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本稿の目的は，重度障害を有する人が，親元でも施設でもなく，地域の中で必要な支援を受けながら暮らす生活について，その経緯と実際を描くことにある。男性障害者Ｚさんの支援現場の参与観察，本人の傍に居続けてきた母親と支援のキーパーソンとなる人物へのインタビュー調査をもとに，本稿を論じていく。Ｚさんの生活史に関する調査結果から，障害者の地域生活に関する論点として次の論点を挙げた。①福祉サービスが提供されないままに，家族のみに責任を負わされてしまう状況があること，②地域生活支援におけるキーパーソンの存在の重要性，③障害者本人に添い，その人と共に居るという認識の醸成が重要であること。

本稿は，2020年以降からの新型コロナウイルス感染防止のための障害福祉サービスの対応を時系列で整理することを目的とする。本稿では主に，厚生労働省から発出される事務連絡を時系列に整理しその概要をまとめることにより，2020年１月から2020年度末までの約１年間の障害福祉サービスでの対応内容を明らかにする。2020年度の厚生労働省による事務連絡の内容を見ると，厚生労働省は，福祉サービスを提供する施設や事業所が新型コロナウイルス感染防止を第一に行うために必要となる「柔軟な対応」を認めてきたことがわかる。また厚生労働省は，介護や支援を要する障害者にとって，福祉サービスは必要不可欠であることから，感染防止を行いながらサービスの継続をするよう，自治体やサービス提供施設や事業所に指示をし続けてきたことも，本稿の整理からわかった。

PolyADP-ribosylation is a posttranslational modification of proteins that results from enzymatic synthesis of poly(ADP-ribose) with NAD

PolyADP-ribosylation is a post-translational modification which is involved in various physiological processes including maintenance of genome stability through DNA repair, regulation of transcription, and development. This process is also involved in pathological events such as cell death. Here, we review the effect of polyADP-ribosylation in signal transduction pathways in Drosophila melanogaster system. It is hoped that such an insight paves the way to develop therapeutics for human diseases.

Alcohol dehydrogenase (ADH) is important for preventing alcohol toxicity and developmental disorders, and may be involved in other diseases including neurodegenerative diseases. We found that the major acceptor protein of polyADP-ribosylation in a model organism of neurodegeneration using a Drosophila melanogaster mutant lacking poly(ADP-ribose) glycohydrolase, was ADH. Thus we postulated that human ADH activity might be regulated by polyADP-ribosylation, a post-translational modification. The radioactivity of [32P]NAD+ was incorporated into human ADH1 by human poly(ADP-ribose) polymerase 1 in vitro, but was not incorporated when heat-inactivated PARP1 or a PARP inhibitor, 3-aminobenzamide, was used. The incorporated radioactivity was not released from ADH1 protein in the presence of excess amount of ADP-ribose or poly(ADP-ribose) as competitors. However, it was released by incubation with 1 M neutral NH2OH or 0.1 N NaOH, but was not with 0.1 N HCl, suggesting the bond between ADH1 and poly(ADP-ribose) is an ester linkage. When HepG2 cells, a human hepatoma cell line, were cultured in the presence of another PARP inhibitor, olaparib, ADH activity of the cell was significantly increased. These results suggest that polyADP-ribosylation could regulate ADH activity in vivo and might be involved in neurodegeneration.

Protein targets of polyADP-ribosylation undergo covalent modification with high-molecular-weight, branched poly(ADP-ribose) (PAR) of lengths up to 200 or more ADP-ribose residues derived from NAD

Bone morphogenetic protein (BMP) 9 is one of the most osteogenic BMPs, but its mechanism of action has not been fully elucidated. Hes1, a transcriptional regulator with a basic helix-loop-helix domain, is a well-known effector of Notch signaling. Here, we find that BMP9 induces periodic increases of Hes1 mRNA and protein expression in osteoblasts, presumably through an autocrine negative feedback mechanism. BMP9-mediated Hes1 induction is significantly inhibited by an ALK inhibitor and overexpression of Smad7, an inhibitory Smad. Luciferase and ChIP assays revealed that two Smad-binding sites in the 5' upstream region of the mouse Hes1 gene are essential for transcriptional activation by BMP9. Thus, our data indicate that BMP9 induces Hes1 expression in osteoblasts via the Smad signaling pathway.

Cancer cells are known to have chromosomal number abnormalities (aneuploidy), a hallmark of malignant tumors. Cancer cells also have an increased number of centrosomes (centrosome amplification). Paradoxically, cancer therapies, including γ-irradiation and some anticancer drugs, are carcinogenic and can induce centrosome amplification and chromosomal aneuploidy. Thus, the processes of carcinogenesis and killing cancer cells might have some mechanisms in common. Previously, we found that the inhibitors of polyADP-ribosylation, a post-translational modification of proteins, caused centrosome amplification. However, the mechanism of action of the inhibitors of polyADP-ribosylation is not fully understood. In this study, we found that an inhibitor of polyADP-ribosylation, 3-aminobenzamide, caused centrosome amplification, as well as aneuploidy of chromosomes in CHO-K1 cells. Moreover, inhibitors of polyADP-ribosylation inhibited AKT phosphorylation, and inhibitors of AKT phosphorylation inhibited polyADP-ribosylation, suggesting the involvement of polyADP-ribosylation in the PI3K/Akt/mTOR signaling pathway for controlling cell proliferation. Our data suggest a possibility for developing drugs that induce centrosome amplification and aneuploidy for therapeutic applications to clinical cancer.

PolyADP-ribosylation is a unique posttranslational modification of proteins, involved in various cellular functions including stability of chromatin. PolyADP-ribosylation modifies acceptor proteins with a large negatively charged poly(ADP-ribose) (PAR) to greatly change the structure and function of the acceptor proteins. In addition various specific motifs of proteins were recently found to interact non-covalently with PAR thereby changing the spaciotemporal activity of protein-protein interaction in cells. However, the structure of PAR to which specific protein motifs should bind is not fully characterized. The present work will review the structure, physicochemical properties and quantification of PAR in vivo, with special reference to PAR binding protein modules.

PolyADP-ribosylation is mediated by poly(ADP-ribose) (PAR) polymerases (PARPs) and may be involved in various cellular events, including chromosomal stability, DNA repair, transcription, cell death, and differentiation. The physiological level of PAR is difficult to determine in intact cells because of the rapid synthesis of PAR by PARPs and the breakdown of PAR by PAR-degrading enzymes, including poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3. Artifactual synthesis and/or degradation of PAR likely occurs during lysis of cells in culture. We developed a sensitive enzyme-linked immunosorbent assay (ELISA) to measure the physiological levels of PAR in cultured cells. We immediately inactivated enzymes that catalyze the synthesis and degradation of PAR. We validated that trichloroacetic acid is suitable for inactivating PARPs, PARG, and other enzymes involved in metabolizing PAR in cultured cells during cell lysis. The PAR level in cells harvested with the standard radioimmunoprecipitation assay buffer was increased by 450-fold compared with trichloroacetic acid for lysis, presumably because of activation of PARPs by DNA damage that occurred during cell lysis. This ELISA can be used to analyze the biological functions of polyADP-ribosylation under various physiological conditions in cultured cells.

Adult T-cell leukemia and human T-cell leukemia virus type 1 (HTLV-1) - associated myelopathy/tropical spastic paraparesis, which develop after HTLV-1 infection, are difficult to cure. In particular, the mode of HTLV-1 propagation is not well understood. Poly (ADP-ribose) polymerase-1 is reported to be a co-activator of HTLV-1 Tax protein; however, the effects of polyADP-ribosylation on infectivity of HTLV-1 have not been fully clarified. We studied the effects of a PARP inhibitor on two modes of HTLV-1 transmission: through cell adhesion between MT-2 cells (an HTLV-1-infected cell line) and uninfected cells and through virus particles produced by HTLV-1-producing c77 cells. Although the PARP inhibitor decreased HTLV-1 infection through cell adhesion, it increased HTLV-1 infection through virion production and caused apoptosis of HTLV-1-infected cells. Thus, careful consideration is required for clinical application of PARP inhibitors in HTLV-1 patients.

The purpose of this study was to examine the relationship between the zinc nutritional status and the factors associated with serum zinc concentration in the elderly patients in two nursing facilities: body mass index (BMI), the level of care, the grade of bedriddenness, and the grade of cognitive function. The estimations of the hematological constituents, physical index, and dietary survey were made based on the examination carried out of the 26 disabled elderly patients (male 6, female 20, mean age 90±6 y). The results obtained from this study can be summarized as follows: 1) The low activities of daily living (ADL) group showed a low level of serum zinc concentration, although the uptake rate of zinc by subjects was shown to be high when compared to the Dietary Reference Intakes 2010. 2) The high ADL group showed a high level of serum zinc concentration. 3) The results of multiple regression analysis among the serum zinc concentration, the determined serum ingredients, and the physical characteristics showed the significant correlation of serum zinc concentration against the BMI, the level of care, height, Alb and iron values. 4) The BMI, the level of care, the grade of bedriddenness, and the grade of cognitive function of the subjects changed according to the zinc nutritional status. These results suggested that the actual requirements of zinc of the subjects were different according to the BMI, the level of care, the grade of bedriddenness, and the grade of cognitive function.

Poly (ADP-ribose) (PAR) is rapidly synthesized by PAR polymerases (PARPs) upon activation by DNA single- and double-strand breaks. In this study, we examined the quantitative amount of PAR in HeLa cells cultured within the physiological temperatures below 41 °C for verification of the effect of shifting-up or -down the temperature from 37.0 °C on the DNA breaks, whether the temperature-shift caused breaks that could be monitored by the level of PAR. While PAR level did not change significantly when HeLa cells were cultured at 33.5 °C or 37.0 °C, it was significantly increased 2- and 3-fold when cells were cultured for 12 h and 24 h, respectively, at 40.5 °C as compared to 37.0 °C. Similar to the results with HeLa cells, PAR level was increased 2-fold in CHO-K1 cells cultured at 40.5 °C for 24 h as compared to 37.0 °C. As the cellular levels of PAR polymerase1 (PARP1) and PAR glycohydrolase (PARG), a major degradation enzyme for PAR, did not seem to change significantly, this increase could be caused by activation of PARP1 by DNA strand breaks. In fact, γH2AX, claimed to be a marker of DNA double-strand breaks, was found in cell extracts of HeLa cells and CHO-K1 cells at elevated temperature vs. 37.0 °C, and these γH2AX signals were intensified in the presence of 3-aminobenzamide, a PARP inhibitor. The γH2AX immunohistochemistry results in HeLa cells were consistent with Western blot analyses. In HeLa cells, proliferation was significantly suppressed at 40.5 °C in 72 h-continuous cultures and decreased viabilities were also observed after 24-72 h at 40.5 °C. Flow cytometric analyses showed that the HeLa cells were arrested at G2/M after temperature shift-up to 40.5 °C. These physiological changes were potentiated in the presence of 3-aminobenzamide. Decrease in growth rates, increased cytotoxicity and G2/M arrest, were associated with the temperature-shift to 40.5 °C and are indirect evidence of DNA breaks. In addition to γH2AX, PAR could be a sensitive marker for DNA single- and double-strand breaks. These two molecular markers provide evidence of physiological changes occurring within cells.

PolyADP-ribosylation is a post-translational modification that plays key roles in cellular physiological functions and DNA damage responses. PolyADP-ribosylation is finely and dynamically regulated by various enzymes and factors involved in the synthesis and degradation of poly(ADP-ribose) (PAR). To better understand the function of polyADP-ribosylation, it is necessary to quantify and monitor the change of the in vivo level of PAR, the product of polyADP-ribosylation, which is rapidly turning over and kept in quite low level in cells or in organs. Recent developments of potent inhibitors of polyADP-ribosylation is expected to kill BRCA1/2-mutated breast cancer cells and ovarian cancer cells (synthetic lethality). To know the efficacy of these inhibitors in vivo, it is necessary to develop highly sensitive and reproducible methods to know PAR levels within cells or organs. However there have been several difficulties in measuring the physiologically low level of PAR without artefacts. Our experiments recently clarified that the method of sample preparation is very important in addition to the sensitivity and specificity. From reviewing the literature, including ours, we would like to emphasize the importance of the procedures of sample preparation for the assay, in addition to the sensitivity by comparing the reported PAR levels in vivo.

70歳女子の嚢胞内出血を来した孤立性非寄生虫性肝嚢胞の1例を報告した.本例は甲状腺機能亢進症で入院中何ら誘因なく激しい腹痛を来し,心窩部に手拳大の表面平滑な腫瘤を触れた.肝機能検査ではアルカリフォスファターゼ及びLDH値が異常高値であったが,血清ビリルビン及びトランスアミナーゼ値などは正常であった.超音波検査,肝シンチグラフィー,腹腔動脈造影及び腹腔鏡検査により孤立性肝嚢胞と診断され,またOchterlony法による寄生蠕虫血清検査は陰性で色虫性嚢胞は否定された.腹痛が持続するため肝左葉外側区域切除術により嚢胞を摘除した.嚢胞壁内面には凝血塊が附着し,嚢胞内容液は黄褐色で沈渣に赤血球が多数認められ,またその成分は血清のそれとほぼ同じであった.組織学的には嚢胞壁は厚いcollagen bandで形成され,一部小胆管の増生もみられ,出血が著明であった.嚢胞の内腔面はやや圧排されたbrush borderを有する一層の円柱上皮から成っていた.

長崎・赤沼により開発された酵素法によるレシチンコレステロールアシルトランスフェラーゼ(LCAT)活性の測定を96例の肝・胆道疾患患者について行なった.正常人24名のLCAT活性は80.7±20.59単位(nmole/ml/hr)であり,肝硬変,肝癌,悪性胆道閉塞で低値を示した.肝硬変ではLCAT値はおおむね40単位以下で慢性肝炎ではそれ以上の値を示し両者の鑑別が可能であった.LCAT活性は血清コリンエステラーゼ,アルプミン,R15 ICG,ビリルビンおよびアルカリホスファターゼと相関し,肝細胞障害や胆道閉塞の診断に有用であると考えられた.LCAT値の経時的変化を各疾患別に観察した結果,急性肝炎では回復期にはいるとともにLCAT活性も上昇しトランスアミナーゼと逆相関を示した.慢性肝炎や肝硬変では変動が乏しく,肝癌では経過とともにLCAT値は低下した.LCAT値は赤血球最大滲透圧抵抗とも相関し,赤血球膜コレステロールの増加とLCAT活性の低下の間に関連のあることが示唆された.