Epigenetics of Delirium and Aging: Potential Role of DNA Methylation Change on Cytokine Genes in Glia and Blood Along With Aging

Background: Delirium in elderly patients is common and dangerous. Major risk factors include aging and exogenous insults, such as infection or surgery. In animal models, aging enhances pro-inflammatory cytokine release from microglia in response to exogenous insults. The epigenetic mechanism DNA methylation (DNAm) regulates gene expression and changes with age. Older individuals may have methylation changes that influence the increased cytokine upon insult, but the degree to which aging affects DNAm of cytokine genes is not fully understood.Methods: The relationship between DNAm and aging of pro-inflammatory cytokine genes (TNF-alpha, IL1-beta, IL-6) was investigated using methylation array data in two cohorts. Brain and blood samples were collected from a neurosurgery cohort (NSG) of 21 subjects who underwent brain resection. A second cohort, the Grady Trauma Project (GTP), included blood samples from 265 subjects.Results: In the NSG cohort, a significant negative correlation between age and DNAm in brain was found at a CpG in IL-6. With the GTP dataset, significant negative correlations between age and DNAm were seen at most of the CpGs in TNF-alpha. Also, TNF-Alpha expression increases with age. These GTP DNAm correlations were also nominally significant in NSG blood samples. In neuronal negative NSG brain tissue, a similar negative trend was observed.Conclusions: With aging, a decrease in DNAm of cytokines gene CpGs in glia and blood was seen. As this can affect their expression, additional research is needed to fully elucidate the role of DNAm in aging and how it may influence the pathogenesis of delirium

The establishment of the GENEQOL consortium to investigate the genetic disposition of patient-reported quality-of-life outcomes

To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported quality-of-life outcomes. The overall objective of this paper is to describe the establishment of an international and interdisciplinary consortium, the GENEQOL Consortium, which intends to investigate the genetic disposition of patient-reported quality-of-life outcomes. We have identified five primary patient-reported quality-of-life outcomes as initial targets: negative psychological affect, positive psychological affect, self-rated physical health, pain, and fatigue. The first tangible objective of the GENEQOL Consortium is to develop a list of potential biological pathways, genes and genetic variants involved in these quality-of-life outcomes, by reviewing current genetic knowledge. The second objective is to design a research agenda to investigate and validate those genes and genetic variants of patient-reported quality-of-life outcomes, by creating large datasets. During its first meeting, the Consortium has discussed draft summary documents addressing these questions for each patient-reported quality-of-life outcome. A summary of the primary pathways and robust findings of the genetic variants involved is presented here. The research agenda outlines possible research objectives and approaches to examine these and new quality-of-life domains. Intriguing questions arising from this endeavor are discussed. Insight into the genetic versus environmental components of patient-reported quality-of-life outcomes will ultimately allow us to explore new pathways for improving patient care. If we can identify patients who are susceptible to poor quality of life, we will be able to better target specific clinical interventions to enhance their quality of life and treatment outcome

粉末粒子の自由配列により極低欠陥で超高強度の精密セラミックスを得る高速遠心成形法

本研究は大きく2部に分かれている. まず第1部では,高速遠心成形法(High-Speed Centrifugal Compaction Process,以下HCPとする)の成形機構および欠陥除去機構を明らかにすることで, HCPアルミナの高強度要因を解明することを目的として,以下の研究を行った. まず, HCP法の成形機構を解明するために原料粉末,成形回転数および成形時間を変化させてHCPを行い,それらの条件が成形途中の据奨挙動,沈降体の形成挙動におよぼす影響を調査した. 次にHCPアルミナの高強度要因を明らかにするために,HCP成形体と加圧鋳込み成形体の粒子充填率に着目して両者を比較し,成形法による粒子充填状況の違いについて検討した. さらに,成形法による欠陥除去機能の違いを調査するために,新しい組織観察方法として浸液透光法を使用して,泥漿中に気泡を導入した泥漿によって作製したHCP成形体および加圧鋳込み成形体内部に存在する欠陥観察を行った. そして, HCPの成形条件と欠陥除去機能の関係を明らかにするために,気泡モデルとしてスチロール球を導入し,流動性を劣化させた泥漿を使用して高速遠心成形を行い,モデル球の挙動について定量的な検討を行った. 次に第2部として, HCPを利用した均質で低欠陥な高品質超硬合金の作製を試みた. まず微粒WC粉末を使用して,粉砕条件および泥漿の分散方法を検討し,高密度で均質な成形体が得られる泥漿調製条件を見出した. 次に, HCPにより成形体を作製し,その後成形体中へ焼結助剤を添加する方法を検討した. さらに,様々な条件で焼結を行い焼結性を検討すると共に,その機械的特性を評価した. 本研究より明らかになったことを以下に要約する. (1)HCPにおける成形途中の泥漿は,原料粉末初期濃度,成形条件研究期間:平成10-12年度 ; 研究種目: 基盤研究A2 ; 課題番号:1035503

Correlation of telomere length in brain tissue with peripheral tissues in living human subjects

Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology