Coronary artery bypass surgery with arterial grafts in familial hypercholesterolemia

AbstractObjective: Familial hypercholesterolemia is a dominantly inherited disorder caused by mutations at the locus for the low-density lipoprotein receptor and is frequently associated with premature coronary artery disease. This study was performed to determine whether arterial grafting was associated with long-term benefits for patients with familial hypercholesterolemia. Methods: During the past 18 years, 101 patients with heterozygous familial hypercholesterolemia underwent primary coronary artery bypass grafting, with one hospital death. Group 1 patients (n = 31) received only saphenous vein grafts. Group 2A patients (n = 47) received one internal thoracic artery graft and supplemental vein grafts, and group 2B patients (n = 23) had multiple arterial grafts. After operation, all patients received diet therapy and intensive cholesterol-lowering drug therapy. Thirteen patients received low-density lipoprotein apheresis. Results: During a mean follow-up period of 95 months, 8 patients died, 9 underwent reoperation, and 12 received catheter intervention. The overall survival was 82% (95% confidence limits, 65%-97%) at 18 years after operation. The survival in group 2 was higher than that found in group 1 (P = .01). The overall freedom from major cardiac events (myocardial infarction, cardiac death, reoperation, and catheter intervention) was 57% (95% confidence limits, 40%-74%) at 16 years after operation. The freedom from reoperation in group 2 was higher than that found in group 1 (P = .03). There was no difference in the survival or freedom from major cardiac events between groups 2A and 2B. Conclusion: Arterial grafting improved the long-term freedom from reoperation in patients with familial hypercholesterolemia. Additional benefit of multiple arterial grafting could not be identified. (J Thorac Cardiovasc Surg 2000;119:1008-14

進行肺癌に対する術前・術後養子免疫療法に関する基礎的並びに臨床的研究

金沢大学医学部進行肺癌に対する補助療法としての養子免疫療法に関する基礎的ならびに臨床的研究を行った。(1)末梢血リンパ球(PBL)、領域リンパ節リンパ球(RLNL)および腫瘍内浸潤リンパ球(TIL)について、抗腫瘍活性の賦活法について検討した。RLNLおよびTILのNK(Natural Killer)活性は、PBLに比べその活性は有意に低かった。一方、肺癌患者のPBLのILー2産生能は対照群(健康人PBL)と比較して有意に低下しているが、肺癌患者の転移のない領域リンパ節からえたRLNLのILー2産生能は、PBLに比べて有意に亢進していることがわかった。肺癌患者のPBL、転移リンパ節RLNL、非転移リンパ節RLNLおよび切除肺の腫瘍内TILをrILー2と5日間培養すると、細胞傷害活性は著しく増強された。これはLAK細胞の誘導によるものであり、TIL、RLNL、PBLで比較すると、PBLで誘導されるLAK活性が最も高い活性を示した。またこれらPBLーLAK細胞の自己腫瘍細胞に対する細胞傷害活性は、rILー2にマイトマイシン処理した自己腫瘍細胞を添加して培養した場合が最も高く賦活された。モノクロナ-ル抗体を用いてのリンパ球亜群を検索した結果、PBLーLAKの大部分はNK細胞期限であるのに対し、RLNLおよびTILから誘導されるLAK細胞の起源の大部分は(一部はNK細胞由来であっても)細胞傷害性T細胞であることが明らかになった。(2)肺癌患者のPBLを高密度自動細胞培養装置にてrILー2を添加、2〜3週間培養し、回収されたPBLーLAK細胞を患者の気管支動脈内に再注入した。その結果、7例中、PR2例、MR3例と5例に何らかの効果がえられ、2例はNCであった。また癌性胸膜炎患者の胸水より分離したTILをrILー2添加のもとに高密度自動細胞培養装置にて培養し、患者の胸腔内に戻す養子免疫療法を3例に施行し、2例に胸水の消失をみとめた。It appears that lymph node metastases are more frequent in lung cancer than in other cancers due to impaired defensive mechanisms in the regional lymph nodes. However, little is known about the immunological function of Regional Lymph Node Lymphocytes (RLNL) in lung cancer patients. We have studied the immunological properties of RLNL in comparison with Peripheral Blood Lymphocytes (PBL). We measured the Natural Killer (NK) cell activity of RLNL and PBL in lung cancer patients and found that the NK activity was significantly more depressed in the RLNL than in the PBL. In contrast, Inter-Leukin-2 (IL-2) production was markedly higher in the RLNL than in the PBL. The cytotoxic effect of RLNL in non-metastatic lymph nodes on target cells, such as K562 cells, or PC-3 and PC-10 cells (NK-resistant, human lung cancer of adenocarcinoma and epidermoid carcinoma, respectively) was significantly enhanced by in vitro incubation with recombinant IL-2 (rIL-2). Furthermore, we clarified that both rIL-2 and OK-432, which is a biological response modifier and IL-2 inducer as well, augmented the cytotoxicity of RLNL and that these effector cells were lymphokine activated killer (LAK) celis. The depletion of lymphocyte subsets by pretreatment with specific monoclonal antibody showed that the LAK activity in RLNL was mediated by CD3^+ and CD8^+ cells, while the lymphocyte subsets contributing the LAK activity in PBL were CD3^+ and CD16^+ cells. It was concluded that a majority of the effector cells in RLNL were LAK cells of the cytotoxic T-cell population. Thus, therapeutic effects can be expected by LAK cells endogenously induced by regional infusion of OK-432 abd addition of exogenous LAK cells which can be produced in vitro by incubating the patient\u27s lymphocytes with rIL-2. Local AIT through bronchial artery was performed on 7 patients with advanced lung cancer. Some therapeutic effects were noted in 5 (71%) out of 7 patients : partial response in 2, minor response in 3 and no change in 2.As the next step, possibility of adpotive immunotherapy using TIL (Tumor Infiltrating Lymphocyte) was studied Substantial augmentation of the cytotoxic activity against K562, Daudi and autologous tumor cell lines were induced by incubating the TILs with OK-432 or rIL-2, although these enhancement of the cytotoxicity was significantily low in comparison with that of the RLNLs and PBLs. By analysis of lymphocyte subsets, it was clarified that the majority of the TILs were T cells (most of them were CD8^+ cells), whereas B cells, macrophages and NK cells were minority. These tesults strongly indicates that, if not all, some part of cultured TIL contains cytotoxic T lymphocytes which have a specificity against autologous tumor cells. Accordingly, it was thought to be probable that some of the cytotoxic T cells (CTLs) in the TILs might have cytotoxicty against AT cells. Adoptive Immuno-Therapy (AIT) was tried on lung cancer patients with carcinomatous pleurosy. TILs were extracted from pleural effusion, and enhanced by rIL-2. The enhanced TILs with rIL-2 were infused into the thoracic cavity, and subsequently in two out of three cases the pleural effusion disappeared.研究課題/領域番号:01570779, 研究期間(年度):1989 – 1990出典：研究課題「進行肺癌に対する術前・術後養子免疫療法に関する基礎的並びに臨床的研究」課題番号01570779（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-01570779/015707791990kenkyu_seika_hokoku_gaiyo/）を加工して作

Unusual features of fibrillarin cDNA and gene structure in Euglena gracilis: evolutionary conservation of core proteins and structural predictions for methylation-guide box C/D snoRNPs throughout the domain Eucarya

Box C/D ribonucleoprotein (RNP) particles mediate O(2′)-methylation of rRNA and other cellular RNA species. In higher eukaryotic taxa, these RNPs are more complex than their archaeal counterparts, containing four core protein components (Snu13p, Nop56p, Nop58p and fibrillarin) compared with three in Archaea. This increase in complexity raises questions about the evolutionary emergence of the eukaryote-specific proteins and structural conservation in these RNPs throughout the eukaryotic domain. In protists, the primarily unicellular organisms comprising the bulk of eukaryotic diversity, the protein composition of box C/D RNPs has not yet been extensively explored. This study describes the complete gene, cDNA and protein sequences of the fibrillarin homolog from the protozoon Euglena gracilis, the first such information to be obtained for a nucleolus-localized protein in this organism. The E.gracilis fibrillarin gene contains a mixture of intron types exhibiting markedly different sizes. In contrast to most other E.gracilis mRNAs characterized to date, the fibrillarin mRNA lacks a spliced leader (SL) sequence. The predicted fibrillarin protein sequence itself is unusual in that it contains a glycine-lysine (GK)-rich domain at its N-terminus rather than the glycine-arginine-rich (GAR) domain found in most other eukaryotic fibrillarins. In an evolutionarily diverse collection of protists that includes E.gracilis, we have also identified putative homologs of the other core protein components of box C/D RNPs, thereby providing evidence that the protein composition seen in the higher eukaryotic complexes was established very early in eukaryotic cell evolution

Water temperature and precipitation stimulate small-sized Japanese eels to climb a low-height vertical weir

Although river-crossing structures can have a detrimental effect on the movement and distribution of anguillid eels (genus Anguilla), they have inhabited locations upstream of river-crossing structures in many rivers. However, the growth stage in which the eels start to climb river-crossing structures remains unclear. In this study, we directly observed, using infrared video camera systems, that the Japanese eel (Anguilla japonica) climbs a low-height vertical weir as a migratory barrier, confirming the ability of eels to climb over a low-height weir within a river. All eels climbed the weir at night, between sunset and sunrise. We observed that the total length of Japanese eels that climbed the weir ranged from 60 to 140 mm, suggesting that eels inhabiting the upstream area of a weir climbed it when they were small and then lived and grew upstream. Moreover, the general additive model showed considerable effects of water temperature and precipitation on eel climbing, suggesting that water temperature and precipitation are important for its activation. The results of this study also show the effectiveness of infrared video cameras in monitoring eel climbing, which could be applied to monitor fish migratory behavior through fish passages. The findings of this study are useful for the comprehensive management and conservation of wild eel stocks

肺癌悪性度に関する基礎的並びに臨床的研究

金沢大学医学部原発性肺癌切除例を対象に核DNA量,増殖細胞核抗原(PCNA),癌抑制遺伝子p53,核小体形成体AgNORなどを測定評価し,悪性度の指標や生物学的予後因子としての意義について検討した。核DNA量はパラフィン包埋ブロックから得た検体にpropidium iodideによる核染色を行ってフローサイトメトリーにて測定し,DNA-diploid腫瘍(Diploid)とDNA-aneuploid腫瘍(Aneuploid)に分類した。増殖細胞核抗原(PCNA),癌抑制遺伝子p53,核小体形成体AgNORもパラフィン材料を用いて測定した。結果は以下のごとくである。1.核DNA量の測定は原発巣の94.7%で可能であり,原発巣556例の測定の結果,Diploidは165例(29.7%),Aneuploidは391例(70.3%)で,原発巣がDiploidで,かつ,リンパ節転移を認めた症例77例中26例(33.8%)で転移巣にAneuploid細胞の出現を認めた。また,原発巣リンパ節転移巣ともにAneuploidでも,それぞれの最大DNA指標には全く相関を認めなかった。この原発巣転移巣間のDNA ploidy heterogeneityは腺癌でより高率であった。多変量解析の結果,核DNA量は年齢,性,腫瘍径,術後病期,術後TNM因子,組織型,分化度などとは独立した予後因子であり,リンパ節転移陽性例に限定しても転移巣の測定結果も加えることで有用な予後因子となることが示された。2.PCNA標識率やp53蛋白発現陽性率はリンパ節転移陽性例や肺内転移陽性例に有意に高く,予後にも有意差を認めた。また,DNA-aneuploid群をPCNA標識率で分類すると,高標識率群が予後不良である傾向を認めた。3.AgNOR数は腫瘍組織では正常細胞に比し有意に多かったが,臨床病理学的因子との有意な関連は認めなかった。4.これら予後因子の臨床応用の可能性について,手術の補助療法としての化学療法や免疫療法の治療成積をretrospectiveに検討したが,観察期間が短く,今後,prospectiveな研究が必要になるものと判断された。The Cellular DNA contents, labeling index of PCNA, p53 protein expression, and number of AgNORs of lung cancer were studied in 556 resected specimens, and a correlation between the prognoses of the patients and them was evaluated. The cellular DNA contents in 1,901 propidium iodide-stained paraffin-embedded specimens were measured by flow cytometry. PCNA and p53 were also measured by immunochemical staining of paraffin-embedded specimens.Results were as followed.1. When the DNA ploidy in primary tumors was analyzed in 556 cases, 165(29.7%) were classified as having a diploid pattern, whereas 391(70.3%) as aneuploid pattern. Furthermore, when the DNA ploidy in the metastatic sites was measured, 26 out of the 77 cases which had a diploid pattern in the primary sites, showed an aneuploid pattern in the metastatic sites. The maximum DI in the primary tumor did not correlate with that in in the metastatic tumor. These data suggests that a high incidence of heterogeneity between the primary and metastatic tumors exists. This heterogeneity was observed more frequently in adenocarcinoma than in epidermoid carcinoma. Cox\u27s multivariate analyses clarified that DNA ploidy was a significant prognostic parameter.2. PCNA labeling index and p53 protein positive rate of N1-3 cases and M1 cases were significantly higher, and prognoses of the cases with high PCNA-L.I. and p53 protein positive rate were significantly poorer.3. Number of AgNORs of the tumors were higher than that of normal lung tissue. But no correlation was observed between number of AgNORs and clinicopathological factors.研究課題/領域番号:03670654, 研究期間(年度):1991 – 1992出典：研究課題「肺癌悪性度に関する基礎的並びに臨床的研究」課題番号03670654（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-03670654/036706541992kenkyu_seika_hokoku_gaiyo/）を加工して作

冷凍手術による不整脈外科治療の研究

金沢大学医学部研究課題/領域番号:56570466, 研究期間(年度):1981出典：「冷凍手術による不整脈外科治療の研究」研究成果報告書　課題番号56570466（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-56570466/）を加工して作

両側開胸の心肺循環動態に及ぼす変化に関する研究

金沢大学医学部研究課題/領域番号58570559, 研究期間(年度):1983 – 1984出典：研究課題「両側開胸の心肺循環動態に及ぼす変化に関する研究」課題番号58570559（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-58570559/）を加工して作

肺癌におけるリンパ行性進展の発生機構ならびに病態に関する基礎的並びに臨床的研究

金沢大学医学部1.リンパ節転移のないI期肺癌切除例を対象とした多変量解析の結果,腫瘍径および核DNA量が独立した予後因子と判定された.腫瘍径が大きくなるにつれ,また,核DNA量がaneuploidに変化したものでは,リンパ節転移・遠隔転移の可能性が高いことが示された.2.転移陽性縦隔リンパ節のsinus histiocytosis(SH),follicular hyperplasia(FH)の程度は組織型と無関係であったが,腺癌ではSHの程度が高いほど,また,扁平上皮癌ではFHの程度が高いほど予後良好であった.3.活性型MMP-2(マトリックスメタロプロテアーゼ)は癌組織特異的に認め,活性化率はリンパ節転移陽性群において有意に高値であった.MT(膜型)-MMPの癌部における過剰発現を認め,MMP-2活性化率とMT-MMPの発現は相関を示し,基底膜を破壊して転移していく過程が明かとなった.4.腫瘍径が同一の場合,PCNA標識率が高値のものの方が発癌から発見までの期間が短いと考えられ,腺癌ではT1でかつPCNA標識率が高値のものでリンパ節転移を認めなかった.PCNA標識率は腫瘍の動的状態を反映すると考えられ,空間的拡がり(進行度)の指標としてのTNM分類とは独立した因子と考えられた.同じ核DNA量であってもPCNA標識率が異なることがあきらかとなった.PCNA標識率と核DNA量の同時定量的解析は生物学的悪性度の指標として有用であることが示された.5.M109マウス肺癌を用いた進行肺癌治療モデルによる実験的検討では,術前全身化学療法および放射線照射施行群でリンパ節転移や肺転移の減少が見られた.1.Cox\u27s multivariate analysis clarified that DNA ploidy and tumor size were significant prognostic factors of stage-1 lung cancer. DNA aneuploid tumors might have lymphnode micrometastasis and subclinical distant metastasis.2.There was no relationship between the degree of sinus histiocytosis (SH) and follicular hyperplasia (FH) of metastatic lymph nodes, and histological types. But the high SH adenocarcinomas and the high FH squamous cell carcinomas showed favorable prognosis.3.The activated matrix-metalloproteinase (MMP-2) was found specifically in cancer tissue. And its activity in the tumors with lymph node involvement was significantly higher than nodenegative ones. Membranous-type MMP was over-expressed in the tumor tissue, and there was relationship between the activity of MMP2 and the expression of MT-MMP.4.The frequency of lymphnode metastasis correlated positively with tumor size but not with PCNA labeling index (LI) %. There was no lymphnode metastasis when the tumor was less than 30mm in diameter and the PCNA LI% was high. Difference of PCNA LI% were detected even in the same DNA ploidy pattern. The double staining technique of PCNA and DNA contents with FCM provided useful biological parameters in evaluating the malignant potential of lung cancer.5.Experimental study of therapy of advanced lung cancer by M109 mouse model showed that preoperative systemic chemo-and radiation therapy was effective to reduce the number of metastatic lesions to lymphnodes and lungs.研究課題/領域番号:05454382, 研究期間(年度):1993 – 1994出典：研究課題「肺癌におけるリンパ行性進展の発生機構ならびに病態に関する基礎的並びに臨床的研究」課題番号05454382（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-05454382/054543821994kenkyu_seika_hokoku_gaiyo/）を加工して作