP3Rs exposed to increased [Ca2+]i is coupled: they are more likely to open and close together, and their simultaneous openings are prolonged. Dynamic clustering of IP3Rs by IP3 thus exposes them to local Ca2+ rises and increases their propensity for a CICR (Ca2+-induced Ca2+ rise), thereby facilitating hierarchical recruitment of the elementary events that underlie all IP3-evoked Ca2+ signals. PMID:22435806
Rahman, Taufiq
Preconditioning with levosimendan before implantation of left ventricular assist devices.
In this retrospective study, we investigated the impact of preconditioning of the right ventricle with the calcium sensitizer levosimendan immediately before left ventricular assist device (LVAD) implantation on outcome and survival. Nine consecutive LVAD patients (seven suffering from dilative cardiomyopathy and two from ischemic cardiomyopathy) with echocardiographic and invasive evidence of right heart insufficiency received levosimendan with 0.1 ?g/kg body weight/min for 24 h before implantation of the assist device (seven HeartWare and two Jarvik 2000). Administration of levosimendan was safe and had not to be discontinued in any patient. We observed no relevant side effects. Twelve-month survival after implantation of the LVAD was 89% representing a superior outcome compared with the fifth INTERMACS registry data with 75% survival. Two temporary extracorporeal membrane-oxygenation implantations were necessary due to intraoperative right ventricular dysfunction. Only one patient died 5 weeks after LVAD implantation of multiorgan failure, five patients were successfully transplanted, and three patients underwent LVAD implantation for destination therapy. Levosimendan might improve clinical outcome and survival when used as pretreatment in patients with right heart insufficiency prior to LVAD implantation. However, we recommend a larger controlled trial in the future to confirm our preliminary results. PMID:24147881
Theiss, Hans D; Grabmaier, Ulrich; Kreissl, Nicole; Hagl, Christian; Steinbeck, Gerhard; Sodian, Ralf; Franz, Wolfgang-M; Kaczmarek, Ingo
Hypoxic preconditioning increases skin oxygenation and viability but does not alter VEGF expression or vascular density.
Intermittent hypoxia is known to elicit adaptive changes that increase tissue oxygen delivery. We investigated the effects of intermittent hypoxic exposure (IHE) in normal skin (course study) and evaluated whether preoperative IHE-preconditioning alleviates acute ischemic injury in skin flaps (flap study). For 4 weeks, 55 rats were exposed to a daily IHE-session (6 hypoxic cycles, 9% O(2), 6 to 10 min) separated by 3 min of reoxygenation (20.9% O(2)). The time course of intracutaneous PO(2) was measured at weekly intervals. VEGF/VEGF-receptor-mRNA and vascular density were measured in normal skin before and after 1, 2, 3, and 4 weeks of the IHE course (20 rats). In 35 rats, skin flaps were elevated after IHE and similar studies were undertaken in samples from 3 flap areas at postoperative days 0.5, 2, and 4. Additionally, flap survival and cutaneous blood flow were quantitated. In normal skin, PO(2) was initially significantly decreased during the hypoxic cycles (PO(2) 4.1 +/- 1.5 mmHg). After 4 weeks of IHE, PO(2) (34.5 +/- 5.8 mmHg) was maintained even under hypoxic conditions. In flaps, IHE led to a 2.6-fold increase in PO(2), increased flap survival (+ 19.4%, day 7), and blood flow (+ 19.1%, day 10) (p < 0.01). In neither study did IHE-preconditioning increase VEGF/VEGF-receptor-mRNA expression or vascular density. We conclude that (1) IHE induces pronounced hypoxia in the skin, but progressive adaptation occurs within 4 weeks, (2) preoperative IHE-preconditioning leads to significantly higher PO(2), blood flow, and tissue survival in ischemic skin flaps, and (3) the transient hypoxia induced by IHE does not alter expression of VEGF or its receptors nor does it trigger angiogenesis. PMID:18331223
Schlaudraff, Kai U; Pepper, Michael S; Tkatchouk, Elena N; Ehrenburg, Igor; Alizadeh, Navid; Montandon, Denys; Pittet, Brigitte
Fetal asphyctic preconditioning modulates the acute cytokine response thereby protecting against perinatal asphyxia in neonatal rats
Background Perinatal asphyxia (PA) is a major cause of brain damage and neurodevelopmental impairment in infants. Recent investigations have shown that experimental sublethal fetal asphyxia (FA preconditioning) protects against a subsequent more severe asphyctic insult at birth. The molecular mechanisms of this protection have, however, not been elucidated. Evidence implicates that inflammatory cytokines play a protective role in the induction of ischemic tolerance in the adult brain. Accordingly, we hypothesize that FA preconditioning leads to changes in the fetal cytokine response, thereby protecting the newborn against a subsequent asphyctic insult. Methods In rats, FA preconditioning was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global PA was induced by placing the uterine horns, containing the pups, in a saline bath for 19 min. We assessed, at different time points after FA and PA, mRNA and protein expression of several cytokines and related receptor mRNA levels in total hemispheres of fetal and neonatal brains. Additionally, we measured pSTAT3/STAT3 levels to investigate cellular responses to these cytokines. Results Prenatally, FA induced acute downregulation in IL-1?, TNF-? and IL-10 mRNA levels. At 96 h post FA, IL-6 mRNA and IL-10 protein expression were increased in FA brains compared with controls. Two hours after birth, all proinflammatory cytokines and pSTAT3/STAT3 levels decreased in pups that experienced FA and/or PA. Interestingly, IL-10 and IL-6 mRNA levels increased after PA. When pups were FA preconditioned, however, IL-10 and IL-6 mRNA levels were comparable to those in controls. Conclusions FA leads to prenatal changes in the neuroinflammatory response. This modulation of the cytokine response probably results in the protective inflammatory phenotype seen when combining FA and PA and may have significant implications for preventing post-asphyctic perinatal encephalopathy.
NSDL National Science Digital Library
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Protein Kinase C Isoform Diversity in Preconditioning
Protein kinase C (PKC) appears to be a common intracellular effector and signal collector during cardiac preconditioning; however, it remains unknown whether agonists that activate different PKC isoforms are also linked to select aspects of myocardial protection. Using agonists that are known to activate unique combinations of PKC isoforms, we interogated the relationship between isoform activation and the different aspects
Daniel R. Meldrum; Joseph C. Cleveland; Xianzhong Meng; Brett C. Sheridan; Fabia Gamboni; Brian S. Cain; Alden H. Harken; Anirban Banerjee
Interagency Collaboration: Preconditions, Progress, and Pressures.
ERIC Educational Resources Information Center
The Down East Partnership for Children (DEPC) was established in 1993 to bring together health, education, and social service agencies to address the needs of children and families in two eastern North Carolina counties. Collaboration theory provided a useful lens through which to examine the development of the partnership, recognize preconditions�
Bradshaw, Lynn K.
China's Pension Reform: A Precondition Approach
China has a relatively young population, but is about to undergo a remarkable demographic transformation. Given the un-sustainability of the old system, the Chinese authorities have initiated a number of pension reforms since the early 1990s. In this paper, based on latest precondition framework, we analyse and conclude that the initial economic and financial conditions within the reform started in
Yu-Wei Hu
Pharmacologic therapy that simulates conditioning for cardiac ischemic/reperfusion injury.
Cardiovascular disease remains a leading cause of deaths due to noncommunicable diseases, of which ischemic heart disease forms a large percentage. The main therapeutic strategy to treat ischemic heart disease is reperfusion that could either be medical or surgical. However, reperfusion following ischemia is known to increase the infarct size further. Newer strategies such as ischemic preconditioning (IPC), ischemic postconditioning, and remote IPC have been shown to condition the myocardium to ischemia-reperfusion injury and thus reduce the final infarct size. Research over the past 3 decades has deepened our understanding of cellular and subcellular pathways that mediate ischemia-reperfusion injury. This in turn has resulted in the development of several pharmacological agents that act as conditioning agents, which reduce the final myocardial infarct size following ischemia-reperfusion. This review discusses many of these agents, their mechanisms of action, and the animal and clinical evidence behind them. PMID:24038018
Sivaraman, Vivek; Yellon, Derek M
Gene expression profiles in hypoxic preconditioning using cDNA microarray analysis: altered expression of an angiogenic factor, carcinoembryonic antigen-related cell adhesion molecule 1.
Hypoxic preconditioning has been shown to exhibit cardioprotective effects on myocardium from ischemic or reperfusion injury. The specific regulated gene involved in the hypoxia-induced cardioprotective effects is profiled in this study. Young male Wistar rats and ICR mice were exposed to sea level (as normal control) or simulated high altitude for 15 h/day for 2, 4, or 8 weeks, or for 4 weeks at high altitude after 2 weeks at sea level. The left ventricles of the animals were isolated for mRNA isolation and cDNA microarray analysis. Our data demonstrated that hypoxic preconditioning significantly ameliorated cardiac ischemic injury by minimizing the infarct size. After cluster analysis of expression profiles after different courses of hypoxic preconditioning (0, 2, 4, and 8 weeks), 386 genes showed an ascending pattern, whereas 301 genes showed a descending pattern. The ascending genes include several angiogenic factors: FGF receptor 4, vascular endothelial growth factor (vEGF), and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). The microvessel density was also significantly increased in hypoxic hearts. Using Western blotting and immunohistochemical analysis, the protein expression level and localization of CEACAM-1 were observed in hypoxic myocardium. The results also indicated that CEACAM-1 was upregulated as with other hypoxic angiogenic factors, heme oxygenase 1 (HO-1) and hypoxia inducible factor-1alpha (HIF-1alpha), in in vitro cultured cardiomyocytes (H9c2) after hypoxia treatment and in vivo hypoxic preconditioning. Furthermore, incubation with recombinant vEGF could also increase the expression level of CEACAM-1 in H9c2 cells. These results demonstrated that hypoxic preconditioning resulted in transcriptional changes, and some of these genes have been correlated with angiogenesis. The HIF-1/vEGF/CEACAM-1 pathway might be important for hypoxia-induced angiogenesis in the heart during hypoxic preconditioning. PMID:16044082
Chen, Wen-Jone; Chen, Huei-Wen; Yu, Sung-Liang; Huang, Chien-Hua; Wang, Tzung-Dau; Chen, Jeremy J W; Chien, Chiang-Ting; Chen, Hsuan-Yu; Yang, Pan-Chyr; Lee, Yuan-Teh
Aging-related Decrease of Human ASC Angiogenic Potential Is Reversed by Hypoxia Preconditioning Through ROS Production
Adipose stroma/stem cells (ASC) represent an ideal source of autologous cells for cell-based therapy. Their transplantation enhances neovascularization after experimental ischemic injury. Aging is associated with a progressive decrease in the regenerative potential of mesenchymal stem cells (MSCs) from bone marrow. This work aims to determine the aging effect on human ASC capacities. First, we show that aging impairs angiogenic capacities of human ASC (hASC) in a mouse ischemic hindlimb model. Although no change in hASC number, phenotype, and proliferation was observed with aging, several mechanisms involved in the adverse effects of aging have been identified in vitro combining a concomitant decrease in (i) ASC ability to differentiate towards endothelial cells, (ii) secretion of proangiogenic and pro-survival factors, and (iii) oxidative stress. These effects were counteracted by a hypoxic preconditioning that improved in vivo angiogenic capacities of hASC from older donors, while hASC from young donors that have a strong ability to manage hypoxic stress were not. Finally, we identified reactive oxygen species (ROS) generation as a key signal of hypoxia on hASC angiogenic capacities. This study demonstrates for the first time that age of donor impaired angiogenic capacities of hASC in ischemic muscle and change in ROS generation by hypoxic preconditioning reverse the adverse effect of aging.
Barros, Sandra De; Dehez, Stephanie; Arnaud, Emmanuelle; Barreau, Corinne; Cazavet, Alexandre; Perez, Guillaume; Galinier, Anne; Casteilla, Louis; Planat-Benard, Valerie
Hypoxic preconditioning and tolerance via hypoxia inducible factor (HIF) 1?-linked induction of P450 2C11 epoxygenase in astrocytes
The brain's adaptive response to ischemic preconditioning (IPC) is mediated in part via hypoxia inducible factor (HIF)-responsive genes. We previously showed that IPC induces cytochrome P450 2C11 expression in the brain, associated with protection from stroke. Cytochrome P450 2C11 is an arachidonic acid (AA) epoxygenase expressed in astrocytes, which metabolizes AA to epoxyeicosatrienoic acids (EETs). We tested the hypotheses that
Mingyue Liu; Nabil J Alkayed
OBJECTIVE Interferon (IFN)-? inducible protein, CXCL10/IP-10, is a member of the CXC chemokine family with pro-inflammatory and anti-angiogenic properties. This chemokine has been proposed to be a key link between inflammation and angiogenesis. The aim of this study was to determine whether preeclampsia and delivery of a small for gestational age (SGA) neonate are associated with changes in maternal serum concentration of CXCL10/IP-10. STUDY DESIGN This cross-sectional study included patients in the following groups: (1) non pregnant women (N=49); (2) women with normal pregnancies (N=89); (3) patients with preeclampsia (N=100); and (4) patients who delivered an SGA neonate (N=78). SGA was defined as birth weight below the 10th percentile. Maternal serum concentrations of CXCL10/IP-10 were measured by sensitive immunoassay. Non-parametric statistics were used for analysis. RESULTS (1) Patients with normal pregnancies had a significantly higher median serum concentration of CXCL10/IP-10 than non-pregnant women (median: 116.1 pg/mL, range: 40.7-1314.3 vs. median: 90.3 pg/mL, range: 49.2-214.7, respectively; p=0.002); (2) no significant correlation was found between maternal serum concentration of CXCL10/IP-10 and gestational age (between 19 and 38 weeks); (3) there were no differences in median serum CXCL10/IP-10 concentrations between patients who delivered an SGA neonate and those with normal pregnancies (median: 122.4 pg/mL, range: 37.3-693.5 vs. median: 116.1 pg/mL, range: 40.7-1314.3, respectively; p>0.05); (4) patients with preeclampsia had a higher median serum concentration of CXCL10/IP-10 than normal pregnant women (median: 156.4 pg/mL, range: 47.4-645.9 vs. median: 116.1 pg/mL, range: 40.7-1314.3, respectively; p<0.05); (5) patients with preeclampsia had a higher median concentration of CXCL10/IP-10 than those who delivered an SGA neonate (median: 156.4 pg/mL, range: 47.4-645.9 vs. median: 122.4 pg/mL, range: 37.3-693.5, respectively; p<0.05). CONCLUSIONS Patients with preeclampsia have significantly higher serum concentrations of CXCL10/IP-10 than both normal pregnant women and mothers who have SGA neonates. These results are likely to reflect an anti-angiogenic state as well as an enhanced systemic inflammatory response in patients with preeclampsia. Alternatively, since preeclampsia and SGA share several mechanisms of disease, it is possible that a higher concentration of this chemokine may contribute to the clinical presentation of preeclampsia in patients with a similar intrauterine insult.
Gotsch, Francesca; Romero, Roberto; Friel, Lara; Kusanovic, Juan Pedro; Espinoza, Jimmy; Erez, Offer; Than, Nandor Gabor; Mittal, Pooja; Edwin, Samuel; Yoon, Bo Hyun; Kim, Chong Jai; Mazaki-Tovi, Shali; Chaiworapongsa, Tinnakorn; Hassan, Sonia S.
Reduced [3H]IP3 binding but unchanged IP3 receptor levels in the rat hippocampus CA1 region following transient global ischemia and tolerance induction.
Changes in inositol (1,4,5)-trisphosphate (IP3) binding properties and the protein level of the IP3 receptor have been reported in different pathological conditions in the brain, e.g. cerebral ischemia, Alzheimer's disease, and Huntingtons disease. We used the 4-vessel occlusion model in rat brain to investigate the effect of transient ischemia insults on the IP3 receptor mRNA level, the IP3 receptor protein level and [3H]IP3 binding. Recirculation periods were limited (1-72 h) to avoid the development of delayed neuronal death. We found that the IP3 receptor mRNA levels were decreased after damage-inducing ischemia (9 min) in the hippocampus CA1 and CA3 regions. The mRNA levels were unaltered after tolerance-inducing ischemia (3 min). However, [3H]IP3 binding was significantly reduced after both damage- and tolerance-inducing ischemia in the hippocampus CA1 region. Furthermore, all investigated brain areas showed a decreased [3H]IP3 binding when tolerance-inducing ischemia was followed by a second ischemic insult (3 + 8.5 min ischemia). The IP3 receptor protein levels remained constant in all investigated brain areas. These results indicate that a reduced [3H]IP3 binding capability in the particularly vulnerable areas occurs as an early consequence of cerebral ischemia, before IP3 receptor protein levels are reduced in these areas. Structural or conformational changes altering IP3 binding may be of necessity on the pathway leading to down-regulation of IP3 receptor protein levels, as observed by others. PMID:10733005
Dahl, C; Haug, L S; Spilsberg, B; Johansen, J; Ostvold, A C; Diemer, N H
Pre-ischemic treadmill training alleviates brain damage via GLT-1-mediated signal pathway after ischemic stroke in rats.
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 2h, 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-? (PKC-?), Akt, and phosphatidylinositol 3 kinase (PI3K) (n=6). Two hundred and eighty minutes (4.67h) 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-? 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-?-GLT-1-Glutamate and PI3K/Akt-GLT-1-Glutamate. PMID:24907601
Wang, X; Zhang, M; Yang, S-D; Li, W-B; Ren, S-Q; Zhang, J; Zhang, F
Cardioprotective effects of anesthetic preconditioning in rats with ischemia-reperfusion injury: propofol versus isoflurane
Objective: We compare the cardioprotective effects of anesthetic preconditioning by propofol and/or isoflurane in rats with ischemia-reperfusion injury. Methods: Male adult Wistar rats were subjected to 60 min of anterior descending coronary artery occlusion followed by 120 min of reperfusion. Before the long ischemia, anesthetics were administered twice for 10 min followed by 5 min washout. Isoflurane was inhaled at 1 MAC (0.016) in I group, whereas propofol was inhaled intravenously at 37.5 mg/(kg�h) in P group. A combination of isoflurane and propofol was administered simultaneously in I+P group. Results: In control (without anesthetic preconditioning, C group), remarkable myocardial infarction and apoptosis accompanied by an increased level of cardiac troponin T were noted 120 min after ischemia-reperfusion. As compared to those of control group, I and P groups had comparable cardioprotection. In addition, I+P group shares with I and P groups the comparable cardioprotective effects in terms of myocardial infarction and cardiac troponin T elevation. Conclusion: A combination of isoflurane and propofol produced no additional cardioprotection.
Tao, Xing; Lu, Ling-qiao; Xu, Qing; Li, Shu-ren; Lin, Mao-tsun
Discrete Fourier Transform IP Generator.
National Technical Information Service (NTIS)
Intellectual Property (IP) libraries are commonly used by hardware designers to increase productivity and reduce the time-to-market. These static IP libraries do not allow the designers flexibility in customizing trade-offs. We propose a parameterized DSP...
G. Nordin J. C. Hoe M. Pueschel
Biological networks in ischemic tolerance - Rethinking the approach to clinical conditioning
The adaptive response (conditioning) to environmental stressors evokes evolutionarily conserved programs in uni- and multicellular organisms that result in increased fitness and resistance to stressor induced injury. Although the concept of conditioning has been around for a while, its translation into clinical therapies targeting neurovascular diseases has only recently begun. The slow pace of clinical adoption might be partially explained by our poor understanding of underpinning mechanisms and of the complex responses of the organism to the stressor. At the 2nd Translational Preconditioning Meeting participants engaged in an intense discussion addressing whether the time has come to more aggressively implement clinical conditioning protocols in the treatment of cerebrovascular diseases or whether it would be better to wait until preclinical data would help to minimize clinical empiricism. This review addresses the complex involvement of biological networks in establishing ischemic tolerance at the organism level using two clinically promising conditioning modalities, namely remote ischemic preconditioning, and per- or post-conditioning, as examples.
Anrather, Josef; Hallenbeck, John M.
Cardiomyocyte overexpression of the ?1a-adrenergic receptor in the rat phenocopies second but not first window preconditioning
We examined ?1A-adrenergic receptor (AR) mediation of preconditioning in a novel ?1A-AR cardiac transgenic (TG) rat model (?1A-TG). Compared with nontransgenic littermates (NTLs), in conscious ?1A-TG rats, heart rate was reduced, contractility [left ventricle (LV) +dP/dt, ejection fraction, end-systolic elastance] was significantly enhanced, and triple product (LV systolic wall stress � LV +dP/dt � heart rate) was unchanged. However, infarct size (IS)/area at risk (AAR) in response to ischemia-reperfusion (30 min coronary occlusion/3 h reperfusion) was reduced to 35 � 4.6% in ?1A-TGs vs. 52 � 2.2% in NTLs (P < 0.05). Second window preconditioning reduced IS/AAR in NTLs to 29 � 2.7% but did not afford further protection in ?1A-TGs. In contrast, with first window preconditioning, IS/AAR was reduced to similar levels in both ?1A-TGs (12 � 1.4%) and NTLs (10 � 1.1%). In untreated ?1A-TGs, cardioprotection was associated with enhanced myocardial phosphorylated (p)-mitogen/extracellular signal-regulated kinase (MEK), p-extracellular signal-regulated kinase (ERK), and inducible nitric oxide synthase (iNOS) at the protein level, along with a 1.3-fold increase in total nitric oxide synthase activity like in second window preconditioning. Affymetrix microarrays revealed that few genes (4.6% of 3,172 upregulated; 8.8% of 3,498 downregulated) showed directionally similar changes in ?1A-TGs vs. NTLs subjected to second window preconditioning. Thus, second, but not first, window cardioprotection is evident in ?1A-TGs in the absence of ischemic preconditioning and is mediated by iNOS activation associated with MEK/ERK phosphorylation. Transcriptionally, however, second window preconditioning is considerably more complex than ?1A-TG preconditioning, with the alteration of thousands of additional genes affording no further protection than that already available in ?1A-TG rats.
Zhao, Xin; Park, Jiyeon; Ho, David; Gao, Shumin; Yan, Lin; Ge, Hui; Iismaa, Siiri; Lin, Lin; Tian, Bin; Vatner, Dorothy E.; Graham, Robert M.
Neuroprotection and P450 2C11 Upregulation After Experimental Transient Ischemic Attack
Background and Purpose�Transient ischemic attack (TIA) is a risk factor for stroke. However, TIA may also serve as a preconditioning stimulus, reducing damage from subsequent stroke. We tested the hypothesis that experimental TIA induces expression of P450 2C11, an arachidonic acid epoxygenase that produces vasodilator epoxyeicosatrienoic acids, leading to increased tissue perfusion and reduced stroke damage. Methods�Wistar rats underwent three
Nabil J. Alkayed; Toru Goyagi; Hung-Dong Joh; Judith Klaus; David R. Harder; Richard J. Traystman; Patricia D. Hurn
A multigrid preconditioned Newton-Krylov method
The authors study multigrid preconditioning of matrix-free Newton-Krylov methods as a means of developing more efficient nonlinear iterative methods for large scale simulation. Newton-Krylov methods have proven dependable in solving nonlinear systems while not requiring the explicit formation or storage of the complete Jacobian. However, the standard algorithmic scaling of Krylov methods is nonoptimal, with increasing linear system dimension. This motivates the use of multigrid-based preconditioning. It is demonstrated that a simple multigrid-based preconditioner can effectively limit the growth of Krylov iterations as the dimension of the linear system is increased. Different performance aspects of the proposed algorithm are investigated on three nonlinear, nonsymmetric, boundary value problems. The goal is to develop a hybrid methodology which has Newton-Krylov nonlinear convergence properties and multigrid-like linear convergence scaling for large scale simulation.
Knoll, D.A.; Rider, W.J.
Preserving Symmetry in Preconditioned Krylov Subspace Methods
NASA Technical Reports Server (NTRS)
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.
Chan, Tony F.; Chow, E.; Saad, Y.; Yeung, M. C.
A multigrid preconditioned Newton-Krylov method
The authors study multigrid preconditioning of matrix-free Newton-Krylov methods as a means of developing more efficient nonlinear iterative methods for large scale simulation. Newton-Krylov methods have proven dependable in solving nonlinear systems while not requiring the explicit formation or storage of the complete Jacobian. However, the standard algorithmic scaling of Krylov methods is nonoptimal, with increasing linear system dimension. This
D. A. Knoll; W. J. Rider
On polynomial preconditioning for indefinite Hermitian matrices
NASA Technical Reports Server (NTRS)
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.
Freund, Roland W.
Role of connexins and pannexins in ischemic stroke.
Synaptic plasticity requires careful synchronization and coordination of neurons and glial cells via various mechanisms of intercellular communication. Among them, are those mediated by i) connexin gap junction channels (GJCs), ii) connexin hemichannels and iii) pannexin channels. Whereas GJCs directly communicate the cytoplasm of contacting cells and coordinate electric and metabolic activities, connexin hemichannels and pannexin channels serve as diffusional pathways for ions and small molecules between the intra- and extracellular compartments. A growing body of evidence has revealed that intercellular communication could be critical in the spread of protective and/or deleterious signals during stroke. Here, we review current findings on the regulation of connexin- and pannexin-based channels in ischemic stroke and how they contribute to cell damage observed in pathology. Depending on intensity of the ischemic event, brain region and connexin subtype expressed, GJCs may provide proper diffusion of energy metabolites and dissipation of toxic substances, whereas, in other circumstances, they could increase damage by spreading toxic molecules. Alternatively, connexin hemichannel and pannexin channel opening may favor the release of neurotoxic substances (e.g., glutamate), but in other cases, they may confer neuroprotection against an ischemic episode by the phenomenon of ischemic preconditioning. Development of new drug modulators using in silico devices for connexin and pannexin-based channels will be crucial for future therapies against stroke. PMID:24372216
Orellana, J A; Avenda�o, B C; Montero, T D
NASA Astrophysics Data System (ADS)
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.
Caramia, M.; Montagna, M.; Furano, G.; Winton, A.
Lubiprostone induced ischemic colitis
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.
Sherid, Muhammed; Sifuentes, Humberto; Samo, Salih; Deepak, Parakkal; Sridhar, Subbaramiah
TIA (Transient Ischemic Attack)
... risk and understand your condition. TIA and Stroke: Medical Emergencies When someone has shown symptoms of a stroke or a TIA (transient ischemic attack), they require immediate medical attention. A doctor will gather information and make ...
Transient Ischemic Attack (TIA)
... Women and Stroke Fibromuscular Dysplasia Patent Foramen Ovale (PFO) Transient Ischemic Attack (TIA) TIA Risk Calculator Recurrent ... have someone take you to the hospital immediately. Treatment can be more helpful if given quickly. Stroke ...
Voice over IP performance monitoring
We describe a method for monitoring Voice over IP (VoIP) applications based upon a reduction of the ITU-T's E-Model to transport level, measurable quantities. In the process, 1) we identify the relevant transport level quantities, 2) we discuss the tradeoffs between placing the monitors within the VoIP gateways versus placement of the monitors within the transport path, and 3) we
Robert G. Cole; J. H. Rosenbluth
Interactions of GSK-3? with mitochondrial permeability transition pore modulators during preconditioning: age-associated differences.
Anesthetic preconditioning (APC) and ischemic preconditioning (IPC) are lost with normal aging. Here, we investigated age-related difference between phosphoglycogen synthase kinase-3beta (pGSK-3?) and pGSK-3? with modulators of mitochondrial permeability transition pore, including adenine nucleotide translocase (ANT), cyclophilin-D, or voltage-dependent anion channel. APC or IPC significantly increased pGSK-3? in the young groups in both the cytosol and the mitochondria and also significantly increased pGSK-3? in co-immunoprecipitates with ANT. Importantly, the level of cyclophilin-D in co-immunoprecipitates with ANT was significantly decreased in the young APC and IPC groups, but not in old rats. We also found that APC or IPC significantly prolonged mitochondrial permeability transition pore opening time in the young cardiomyocytes under oxidative stress, but not in the elderly. Attenuation of APC or IPC protection in the aging heart is associated with failure to reduce ANT-cyclophilin-D interactions and to decreased pGSK-3? responsiveness of ANT, critical modulators of mitochondrial permeability transition pore. PMID:23070879
Zhu, Jiang; Rebecchi, Mario J; Glass, Peter S A; Brink, Peter R; Liu, Lixin
Toward the Optimal Preconditioned Eigensolver: Locally Optimal Block Preconditioned Conjugate Gradient Method
We describe new algorithms of the locally optimal block preconditioned conjugate gradient (LOBPCG) method for symmetric eigenvalue problems, based on a local optimization of a three-term recurrence, and suggest several other new methods. To be able to compare numerically different methods in the class, with different preconditioners, we propose a common system of model tests, using random preconditioners and initial
Andrew V. Knyazev
Seamless mobility across IP networks using Mobile IP
The landscape of today's telecommunications portrays an amazing patchwork of heterogeneous networks, with very few and complex bridges between them. In this context, IP technology has emerged as a natural means of initiating network convergence and the �All-IP� paradigm has become the implicit assumption for most studies on the next generation architecture design. However, the real added value of such
Maria-amparo Sanmateu; Fr�d�ric Paint; Lionel Morand; S. Tessier; Philippe Fouquart; A. Sollund; E. Bustos
IP is Dead, Long Live IP for Wireless Sensor Networks
A decade ago as wireless sensor network research took off many researchers in the field denounced the use of IP as inadequate and in contradiction to the needs of wireless sensor networking. Since then the field has matured, standard links have emerged, and IP has evolved. In this paper, we present the design of a complete IPv6-based network architecture for
Jonathan W. Hui; David E. Culler
The volatile anesthetic isoflurane is capable of inducing preconditioning and postconditioning effects in the brain. However, the mechanisms for these neuroprotective effects are not fully understood. Here, we showed that rat hippocampal neuronal cultures exposed to 2% isoflurane for 30 min at 24 h before a 1-h oxygen-glucose deprivation (OGD) and a 24-h simulated reperfusion had a reduced lactate dehydrogenase release. Similarly, this OGD and simulated reperfusion-induced lactate dehydrogenase release was attenuated by exposing the neuronal cultures to 2% isoflurane for 1 h at various times after the onset of the simulated reperfusion (isoflurane postconditioning). The combination of isoflurane preconditioning and postconditioning induced a better neuroprotection than either alone. Inhibition of the calcium/calmodulin-dependent protein kinase II (CaMKII), inhibition of N-methyl D-aspartate (NMDA) receptors, or activation of adenosine A2A receptors resulted in reduction of the OGD and simulated reperfusion-induced cell injury. The combination of CaMKII inhibition and isoflurane preconditioning or postconditioning did not provide better protection than CaMKII inhibition, isoflurane preconditioning, or isoflurane postconditioning alone. The combination of NMDA receptor inhibition and isoflurane postconditioning was not better than NMDA receptor inhibition or isoflurane postconditioning alone for neuroprotection. However, the combination of adenosine A2A receptor activation with either isoflurane preconditioning or isoflurane postconditioning induced a better neuroprotective effect than adenosine A2A receptor activation, isoflurane preconditioning, or isoflurane postconditioning alone. The combination of NMDA receptor inhibition and isoflurane preconditioning caused a better neuroprotective effect than NMDA receptor inhibition or isoflurane preconditioning alone. These results suggest that isoflurane preconditioning- and postconditioning-induced neuroprotection can be additive. Isoflurane preconditioning and isoflurane postconditioning may involve CaMKII inhibition, but may not involve adenosine A2A receptor activation. Inhibition of NMDA receptors may mediate the effects of isoflurane postconditioning, but not isoflurane preconditioning.
McMurtrey, Richard J.; Zuo, Zhiyi
TLR7 preconditioning induces robust neuroprotection against stroke by a novel type I interferon-mediated mechanism
Background and Purpose Systemic administration of Toll-like receptor 4 (TLR4) and TLR9 agonists prior to cerebral ischemia, have been shown to reduce ischemic injury by reprogramming the brain�s response to stroke. Our goal was to explore the mechanism of TLR induced neuroprotection by determining whether a TLR7 agonist also protects against stroke injury. Methods C57Bl/6, TNF?/?, interferon regulatory factor (IRF)7?/?, or type I interferon receptor (IFNAR)?/? mice were subcutaneously administered the TLR7 agonist Gardiquimod (GDQ) 72 hr prior to middle cerebral artery occlusion (MCAO). Infarct volume and functional outcome were determined following reperfusion. Plasma cytokine responses and induction of mRNA for IFN related genes in the brain were measured. IFNAR?/? mice were also treated with the TLR4 agonist (lipopolysaccharide) or the TLR9 agonist (CpG) prior to MCAO and infarct volumes measured. Results The results show that GDQ reduces infarct volume as well as functional deficits in mice. GDQ pretreatment provided robust neuroprotection in TNF?/? mice indicating that TNF was not essential. GDQ induced a significant increase in plasma IFN? levels and both IRF7?/? and IFNAR?/? mice failed to be protected, implicating a role for IFN signaling in TLR7 mediated protection. Conclusion Our studies provide the first evidence that TLR7 preconditioning can mediate neuroprotection against ischemic injury. Moreover, we show that the mechanism of protection is unique from other TLR preconditioning ligands in that it is independent of TNF and dependent on IFNAR.
Leung, Philberta Y.; Stevens, Susan L.; Packard, Amy E.B.; Lessov, Nikola S.; Yang, Tao; Conrad, Valerie K.; van den Dungen, Noortje N.A.M.; Simon, Roger P.; Stenzel-Poore, Mary P.
Heat stress preconditioning and delayed myocardial protection: what is new?
As other preconditioning phenomena, heat stress is able to induce a delayed myocardial protection against ischaemia-reperfusion injury by preserving ventricular function, preventing arrhythmia occurrence and reducing cellular necrosis. The development of heat stress response has been extensively studied in order to characterize the different steps of this form of preconditioning. It appears that chemical signals (such as nitric oxide, reactive
Marie Joyeux-Faure; Claire Arnaud; Diane Godin-Ribuot; Christophe Ribuot
Preconditioning an Entire Stope Block for Rock Burst Control.
National Technical Information Service (NTIS)
Rock preconditioning in advance of mining has been an effective means of rock-burst control based on small-scale field demonstrations. The objective of this investigation was to test the effectiveness of rock preconditioning on a larger scale and to deter...
W. Blake
Abstract. IP addresses are an important tool for fighting spam, used for safe lists, blackhole lists, anti-spoofing and related purposes. While it is trivial to find the sender's IP address in most email server software, it turns out to be surprisingly di cult to do so in email client software: we explain why. This implies that either alternative approaches are
Joshua Goodman
The IP landscape for photovoltaics
The photovoltaic industry, originally established in the 1950s, remains far from financial parity with conventional energy sources. Nevertheless the intellectual property (IP) aspects of this field already encompass more than 3000 patents in the US alone not including a wide variety of enabling technologies not directly identified as photovoltaic! The authors review the relevant IP and organize it by generic
C. E. Bauer; H. J. Neuhaus
NASA Astrophysics Data System (ADS)
ATEL #4412 (Smith & Mauerhan) recently suggested that supernova impostor SN2009ip has re-brightened as a true supernova. ATEL #4414 (Margutti et al.) reported Swift observations indicating that SN2009ip is declining in magnitude and not a true supernova. We obtained V and R observations with the 20-inch telescope at the Henry R. Barber Astronomical Observatory (University of Illinois Springfield).
Martin, J. C.; O'Brien, J.; Hubbell-Thomas, J.
An IP Central Office Architecture
The primary goal of this work is to design an IP based voice, video, and data communication infrastructure that will eventually replace, and far surpass, the a bilities of the existing TDM based local switching infrastructure; that i s, local, and PBX switches. The ce ntral point of this new infrastructure is an IP technology based central office (IPCO) that
Michael S. Borella; Ikhlaq Sidhu; Guido M. Schuster; David Grabelsky; Jerry Mahler; Jacek Grabiec; Thomas J. Kostas
NSDL National Science Digital Library
This site is a collection of architectural specifications, network and signaling protocols, and technical papers related to virtually every aspect of VoIP. Detailed articles and standards information are regularly updated on the site. There is also a collection of documents containing VoIP references, and in this sections, visitors will find an H.323 tutorial.
The multigrid preconditioned conjugate gradient method
NASA Technical Reports Server (NTRS)
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.
Tatebe, Osamu
Management of Ischemic Colitis
Ischemic colitis is a commonly misunderstood clinical condition. Although the colon is the most common region of ischemia in the gastrointestinal tract, many surgeons have difficulty with diagnosis and treatment of ischemic colitis. The process can occur from either occlusive vascular disease or nonocclusive disease, and can be gangrenous or nongangrenous. Differentiating gangrenous from nongangrenous disease can be a difficult clinical challenge as both sets of patients generally present with abdominal pain and bloody diarrhea. Although the majority of patients have transient ischemia with nongangrenous colitis that can be successfully managed nonoperatively, prompt recognition and surgical intervention is critical in patients with gangrenous colitis. In this article, the diagnosis and treatment of ischemic colitis is reviewed with emphasis on a systematic, evidence-based approach to management.
Washington, Christopher; Carmichael, Joseph C.
Preconditioning Newton-Krylor Methods for Variably Saturated Flow
In this paper, we compare the effectiveness of three preconditioning strategies in simulations of variably saturated flow. Using Richards' equation as our model, we solve the nonlinear system using a Newton-Krylov method. Since Krylov solvers can stagnate, resulting in slow convergence, we investigate different strategies of preconditioning the Jacobian system. Our work uses a multigrid method to solve the preconditioning systems, with three different approximations to the Jacobian matrix. One approximation lags the nonlinearities, the second results from discarding selected off-diagonal contributions, and the third matrix considered is the full Jacobian. Results indicate that although the Jacobian is more accurate, its usage as a preconditioning matrix should be limited, as it requires much more storage than the simpler approximations. Also, simply lagging the nonlinearities gives a preconditioning matrix that is almost as effective as the full Jacobian but much easier to compute.
Woodward, C.; Jones, J
Ischemic Colitis Revealing Polyarteritis Nodosa
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.
Hamzaoui, Amira; Litaiem, Noureddine; Smiti Khanfir, M.; Ayadi, Sofiene; Nfoussi, Haifa; Houman, M. H.
Redox activation of aldose reductase in the ischemic heart.
Aldose reductase (AR) reduces cytotoxic aldehydes and glutathione conjugates of aldehydes derived from lipid peroxidation. Its inhibition has been shown to increase oxidative injury and abolish the late phase of ischemic preconditioning. However, the mechanisms by which ischemia regulates AR activity remain unclear. Herein, we report that rat hearts subjected to ischemia, in situ or ex vivo, display a 2-4-fold increase in AR activity. The AR activity was not further enhanced by reperfusion. Activation increased Vmax of the enzyme without affecting the Km and decreased the sensitivity of the enzyme to inhibition by sorbinil. Enzyme activation could be prevented by pretreating the hearts with the radical scavenging thiol, N-(2-mercaptoproprionyl)glycine or the superoxide dismutase mimetic, Tiron, or by treating homogenates with dithiothreitol. In vitro, the recombinant enzyme was activated upon treatment with H2O2 and the activated, but not the native enzyme, formed a covalent adduct with the sulfenic acid-specific reagent dimedone. The enzyme activity in the ischemic, but not the nonischemic heart homogenates was inhibited by dimedone. Separation of proteins from hearts subjected to coronary occlusion by two-dimensional electrophoresis and subsequent matrix-assisted laser desorption ionization time-of-flight/mass spectrometry analysis revealed the formation of sulfenic acids at Cys-298 and Cys-303. These data indicate that reactive oxygen species formed in the ischemic heart activate AR by modifying its cysteine residues to sulfenic acids. PMID:16567803
Kaiserova, Karin; Srivastava, Sanjay; Hoetker, Joseph D; Awe, Sunday O; Tang, Xian-Liang; Cai, Jian; Bhatnagar, Aruni
Protective role of normothermic, hyperthermic and estrogen preconditioning and pretreatment on tumour necrosis factor-alpha-induced damage
BACKGROUND: Tumour necrosis factor-alpha (TNF-?) has been reported to play an important role in ischemia reperfusion injury and ischemic preconditioning (IPC). However, its role is not completely understood. Recently, normothermic IPC (NIPC), hyperthermic IPC (HIPC), preconditioning (PC) with 17-beta estradiol (estrogen, E2) and E2 pretreatment were proven to be effective in reducing ischemia reperfusion injury. OBJECTIVES: To investigate the detrimental effects of TNF-? on the heart, and the protective effects of NIPC, HIPC, E2 PC and pretreatment on TNF-?-induced injury. METHODS: A Langendorff-perfused rat heart model was used for the present study. Hearts isolated from male rats were studied under eight different conditions (n=5 each): negative control; control treated with TNF-? without any further treatment; NIPC (preconditioned at 37�C); HIPC (preconditioned at 42�C); E2 PC; E2 pretreatment; normal, untreated hearts plus E2; or pretreated hearts perfused for 60 min with TNF-? and an E2-containing buffer. RESULTS: TNF-? treatment resulted in deterioration of heart function. HIPC offered better protection by significantly increasing left ventricular developed pressure (Pmax) and coronary flow (P<0.01), and by decreasing left ventricular end-diastolic pressure (P<0.01). NIPC or pretreatment of the hearts with E2 normalized left ventricular end-diastolic pressure, coronary flow and coronary vascular resistance (P<0.001); however, it did not normalize Pmax. The combination of E2 and HIPC did not show any synergetic protection; however, the addition of HIPC normalized Pmax (P<0.001). CONCLUSIONS: TNF-? treatment resulted in deterioration of heart hemodynamics, which were reversed by HIPC, E2 PC and pretreatment. The combination of these treatments did not add to the previously observed protection compared with when they were used individually.
Juggi, Jasbir S; Hoteit, Lamia J; Babiker, Fawzi A; Joseph, Shaji; Mustafa, Abu Salim
Post-Ischemic Activation of Protein Kinase C Epsilon Protects the Hippocampus from Cerebral Ischemic Injury via Alterations in Cerebral Blood Flow
Protein Kinase C (PKC) is a family of serine/threonine-isozymes that are involved in many signaling events in normal and disease states. Previous studies from our lab have demonstrated that ?PKC plays a pivotal role in neuroprotection induced by ischemic preconditioning. However, the role of ?PKC during and after brain ischemia is not clearly defined. Therefore, in the present study, we tested the hypothesis that activation of ?PKC during an ischemic event is neuroprotective. Furthermore, other studies have demonstrated that ?PKC mediates cerebral ischemic tolerance in the rat brain by decreasing vascular tone. Thus, we also tested the effects of ?PKC activation during ischemia on cerebral blood flow (CBF). We found that ??-Receptors for activated C kinase (RACK), a ?PKC-selective peptide activator, injected intravenously 30 minutes before induction of global cerebral ischemia conferred neuroprotection in the CA1 region of the rat hippocampus. Moreover, measurements of CBF before, during and after cerebral ischemia revealed a significant reduction in the reperfusion phase of rats pretreated with ??RACK compared to Tat peptide (vehicle). Our results suggest that ?PKC can protect the rat brain against ischemic damage by regulating CBF. Thus, ?PKC may be one of the treatment modalities against ischemic injury.
Della-Morte, D.; Raval, A.P.; Dave, K.R.; Lin, H.W.; Perez-Pinzon, M.A.
Intermittent warm blood cardioplegia induces the expression of heat shock protein-72 by ischemic myocardial preconditioning
Objective: Recent studies have demonstrated that the induction of heat shock protein-72 (HSP72) by different stimuli preserves the heart function after cardioplegic arrest. Based on these findings, we investigated whether intermittent warm blood cardioplegia would induce changes in the myocardial expression of HSP72.Methods: Forty patients scheduled for aortocoronary bypass were randomly assigned to receive either cold or warm intermittent blood
M Chello; P Mastroroberto; G Patti; A D�Ambrosio; G Di Sciascio; E Covino
This content discusses the individual components of multi-modal CT and multi-modal MRI, present the current status of neuroimaging for the evaluation of the acute ischemic stroke, and address the potential role of a combined multimodal stroke protocol.
Leiva-Salinas, Carlos; Wintermark, Max
Hypoxic Preconditioning Differentially Affects GABAergic and Glutamatergic Neuronal Cells in the Injured Cerebellum of the Neonatal Rat
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 protected by a preconditioning hypoxia while the latter are not.
Patterson, Sean I.; Munoz, Estela M.; Seltzer, Alicia M.
Remote preconditioning in normal and hypertrophic rat hearts
Background The aim of our study was to investigate whether remote preconditioning (RPC) improves myocardial function after ischemia/reperfusion injury in both normal and hypertrophic isolated rat hearts. This is the first time in world literature that cardioprotection by RPC in hypertrophic myocardium is investigated. Methods Four groups of 7 male Wistar rats each, were used: Normal control, normal preconditioned, hypertrophic control and hypertrophic preconditioned groups. Moderate cardiac hypertrophy was induced by fludrocortisone acetate and salt administration for 30 days. Remote preconditioning of the rat heart was achieved by 20 minutes transient right hind limb ischemia and 10 minutes reperfusion of the anaesthetized animal. Isolated Langendorff-perfused animal hearts were then subjected to 30 minutes of global ischemia and reperfusion for 60 minutes. Contractile function and heart rhythm were monitored. Preconditioned groups were compared to control groups. Results Left ventricular developed pressure (LVDP) and the product LVDP � heart rate (HR) were significantly higher in the hypertrophic preconditioned group than the hypertrophic control group while left ventricular end diastolic pressure (LVEDP) and severe arrhythmia episodes did not differ. Variances between the normal heart groups were not significantly different except for the values of the LVEDP in the beginning of reperfusion. Conclusions Remote preconditioning seems to protect myocardial contractile function in hypertrophic myocardium, while it has no beneficial effect in normal myocardium.
Mitochondria: The Missing Link Between Preconditioning and Neuroprotection
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.
Correia, Sonia C.; Santos, Renato X.; Perry, George; Zhu, Xiongwei; Moreira, Paula I.; Smith, Mark A.
Hyperbaric oxygen preconditioning attenuates postoperative cognitive impairment in aged rats.
Cognitive decline after surgery in the elderly population is a major clinical problem with high morbidity. Hyperbaric oxygen (HBO) preconditioning can induce significant neuroprotection against acute neurological injury. We hypothesized that HBO preconditioning would prevent the development of postoperative cognitive impairment. Elderly male rats (20 months old) underwent stabilized tibial fracture operation under general anesthesia after HBO preconditioning (once a day for 5 days). Separate cohorts of animals were tested for cognitive function with fear conditioning and Y-maze tests, or euthanized at different times to assess the blood-brain barrier integrity, systemic and hippocampal proinflammatory cytokines, and caspase-3 activity. Animals exhibited significant cognitive impairment evidenced by a decreased percentage of freezing time and an increased number of learning trials on days 1, 3, and 7 after surgery, which were significantly prevented by HBO preconditioning. Furthermore, HBO preconditioning significantly ameliorated the increase in serum and hippocampal proinflammatory cytokines tumor necrosis factor-?, interleukin-1 ? (IL-1?), IL-6, and high-mobility group protein 1 in surgery-challenged animals. Moreover, HBO preconditioning markedly improved blood-brain barrier integrity and caspase-3 activity in the hippocampus of surgery-challenged animals. These findings suggest that HBO preconditioning could significantly mitigate surgery-induced cognitive impairment, which is strongly associated with the reduction of systemic and hippocampal proinflammatory cytokines and caspase-3 activity. PMID:24870985
Sun, Li; Xie, Keliang; Zhang, Changsheng; Song, Rui; Zhang, Hong
The preconditioning of major sudden stratospheric warmings
NASA Astrophysics Data System (ADS)
The preconditioning of major sudden stratospheric warmings (SSWs) is investigated with two long time series using reanalysis (ERA-40) and model (MAECHAM5/MPI-OM) data. Applying planetary wave analysis, we distinguish between wavenumber-1 and wavenumber-2 major SSWs based on the wave activity of zonal wavenumbers 1 and 2 during the prewarming phase. For this analysis an objective criterion to identify and classify the preconditioning of major SSWs is developed. Major SSWs are found to occur with a frequency of six and seven events per decade in the reanalysis and in the model, respectively, thus highlighting the ability of MAECHAM5/MPI-OM to simulate the frequency of major SSWs realistically. However, from these events only one quarter are wavenumber-2 major warmings, representing a low (�0.25) wavenumber-2 to wavenumber-1 major SSW ratio. Composite analyses for both data sets reveal that the two warming types have different dynamics; while wavenumber-1 major warmings are preceded only by an enhanced activity of the zonal wavenumber-1, wavenumber-2 events are either characterized by only the amplification of zonal wavenumber-2 or by both zonal wavenumber-1 and zonal wavenumber-2, albeit at different time intervals. The role of tropospheric blocking events influencing these two categories of major SSWs is evaluated in the next step. Here, the composite analyses of both reanalysis and model data reveal that blocking events in the Euro-Atlantic sector mostly lead to the development of wavenumber-1 major warmings. The blocking-wavenumber-2 major warming connection can only be statistical reliable analyzed with the model time series, demonstrating that blocking events in the Pacific region mostly precede wavenumber-2 major SSWs.
Bancal�, S.; Kr�ger, K.; Giorgetta, M.
Hyperbaric oxygen preconditioning protects rats against CNS oxygen toxicity.
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 202kPa 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 608kPa, 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 608kPa, latency to CNS-OT increased from 12.8 to 22.4min 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
Arieli, Yehuda; Kotler, Doron; Eynan, Mirit; Hochman, Ayala
Preconditioned Minimal Residual Methods for Chebyshev Spectral Caluclations
NASA Technical Reports Server (NTRS)
The problem of preconditioning the pseudospectral Chebyshev approximation of an elliptic operator is considered. The numerical sensitiveness to variations of the coefficients of the operator are investigated for two classes of preconditioning matrices: one arising from finite differences, the other from finite elements. The preconditioned system is solved by a conjugate gradient type method, and by a DuFort-Frankel method with dynamical parameters. The methods are compared on some test problems with the Richardson method and with the minimal residual Richardson method.
Canuto, C.; Quarteroni, A.
TCP\\/IP protocol accelaration
TCP\\/UDP\\/IP and Ethernet have become undisputed leaders of network communication since last decade. TCP\\/IP stacks are usually implemented in operating system software and packets are handled by the main (host) processor due to which protocol processing of incoming and outgoing network traffic consumes processor cycle. Usually in the application of data transfer, there are several copies of data from user
Ketaki Mahabaleshwarkar; Neha Mundada; Amruta Chavan; Amruta Panage
Speech Recognition Over IP Networks
This chapter introduces the basic features of speech recognition over an IP-based network. First of all, we review typical\\u000a lossy packet channel models and several speech coders used for voice over IP, where the performance of a network speech recognition\\u000a (NSR) system can significantly degrade. Second, several techniques for maintaining the performance of NSR against packet loss\\u000a are addressed. The
Hong Kook Kim
NSDL National Science Digital Library
This page offers five videos of lectures from Sam Bowne's IP Version 6 course. Each video varies in length from ten minutes to an hour. These materials would be most useful for individuals with some experience with IP technology; the end goal of the course was for individuals enrolled to gain IPv6 certification and be able to set up IPv6 on a router. Flash is required to view the videos.
Bowne, Sam
Involvement of SIRT1 in hypoxic down-regulation of c-Myc and ?-catenin and hypoxic preconditioning effect of polyphenols
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 ?-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-1? and down-regulation of c-Myc and ?-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-1? expression but increased c-Myc and ?-catenin expression. SIRT1 was also found to stabilize HIF-1? protein and destabilize c-Myc, ?-catenin and PHD2 under hypoxia. We also found that myricetin, quercetin, piceatannol and resveratrol up-regulated HIF-1? and down-regulated c-Myc, PHD2 and ?-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-1? and SIRT1 and down-regulating c-Myc, PHD2, and ?-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-1?, SIRT1, c-Myc, ?-catenin, and PHD2 were determined by western blot analysis. The data are representative of three individual experiments. Highlights: ? SIRT1 expression is increased in hypoxia-exposed or hypoxic preconditioned cells. ? SIRT1 deacetylates c-Myc and ?-catenin ? HIF-1? is up-regulated by down-regulation of c-Myc and ?-catenin expression. ? Polyphenolic SIRT1 activators mimics hypoxic preconditioning.
Hong, Kyung-Soo [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of) [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Research Center for Ischemic Tissue regeneration, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Park, Jun-Ik [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of)] [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Kim, Mi-Ju; Kim, Hak-Bong; Lee, Jae-Won [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of) [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Research Center for Ischemic Tissue regeneration, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Dao, Trong Tuan; Oh, Won Keun [BK21 Project Team, College of Pharmacy, Chosun University, Gwangju (Korea, Republic of)] [BK21 Project Team, College of Pharmacy, Chosun University, Gwangju (Korea, Republic of); Kang, Chi-Dug, E-mail: email@example.com [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of)] [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Kim, Sun-Hee, E-mail: email@example.com [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of) [Department of Biochemistry, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Research Center for Ischemic Tissue regeneration, Pusan National University School of Medicine, Yangsan (Korea, Republic of)
Progress in Parallel Schur Complement Preconditioning for Computational Fluid Dynamics
NASA Technical Reports Server (NTRS)
We consider preconditioning methods for nonself-adjoint advective-diffusive systems based on a non-overlapping Schur complement procedure for arbitrary triangulated domains. The ultimate goal of this research is to develop scalable preconditioning algorithms for fluid flow discretizations on parallel computing architectures. In our implementation of the Schur complement preconditioning technique, the triangulation is first partitioned into a number of subdomains using the METIS multi-level k-way partitioning code. This partitioning induces a natural 2X2 partitioning of the p.d.e. discretization matrix. By considering various inverse approximations of the 2X2 system, we have developed a family of robust preconditioning techniques. A computer code based on these ideas has been developed and tested on the IBM SP2 and the SGI Power Challenge array using MPI message passing protocol. A number of example CFD calculations will be presented to illustrate and assess various Schur complement approximations.
Barth, Timothy J.; Chan, Tony F.; Tang, Wei-Pai; Chancellor, Marisa K. (Technical Monitor)
40 CFR 86.1232-96 - Vehicle preconditioning.
Code of Federal Regulations, 2013 CFR
...Vehicle preconditioning. (a) Fuel tank cap(s) of gasoline...damage to the components and the integrity of the fuel system. A replacement canister...damage to the components and the integrity of the fuel system. A replacement...
40 CFR 86.132-96 - Vehicle preconditioning.
Code of Federal Regulations, 2013 CFR
...Vehicle preconditioning. (a) Fuel tank cap(s) of gasoline...damage to the components and the integrity of the fuel system. A replacement canister...damage to the components and the integrity of the fuel system. A replacement...
Ischemic stroke is an uncommon, but significant cause of disability in childhood. Children with strokes present with predictable\\u000a deficits as adults do; however, fever and seizures at stroke onset are more common in children than in adults. Strokes in\\u000a children have diverse etiologies and require extensive evaluation. Etiology remains obscure in up to half of the patients.\\u000a Prognosis in childhood
Laurence E. Walsh; Bhuwan P. Garg
\\u000a Ischemic stroke is a heterogeneous disease and occurs due to a multitude of underlying pathologic processes. The brain is\\u000a such an exquisitely sensitive reporting system that small infarctions, well below the size that causes clinical signs in other\\u000a organ systems, can cause major disability in the brain. About 85% of all strokes are due to ischemia, and in the majority
Gisele S. Silva; Walter J. Koroshetz; R. Gilberto Gonz�lez; Lee H. Schwamm
Preconditioning in Cardiomyocytes Protects by Attenuating Oxidant Stress at Reperfusion
Cardiomyocyte death after ischemia\\/reperfusion correlates with oxidant stress, and antioxidants confer protection in that model. Preconditioning (PC) with hypoxia or adenosine also confers protection, leading us to hypothesize that PC protects by attenuating oxidant generation during subsequent ischemia\\/reperfusion. Chick cardiomyocytes were preconditioned with 10 minutes of hypoxia or adenosine (100 mmol\\/L), followed by 1 hour of simulated ischemia and 3
Terry L. Vanden Hoek; Lance B. Becker; Zuo-Hui Shao; Chang-Qing Li; Paul T. Schumacker
Running TCP/IP over ATM Networks.
ERIC Educational Resources Information Center
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)
Witt, Michael
Protein redox modification as a cellular defense mechanism against tissue ischemic injury.
Protein oxidative or redox modifications induced by reactive oxygen species (ROS) or reactive nitrogen species (RNS) not only can impair protein function, but also can regulate and expand protein function under a variety of stressful conditions. Protein oxidative modifications can generally be classified into two categories: irreversible oxidation and reversible oxidation. While irreversible oxidation usually leads to protein aggregation and degradation, reversible oxidation that usually occurs on protein cysteine residues can often serve as an "on and off" switch that regulates protein function and redox signaling pathways upon stress challenges. In the context of ischemic tolerance, including preconditioning and postconditioning, increasing evidence has indicated that reversible cysteine redox modifications such as S-sulfonation, S-nitrosylation, S-glutathionylation, and disulfide bond formation can serve as a cellular defense mechanism against tissue ischemic injury. In this review, I highlight evidence of cysteine redox modifications as protective measures in ischemic injury, demonstrating that protein redox modifications can serve as a therapeutic target for attenuating tissue ischemic injury. Prospectively, more oxidatively modified proteins will need to be identified that can play protective roles in tissue ischemic injury, in particular, when the oxidative modifications of such identified proteins can be enhanced by pharmacological agents or drugs that are available or to be developed. PMID:24883175
Yan, Liang-Jun
Non-Coding RNAs as Potential Neuroprotectants against Ischemic Brain Injury
Over the past decade, scientific discoveries have highlighted new roles for a unique class of non-coding RNAs. Transcribed from the genome, these non-coding RNAs have been implicated in determining the biological complexity seen in mammals by acting as transcriptional and translational regulators. Non-coding RNAs, which can be sub-classified into long non-coding RNAs, microRNAs, PIWI-interacting RNAs and several others, are widely expressed in the nervous system with roles in neurogenesis, development and maintenance of the neuronal phenotype. Perturbations of these non-coding transcripts have been observed in ischemic preconditioning as well as ischemic brain injury with characterization of the mechanisms by which they confer toxicity. Their dysregulation may also confer pathogenic conditions in neurovascular diseases. A better understanding of their expression patterns and functions has uncovered the potential use of these riboregulators as neuroprotectants to antagonize the detrimental molecular events taking place upon ischemic-reperfusion injury. In this review, we discuss the various roles of non-coding RNAs in brain development and their mechanisms of gene regulation in relation to ischemic brain injury. We will also address the future directions and open questions for identifying promising non-coding RNAs that could eventually serve as potential neuroprotectants against ischemic brain injury.
Kaur, Prameet; Liu, Fujia; Tan, Jun Rong; Lim, Kai Ying; Sepramaniam, Sugunavathi; Karolina, Dwi Setyowati; Armugam, Arunmozhiarasi; Jeyaseelan, Kandiah
Protein Redox Modification as a Cellular Defense Mechanism against Tissue Ischemic Injury
Protein oxidative or redox modifications induced by reactive oxygen species (ROS) or reactive nitrogen species (RNS) not only can impair protein function, but also can regulate and expand protein function under a variety of stressful conditions. Protein oxidative modifications can generally be classified into two categories: irreversible oxidation and reversible oxidation. While irreversible oxidation usually leads to protein aggregation and degradation, reversible oxidation that usually occurs on protein cysteine residues can often serve as an �on and off� switch that regulates protein function and redox signaling pathways upon stress challenges. In the context of ischemic tolerance, including preconditioning and postconditioning, increasing evidence has indicated that reversible cysteine redox modifications such as S-sulfonation, S-nitrosylation, S-glutathionylation, and disulfide bond formation can serve as a cellular defense mechanism against tissue ischemic injury. In this review, I highlight evidence of cysteine redox modifications as protective measures in ischemic injury, demonstrating that protein redox modifications can serve as a therapeutic target for attenuating tissue ischemic injury. Prospectively, more oxidatively modified proteins will need to be identified that can play protective roles in tissue ischemic injury, in particular, when the oxidative modifications of such identified proteins can be enhanced by pharmacological agents or drugs that are available or to be developed.
Yan, Liang-Jun
Protection of the ischemic myocardium during the reperfusion: between hope and reality
The heart is an organ that requires an important energy input to ensure its contractile function. Myocardial ischemia happens when there is a deficiency of blood flow that is responsible for the passage from an aerobic to anaerobic metabolism. Myocardial ischemia results from an imbalance between inputs and the needs of nutrient and oxygen to the myocardium. The restoration of myocardial perfusion called reperfusion is a way to save the ischemic myocardium. However, although reperfusion is beneficial for the survival of the ischemic myocardium, it also induces a deleterious effect in addition to that of ischemic stress. Three decade ago, while several studies, strived to elucidate the protective effect of preconditioning, a phenomenon performed before ischemia and having a powerful protective effects against ischemia/reperfusion injury, very few have believed in the possibility of protecting the myocardium after ischemia (during reperfusion). Actually, both ischemic and pharmacological postconditioning as well as controlled reperfusion methods to protect the ischemic heart have proved effective in the reduction of damage related to ischemia/reperfusion. The possibility of protecting the myocardium during reperfusion opens a new area in the research against damage caused by ischemia/reperfusion because these methods are easily transferable in a clinic setting.
Bopassa, Jean Chrisostome
The Mitochondria-Targeted Antioxidants and Remote Kidney Preconditioning Ameliorate Brain Damage through Kidney-to-Brain Cross-Talk
Background Many ischemia-induced neurological pathologies including stroke are associated with high oxidative stress. Mitochondria-targeted antioxidants could rescue the ischemic organ by providing specific delivery of antioxidant molecules to the mitochondrion, which potentially suffers from oxidative stress more than non-mitochondrial cellular compartments. Besides direct antioxidative activity, these compounds are believed to activate numerous protective pathways. Endogenous anti-ischemic defense may involve the very powerful neuroprotective agent erythropoietin, which is mainly produced by the kidney in a redox-dependent manner, indicating an important role of the kidney in regulation of brain ischemic damage. The goal of this study is to track the relations between the kidney and the brain in terms of the amplification of defense mechanisms during SkQR1 treatment and remote renal preconditioning and provide evidence that the kidney can generate signals inducing a tolerance to oxidative stress-associated brain pathologies. Methodology/Principal Findings We used the cationic plastoquinone derivative, SkQR1, as a mitochondria-targeted antioxidant to alleviate the deleterious consequences of stroke. A single injection of SkQR1 before cerebral ischemia in a dose-dependent manner reduces infarction and improves functional recovery. Concomitantly, an increase in the levels of erythropoietin in urine and phosphorylated glycogen synthase kinase-3? (GSK-3?) in the brain was detected 24 h after SkQR1 injection. However, protective effects of SkQR1 were not observed in rats with bilateral nephrectomy and in those treated with the nephrotoxic antibiotic gentamicin, indicating the protective role of humoral factor(s) which are released from functional kidneys. Renal preconditioning also induced brain protection in rats accompanied by an increased erythropoietin level in urine and kidney tissue and P-GSK-3? in brain. Co-cultivation of SkQR1-treated kidney cells with cortical neurons resulted in enchanced phosphorylation of GSK-3? in neuronal cells. Conclusion The results indicate that renal preconditioning and SkQR1-induced brain protection may be mediated through the release of EPO from the kidney.
Silachev, Denis N.; Isaev, Nikolay K.; Pevzner, Irina B.; Zorova, Ljubava D.; Stelmashook, Elena V.; Novikova, Svetlana V.; Plotnikov, Egor Y.; Skulachev, Vladimir P.; Zorov, Dmitry B.
iPS cell sheets created by a novel magnetite tissue engineering method for reparative angiogenesis
Angiogenic cell therapy represents a novel strategy for ischemic diseases, but some patients show poor responses. We investigated the therapeutic potential of an induced pluripotent stem (iPS) cell sheet created by a novel magnetite tissue engineering technology (Mag-TE) for reparative angiogenesis. Mouse iPS cell-derived Flk-1+ cells were incubated with magnetic nanoparticle-containing liposomes (MCLs). MCL-labeled Flk-1+ cells were mixed with diluted extracellular matrix (ECM) precursor and a magnet was placed on the reverse side. Magnetized Flk-1+ cells formed multi-layered cell sheets according to magnetic force. Implantation of the Flk-1+ cell sheet accelerated revascularization of ischemic hindlimbs relative to the contralateral limbs in nude mice as measured by laser Doppler blood flow and capillary density analyses. The Flk-1+ cell sheet also increased the expressions of VEGF and bFGF in ischemic tissue. iPS cell-derived Flk-1+ cell sheets created by this novel Mag-TE method represent a promising new modality for therapeutic angiogenesis.
Kito, Tetsutaro; Shibata, Rei; Ishii, Masakazu; Suzuki, Hirohiko; Himeno, Tatsuhito; Kataoka, Yoshiyuki; Yamamura, Yumiko; Yamamoto, Takashi; Nishio, Naomi; Ito, Sachiko; Numaguchi, Yasushi; Tanigawa, Tohru; Yamashita, Jun K.; Ouchi, Noriyuki; Honda, Hiroyuki; Isobe, Kenichi; Murohara, Toyoaki
Analysis for IP transmission network technologies
Summary form only given, as follows. As applications based on TCP\\/IP will become the main method for data communication and multimedia communication, the IP transmission technology becomes more and more important. Methods have developed from the traditional PPP (point-to-point protocol) mode to IP over ATM, IP over SDH\\/SONET, and IP over DWDM. With applications requiring more and more bandwidth, some
Weidong Ma
Chronic Tempol treatment restores pharmacological preconditioning in the senescent rat heart.
Cardioprotective effects of anesthetic preconditioning and cyclosporine A (CsA) are lost with aging. To extend our previous work and address a possible mechanism underlying age-related differences, we investigated the role of oxidative stress in the aging heart by treating senescent animals with the oxygen free radical scavenger Tempol. Old male Fischer 344 rats (22-24 mo) were randomly assigned to control or Tempol treatment groups for 2 or 4 wk (T�2wk and T�4wk, respectively). Rats received isoflurane 30 min before ischemia-reperfusion injury or CsA just before reperfusion. Myocardial infarction sizes were significantly reduced by isoflurane or CsA in the aged rats treated with Tempol (T�4wk) compared with old control rats. In other experiments, young (4-6 mo) and old rats underwent either chronic Tempol or vehicle treatment, and the levels of myocardial protein oxidative damage, antioxidant enzymes, mitochondrial Ca(2+) uptake, cyclophilin D protein, and mitochondrial permeability transition pore opening times were measured. T�4wk significantly increased MnSOD enzyme activity, GSH-to-GSSH ratios, MnSOD protein level, mitochondrial Ca(2+) uptake capacity, reduced protein nitrotyrosine levels, and normalized cyclophilin D protein expression in the aged rat heart. T�4wk also significantly prolonged mitochondrial permeability transition pore opening times induced by reactive oxygen species in old cardiomyocytes. Our studies demonstrate that 4 wk of Tempol pretreatment restores anesthetic preconditioning and cardioprotection by CsA in the old rat and that this is associated with decreased oxidative stress and improved mitochondrial function. Our results point to a new protective strategy for the ischemic myocardium in the high-risk older population. PMID:23275621
Zhu, Jiang; Rebecchi, Mario J; Wang, Qiang; Glass, Peter S A; Brink, Peter R; Liu, Lixin
Reduction of skeletal muscle injury in composite tissue allotransplantation by heat stress preconditioning.
Ischemia-reperfusion injury is a dominant factor limiting tissue survival in any microsurgical tissue transplantation, a fact that also applies to allogeneic hand transplantation. The clinical experience of the 12 human hand transplantations indicates that shorter ischemia times result in reduced tissue damage and, ultimately, in better hand function. Heat stress preconditioning and the accompanying up-regulation of the heat shock protein 72 have been shown to reduce the ischemia-reperfusion injury following ischemia of various organs, including organ transplantation. The aim of this study was to reduce the ischemia-reperfusion injury in a model of composite tissue allotransplantation. Allogeneic hind limb transplantations were performed from Lewis (donor) to Brown-Norway rats. Donor rats in group A (n = 10) received a prior heat shock whereas rats in group B (n = 10) did not receive any prior heat shock. Group C served as a control group without transplantation. The transplantations were performed 24 hours after the heat shock, at which time the heat shock protein 72 was shown to be up-regulated. The outcome was evaluated 24 hours after transplantation by nitroblue tetrazolium staining and wet-to-dry weight ratio of muscle slices (anterior tibial muscle). The nitroblue tetrazolium staining showed a significant reduction of necrotic muscle in group A (prior heat shock) (p = 0.005). The wet-to-dry ratio was significantly reduced in group A (prior heat shock), indicating less muscle edema and less tissue damage (p = 0.05). Heat shock preconditioning 24 hours before an ischemic event leads to an up-regulation of heat shock protein 72 in muscle and to a tissue protection reducing ischemia-reperfusion injury in composite tissue transplantation. PMID:15577355
Baumeister, Steffen; Ofer, Nina; Kleist, Christian; Terne, Peter; Opelz, Gerhard; Gebhard, Martha Maria; Germann, G�nter; Heitmann, Christoph
Glutamate transporter type 3 mediates isoflurane preconditioning-induced acute phase of neuroprotection in mice.
A pre-exposure to isoflurane reduces ischemic brain injury in rodents (isoflurane preconditioning). This neuroprotection has acute and delayed phases. Our previous in vitro studies suggest that the acute phase may involve excitatory amino acid transporters (EAATs). We determine whether this protection involves EAAT3, the major neuronal EAAT. Adult male EAAT3 knockout mice and their wild-type littermates were exposed or were not exposed to 1.5% isoflurane for 30 min. Sixty minutes later, they were subjected to a 90- or 60-min middle cerebral arterial occlusion (MCAO). Their neurological outcomes were evaluated 24h after the MCAO. In another experiment, cerebral cortex was harvested for Western blotting at 30 min after animals were exposed to 1.5% isoflurane for 30 min. Here, we showed that isoflurane reduced brain infarct volumes and improved neurological functions of wild-type mice after a 90-min MCAO. However, isoflurane pre-exposure did not change the neurological outcome of EAAT3 knockout mice no matter whether the MCAO was for 90 min or 60 min. Isoflurane increased phospho-Akt, a survival-promoting protein, in the wild-type mice but not in the EAAT3 knockout mice. The isoflurane-induced neuroprotection in the wild-type mice was abolished by LY294004, an Akt activation inhibitor. LY294004 alone did not affect the neurological outcome of the wild-type or EAAT3 knockout mice after focal brain ischemia. These results suggest that the isoflurane preconditioning-induced acute phase of neuroprotection involves EAAT3. The downstream event includes Akt activation. PMID:23827345
Li, Liaoliao; Deng, Jiao; Zuo, Zhiyi
NASA Astrophysics Data System (ADS)
On 2012 Aug. 24 Drake et al. (2012, ATel#4334) reported a new outburst from supernova impostor (LBV) SN 2009ip (Smith et al., 2010, AJ, 139, 1451; Foley et al., 2011, ApJ, 732, 32). Observations by Foley et al. (2012, Atel#4338) on Aug 26 UT showed an outburst spectrum similar to a previous event (Foley et al., 2011). Spectroscopic observations by Smith & Mauerhan (2012, ATel#4412) on Sept. 15 & 16 exhibited very broad lines strongly suggesting that SN 2009ip had become a real supernova.
Brimacombe, J.
Ischemic pretreatment delays ischemic brain vasospasm injury in gerbils.
Three experiments were conducted for the present study. First, to elucidate the mechanism and functional significance underlying ischemic vasoconstriction, we investigated the relationship between arteriolar constriction and tissue energy metabolism during bilateral common carotid artery occlusion in gerbils. Second, to identify differences in the postischemic recovery of physiologic parameters between short and prolonged brain ischemia, we measured changes in regional cerebral blood flow, microvessel diameter, brain temperature, and electrophysiologic response. Third, to explore the physiological mechanism of ischemic tolerance, we studied vascular response and intracerebral oxygenation states after acute global ischemia with and without pretreatment by mild ischemic stress. Here, we identify one of the physiologic mechanisms of the ischemic tolerance caused by brief ischemic pretreatment. PMID:24729240
Seiyama, Akitoshi; Yoshikawa, Nao; Imamura, Yukio
Fetal asphyctic preconditioning alters the transcriptional response to perinatal asphyxia
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 mechanisms are likely to play a role in preconditioning-induced neuroprotection.
Reduction in postsystolic wall thickening during late preconditioning.
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
Monnet, Xavier; Lucats, Laurence; Colin, Patrice; Derumeaux, Genevi�ve; Dubois-Rande, Jean-Luc; Hittinger, Luc; Ghaleh, Bijan; Berdeaux, Alain
Pediatric arterial ischemic stroke.
Arterial ischemic stroke (AIS) is a rare disorder in children. Research suggests that risk factors, outcomes, and presentation are different from those of adult stroke. In particular, prothrombotic abnormalities and large vessel arteriopathies that are nonatherosclerotic seem to play a large role in the pathogenesis of childhood AIS. This review examines the epidemiology and etiologies of neonatal and childhood AIS and provides a detailed discussion of approaches to the clinical characterization, diagnostic evaluation, and management. Long-term outcomes of recurrent AIS and neuromotor, speech, cognitive, and behavioral deficits are considered. Emphasis is on evidence underlying current knowledge and key questions for further investigation. PMID:18381089
Bernard, Timothy J; Goldenberg, Neil A
Pediatric arterial ischemic stroke.
Arterial ischemic stroke (AIS) is a rare disorder in children. Research suggests that risk factors, outcomes, and presentation are different from those of adult stroke. In particular, prothrombotic abnormalities and large vessel arteriopathies that are nonatherosclerotic seem to play a large role in the pathogenesis of childhood AIS. This review examines the epidemiology and etiologies of neonatal and childhood AIS and provides a detailed discussion of approaches to the clinical characterization, diagnostic evaluation, and management. Long-term outcomes of recurrent AIS and neuromotor, speech, cognitive, and behavioral deficits are considered. Emphasis is on evidence underlying current knowledge and key questions for further investigation. PMID:20113901
Bernard, Timothy J; Goldenberg, Neil A
IP and ATM integration perspectives
ATM is a widespread technology adopted by many operators to support advanced data communication, in particular efficient Internet services provision. The expected challenges of multimedia communication together with the increasing massive utilization of IP-based applications urgently require redesign of networking solutions in terms of both new functionalities and enhanced performance. An approach based on finding out the best match between
E. Guarene; P. Fasano; V. Vercellone
IP-based hardware design became an important topi c during the past years. There may be an even older tradition of reuse of so ftware components. In this contribution we try to address some key problems of software reuse. First of all, in a bottom-up approach we study the underlying communic ation technique used to couple different software components. As the
Carsten B�ke; Carsten Ditze; H. J. Eickerling; Uwe Gl�sser; Bernd Kleinjohann; Franz Rammig
Wireless cellular networks are quickly evolving towards broadband wireless access networks, going from 2G, classical telephony networks such as Global System for Mobile communication (GSM), towards 3G and beyond, with, for example, Universal Mobile Telecommunication System (UMTS). At the same time, these networks are also moving towards all-IP networks. In this paper, we first describe the global mobility landscape for
Pierre Reinbold; Olivier Bonaventure
Continuously Connected With Mobile IP
NASA Technical Reports Server (NTRS)
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.
Cardiac Protection by Preconditioning Is Generated via an Iron-Signal Created by Proteasomal Degradation of Iron Proteins
Ischemia associated injury of the myocardium is caused by oxidative damage during reperfusion. Myocardial protection by ischemic preconditioning (IPC) was shown to be mediated by a transient �iron-signal� that leads to the accumulation of apoferritin and sequestration of reactive iron released during the ischemia. Here we identified the source of this �iron signal� and evaluated its role in the mechanisms of cardiac protection by hypoxic preconditioning. Rat hearts were retrogradely perfused and the effect of proteasomal and lysosomal protease inhibitors on ferritin levels were measured. The iron-signal was abolished, ferritin levels were not increased and cardiac protection was diminished by inhibition of the proteasome prior to IPC. Similarly, double amounts of ferritin and better recovery after ex vivo ischemia-and-reperfusion (I/R) were found in hearts from in vivo hypoxia pre-conditioned animals. IPC followed by normoxic perfusion for 30 min (�delay�) prior to I/R caused a reduced ferritin accumulation at the end of the ischemia phase and reduced protection. Full restoration of the IPC-mediated cardiac protection was achieved by employing lysosomal inhibitors during the �delay�. In conclusion, proteasomal protein degradation of iron-proteins causes the generation of the �iron-signal� by IPC, ensuing de-novo apoferritin synthesis and thus, sequestering reactive iron. Lysosomal proteases are involved in subsequent ferritin breakdown as revealed by the use of specific pathway inhibitors during the �delay�. We suggest that proteasomal iron-protein degradation is a stress response causing an expeditious cytosolic iron release thus, altering iron homeostasis to protect the myocardium during I/R, while lysosomal ferritin degradation is part of housekeeping iron homeostasis.
Bulvik, Baruch E.; Berenshtein, Eduard; Meyron-Holtz, Esther G.
Chinese Ischemic Stroke Subclassification
Accurate classification of stroke has significant impact on patient care and conduction of stroke clinical trials. The current systems such as TOAST, SSS-TOAST, Korean TOAST, and A�S�C�O have limitations. With the advent of new imaging technology, there is a need to have a more accurate stroke subclassification system. Chinese ischemic stroke subclassification (CISS) system is a new two step system aims at the etiology and then underlying mechanism of a stroke. The first step classify stroke into five categories: large artery atherosclerosis (LAA), including atherosclerosis of aortic arch and intra-/extracranial large arteries, cardiogenic stroke, penetrating artery disease, other etiology, and undetermined etiology. The second step is to further classify the underlying mechanism of ischemic stroke from the intracranial and extracranial LAA into the parent artery (plaque or thrombosis) occluding penetrating artery, artery-to-artery embolism, hypoperfusion/impaired emboli clearance, and multiple mechanisms. Although clinical validation of CISS is being planned, CISS is an innovative system that offers much more detailed information on the pathophysiology of a stroke.
Gao, S.; Wang, Y. J.; Xu, A. D.; Li, Y. S.; Wang, D. Z.
Nanoparticle Pre-Conditioning for Enhanced Thermal Therapies in Cancer
Nanoparticles show tremendous promise in the safe and effective delivery of molecular adjuvants to enhance local cancer therapy. One important form of local cancer treatment that suffers from local recurrence and distant metastases is thermal therapy. Here we review a new concept involving the use of nanoparticle delivered adjuvants to �pre-condition� or alter the vascular and immunological biology of the tumor to enhance its susceptibility to thermal therapy. To this end, a number of opportunities to combine nanoparticles with vascular and immunologically active agents are reviewed. One specific example of pre-conditioning involves a gold nanoparticle tagged with a vascular targeting agent (i.e. TNF-?). This nanoparticle embodiment demonstrates pre-conditioning through a dramatic reduction in tumor blood flow and induction of vascular damage which recruits a strong and sustained inflammatory infiltrate in the tumor. The ability of this nanoparticle pre-conditioning to enhance subsequent heat or cold thermal therapy in a variety of tumor models is reviewed. Finally, the potential for future clinical imaging to judge the extent of pre-conditioning and thus the optimal timing and extent of combinatorial thermal therapy is discussed.
Shenoi, Mithun M.; Shah, Neha B.; Griffin, Robert J.; Vercellotti, Gregory M.; Bischof, John C.
Implementation of Preconditioned Dual-Time Procedures in OVERFLOW
NASA Technical Reports Server (NTRS)
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.
Pandya, Shishir A.; Venkateswaran, Sankaran; Pulliam, Thomas H.; Kwak, Dochan (Technical Monitor)
Pharmacological preconditioning with adenosine A1 receptor agonist suppresses cellular immune response by an A2A receptor dependent mechanism.
Under stressful conditions such as ischemia, sepsis, and severe trauma, adenosine levels are elevated and protect the tissue by interaction with G coupled receptors. In a model of peritonitis, we previously found that pharmacological preconditioning (PPC) of mice with a selective adenosine A1 receptor (A1R) agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA), induced the A2AR which reduces cytokine secretion and leukocyte recruitment. In our present study we determined whether mice PPC will moderate cellular immune response by the same mechanism. Similar to the effect on inflammation, PPC reduced the response to lymphocyte mitogens and allogeneic MLR response. The inhibitory effect of PPC on the immune response was A1R and A2AR dependent as illustrated by experiments with antagonists of these receptors and mice with knock down (KO) receptors. In MLR with PPC splenocytes we found reduced levels of pro-inflammatory cytokines (IFN-?, IL-15, TNF-?) and elevation of IL-10, as well as elevation of regulatory T-cell. Our data indicate that PPC is able to remarkably suppress cellular immune response due to the sensitization A2AR. This effect of PPC sheds light on the protective role of adenosine in ischemic preconditioning and makes this treatment candidate for the prevention of graft rejection. PMID:24560904
Naamani, Oshri; Chaimovitz, Cidio; Douvdevani, Amos
Ozone preconditioning and exposure to ketamine attenuates hepatic inflammation in septic rats
Introduction The objective of this study was to evaluate the interaction between ozone oxidative preconditioning and the anesthetic ketamine on cytoplasmic nuclear factor ?B (NF-?B) levels in a rat endotoxic shock model. Material and methods Forty Wistar rats were randomly divided into 5 groups: I � control group; II � rats intraperitoneally (i.p.) treated with LPS; III � rats treated with LPS and then treated with ketamine; IV � animals pre-treated with O3/O2 mixture for 5 days, then treated with LPS for 24 h followed by infusion with ketamine; V � O3/O2 pre-treatment, as described above for IV, followed by LPS infusion, and then 0.9% saline. In addition to histological examination of the liver, the levels of NF-?B were determined by SABC immunohistochemistry in each group. Results Histological damage was observed in the lipopolysaccharide (LPS) group. It was characterized by hepatic disarray, hepatic lobule distortion, congestion of liver sinusoids, hepatocyte swelling and necrosis, and granulocyte infiltration. These changes were not obvious in the O3/O2 + LPS + ketamine group. The normal control group had low activity of NF-?B, but that activity was markedly increased in the LPS group (p < 0.05). The NF-?B level was significantly decreased in the O3/O2 + LPS + ketamine group (p < 0.05) when compared with the ketamine-treated group, and was almost equal to the control group. Conclusions We confirmed that the preconditioning effect of ozone enhances the biological effectiveness of ketamine by altering NF-?B activity, which may play an important role in sepsis-induced liver injury in rats.
Sun, Wenchong
Hyperthermia conditioned astrocyte-cultured medium protects neurons from ischemic injury by the up-regulation of HIF-1 alpha and the increased anti-apoptotic ability
It has been demonstrated that conditioned medium from astrocytes challenged by in vitro ischemia (oxygen�glucose deprivation, OGD) improved neuronal survival. In addition, preconditioning stimuli can be cross-tolerant, safeguarding against other types of injury. We therefore hypothesized that hyperthermia-conditioned astrocyte-cultured medium (ACM) might also have protective effect on neurons against ischemic injury. The cultured-media, named 38ACM and 40ACM respectively, were collected
Fang Du; Xiao Mei Wu; Qi Gong; Xuan He; Ya Ke
Intravenous transplantation of mesenchymal stem cells preconditioned with early phase stroke serum: current evidence and study protocol for a randomized trial
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.
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
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.
Wikiel, H.; Halat, G.; Strosznajder, J.
Liquid hydrogen turbopump rapid start program. [thermal preconditioning using coatings
NASA Technical Reports Server (NTRS)
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.
Wong, G. S.
On adaptive weighted polynomial preconditioning for Hermitian positive definite matrices
NASA Technical Reports Server (NTRS)
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.
Fischer, Bernd; Freund, Roland W.
Neuroprotective strategies in acute ischemic stroke
Focal ischemic injury in the brain is related to both the intensity and the duration of the decrement of cerebral blood flow. The ischemic penumbra is an area characterized by levels of blood flow slightly greater than that in the ischemic core itself. In this area, metabolic rate is preserved or is even higher, probably because of a recurrent ischemic
G. A. Ottonello; G. Brusa; V. Montano; G. Regesta; T. Regesta; A. Seneghini
The Role of Ionospheric Outflow Preconditioning in Determining Storm Geoeffectiveness
NASA Astrophysics Data System (ADS)
It is now well accepted that ionospheric outflow plays an important role in the development of the plasma sheet and ring current during geomagnetic storms. Furthermore, even during quiet times, ionospheric plasma populates the magnetospheric lobes, producing a reservoir of hydrogen and oxygen ions. When the Interplanetary Magnetic Field (IMF) turns southward, this reservoir is connected to the plasma sheet and ring current through magnetospheric convection. Hence, the conditions of the ionosphere and magnetospheric lobes leading up to magnetospheric storm onset have important implications for storm development. Despite this, there has been little research on this preconditioning; most global simulations begin just before storm onset, neglecting preconditioning altogether. This work explores the role of preconditioning in determining the geoeffectiveness of storms using a coupled global model system. A model of ionospheric outflow (the Polar Wind Outflow Model, PWOM) is two-way coupled to a global magnetohydrodynamic model (the Block-Adaptive Tree Solar wind Roe-type Upwind Scheme, BATS-R-US), which in turn drives a ring current model (the Ring current Atmosphere interactions Model, RAM). This unique setup is used to simulate an idealized storm. The model is started at many different times, from 1 hour before storm onset to 12 hours before. The effects of storm preconditioning are examined by investigating the total ionospheric plasma content in the lobes just before onset, the total ionospheric contribution in the ring current just after onset, and the effects on Dst, magnetic elevation angle at geosynchronous, and total ring current energy density. This experiment is repeated for different solar activity levels as set by F10.7 flux. Finally, a synthetic double-dip storm is constructed to see how two closely spaced storms affect each other by changing the preconditioning environment. It is found that preconditioning of the magnetospheric lobes via ionospheric outflow greatly influences the geoeffectiveness of magnetospheric storms.
Welling, D. T.; Liemohn, M. W.; Ridley, A. J.
Newton-preconditioned Krylov subspace solvers for system of nonlinear equations: A numerical experiment
In this paper, we present a numerical comparative study of the Newton-preconditioned Lanczos algorithms and Newton-preconditioned CG-like methods, with respect to convergence speed and CPU-time, by considering appropriate test problems.
S. Sundar; B. K. Bhagavan; S. Prasad
40 CFR 92.125 - Pre-test procedures and preconditioning.
Code of Federal Regulations, 2013 CFR
...2013-07-01 2013-07-01 false Pre-test procedures and preconditioning. 92.125 Section...POLLUTION FROM LOCOMOTIVES AND LOCOMOTIVE ENGINES Test Procedures § 92.125 Pre-test procedures and preconditioning. (a)...
40 CFR 85.2218 - Preconditioned idle test-EPA 91.
Code of Federal Regulations, 2013 CFR
... 2013-07-01 false Preconditioned idle test-EPA 91. 85.2218 Section 85.2218 ...Emission Control System Performance Warranty Short Tests § 85.2218 Preconditioned idle test�EPA 91. (a) General requirements...
IP 3 receptors: the search for structure
Inositol (1,4,5)-trisphosphate receptors (IP3R) are intracellular Ca2+ channels that are regulated by Ca2+ and IP3, and are modulated by many additional signals. They thereby allow both receptors that stimulate IP3 formation and Ca2+ to control release of Ca2+ from intracellular stores. IP3Rs share many features with their close relatives, ryanodine receptors; each provides insight into the structure and function of
Colin W. Taylor; Paula C. A. da Fonseca; Edward P. Morris
Choice of Variables and Preconditioning for Time Dependent Problems
NASA Technical Reports Server (NTRS)
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.
Turkel, Eli; Vatsa, Verr N.
Mitochondrial reactive oxygen species: A double edged sword in ischemia/reperfusion vs preconditioning
Reductions in the blood supply produce considerable injury if the duration of ischemia is prolonged. Paradoxically, restoration of perfusion to ischemic organs can exacerbate tissue damage and extend the size of an evolving infarct. Being highly metabolic organs, the heart and brain are particularly vulnerable to the deleterious effects of ischemia/reperfusion (I/R). While the pathogenetic mechanisms contributing to I/R-induced tissue injury and infarction are multifactorial, the relative importance of each contributing factor remains unclear. However, an emerging body of evidence indicates that the generation of reactive oxygen species (ROS) by mitochondria plays a critical role in damaging cellular components and initiating cell death. In this review, we summarize our current understanding of the mechanisms whereby mitochondrial ROS generation occurs in I/R and contributes to myocardial infarction and stroke. In addition, mitochondrial ROS have been shown to participate in preconditioning by several pharmacologic agents that target potassium channels (e.g., ATP-sensitive potassium (mKATP) channels or large conductance, calcium-activated potassium (mBKCa) channels) to activate cell survival programs that render tissues and organs more resistant to the deleterious effects of I/R. Finally, we review novel therapeutic approaches that selectively target mROS production to reduce postischemic tissue injury, which may prove efficacious in limiting myocardial dysfunction and infarction and abrogating neurocognitive deficits and neuronal cell death in stroke.
Kalogeris, Theodore; Bao, Yimin; Korthuis, Ronald J.
Diabetic Inhibition of Preconditioning- and Postconditioning-Mediated Myocardial Protection against Ischemia/Reperfusion Injury
Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortality of diabetic patients with acute myocardial infarction was found to be 2�6 folds higher than that of non-diabetic patients with same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms. Both IPC- and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3? pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3? pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibition of IPC- and Ipost-mediated myocardial protection may be mediated by inhibiting PI3K/Akt and associated GSK-3? pathway. Therefore any strategy to activate PI3K/Akt and associated GSK-3? pathway to release the diabetic inhibition of both IPC and Ipost-mediated myocardial protection may provide the protective effect against ischemia/reperfusion injuries.
Yin, Xia; Zheng, Yang; Zhai, Xujie; Zhao, Xin; Cai, Lu
The Impact of Experimental Preconditioning Using Vascular Endothelial Growth Factor in Stroke and Subarachnoid Hemorrhage
Vascular endothelial growth factor (VEGF) stimulating angiogenesis was shown to be a potential novel therapeutic approach for the treatment of ischemic vascular diseases. The goal of the present study was to examine whether transfection of VEGF before occurrence of major stroke (part I) and cerebral vasospasm after experimental subarachnoid hemorrhage (SAH; part II) develops neuroprotective qualities. A total of 25 (part I) and 26 (part II) brains were analyzed, respectively. In part one, a significant reduction of infarct volume in the VEGF-treated stroke animals (43% reduction, P < 0.05) could be detected. In part two, significant vasospasm was induced in all hemorrhage groups (P < 0.02). Analyzing microperfusion, a significant higher amount of perfused vessels could be detected (P < 0.01), whereas no significant effect could be detected towards macroperfusion. Histologically, no infarctions were observed in the VEGF-treated SAH group and the sham-operated group. Minor infarction in terms of vasospasm-induced small lesions could be detected in the control vector transduced group (P = 0.05) and saline-treated group (P = 0.09). The present study demonstrates the preconditioning impact of systemic intramuscular VEGF injection in animals after major stroke and induced severe vasospasm after SAH.
Eicker, Sven Oliver; Hoppe, Moritz; Etminan, Nima; Macht, Stephan; Perrin, Jason; Steiger, Hans-Jakob; Hanggi, Daniel
The impact of experimental preconditioning using vascular endothelial growth factor in stroke and subarachnoid hemorrhage.
Vascular endothelial growth factor (VEGF) stimulating angiogenesis was shown to be a potential novel therapeutic approach for the treatment of ischemic vascular diseases. The goal of the present study was to examine whether transfection of VEGF before occurrence of major stroke (part I) and cerebral vasospasm after experimental subarachnoid hemorrhage (SAH; part II) develops neuroprotective qualities. A total of 25 (part I) and 26 (part II) brains were analyzed, respectively. In part one, a significant reduction of infarct volume in the VEGF-treated stroke animals (43% reduction, P < 0.05) could be detected. In part two, significant vasospasm was induced in all hemorrhage groups (P < 0.02). Analyzing microperfusion, a significant higher amount of perfused vessels could be detected (P < 0.01), whereas no significant effect could be detected towards macroperfusion. Histologically, no infarctions were observed in the VEGF-treated SAH group and the sham-operated group. Minor infarction in terms of vasospasm-induced small lesions could be detected in the control vector transduced group (P = 0.05) and saline-treated group (P = 0.09). The present study demonstrates the preconditioning impact of systemic intramuscular VEGF injection in animals after major stroke and induced severe vasospasm after SAH. PMID:23634319
Eicker, Sven Oliver; Hoppe, Moritz; Etminan, Nima; Macht, Stephan; Perrin, Jason; Steiger, Hans-Jakob; H�nggi, Daniel
Two vendor-independent network protocols that have risen to the top of the list of contenders for the title of `the' standard are described and compared. They are the transmission control protocol\\/internet protocol (TCP\\/IP), which was developed in the late 1960s as a research project conducted by the US Department of Defense, and the open systems interconnection reference model (OSIRM, or
D. Meyer; G. Zobrist
NASA Technical Reports Server (NTRS)
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.
Randolph, Lynwood P.
On Service Level Agreements for IP Networks
Many corporate WAN architects are considering migrating from costly leased line circuits to 'private IP' services. In order to do so IP service providers must provide Service Level Agreements (SLAs) that offer robust assurances that cover service availability and performance. The industry direction is to model IP SLAs after those offered by frame relay networks. The reality however is that
Jim Martin; Arne A. Nilsson
PSAT: Proactive Signaling Architecture for IP Traceback
As the Internet becomes pervasive, the vulnerability of some fundamental design aspects of the Internet has also become relevant. The rising threat of cyber attacks makes the IP traceback problem very relevant to today's Internet security. Unfortunately, there is no easy way to track IP traffic to its source due to the stateless nature of the IP protocol, and to
Ahmad Fadlallah; Ahmed Serhrouchni
Securing IP backbones in building automation networks
The use of IP networks as common backbone is becoming of increased interest in today's building automation systems (BAS). With the use of IP also new attack scenarios that threaten the overall security of BAS are introduced. Due to the absence of native security mechanisms in IP and because of its long standing and pervasive use in the IT world,
Wolfgang Granzer; Daniel Lechner; Fritz Praus; Wolfgang Kastner
Faster IP Lookups Using Controlled Prefix Expansion
Internet (IP) address lookup is a major bottleneck in high performance routers. IP address lookup is challenging because it requires . Controlled prefix expansion, together with optimization techniques based on dynamic programming, can be used to improve the speed of the best known IP lookup algorithms by at least a factor of two. When applied to trie search, our techniques
Venkatachary Srinivasan; George Varghese
ERIC Educational Resources Information Center
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,�
Young, Dan
Mobile IP in a heterogenous environment
Mobile IP is a network layer protocol that enables mobility across IP networks without having to change any configuration parameters or IP addresses. It is specified as an IETF standard and appears in two versions, MIPv4 and MIPv6. This paper describes a testbed and some experiments that were conducted to ascertain the functionality of an implementation of MIPv4. The testbed
S. Jayasinghe; J. Ball; C. Tran; C. Lee
The Spacelab IPS Star Simulator
NASA Astrophysics Data System (ADS)
The cost of doing business in space is very high. If errors occur while in orbit the costs grow and desired scientific data may be corrupted or even lost. The Spacelab Instrument Pointing System (IPS) Star Simulator is a unique test bed that allows star trackers to interface with simulated stars in a laboratory before going into orbit. This hardware-in-the-loop testing of equipment on earth increases the probability of success while in space. The IPS Star Simulator provides three fields of view 2.55 x 2.55 deg each for input into star trackers. The fields of view are produced on three separate monitors. Each monitor has 4096 x 4096 addressable points and can display 50 stars (pixels) maximum at a given time. The pixel refresh rate is 1000 Hz. The spectral output is approximately 550 nm. The available relative visual magnitude range is two to eight visual magnitudes. The star size is less than 100 arcsec. The minimum star movement is less than 5 arcsec and the relative position accuracy is approximately 40 arcsec. The purpose of this paper is to describe the IPS Star Simulator design and to provide an operational scenario so others may gain from the approach and possible use of the system.
Wessling, Francis C., III
The Spacelab IPS Star Simulator
NASA Technical Reports Server (NTRS)
The cost of doing business in space is very high. If errors occur while in orbit the costs grow and desired scientific data may be corrupted or even lost. The Spacelab Instrument Pointing System (IPS) Star Simulator is a unique test bed that allows star trackers to interface with simulated stars in a laboratory before going into orbit. This hardware-in-the-loop testing of equipment on earth increases the probability of success while in space. The IPS Star Simulator provides three fields of view 2.55 x 2.55 deg each for input into star trackers. The fields of view are produced on three separate monitors. Each monitor has 4096 x 4096 addressable points and can display 50 stars (pixels) maximum at a given time. The pixel refresh rate is 1000 Hz. The spectral output is approximately 550 nm. The available relative visual magnitude range is two to eight visual magnitudes. The star size is less than 100 arcsec. The minimum star movement is less than 5 arcsec and the relative position accuracy is approximately 40 arcsec. The purpose of this paper is to describe the IPS Star Simulator design and to provide an operational scenario so others may gain from the approach and possible use of the system.
Wessling, Francis C., III
Preconditioning decreases ischemia\\/reperfusion-induced release and activation of matrix metalloproteinase-2
Release and activation of matrix metalloproteinases (MMPs) significantly contribute to myocardial stunning injury immediately after ischemia and reperfusion, however, their role in preconditioning remains unknown. We therefore examined the effects of preconditioning and subsequent ischemia\\/reperfusion on MMP activity in isolated rat hearts. Hearts were subjected to a preconditioning protocol (three consecutive 5-min periods of global ischemia interspersed with 5min of
Manoj M Lalu; Csaba Csonka; Zolt�n Giricz; Tam�s Csont; Richard Schulz; P�ter Ferdinandy
Mobile-ip Aeronautical Network Simulation Study
NASA Technical Reports Server (NTRS)
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.
Ivancic, William D.; Tran, Diepchi T.
Neuroprotective properties of prostaglandin I2 IP receptor in focal cerebral ischemia.
We and others have identified that inhibition of cyclooxygenase might not be the optimal approach to limiting brain damage after stroke. Now we are investigating the unique properties of the various prostaglandin receptors to determine whether blocking those that mediate toxicity or stimulating those that reduce toxicity will improve neurological outcomes. Here, we determined the respective contribution of the prostaglandin I(2) (PGI(2)) receptor in transient middle cerebral artery (MCA) occlusion (tMCAO) and permanent MCAO (pMCAO) preclinical stroke models by using male wildtype (WT) and IP receptor knockout (IP(-/-)) C57Bl/6 mice. In addition, we investigated the putative preventive and therapeutic effects of the IP receptor agonist beraprost. The infarct volumes and neurological deficit scores (NDS) were significantly greater in IP(-/-) than in WT mice after both tMCAO and pMCAO. Interestingly, beraprost pretreatment (50 or 100 microg/kg p.o.) 30 min before tMCAO and post-treatment (100 microg/kg p.o.) at 2 or 4.5 h of reperfusion significantly reduced the neurological deficit score and infarct volume in WT mice. Post-treatment with beraprost (100 microg/kg p.o.) 4.5 h after pMCAO also significantly decreased neurological deficits and infarct volume in WT mice. Together, these novel findings suggest for the first time that PGI(2) IP receptor activation can attenuate anatomical and functional damage following ischemic stroke. PMID:20621166
Saleem, S; Shah, Z A; Maruyama, T; Narumiya, S; Dor�, S
Ischemic heart disease in pregnancy.
While ischemic heart disease in reproductive-age women is rare, cardiac disease is a leading cause of maternal mortality. In turn, coronary artery disease is one of the most common causes of maternal cardiac death. The incidence of coronary artery disease in pregnancy may be rising due to the increasing prevalence of comorbid risk factors. Diagnosis and clinical management of ischemic cardiac disease is largely similar in the pregnant and non-pregnant patient, and the majority of medications and diagnostic and interventional procedures are compatible with pregnancy with a few important exceptions. Care for ischemic cardiac disease in pregnancy may be suboptimal because: (1) diagnosis is delayed because many symptoms of ischemic cardiac disease are common in pregnancy, (2) a diagnostic workup is insufficiently thorough, and/or (3) consultants may be hesitant to perform diagnostic and interventional procedures in obstetric patients. Obstetric providers should be aware of the possibility of ischemic cardiac disease in pregnancy, particularly in patients with comorbid risk factors. If ischemic cardiac disease is suspected, a thorough workup should be performed. PMID:25037521
Turitz, Amy L; Friedman, Alexander M
40 CFR 86.132-00 - Vehicle preconditioning.
Code of Federal Regulations, 2013 CFR
...highway, US06 or SC03 test cycles. (ii) [Reserved] (iii) If a manufacturer has concerns about fuel effects on adaptive memory systems, a manufacturer may precondition a test vehicle on test fuel and the US06 cycle. Upon request from a...
Toward Knowledge Preconditions for Composition of SemanticWeb Services
Several researches have been proposed to formalize the knowledge preconditions problem; an action or a plan is epistemically feasible. However, since the feasibility is only checked at design-time and is assumed that it also will be carried out at run-time, it is not suitable in the context of Web services composition, where the transaction is important in the distributed environment.
Sang-kyun Kim; Taekyung Lee; Kyu-chul Lee
Application of Dijkstra's weakest precondition calculus to Dining Philosophers problem
Dijkstra's weakest precondition calculus is used to model the well known Dining Philosophers problem. Process and state definitions are done in such a manner that only the deadlock property of the system is highlighted. Care has been taken to choose the proper details such that it is not too elaborate to obscure the requirements also not be too abstract to
Jayasri Banerjee; Anup Kumar Bandyopadhyay; Ajit Kumar Mandal
Weighted graph based ordering techniques for preconditioned conjugate gradient methods
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,
SIMON S. CLIFTIand; Wei-Pai Tang
A component decomposition preconditioning for 3D stress analysis problems
SUMMARY A preconditioning methodology for an iterative solution of discrete stress analysis problems based on a space decomposition and subspace correction framework is analysed in this paper. The principle idea of our approach is the decomposition of a global discrete system into the ser ies of subproblems that correspond to the different Cartesian coordinates of the solution (displacement) vect or.
M. D. Mihajlovic; S. Mijalkovic
Preconditioning Indefinite Systems in Interior Point Methods for Optimization
Every Newton step in an interior-point method for optimization requires a solution of a symmetric indefinite system of linear equations. Most of today's codes apply direct solution methods to perform this task. The use of logarithmic barriers in interior point methods causes unavoidable ill-conditioning of linear systems and, hence, iterative methods fail to provide sufficient accuracy unless appropriately preconditioned. Two
Luca Bergamaschi; Jacek Gondzio; Giovanni Zilli
Towards bulk based preconditioning for quantum dot computations
This article describes how to accelerate the con- vergence 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
Jack Dongarra; Julien Langou; Stanimire Tomov; Christof V; Lin-Wang Wang
Time-derivative preconditioning method for multicomponent flow
NASA Astrophysics Data System (ADS)
A time-derivative preconditioned system of equations suitable for the numerical simulation of single component and multicomponent inviscid flows at all speeds is formulated. The system is shown to be hyperbolic in time and remain well-posed at low Mach numbers, allowing an efficient time marching solution strategy to be utilized from transonic to incompressible flow speeds. For multicomponent flow at low speed, a preconditioned nonconservative discretization scheme is described which preserves pressure and velocity equilibrium across fluid interfaces, handles sharp liquid/gas interfaces with large density ratios, while remaining well-conditioned for time marching methods. The method is then extended to transonic and supersonic flows using a hybrid conservative/nonconservative formulation which retains the pressure/velocity equilibrium property and converges to the correct weak solution when shocks are present. In order to apply the proposed model to complex flow applications, the overset grid methodology is used where the equations are transformed to a nonorthogonal curvilinear coordinate system and discretized on structured body-fitted curvilinear grids. The multicomponent model and its extension to homogeneous multiphase mixtures is discussed and the hyperbolicity of the governing equations is demonstrated. Low Mach number perturbation analysis is then performed on the system of equations and a local time-derivative preconditioning matrix is derived allowing time marching numerical methods to remain efficient at low speeds. Next, a particular time marching numerical method is presented along with three discretization schemes for the convective terms. These include a conservative preconditioned Roe type method, a nonconservative preconditioned Split Coefficient Matrix (SCM) method, and hybrid formulation which combines the conservative and nonconservative schemes using a simple switching function. A characteristic boundary treatment which includes time-derivative preconditioning as well as an implicit line relaxation procedure including a semi-implicit boundary update procedure is described. For unsteady flow analysis, a dual time stepping framework is also described. Results for single component and multicomponent/multiphase flows are reported to demonstrate the capability of the proposed time-derivative preconditioning methods. The robustness, performance, and accuracy of the nonconservative and hybrid approaches are emphasized, and comparisons between these methods and a conservative approach are discussed.
Housman, Jeffrey Allen
The Role of Preconditioning on Thermosphere Mass Density (Invited)
NASA Astrophysics Data System (ADS)
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 behaviors in the mass density at altitudes near 500 km throughout the extended solar minimum from 2007 to 2010. Consequently it will be shown that the level of response of the thermosphere mass density will vary with altitude that depends on the thermosphere preconditioned state, with significant contributions provided by the relative dynamics of the thermosphere composition.
Thayer, J. P.; Liu, X.
Protective Effect of Grape Seed Proanthocyanidins against Liver Ischemic Reperfusion Injury: Particularly in Diet-Induced Obese Mice
Background: Hepatic ischemia and reperfusion injury (IRI) is a major complication in liver surgery, and hepatic steatosis is a primary factor aggravating cellular injury during IRI. Both pro-inflammatory cytokines and reactive oxygen species (ROS) are key mediators of hepatic IRI. Ischemic preconditioning (IpreC), remote ischemia preconditioning (RIPC) and ischemic postconditioning (IpostC) have offered protections on hepatic IRI, but all these methods have their own shortcomings. Grape seed proanthocyanidins (GSP) has a broad spectrum of pharmacological properties against oxidative stress. Thus, GSP has potential protective effects against hepatic IRI. Methods: C57BL/6 mice suffering 30mins hepatic ischemia process were sacrificed after 1h reperfusion to build murine warm hepatic IRI model. The mice were injected GSP intraperitoneally 10, 20, 40mg/kg/day for 3 weeks as pharmacological preconditioning. Obese mice fed with high-fat diet for 24 weeks before used. Three pathways related to IRI, including ROS elimination, pro-inflammatory cytokines release and hypoxia responses were examined. Results: Our data show that GSP could significantly reduce hepatic IRI by protecting hepatocyte function and increasing the activity of ROS scavengers, as well as decreasing cytokines levels. At the same time, GSP also enhance the hypoxia tolerance response. Combined GSP and postconditioning can provided synergistic protection. In the obese mice suffering hepatic IRI group, GSP was more effective than postconditioning on protecting liver against IRI, and the combined strategy was obviously superior to the solo treatment. Conclusion: GSP could protect liver against IRI: particularly in high-fat diet induced obese mice. GSP used as pharmacological preconditioning and combined with other protocols have huge potential to be used in clinical.
Song, Xiaoyu; Xu, Hongde; Feng, Yanling; Li, Xiaoman; Lin, Meina; Cao, Liu
Applying a gaming approach to IP strategy.
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
Gasnier, Arnaud; Vandamme, Luc
The Spacelab IPS Star Simulator
NASA Technical Reports Server (NTRS)
The cost of doing business in space is very high. If errors occur while in orbit the costs grow and desired scientific data may be corrupted or even lost. The Spacelab Instrument Pointing System (IPS) Star Simulator is a unique test bed that allows star trackers to interface with simulated stars in a laboratory before going into orbit. This hardware-in-the loop testing of equipment on earth increases the probability of success while in space. The IPS Star Simulator provides three fields of view 2.55 x 2.55 degrees each for input into star trackers. The fields of view are produced on three separate monitors. Each monitor has 4096 x 4096 addressable points and can display 50 stars (pixels) maximum at a given time. The pixel refresh rate is 1000 Hz. The spectral output is approximately 550 nm. The available relative visual magnitude range is 2 to 8 visual magnitudes. The star size is less than 100 arc seconds. The minimum star movement is less than 5 arc seconds and the relative position accuracy is approximately 40 arc seconds. The purpose of this paper is to describe the LPS Star Simulator design and to provide an operational scenario so others may gain from the approach and possible use of the system.
Wessling, Francis C., III
Analysis of Handoff Mechanisms in Mobile IP
NASA Astrophysics Data System (ADS)
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.
Jayaraj, Maria Nadine Simonel; Issac, Biju; Haldar, Manas Kumar
Empirical comparison of IP reputation databases
IP reputation is a common technique to address email spam problem and while there are commercial implementations available, the algorithms behind them are confidential. A few open source implementations (gossip, RepuScore, IP-GroupREP, etc.) are available, but few studies compare their commercial counterparts. For this reason, we have made an empirical comparison of six popular commercial IP reputation databases and three
Jernej Porenta; Mojca Ciglari?
Selective inhibition of inositol hexakisphosphate kinases (IP6Ks) enhances mesenchymal stem cell engraftment and improves therapeutic efficacy for myocardial infarction.
5-Diphosphoinositol pentakisphosphate (IP7), formed by a family of inositol hexakisphosphate kinases (IP6Ks), has been demonstrated to be a physiologic inhibitor of Akt. IP6K inhibition may increase Akt activation in mesenchymal stem cells (MSCs), resulting in enhanced cardiac protective effect after transplantation. The aim of this study was to investigate the role of IP6Ks for improving MSCs' functional survival and cardiac protective effect after transplantation into infarcted mice hearts. Bone marrow-derived mesenchymal stem cells, isolated from dual-reporter firefly luciferase and enhanced green fluorescent protein positive (Fluc(+)-eGFP(+)) transgenic mice, were preconditioned with IP6Ks inhibitor TNP (0.5, 1, 5, and 10�?mol/L) for 2�h followed by 6�h of hypoxia and serum deprivation (H/SD) injury. TNP concentration dependently significantly decreased IP7 production with increased Akt phosphorylation. Moreover, TNP at 10�?mol/L significantly improved the viability and enhanced the paracrine effect of MSCs after H/SD. Furthermore, MSCs were transplanted into infarcted hearts with or without selective IP6Ks inhibition. Longitudinal in vivo bioluminescence imaging and immunofluorescent staining revealed that TNP pretreatment enhanced the survival of engrafted MSCs, which promoted the anti-apoptotic and pro-angiogenic efficacy of MSCs in vivo. Furthermore, MSC therapy with IP6Ks inhibition significantly decreased fibrosis and preserved heart function. This study demonstrates that inhibition of IP6Ks promotes MSCs engraftment and paracrine effect in infarcted hearts at least in part by down-regulating IP7 production and enhancing Akt activation, which might contribute to the preservation of myocardial function after MI. PMID:24847908
Zhang, Zheng; Liang, Dong; Gao, Xue; Zhao, Chuanxu; Qin, Xing; Xu, Yong; Su, Tao; Sun, Dongdong; Li, Weijie; Wang, Haichang; Liu, Bing; Cao, Feng
Mitochondrial ROS production and subsequent ERK phosphorylation are necessary for temperature preconditioning of isolated ventricular myocytes
Hypothermia and hypothermic preconditioning are known to be profoundly cardioprotective, but the molecular mechanisms of this protection have not been fully explained. In this study, temperature preconditioning (16?�C) was found to be cardioprotective in isolated adult rat ventricular myocytes, enhancing contractile recovery and preventing calcium dysregulation after oxidative stress. Hypothermic preconditioning preserved mitochondrial function by delaying the pathological opening of the mitochondrial permeability transition pore (mPTP), whereas transient mPTP flickering remained unaltered. For the first time, reactive oxygen species (ROS) from the mitochondria are shown to be released exclusively during the hypothermic episodes of the temperature-preconditioning protocol. Using a mitochondrially targeted ROS biosensor, ROS release was shown during the brief bursts to 16?�C of temperature preconditioning. The ROS scavenger N-(2-mercaptopropionyl) glycine attenuated ROS accumulation during temperature preconditioning, abolishing the protective delay in mPTP opening. Temperature preconditioning induces ROS-dependant phosphorylation of the prosurvival kinase extracellular signal-regulated kinase (ERK)1/2. ERK1/2 activation was shown to be downstream of ROS release, as the presence of a ROS scavenger during temperature preconditioning completely blocked ERK1/2 activation. The cardioprotective effects of temperature preconditioning on mPTP opening were completely lost by inhibiting ERK1/2 activation. Thus, mitochondrial ROS release and ERK1/2 activation are both necessary to signal the cardioprotective effects of temperature preconditioning in cardiac myocytes.
Bhagatte, Y; Lodwick, D; Storey, N
Is There a Place for Cerebral Preconditioning in the Clinic?
Preconditioning (PC) describes a phenomenon whereby a sub-injury-inducing stress can protect against a later injurious stress.\\u000a Great strides have been made in identifying the mechanisms of PC-induced protection in animal models of brain injury. While\\u000a these may help elucidate potential therapeutic targets, there are questions over the clinical utility of cerebral PC, primarily\\u000a because of questions over the need to
Richard F. Keep; Michael M. Wang; Jianming Xiang; Ya Hua; Guohua Xi
Can preconditioning reduce laparoscopy-induced tissue injury?
Background: Pneumoperitoneum (P) created to facilitate laparoscopy (L) is associated with splanchnic perfusion, ischemia\\/reperfusion (I\\/R) injury, and oxidative stress. In this randomized controlled experimental study with blind outcome assessment, we evaluated the effect of preconditioning (PRE) on L-induced I\\/R injury. Methods: The subjects were 40 Sprague-Dawley male rats. P was created in all except controls, using carbondioxide (CO 2) insufflation
S. Yilmaz; T. Koken; C. Tokyol; A. Kahraman; G. Akbulut; M. Serteser; C. Polat; C. Gokce; O. Gokce
Preconditioned Alternating Projection Algorithms for Maximum a Posteriori ECT Reconstruction
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.
Krol, Andrzej; Li, Si; Shen, Lixin; Xu, Yuesheng
Parallel Domain Decomposition Preconditioning for Computational Fluid Dynamics
NASA Technical Reports Server (NTRS)
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.
Barth, Timothy J.; Chan, Tony F.; Tang, Wei-Pai; Kutler, Paul (Technical Monitor)
Analysis of TCP\\/IP Protocol Stack for a Hybrid TCP\\/IP Offload Engine
\\u000a TCP\\/IP, the most popular communication protocol, is processed on a host CPU in traditional computer systems and this imposes\\u000a heavy loads on the host CPU. Recently TCP\\/IP Offload Engine (TOE) technology, which processes TCP\\/IP on a network adapter\\u000a instead of the host CPU, has become an important alternative approach to this problem. In this paper, we analyze TCP\\/IP components\\u000a that
Oh Soo-cheol; Hankook Jang; Sang-hwa Chung
Implementation Of A Portable-IP System For Mobile TCP\\/IP
In the current TCP\\/IP-based systems, the hardnessof mobile communication stems from the IProuting and addressing schemes. In this paper,we refine our mobile solution using two mappings:namely, a portable-IP mapping and a mobile mapping.We also explicitly distinguish our two mappingapproach from the existing mobile-IP solutionswhich are of a single mapping scheme. Theportable-IP mapping is supported using DHCPand DNS functions and requiring
Xun Qu; Jeffrey Xu Yu
An integrated software system for analyzing ChIP-chip and ChIP-seq data
We present CisGenome, a software system for analyzing genome-wide chromatin immunoprecipitation (ChIP) data. CisGenome is designed to meet all basic needs of ChIP data analyses, including visualization, data normalization, peak detection, false discovery rate computation, gene-peak association, and sequence and motif analysis. In addition to implementing previously published ChIP�microarray (ChIP-chip) analysis methods, the software contains statistical methods designed specifically for
Hongkai Ji; Hui Jiang; Wenxiu Ma; David S Johnson; Richard M Myers; Wing H Wong
Preconditioned conjugate gradient methods for the Navier-Stokes equations
NASA Technical Reports Server (NTRS)
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.
Ajmani, Kumud; Ng, Wing-Fai; Liou, Meng-Sing
Preconditioning the bidomain model with almost linear complexity
NASA Astrophysics Data System (ADS)
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 ?( n) (for some constant ?) which is optimal complexity for such problems.
Pierre, Charles
A Thin Security Layer Protocol over IP Protocol on TCP\\/IP Suite for Security Enhancement
In this paper, we proposed a security enhancement for TCP\\/IP suite. This enhancement adds three modules to TCP\\/IP. These are security policy, security control, and data security layer. Unlike IPsec, which plugs all security enforcements into IP layer, the proposed architecture distributes the proposed module into their relevant layer. The security policy belongs to application layer, and the security control
Mohammad Al-Jarrah; Abdel-Karim R. Tamimi
Towards Evolvable IP Cores for FPGAs
The paper deals with a new approach to the design of adaptive hardware using common Field Programmable Gate Arrays (FPGA). The ultimate aim is to develop evolv- able IP (Intellectual Property) cores. The cores should be reused in the same way as ordinary IP cores are reused. In contrast to the conventional cores, the evolvable cores are able to perform
Bo� zet� echova
Visualization Tools for Learning TCP\\/IP
This paper describes TCP\\/IP visualization tools for students who plan to become communication and computer engineers. TCP\\/IP protocols are fundamental for computer networks and the Internet. For this reason, communication and computer engineers have to learn the protocols. However, learning the protocols is difficult, because students cannot fully understand or gain experience with the protocols by using traditional learning methods,
Masayuki Arai; Shogo Takahashi; Gun Kitamura
Nymble: Anonymous IP-Address Blocking
Anonymizing networks such as Tor allow users to access Internet ser- vices privately using a series of routers to hide the client's IP address from the server. Tor's success, however, has been limited by users employing this anonymity for abusive purposes, such as defacing Wikipedia. Website administrators rely on IP- address blocking for disabling access to misbehaving users, but this
Peter C. Johnson; Apu Kapadia; Patrick P. Tsang; Sean W. Smith
IP over WDM network traffic engineering approaches
The wide spread deployment of DWDM and reconfigurable optical cross-connect equipment gives rise to a new generation of IP over WDM networks. These network combine gigabit and terabit IP routers with WDM switching and transmission systems to create a more flexible and dynamic network. As these networks grow, there is an urgent need to develop and implement new traffic engineering
J. Y. Wei
Mobile IP and security issue: an overview
Mobile IP enables a wireless network node to move freely from one point of connection to the Internet to another point, without causing disruption of established TCP end-to-end connectivity. Our model for extending Mobile IP relies on the existence of servers that are capable of performing accounting, authentication, and authorization (AAA) services. The model is known to be reasonable, because
Charlie Perkins
Hierarchical IP distribution mechanism for VANET
Vehicular Ad Hoc Network (VANET) is characterized by high speed, high efficient addressing mechanism is required for vehicles to access to Internet or communicate with each other for some practical or emergent information. The existing methods of addressing for VANET usually do not cope with instant IP address assignment and recycling. This paper proposed an AP-based centralized IP distribution system
Shu-Jun Chao; Jia-Ming Zhang; Chiu-Ching Tuan
Mining the Web for IP Address Geolocations
In this paper, we observe that many Web pages contain geolocation information (address, zipcode, and telephone area code) and many of these geolocation items are directly related to the locations of the IP addresses that host the Web pages. We then design Structon, a system that mines Web pages for IP address geolocations. In Structon, we first extract geolocation information
Chen Chen; Chuanxiong Guo; Yunxin Liu; Helen J. Wang; Qing Yu; Yong Guang Zhang
The ability to characterize IP traffic and understand how and where it flows is critical for network availability, performance, security and troubleshooting. Monitoring IP traffic flows facilitates more accurate capacity planning and ensures that resources are used appropriately in support of organizational goals. It helps to determine where to apply Quality of Service (QoS), optimize resource usage and it plays
H. Abdul Rauf; A. Ebenezer Jeyakumar
Structure of mouse IP-10, a chemokine.
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
Jabeen, Talat; Leonard, Philip; Jamaluddin, Haryati; Acharya, K Ravi
Congestion control in IP\\/TCP internetworks
Congestion control is a recognized problem in complex networks. We have discovered that the Department of Defense's Internet Protocol (IP), a pure datagram protocol, and Transmission Control Protocol (TCP), a transport layer protocol, when used together, are subject to unusual congestion problems caused by interactions between the transport and datagram layers. In particular, IP gateways are vulnerable to a phenomenon
John Nagle
Scalable High Speed IP Routing Lookups
Internet address lookup is a challenging problem because of increasing routing table sizes, increased traffic, higher speed links, and the migration to 128 bit IPv6 addresses. IP routing lookup requires computing the best matching prefix, for which standard solutions like hashing were believed to be inapplicable. The best existing solution we know of, BSD radix tries, scales badly as IP
Marcel Waldvogel; George Varghese; Jonathan S. Turner; Bernhard Plattner
Congestion control in IP\\/TCP internetworks
Congestion control is a recognized problem in complex networks. We have discovered that the Department of Defense's Internet Protocol (IP), a pure datagram protocol, and Transmission Control Protocol (TCP), a transport layer protocol, when used together, are subject to unusual congestion problems caused by interactions between the transport and datagram layers. In particular, IP gateways are vulnerable to a phenomenon
John Nagle
Organization of IP backbone on technology Ethernet
The tendency of last time - transition on city and backbone networks on technology IP, with transfer of packages in the pure state on a .dark fiber. The concept of the organization of the backbone on technology Ethernet is offered. The model is developed, allowing to predict the traffic main IP networks, on the basis of the data on average
Nikolaj V. Dudin
HPC Access Using 'KVM over IP'.
National Technical Information Service (NTIS)
A persistent challenge in the High-Performance Computing (HPC) community is how to provide remote visualization capability to its users. A dynamic and economical solution is a KVM-over-IP technology, which uses a pre- existing TCP/IP network to transmit K...
D. Kedziorek G. P. Czerniak
MEMS packaging IP and market status
Early MEMS devices employed packages developed for conventional semiconductor microelectronics. Today, MEMS packages reflect the unique environment, mechanical, chemical and thermal requirements of MEMS devices themselves. A casual search of on-line databases reveals nearly 40,000 patents worldwide containing the words �MEMS� and �package.� While not all relevant, the number of IP documents easily overwhelms researchers, investors and IP practitioners. Similarly,
C. E. Bauer; R. A. Fillion; H. J. Neuhaus; Marc Papageorge
Performance evaluation of an IP voice terminal
This paper examines the issues related to the transmission of voice over packet networks using the Internet Protocol (IP). We focus on studying the delays that are generated in the terminal, which is a Unix workstation equipped with IP voice application software. Delay components in the terminal are presented. We measure the processing delays in the terminal using different audio
Harri Marjam�ki
A Comparison of IP mobility protocols
This paper presents a detailed comparison, in a comprehen- sive framework, of Mobile IP and four of the main IP Micro-mobility pro- tocols. We first describe the global mobility landscape and point out the im- portant problems that must be addressed. These are mainly Handoff man- agement, Passive Connectivity and Paging support, Scalability, Robustness, Quality of Service and Security. Based
Pierre Reinbold; Olivier Bonaventure
Approaches for Resolving Dynamic IP Addressing.
ERIC Educational Resources Information Center
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�
Foo, Schubert; Hui, Siu Cheung; Yip, See Wai; He, Yulan
IP Traceback in a Switched Ethernet Network.
National Technical Information Service (NTIS)
IP traceback is the generic term given to systems that allow the tracing of IP packets back to their originating machine. A common shortcoming shared by existing traceback proposals is that they are able to identify the source network, but not the source ...
A. van Moorsel M. S. Andreou
Hyperbaric oxygen preconditioning attenuates hyperglycemia enhanced hemorrhagic transformation after transient MCAO in rats
Background Hemorrhagic transformation (HT) can be a devastating complication of ischemic stroke. Hyperbaric oxygen preconditioning (HBO-PC) has been shown to improve blood-brain barrier (BBB) permeability in stroke models. The purpose of this study is to examine whether HBO-PC attenuates HT after focal cerebral ischemia, and to investigate whether the mechanism of HBO-PC against HT includes up-regulation of antioxidants in hyperglycemic rats. Methods Male Sprague-Dawley rats (280-320 g) were divided into the following groups: sham, middle cerebral artery occlusion (MCAO) for 2 h, and MCAO treated with HBO-PC. HBO-PC was conducted giving 100% oxygen at 2.5 atm absolute (ATA), for 1 h at every 24 h interval for 5 days. At 24 h after the last session of HBO-PC, rats received an injection of 50% glucose (6 ml/kg intraperitoneally) and were subjected to MCAO 15 min later. At 24 h after MCAO, neurological behavior tests, infarct volume, blood-brain barrier permeability, and hemoglobin content were measured to evaluate the effect of HBO-PC. Western blot analysis of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was evaluated at multiple time-points before and after MCAO. Results HBO-PC improved neurological behavior test, and reduced infarction volume, HT and Evans blue extravasation in the ipsilateral hemisphere at 24 h after MCAO. Western blot analysis failed to demonstrate up-regulation of Nrf2 in HBO-PC group before and after MCAO. Paradoxically, HBO-PC decreased HO-1 expression at 24 h after MCAO, as compared with htMCAO group. Conclusions HBO-PC improved neurological deficits, infarction volume, BBB disruption, and HT after focal cerebral ischemia. However, its mechanism against focal cerebral ischemia and HT may not include activation of Nrf2 and subsequent HO-1 expression.
Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning
Overexpression of mitochondrial uncoupling proteins (UCPs) attenuates ischemia-reperfusion (I/R) injury in cultured cardiomyocytes. However, it is not known whether UCPs play an essential role in cardioprotection in the intact heart. This study evaluated the cardioprotective efficacy of UCPs against I/R injury and characterized the mechanism of UCP-mediated protection in addition to the role of UCPs in ischemic preconditioning (IPC). Cardiac UCP3 knockout (UCP3?/?) and wild-type (WT) mice hearts were subjected to ex vivo and in vivo models of I/R injury and IPC. Isolated UCP3?/? mouse hearts were retrogradely perfused and found to have poorer recovery of left ventricular function compared with WT hearts under I/R conditions. In vivo occlusion of the left coronary artery resulted in twofold larger infarcts in UCP3?/? mice compared with WT mice. Moreover, the incidence of in vivo I/R arrhythmias was higher in UCP3?/? mice. Myocardial energetics were significantly impaired with I/R, as reflected by a decreased ATP content and an increase in the AMP-to-ATP ratio. UCP3?/? hearts generated more reactive oxygen species (ROS) than WT hearts during I/R. Pretreatment of UCP3?/? hearts with the pharmacological uncoupling agent carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone improved postischemic functional recovery. Also the protective efficacy of IPC was abolished in UCP3?/? mice. We conclude that UCP3 plays a critical role in cardioprotection against I/R injury and the IPC phenomenon. There is increased myocardial vulnerability to I/R injury in hearts lacking UCP3. The mechanisms of UCP3-mediated cardioprotection include regulation of myocardial energetics and ROS generation by UCP3 during I/R.
Ozcan, Cevher; Palmeri, Monica; Horvath, Tamas L.; Russell, Kerry S.
Autophagy in chronically ischemic myocardium
We tested the hypothesis that chronically ischemic (IS) myocardium induces autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, which could protect against the consequences of further ischemia. Chronically instrumented pigs were studied with repetitive myocardial ischemia produced by one, three, or six episodes of 90 min of coronary stenosis (30% reduction
Lin Yan; Dorothy E. Vatner; Song-Jung Kim; Hui Ge; Malthi Masurekar; William H. Massover; Guiping Yang; Yutaka Matsui; Junichi Sadoshima; Stephen F. Vatner
Genetic susceptibility to ischemic stroke
Clinicians who treat patients with stroke need to be aware of several single-gene disorders that have ischemic stroke as a major feature, including sickle cell disease, Fabry disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and retinal vasculopathy with cerebral leukodystrophy. The reported genome-wide association studies of ischemic stroke and several related phenotypes (for example, ischemic white matter disease) have shown that no single common genetic variant imparts major risk. Larger studies with samples numbering in the thousands are ongoing to identify common variants with smaller effects on risk. Pharmacogenomic studies have uncovered genetic determinants of response to warfarin, statins and clopidogrel. Despite increasing knowledge of stroke genetics, incorporating this new knowledge into clinical practice remains a challenge. The goals of this article are to review common single-gene disorders relevant to ischemic stroke, summarize the status of candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors, and to briefly discuss pharmacogenomics related to stroke treatment.
Meschia, James F.; Worrall, Bradford B.; Rich, Stephen S.
Systemic LPS protects the brain from ischemic injury by reprogramming the brain's response to stroke: a critical role for IRF3
Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury through activation of its receptor, Toll-like receptor 4 (TLR4). Paradoxically, TLR activation by endogenous ligands following ischemia worsens stroke damage. Here, we define a novel, protective role for TLRs following ischemia in the context of LPS preconditioning. Microarray analysis of brains collected 24 hours following stroke revealed a unique set of up-regulated genes in LPS pretreated animals. Promoter analysis of the unique gene set identified an over representation of Type I IFN associated transcriptional regulatory elements. This finding suggested the presence of Type I IFNs or interferon regulatory factors (IRFs), which up-regulate interferon-stimulated genes. Up-regulation of IFN? was confirmed by real-time RT-PCR. Direct administration of IFN? icv at the time of stroke was sufficient for neuroprotection. TLR4 can induce both IFN? and interferon-stimulated genes through its adapter molecule TRIF and the IRF3 transcription factor. We show in oxygen glucose deprivation of cortical neurons, an in vitro model of stroke, that activation of TRIF following stroke reduces neuronal death. Further, mice lacking IRF3 were not protected by LPS preconditioning in our in vivo model. Our studies constitute the first demonstration of the neuroprotective capacity of TRIF/IRF3 signaling and suggest that interferon stimulated genes, whether induced by IFN? or by enhanced TLR signaling to IRF3, are a potent means of protecting the brain against ischemic damage.
Marsh, Brenda; Stevens, Susan L.; Packard, Amy E. B.; Gopalan, Banu; Hunter, Brian; Leung, Philberta Y.; Harrington, Christina A.; Stenzel-Poore, Mary P.
Mobility management in IP networks providing real-time services
The evolution of IP toward the complete interworking among fixed and mobile hosts is called mobile IP. Several issues related to different aspects of the mobile IP definition have been singled out: impact of mobility on TCP\\/IP performance, route optimisation, authentication, reliability, location, addressing, etc. An important topic in the IP evolution is the provisioning of real-time services by employing
C. Andreoli; N. Blefari-Melazzi; M. Listanti; M. Palermo
Preconditioning improves cardioplegia-related coronary microvascular smooth muscle hypercontractility: Role of KATP channels
Objectives: The effect of preconditioning before hyperkalemic cardioplegia on the coronary smooth muscle remains to be elucidated. We tested the hypothesis that hypoxic preconditioning could protect coronary smooth muscle against subsequent hyperkalemic cardioplegia-induced coronary vasospasm and that this preconditioning effect could be mediated by KATP channels. Methods: Rat coronary arterioles (endothelium-denuded) were studied in a pressurized, no-flow, normothermic state. Simultaneous
Naruto Matsuda; Kathleen G. Morgan; Frank W. Sellke
Activation of K2P channel-TREK1 mediates the neuroprotection induced by sevoflurane preconditioning
Background Preconditioning with volatile anaesthetic agents induces tolerance to focal cerebral ischaemia, although the underlying mechanisms have not been clearly defined. The present study analyses whether TREK-1, a two-pore domain K+ channel and target for volatile anaesthetics, plays a role in mediating neuroprotection by sevoflurane. Methods Differentiated SH-SY5Y cells were preconditioning with sevoflurane and challenged by oxygen�glucose deprivation (OGD). Cell viability and expression of caspase-3 and TREK-1 were evaluated. Rats that were preconditioned with sevoflurane were subjected to middle cerebral artery occlusion (MCAO), and the expression of TREK-1 protein and mRNA was analysed. Neurological scores were evaluated and infarction volume was examined. Results Sevoflurane preconditioning reduced cell death in differentiated SH-SY5Y cells challenged by OGD. Sevoflurane preconditioning reduced infarct volume and improved neurological outcome in rats subjected to MCAO. Sevoflurane preconditioning increased levels of TREK-1 mRNA and protein. Knockdown of TREK-1 significantly attenuated sevoflurane preconditioning-induced neuroprotective effects in vitro and in vivo. Conclusions Sevoflurane preconditioning-induced neuroprotective effects against transient cerebral ischaemic injuries involve TREK-1 channels. These results suggest a novel mechanism for sevoflurane preconditioning-induced tolerance to focal cerebral ischaemia.
Tong, L.; Cai, M.; Huang, Y.; Zhang, H.; Su, B.; Li, Z.; Dong, H.
Integrated Pest Management Guide: Arizona Five-Spined Ips, 'Ips lecontei' Swaine, and Pine Engraver, 'Ips pini' (Say) in Ponderosa Pine.
National Technical Information Service (NTIS)
The Arizona five-spined ips, 'Ips lecontei' Swaine, and the pine engraver, 'Ips pini' (Say), are common and destructive bark beetles that attack pole-size ponderosa pines in Arizona and New Mexico. The Arizona five-spined ips is mostly a pest in low eleva...
D. L. Parker
Determination of an Empirically Derived IP/TSP Relationship.
National Technical Information Service (NTIS)
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 particul...
A. C. Nelson L. Wijnberg
An Introduction to Voice over the IP: Laboratory Exercise
NSDL National Science Digital Library
This document provides a sample laboratory exercise which may be used in classes studying Voice over IP. The exercise includes three parts: 1. Configure the classroom network; 2. Simulate VoIP calls; and 3. VoIP Network configuration.
Cherri, Mona
Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke.
Disruption of the blood-brain barrier (BBB) and cerebral edema are the major pathogenic mechanisms leading to neurological dysfunction and death after ischemic stroke. The brain protects itself against infarction via activation of endogenous antioxidant defense mechanisms, and we here report the first evidence that sulforaphane-mediated preactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target heme oxygenase-1 (HO-1) in the cerebral vasculature protects the brain against stroke. To induce ischemic stroke, Sprague-Dawley rats were subjected to 70 min middle cerebral artery occlusion (MCAo) followed by 4, 24, or 72 h reperfusion. Nrf2 and HO-1 protein expression was upregulated in cerebral microvessels of peri-infarct regions after 4-72 h, with HO-1 preferentially associated with perivascular astrocytes rather than the cerebrovascular endothelium. In na�ve rats, treatment with sulforaphane increased Nrf2 expression in cerebral microvessels after 24h. Upregulation of Nrf2 by sulforaphane treatment prior to transient MCAo (1h) was associated with increased HO-1 expression in perivascular astrocytes in peri-infarct regions and cerebral endothelium in the infarct core. BBB disruption, lesion progression, as analyzed by MRI, and neurological deficits were reduced by sulforaphane pretreatment. As sulforaphane pretreatment led to a moderate increase in peroxynitrite generation, we suggest that hormetic preconditioning underlies sulforaphane-mediated protection against stroke. In conclusion, we propose that pharmacological or dietary interventions aimed to precondition the brain via activation of the Nrf2 defense pathway in the cerebral microvasculature provide a novel therapeutic approach for preventing BBB breakdown and neurological dysfunction in stroke. PMID:24017972
Alfieri, Alessio; Srivastava, Salil; Siow, Richard C M; Cash, Diana; Modo, Michel; Duchen, Michael R; Fraser, Paul A; Williams, Steven C R; Mann, Giovanni E
Optical Spectroscopy of SN 2009ip
NASA Astrophysics Data System (ADS)
It was recently reported (Drake et al., ATEL #4334) that SN 2009ip, an LBV with a ZAMS of >60 M_sun (Smith et al., 2010, AJ, 139, 1451; Foley et al., 2011, ApJ, 732, 32), is currently undergoing a new outburst. We obtained a high-resolution optical spectrum of SN 2009ip with MIKE mounted on the Magellan/Clay 6.5-m telescope on 2012 August 26.14 UT. The spectrum is remarkably similar to those of SN 2009ip during its previous outburst, being dominated by hydrogen Balmer and He I lines.
Foley, Ryan J.; Berger, Edo; Roederer, Ian U.; Chomiuk, Laura
Uniform communications software using TCP/IP
Data acquisition applications at Fermilab require a reliable, distributed communication system for downloading, diagnostics, control, and data distribution. TCP/IP over Ethernet was chosen because of its uniform user interface and commercial availability for a number of processors and operating systems. This paper describes the authors software and hardware support for TCP/IP on VAX/VMS, VME/rhoSOS, FASTBUS/rhoSOS, and Unix systems. It includes plans to provide a portable, hardware independent implementation of TCP/IP based on Berkeley BSD software.
Bernett, M.; Oleynik, G. (Fermi National Accelerator Lab., Batavia, IL (USA))
Uniform communications software using TCP/IP
Data acquisition applications at Fermilab require a reliable, distributed communication system for downloading, diagnostics, control, and data distribution. TCP/IP over Ethernet was chosen because of its uniform user interface and commercial availability for a number of processors and operating systems. This paper describes our software and hardware support for TCP/IP on VAX/VMS, VME/pSOS, FASTBUS/pSOS, and Unix systems. It includes plans to provide a portable, hardware independent implementation of TCP/IP based on Berkeley BSD software. 8 refs., 3 figs.
Bernett, M.; Oleynik, G.
Scalable architecture for VoIP privacy
NASA Astrophysics Data System (ADS)
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 strengthen VoIP privacy under the PacketCable architecture.
Medvinsky, Alexander
IPS guidestar selection for stellar mode (ASTRO)
NASA Technical Reports Server (NTRS)
This report describes how guide stars are selected for the Optical Sensor Package (OSP) for the Instrument Pointing System (IPS) when it is operating in the stellar mode on the ASTRO missions. It also describes how the objective loads are written and how the various roll angles are related; i.e., the celestial roll or position angle, the objective load roll angles, and the IPS gimbal angles. There is a brief description of how the IPS operates and its various modes of operation; i.e., IDOP, IDIN, and OSPCAL.
Mullins, Larry; Wooten, Lewis
ChIP-PED enhances the analysis of ChIP-seq and ChIP-chip data
Motivation: Although chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) or tiling array hybridization (ChIP-chip) is increasingly used to map genome-wide�binding sites of transcription factors (TFs), it still remains difficult to generate a quality ChIPx (i.e. ChIP-seq or ChIP-chip) dataset because of the tremendous amount of effort required to develop effective antibodies and efficient protocols. Moreover, most laboratories are unable to easily obtain ChIPx data for one or more TF(s) in more than a handful of biological contexts. Thus, standard ChIPx analyses primarily focus on analyzing data from one experiment, and the discoveries are restricted to a specific biological context. Results: We propose to enrich this existing data analysis paradigm by developing a novel approach, ChIP-PED, which superimposes ChIPx data on large amounts of publicly available human and mouse gene expression data containing a diverse collection of cell types, tissues and disease conditions to discover new biological contexts with potential TF regulatory activities. We demonstrate ChIP-PED using a number of examples, including a novel discovery that MYC, a human TF, plays an important functional role in pediatric Ewing sarcoma cell lines. These examples show that ChIP-PED increases the value of ChIPx data by allowing one to expand the scope of possible discoveries made from a ChIPx experiment. Availability: http://www.biostat.jhsph.edu/?gewu/ChIPPED/ Contact: firstname.lastname@example.com Supplementary information: Supplementary data are available at Bioinformatics online.
Wu, George; Yustein, Jason T.; McCall, Matthew N.; Zilliox, Michael; Irizarry, Rafael A.; Zeller, Karen; Dang, Chi V.; Ji, Hongkai
Calcium preconditioning triggers neuroprotection in retinal ganglion cells
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 concerning therapeutic agents developed to combat various diseases involved with glutamate-induced excitotoxicity.
Brandt, Sean K.; Weatherly, Monique E.; Ware, Lillian; Linn, David M.; Linn, Cindy L.
Steps to translate preconditioning from basic research to the clinic
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.
Bahjat, Frances R; Gesuete, Raffaella; Stenzel-Poore, Mary P
Preconditioned Conjugate Gradient methods for low speed flow calculations
NASA Technical Reports Server (NTRS)
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.
Ajmani, Kumud; Ng, Wing-Fai; Liou, Meng-Sing
The SDF-1/CXCR4 axis in stem cell preconditioning.
We review the pivotal role of the stromal derived factor (SDF)-1 chemokine in tissue ischaemia and how it orchestrates the rapid revascularization of injured, ischaemic, and regenerating tissues via the CXC chemokine receptors CXCR4 and CXCR7. Furthermore, we discuss the effects of preconditioning (PC), which is a well-known protective phenomenon for tissue ischaemia. The positive effect of both hypoxic and acidic PC on progenitor cell therapeutic potential is reviewed, while stressing the role of the SDF-1/CXCR4 axis in this process. PMID:22451511
Cencioni, Chiara; Capogrossi, Maurizio C; Napolitano, Monica
Preconditioning a product of matrices arising in trust region subproblems
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.
Hribar, M.E.; Plantenga, T.D.
Weighted graph based ordering techniques for preconditioned conjugate gradient methods
NASA Technical Reports Server (NTRS)
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.
Clift, Simon S.; Tang, Wei-Pai
Preconditioning methods for ideal and multiphase fluid flows
NASA Astrophysics Data System (ADS)
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 cavitation on two basic geometries for which experimental data are available, that is, flow over simple foil and a quarter caliber hydrofoil in a tunnel using liquid nitrogen as a fluid. For non-cryogenic conditions, water near boiling conditions is used to predict cavitation on two simple geometries, that is, flow over simple foil in a tunnel and flow over a one caliber ogive. Cavitation predictions in both cryogenic and non-cryogenic cases are shows to agree well with available experimental data.
Gupta, Ashish
77 FR 33227 - Assessment Questionnaire-IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT)
Federal Register 2010, 2011, 2012, 2013
...DHS-2011-0069] Assessment Questionnaire--IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT) AGENCY: National Protection and...NPPD), Office of Infrastructure Protection (IP), Sector Outreach and Programs...
76 FR 81955 - Assessment Questionnaire-IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT)
Federal Register 2010, 2011, 2012, 2013
...DHS-2011-0069] Assessment Questionnaire--IP Sector Specific Agency Risk Self Assessment Tool (IP-SSARSAT) AGENCY: National Protection and...NPPD), Office of Infrastructure Protection (IP), Sector Specific Agency Executive...
Neonatal Hypoxic-Ischemic Encephalopathy
\\u000a Hypoxic-ischemic encephalopathy (HIE) is the major recognized perinatal cause of neurological morbidity both in premature\\u000a and full-term newborns [1]. During the perinatal period, hypoxemia and\\/or ischemia usually occur as a result of asphyxia; brain biochemical changes\\u000a associated with hypoxemia, ischemia, and asphyxia are extremely complex and, other than to duration and severity of the event,\\u000a are strictly related to the
Fabio Triulzi; Cristina Baldoli; Andrea Righini
Ischemic stroke after electroconvulsive therapy.
Stroke is an exceptionally rare complication of electroconvulsive therapy since modern anesthesia and appropriate medical screening were instituted in the 1950s. Postictal focal neurological deficits mimicking stroke are common, but the advent of acute stroke therapies has made the differentiation of these from true cerebrovascular events critical. We present the first case report of ischemic stroke after electroconvulsive therapy with radiographic confirmation. PMID:16801834
Bruce, Beau B; Henry, Michael E; Greer, David M
Hypothermia after Acute Ischemic Stroke
Abstract Induced hypothermia after ischemic stroke is a promising neuroprotective therapy and is the most potent in pre-clinical models. Technological limitations and homeostatic mechanisms that maintain core body temperature, however, have limited the clinical application of hypothermia. Advances in intravascular cooling and successful trials of hypothermia after global cerebral ischemia, such as in cardiac arrest and neonatal asphyxia, have renewed interest in hypothermia for stroke.
Lyden, Patrick D.
Uniform Communications Software Using TCP/IP.
National Technical Information Service (NTIS)
Data acquisition applications at Fermilab require a reliable, distributed communication system for downloading, diagnostics, control, and data distribution. TCP/IP over Ethernet was chosen because of its uniform user interface and commercial availability ...
M. Bernett G. Oleynik
Routing Protocol Evaluation for IP Mobility.
National Technical Information Service (NTIS)
Since IP is becoming the leading protocol to interconnect heterogeneous networks, much effort is done to investigate if Internet technology can be usefully employed for military applications. This paper deals with some aspects related to mobility manageme...
R. Marchessni S. Schillaci
Measuring an IP Network In Situ.
National Technical Information Service (NTIS)
The Internet, and Internet Protocol (IP) networking in general, have become vital to the scientific community and the global economy. This growth has increased the importance of measuring and monitoring the Internet to ensure that it runs smoothly and to ...
H. Burch
Abstract: The aim of this paper is to study the effects ofTriangle Routing and Mobile IP handoffs on TCPPerformance. The majority of Internet hosts today do notcomply with the considerations for routing optimisation.
N. A. Fikouras; K. El Malki; S. R. Cvetkovic; C. Smythe
VoIP, Asterisk, and Emerging Technology
NSDL National Science Digital Library
This Power Point presentation provides some information on Voice over IP, Asterisk and related emerging technologies. The fourth slide of the presentation includes a number of useful links on these topics.
D���ingianni, Vincente
Soluble Thrombomodulin Protects Ischemic Kidneys
Altered coagulation and inflammation contribute to the pathogenesis of ischemic renal injury. Thrombomodulin is a necessary factor in the anticoagulant protein C pathway and has inherent anti-inflammatory properties. We studied the effect of soluble thrombomodulin (sTM) in a hypoperfusion model of ischemic kidney injury. To markedly reduce infrarenal aortic blood flow and femoral arterial pressures, we clamped the suprarenal aorta of rats, occluding them 90%, for 60 min. Reversible acute kidney injury (AKI) occurred at 24 h in rats subjected to hypoperfusion. Histologic analysis at 24 h revealed acute tubular necrosis (ATN), and intravital two-photon microscopy showed flow abnormalities in the microvasculature and defects of endothelial permeability. Pretreatment with rat sTM markedly reduced both I-R-induced renal dysfunction and tubular histologic injury scores. sTM also significantly improved microvascular erythrocyte flow rates, reduced microvascular endothelial leukocyte rolling and attachment, and minimized endothelial permeability to infused fluorescence dextrans, assessed by intravital quantitative multiphoton microscopy. Furthermore, sTM administered 2 h after reperfusion protected against ischemia-induced renal dysfunction at 24 h and improved survival. By using an sTM variant, we also determined that the protective effects of sTM were independent of its ability to generate activated protein C. These data suggest that sTM may have therapeutic potential for ischemic AKI.
Sharfuddin, Asif A.; Sandoval, Ruben M.; Berg, David T.; McDougal, Grant E.; Campos, Silvia B.; Phillips, Carrie L.; Jones, Bryan E.; Gupta, Akanksha; Grinnell, Brian W.; Molitoris, Bruce A.
Towards Evolvable IP Cores for FPGAs
Abstract The paper deals with a new approach,to the design of adaptive hardware,using common,Field Programmable Gate Arrays (FPGA). The ultimate aim is to develop evolvable IP (Intellectual Property) cores. The cores should be reused in the same way as ordinary IP cores are reused. In contrast to the conventional cores, the evolvable cores are able to perform autonomous,evolution of their
Luk�s Sekanina
Uniform communications software using TCP\\/IP
Data acquisition applications at Fermilab require a reliable, distributed communication system for downloading, diagnostics, control, and data distribution. TCP\\/IP over Ethernet was chosen because of its uniform user interface and commercial availability for a number of processors and operating systems. This paper describes our software and hardware support for TCP\\/IP on VAX\\/VMS, VME\\/pSOS, FASTBUS\\/pSOS, and Unix systems. It includes plans
M. Bernett; Gene Oleynik
Capacity planning tool for multiservice IP networks
This paper describes a network planning tool that has been developed in order to provide support for network planners who need to dimension next generation IP networks to meet quality of service (QoS) objectives. Specifically, the proposed network planning tool takes account of the new technologies that enable QoS in IP-based networks (i.e., DiffServ\\/MPLS) and allows for multiple QoS constraints
Irena Atov; Richard J. Harris; Andrew Cassin
IP multicast security: Issues and directions
\\u000a Abstract��Security represents one of the major current obstacles to the wider deployment of IP multicast. The present work identifies\\u000a and discusses various concepts and issues underlying multicast security. A classification of the current issues is provided,\\u000a covering some core problems, infrastructure problems, and certain complex applications that might be built atop secure ip\\u000a multicast. Three broad core problems are defined,
Thomas Hardjono; Gene Tsudik

subset: commoncrawl