Hardy JA, Higgins GA. Alzheimer’s disease: The amyloid cascade hypothesis.Science.1992;256:184–185.
抗アミロイドβ(Aβ)抗体donanemab
抗Aβ抗体donanemab、半数例で薬剤を中止可能 2023年10月11日 MedicalTribune イーライリリー・アンド・カンパニー エグゼクティブ・バイスプレジデント ダニエル M. スコブロンスキー氏「donanemabは迅速かつ高率に脳内のアミロイドプラークを除去できるのが特徴。同薬投与例の半数で投与1年後にアミロイドプラークを除去できたことが確認されており、アミロイド除去例では投与をやめる(離脱)こともできる」「脳内にタウ蛋白質の蓄積が認められない早期ADの段階であれば効果が期待される一方で、タウ蛋白質が脳内に認められた状態では抗Aβ抗体に抗タウ薬を組み合わせた治療が必要になる」
Donanemab in Early Symptomatic Alzheimer Disease The TRAILBLAZER-ALZ 2 Randomized Clinical Trial July 17, 2023 https://jamanetwork.com/journals/jama/fullarticle/2807533 第Ⅲ相試験TRAILBLAZER-ALZ 2 donanemabの有効性と安全性を検討 8カ国においてPET検査によりAβおよびタウ蛋白質蓄積が認められる軽度認知障害(MCI)および軽度認知症を含む60~85歳の早期症候性AD患者1,736例(平均年齢73.0歳)を対象
Treatments for Alzheimer’s disease emerge DENNIS J. SELKOE SCIENCE • 6 Aug 2021 • Vol 373, Issue 6555 • pp. 624-626 • DOI: 10.1126/science.abi6401 アルツハイマー病の治療薬に関する総説。
Group Wants FDA Leaders Ousted Over Alzheimer’s Drug Approval By Alicia Ault June 17, 2021 — A high-profile Washington-based consumer advocacy group is calling for the removal of the FDA’s acting commissioner and two other top officials, saying the agency’s approval of the Alzheimer’s drug aducanumab (Aduhelm) was “reckless.”
Three F.D.A. Advisers Resign Over Agency’s Approval of Alzheimer’s Drug By Pam Belluck and Rebecca Robbins Published June 10, 2021 Updated Sept. 2, 2021 The New York Times “This might be the worst approval decision that the F.D.A. has made that I can remember,” said Dr. Aaron Kesselheim, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, who submitted his resignation Thursday after six years on the committee.
The Controversy Over the FDA’s Approval of The First Alzheimer’s Treatment Keeps Growing BY ALICE PARK JUNE 11, 2021 TIME Neurology and dementia experts, as well as statisticians who have looked at the data the drug makers submitted for approval are more skeptical. They note that the two large studies of the drug were hardly convincing in showing effectiveness. One study showed no significant benefit among people who received the drug compared to those getting a placebo, while the other showed only marginal improvement in cognitive tests among people getting the drug.
In diabetes, especially type 2 diabetes, insulin resistance occurs when the body’s cells become less responsive to insulin’s action. This resistance affects multiple tissues, each at a different “action point” in glucose metabolism.
🔍 Main action points of insulin resistance:
1. Liver (Hepatic insulin resistance)
Normal insulin action: Suppresses hepatic glucose production (gluconeogenesis & glycogenolysis)
In insulin resistance:
🔺 Liver continues to produce glucose even when blood glucose is high
🔺 → Fasting hyperglycemia
2. Muscle (Skeletal muscle insulin resistance)
Normal insulin action: Stimulates glucose uptake via GLUT4 transporters
In insulin resistance:
🔻 Glucose uptake is impaired
🔻 Less glucose is stored as glycogen
🔻 → Postprandial hyperglycemia
3. Adipose tissue (Adipocyte insulin resistance)
Normal insulin action:
Suppresses lipolysis (fat breakdown)
Promotes fat storage
In insulin resistance:
🔺 Lipolysis is increased
🔺 More free fatty acids (FFA) are released into the blood
🔺 FFAs worsen hepatic insulin resistance and promote ketogenesis
4. Brain (Central insulin resistance, under debate)
Insulin may regulate appetite and energy balance in the hypothalamus
Resistance may impair satiety signaling, contributing to overeating and obesity
Vascular complications of diabetes: mechanisms of injury and protective factors Christian Rask-Madsen and George L. King Cell Metab. 2013 Jan 8; 17(1): 20–33. doi: 10.1016/j.cmet.2012.11.012 Overproduction of reactive oxygen species (ROS) as a result of altered glucose metabolism and formation of advanced glycation end-products (AGE) further amplifies this process by activating nuclear factor κB (NFκB) and other proinflammatory pathways.
W Henle, G Henle. INTERFERENCE OF INACTIVE VIRUS WITH THE PROPAGATION OF VIRUS OF INFLUENZA Science . 1943 Jul 23;98(2534):87-9. doi: 10.1126/science.98.2534.87.
In 1957, Alick Isaacs (1921–1965) and a post-doctoral Swiss student, Jean Lindenmann, were studying the phenomenon of “viral interference”—the ability of one virus to inhibit the replication of another virus. When 10-day-old chick chorioallontoic membranes from chick embryos were infected with heat or UV inactivated influenza virus, a material was produced that interfered with subsequent viral replication. (Interferons by Milton W. Taylor)
Interferons by Milton W. Taylor. Viruses and Man: A History of Interactions. 2014 Jul 22 : 101–119. Published online 2014 Jul 22. doi: 10.1007/978-3-319-07758-1_7 PMCID: PMC7123835
Isaacs, A., Lindenmann, J. (1957). Virus interference. I. The interferon. Proceedings of the Royal Society of London Series B, Containing papers of a Biological character Royal Society, 147(927), 258–267.
インターフェロンγは細胞傷害性T細胞によるがんゲノムの免疫エディティングに必要である IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting 2017年2月24日 Nature Communications 8 : 14607 doi: 10.1038/ncomms14607
インターフェロンに関するセミナー動画
Hertzog P (2014): Interferon Signalling WEHI Seminars (Walter and Eliza Hall Institute Postgraduate lecture 14 April 2014 Professor Paul Hertzog Monash Institute of Medical Research)
COVID-19 INCIDENCE RATE The incidence rate is a measure of the frequency with which the event, in this case COVID-19, occurs over a specific period. Numerically, it is defined it as the number of new cases for the disease within a time frame, as a proportion of the number of people at risk for the disease.
Daily Case Incidence Rate Maps The seven-day incidence is calculated by taking the total number of unique cases in each county over the past seven days, divided by seven to get a daily average, divided by the U.S. census bureau county population and multiplied by 100,000 to get the incidence per 100,000 people.