Ageing and Parkinson's disease: Why is advancing age the biggest risk factor?☆

[1]  R. Edwards,et al.  The Function of α-Synuclein , 2013, Neuron.

[2]  Sungwook Han,et al.  HtrA2/Omi deficiency causes damage and mutation of mitochondrial DNA. , 2013, Biochimica et biophysica acta.

[3]  T. Prolla,et al.  Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms. , 2013, Brain : a journal of neurology.

[4]  N. Lax,et al.  Newcastle University Eprints Date Deposited: 24 the Impact of Pathogenic Mitochondrial Dna Mutations on Substantia Nigra Neurons , 2022 .

[5]  A. Negro,et al.  The Parkinson disease-related protein DJ-1 counteracts mitochondrial impairment induced by the tumour suppressor protein p53 by enhancing endoplasmic reticulum-mitochondria tethering. , 2013, Human molecular genetics.

[6]  M. Nalls,et al.  Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease , 2013, Neurology.

[7]  Ana M. Daugherty,et al.  Age-related differences in iron content of subcortical nuclei observed in vivo: A meta-analysis , 2013, NeuroImage.

[8]  Gennifer E. Merrihew,et al.  The PINK1–Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo , 2013, Proceedings of the National Academy of Sciences.

[9]  J. Paul Bolam,et al.  The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson's disease , 2013, Front. Comput. Neurosci..

[10]  J. Obeso,et al.  Influence of microRNA deregulation on chaperone-mediated autophagy and α-synuclein pathology in Parkinson's disease , 2013, Cell Death and Disease.

[11]  Suneil K. Kalia,et al.  α‐Synuclein oligomers and clinical implications for Parkinson disease , 2013, Annals of neurology.

[12]  D. Surmeier,et al.  The pathology roadmap in Parkinson disease , 2013, Prion.

[13]  E. Katunina,et al.  [Epidemiology of Parkinson's disease]. , 2013, Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova.

[14]  G. Cortopassi,et al.  Mutant Twinkle increases dopaminergic neurodegeneration, mtDNA deletions and modulates Parkin expression. , 2012, Human molecular genetics.

[15]  S. Cullheim,et al.  Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons. , 2012, Human molecular genetics.

[16]  O. Tysnes,et al.  Number of CAG repeats in POLG1 and its association with Parkinson disease in the Norwegian population. , 2012, Mitochondrion.

[17]  D. Turnbull,et al.  Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer's disease , 2012, Neurobiology of Aging.

[18]  D. Surmeier,et al.  Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson’s disease , 2012, Nature Neuroscience.

[19]  Joseph A. Hill,et al.  Impaired Autophagosome Clearance Contributes to Cardiomyocyte Death in Ischemia/Reperfusion Injury , 2012, Circulation.

[20]  Xiongwei Zhu,et al.  Parkinson’s disease‐associated DJ‐1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction , 2012, Journal of neurochemistry.

[21]  Xiaoyan Deng,et al.  Monitoring autophagic flux by an improved tandem fluorescent-tagged LC3 (mTagRFP-mWasabi-LC3) reveals that high-dose rapamycin impairs autophagic flux in cancer cells , 2012, Autophagy.

[22]  Vishwanath T. Anekonda,et al.  Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: implications to mitochondria-targeted antioxidant therapeutics. , 2012, Biochimica et biophysica acta.

[23]  H. Braak,et al.  Lewy pathology and neurodegeneration in premotor Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[24]  B. Boeve,et al.  Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to rapid eye movement (REM) sleep behaviour disorder , 2012, Neuropathology and applied neurobiology.

[25]  N. Jana Protein homeostasis and aging: Role of ubiquitin protein ligases , 2012, Neurochemistry International.

[26]  A. Negro,et al.  α-Synuclein Controls Mitochondrial Calcium Homeostasis by Enhancing Endoplasmic Reticulum-Mitochondria Interactions* , 2012, The Journal of Biological Chemistry.

[27]  I. McKeith,et al.  The relationship between mitochondria and α-synuclein-A study of single substantia nigra neurons , 2011 .

[28]  S. Leurgans,et al.  Nigral pathology and parkinsonian signs in elders without Parkinson disease , 2012, Annals of neurology.

[29]  Vladimir N Uversky,et al.  Α-synuclein misfolding and Parkinson's disease. , 2012, Biochimica et biophysica acta.

[30]  P. Reddy,et al.  Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington's disease. , 2012, Biochimica et biophysica acta.

[31]  Robert W. Taylor,et al.  Cerebellar Ataxia in Patients With Mitochondrial DNA Disease: A Molecular Clinicopathological Study , 2012, Journal of neuropathology and experimental neurology.

[32]  Torsten Rohlfing,et al.  MRI estimates of brain iron concentration in normal aging using quantitative susceptibility mapping , 2011, NeuroImage.

[33]  L. Leidolt,et al.  Neuromelanin, neurotransmitter status and brainstem location determine the differential vulnerability of catecholaminergic neurons to mitochondrial DNA deletions , 2011, Molecular Brain.

[34]  G. Vivacqua,et al.  The role of alpha-synuclein in neurotransmission and synaptic plasticity , 2011, Journal of Chemical Neuroanatomy.

[35]  C. Moraes,et al.  Striatal Dysfunctions Associated with Mitochondrial DNA Damage in Dopaminergic Neurons in a Mouse Model of Parkinson's Disease , 2011, The Journal of Neuroscience.

[36]  D. Rubinsztein,et al.  Autophagy and Aging , 2011, Cell.

[37]  F. Sterky,et al.  Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo , 2011, Proceedings of the National Academy of Sciences.

[38]  Shihua Li,et al.  Proteasomal dysfunction in aging and Huntington disease , 2011, Neurobiology of Disease.

[39]  J. Hardy,et al.  Milestones in PD genetics , 2011, Movement disorders : official journal of the Movement Disorder Society.

[40]  R. Nussbaum,et al.  Direct Membrane Association Drives Mitochondrial Fission by the Parkinson Disease-associated Protein α-Synuclein*♦ , 2011, The Journal of Biological Chemistry.

[41]  Richard Reynolds,et al.  Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis , 2011, Annals of neurology.

[42]  S. Berman,et al.  Integrating multiple aspects of mitochondrial dynamics in neurons: Age-related differences and dynamic changes in a chronic rotenone model , 2011, Neurobiology of Disease.

[43]  David W. Miller,et al.  DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy. , 2011, Human molecular genetics.

[44]  I. Ferrer,et al.  Chaperone-mediated autophagy markers in Parkinson disease brains. , 2010, Archives of neurology.

[45]  H. Mortiboys,et al.  Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2 , 2010, Neurology.

[46]  O. Sydow,et al.  Variations of the CAG trinucleotide repeat in DNA polymerase gamma (POLG1) is associated with Parkinson's disease in Sweden , 2010, Neuroscience Letters.

[47]  E Mark Haacke,et al.  Correlation of putative iron content as represented by changes in R2* and phase with age in deep gray matter of healthy adults , 2010, Journal of magnetic resonance imaging : JMRI.

[48]  Sonja W. Scholz,et al.  POLG1 polyglutamine tract variants associated with Parkinson's disease , 2010, Neuroscience Letters.

[49]  Kostas Vekrellis,et al.  Cell-produced α-synuclein oligomers are targeted to, and impair, the 26S proteasome , 2010, Neurobiology of Aging.

[50]  Zayd M. Khaliq,et al.  Pacemaking in Dopaminergic Ventral Tegmental Area Neurons: Depolarizing Drive from Background and Voltage-Dependent Sodium Conductances , 2010, The Journal of Neuroscience.

[51]  M. Whittington,et al.  Mitochondrial DNA mutations affect calcium handling in differentiated neurons , 2010, Brain : a journal of neurology.

[52]  D. Turnbull,et al.  Mechanism of neurodegeneration of neurons with mitochondrial DNA mutations , 2010, Brain : a journal of neurology.

[53]  M. Parihar,et al.  Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. , 2009, The international journal of biochemistry & cell biology.

[54]  Robert W. Taylor,et al.  The low abundance of clonally expanded mitochondrial DNA point mutations in aged substantia nigra neurons , 2009, Aging cell.

[55]  M. Cookson,et al.  Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. , 2009, Biochemistry.

[56]  D. Turnbull,et al.  Alpha‐synuclein pathology and Parkinsonism associated with POLG1 mutations and multiple mitochondrial DNA deletions , 2009, Neuropathology and applied neurobiology.

[57]  Jie-Jin Wang,et al.  Mitochondrial DNA haplogroups J and K are not protective for Parkinson's disease in the Australian community , 2009, Movement disorders : official journal of the Movement Disorder Society.

[58]  Jongkyeong Chung,et al.  The PINK1-Parkin pathway is involved in the regulation of mitochondrial remodeling process. , 2009, Biochemical and biophysical research communications.

[59]  L. Scorrano,et al.  Mitofusin 2 tethers endoplasmic reticulum to mitochondria , 2008, Nature.

[60]  Kostas Vekrellis,et al.  Wild Type α-Synuclein Is Degraded by Chaperone-mediated Autophagy and Macroautophagy in Neuronal Cells* , 2008, Journal of Biological Chemistry.

[61]  P. Hollenbeck,et al.  Mitochondrial Membrane Potential in Axons Increases with Local Nerve Growth Factor or Semaphorin Signaling , 2008, The Journal of Neuroscience.

[62]  James Lowe,et al.  Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies , 2008, The Journal of Neuroscience.

[63]  M. Elstner,et al.  Dopaminergic midbrain neurons are the prime target for mitochondrial DNA deletions , 2008, Journal of Neurology.

[64]  N. Avadhani,et al.  Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain* , 2008, Journal of Biological Chemistry.

[65]  J. A. Botella,et al.  Superoxide dismutase overexpression protects dopaminergic neurons in a Drosophila model of Parkinson's disease , 2008, Neurobiology of Disease.

[66]  David C Samuels,et al.  What causes mitochondrial DNA deletions in human cells? , 2008, Nature Genetics.

[67]  M. Parihar,et al.  Mitochondrial association of alpha-synuclein causes oxidative stress , 2008, Cellular and Molecular Life Sciences.

[68]  Susan M. Resnick,et al.  Morphometry of the human substantia nigra in ageing and Parkinson’s disease , 2008, Acta Neuropathologica.

[69]  A. Plaitakis,et al.  Mitochondrial DNA polymorphisms and haplogroups in Parkinson's disease and control individuals with a similar genetic background , 2008, Journal of Human Genetics.

[70]  K. Double,et al.  The comparative biology of neuromelanin and lipofuscin in the human brain , 2008, Cellular and Molecular Life Sciences.

[71]  T. Montine,et al.  RESEARCH ARTICLE: Empiric Refinement of the Pathologic Assessment of Lewy‐Related Pathology in the Dementia Patient , 2008, Brain pathology.

[72]  Min Wu,et al.  Fission and selective fusion govern mitochondrial segregation and elimination by autophagy , 2008, The EMBO journal.

[73]  J. Lowe Neuropathology of dementia with Lewy bodies. , 2008, Handbook of clinical neurology.

[74]  D. James Surmeier,et al.  ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease , 2007, Nature.

[75]  D. Sulzer,et al.  Multiple hit hypotheses for dopamine neuron loss in Parkinson's disease , 2007, Trends in Neurosciences.

[76]  Robert W. Taylor,et al.  Mutation of the linker region of the polymerase gamma-1 (POLG1) gene associated with progressive external ophthalmoplegia and Parkinsonism. , 2007, Archives of neurology.

[77]  Eva Lindqvist,et al.  Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons , 2007, Proceedings of the National Academy of Sciences.

[78]  M. Vorgerd,et al.  Parkinson syndrome, neuropathy, and myopathy caused by the mutation A8344G (MERRF) in tRNALys , 2007, Neurology.

[79]  A. Friedman,et al.  Iron as a trigger of neurodegeneration in Parkinson's disease. , 2007, Handbook of clinical neurology.

[80]  S. Dimauro,et al.  Mitochondrial DNA deletions inhibit proteasomal activity and stimulate an autophagic transcript. , 2007, Free radical biology & medicine.

[81]  N. Wood,et al.  Understanding the molecular causes of Parkinson's disease. , 2006, Trends in molecular medicine.

[82]  Stavros J. Baloyannis,et al.  Morphological alterations of the synapses in the locus coeruleus in Parkinson's disease , 2006, Journal of the Neurological Sciences.

[83]  D. Kirik,et al.  Ventral tegmental area dopamine neurons are resistant to human mutant alpha-synuclein overexpression , 2006, Neurobiology of Disease.

[84]  Dennis W. Dickson,et al.  Alzheimer Disease With Amygdala Lewy Bodies: A Distinct Form of &agr;-Synucleinopathy , 2006, Journal of neuropathology and experimental neurology.

[85]  Changan Jiang,et al.  Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin , 2006, Nature.

[86]  Masaaki Komatsu,et al.  Loss of autophagy in the central nervous system causes neurodegeneration in mice , 2006, Nature.

[87]  Hideyuki Okano,et al.  Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice , 2006, Nature.

[88]  C. Dobson,et al.  Protein misfolding, functional amyloid, and human disease. , 2006, Annual review of biochemistry.

[89]  M. Breteler,et al.  Epidemiology of Parkinson's disease , 2006, The Lancet Neurology.

[90]  C. Geula,et al.  Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons , 2006, Nature Genetics.

[91]  S. Dimauro,et al.  Early‐onset familial parkinsonism due to POLG mutations , 2006, Annals of neurology.

[92]  P. Riederer,et al.  Evidence for specific phases in the development of human neuromelanin , 2006, Journal of Neural Transmission.

[93]  Robert W. Taylor,et al.  High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease , 2006, Nature Genetics.

[94]  D. Price,et al.  Parkinson's Disease α-Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell Death , 2006, The Journal of Neuroscience.

[95]  D. Price,et al.  Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. , 2006, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[96]  G. Cha,et al.  Drosophila DJ-1 mutants show oxidative stress-sensitive locomotive dysfunction. , 2005, Gene.

[97]  Kay L. Double,et al.  α-Synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson's disease , 2005 .

[98]  V. Álvarez,et al.  Mitochondrial DNA polymorphisms and risk of Parkinson's disease in Spanish population , 2005, Journal of the Neurological Sciences.

[99]  J. Keller,et al.  α-Synuclein Alters Proteasome Function, Protein Synthesis, and Stationary Phase Viability* , 2005, Journal of Biological Chemistry.

[100]  S. Lewis,et al.  Mitochondrial DNA haplogroup cluster UKJT reduces the risk of PD , 2005, Annals of neurology.

[101]  K. Double,et al.  Alpha-synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson's disease. , 2005, Brain : a journal of neurology.

[102]  S. Dimauro,et al.  A Novel Polymerase γ Mutation in a Family With Ophthalmoplegia, Neuropathy, and Parkinsonism , 2004 .

[103]  L. Peltonen,et al.  Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study , 2004, The Lancet.

[104]  Hansjürgen Bratzke,et al.  Stages in the development of Parkinson’s disease-related pathology , 2004, Cell and Tissue Research.

[105]  Michael P. Sheetz,et al.  Axonal mitochondrial transport and potential are correlated , 2004, Journal of Cell Science.

[106]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[107]  I. Katz,et al.  Ageing Research Reviews , 2004 .

[108]  S. Dimauro,et al.  A novel polymerase gamma mutation in a family with ophthalmoplegia, neuropathy, and Parkinsonism. , 2004, Archives of neurology.

[109]  Laura C. Greaves,et al.  Mitochondrial DNA mutations in human colonic crypt stem cells. , 2003, The Journal of clinical investigation.

[110]  P. Riederer,et al.  Iron-binding characteristics of neuromelanin of the human substantia nigra. , 2003, Biochemical pharmacology.

[111]  R. Nussbaum,et al.  Alzheimer's disease and Parkinson's disease. , 2003, The New England journal of medicine.

[112]  J. Haines,et al.  Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. , 2003, American journal of human genetics.

[113]  J. C. Greene,et al.  Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[114]  C. Warren Olanow,et al.  Altered Proteasomal Function in Sporadic Parkinson's Disease , 2003, Experimental Neurology.

[115]  E. Masliah,et al.  α-Synuclein is phosphorylated in synucleinopathy lesions , 2002, Nature Cell Biology.

[116]  E. Masliah,et al.  alpha-Synuclein is phosphorylated in synucleinopathy lesions. , 2002, Nature cell biology.

[117]  D. Sulzer,et al.  Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour , 2001, Molecular pathology : MP.

[118]  M. Mancuso,et al.  Mitochondrial DNA rearrangements in young onset parkinsonism: two case reports , 2001, Journal of neurology, neurosurgery, and psychiatry.

[119]  C. Ross,et al.  Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. , 2001, Human molecular genetics.

[120]  R. Carrozzo,et al.  Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family , 2001, Neurology.

[121]  D. Turnbull,et al.  Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. , 2001, American journal of human genetics.

[122]  H. Braak,et al.  α-Synuclein immunopositive Parkinson's disease-related inclusion bodies in lower brain stem nuclei , 2001, Acta Neuropathologica.

[123]  K. McNaught,et al.  Proteasomal function is impaired in substantia nigra in Parkinson's disease , 2001, Neuroscience Letters.

[124]  Todd B. Sherer,et al.  Chronic systemic pesticide exposure reproduces features of Parkinson's disease , 2000, Nature Neuroscience.

[125]  J. Trojanowski,et al.  Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. , 2000, Science.

[126]  P. Pahapill,et al.  The pedunculopontine nucleus and Parkinson's disease. , 2000, Brain : a journal of neurology.

[127]  F. Fornai,et al.  The role of the locus coeruleus in the development of Parkinson's disease , 2000, Neuroscience & Biobehavioral Reviews.

[128]  J. Trojanowski,et al.  Synucleins Are Developmentally Expressed, and α-Synuclein Regulates the Size of the Presynaptic Vesicular Pool in Primary Hippocampal Neurons , 2000, The Journal of Neuroscience.

[129]  S. Pulst,et al.  Familial multisystem degeneration with parkinsonism associated with the 11778 mitochondrial DNA mutation , 1999, Neurology.

[130]  Ma,et al.  Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing , 1999, Neuropathology and applied neurobiology.

[131]  D. Mash,et al.  Dopamine transporter‐immunoreactive neurons decrease with age in the human substantia nigra , 1999, The Journal of comparative neurology.

[132]  B. Pakkenberg,et al.  Neocortical neuron number in humans: Effect of sex and age , 1997, The Journal of comparative neurology.

[133]  T. Shima,et al.  Binding of iron to neuromelanin of human substantia nigra and synthetic melanin: an electron paramagnetic resonance spectroscopy study. , 1997, Free radical biology & medicine.

[134]  Y. Agid,et al.  Apoptosis and autophagy in nigral neurons of patients with Parkinson's disease. , 1997, Histology and histopathology.

[135]  S. Weis,et al.  Cytochrome c oxidase defects of the human substantia nigra in normal aging , 1996, Neurobiology of Aging.

[136]  H. Braak,et al.  Nigral and extranigral pathology in Parkinson's disease. , 1995, Journal of neural transmission. Supplementum.

[137]  N. Arnheim,et al.  Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain , 1992, Nature Genetics.

[138]  M. Beal,et al.  Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age , 1992, Nature Genetics.

[139]  Y. Agid,et al.  Is the Vulnerability of Neurons in the Substantia Nigra of Patients with Parkinson's Disease Related to Their Neuromelanin Content? , 1992, Journal of neurochemistry.

[140]  A. Lees,et al.  Ageing and Parkinson's disease: substantia nigra regional selectivity. , 1991, Brain : a journal of neurology.

[141]  W. Gibb,et al.  Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease. , 1991, Journal of neurology, neurosurgery, and psychiatry.

[142]  P Riederer,et al.  Selective Increase of Iron in Substantia Nigra Zona Compacta of Parkinsonian Brains , 1991, Journal of neurochemistry.

[143]  A. H. V. Schapira,et al.  MITOCHONDRIAL COMPLEX I DEFICIENCY IN PARKINSON'S DISEASE , 1989, The Lancet.

[144]  C. Marsden,et al.  Increased Nigral Iron Content and Alterations in Other Metal Ions Occurring in Brain in Parkinson's Disease , 1989, Journal of neurochemistry.

[145]  A M Graybiel,et al.  Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[146]  Langston Jw,et al.  Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. , 1983 .

[147]  Diana Brahams,et al.  Medicine and the Law , 1983, The Lancet.

[148]  J. Langston,et al.  Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. , 1983, Science.

[149]  P. Ballard,et al.  Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. , 1983, The New England journal of medicine.