周產期缺氧窒息腦病變是造成嬰兒死亡率及神經後遺症之一大原因，雖然目前對新生兒窒息腦傷機制的瞭解不少，但至今除了低體溫療法外仍無有效的治療。近年來有學者提出「Neurovascular unit｣的概念。它是由神經元、星狀細胞、血管上皮細胞所組成的單元。缺氧窒息腦傷後，維持neurovascular unit的完整性，神經元才能繼續存活發揮功能。所以著手於尋找影響缺氧窒息腦傷害耐受性的因子，及其對neurovascular unit的影響，也是能預防甚至於治療缺氧窒息腦病變的方向。
臨床上的觀察發現，出生體重過重的新生兒易有產傷及遭遇周產期缺氧窒息的情形，而有神經後遺症。反之，體重不足的新生兒遭遇「周產期缺氧窒息｣後卻較少有像腦性麻痺等嚴重的腦傷後遺症。這些臨床上的觀察顯示體重似乎會影響新生兒腦部對缺氧窒息腦傷害的耐受性。由一些關於肥胖的研究發現肥胖會促使脂肪細胞可分泌出許多促發炎細胞激素進而刺激活化c-Jun N-terminal kinase (JNK) 這個重要的kinase，JNK的活化也已知與細胞死亡機制相關，暗示體重過重的新生兒可能誘發JNK的過度激活惡化缺氧窒息性腦傷。另一方面的研究發現生物體在攝食量節制後，可以穩定細胞內的鈣離子，降低oxidative stress，減輕apoptosis，也可以影響p53的功能。p53 已知是個能調控細胞存亡的重要因子，所以攝食量節制可能可以藉由調控p53來幫助減輕缺氧窒息腦部的傷害。所以我們假設新生兒體重會影響新生兒腦部的「Neurovascular unit｣ 對缺氧窒息腦傷害的耐受性。
我們利用改變胎數的方法來建立過重及攝食量節制後減重的幼鼠模型。同天出生的幼鼠於出生第一天隨意分組: 正常組的母鼠一胎哺育12隻幼鼠，過重組的母鼠一胎只哺育6隻幼鼠，攝食量節制減重組的母鼠一胎則哺育18隻幼鼠。並於出生後第7天利用單側頸動脈結紮结合缺氧來誘發缺氧窒息腦傷害，藉由這些模型來測試體重對於新生兒期缺氧窒息腦傷害的影響。結果顯示，過重的幼鼠會誘發缺氧窒息後早期JNK的過度激活，引起細胞apoptosis且破壞neurovascular unit的完整性，造成球蛋白外漏、星狀細胞增加，加重缺氧窒息性腦傷。若抑制過重幼鼠的JNK表現，能改善過重的幼鼠在缺氧窒息腦傷後的傷害，減輕細胞apoptosis的程度及對 neurovascular unit的傷害。另一方面，減重的幼鼠在缺氧窒息後，減少p53的表現，降低了apoptosis、球蛋白外漏和星狀細胞，維持neurovascular unit的完整性，進而改善缺氧窒息性腦傷。進一步利用抑制Mdm2來增加p53在減重幼鼠的表現量，則發現減重的幼鼠會失去對缺氧窒息腦傷的保護效果，表示攝食量節制後減重的幼鼠能藉由調控p53來改善缺氧窒息性腦傷。
我們的結果發現單純的體重變化就能明顯影響新生兒腦部的「Neurovascular unit｣ 對周產期缺氧窒息腦傷害的耐受性，增加體重會藉由JNK的過度激活惡化缺氧窒息性腦傷，而攝食量節制後減重的幼鼠能藉由降低p53來改善缺氧窒息性腦傷。之後，我們會進一步探索攝食量節制後減重的幼鼠調控p53的機制，以期能運用在臨床周產期缺氧窒息腦傷害的治療上。

Perinatal hypoxic-ischemia (HI) is a major cause of neonatal mortality and of subsequent neurological disabilities among survivors. Neurovascular unit, comprised of neurons, astrocytes, microglia and endothelial cells, maintains the integrity of the blood-brain barrier and regulates the cerebral blood supply in response to the metabolic demand of the neurons. Modalities that target this integrated unit may yield more therapeutically useful results in treating perinatal HI.
From clinical observation in human newborns, large-for-gestational-age newborns who have above-average birthweights have higher incidences of birth complications, such as perinatal asphyxia, than appropriate-for-gestational-age (AGA) newborns. In contrast, small-for-gestational-age newborns with low birthweights have a lower incidence of cerebral palsy after perinatal insults than AGA newborns. These findings indicate that bodyweight may play an important role in the susceptibility of neonatal HI brain injury. Obesity studies showed that c-Jun N-terminal kinase (JNK) activated by obesity could precede cell death by apoptosis and inflammation in many cell types. Dietary restriction (DR) studies demonstrated that DR induced bodyweight reduction and protected neurons against focal ischemic brain damage. The gene profile in DR animals showed a decrease of p53, a transcription factor regulating cell cycle, DNA repair and cell apoptosis. Thus, we hypothesized that bodyweights have differential influence on the HI susceptibility in neonatal brain: overweight aggravated neurovascular damage and worsened HI injury through hyperactivation of JNK while DR-induced underweight reduced neurovascular damage and protected against HI injury via downregulation of p53.
We used changes of litter size to create overweight and underweight pup model. The overweight rat pups were induced by culling the litter size to 6 pups per dam from postnatal day 1 until weaning, and the control pups by keeping the litter size at 12. The underweight pups were raised in the litter size of 18 pups per dam. Our data showed that compared with normal bodyweight rat pups, overweight pups from a small litter size had increased susceptibility to HI injury on P7, evidenced by a high HI mortality, and worsened neurobehavioral performance and aggravated brain injury at long-term follow up. Overweight pups also had JNK hyperactivation soon after HI and increased neurovascular destruction, such as neuronal apoptosis, microglia activation and BBB damage, 24 hours after HI. Inhibiting JNK activity in overweight pups caused attenuation of cleaved caspase-3 and PARP, reduction of microglial activation and BBB damage and significantly reduced infarct brain volume after HI. On the other hand, compared with normal control pups, underweight pups induced by DR had decreased susceptibility to HI, supported by improved neurobehavioral performance and decreased brain injury at long-term follow up. Underweight pups also showed reduction of neuronal apoptosis, BBB damage and microglia activation and attenuation of p53 expression after HI. The neurovascular protection of underweight induced by DR was attenuated when p53 was activated by an Mdm2 inhibitor.
In conclusion, bodyweight has differential effects on the vulnerability of neonatal brain to HI injury involving the integrity of neurovascular unit. Overweight aggravated neurovascular damage through hyperactivation of JNK while DR-induced underweight protected against neurovascular damage via downregulation of p53.

1. Volpe JJ. Neurology of the newborn. 5th ed. Philadelphia: Saunders, 2008
2. Beger R, Garnier Y. Pathophysiology of perinatal brain damage. Brain Res Rev 1999;30:107-134
3. Johnstom MV, Fatemi A, Wilson MA, Northington F. Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011;10:372-382
4. Butler TL. Kassed CA, Pennupacker KR. Signal transduction and neuronal survival in experimental models of brain injury. Brain Res Bull 2003;59:339-351
5. Walton MR, Dragunow I. Is CREB a key to neuronal survival? Trends Neurosci 2000;23:48-53
6. Huang CC, Wang ST, Chang YC, Lin KP, Wu PL. Measurement of the urinary lactate:creatinine ratio for the early identification of newborn infants at risk for hypoxic-ischemic encephalopathy. N Engl J Med. 1999;34:328-335
7. Whitelaw A. Systemic review of therapy after hypoxic-ischemic brain injury in the prenatal period. Semin Neonatol 2000;5:33-40
8. Chang YC, Huang CC. Perinatal brain injury and regulation of transcription. Curr Opin Neurol 2006;19:141-147
9. Arai K, Jin G, Navaratna D, Lo EH. Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke. FEBS J 2009;276:4644-4652
10. Lok J, Gupta P, Guo S, Kim WJ, Whalen MJ, van Leyen K, Lo EH. Cell-cell signaling in the neurovascular unit. Neurochem Res 2007;32:2032-2045
11. Chew LJ, Takanohashi A, Bell M. Microglia and inflammation: impact on developmental brain injuries. Ment Retard Dev Disabil Res Rev 2006;12:105-112
12. Renolleau S, Fau S, Charriaut-Marlangue C. Gender-related differences in apoptotic pathways after neonatal cerebral ischemia. Neuroscientist. 2008;14:46-52
13. Das UG, Sysyn GD. Abnormal fetal growth: intrauterine growth retardation, small for gestational age, large for gestational age. Pediatr Clin North Am 2004;51:639-654
14. Wiberg B, Sundstrom J, Arnlov J, Terent A, Vessby B, Zethelius B, Lind L. Metabolic risk factors for stroke and transient ischemic attacks in middle-aged men: a community-based study with long-term follow-up. Stroke 2006;37:2898-903.
15. Ribo M, Molina CA, Delgado P, Rubiera M, Delgado-Mederos R, Rovira A, Munuera J, Alvarez-Sabin J. Hyperglycemia during ischemia rapidly accelerates brain damage in stroke patients treated with tPA. J Cereb Blod Flow Metab. 2007;27:1616-1622
16. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 2002;420:333-336
17. Cao J, Semenova MM, Solovyan VT, Han J, Coffey ET, Courtney MJ. Distinct requirements for p38alpha and c-Jun N-terminal kinase stress-activated protein kinases in different forms of apoptotic neuronal death. J Biol Chem 2004;279:35903-35913
18. Stollhoff NVK, Claussen M. Developmental and perinatal risk factors of very low-birth-weight infants. Small versus appropriate for gestational age. Neuropediatrics. 1992;23:102-107.
19. Weindruch R, Sohal RS. Caloric intake and aging. N Engl J Med. 1997;337:986-994
20. Mattson MP, Duan W, Guo Z. Meal size and frequency affect neuronal plasiticity and vulnerability to disease: cellular and molecular mechanism. J Neurochem. 2003;84:417-431
21. Yu Z, Mattson MP. Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J Neurosci Res. 1999;57:830-839.
22. Guo Z, Mattson MP. In vivo 2-deoxyglucose administration preserves glucose and glutamate transport and mitochondrial function in cortical synaptic terminals after exposure to amyloid -peptide and iron: evidence for a stress response. Exp. Neurol. 2000;166:173-179
23. Chiba T, Ezaki O. Dietary restriction suppresses inflammation and delays the onset of stroke in stroke-prone spontaneously hypertensive rats. Biochem Biophys Res Commun. 2010;399:98-103.
24. Ketonen J, Pilvi T, Mervaala E. Caloric restriction reverses high-fat diet-induced endothelial dysfunction and vascular superoxide production in C57B1/6 mice. Heart Vessels. 2010;25:254-262
25. Ando K, Higami Y, Tsuchiya T, Kanematsu T, Shimokawa I. Impact of aging and life-ling caloric restriction on expression of apoptosis-related genes in male F344 rat liver. Microsc Res Tech 2002;59:293-300
26. Culmsee C, Mattson MP. p53 in neuronal apoptosis. Biochem Biophys Res Commun. 2005;331:761-777.
27. Nijboer CH, Heijnen CJ, van der Kooij MA, Zijlstra J, van Velthoven CTJ, Culmsee C, Van Bel F, Hagberg H, Kavelaars A. Targeting the p53 pathway to protect the neonatal ischemic brain. Ann Neurol. 2011;70:252-264
28. Stempien-Otero A, Karsan A, Cornejol CJ, Xiang H, Eunson T, Morrison RS, Kay M, Winn R, Harian J. Mechanisms of hypoxia-induced endothelial cell death. Role of p53 in apoptosis. J Bio Chem. 1999;19:8039-8045.
29. Davenport CM, Sevastou IG, Hooper C, Pocock JM. Inhibiting p53 pathways in microglia attenuates microglial-evoked neurotoxicity following exposure to Alzheimer peptides. J Neurochem. 2010;112:552-563
30. Levine S. Anoxic-ischemic encephalopathy in rats. Am J Pathol 1960;36:1-17
31. Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates, 2nd ed. Academic Press, San Diego, CA. 1986
32. Lin WY, Chang YC, Lee HT, Huang CC. CREB activation in the rapid, intermediate and delayed ischemic preconditioning against hypoxic-ischemia in neonatal rat. J Neurochem 2009;108:847-859
33. Blomgren K, Hagberg H. Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med 2006;40:388-397
34. Ito D, Tanaka K, Suzuki S, Dembo T, Fukuuchi Y. Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke 2001;32:1208-1215
35. Sury MD, Agarinis C, Widmer HR, Leib SL, Christen S. JNK is activated but does not mediate hippocampal neuronal apoptosis in experimental neonatal pneumococcal meningitis. Neurobiol Dis 2008;32:142-150
36. Gaillard P, Jeanclaude-Etter I, Ardissone V, Arkinstall S, Cambet Y, Camps M, Chabert C, Church D, Cirillo R, Gretener D, Halazy S, Nichols A, Szyndralewiez C, Vitte PA, Gotteland JP. Design and synthesis of the first generation of novel potent, selective, and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase. J Med Chem 2005;48:4596-4607
37. Armitage JA, Taylor PD, Poston L. Experimental models of developmental programming: consequences of exposure to an energy rich diet during development. J Physiol 2005;565:3-8
38. Srinivasan M, Katewa SD, Palaniyappan A, Pandya JD, Patel MS. Maternal high-fat diet consumption results in fetal malprogramming predisposing to the onset of metabolic syndrome-like phenotype in adulthood. Am J Physiol Endocrinol Metab 2006;291:E792-799
39. Cryer A, Jones HM. The early development of white adipose tissue. Effects of litter size on the lipoprotein lipase activity of four adipose-tissue depots, serum immunoreactive insulin and tissue cellularity during the first four weeks of life in the rat. Biochem J 1979;178:711-724
40. Boullu-Ciocca S, Dutour A, Guillaume V, Achard V, Oliver C, Grino M. Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome. Diabetes 2005;54:197-203
41. Wurtman JJ, Miller SA. Effect of litter size on weight gain in rats. J Nutr 1976;106:697-701
42. Desai M, Hales CN. Role of fetal and infant growth in programming metabolism in later life. Biol Rev Camb Philos Soc. 1997;72: 329-348
43. Plagemann A, Rake A, Melchior K, Rohde W, Do¨rner G. Reduction of cholecystokinin-8S-neurons in the paraventricular hypothalamic nucleus of neonatally overfed weanling rats. Neurosci Lett.1998; 258: 13–16
44. Rocha-de-Melo AP, Picanço-Diniz CW, Borba JM, Santos-Monteiro J, Guedes RC. NADPH-diaphorase histochemical labeling patterns in the hippocampal neuropil and visual cortical neurons in weaned rats reared during lactation on different litter sizes. Nutr Neurosci. 2004;7:207-216
45. Seidler FJ, Bell JM, Slotkin TA. Undernutrition and overnutrition in the neonatal rat: long-term effects on noradrenergic pathways in brain regions. Pediatr Res 1990;27:191-197
46. Lau C, Seidler FJ, Cameron AM, Navarro HA, Bell JM, Bartolome J, Slotkin TA. Nutritional influences on adrenal chromaffin cell development: comparison with central neurons. Pediatr Res 1988;24: 583-587
47. McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev. 2005;S5:571-633
48. Trescher WH, Lehman RA, Vannucci RC. The influence of growth retardation on perinatal hypoxic-ischemic brain damage. Early Hum Dev 1990;21:165-173
49. Oakden E, Chiswick M, Rothwell N, Loddick S. The influence of litter size on brain damage caused by hypoxic-ischemic injury in the neonatal rat. Pediatr Res 2002;52:692-696
50. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 2003, 4:399-415
51. del Zoppo G.J. Stroke and neurovascular protection. New Engl J Med 2006, 354:553-555
52. Blomgren K, Leist M, Groc L. Pathoglical apoptosis in the developing brain. Apoptosis 2007;12:993-1010
53. Vannucci SJ, Hagberg H. Hypoxia-ischemia in the immature brain. J Exp Biol. 2004;207:3149-3154
54. Ivacko JA, Sun R, Silverstein FS. Hypoxic-ischemic brain injury induces an acute microglial reaction in perinatal rats. Pediatr Res 1996;39:39-47
55. Fan LW, Lin S, Pang Y, Rhodes PG, Cai Z. Minocycline attenuates hypoxia-ischemia-induced neurological dysfunction and brain injury in the juvenile rat. Eur J Neurosci 2006;24:341-350.
56. Muramatsu K, Fukuda A, Togari H, Wada Y, Nishino H. Vulnerability to cerebral hypoxic-ischemic insult in neonatal but not in adult rats is in parallel with disruption of the blood-brain barrier. Stroke 1997;28:2281-2288.
57. Lee HT, Chang YC, Tu YF, Huang CC. VEGF-A/VEGFR-2 signaling leading to CREB phosphorylation is a shared pathway underlying the protective effect of preconditioning on neurons and endothelial cells. J Neurosci 2009;29:4356-4368
58. Svedin P, Hagberg H, Savman K, Zhu C, Mallard C. Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neurosci 2007;27:1511-1518
59. Zoppo GJ, Milner R, Mabuchi T, Hung S, Wang X, Berg GI, Koziol JA. Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke 2007;38:646-651
60. Yenari MA, Xu L, Tang XN, Qiao Y, Giffard RG. Microglia potentiate damage to blood–brain barrier constituents: Improvement by minocycline in vivo and in vitro. Stroke 2006;37:1087-1093
61. Stoll G., Jander S. The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 1999;58:233-247
62. Dammann O, Durum S, Leviton A. Do white cells matter in white matter damage? Trends Neurosci 2001;24:320-324
63. Chen HJ, Bai CH, Yeh WT, Chiu HC, Pan WH. Influence of metabolic syndrome and general obesity on the risk of ischemic stroke. Stroke 2006;37:1060-1064
64. Hankey GJ. Potential new risk factors for ischemic stroke: what is their potential? Stroke 2006;37:2181-2188
65. Vincent HK, Innes KE, Vincent KR. Oxidative stress and potential interventions to reduce oxidative stress in overweight and obesity. Diabetes Obes Metab 2007;9:813-839
66. Lago F, Dieguez C, Gómez-Reino J, Gualillo O. Adipokines as emerging mediators of immune response and inflammation. Nat Clin Practice Rheum 2007;3:716-724
67. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-808
68. Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 2008; 94:206-218
69. Gustafson B. Adipose tissue, inflammation and atherosclerosis. J Atheroscler Thromb 2010;17:332-341
70. Ye H, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007; 293:E1118-1128
71. Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr 2008;100:227-235
72. Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition- the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 2002, 50:2041-2056.
73. Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 2003; 9;1180-1186
74. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005, 115:1111-1119
75. Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 2000; 288:870-874
76. Okuno S, Saito A, Hayashi T, Chan PH. The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 2004;24:7879-7887
77. Becker E, Howell J, Kodama Y, Barker PA, Bonni A. Characterization of the c-Jun N-terminal kinase-BimEL signaling pathway in neuronal apoptosis. J Neurosci 2004;24:8762-8770
78. Uesugi M, Nakajima K, Tohyama Y, Kohsaka S, Kurihara T. Nonparticipation of nuclear factor kappa B in the signaling cascade of c-Jun N-terminal kinases-and p38 mitogen-activated protein kinase-dependent tumor necrosis factor alpha induction in lipopolysaccharide-stimulated microglia. Brain Res 2006;1073:48-59
79. Deng YY, Lu J, Sivakumar V, Ling EA, Kaur C. Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats. Brain Pathol 2008;18:387-400.
80. Yatsusshige H, Ostrowski RP, Tsubokawa T, Colohan A, Zhang JH. Role of c-Jun N-terminal Kinase in early brain injury after subarachnoid hemorrhage. J Neurosci Res 2007, 85:1436-1448.
81. Karahashi H, Michelsen KS, Arditi M. Lipopolysaccharide-induced apoptosis in transformed bovine brain endothelial cells and human dermal microvessel endothelial cells: the role of JNK. J Immunol 2009, 182:7280-7286
82. McCay CM, Cromwell MF, Maynard LA. The effect of retarded growth upon the length of life span and ultimate body size. J Nutr. 1935;10:63-79
83. Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Springfield, Illinois: Charles C. Thomas. 1988
84. Koubova J, Guarente L. How dose calorie restriction work? 2003;17:313-321
85. Yu Z, Luo H, Fu W, Mattson MP. The endoplasmic reticulum stress-responsive protein GRP-78 protects neurons against excitoxicity and apoptosis: suppression of oxidative stress and stabilization of calcium homeostasis. Exp. Neurol. 1999;155:302-314
86. Lowenstein DH, Chan P, Miles M. The stress protein response in culture neurons: characterization and evidence for a protective role in excitotoxicity. Neuron 1991;7:1053-1060
87. Mattson MP, Lindvall O. Neurotrophic factor and cytokine signaling in the aging brain: In The Aging Brain (Mattson MP, Geddes JW. Eds.) JAI Press, Greewich CT. 1997;pp 299-345
88. Bordaone L, Guarente L. Calorie restriction, sirt1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol. 2005;6:298-305
89. Ferriero DM. Neonatal brain injury. N Engl J Med 2004;351:1985-1995
90. Meek DW, Knippschild U. Posttransilational modification of MDM2. Mol Cancer Res 2003;1:1017-1026
91. Yan J, Chen C, Hu Q, Yang X, Lei J, Yang L, Wang K, Qin L, Huang H, Zhou C. The role of p53 in brain edema after 24h of experimental subarachnoid hemorrhage in a rat model. Exp Neurol. 2008;214:37-46
92. Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003;9:338-342
93. Jayadev S, Nesser NK, Hopkins S, Myers SJ, Case A, Lee RJ, Seaburg LA, Uo T, Murphy SP, Morrison RS, Garden GA. Transcription factor p53 influences microglial activation phenotype. Glia 2011;59:1402-1413
94. Osmond C, Barker DJP, Winter PD, Fall CHD, Simmonds SJ. Early growth and death from cardiovascular disease in women. Bone Miner J. 1993;307:1519-1524
95. Wyatt JS, Gluckman PD, Liu PY, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. CoolCap Study Group: Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics 2007;119:912-921