犬モデルにおける ex vivo および in vivo 遺伝子治療のための代替遺伝子導入技術の開発

Introduction: Gene therapy have recently attracted much attention as a curative therapeutic option for inherited single gene disorders such as hemophilia. Hemophilia is a hereditary bleeding disorder caused by the deficiency of clotting activity of factor VIII (FVIII) or factor IX (FIX), and gene therapy for hemophilia using viral vector have been vigorously investigated worldwide. Toward further advancement of gene therapy for hemophilia, we have previously developed and validated the efficacy of novel two types of gene transfer technologies using a mouse model of hemophilia A. Here we investigated the efficacy and safety of the technologies in canine model. Especially, validations of technical procedures of the gene transfers for dogs were focused. Methods: Green fluorescence protein (GFP) gene were transduced into normal beagle dogs by ex vivo and in vivo gene transfer techniques. For ex vivo gene transfer, blood outgrowth endothelial cells (BOECs) derived from peripheral blood of normal dogs were transduced with GFP gene using lentivirus vector, propagated, fabricated as cell sheets, then implanted onto the omentum of the same dogs. For in vivo gene transfer, normal dogs were subjected to GFP gene transduction with non-viral piggyBac vector by liver-targeted hydrodynamic injections. Results: No major adverse events were observed during the gene transfers in both gene transfer systems. As for ex vivo gene transfer, histological findings from the omental biopsy performed 4 weeks after implantation revealed the tube formation by implanted GFP-positive BOECs in the sub-adipose tissue layer without any inflammatory findings, and the detected GFP signals were maintained over 6 months. Regarding in vivo gene transfer, analyses of liver biopsy samples revealed more than 90% of liver cells were positive for GFP signals in the injected liver lobes 1 week after gene transfers, then the signals gradually declined overtime. Conclusions: Two types of gene transfer techniques were successfully applied to a canine model, and the transduced gene expressions persisted for a long term. Toward clinical application for hemophilia patients, practical assessments of therapeutic efficacy of these techniques will need to be performed using a dog model of hemophilia and FVIII (or FIX) gene.博士（医学）・乙第1517号・令和3年12月21日© 2021, The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/)

包括的凝固/線溶動態に基づく敗血症性DIC（播種性血管内凝固）の病態解明

Background: The functional dynamics of coagulation and fibrinolysis in patients with disseminated intravascular coagulation (DIC) vary due to the pathology and severity of various underlying diseases. Conventional measurements of hemostasis such as thrombin-antithrombin complex, plasmin-α2-plasmin-inhibitor complex, and fibrinogen-fibrin degradation products may not always reflect critical pathophysiologic mechanisms in DIC. This article aims to clarify the pathology of sepsis-associated DIC using assessment of comprehensive coagulation and fibrinolysis. Methods: Plasma samples were obtained from 57 patients with sepsis-associated DIC at the time of initial diagnosis. Hemostasis parameters were quantified by clot-fibrinolysis waveform analysis (CFWA) and thrombin/plasmin generation assays (T/P-GA). The results were expressed as ratios relative to normal plasma. Results: CFWA demonstrated that the maximum coagulation velocity (|min1|) ratio modestly increased to median 1.40 (min - max: 0.10 - 2.60) but the maximum fibrinolytic velocity (|FL-min1|) ratio decreased to 0.61 (0 - 1.19). T/P-GA indicated that the peak thrombin (Th-Peak) ratio moderately decreased to 0.71 (0.22 - 1.20), whereas the peak plasmin (Plm-Peak) ratio substantially decreased to 0.35 (0.02 - 1.43). Statistical comparisons identified a correlation between |min1| and Th-Peak ratios (ρ = 0.55, p < 0.001), together with a strong correlation between |FL-min1| and Plm-Peak ratios (ρ = 0.71, p < 0.001), suggesting that CFWA reflected the balance between thrombin and plasmin generation. With |min1| and |FL-min1| ratios, DIC was classified as follows: coagulation-predominant, coagulation/fibrinolysis-balanced, fibrinolysis-predominant, and consumption-impaired coagulation. The majority of patients in our cohort (80.7%) were coagulation-predominant. Conclusion: A pathological clarification of sepsis-associated DIC based on the assessment of coagulation and fibrinolysis dynamics may be useful for the hemostatic monitoring and management of optimal treatment in these individuals.博士（医学）・甲第786号・令和3年3月15日© 2020. Thieme. All rights reserved.This is a non-final version of an article published in final form in "http://dx.doi.org/10.1055/s-0040-1713890

Herbal Medicine Containing Licorice May Be Contraindicated for a Patient with an HSD11B2 Mutation

Licorice ingestion, as well as mutations in the HSD11B2 gene, inhibits 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) enzyme activity, causing the syndrome of apparent mineral corticoid excess (AME). However, the combined effect of licorice ingestion and an HSD11B2 mutation has never been reported, until now. In this study, we demonstrated that licorice ingestion can produce overt hypertension in an individual without medical history of hypertension who is heterozygous for wild-type and mutant HSD11B2 genes. Our patient was a 51-year-old female with serious hypertension who had been taking herbal medicine containing licorice for more than one year. She was clinically diagnosed as having licorice intoxication, because she did not present with hypertension after ceasing the herbal medicine. Molecular analysis showed that she carried a missense mutation, c.40C>T, in HSD11B2. In conclusion, licorice ingestion is an environmental risk factor for hypertension or AME state in patients with a mutation in HSD11B2. Carrying a mutation in HSD11B2 is, conversely, a genetic risk factor for licorice-induced hypertension or AME state. Herbal medicine containing licorice may, therefore, be contraindicated in patients with an HSD11B2 mutation

チイキ コウレイシャ ノ セイカツ シュウカン エイヨウ ト サルコペニア ニ カンスル ジッタイ チョウサ

本研究では，地域高齢者の生活習慣，栄養，サルコペニアに関する実態調査を行い，高齢者が在宅で元気に自立して過ごすための健康支援策を検討するための基礎資料を得ることを目的とした．地方の商業施設で開催された健康測定会に参加した65 歳以上の高齢者120 名を対象に，生活習慣，栄養，サルコペニア，QOL に関する調査を行った．全対象者のうち，サルコペニアの診断に該当した者は3 名のみであった．対象者はほとんど無職で，7 割が健康的な生活習慣をもち，栄養状態も良好であった．全般的にQOL は同世代並みであった．女性は男性に比べて運動習慣をもつ者が少なく，さらに女性の中でも75 歳以上の後期高齢者は前期高齢者に比べて歩行速度が有意に遅く，運動に関わる身体計測値が低い一方，体脂肪率は高かった．高齢者は，積極的に家庭内外での活動を行うことが重要であり，特に75 歳以上の女性は，運動習慣を身につけ，身体活動量を上げるような対策をとることが重要である．We conducted a fact-finding survey on lifestyles, nutrition, and sarcopenia in community-dwelling elderly residents. The objective was to obtain the basic data for developing health-support measures that would help elderly people live healthy and independent lives in their homes. In 120 elderly people 65 years of age or older who participated in a health checkup held at a regional commercial facility, a survey was conducted on lifestyle, nutrition, sarcopenia, and quality of life (QOL). Of all subjects, only 3 met the diagnostic criteria for sarcopenia. Most subjects were retired, while 70% of the subjects had healthy lifestyles and good nutritional status. Overall, QOL of the subjects was comparable to that of elderly people in the same age groups. Compared with men, fewer women exercised regularly. Even among the female subjects, very elderly women, those 75 years of age or older, walked significantly more slowly, showed lower physical measurements associated with physical activities, but had a higher body fat percentage than the women less than 75 years of age. For elderly people, It is important to perform activities inside and outside the home positively. Particularly for women 75 years of age or older, measures that help them build an exercise habit and increase physical activity are important.原著論文 = Original articl

ザイタク デ ニンチショウ オ ユウスル リョウヨウシャ オ カイゴ スル ダンセイ カイゴシャ ノ タイショ シャクド コウモク ノ ケントウ

在宅で認知症を介護する男性は年々増えている。最近の報告では、介護にかかわる事件の約2/3は、男性介護者である。介護を抱え困ったことがあっても悩みを人にうちあけない、相談しないなど、ソーシャルサポートに繋がることができない男性介護者の問題点が報告されている。しかし、現在、男性介護者の特徴や抱えている問題を客観的に測定するための対処尺度はない。今回の研究の目的は、男性介護者の対処尺度の項目を検討することである。まず、先行研究から男性介護者の対処における記述を抽出し既存の尺度と照合した。次に認知症療養者を在宅で介護している男性9名へ対処について調査を行った。さらに専門家と男性の対処について検討し、既存の対処尺度19項目に納まりきれない2項目を、新たに対処尺度の項目として追加した。The purpose of this paper was to report the development process of the scale for measuring for home care of male caregiver of dementia. First, male caregiver\u27s coping in precedence literatures reporting male caregivers of dementia applies with the pre-existing coping scale. Add questionnaire survey was given to 9 caregivers. And Experts in the field, consisting of university associate professors and specialists of dementia, established the content validity of the scale. Second, the category based on the main subject of the sentences. Each coping of sentences in a category was classified into 21 concepts, which form patients\u27 roles, and the sentences were then organized into 19 items for the primary questionnaire. Finally, the items were refined to represent the concepts, and carefully selected. Finally, the scale for measuring for home care of male caregiver of elderly of dementia, which consist of 21 items, was developed原著論文 = Original articl

ザイタク デ ニンチショウ ノ ヒト オ カイゴ スル ダンセイ ノ カイゴ モンダイ タイショ スタイル ノ サンシュツ ホウホウ

男性介護者の介護問題対処スタイルの算出方法を明らかにすることを目的とした．対象者は男性介護者298 名である．対処スタイルの平均得点と標準偏差，寄与率による各対処スタイルの独立性の検討と，基準関連法による各対処スタイルの妥当性を検討した．結果・考察: 平均得点と標準偏差，寄与率から似た特徴を持つ対処スタイルであることが考えられたが，基準関連法により独立した対処スタイルであることが明らかとなり，各対処スタイルは独立した特徴を持つことが明らかとなった．男性の介護問題対処の算出方法は，各対処スタイルの平均得点とし，最も得点が高い対処スタイルが，介護問題へ活用する対処であると考えられる．The purpose of this paper was to calculation of the coping scale for Nursing Care Problems Coping Scale for Male Caregivers for People with Dementia Living at Home. The subjects were 298 men who care for people with dementia at home. It was independence and investigated validity the coping style; the result of av erage score, standard deviation and Contribution ratio of coping style. Each coping styles are independent, it became clear that each with its own characteristics. Calculation method is the average score of each coping style. Most high score of average of coping style is the coping style of nursing care problem.原著論文 = Original articl

ドッキョ コウレイシャ エ ノ サイガイ タイサク ノ ジョウホウ テイキョウ ニ オケル ケンキュウ

福岡市の高齢者における地域の災害避難場所の認知について, 実態調査を行い, 独居高齢者への災害支援のありかたについて検討した. 地域包括ケアシステムと介護の啓発を目的とした集会の参加者258 名を分析対象とし, 基本属性, フォーマルな相談窓口の認知と活用の有無, 活用している相談窓口数, 地域の避難場所の認知, 楽しみの有無, 情緒的支援, 自尊感情尺度について調査した. 分析は同居群と独居群の２群の差のカテゴリ変数にはχ2 検定, 連続変数にはMann–Whitney U 検定行い群間差を検定した. その結果, 独居高齢者は同居者がいる高齢者より有意に高齢で, 公の相談窓口を知らず, 相談談窓口数が少なく, 避難場所を知らず, 楽しみを有さず, 情的支援を受けていなかった. 都市部における高齢者への災害支援を充実させるためには, 特に独居高齢者が情的な交流のある生活の中で, 楽しみながら社会活動ができる場づくりを行う必要がある. また, 災害支援の情報提供は，社会活動ができる場で行うことが有益であることが示唆された.The purpose of this study was to countermeasure to living alone elderly when disaster occurs. A total of 258 elderly residents participates. A questionnaire included the following scales and items: Disaster shelter. Recognition a formal consultation. Take advantage of a formal consultation. Take advantage number of adviser. Recognition a countermeasure. In life a pleasure. Emotional support. Self Esteem scale. The more elderly, living alone elderly than living with family elderly. The living alone elderly did not know that Fukuoka-city hall and town office is daily living consultation. The urban area to progress in disaster countermeasures, attention to live-alone elderly, whose are provided emotional support, have in life a pleasure, have a place of social activities.原著論文 = Original articl

クマモト ジシン 6カゲツ ニ オケル シュウロウシャ ノ スイミン ト シュカンテキ ケンコウ ジョウタイ ト ノ カンレン ヨウイン

Objective：This study aimed to clarify the relationship between sleep and subjective health condition by focusing on disaster-affected workers six months after the Kumamoto earthquake.Methods：The study population comprised 676 workers at small and medium-sized companies located in Kamimashikigun, Kumamoto Prefecture, where damage after the Kumamoto earthquake was severe. Participants were sent a questionnaire with items related to basic characteristics （sex, age, and family members）, damage to home after the earthquake, subjective symptoms after the earthquake, injury from the earthquakes, changes in income, subjective wellbeing, changes in workload after the earthquake, Athens Insomnia Scale（AIS）, Impact of Event Scale-Revised（IES-R）, General Health Questionnaire（GHQ 28）, and health related QOL Short-Form Health Survey（SF-8）. Responses were collected from 456 people at 13 companies（68.1% response rate）. Of these, 438 responses（96.1%） were valid. This study was approved by the ethical review committee of Fukuoka University School of Medicine.Results：The participants included 334 males and 104 females with an average age of 43.3 years. Two groups were created based on Abbreviated Injury Scale（AIS）scores：279 participants were in the insomnia group and 159 participants were in the non-insomnia group. Compared with that in the non-insomnia group, the patients in the insomnia group were old, had poor subjective health status, and were more likely to have subjective symptoms and injury after the earthquake. The study found a significant positive correlation with intrusion and hyperarousal symptoms in the IES-R subscales. In the SF-8 responses, there were significant negative correlations with BP（Bodily Pain）, GH（General Health）, VT（Vitality）, SF（Social Functioning）, RE（Role Emotional）, MH（Mental Health）, and MCS（Mental Component Summary）. In a logistic regression analysis of sleeping condition in Athens Insomnia Scale（AIS）, BP［OR： 0.942, CI： 0.907-0.978］and avoidance symptoms［OR：0.881, CI：0.799-0.971］improved sleeping condition, whereas hyperarousal symptoms［OR：1.553, CI：1.324-1.823］, social life function［OR：0.954, CI：0.916-0.994］, and daily role function（mental）［OR：0.916, CI：0.866-0.97］were negatively related with good sleeping condition.Discussion：The Kumamoto earthquake influenced the sleep quality for most disaster-affected workers, with approximately 60% reporting insomnia. Because workers with insomnia may exhibit hidden subjective symptoms or suffer from mental stress, long-term preventive systems should be developed and established by companies to improve worker health. Longitudinal studies are required to further examine factors related to sleep condition and outcomes of support systems.原著論文 = Original articl

ショク ノ タヨウセイ オ ツイキュウ スル

第13回日本機能性食品医用学会総会会長講

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection