The advances of diabetic retinal neurodegeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Hongrong ,  Wang Hao

Department of ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, China;

Corresponding author：

Wang Hao, Email: whpp_cn@163.com

Keywords：

Nerve degeneration; Diabetic retinopathy; Diabetic angiopathies; Review

DOI：

10.3760/cma.j.cn511434-20190702-00208

Video：

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Abstract Full text Figures/Tables Video References Cited by

Diabetic retinal neurodegeneration (DRN) is a condition in which the normal function of retinal neurovascular units is impaired due to various factors such as oxidative stress, microvascular damage, metabolic disorders, neurotrophic factor imbalance, and immune damage in hyperglycemia environment. The loss of neurons and glial dysfunction is involved in the destruction of the blood-retinal barrier, impaired vascular response and neurovascular coupling, leading to microvascular disease and neurodegeneration. More and more studies have proved that DRN is associated with microangiopathy and diabetic retinopathy pathogenesis. A deeper understanding of the pathogenesis of neurovascular injury may provide new and more effective prevention strategies for diabetic retinopathy.

Citation： Li Hongrong, Wang Hao. The advances of diabetic retinal neurodegeneration. Chinese Journal of Ocular Fundus Diseases, 2020, 36(6): 479-482. doi: 10.3760/cma.j.cn511434-20190702-00208 Copy

1.	Simó R, Villarroel M, Corraliza L, et al. The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier--implications for the pathogenesis of diabetic retinopathy[J/OL]. J Biomed Biotechnol, 2010, 2010: 190724[2010-02-17]. https://doi.org/10.1155/2010/190724. DOI:10.1155/2010/190724.
2.	Barber AJ. Diabetic retinopathy: recent advances towards understanding neurodegeneration and vision loss[J]. Sci China Life Sci, 2015, 58(6): 541-549. DOI: 10.1007/s11427-015-4856-x.
3.	Jiang MN, Zhou YY, Hua DH, et al. Vagal nerve stimulation attenuates ischemia-reperfusion induced retina dysfunction in acute ocular hypertension[J]. Front Neurosci, 2019, 13: 87. DOI: 10.3389/fnins.2019.00087.
4.	Eliasdottir TS. Retinal oximetry and systemic arterial oxygen levels[J]. Acta Ophthalmol, 2018, 96(Suppl A113): 1-44. DOI: 10.1111/aos.13932.
5.	Russo R, Varano GP, Adornetto A, et al. Rapamycin and fasting sustain autophagy response activated by ischemia/reperfusion injury and promote retinal ganglion cell survival[J]. Cell Death Dis, 2018, 9(10): 981. DOI: 10.1038/s41419-018-1044-5.
6.	Ng DS, Chiang PP, Tan G, et al. Retinal ganglion cell neuronal damage in diabetes and diabetic retinopathy[J]. Clin Exp Ophthalmol, 2016, 44(4): 243-250. DOI: 10.1111/ceo.12724.
7.	Araszkiewicz A, Zozulinska-Ziolkiewicz D. Retinal neurodegeneration in the course of diabetes-pathogenesis and clinical perspective[J]. Curr Neuropharmacol, 2016, 14(8): 805-809. DOI: 10.2174/1570159x14666160225154536.
8.	Metea MR, Newman EA. Signalling within the neurovascular unit in the mammalian retina[J]. Exp Physiol, 2007, 92(4): 635-640. DOI: 10.1113/expphysiol.2006.036376.
9.	Simó R, Hernández C, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR). Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives[J]. Trends Endocrinol Metab, 2014, 25(1): 23-33. DOI: 10.1016/j.tem.2013.09.005.
10.	Abcouwer SF, Gardner TW. Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment[J]. Ann N Y Acad Sci, 2014, 1311: 174-190. DOI: 10.1111/nyas.12412.
11.	Feng Y, Busch S, Gretz N, et al. Crosstalk in the retinal neurovascular unit - lessons for the diabetic retina[J]. Exp Clin Endocrinol Diabetes, 2012, 120(4): 199-201. DOI: 10.1055/s-0032-1304571.
12.	Aung MH, Park HN, Han MK, et al. Dopamine deficiency contributes to early visual dysfunction in a rodent model of type 1 diabetes[J]. J Neurosci, 2014, 34(3): 726-736. DOI: 10.1523/jneurosci.3483-13.2014.
13.	D'Cruz TS, Weibley BN, Kimball SR, et al. Post-translational processing of synaptophysin in the rat retina is disrupted by diabetes[J/OL]. PLoS One, 2012, 7(9): 44711[2012-09-06]. https://doi.org/10.1371/journal.pone.0044711. DOI:10.1371/journal.pone.0044711.
14.	Arboleda-Velasquez JF, Valdez CN, Marko CK, et al. From pathobiology to the targeting of pericytes for the treatment of diabetic retinopathy[J]. Curr Diab Rep, 2015, 15(2): 573. DOI: 10.1007/s11892-014-0573-2.
15.	Gardner TW, Davila JR. The neurovascular unit and the pathophysiologic basis of diabetic retinopathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2017, 255(1): 1-6. DOI: 10.1007/s00417-016-3548-y.
16.	Lynch SK, Abràmoff MD. Diabetic retinopathy is a neurodegenerative disorder[J]. Vision Res, 2017, 139: 101-107. DOI: 10.1016/j.visres.2017.03.003.
17.	Hernández C, Dal Monte M, Simó R, et al. Neuroprotection as a therapeutic target for diabetic retinopathy[J/OL]. J Diabetes Res, 2016, 2016: 9508541[2016-03-31]. https://doi.org/10.1155/2016/9508541. DOI:10.1155/2016/9508541.
18.	Hernández C, Simó-Servat O, Simó R. Somatostatin and diabetic retinopathy: current concepts and new therapeutic perspectives[J]. Endocrine, 2014, 46(2): 209-214. DOI: 10.1007/s12020-014-0232-z.
19.	Iwona BS. Growth factors in the pathogenesis of retinal neurodegeneration in diabetes mellitus[J]. Curr Neuropharmacol, 2016, 14(8): 792-804. DOI: 10.2174/1570159x14666160813182009.
20.	Farnoodian M, Sorenson CM, Sheibani N. PEDF expression affects the oxidative and inflammatory state of choroidal endothelial cells[J]. Am J Physiol Cell Physiol, 2018, 314(4): 456-472. DOI: 10.1152/ajpcell.00259.2017.
21.	Hernández C, Simó R, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR). Somatostatin replacement: a new strategy for treating diabetic retinopathy[J]. Curr Med Chem, 2013, 20(26): 3251-3257. DOI: 10.2174/09298673113209990024.
22.	Zhu L, Shen WY, Lyons B, et al. Dysregulation of inter-photoreceptor retinoid-binding protein (IRBP) after induced Müller cell disruption[J]. J Neurochem, 2015, 133(6): 909-918. DOI: 10.1111/jnc.13075.
23.	Carlino D, Francavilla R, Baj G, et al. Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism[J/OL]. PeerJ, 2015, 3: 1252[2015-10-29]. https://doi.org/10.7717/peerj.1252. DOI:10.7717/peerj.1252.
24.	Mysona BA, Shanab AY, Elshaer SL, et al. Nerve growth factor in diabetic retinopathy: beyond neurons[J]. Expert Rev Ophthalmol, 2014, 9(2): 99-107. DOI: 10.1586/17469899.2014.903157.
25.	Ola MS, Nawaz MI, El-Asrar AA, et al. Reduced levels of brain derived neurotrophic factor (BDNF) in the serum of diabetic retinopathy patients and in the retina of diabetic rats[J]. Cell Mol Neurobiol, 2013, 33(3): 359-367. DOI: 10.1007/s10571-012-9901-8.
26.	Chakravarthy H, Devanathan V. Molecular mechanisms mediating diabetic retinal neurodegeneration: potential research avenues and therapeutic targets[J]. J Mol Neurosci, 2018, 66(3): 445-461. DOI: 10.1007/s12031-018-1188-x.
27.	Ctori I, Huntjens B. Repeatability of foveal measurements using spectralis optical coherence tomography segmentation software[J/OL]. PLoS One, 2015, 10(6): 0129005[2015-06-15]. https://doi.org/10.1371/journal.pone.0129005. DOI:10.1371/journal.pone.0129005.
28.	Zafar S, Sachdeva M, Frankfort BJ, et al. Retinal neurodegeneration as an early manifestation of diabetic eye disease and potential neuroprotective therapies[J]. Curr Diab Rep, 2019, 19(4): 17. DOI: 10.1007/s11892-019-1134-5.
29.	Lévêque PM, Zéboulon P, Brasnu E, et al. Optic disc vascularization in glaucoma: value of spectral-domain optical coherence tomography angiography[J/OL]. J Ophthalmol, 2016, 2016: 6956717[2016-02-22]. https://doi.org/10.1155/2016/6956717. DOI:10.1155/2016/6956717.
30.	Cao D, Yang DW, Huang ZN, et al. Optical coherence tomography angiography discerns preclinical diabetic retinopathy in eyes of patients with type 2 diabetes without clinical diabetic retinopathy[J]. Acta Diabetol, 2018, 55(5): 469-477. DOI: 10.1007/s00592-018-1115-1.
31.	Lakhani E, Wright T, Abdolell M, et al. Multifocal ERG defects associated with insufficient long-term glycemic control in adolescents with type 1 diabetes[J]. Invest Ophthalmol Vis Sci, 2010, 51(10): 5297-5303. DOI: 10.1167/iovs.10-5200.
32.	Laron M, Bearse MA Jr, Bronson-Castain K, et al. Interocular symmetry of abnormal multifocal electroretinograms in adolescents with diabetes and no retinopathy[J]. Invest Ophthalmol Vis Sci, 2012, 53(1): 316-321. DOI: 10.1167/iovs.11-8825.
33.	Ziccardi L, Parisi V, Picconi F, et al. Early and localized retinal dysfunction in patients with type 1 diabetes mellitus studied by multifocal electroretinogram[J]. Acta Diabetol, 2018, 55(11): 1191-1200. DOI: 10.1007/s00592-018-1209-9.
34.	Awad AS, Gao T, Gvritishvili A, et al. Protective role of small pigment epithelium-derived factor (PEDF) peptide in diabetic renal injury[J]. Am J Physiol Renal Physiol, 2013, 305(6): 891-900. DOI: 10.1152/ajprenal.00149.2013.
35.	Elahy M, Baindur-Hudson S, Cruzat VF, et al. Mechanisms of PEDF-mediated protection against reactive oxygen species damage in diabetic retinopathy and neuropathy[J]. J Endocrinol, 2014, 222(3): 129-139. DOI: 10.1530/joe-14-0065.
36.	Hernández C, García-Ramírez M, Corraliza L, et al. Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes[J]. Diabetes, 2013, 62(7): 2569-2578. DOI: 10.2337/db12-0926.
37.	Colafrancesco V, Coassin M, Rossi S, et al. Effect of eye NGF administration on two animal models of retinal ganglion cells degeneration[J]. Ann Ist Super Sanita, 2011, 47(3): 284-289. DOI: 10.4415/ann_11_03_08.
38.	Rohowetz LJ, Kraus JG, Koulen P, et al. Reactive oxygen species-mediated damage of retinal neurons: drug development targets for therapies of chronic neurodegeneration of the retina[J]. Int J Mol Sci, 2018, 19(11): 3362. DOI: 10.3390/ijms19113362.
39.	Mishra A, Newman EA. Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy[J]. Glia, 2010, 58(16): 1996-2004. DOI: 10.1002/glia.21068.
40.	Ola MS, Alhomida AS. Neurodegeneration in diabetic retina and its potential drug targets[J]. Curr Neuropharmacol, 2014, 12(4): 380-386. DOI: 10.2174/1570159x12666140619205024.
41.	Kusari J, Zhou S, Padillo E, et al. Effect of memantine on neuroretinal function and retinal vascular changes of streptozotocin-induced diabetic rats[J]. Invest Ophthalmol Vis Sci, 2007, 48(11): 5152-5159. DOI: 10.1167/iovs.07-0427.
42.	Rupenthal ID. Drug-device combination approaches for delivery to the eye[J]. Curr Opin Pharmacol, 2017, 36: 44-51. DOI: 10.1016/j.coph.2017.08.003.
43.	Aiello LP. Targeting intraocular neovascularization and edema--one drop at a time[J]. N Engl J Med, 2008, 359(9): 967-969. DOI: 10.1056/NEJMcibr0804551.

1. Simó R, Villarroel M, Corraliza L, et al. The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier--implications for the pathogenesis of diabetic retinopathy[J/OL]. J Biomed Biotechnol, 2010, 2010: 190724[2010-02-17]. https://doi.org/10.1155/2010/190724. DOI:10.1155/2010/190724.
2. Barber AJ. Diabetic retinopathy: recent advances towards understanding neurodegeneration and vision loss[J]. Sci China Life Sci, 2015, 58(6): 541-549. DOI: 10.1007/s11427-015-4856-x.
3. Jiang MN, Zhou YY, Hua DH, et al. Vagal nerve stimulation attenuates ischemia-reperfusion induced retina dysfunction in acute ocular hypertension[J]. Front Neurosci, 2019, 13: 87. DOI: 10.3389/fnins.2019.00087.
4. Eliasdottir TS. Retinal oximetry and systemic arterial oxygen levels[J]. Acta Ophthalmol, 2018, 96(Suppl A113): 1-44. DOI: 10.1111/aos.13932.
5. Russo R, Varano GP, Adornetto A, et al. Rapamycin and fasting sustain autophagy response activated by ischemia/reperfusion injury and promote retinal ganglion cell survival[J]. Cell Death Dis, 2018, 9(10): 981. DOI: 10.1038/s41419-018-1044-5.
6. Ng DS, Chiang PP, Tan G, et al. Retinal ganglion cell neuronal damage in diabetes and diabetic retinopathy[J]. Clin Exp Ophthalmol, 2016, 44(4): 243-250. DOI: 10.1111/ceo.12724.
7. Araszkiewicz A, Zozulinska-Ziolkiewicz D. Retinal neurodegeneration in the course of diabetes-pathogenesis and clinical perspective[J]. Curr Neuropharmacol, 2016, 14(8): 805-809. DOI: 10.2174/1570159x14666160225154536.
8. Metea MR, Newman EA. Signalling within the neurovascular unit in the mammalian retina[J]. Exp Physiol, 2007, 92(4): 635-640. DOI: 10.1113/expphysiol.2006.036376.
9. Simó R, Hernández C, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR). Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives[J]. Trends Endocrinol Metab, 2014, 25(1): 23-33. DOI: 10.1016/j.tem.2013.09.005.
10. Abcouwer SF, Gardner TW. Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment[J]. Ann N Y Acad Sci, 2014, 1311: 174-190. DOI: 10.1111/nyas.12412.
11. Feng Y, Busch S, Gretz N, et al. Crosstalk in the retinal neurovascular unit - lessons for the diabetic retina[J]. Exp Clin Endocrinol Diabetes, 2012, 120(4): 199-201. DOI: 10.1055/s-0032-1304571.
12. Aung MH, Park HN, Han MK, et al. Dopamine deficiency contributes to early visual dysfunction in a rodent model of type 1 diabetes[J]. J Neurosci, 2014, 34(3): 726-736. DOI: 10.1523/jneurosci.3483-13.2014.
13. D'Cruz TS, Weibley BN, Kimball SR, et al. Post-translational processing of synaptophysin in the rat retina is disrupted by diabetes[J/OL]. PLoS One, 2012, 7(9): 44711[2012-09-06]. https://doi.org/10.1371/journal.pone.0044711. DOI:10.1371/journal.pone.0044711.
14. Arboleda-Velasquez JF, Valdez CN, Marko CK, et al. From pathobiology to the targeting of pericytes for the treatment of diabetic retinopathy[J]. Curr Diab Rep, 2015, 15(2): 573. DOI: 10.1007/s11892-014-0573-2.
15. Gardner TW, Davila JR. The neurovascular unit and the pathophysiologic basis of diabetic retinopathy[J]. Graefe's Arch Clin Exp Ophthalmol, 2017, 255(1): 1-6. DOI: 10.1007/s00417-016-3548-y.
16. Lynch SK, Abràmoff MD. Diabetic retinopathy is a neurodegenerative disorder[J]. Vision Res, 2017, 139: 101-107. DOI: 10.1016/j.visres.2017.03.003.
17. Hernández C, Dal Monte M, Simó R, et al. Neuroprotection as a therapeutic target for diabetic retinopathy[J/OL]. J Diabetes Res, 2016, 2016: 9508541[2016-03-31]. https://doi.org/10.1155/2016/9508541. DOI:10.1155/2016/9508541.
18. Hernández C, Simó-Servat O, Simó R. Somatostatin and diabetic retinopathy: current concepts and new therapeutic perspectives[J]. Endocrine, 2014, 46(2): 209-214. DOI: 10.1007/s12020-014-0232-z.
19. Iwona BS. Growth factors in the pathogenesis of retinal neurodegeneration in diabetes mellitus[J]. Curr Neuropharmacol, 2016, 14(8): 792-804. DOI: 10.2174/1570159x14666160813182009.
20. Farnoodian M, Sorenson CM, Sheibani N. PEDF expression affects the oxidative and inflammatory state of choroidal endothelial cells[J]. Am J Physiol Cell Physiol, 2018, 314(4): 456-472. DOI: 10.1152/ajpcell.00259.2017.
21. Hernández C, Simó R, European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR). Somatostatin replacement: a new strategy for treating diabetic retinopathy[J]. Curr Med Chem, 2013, 20(26): 3251-3257. DOI: 10.2174/09298673113209990024.
22. Zhu L, Shen WY, Lyons B, et al. Dysregulation of inter-photoreceptor retinoid-binding protein (IRBP) after induced Müller cell disruption[J]. J Neurochem, 2015, 133(6): 909-918. DOI: 10.1111/jnc.13075.
23. Carlino D, Francavilla R, Baj G, et al. Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism[J/OL]. PeerJ, 2015, 3: 1252[2015-10-29]. https://doi.org/10.7717/peerj.1252. DOI:10.7717/peerj.1252.
24. Mysona BA, Shanab AY, Elshaer SL, et al. Nerve growth factor in diabetic retinopathy: beyond neurons[J]. Expert Rev Ophthalmol, 2014, 9(2): 99-107. DOI: 10.1586/17469899.2014.903157.
25. Ola MS, Nawaz MI, El-Asrar AA, et al. Reduced levels of brain derived neurotrophic factor (BDNF) in the serum of diabetic retinopathy patients and in the retina of diabetic rats[J]. Cell Mol Neurobiol, 2013, 33(3): 359-367. DOI: 10.1007/s10571-012-9901-8.
26. Chakravarthy H, Devanathan V. Molecular mechanisms mediating diabetic retinal neurodegeneration: potential research avenues and therapeutic targets[J]. J Mol Neurosci, 2018, 66(3): 445-461. DOI: 10.1007/s12031-018-1188-x.
27. Ctori I, Huntjens B. Repeatability of foveal measurements using spectralis optical coherence tomography segmentation software[J/OL]. PLoS One, 2015, 10(6): 0129005[2015-06-15]. https://doi.org/10.1371/journal.pone.0129005. DOI:10.1371/journal.pone.0129005.
28. Zafar S, Sachdeva M, Frankfort BJ, et al. Retinal neurodegeneration as an early manifestation of diabetic eye disease and potential neuroprotective therapies[J]. Curr Diab Rep, 2019, 19(4): 17. DOI: 10.1007/s11892-019-1134-5.
29. Lévêque PM, Zéboulon P, Brasnu E, et al. Optic disc vascularization in glaucoma: value of spectral-domain optical coherence tomography angiography[J/OL]. J Ophthalmol, 2016, 2016: 6956717[2016-02-22]. https://doi.org/10.1155/2016/6956717. DOI:10.1155/2016/6956717.
30. Cao D, Yang DW, Huang ZN, et al. Optical coherence tomography angiography discerns preclinical diabetic retinopathy in eyes of patients with type 2 diabetes without clinical diabetic retinopathy[J]. Acta Diabetol, 2018, 55(5): 469-477. DOI: 10.1007/s00592-018-1115-1.
31. Lakhani E, Wright T, Abdolell M, et al. Multifocal ERG defects associated with insufficient long-term glycemic control in adolescents with type 1 diabetes[J]. Invest Ophthalmol Vis Sci, 2010, 51(10): 5297-5303. DOI: 10.1167/iovs.10-5200.
32. Laron M, Bearse MA Jr, Bronson-Castain K, et al. Interocular symmetry of abnormal multifocal electroretinograms in adolescents with diabetes and no retinopathy[J]. Invest Ophthalmol Vis Sci, 2012, 53(1): 316-321. DOI: 10.1167/iovs.11-8825.
33. Ziccardi L, Parisi V, Picconi F, et al. Early and localized retinal dysfunction in patients with type 1 diabetes mellitus studied by multifocal electroretinogram[J]. Acta Diabetol, 2018, 55(11): 1191-1200. DOI: 10.1007/s00592-018-1209-9.
34. Awad AS, Gao T, Gvritishvili A, et al. Protective role of small pigment epithelium-derived factor (PEDF) peptide in diabetic renal injury[J]. Am J Physiol Renal Physiol, 2013, 305(6): 891-900. DOI: 10.1152/ajprenal.00149.2013.
35. Elahy M, Baindur-Hudson S, Cruzat VF, et al. Mechanisms of PEDF-mediated protection against reactive oxygen species damage in diabetic retinopathy and neuropathy[J]. J Endocrinol, 2014, 222(3): 129-139. DOI: 10.1530/joe-14-0065.
36. Hernández C, García-Ramírez M, Corraliza L, et al. Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes[J]. Diabetes, 2013, 62(7): 2569-2578. DOI: 10.2337/db12-0926.
37. Colafrancesco V, Coassin M, Rossi S, et al. Effect of eye NGF administration on two animal models of retinal ganglion cells degeneration[J]. Ann Ist Super Sanita, 2011, 47(3): 284-289. DOI: 10.4415/ann_11_03_08.
38. Rohowetz LJ, Kraus JG, Koulen P, et al. Reactive oxygen species-mediated damage of retinal neurons: drug development targets for therapies of chronic neurodegeneration of the retina[J]. Int J Mol Sci, 2018, 19(11): 3362. DOI: 10.3390/ijms19113362.
39. Mishra A, Newman EA. Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy[J]. Glia, 2010, 58(16): 1996-2004. DOI: 10.1002/glia.21068.
40. Ola MS, Alhomida AS. Neurodegeneration in diabetic retina and its potential drug targets[J]. Curr Neuropharmacol, 2014, 12(4): 380-386. DOI: 10.2174/1570159x12666140619205024.
41. Kusari J, Zhou S, Padillo E, et al. Effect of memantine on neuroretinal function and retinal vascular changes of streptozotocin-induced diabetic rats[J]. Invest Ophthalmol Vis Sci, 2007, 48(11): 5152-5159. DOI: 10.1167/iovs.07-0427.
42. Rupenthal ID. Drug-device combination approaches for delivery to the eye[J]. Curr Opin Pharmacol, 2017, 36: 44-51. DOI: 10.1016/j.coph.2017.08.003.
43. Aiello LP. Targeting intraocular neovascularization and edema--one drop at a time[J]. N Engl J Med, 2008, 359(9): 967-969. DOI: 10.1056/NEJMcibr0804551.

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