Medical hypotheses
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Delirium is conceptually elusive and falls outside of conventional biomedical models. Positivist theoretical paradigms of single linear causality are therefore insufficient to provide mechanistic enlightenment. Delirium does, however, share parallels with features of failure within a complex system. ⋯ An alternative emphasis away from end of chain analysis and oversimplification of cause and an attempt to avoid introduction of new forms of failure in a responsive healthcare environment are lessons from complex system theory. Insights from complex systems provide potentially important mechanistic underpinnings and new lines of research enquiry for delirium. Not least, a fuller understanding of delirium from a complex system viewpoint may help transform management and outcomes in one of the biggest challenges of acute healthcare.
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Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by an accelerated aging phenotype that typically leads to death via stroke or myocardial infarction at approximately 14.6 years of age. Most cases of HGPS have been linked to the extensive use of a cryptic splice donor site located in the LMNA gene due to a de novo mutation, generating a truncated and toxic protein known as progerin. Progerin accumulation in the nuclear membrane and within the nucleus distorts the nuclear architecture and negatively effects nuclear processes including DNA replication and repair, leading to accelerated cellular aging and premature senescence. ⋯ Each of these compounds has also been independently shown to induce AMPK activation. Because these compounds improve accelerated aging defects in HGPS cells either by enhancing mitochondrial functionality, increasing Nrf2 activity, inducing autophagy, or by altering gene splicing and because AMPK activation beneficially modulates each of the aforementioned processes, it is our hypothesis that cellular stress-induced AMPK activation represents an indirect yet common mechanism of action linking such chemically diverse compounds with the beneficial effects of those compounds observed in HGPS cells. As normal humans also produce progerin at much lower levels through a similar mechanism, compounds that safely induce AMPK activation may have wide-ranging implications for both normal and pathological aging.
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Transposable elements (TEs), also known as "jumping genes", are DNA sequences first described by Nobel laureate Barbara McClintock that comprise nearly half of the human genome and are able to transpose or move from one genomic location to another. As McClintock also noted that a genome "shock" or stress may induce TE activation and transposition, accumulating evidence suggests that cellular stress (e.g. mediated by increases in intracellular reactive oxygen species [ROS] and calcium [Ca2+], etc.) induces TE mobilization in several model organisms and L1s (a member of the retrotransposon class of TEs) are active and capable of retrotransposition in human oocytes, human sperm, and in human neural progenitor cells. Cellular stress also plays a critical role in human placental development, with cytotrophoblast (CTB) differentiation leading to the formation of the syncytiotrophoblast (STB), a cellular layer that facilitates nutrient and gas exchange between the mother and the fetus. ⋯ Both RAG1 and telomerase are derived from TEs. It is our hypothesis that cellular stress and AMPK links TE activation and transposition with placental development and oocyte activation, facilitating both human genome evolution and the creation of all human life. We also propose the novel observation that various cellular stress-inducing compounds (e.g. metformin, resveratrol, etc.) may facilitate beneficial TE activation and transposition and enhance fertilization and embryological development through a common mechanism of AMPK activation.