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Erschienen in: Translational Stroke Research 2/2012

01.06.2012

Muscle Microdialysis to Confirm Sublethal Ischemia in the Induction of Remote Ischemic Preconditioning

verfasst von: Arzu Bilgin-Freiert, Joshua R. Dusick, Nathan R. Stein, Maria Etchepare, Paul Vespa, Nestor R. Gonzalez

Erschienen in: Translational Stroke Research | Ausgabe 2/2012

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Abstract

Exposure of one tissue to ischemia–reperfusion confers a systemic protective effect, referred to as remote ischemic preconditioning (RIPC). Confirmation that the desired effect of ischemia is occurring in tissues used to induce RIPC requires an objective demonstration before this technique can be used consistently in the clinical practice. Enrolled patients underwent three to four RIPC sessions on non-consecutive days. Sessions consisted of 4 cycles of 5 min of leg cuff inflation to 30 mmHg above the systolic blood pressure followed by reperfusion. Absence of leg pulse was confirmed by Doppler evaluation. To evaluate limb transient ischemia, patients were monitored with muscle microdialysis. Glucose, lactate, lactate/pyruvate ratio, and glycerol levels were measured. Fourteen microdialysis sessions were performed in seven patients undergoing RIPC (42.8 % male; mean age, 51.8; Fisher grade 4 in all seven patients, Hunt and Hess grade 5 in five patients, four in one patient and one in one patient). An average follow-up of 29 days demonstrated no complications associated with the procedure. Muscle microdialysis during RIPC sessions showed a significant increase in lactate/pyruvate ratio (21.2 to 26.8, p = 0.001) and lactate (3.0 to 3.9 mmol/L, p = 0.002), indicating muscle ischemia. There was no significant variation in glycerol (234 to 204 μg/L, p = 0.43), indicating no permanent cell damage. The RIPC protocol used in this study is safe, well tolerated, and induces transient metabolic changes consistent with sublethal ischemia. Muscle microdialysis can be used safely as a confirmatory tool in the induction of RIPC.
Literatur
1.
Zurück zum Zitat Chen YS, Chien CT, Ma MC, Tseng YZ, Lin FY, Wang SS, et al. Protection "outside the box" (skeletal remote preconditioning) in rat model is triggered by free radical pathway. J Surg Res. 2005;126(1):92–101.PubMedCrossRef Chen YS, Chien CT, Ma MC, Tseng YZ, Lin FY, Wang SS, et al. Protection "outside the box" (skeletal remote preconditioning) in rat model is triggered by free radical pathway. J Surg Res. 2005;126(1):92–101.PubMedCrossRef
2.
Zurück zum Zitat Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26(5):248–54.PubMedCrossRef Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26(5):248–54.PubMedCrossRef
3.
Zurück zum Zitat Hausenloy DJ, Yellon DM. The evolving story of "conditioning" to protect against acute myocardial ischaemia–reperfusion injury. Heart. 2007;93(6):649–51.PubMedCrossRef Hausenloy DJ, Yellon DM. The evolving story of "conditioning" to protect against acute myocardial ischaemia–reperfusion injury. Heart. 2007;93(6):649–51.PubMedCrossRef
4.
Zurück zum Zitat Muramatsu H, Kariko K, Welsh FA. Induction of tolerance to focal ischemia in rat brain: dissociation between cortical lesioning and spreading depression. J Cereb Blood Flow Metab. 2004;24(10):1167–71.PubMedCrossRef Muramatsu H, Kariko K, Welsh FA. Induction of tolerance to focal ischemia in rat brain: dissociation between cortical lesioning and spreading depression. J Cereb Blood Flow Metab. 2004;24(10):1167–71.PubMedCrossRef
5.
Zurück zum Zitat Ren C, Yan Z, Wei D, Gao X, Chen X, Zhao H. Limb remote ischemic postconditioning protects against focal ischemia in rats. Brain Res. 2009;1288:88–94.PubMedCrossRef Ren C, Yan Z, Wei D, Gao X, Chen X, Zhao H. Limb remote ischemic postconditioning protects against focal ischemia in rats. Brain Res. 2009;1288:88–94.PubMedCrossRef
6.
Zurück zum Zitat Kanoria S, Jalan R, Seifalian AM, Williams R, Davidson BR. Protocols and mechanisms for remote ischemic preconditioning: a novel method for reducing ischemia reperfusion injury. Transplantation. 2007;84(4):445–58.PubMedCrossRef Kanoria S, Jalan R, Seifalian AM, Williams R, Davidson BR. Protocols and mechanisms for remote ischemic preconditioning: a novel method for reducing ischemia reperfusion injury. Transplantation. 2007;84(4):445–58.PubMedCrossRef
7.
Zurück zum Zitat Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106(23):2881–3.PubMedCrossRef Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106(23):2881–3.PubMedCrossRef
8.
Zurück zum Zitat Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87(3):893–9.PubMed Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87(3):893–9.PubMed
9.
Zurück zum Zitat Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review. J Surg Res. 2008;150(2):304–30.PubMedCrossRef Tapuria N, Kumar Y, Habib MM, Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review. J Surg Res. 2008;150(2):304–30.PubMedCrossRef
10.
Zurück zum Zitat Takagi H, Manabe H, Kawai N, Goto SN, Umemoto T. Review and meta-analysis of randomized controlled clinical trials of remote ischemic preconditioning in cardiovascular surgery. Am J Cardiol. 2008;102(11):1487–8.PubMedCrossRef Takagi H, Manabe H, Kawai N, Goto SN, Umemoto T. Review and meta-analysis of randomized controlled clinical trials of remote ischemic preconditioning in cardiovascular surgery. Am J Cardiol. 2008;102(11):1487–8.PubMedCrossRef
11.
Zurück zum Zitat Kloner RA. Clinical application of remote ischemic preconditioning. Circulation. 2009;119(6):776–8.PubMedCrossRef Kloner RA. Clinical application of remote ischemic preconditioning. Circulation. 2009;119(6):776–8.PubMedCrossRef
12.
Zurück zum Zitat Chan MT, Boet R, Ng SC, Poon WS, Gin T. Effect of ischemic preconditioning on brain tissue gases and pH during temporary cerebral artery occlusion. Acta Neurochir Suppl. 2005;95:93–6.PubMedCrossRef Chan MT, Boet R, Ng SC, Poon WS, Gin T. Effect of ischemic preconditioning on brain tissue gases and pH during temporary cerebral artery occlusion. Acta Neurochir Suppl. 2005;95:93–6.PubMedCrossRef
14.
Zurück zum Zitat Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics. 2004;19(1):143–50.PubMedCrossRef Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics. 2004;19(1):143–50.PubMedCrossRef
15.
Zurück zum Zitat Konstantinov IE, Arab S, Li J, Coles JG, Boscarino C, Mori A, et al. The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J Thorac Cardiovasc Surg. 2005;130(5):1326–32.PubMedCrossRef Konstantinov IE, Arab S, Li J, Coles JG, Boscarino C, Mori A, et al. The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J Thorac Cardiovasc Surg. 2005;130(5):1326–32.PubMedCrossRef
16.
Zurück zum Zitat Dahl NA, Balfour WM. Prolonged anoxic survival due to anoxia pre-exposure: brain ATP, lactate, and pyruvate. A J Physiol. 1964;207(2):452. Dahl NA, Balfour WM. Prolonged anoxic survival due to anoxia pre-exposure: brain ATP, lactate, and pyruvate. A J Physiol. 1964;207(2):452.
17.
Zurück zum Zitat Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–36.PubMedCrossRef Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–36.PubMedCrossRef
18.
Zurück zum Zitat Barone FC, White RF, Spera PA, Ellison J, Currie RW, Wang X, et al. Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke. 1998;29(9):1937–50. Barone FC, White RF, Spera PA, Ellison J, Currie RW, Wang X, et al. Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke. 1998;29(9):1937–50.
19.
20.
Zurück zum Zitat Janier MF, Vanoverschelde J, Bergmann SR. Ischemic preconditioning stimulates anaerobic glycolysis in the isolated rabbit heart. Am J Physiol Heart Circ Physiol. 1994;267(4):H1353. Janier MF, Vanoverschelde J, Bergmann SR. Ischemic preconditioning stimulates anaerobic glycolysis in the isolated rabbit heart. Am J Physiol Heart Circ Physiol. 1994;267(4):H1353.
21.
Zurück zum Zitat Bolte CS, Liao S, Gross GJ, Schultz Jel J. Remote preconditioning-endocrine factors in organ protection against ischemic injury. Endocr Metab Immune Disord Drug Targets. 2007;7(3):167–75.PubMedCrossRef Bolte CS, Liao S, Gross GJ, Schultz Jel J. Remote preconditioning-endocrine factors in organ protection against ischemic injury. Endocr Metab Immune Disord Drug Targets. 2007;7(3):167–75.PubMedCrossRef
22.
Zurück zum Zitat Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res. 2008;79(3):377–86.PubMedCrossRef Hausenloy DJ, Yellon DM. Remote ischaemic preconditioning: underlying mechanisms and clinical application. Cardiovasc Res. 2008;79(3):377–86.PubMedCrossRef
23.
Zurück zum Zitat Kharbanda RK, Nielsen TT, Redington AN. Translation of remote ischaemic preconditioning into clinical practice. Lancet. 2009;374(9700):1557–65.PubMedCrossRef Kharbanda RK, Nielsen TT, Redington AN. Translation of remote ischaemic preconditioning into clinical practice. Lancet. 2009;374(9700):1557–65.PubMedCrossRef
24.
Zurück zum Zitat Oxman T, Arad M, Klein R, Avazov N, Rabinowitz B. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol Heart Circ Physiol. 1997;273(4):H1707. Oxman T, Arad M, Klein R, Avazov N, Rabinowitz B. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol Heart Circ Physiol. 1997;273(4):H1707.
25.
Zurück zum Zitat Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation. 1997;96(5):1641–6.PubMed Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation. 1997;96(5):1641–6.PubMed
26.
Zurück zum Zitat Sun XC, Li WB, Li QJ, Zhang M, Xian XH, Qi J, et al. Limb ischemic preconditioning induces brain ischemic tolerance via p38 MAPK. Brain Res. 2006;1084(1):165–74.PubMedCrossRef Sun XC, Li WB, Li QJ, Zhang M, Xian XH, Qi J, et al. Limb ischemic preconditioning induces brain ischemic tolerance via p38 MAPK. Brain Res. 2006;1084(1):165–74.PubMedCrossRef
27.
Zurück zum Zitat Ren C, Gao X, Steinberg GK, Zhao H. Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience. 2008;151(4):1099–103.PubMedCrossRef Ren C, Gao X, Steinberg GK, Zhao H. Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. Neuroscience. 2008;151(4):1099–103.PubMedCrossRef
28.
Zurück zum Zitat Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ. Remote ischemic preconditioning provides early and late protection against endothelial ischemia–reperfusion injury in humans: role of the autonomic nervous system. J Am Coll Cardiol. 2005;46(3):450–6.PubMedCrossRef Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ. Remote ischemic preconditioning provides early and late protection against endothelial ischemia–reperfusion injury in humans: role of the autonomic nervous system. J Am Coll Cardiol. 2005;46(3):450–6.PubMedCrossRef
29.
Zurück zum Zitat Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, et al. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol. 2006;47(11):2277–82.PubMedCrossRef Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, et al. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol. 2006;47(11):2277–82.PubMedCrossRef
30.
Zurück zum Zitat Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet. 2007;370(9587):575–9.PubMedCrossRef Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet. 2007;370(9587):575–9.PubMedCrossRef
31.
Zurück zum Zitat Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, et al. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation. 2007;116(11 Suppl):I98–105.PubMed Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, et al. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation. 2007;116(11 Suppl):I98–105.PubMed
32.
Zurück zum Zitat Hoole SP, Heck PM, Sharples L, Khan SN, Duehmke R, Densem CG, et al. Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial. Circulation. 2009;119(6):820–7.PubMedCrossRef Hoole SP, Heck PM, Sharples L, Khan SN, Duehmke R, Densem CG, et al. Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial. Circulation. 2009;119(6):820–7.PubMedCrossRef
33.
Zurück zum Zitat Venugopal V, Hausenloy DJ, Ludman A, Di Salvo C, Kolvekar S, Yap J, et al. Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial. Heart. 2009;95(19):1567–71.PubMedCrossRef Venugopal V, Hausenloy DJ, Ludman A, Di Salvo C, Kolvekar S, Yap J, et al. Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial. Heart. 2009;95(19):1567–71.PubMedCrossRef
34.
Zurück zum Zitat Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375(9716):727–34.PubMedCrossRef Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010;375(9716):727–34.PubMedCrossRef
35.
Zurück zum Zitat Muller M, Schmid R, Nieszpaur-Los M, Fassolt A, Lonnroth P, Fasching P, et al. Key metabolite kinetics in human skeletal muscle during ischaemia and reperfusion: measurement by microdialysis. Eur J Clin Investig. 1995;25(8):601–7.CrossRef Muller M, Schmid R, Nieszpaur-Los M, Fassolt A, Lonnroth P, Fasching P, et al. Key metabolite kinetics in human skeletal muscle during ischaemia and reperfusion: measurement by microdialysis. Eur J Clin Investig. 1995;25(8):601–7.CrossRef
36.
Zurück zum Zitat Korth U, Merkel G, Fernandez FF, Jandewerth O, Dogan G, Koch T, et al. Tourniquet-induced changes of energy metabolism in human skeletal muscle monitored by microdialysis. Anesthesiology. 2000;93(6):1407.PubMedCrossRef Korth U, Merkel G, Fernandez FF, Jandewerth O, Dogan G, Koch T, et al. Tourniquet-induced changes of energy metabolism in human skeletal muscle monitored by microdialysis. Anesthesiology. 2000;93(6):1407.PubMedCrossRef
37.
Zurück zum Zitat Ostman B, Michaelsson K, Rahme H, Hillered L. Tourniquet-induced ischemia and reperfusion in human skeletal muscle. Clin Orthop Relat Res. 2004;418:260.PubMedCrossRef Ostman B, Michaelsson K, Rahme H, Hillered L. Tourniquet-induced ischemia and reperfusion in human skeletal muscle. Clin Orthop Relat Res. 2004;418:260.PubMedCrossRef
38.
Zurück zum Zitat Desvigne N, Barthelemy JC, Bertholon F, Gay-Montchamp JP, Freyssenet D, Costes F. Validation of a new calibration method for human muscle icrodialysis at rest and during exercise. Eur J Appl Physiol. 2004;92:312–20.PubMedCrossRef Desvigne N, Barthelemy JC, Bertholon F, Gay-Montchamp JP, Freyssenet D, Costes F. Validation of a new calibration method for human muscle icrodialysis at rest and during exercise. Eur J Appl Physiol. 2004;92:312–20.PubMedCrossRef
39.
Zurück zum Zitat Hansen DK, Davies MI, Lunte SM, Lunte CE. Pharmacokinetic and metabolism studies using microdialysis sampling. J Pharm Sci. 1999;88(1):14–27.PubMedCrossRef Hansen DK, Davies MI, Lunte SM, Lunte CE. Pharmacokinetic and metabolism studies using microdialysis sampling. J Pharm Sci. 1999;88(1):14–27.PubMedCrossRef
40.
Zurück zum Zitat Davies MI, Cooper JD, Desmond SS, Lunte CE, Lunte SM. Analytical considerations for microdialysis sampling. Adv Drug Deliv Rev. 2000;45(2–3):169–88.PubMedCrossRef Davies MI, Cooper JD, Desmond SS, Lunte CE, Lunte SM. Analytical considerations for microdialysis sampling. Adv Drug Deliv Rev. 2000;45(2–3):169–88.PubMedCrossRef
41.
Zurück zum Zitat Rosdahl H, Ungerstedt U, Jorfeldt L, Henriksson J. Interstitial glucose and lactate balance in human skeletal muscle and adipose tissue studied by microdialysis. J Physiol. 1993;471(1):637.PubMed Rosdahl H, Ungerstedt U, Jorfeldt L, Henriksson J. Interstitial glucose and lactate balance in human skeletal muscle and adipose tissue studied by microdialysis. J Physiol. 1993;471(1):637.PubMed
42.
Zurück zum Zitat Rosdahl H, Hamrin K, Ungerstedt U, Henriksson J. Metabolite levels in human skeletal muscle and adipose tissue studied with microdialysis at low perfusion flow. Am J Physiol Endocrinol Metab. 1998;274(5):E936–E45. Rosdahl H, Hamrin K, Ungerstedt U, Henriksson J. Metabolite levels in human skeletal muscle and adipose tissue studied with microdialysis at low perfusion flow. Am J Physiol Endocrinol Metab. 1998;274(5):E936–E45.
43.
Zurück zum Zitat Ren G, Eiskjaer S, Kaspersen J, Christensen FB, Rasmussen S. Microdialysis of paraspinal muscle in healthy volunteers and patients underwent posterior lumbar fusion surgery. Eur Spine J. 2009;18(11):1604–9.PubMedCrossRef Ren G, Eiskjaer S, Kaspersen J, Christensen FB, Rasmussen S. Microdialysis of paraspinal muscle in healthy volunteers and patients underwent posterior lumbar fusion surgery. Eur Spine J. 2009;18(11):1604–9.PubMedCrossRef
44.
Zurück zum Zitat Ungerstedt U. Microdialysis—principles and applications for studies in animals and man. J Intern Med. 1991;230(4):365–73.PubMedCrossRef Ungerstedt U. Microdialysis—principles and applications for studies in animals and man. J Intern Med. 1991;230(4):365–73.PubMedCrossRef
45.
Zurück zum Zitat Birke-Sorensen H, Toft G, Bengaard J. Pure muscle transfers can be monitored by use of microdialysis. J Reconstr Microsurg. 2010;26(9):623–9.PubMedCrossRef Birke-Sorensen H, Toft G, Bengaard J. Pure muscle transfers can be monitored by use of microdialysis. J Reconstr Microsurg. 2010;26(9):623–9.PubMedCrossRef
Metadaten
Titel
Muscle Microdialysis to Confirm Sublethal Ischemia in the Induction of Remote Ischemic Preconditioning
verfasst von
Arzu Bilgin-Freiert
Joshua R. Dusick
Nathan R. Stein
Maria Etchepare
Paul Vespa
Nestor R. Gonzalez
Publikationsdatum
01.06.2012
Verlag
Springer-Verlag
Erschienen in
Translational Stroke Research / Ausgabe 2/2012
Print ISSN: 1868-4483
Elektronische ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-012-0153-1

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