Neuroprotection for ischaemic stroke: Translation from the bench to the bedside

International Journal of Stroke

Volumn 7, Issue 5, 2012, Pages 407-418

  Sutherland, Brad A ^a   Minnerup, Jens ^b   Balami, Joyce S ^c   Arba, Francesco ^a   Buchan, Alastair M ^a   Kleinschnitz, Christoph ^d  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF MÜNSTER   (Germany)

^c OXFORD UNIVERSITY HOSPITALS NHS FOUNDATION TRUST   (United Kingdom)

^d UNIVERSITY OF WÜRZBURG   (Germany)

Author keywords

Acute stroke therapy; Ischaemic cascade; Ischaemic stroke; Neuroprotection; STAIR; Translation

Indexed keywords

ALBUMIN; CITICOLINE; DEFEROXAMINE MESYLATE; DISUFENTON SODIUM; EBSELEN; ETHYLENEGLYCOL 1,2 BIS(2 AMINOPHENYL) ETHER N,N,N',N' TETRAACETIC ACID BIS(2 OCTYLOXYETHYL) ESTER; GLUCOSE; HEMOPOIETIC GROWTH FACTOR; INSULIN; MAGNESIUM; MAGNESIUM SULFATE; MEVINOLIN; MINOCYCLINE; NORPHENAZONE; OXYGEN; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE; SIMVASTATIN; TIRILAZAD;

BLOOD CLOT LYSIS; BRAIN INJURY; BRAIN ISCHEMIA; CELL DEATH; CLINICAL PRACTICE; HUMAN; HYPOTHERMIA; NEUROPROTECTION; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; STROKE;

ACUTE DISEASE; ANIMALS; BENZENESULFONATES; BRAIN ISCHEMIA; CHELATING AGENTS; CLINICAL TRIALS AS TOPIC; COMBINED MODALITY THERAPY; DIFFUSION OF INNOVATION; DISEASE MODELS, ANIMAL; DRUG EVALUATION, PRECLINICAL; EGTAZIC ACID; HEMATOPOIETIC CELL GROWTH FACTORS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPOTHERMIA, INDUCED; MAGNESIUM; MINOCYCLINE; NADPH OXIDASE; NEUROPROTECTIVE AGENTS; PREGNATRIENES; SERUM ALBUMIN; STROKE; THROMBOLYTIC THERAPY; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84862658611     PISSN: 17474930     EISSN: 17474949     Source Type: Journal    
DOI: 10.1111/j.1747-4949.2012.00770.x     Document Type: Review

References (111)

1. Durukan A, Tatlisumak T. Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav 2007; 87:179-197.
2. O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1, 026 experimental treatments in acute stroke. Ann Neurol 2006; 59:467-477.
3. Strokecenter.org, Stroke Trials Registry, Dallas: UT Southwestern Medical Center. 1997 Available at: (accessed April 2011).
4. Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008; 55:363-389.
5. Fisher M, Feuerstein G, Howells DW etal. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 2009; 40:2244-2250.
6. STAIR. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999; 30:2752-2758.
7. Cheng YD, Al-Khoury L, Zivin JA. Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx 2004; 1:36-45.
8. Endres M, Engelhardt B, Koistinaho J etal. Improving outcome after stroke: overcoming the translational roadblock. Cerebrovasc Dis 2008; 25:268-278.
9. Hoyte L, Kaur J, Buchan AM. Lost in translation: taking neuroprotection from animal models to clinical trials. Exp Neurol 2004; 188:200-204.
10. Buchan A, Pulsinelli WA. Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci 1990; 10:311-316.
11. Buchan AM, Slivka A, Xue D. The effect of the NMDA receptor antagonist MK-801 on cerebral blood flow and infarct volume in experimental focal stroke. Brain Res 1992; 574:171-177.
12. Sutherland BA, Papadakis M, Chen R-L, Buchan AM. Cerebral blood flow alteration in neuroprotection following cerebral ischemia. J Physiol 2011; 589:4105-4114.
13. Nikic I, Merkler D, Sorbara C etal. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 2011; 17:495-499.
14. Sena ES, van der Worp HB, Bath PM, Howells DW, Macleod MR. Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. PLoS Biol 2010; 8:e1000344.
15. Fisher M. New approaches to neuroprotective drug development. Stroke 2011; 42(Suppl. 1):S24-27.
16. Minnerup J, Schabitz WR. Multifunctional actions of approved and candidate stroke drugs. Neurother 2009; 6:43-52.
17. Dirnagl U, Macleod MR. Stroke research at a road block: the streets from adversity should be paved with meta-analysis and good laboratory practice. Br J Pharmacol 2009; 157:1154-1156.
18. Macleod MR, van der Worp HB, Sena ES, Howells DW, Dirnagl U, Donnan GA. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke 2008; 39:2824-2829.
19. Minnerup J, Heidrich J, Wellmann J, Rogalewski A, Schneider A, Schabitz WR. Meta-analysis of the efficacy of granulocyte-colony stimulating factor in animal models of focal cerebral ischemia. Stroke 2008; 39:1855-1861.
20. Thecochranelibrary.com, The Cochrane Library, Chichester, UK: John wiley & Sons Ltd. 1996 Available at: (accessed April 2011).
21. van der Worp HB, Sena ES, Donnan GA, Howells DW, Macleod MR. Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain 2007; 130(Pt 12):3063-3074.
22. Yenari M, Kitagawa K, Lyden P, Perez-Pinzon M. Metabolic downregulation: a key to successful neuroprotection? Stroke 2008; 39:2910-2917.
23. Berger C, Schabitz WR, Georgiadis D, Steiner T, Aschoff A, Schwab S. Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study. Stroke 2002; 33:519-524.
24. Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD. Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem 1995; 65:1704-1711.
25. Krieger DW, De Georgia MA, Abou-Chebl A etal. Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 2001; 32:1847-1854.
26. De Georgia MA, Krieger DW, Abou-Chebl A etal. Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Neurology 2004; 63:312-317.
27. Hemmen TM, Raman R, Guluma KZ etal. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke 2010; 41:2265-2270.
28. Hemmen TM, Lyden PD. Induced hypothermia for acute stroke. Stroke 2007; 38(Suppl. 2):794-799.
29. Lyden PD, Krieger D, Yenari M, Dietrich WD. Therapeutic hypothermia for acute stroke. Int J Stroke 2006; 1:9-19.
30. Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA. Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke 2001; 32:2033-2035.
31. +]i. Am J Physiol 1993; 265(1 Pt 2):H74-82.
32. Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke 2001; 32:553-560.
33. Ginsberg MD, Hill MD, Palesch YY, Ryckborst KJ, Tamariz D. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke - I: Physiological responses and safety results. Stroke 2006; 37:2100-2106.
34. Palesch YY, Hill MD, Ryckborst KJ, Tamariz D, Ginsberg MD. The ALIAS Pilot Trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke - II: neurologic outcome and efficacy analysis. Stroke 2006; 37:2107-2114.
35. Ginsberg MD, Palesch YY, Hill MD. The ALIAS (ALbumin In Acute Stroke) Phase III randomized multicentre clinical trial: design and progress report. Biochem Soc Trans 2006; 34(Pt 6):1323-1326.
36. O'Collins VE, Macleod MR, Cox SF etal. Preclinical drug evaluation for combination therapy in acute stroke using systematic review, meta-analysis, and subsequent experimental testing. J Cereb Blood Flow Metab 2011; 31:962-975.
37. Ovbiagele B, Kidwell CS, Starkman S, Saver JL. Neuroprotective agents for the treatment of acute ischemic stroke. Curr Neurol Neurosci Rep 2003; 3:9-20.
38. Meloni BP, Zhu H, Knuckey NW. Is magnesium neuroprotective following global and focal cerebral ischaemia? A review of published studies. Magnes Res 2006; 19:123-137.
39. Saver JL, Kidwell C, Eckstein M, Starkman S. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial. Stroke 2004; 35:e106-108.
40. Lampl Y, Boaz M, Gilad R etal. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 2007; 69:1404-1410.
41. Prass K, Meisel C, Hoflich C etal. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med 2003; 198:725-736.
42. Fagan SC, Waller JL, Nichols FT etal. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke 2010; 41:2283-2287.
43. Clinicaltrials.gov. Neuroprotection With Minocycline Therapy for Acute Stroke Recovery Trial (NeuMAST), Bethesda: US National Institutes of Health. 2009 Available at: (accessed April 2011).
44. Cimino M, Balduini W, Carloni S etal. Neuroprotective effect of simvastatin in stroke: a comparison between adult and neonatal rat models of cerebral ischemia. Neurotoxicology 2005; 26:929-933.
45. Cimino M, Gelosa P, Gianella A, Nobili E, Tremoli E, Sironi L. Statins: multiple mechanisms of action in the ischemic brain. Neuroscientist 2007; 13:208-213.
46. Elkind MS, Sacco RL, Macarthur RB etal. High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART). Cerebrovasc Dis 2009; 28:266-275.
47. Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology 2008; 71:1390-1395.
48. Angel I, Bar A, Horovitz T etal. Metal ion chelation in neurodegenerative disorders. Drug Dev Res 2002; 56:300-309.
49. Diener HC, Schneider D, Lampl Y, Bornstein NM, Kozak A, Rosenberg G. DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke. Stroke 2008; 39:1774-1778.
50. Braughler JM, Pregenzer JF, Chase RL, Duncan LA, Jacobsen EJ, McCall JM. Novel 21-amino steroids as potent inhibitors of iron-dependent lipid peroxidation. J Biol Chem 1987; 262:10438-10440.
51. Xue D, Slivka A, Buchan AM. Tirilazad reduces cortical infarction after transient but not permanent focal cerebral ischemia in rats. Stroke 1992; 23:894-899.
52. Sena E, Wheble P, Sandercock P, Macleod M. Systematic review and meta-analysis of the efficacy of tirilazad in experimental stroke. Stroke 2007; 38:388-394.
53. RANTTAS. A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). The RANTTAS Investigators. Stroke 1996; 27:1453-1458.
54. TISC. Tirilazad mesylate in acute ischemic stroke: A systematic review. Tirilazad International Steering Committee. Stroke 2000; 31:2257-2265.
55. Green AR, Ashwood T, Odergren T, Jackson DM. Nitrones as neuroprotective agents in cerebral ischemia, with particular reference to NXY-059. Pharmacol Ther 2003; 100:195-214.
56. Bath PM, Gray LJ, Bath AJ, Buchan A, Miyata T, Green AR. Effects of NXY-059 in experimental stroke: an individual animal meta-analysis. Br J Pharmacol 2009; 157:1157-1171.
57. Marshall JW, Cummings RM, Bowes LJ, Ridley RM, Green AR. Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke 2003; 34:2228-2233.
58. Papadakis M, Nagel S, Buchan AM. Development and efficacy of NXY-059 for the treatment of acute ischemic stroke. Future Neurol 2008; 3:229-240.
59. Lees KR, Zivin JA, Ashwood T etal. NXY-059 for acute ischemic stroke. N Engl J Med 2006; 354:588-600.
60. Shuaib A, Lees KR, Lyden P etal. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 2007; 357:562-571.
61. Diener HC, Lees KR, Lyden P etal. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials. Stroke 2008; 39:1751-1758.
62. Papadakis M, Buchan AM. NXY-059: brain or vessel protection. Stroke 2006; 37:2189-2190.
63. Zhao Z, Cheng M, Maples KR, Ma JY, Buchan AM. NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat. Brain Res 2001; 909:46-50.
64. Philip M, Benatar M, Fisher M, Savitz SI. Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials. Stroke 2009; 40:577-581.
65. Savitz SI. Cosmic implications of NXY-059. Stroke 2009; 40(Suppl. 3):S115-118.
66. Savitz SI. A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp Neurol 2007; 205:20-25.
67. Kleinschnitz C, Grund H, Wingler K etal. Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol 2010; 8:pii:e1000479
68. Tymianski M. Can molecular and cellular neuroprotection be translated into therapies for patients?: yes, but not the way we tried it before. Stroke 2010; 41(Suppl. 10):S87-90.
69. Wahlgren NG, Ahmed N. Neuroprotection in cerebral ischaemia: facts and fancies-the need for new approaches. Cerebrovasc Dis 2004; 17(Suppl. 1):153-166.
70. Lyden P, Wahlgren NG. Mechanisms of action of neuroprotectants in stroke. J Stroke Cerebrovasc Dis 2000; 9(6 Pt 2):9-14.
71. Small DL, Buchan AM. Animal models. Br Med Bull 2000; 56:307-317.
72. Chen RL, Balami JS, Esiri MM, Chen LK, Buchan AM. Ischemic stroke in the elderly: an overview of evidence. Nat Rev Neurol 2010; 6:256-265.
73. Grotta JC, Burgin WS, El-Mitwalli A etal. Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000. Arch Neurol 2001; 58:2009-2013.
74. Sumii T, Involvement LEH. of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 2002; 33:831-836.
75. Asahi M, Asahi K, Wang X, Lo EH. Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2000; 20:452-457.
76. Lapchak PA, Araujo DM, Song D, Wei J, Zivin JA. Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl]benzene-1, 3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 2002; 33:1411-1415.
77. Lekieffre D, Benavides J, Scatton B, Nowicki JP. Neuroprotection afforded by a combination of eliprodil and a thrombolytic agent, rt-PA, in a rat thromboembolic stroke model. Brain Res 1997; 776:88-95.
78. Suzuki M, Sasamata M, Miyata K. Neuroprotective effects of YM872 coadministered with t-PA in a rat embolic stroke model. Brain Res 2003; 959:169-172.
79. Lapchak PA, Zivin JA. Ebselen, a seleno-organic antioxidant, is neuroprotective after embolic strokes in rabbits: synergism with low-dose tissue plasminogen activator. Stroke 2003; 34:2013-2018.
80. Zhang RL, Zhang ZG, Chopp M. Increased therapeutic efficacy with rt-PA and anti-CD18 antibody treatment of stroke in the rat. Neurology 1999; 52:273-279.
81. Ding G, Jiang Q, Zhang L etal. Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor. J Cereb Blood Flow Metab 2005; 25:87-97.
82. Shuaib A, Yang Y, Nakada MT, Li Q, Yang T. Glycoprotein IIb/IIIa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia: evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab 2002; 22:215-222.
83. Stoll G, Kleinschnitz C, Nieswandt B. Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood 2008; 112:3555-3562.
84. Grotta J. Combination Therapy Stroke Trial: recombinant tissue-type plasminogen activator with/without lubeluzole. Cerebrovasc Dis 2001; 12:258-263.
85. Lyden P, Jacoby M, Schim J etal. The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results. Neurology 2001; 57:1199-1205.
86. Krams M, Lees KR, Hacke W, Grieve AP, Orgogozo JM, Ford GA. Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): an adaptive dose-response study of UK-279, 276 in acute ischemic stroke. Stroke 2003; 34:2543-2548.
87. Harston GW, Sutherland BA, Kennedy J, Buchan AM. The contribution of L-arginine to the neurotoxicity of recombinant tissue plasminogen activator following cerebral ischemia: a review of rtPA neurotoxicity. J Cereb Blood Flow Metab 2010; 30:1804-1816.
88. Sachs L. The molecular control of hematopoiesis: from clonal development in culture to therapy in the clinic. Int J Cell Cloning 1992; 10:196-204.
89. Schneider A, Kruger C, Steigleder T etal. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005; 115:2083-2098.
90. Siren AL, Knerlich F, Poser W, Gleiter CH, Bruck W, Ehrenreich H. Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol 2001; 101:271-276.
91. Ruscher K, Freyer D, Karsch M etal. Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci 2002; 22:10291-10301.
92. Solaroglu I, Cahill J, Tsubokawa T, Beskonakli E, Zhang JH. Granulocyte colony-stimulating factor protects the brain against experimental stroke via inhibition of apoptosis and inflammation. Neurol Res 2009; 31:167-172.
93. Villa P, Bigini P, Mennini T etal. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med 2003; 198:971-975.
94. Lee ST, Chu K, Jung KH etal. Granulocyte colony-stimulating factor enhances angiogenesis after focal cerebral ischemia. Brain Res 2005; 1058:120-128.
95. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 2004; 35:1732-1737.
96. England TJ, Gibson CL, Bath PM. Granulocyte-colony stimulating factor in experimental stroke and its effects on infarct size and functional outcome: a systematic review. Brain Res Rev 2009; 62:71-82.
97. Jerndal M, Forsberg K, Sena ES etal. A systematic review and meta-analysis of erythropoietin in experimental stroke. J Cereb Blood Flow Metab 2010; 30:961-968.
98. Minnerup J, Heidrich J, Rogalewski A, Schabitz WR, Wellmann J. The efficacy of erythropoietin and its analogues in animal stroke models: a meta-analysis. Stroke 2009; 40:3113-3120.
99. Ehrenreich H, Hasselblatt M, Dembowski C etal. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 2002; 8:495-505.
100. Ehrenreich H, Weissenborn K, Prange H etal. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 2009; 40:e647-656.
101. Minnerup J, Wersching H, Schabitz WR. EPO for stroke therapy - Is there a future for further clinical development? Exp Transl Stroke Med 2010; 2:10.
102. Schabitz WR, Laage R, Vogt G etal. AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke 2010; 41:2545-2551.
103. Clinicaltrials.gov. AXIS 2: AX200 for the Treatment of Ischemic Stroke (AXIS-2), Bethesda: US National Institute for Health. 2009 Available at: (accessed April 2011).
104. Flamm ES, Demopoulos HB, Seligman ML, Poser RG, Ransohoff J. Free radicals in cerebral ischemia. Stroke 1978; 9:445-447.
105. Crack PJ, Taylor JM. Reactive oxygen species and the modulation of stroke. Free Radic Biol Med 2005; 38:1433-1444.
106. Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens 2000; 18:655-673.
107. Miller AA, Drummond GR, Sobey CG. Novel isoforms of NADPH-oxidase in cerebral vascular control. Pharmacol Ther 2006; 111:928-948.
108. Sedwick C. NOX4: a guilty party in stroke damage. PLoS Biol 2010; 8:pii:e1000478
109. Sancho P, Fabregat I. The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-beta-induced apoptosis of liver tumor cells. Biochem Pharmacol 2011; 81:917-924.
110. NINDS. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995; 333:1581-1587.
111. Schiermeier Q. Primate work faces German veto. Nature 2007; 446:955.