術後神経認知障害 —脳内炎症を標的とした予防・治療戦略

高齢手術患者の増加に伴い，術後神経認知障害への対策が重要課題となっている。術後神経認知障害として，術後せん妄と術後認知機能障害が挙げられる。術後せん妄と術後認知機能障害はそれぞれ異なる疾患単位と考えられているが，共通する病態として脳内炎症が注目されている。脳内炎症は，活性化したミクログリアから過剰に炎症性サイトカインが産生・放出された状態である。特に，海馬ミクログリアは加齢により炎症性反応性が増加することが知られており，高齢者に術後神経認知障害が生じやすい原因と考えられる。また，全身麻酔，手術侵襲に伴う全身炎症，痛み，急性ストレス反応，神経障害などは脳内炎症を誘発する。したがって，これらの要因...

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Published in日本集中治療医学会雑誌 Vol. 25; no. 1; pp. 12 - 19
Main Author 河野, 崇
Format Journal Article
LanguageJapanese
Published 一般社団法人 日本集中治療医学会 01.01.2018
Online AccessGet full text
ISSN1340-7988
1882-966X
DOI10.3918/jsicm.25_12

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Abstract 高齢手術患者の増加に伴い，術後神経認知障害への対策が重要課題となっている。術後神経認知障害として，術後せん妄と術後認知機能障害が挙げられる。術後せん妄と術後認知機能障害はそれぞれ異なる疾患単位と考えられているが，共通する病態として脳内炎症が注目されている。脳内炎症は，活性化したミクログリアから過剰に炎症性サイトカインが産生・放出された状態である。特に，海馬ミクログリアは加齢により炎症性反応性が増加することが知られており，高齢者に術後神経認知障害が生じやすい原因と考えられる。また，全身麻酔，手術侵襲に伴う全身炎症，痛み，急性ストレス反応，神経障害などは脳内炎症を誘発する。したがって，これらの要因を最小化することが術後神経認知障害の予防・治療に重要である。本稿では術後神経認知障害の病態に関する最新の研究動向を示すとともに，脳内炎症を標的とした予防・治療戦略を考察したい。
AbstractList 高齢手術患者の増加に伴い，術後神経認知障害への対策が重要課題となっている。術後神経認知障害として，術後せん妄と術後認知機能障害が挙げられる。術後せん妄と術後認知機能障害はそれぞれ異なる疾患単位と考えられているが，共通する病態として脳内炎症が注目されている。脳内炎症は，活性化したミクログリアから過剰に炎症性サイトカインが産生・放出された状態である。特に，海馬ミクログリアは加齢により炎症性反応性が増加することが知られており，高齢者に術後神経認知障害が生じやすい原因と考えられる。また，全身麻酔，手術侵襲に伴う全身炎症，痛み，急性ストレス反応，神経障害などは脳内炎症を誘発する。したがって，これらの要因を最小化することが術後神経認知障害の予防・治療に重要である。本稿では術後神経認知障害の病態に関する最新の研究動向を示すとともに，脳内炎症を標的とした予防・治療戦略を考察したい。
Author 河野, 崇
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References 11) Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol 2014;10:217-24.
41) Frank MG, Thompson BM, Watkins LR, et al. Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses. Brain Behav Immun 2012;26:337-45.
1) Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction. Br J Anaesth 2009;103 Suppl:i41-6.
53) Schnyder S, Handschin C. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone 2015;80:115-25.
2) Steinmetz J, Christensen KB, Lund T, et al; ISPOCD Group. Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 2009;110:548-55.
7) Hosker C, Ward D. Hypoactive delirium. BMJ 2017;357:j2047.
8) Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 1998;351:857-61.
10) Steinman L. Modulation of postoperative cognitive decline via blockade of inflammatory cytokines outside the brain. Proc Natl Acad Sci U S A 2010;107:20595-6.
16) Kawano T, Eguchi S, Iwata H, et al. Impact of preoperative environmental enrichment on prevention of development of cognitive impairment following abdominal surgery in a rat model. Anesthesiology 2015;123:160-70.
3) Bilotta F, Lauretta MP, Borozdina A, et al. Postoperative delirium: risk factors, diagnosis and perioperative care. Minerva Anesthesiol 2013;79:1066-76.
17) Wu X, Lu Y, Dong Y, et al. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-α, IL-6, and IL-1β. Neurobiol Aging 2012;33:1364-78.
24) Zaidan JR, Klochany A, Martin WM, et al. Effect of thiopental on neurologic outcome following coronary artery bypass grafting. Anesthesiology 1991;74:406-11.
15) Lull ME, Block ML. Microglial activation and chronic neurodegeneration. Neurotherapeutics 2010;7:354-65.
39) Calcia MA, Bonsall DR, Bloomfield PS, et al. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl) 2016;233:1637-50.
32) Kawano T, Eguchi S, Iwata H, et al. Pregabalin can prevent, but not treat, cognitive dysfunction following abdominal surgery in aged rats. Life Sci 2016;148:211-9.
54) Pedersen BK. Edward F. Adolph distinguished lecture: muscle as an endocrine organ: IL-6 and other myokines. J Appl Physiol (1985) 2009;107:1006-14.
26) La Monaca E, Fodale V. Effects of anesthetics on mitochondrial signaling and function. Curr Drug Saf 2012;7:126-39.
30) Kawano T, Morikawa A, Imori S, et al. Preventive effects of multisensory rehabilitation on development of cognitive dysfunction following systemic inflammation in aged rats. J Anesth 2014;28:780-4.
21) Yamanaka D, Kawano T, Nishigaki A, et al. Preventive effects of dexmedetomidine on the development of cognitive dysfunction following systemic inflammation in aged rats. J Anesth 2017;31:25-35.
47) Al Tmimi L, Van de Velde M, Meyns B, et al. Serum protein S100 as marker of postoperative delirium after off-pump coronary artery bypass surgery: secondary analysis of two prospective randomized controlled trials. Clin Chem Lab Med 2016;54:1671-80.
34) Sampson EL, White N, Lord K, et al. Pain, agitation, and behavioural problems in people with dementia admitted to general hospital wards: a longitudinal cohort study. Pain 2015;156:675-83.
50) Hakim SM, Othman AI, Naoum DO. Early treatment with risperidone for subsyndromal delirium after on-pump cardiac surgery in the elderly: a randomized trial. Anesthesiology 2012;116:987-97.
12) Niraula A, Sheridan JF, Godbout JP. Microglia Priming with Aging and Stress. Neuropsychopharmacology 2017;42:318-33.
18) Culley DJ, Baxter M, Yukhananov R, et al. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth Analg 2003;96:1004-9.
31) Catorce MN, Gevorkian G. LPS-induced murine neuroinflammation model: main features and suitability for pre-clinical assessment of nutraceuticals. Curr Neuropharmacol 2016;14:155-64.
42) Nair A, Bonneau RH. Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J Neuroimmunol 2006;171:72-85.
9) Avidan MS, Evers AS. The Fallacy of Persistent Postoperative Cognitive Decline. Anesthesiology 2016;124:255-8.
27) Peng M, Zhang C, Dong Y, et al. Battery of behavioral tests in mice to study postoperative delirium. Sci Rep 2016;6:29874.
28) Payne BA, Chinnery PF. Mitochondrial dysfunction in aging: Much progress but many unresolved questions. Biochim Biophys Acta 2015;1847:1347-53.
13) Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011;25:181-213.
48) American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults. J Am Geriatr Soc 2015;63:142-50.
45) Donato R, Sorci G, Riuzzi F, et al. S100B's double life: intracellular regulator and extracellular signal. Biochim Biophys Acta 2009;1793:1008-22.
52) Spielman LJ, Little JP, Klegeris A. Physical activity and exercise attenuate neuroinflammation in neurological diseases. Brain Res Bull 2016;125:19-29.
55) Chan MT, Cheng BC, Lee TM, et al; CODA Trial Group. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol 2013;25:33-42.
20) Tanaka T, Kai S, Matsuyama T, et al. General anesthetics inhibit LPS-induced IL-1β expression in glial cells. PLoS One 2013;8:e82930.
22) Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med 2010;363:2638-50.
36) Kawano T, Takahashi T, Iwata H, et al. Effects of ketoprofen for prevention of postoperative cognitive dysfunction in aged rats. J Anesth 2014;28:932-6.
25) Fritz BA, Kalarickal PL, Maybrier HR, et al. Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium. Anesth Analg 2016;122:234-42.
38) Gaudreau JD, Gagnon P, Roy MA, et al. Opioid medications and longitudinal risk of delirium in hospitalized cancer patients. Cancer 2007;109:2365-73.
5) Davis DH, Muniz Terrera G, Keage H, et al. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain 2012;135:2809-16.
33) Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and cognitive decline in elderly patients: a systematic review. Anesth Analg 2006;102:1255-66.
43) Ottens TH, Dieleman JM, Sauër AM; DExamethasone for Cardiac Surgery (DECS) Study Group. Effects of dexamethasone on cognitive decline after cardiac surgery: a randomized clinical trial. Anesthesiology 2014;121:492-500.
14) Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev 2015;2015:610813.
56) Radtke FM, Franck M, Lendner J, et al. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction. Br J Anaesth 2013;110:i98-105.
40) Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry 2003;25:27-33.
29) Rabin BS, Cohen S, Ganguli R, et al. Bidirectional interaction between the central nervous system and the immune system. Crit Rev Immunol 1989;9:279-312.
46) Khan BA, Farber MO, Campbell N, et al. S100 calcium binding protein B as a biomarker of delirium duration in the intensive care unit - an exploratory analysis. Int J Gen Med 2013;6:855-61.
57) Su X, Meng ZT, Wu XH, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet 2016;388:1893-902.
51) Svensson M, Lexell J, Deierborg T. Effects of Physical Exercise on Neuroinflammation, Neuroplasticity, Neurodegeneration, and Behavior: What We Can Learn From Animal Models in Clinical Settings. Neurorehabil Neural Repair 2015;29:577-89.
35) Chi H, Kawano T, Tamura T, et al. Postoperative pain impairs subsequent performance on a spatial memory task via effects on N-methyl-D-aspartate receptor in aged rats. Life Sci 2013;93:986-93.
37) Morrison RS, Magaziner J, Gilbert M, et al. Relationship between pain and opioid analgesics on the development of delirium following hip fracture. J Gerontol A Biol Sci Med Sci 2003;58:76-81.
19) Callaway JK, Jones NC, Royse AG, et al. Memory impairment in rats after desflurane anesthesia is age and dose dependent. J Alzheimers Dis 2015;44:995-1005.
4) Hovens IB, Schoemaker RG, van der Zee EA, et al. Postoperative cognitive dysfunction: Involvement of neuroinflammation and neuronal functioning. Brain Behav Immun 2014;38:202-10.
6) Martins S, Fernandes L. Delirium in elderly people: a review. Front Neurol 2012;3:101.
44) Sen J, Belli A. S100B in neuropathologic states: the CRP of the brain?. J Neurosci Res 2007;85:1373-80.
23) Ferron JF, Kroeger D, Chever O, et al. Cortical inhibition during burst suppression induced with isoflurane anesthesia. J Neurosci 2009;29:9850-60.
49) Girard TD, Pandharipande PP, Carson SS, et al; MIND Trial Investigators. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med 2010;38:428-37.
References_xml – reference: 3) Bilotta F, Lauretta MP, Borozdina A, et al. Postoperative delirium: risk factors, diagnosis and perioperative care. Minerva Anesthesiol 2013;79:1066-76.
– reference: 56) Radtke FM, Franck M, Lendner J, et al. Monitoring depth of anaesthesia in a randomized trial decreases the rate of postoperative delirium but not postoperative cognitive dysfunction. Br J Anaesth 2013;110:i98-105.
– reference: 21) Yamanaka D, Kawano T, Nishigaki A, et al. Preventive effects of dexmedetomidine on the development of cognitive dysfunction following systemic inflammation in aged rats. J Anesth 2017;31:25-35.
– reference: 41) Frank MG, Thompson BM, Watkins LR, et al. Glucocorticoids mediate stress-induced priming of microglial pro-inflammatory responses. Brain Behav Immun 2012;26:337-45.
– reference: 26) La Monaca E, Fodale V. Effects of anesthetics on mitochondrial signaling and function. Curr Drug Saf 2012;7:126-39.
– reference: 7) Hosker C, Ward D. Hypoactive delirium. BMJ 2017;357:j2047.
– reference: 45) Donato R, Sorci G, Riuzzi F, et al. S100B's double life: intracellular regulator and extracellular signal. Biochim Biophys Acta 2009;1793:1008-22.
– reference: 42) Nair A, Bonneau RH. Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation. J Neuroimmunol 2006;171:72-85.
– reference: 27) Peng M, Zhang C, Dong Y, et al. Battery of behavioral tests in mice to study postoperative delirium. Sci Rep 2016;6:29874.
– reference: 20) Tanaka T, Kai S, Matsuyama T, et al. General anesthetics inhibit LPS-induced IL-1β expression in glial cells. PLoS One 2013;8:e82930.
– reference: 8) Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 1998;351:857-61.
– reference: 15) Lull ME, Block ML. Microglial activation and chronic neurodegeneration. Neurotherapeutics 2010;7:354-65.
– reference: 9) Avidan MS, Evers AS. The Fallacy of Persistent Postoperative Cognitive Decline. Anesthesiology 2016;124:255-8.
– reference: 30) Kawano T, Morikawa A, Imori S, et al. Preventive effects of multisensory rehabilitation on development of cognitive dysfunction following systemic inflammation in aged rats. J Anesth 2014;28:780-4.
– reference: 48) American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults. American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults. J Am Geriatr Soc 2015;63:142-50.
– reference: 52) Spielman LJ, Little JP, Klegeris A. Physical activity and exercise attenuate neuroinflammation in neurological diseases. Brain Res Bull 2016;125:19-29.
– reference: 16) Kawano T, Eguchi S, Iwata H, et al. Impact of preoperative environmental enrichment on prevention of development of cognitive impairment following abdominal surgery in a rat model. Anesthesiology 2015;123:160-70.
– reference: 2) Steinmetz J, Christensen KB, Lund T, et al; ISPOCD Group. Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 2009;110:548-55.
– reference: 13) Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 2011;25:181-213.
– reference: 47) Al Tmimi L, Van de Velde M, Meyns B, et al. Serum protein S100 as marker of postoperative delirium after off-pump coronary artery bypass surgery: secondary analysis of two prospective randomized controlled trials. Clin Chem Lab Med 2016;54:1671-80.
– reference: 28) Payne BA, Chinnery PF. Mitochondrial dysfunction in aging: Much progress but many unresolved questions. Biochim Biophys Acta 2015;1847:1347-53.
– reference: 24) Zaidan JR, Klochany A, Martin WM, et al. Effect of thiopental on neurologic outcome following coronary artery bypass grafting. Anesthesiology 1991;74:406-11.
– reference: 39) Calcia MA, Bonsall DR, Bloomfield PS, et al. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl) 2016;233:1637-50.
– reference: 40) Sirois F. Steroid psychosis: a review. Gen Hosp Psychiatry 2003;25:27-33.
– reference: 14) Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev 2015;2015:610813.
– reference: 44) Sen J, Belli A. S100B in neuropathologic states: the CRP of the brain?. J Neurosci Res 2007;85:1373-80.
– reference: 43) Ottens TH, Dieleman JM, Sauër AM; DExamethasone for Cardiac Surgery (DECS) Study Group. Effects of dexamethasone on cognitive decline after cardiac surgery: a randomized clinical trial. Anesthesiology 2014;121:492-500.
– reference: 6) Martins S, Fernandes L. Delirium in elderly people: a review. Front Neurol 2012;3:101.
– reference: 55) Chan MT, Cheng BC, Lee TM, et al; CODA Trial Group. BIS-guided anesthesia decreases postoperative delirium and cognitive decline. J Neurosurg Anesthesiol 2013;25:33-42.
– reference: 54) Pedersen BK. Edward F. Adolph distinguished lecture: muscle as an endocrine organ: IL-6 and other myokines. J Appl Physiol (1985) 2009;107:1006-14.
– reference: 32) Kawano T, Eguchi S, Iwata H, et al. Pregabalin can prevent, but not treat, cognitive dysfunction following abdominal surgery in aged rats. Life Sci 2016;148:211-9.
– reference: 4) Hovens IB, Schoemaker RG, van der Zee EA, et al. Postoperative cognitive dysfunction: Involvement of neuroinflammation and neuronal functioning. Brain Behav Immun 2014;38:202-10.
– reference: 23) Ferron JF, Kroeger D, Chever O, et al. Cortical inhibition during burst suppression induced with isoflurane anesthesia. J Neurosci 2009;29:9850-60.
– reference: 38) Gaudreau JD, Gagnon P, Roy MA, et al. Opioid medications and longitudinal risk of delirium in hospitalized cancer patients. Cancer 2007;109:2365-73.
– reference: 10) Steinman L. Modulation of postoperative cognitive decline via blockade of inflammatory cytokines outside the brain. Proc Natl Acad Sci U S A 2010;107:20595-6.
– reference: 5) Davis DH, Muniz Terrera G, Keage H, et al. Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study. Brain 2012;135:2809-16.
– reference: 33) Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and cognitive decline in elderly patients: a systematic review. Anesth Analg 2006;102:1255-66.
– reference: 36) Kawano T, Takahashi T, Iwata H, et al. Effects of ketoprofen for prevention of postoperative cognitive dysfunction in aged rats. J Anesth 2014;28:932-6.
– reference: 34) Sampson EL, White N, Lord K, et al. Pain, agitation, and behavioural problems in people with dementia admitted to general hospital wards: a longitudinal cohort study. Pain 2015;156:675-83.
– reference: 37) Morrison RS, Magaziner J, Gilbert M, et al. Relationship between pain and opioid analgesics on the development of delirium following hip fracture. J Gerontol A Biol Sci Med Sci 2003;58:76-81.
– reference: 49) Girard TD, Pandharipande PP, Carson SS, et al; MIND Trial Investigators. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med 2010;38:428-37.
– reference: 51) Svensson M, Lexell J, Deierborg T. Effects of Physical Exercise on Neuroinflammation, Neuroplasticity, Neurodegeneration, and Behavior: What We Can Learn From Animal Models in Clinical Settings. Neurorehabil Neural Repair 2015;29:577-89.
– reference: 35) Chi H, Kawano T, Tamura T, et al. Postoperative pain impairs subsequent performance on a spatial memory task via effects on N-methyl-D-aspartate receptor in aged rats. Life Sci 2013;93:986-93.
– reference: 1) Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction. Br J Anaesth 2009;103 Suppl:i41-6.
– reference: 12) Niraula A, Sheridan JF, Godbout JP. Microglia Priming with Aging and Stress. Neuropsychopharmacology 2017;42:318-33.
– reference: 31) Catorce MN, Gevorkian G. LPS-induced murine neuroinflammation model: main features and suitability for pre-clinical assessment of nutraceuticals. Curr Neuropharmacol 2016;14:155-64.
– reference: 46) Khan BA, Farber MO, Campbell N, et al. S100 calcium binding protein B as a biomarker of delirium duration in the intensive care unit - an exploratory analysis. Int J Gen Med 2013;6:855-61.
– reference: 50) Hakim SM, Othman AI, Naoum DO. Early treatment with risperidone for subsyndromal delirium after on-pump cardiac surgery in the elderly: a randomized trial. Anesthesiology 2012;116:987-97.
– reference: 18) Culley DJ, Baxter M, Yukhananov R, et al. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth Analg 2003;96:1004-9.
– reference: 11) Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat Rev Neurol 2014;10:217-24.
– reference: 57) Su X, Meng ZT, Wu XH, et al. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet 2016;388:1893-902.
– reference: 29) Rabin BS, Cohen S, Ganguli R, et al. Bidirectional interaction between the central nervous system and the immune system. Crit Rev Immunol 1989;9:279-312.
– reference: 17) Wu X, Lu Y, Dong Y, et al. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-α, IL-6, and IL-1β. Neurobiol Aging 2012;33:1364-78.
– reference: 19) Callaway JK, Jones NC, Royse AG, et al. Memory impairment in rats after desflurane anesthesia is age and dose dependent. J Alzheimers Dis 2015;44:995-1005.
– reference: 53) Schnyder S, Handschin C. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone 2015;80:115-25.
– reference: 22) Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med 2010;363:2638-50.
– reference: 25) Fritz BA, Kalarickal PL, Maybrier HR, et al. Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium. Anesth Analg 2016;122:234-42.
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Snippet 高齢手術患者の増加に伴い，術後神経認知障害への対策が重要課題となっている。術後神経認知障害として，術後せん妄と術後認知機能障害が挙げられる。術後せん妄と術後認知...
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StartPage 12
Title 術後神経認知障害 —脳内炎症を標的とした予防・治療戦略
URI https://www.jstage.jst.go.jp/article/jsicm/25/1/25_25_12/_article/-char/ja
Volume 25
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ispartofPNX 日本集中治療医学会雑誌, 2018/01/01, Vol.25(1), pp.12-19
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