臺灣博碩士論文加值系統

頭部外傷的不良健康狀態及死亡率很高。頭部外傷藉由發炎、血紅素的釋放等各種不同的機制誘發氧化壓力產生。我們先前的研究顯示，分別由花生四烯酸與二十二碳六烯酸衍生出之可靠的脂質過氧化指標－F2-isoprostanes (F2-IsoPs) 與 F4-neuroprostanes (F4-NPs) 在腦脊髓液中的含量可預測動脈瘤蜘蛛膜下腔出血病患的不良癒後。本研究中，我們率先以高專一性之氣相層析/負離子化學游離質譜儀分析頭部外傷病患的F2-IsoPs與F4-NPs，選擇性地評估頭部外傷病患的全腦或神經元細胞。我們亦分析總nitrate/nitrite含量，以評估活性氮分子含量。我們收集11位非頭部外傷病患與15位頭部外傷病患手術後連續10天的腦脊髓液檢體。由結果可知頭部外傷病患中F2-IsoPs與F4-NPs的平均值、最高值、第一天與前兩天平均值均顯著高於非頭部外傷病患。然而，僅最高值之總nitrate/nitrite含量顯著高於非頭部外傷病患。雖然上述這些指標在中度及重度頭部外傷病患間沒有差異，但平均及最高值之F2-IsoPs含量與病患3個月後之不良癒後情形有顯著正相關。我們的結果也顯示出頭部外傷病患之F4-NPs含量增加之結果則首度指出神經元氧化傷害的現象，F2-IsoPs與F4-NPs或許可作為早期評估頭部外傷氧化傷害情形的指標。更進一步地，F2-IsoPs可藉由代表頭部外傷之全腦氧化傷害情形，作為指示頭部外傷病患不良癒後相關的新穎性生化指標。

Traumatic brain injury (TBI) causes high mortality and morbidity rate in humans. TBI may induce oxidative stress by several mechanism, such as inflammation and hemoglobin release. We have previously shown that levels of F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NPs), the most reliable markers of lipid peroxidation derived from arachidonic acid and docosahexaenoic acid, respectively, in cerebrospinal fluid (CSF) predicted poor outcome of aneurysmal subarachnoid hemorrhage in patients. In this study, we first used the specific gas chromatography/negative-ion chemical-ionization mass spectrometry method to detect F2-IsoPs and F4-NPs in TBI patients to evaluate oxidative damage of whole brain or neurons selectively. Total nitrate/nitrite levels were also analyzed to access levels of reactive nitrogen species. CSF samples were collected from 15 TBI patients every day after surgery for 10 days and 11 non-TBI controls. Results showed that the mean, peak, first-day, and first 2-day levels of F2-IsoPs and F4-NPs in TBI patients were significantly higher than controls. However, only peak levels of total nitrate/nitrite in TBI patients were elevated. Although there was no difference between moderate and severe TBI patients for the above markers, mean and peak levels of F2-IsoPs positively correlated with poor Glasgow Outcome Scale three months after surgery. Our results of increased F4-NPs levels in TBI patients first indicate oxidative damage to neurons following TBI. Theses results also suggest that F2-IsoPs and F4-NPs could be early markers for oxidative damage following TBI. Furthermore, F2-IsoPs could be a novel biomarker to indicate poor outcome of TBI patients by representing oxidative damage of whole brain following TBI.

目 錄
指導教授推薦書
口試委員會審定書
授權書............................................. iii
誌謝............................................... iv
中文摘要............................................ vi
英文摘要............................................ vii
目錄............................................... viii
第一章 研究背景與文獻回顧............................. 1
1.1 氧化壓力（Oxidative Stress）及氧化傷害指標.... 1
1.2 脂質過氧化（Lipid Peroxidation）與其專一性指標物質.... 3
1.2.1 F2-isoprostanes（F2-IsoPs）............... 5
1.2.2 F4-neuroprostanes（F4-NPs）............... 8
1.3 一氧化氮及Peroxynitrite.........................................10
1.4 頭部外傷（Traumatic Brain Injury ）........ 12
1.4.1 頭部外傷之病理現象......................... 13
1.4.2 頭部外傷之臨床分類及癒後評估................. 16
1.4.3 頭部外傷與氧化壓力......................... 16
第二章 研究動機、假說及目標......................... 24
第三章 實驗材料與方法.............................. 29
3.1 病患挑選準則、檢體收集與實驗操作之品管控制.... 29
3.2 腦脊髓液中之游離態F2-IsoPs的萃取與分析....... 31
3.3 腦脊髓液中之游離態 F4-NPs的萃取與分析........ 33
3.4 腦脊髓液中之Nitrite/Nitrate含量的偵測....... 35
3.5 統計分析與繪圖..............................36
第四章 實驗結果.................................... 38
4.1 頭部外傷病患的臨床診斷情形與控制組病患的基本資料 ..........................................38
4.2 頭部外傷病患連續10天與控制組病患腦脊髓液中F2-IsoPs含量的變化情形........................................... 38
4.3 頭部外傷病患連續10天與控制組病患腦脊髓液中F4-NPs含量的變化情形.............................................39
4.4 頭部外傷病患連續10天與控制組病患腦脊髓液中F4-NPs含量的變化情形............................................ 40
4.5 頭部外傷病患與控制組病患腦脊髓液中F2-IsoPs、F4-NPs與總nitrate/nitrite含量之箱型圖比較和統計分析結果........ 41
4.6 中度、重度頭部外傷病患腦脊髓液中F2-IsoPs、F4-NPs與總nitrate/nitrite含量之箱型圖比較和統計分析結果 .........42
4.7 有顱內出血及無顱內出血之頭部外傷病患腦脊髓液中F2-IsoPs、F4-NPs與總nitrate/nitrite含量之比較和統計分析結果.... 43
4.8 頭部外傷病患三個月後之癒後情形與其腦脊髓液中F2-IsoPs、F4-NPs與總nitrate/nitrite含量的相關性分析.............. 44
第五章 結論與討論.................................. 46
參考文獻........................................... 59
縮寫表............................................ 69
圖表.............................................. 70
表1. 非頭部外傷病患之情形........................... 70
表2. 頭部外傷病患之臨床診斷情形...................... 71
表3. 頭部外傷病患三個月後之癒後情形與腦脊髓液中F2-isoPs、F4-NPs與總Nitrate/Nitrite含量的相關性分析................................................73
圖1. 頭部外傷病患與控制組病患腦脊髓液中之連續10天的F2-isoPs含量的變化情形........................................... 74
圖2. 頭部外傷病患與控制組病患腦脊髓液中之連續10天的F4-NPs含量的變化情形............................................ 75
圖3. 頭部外傷病患與控制組病患腦脊髓液中之連續10天的總nitrate/nitrite含量的變化情形...................... 76
圖4. 以箱形圖表示頭部外傷病患與控制組病患腦脊髓液中F2-isoPs、F4-NPs與總nitrate/nitrite含量......................... 77
圖5. 以箱形圖表示中度與重度頭部外傷病患腦脊髓液中F2-isoPs、F4-NPs與總nitrate/nitrite含量............................ 79
圖6. 以散布圖呈現頭部外傷病患之出血種類與其腦脊髓液中F2-isoPs與F4-NPs含量........................................... 81
圖7. 以箱形圖表示有顱內出血之頭部外傷病患與無顱內出血之頭部外傷病患的腦脊髓液中F2-isoPs、F4-NPs與總nitrate/nitrite含量. 83
附錄.............................................. 85
附圖1. F2-IsoPs生成機制............................ 85
附圖2. F4-NPs生成機制.............................. 86
附圖3. F2-IsoPs之層析圖............................ 87
附圖4. F4-NPs之層析圖.............................. 88
附表1. 昏迷指數（Glasgow Coma Scale；GCS）.......... 89
長庚紀念醫院人體試驗倫理委員會同意臨床試驗證明書........ 90

[1] B. Halliwell and M. C. Gutteridge. Free Radicals in Biology and Medicine, fourth ed. New York: Oxford University Press, 2007.
[2] Shen, H.; Ong, C. Detection of oxidative DNA damage in human sperm and its association with sperm function and male infertility. Free Radic Biol Med 28:529-536; 2000.
[3] Spencer, J. P.; Jenner, A.; Chimel, K.; Aruoma, O. I.; Cross, C. E.; Wu, R.; Halliwell, B. DNA strand breakage and base modification induced by hydrogen peroxide treatment of human respiratory tract epithelial cells. FEBS Lett 374:233-236; 1995.
[4] Henriksen, T.; Hillestrom, P. R.; Poulsen, H. E.; Weimann, A. Automated method for the direct analysis of 8-oxo-guanosine and 8-oxo-2'-deoxyguanosine in human urine using ultraperformance liquid chromatography and tandem mass spectrometry. Free Radic Biol Med 47:629-635; 2009.
[5] Mundt, J. M.; Hah, S. S.; Sumbad, R. A.; Schramm, V.; Henderson, P. T. Incorporation of extracellular 8-oxodG into DNA and RNA requires purine nucleoside phosphorylase in MCF-7 cells. Nucleic Acids Res 36:228-236; 2008.
[6] Dean, R. T.; Fu, S.; Stocker, R.; Davies, M. J. Biochemistry and pathology of radical-mediated protein oxidation. Biochem J 324 ( Pt 1):1-18; 1997.
[7] Lyras, L.; Evans, P. J.; Shaw, P. J.; Ince, P. G.; Halliwell, B. Oxidative damage and motor neurone disease difficulties in the measurement of protein carbonyls in human brain tissue. Free Radic Res 24:397-406; 1996.
[8] Holley, A. E.; Cheeseman, K. H. Measuring free radical reactions in vivo. Br Med Bull 49:494-505; 1993.
[9] Brown, E. D.; Morris, V. C.; Rhodes, D. G.; Sinha, R.; Levander, O. A. Urinary malondialdehyde-equivalents during ingestion of meat cooked at high or low temperatures. Lipids 30:1053-1056; 1995.
[10] Wilson, R.; Lyall, K.; Smyth, L.; Fernie, C. E.; Riemersma, R. A. Dietary hydroxy fatty acids are absorbed in humans: implications for the measurement of 'oxidative stress' in vivo. Free Radic Biol Med 32:162-168; 2002.
[11] Kikugawa, K.; Beppu, M. Involvement of lipid oxidation products in the formation of fluorescent and cross-linked proteins. Chem Phys Lipids 44:277-296; 1987.
[12] Yeo, H. C.; Helbock, H. J.; Chyu, D. W.; Ames, B. N. Assay of malondialdehyde in biological fluids by gas chromatography-mass spectrometry. Anal Biochem 220:391-396; 1994.
[13] Mateos, R.; Bravo, L. Chromatographic and electrophoretic methods for the analysis of biomarkers of oxidative damage to macromolecules (DNA, lipids, and proteins). J Sep Sci 30:175-191; 2007.
[14] Morrow, J. D.; Hill, K. E.; Burk, R. F.; Nammour, T. M.; Badr, K. F.; Roberts, L. J., 2nd. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci U S A 87:9383-9387; 1990.
[15] Morrow, J. D.; Awad, J. A.; Boss, H. J.; Blair, I. A.; Roberts, L. J., 2nd. Non-cyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids. Proc Natl Acad Sci U S A 89:10721-10725; 1992.
[16] Morrow, J. D.; Roberts, L. J. The isoprostanes: unique bioactive products of lipid peroxidation. Prog Lipid Res 36:1-21; 1997.
[17] Taber, D. F.; Morrow, J. D.; Roberts, L. J., 2nd. A nomenclature system for the isoprostanes. Prostaglandins 53:63-67; 1997.
[18] Roberts, L. J., 2nd; Morrow, J. D. Products of the isoprostane pathway: unique bioactive compounds and markers of lipid peroxidation. Cell Mol Life Sci 59:808-820; 2002.
[19] Waugh, R. J.; Morrow, J. D.; Roberts, L. J., 2nd; Murphy, R. C. Identification and relative quantitation of F2-isoprostane regioisomers formed in vivo in the rat. Free Radic Biol Med 23:943-954; 1997.
[20] Morrow, J. D.; Minton, T. A.; Badr, K. F.; Roberts, L. J., 2nd. Evidence that the F2-isoprostane, 8-epi-prostaglandin F2 alpha, is formed in vivo. Biochim Biophys Acta 1210:244-248; 1994.
[21] Stafforini, D. M.; Sheller, J. R.; Blackwell, T. S.; Sapirstein, A.; Yull, F. E.; McIntyre, T. M.; Bonventre, J. V.; Prescott, S. M.; Roberts, L. J., 2nd. Release of free F2-isoprostanes from esterified phospholipids is catalyzed by intracellular and plasma platelet-activating factor acetylhydrolases. J Biol Chem 281:4616-4623; 2006.
[22] Roberts, L. J.; Morrow, J. D. Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo. Free Radic Biol Med 28:505-513; 2000.
[23] Halliwell, B.; Lee, C. Y. Using isoprostanes as biomarkers of oxidative stress: some rarely considered issues. Antioxid Redox Signal 13:145-156; 2010.
[24] Roberts, L. J., 2nd; Moore, K. P.; Zackert, W. E.; Oates, J. A.; Morrow, J. D. Identification of the major urinary metabolite of the F2-isoprostane 8-iso-prostaglandin F2alpha in humans. J Biol Chem 271:20617-20620; 1996.
[25] 謝育萍; 顏秀娟. 氧化壓力臨床指標: Isoprostanes和Neuroprostanes. 生物醫學 1:53-67; 2009.
[26] Lin, C. L.; Hsu, Y. T.; Lin, T. K.; Morrow, J. D.; Hsu, J. C.; Hsu, Y. H.; Hsieh, T. C.; Tsay, P. K.; Yen, H. C. Increased levels of F2-isoprostanes following aneurysmal subarachnoid hemorrhage in humans. Free Radic Biol Med 40:1466-1473; 2006.
[27] Pratico, D.; Iuliano, L.; Mauriello, A.; Spagnoli, L.; Lawson, J. A.; Rokach, J.; Maclouf, J.; Violi, F.; FitzGerald, G. A. Localization of distinct F2-isoprostanes in human atherosclerotic lesions. J Clin Invest 100:2028-2034; 1997.
[28] Gopaul, N. K.; Anggard, E. E.; Mallet, A. I.; Betteridge, D. J.; Wolff, S. P.; Nourooz-Zadeh, J. Plasma 8-epi-PGF2 alpha levels are elevated in individuals with non-insulin dependent diabetes mellitus. FEBS Lett 368:225-229; 1995.
[29] Montine, T. J.; Beal, M. F.; Cudkowicz, M. E.; O'Donnell, H.; Margolin, R. A.; McFarland, L.; Bachrach, A. F.; Zackert, W. E.; Roberts, L. J.; Morrow, J. D. Increased CSF F2-isoprostane concentration in probable AD. Neurology 52:562-565; 1999.
[30] Basu, S. F2-isoprostanes in human health and diseases: from molecular mechanisms to clinical implications. Antioxid Redox Signal 10:1405-1434; 2008.
[31] Milne, G. L.; Yin, H.; Morrow, J. D. Human biochemistry of the isoprostane pathway. J Biol Chem 283:15533-15537; 2008.
[32] Sircar, D.; Subbaiah, P. V. Isoprostane measurement in plasma and urine by liquid chromatography-mass spectrometry with one-step sample preparation. Clin Chem 53:251-258; 2007.
[33] Proudfoot, J.; Barden, A.; Mori, T. A.; Burke, V.; Croft, K. D.; Beilin, L. J.; Puddey, I. B. Measurement of urinary F(2)-isoprostanes as markers of in vivo lipid peroxidation-A comparison of enzyme immunoassay with gas chromatography/mass spectrometry. Anal Biochem 272:209-215; 1999.
[34] Wang, Z.; Ciabattoni, G.; Creminon, C.; Lawson, J.; Fitzgerald, G. A.; Patrono, C.; Maclouf, J. Immunological characterization of urinary 8-epi-prostaglandin F2 alpha excretion in man. J Pharmacol Exp Ther 275:94-100; 1995.
[35] Milne, G. L.; Sanchez, S. C.; Musiek, E. S.; Morrow, J. D. Quantification of F2-isoprostanes as a biomarker of oxidative stress. Nat Protoc 2:221-226; 2007.
[36] Roberts, L. J., 2nd; Montine, T. J.; Markesbery, W. R.; Tapper, A. R.; Hardy, P.; Chemtob, S.; Dettbarn, W. D.; Morrow, J. D. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem 273:13605-13612; 1998.
[37] Yin, H.; Musiek, E. S.; Gao, L.; Porter, N. A.; Morrow, J. D. Regiochemistry of neuroprostanes generated from the peroxidation of docosahexaenoic acid in vitro and in vivo. J Biol Chem 280:26600-26611; 2005.
[38] Salem, N., Jr.; Litman, B.; Kim, H. Y.; Gawrisch, K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 36:945-959; 2001.
[39] Kim, H. Y. Novel metabolism of docosahexaenoic acid in neural cells. J Biol Chem 282:18661-18665; 2007.
[40] Eric R. Kandel, J. H. S., Thomas M. Jessell. Principles of Neural Scienc, fourth ed 2000.
[41] Guix, F. X.; Uribesalgo, I.; Coma, M.; Munoz, F. J. The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 76:126-152; 2005.
[42] Mungrue, I. N.; Bredt, D. S.; Stewart, D. J.; Husain, M. From molecules to mammals: what's NOS got to do with it? Acta Physiol Scand 179:123-135; 2003.
[43] Iadecola, C.; Zhang, F.; Xu, S.; Casey, R.; Ross, M. E. Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 15:378-384; 1995.
[44] Bolanos, J. P.; Almeida, A. Roles of nitric oxide in brain hypoxia-ischemia. Biochim Biophys Acta 1411:415-436; 1999.
[45] Lundberg, J. O.; Weitzberg, E.; Gladwin, M. T. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 7:156-167; 2008.
[46] Tran, M. H.; Yamada, K.; Nakajima, A.; Mizuno, M.; He, J.; Kamei, H.; Nabeshima, T. Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid beta-peptide-induced cholinergic dysfunction. Mol Psychiatry 8:407-412; 2003.
[47] West, A. R.; Galloway, M. P. Endogenous nitric oxide facilitates striatal dopamine and glutamate efflux in vivo: role of ionotropic glutamate receptor-dependent mechanisms. Neuropharmacology 36:1571-1581; 1997.
[48] Cherian, L.; Hlatky, R.; Robertson, C. S. Nitric oxide in traumatic brain injury. Brain Pathol 14:195-201; 2004.
[49] Maas, A. I.; Stocchetti, N.; Bullock, R. Moderate and severe traumatic brain injury in adults. Lancet Neurol 7:728-741; 2008.
[50] Langlois JA, R.-B. W., Thomas KE. . Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2006.
[51] Lin, J. W.; Tsai, S. H.; Tsai, W. C.; Chiu, W. T.; Chu, S. F.; Lin, C. M.; Yang, C. M.; Hung, C. C. Survey of traumatic intracranial hemorrhage in Taiwan. Surg Neurol 66 Suppl 2:S20-25; 2006.
[52] Werner, C.; Engelhard, K. Pathophysiology of traumatic brain injury. Br J Anaesth 99:4-9; 2007.
[53] Mazzeo, A. T.; Beat, A.; Singh, A.; Bullock, M. R. The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI. Exp Neurol 218:363-370; 2009.
[54] Potts, M. B.; Koh, S. E.; Whetstone, W. D.; Walker, B. A.; Yoneyama, T.; Claus, C. P.; Manvelyan, H. M.; Noble-Haeusslein, L. J. Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets. NeuroRx 3:143-153; 2006.
[55] Ghajar, J. Traumatic brain injury. Lancet 356:923-929; 2000.
[56] Jennett, B.; Bond, M. Assessment of outcome after severe brain damage. Lancet 1:480-484; 1975.
[57] Everse, J.; Hsia, N. The toxicities of native and modified hemoglobins. Free Radic Biol Med 22:1075-1099; 1997.
[58] Chang, E. F.; Claus, C. P.; Vreman, H. J.; Wong, R. J.; Noble-Haeusslein, L. J. Heme regulation in traumatic brain injury: relevance to the adult and developing brain. J Cereb Blood Flow Metab 25:1401-1417; 2005.
[59] Huang, F. P.; Xi, G.; Keep, R. F.; Hua, Y.; Nemoianu, A.; Hoff, J. T. Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg 96:287-293; 2002.
[60] Dennery, P. A.; Visner, G.; Weng, Y. H.; Nguyen, X.; Lu, F.; Zander, D.; Yang, G. Resistance to hyperoxia with heme oxygenase-1 disruption: role of iron. Free Radic Biol Med 34:124-133; 2003.
[61] Wagner, K. R.; Sharp, F. R.; Ardizzone, T. D.; Lu, A.; Clark, J. F. Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 23:629-652; 2003.
[62] Lifshitz, J.; Sullivan, P. G.; Hovda, D. A.; Wieloch, T.; McIntosh, T. K. Mitochondrial damage and dysfunction in traumatic brain injury. Mitochondrion 4:705-713; 2004.
[63] Rodrigo, J.; Fernandez, A. P.; Serrano, J.; Peinado, M. A.; Martinez, A. The role of free radicals in cerebral hypoxia and ischemia. Free Radic Biol Med 39:26-50; 2005.
[64] Pun, P. B.; Lu, J.; Moochhala, S. Involvement of ROS in BBB dysfunction. Free Radic Res 43:348-364; 2009.
[65] Clark, R. S.; Kochanek, P. M.; Obrist, W. D.; Wong, H. R.; Billiar, T. R.; Wisniewski, S. R.; Marion, D. W. Cerebrospinal fluid and plasma nitrite and nitrate concentrations after head injury in humans. Crit Care Med 24:1243-1251; 1996.
[66] Heo, J. H.; Han, S. W.; Lee, S. K. Free radicals as triggers of brain edema formation after stroke. Free Radic Biol Med 39:51-70; 2005.
[67] Gursoy-Ozdemir, Y.; Can, A.; Dalkara, T. Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke 35:1449-1453; 2004.
[68] Marikovsky, M.; Ziv, V.; Nevo, N.; Harris-Cerruti, C.; Mahler, O. Cu/Zn superoxide dismutase plays important role in immune response. J Immunol 170:2993-3001; 2003.
[69] Nayak, C.; Nayak, D.; Bhat, S.; Raja, A.; Rao, A. Relationship between neurological outcome and early oxidative changes in erythrocytes in head injury patients. Clin Chem Lab Med 45:629-633; 2007.
[70] Nayak, C.; Nayak, D.; Raja, A.; Rao, A. Relationship between markers of lipid peroxidation, thiol oxidation and Glasgow coma scale scores of moderate head injury patients in the 7 day post-traumatic period. Neurol Res 30:461-464; 2008.
[71] Kasprzak, H. A.; Wozniak, A.; Drewa, G.; Wozniak, B. Enhanced lipid peroxidation processes in patients after brain contusion. J Neurotrauma 18:793-797; 2001.
[72] Paolin, A.; Nardin, L.; Gaetani, P.; Rodriguez, Y. B. R.; Pansarasa, O.; Marzatico, F. Oxidative damage after severe head injury and its relationship to neurological outcome. Neurosurgery 51:949-954; discussion 954-945; 2002.
[73] Bayir, H.; Kagan, V. E.; Tyurina, Y. Y.; Tyurin, V.; Ruppel, R. A.; Adelson, P. D.; Graham, S. H.; Janesko, K.; Clark, R. S.; Kochanek, P. M. Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatr Res 51:571-578; 2002.
[74] Bayir, H.; Marion, D. W.; Puccio, A. M.; Wisniewski, S. R.; Janesko, K. L.; Clark, R. S.; Kochanek, P. M. Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients. J Neurotrauma 21:1-8; 2004.
[75] Seifman, M. A.; Adamides, A. A.; Nguyen, P. N.; Vallance, S. A.; Cooper, D. J.; Kossmann, T.; Rosenfeld, J. V.; Morganti-Kossmann, M. C. Endogenous melatonin increases in cerebrospinal fluid of patients after severe traumatic brain injury and correlates with oxidative stress and metabolic disarray. J Cereb Blood Flow Metab 28:684-696; 2008.
[76] Benzie, I. F.; Strain, J. J. The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Anal Biochem 239:70-76; 1996.
[77] Hsieh, Y. P.; Lin, C. L.; Shiue, A. L.; Yin, H.; Morrow, J. D.; Hsu, J. C.; Hsieh, T. C.; Wei, H. J.; Yen, H. C. Correlation of F4-neuroprostanes levels in cerebrospinal fluid with outcome of aneurysmal subarachnoid hemorrhage in humans. Free Radic Biol Med 47:814-824; 2009.
[78] Yen, H. C. Detection of F2-isoprostanes and F4-neuroprostanes in clinical studies. J Biomed Lab Sci 2:1-10; 2010.
[79] Arneson, K. O.; Roberts, L. J., 2nd. Measurement of products of docosahexaenoic acid peroxidation, neuroprostanes, and neurofurans. Methods Enzymol 433:127-143; 2007.
[80] Dankbaar, J. W.; Rijsdijk, M.; van der Schaaf, I. C.; Velthuis, B. K.; Wermer, M. J.; Rinkel, G. J. Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neuroradiology 51:813-819; 2009.
[81] Greenberg, M. S. Handbook of neurosurgery, sixth ed. New York: Thieme, 2006.
[82] Kochanek, P. M.; Berger, R. P.; Bayir, H.; Wagner, A. K.; Jenkins, L. W.; Clark, R. S. Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making. Curr Opin Crit Care 14:135-141; 2008.
[83] Hayakata, T.; Shiozaki, T.; Tasaki, O.; Ikegawa, H.; Inoue, Y.; Toshiyuki, F.; Hosotubo, H.; Kieko, F.; Yamashita, T.; Tanaka, H.; Shimazu, T.; Sugimoto, H. Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock 22:102-107; 2004.
[84] Kleindienst, A.; Hesse, F.; Bullock, M. R.; Buchfelder, M. The neurotrophic protein S100B: value as a marker of brain damage and possible therapeutic implications. Prog Brain Res 161:317-325; 2007.
[85] Varma, S.; Janesko, K. L.; Wisniewski, S. R.; Bayir, H.; Adelson, P. D.; Thomas, N. J.; Kochanek, P. M. F2-isoprostane and neuron-specific enolase in cerebrospinal fluid after severe traumatic brain injury in infants and children. J Neurotrauma 20:781-786; 2003.
[86] Zimmer, D. B.; Cornwall, E. H.; Landar, A.; Song, W. The S100 protein family: history, function, and expression. Brain Res Bull 37:417-429; 1995.
[87] Rothermundt, M.; Peters, M.; Prehn, J. H.; Arolt, V. S100B in brain damage and neurodegeneration. Microsc Res Tech 60:614-632; 2003.
[88] Chen, D. Q.; Zhu, L. L. Dynamic change of serum protein S100b and its clinical significance in patients with traumatic brain injury. Chin J Traumatol 8:245-248; 2005.
[89] Anderson, R. E.; Hansson, L. O.; Nilsson, O.; Dijlai-Merzoug, R.; Settergren, G. High serum S100B levels for trauma patients without head injuries. Neurosurgery 48:1255-1258; discussion 1258-1260; 2001.
[90] Marangos, P. J.; Schmechel, D. E. Neuron specific enolase, a clinically useful marker for neurons and neuroendocrine cells. Annu Rev Neurosci 10:269-295; 1987.
[91] Darwish, R. S.; Amiridze, N.; Aarabi, B. Nitrotyrosine as an oxidative stress marker: evidence for involvement in neurologic outcome in human traumatic brain injury. J Trauma 63:439-442; 2007.