Little Father Time, the most troubling character in Thomas Hardy's the Obscure (1895), has been considered by many critics a kind of monster spoiling the whole fabric of the novel. The purpose of this paper is to find out what makes the character strange by analyzing how the novel represents the railway, which frequently appears in the story and transports him to and Sue. Firstly, this paper examines the first part of , in which it is suggested that the extension of railroads is the cause of not only the divorce between signs and things but also the impossibility of sympathy between people in Marygreen. Next, this paper explores the functions of the railway in the main story of the novel. This implies that the story is the contingency of the modern railway system, which has become the center of the city life, decentering everything and making it a wandering sign. Therefore, and Sue cannot share each other's emotions nor be together in perfect union, and neither can reach Christminster, the center of universe for him. Thirdly, this paper argues that having no name except the enigmatical nickname 'Little Father Time' and being regarded as a burden on others, he is the very embodiment of humankind becoming a wandering sign under the modern railway system. Little Father Time cannot be read because he embodies the materiality of signifiers or letters, which undermines signifieds. Finally, this paper proceeds to suggest that Little Father Time is an allegory of the Obscure, which has the epigraph "the letter killeth" and circulates all over the world by steam train or ship.

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Published studies report the incidence of pannus formation with the St. Medical^R prosthetic mitral valve to be 0.02%. The following report details a mitral valve malfunction due to pannus formation and thrombosis in a 70-year-old woman which occurred 16 months after the initial operation (SJM^R 27mm) using Dacron-cuff. A second replacement using a mitral valve prosthesis (SJM^R 27mm) using Teflon-cuff was successfully performed and the postperative course was uneventful. The possibility of pannus formation of St. Medical^R aortic valve and its mechanism are discussed in this report.

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The ionotropic glutamate receptors (iGluRs) form ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the mammalian brain. These receptors play central roles not only in normal neurodevelopmental and neurophysiological processes but also in certain neuropathological processes. Molecular cloning of genes for iGluRs in the past decade has advanced our understanding of the basic properties of iGluRs, such as ion selectivity, ligand binding, and anchoring at synapses. Although the gene for the δ2 glutamate receptor (GluRδ2) was cloned on the basis of homology screening, GluRδ2 has been referred to as an “orphan” receptor because it does not form functional glutamate-gated ion channels. However, ataxia in many types of mice is caused by spontaneous mutation of GluRδ2. Analysis of two such mutants, lurcher and hotfoot, has provided key insights into the GluRδ2 signaling in neurons. Furthermore, characterization of mutant GluRδ2 has revealed unexpected clues to two fundamental features regarding the structure and function of iGluRs gating and assembly. Studies have recently shown that the transmembrane region where the lurcher mutation is located probably plays a crucial role in channel gating. The mechanism that controls iGluR subunit assembly seems to involve the extracellular N-terminal domain where the hotfoot mutation is located. An understanding of mechanisms responsible for gating and assembly is essential for the comprehension of neuronal function and dysfunction. Although reverse genetics is useful in deciphering glutamate signaling, these findings demonstrate the power of classic approaches to forward genetics on mutant mice.

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When Thomas Hardy published the Obscure, it was bitterly criticized by reviewers chiefly for its unconventional discourses on "marriage," "family," and "sexual instinct." Although it is, as critics have agreed unanimously, obvious that an antagonistic attitude to Victorian domestic ideology provoked the reader's antipathy, a more accurate analysis of the socio-cultural context in which was written and read would be needed to clarify what the radicalism of "the marriage question" in the text was. This paper first gives a brief outline of the institution of marriage which was strongly conditioned by social evolutionary theory. This theory identified the patriarchal and monogamous family as one of the most important achievements of evolutionary advance. While evolutionist anthropologists formulated the late Victorian norm of marriage, the 1890s marked a turning point in the interpretation of marriage as a result of the publication of Edyard Westermarck's The History of Human Marriage; it rejected the evolutionist theory of primitive matrimonial anarchy and cast a doubt upon the patriarchal tradition inimical to the idea of sexual equality. Accepting a new historical point of view through which the contemporary institution of marriage loses its historical legitimacy, redefines marriage as a private act whose duration depends only on the couple's will, and also revolts against the evolutionist ideology which, looking on a family as the social unit, coerces people into compulsory monogamy. In the process of analysing matrimonial conventions, the text discloses their exclusive structure and detects that they arise from the desire to monopolize wealth. While symbolizing the historical shift of the idea of "marriage" in the 1890s, attack on the hypocrisy of the middle-class ideology was, we can conclude, premature (only four years after the publication of Westermarck's book) and drew heavy criticism from many readers.

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82症例の弁置換術に計96個(僧帽弁位67個, 大動脈弁位29個)のSt. Medical(SJM)弁を使用した。病院死は僧帽弁置換群5/54例(9.3%), 大動脈弁置換群2/17例(11.8%), 二弁置換群2/13例(15.4%)であった。術後合併症で致死的なものはPerioperative myocardial infarction, 低拍出量症候群, 急性腎不全, 多臓器不全などであった。NYHA機能分類では術後遠隔期にはほぼ全例I一II度と改善し, CTRも全群で低下した。術後早期の血栓塞栓症の発症はなく, 晩期に重篤な脳血栓を1例, 四肢の一過性のしびれを3例に経験し, その発症率は4.1/100患者・年となった。これらの症例は何れも抗凝固療法が不十分であった。術後の溶血を生体弁(Hancock, Carpentier-Edwards)群と比較するとSJM群でやや高い傾向を示したが臨床上問題とはならなかった。prosthetic infectionを2例に併発し再弁置換術を施行した。弁機能不全例は皆無であるが, 最近報告が散見されるので今後も注意深いfollow-upが必要と考える。

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The 2nd Department of Surgery. Nihon University School of Medicine
Since October 1963, artificial valve prosthesis, which is Starr-Edwards, Xenograft and St. Medical valve prosthesis has been used for cardiae valve replacement in a series of valvular disease in our Nihon university hospital.
There is no ideal artificial cardiac valve as the normal human valve. St. Medical valve with their central flow orifice have provided fine valvular functions and, in contrast to other mechanical artificial valvular prosthesis, have caused no significant hemolysis. Lifewise, St. mechanical valves have not caused other abnormal vital reactions.
Therefore, St. Medical valve prosthesis, with its advantage of durability, least hemolysis and hemodynamic quality, may be anticipated to move of salient in the management of valve disorders.

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The valve replacement with St. Medical cardiac valve was undertaken in 20 patients between July, 1978 and October, 1979 (AVR 8, MVR 7, TVR 1, AVR+MVR 2, MVR+TVR 1, AVR+MVR+TVR 1). One patient in AVR died on fifth postoperative day from pulmonary edema, and three patients in MVR died in the hospital from low cardiac output syndrome (two patients) and arrhythmia (one patient). In the eight patients who had postoperative cardiac catheterization, the mean resting cardiac output was 5.48L/min, LV/Ao pressure gradient in the AVR group was not recognized and transvalvar gradient in the MVR was 7.5±4.50mmHg. In the single mitral valve replacement, intraoperative mean left atrial pressure was 24.7±4.21mmHg, and mean pulmonary capillary wedge pressure was 15.5±4.50mmHg in the postoperative cardiac catheterization.
In conclusion, the St. Medical cardiac valve was hemodynamically excellent, but in the single MVR our result was not so good.

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From July 1978 to June 1984, 540 St. Medical valve prostheses were implanted in 462 adult patients. Overall operative mortality was 4.8% (22/462): 5.7% after aortic valve replacement (AVR) (8/140); 3.3% after mitral valve replacement (MVR) (8/244); and 7.7% after aortic and mitral valve replacement (DVR) (6/78). There were 16 late deaths among 440 operative survivors: six (38%) were valve related. The actuarial survival rate at six years was 94.5% in AVR and 93.5% in MVR. At five years it was 91.6% in DVR. The freedom from valve-related death at six years after AVR, MVR and at five years after DVR was 97.8%, 98.6% and 95.8%, respectively. The incidence of valve-related complications (expressed as %/patient-year (number of events)) was as follows: thrombo-embolism (AVR 0.7 (2), MVR 2.0(13), DVR 2.8 (5)), valve thrombosis (AVR 0.3 (1), MVR 0.2 (1), DVR 0 (0)), prosthetic valve endocarditis (AVR 0.3 (1), MVR or DVR 0 (0)). There were no cases of primary structural failure, serious anticoagulant-related hemorrhage or clinical event of hemolysis. The incidence of all valve-related complications in AVR, MVR and DVR was 1.3, 2.2 and 2.8%/pt-yr, respectively. The freedom from thrombo-embolism at six years after AVR and MVR and at five years after DVR were 91.4%, 92.4% and 88.7% respectively. Re-operation was performed in only one patient with MAR because of valve thrombosis (0.2%/pt-yr after MAR, overall 0.1%/pt-yr). These results indicate that St. Medical prosthesis has provided a satisfactory performance with acceptable risks of late complications in patients who were properly anticoagulated during six-year follow-up period.

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Three typical mechanical heart valves (Starr-Edwards, Bjork-Shiley c-c and St. Medical) have been tested in the mitral position under pulsatile flow conditions, The test program included measurements of velocity and turbulent stresses at six downstream locations. The study was carried out using a sophisticated cardiac simulator in conjunction with a highly sensitive two-component laser Doppler anemometer system. The continuous monitoring of parametric time histories revealed useful details about the complex flow and also helped established location and time of the peak parameter values. Based on the experimental data, the following general conclusions can be drawn: (i) all 3 valve designs generated elevated turbulent stresses during acceleration and peak flow phases, presenting a possibility of thromboembolism, and perhaps, hemolysis; (ii) valve configuration and valve orientation significantly affect the flow characteristics; (iii) the Starr-Edwards valve with relatively a small opening area shows lower turbulent stresses; and (iv) the bileaflet design of the St. Medical valve is also associated with lower turbulent stresses, as compared to the Bjork-Shiley c-c valve.

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We have used in vivo murine cancer models to demonstrate the feasibility of ABCG2 inhibition, when coupled with a conventional chemotherapeutic drug, as a strategy to improve therapeutic efficacy for the treatment of both medulloblastoma and acute myeloid leukemia (1,2). We hypothesized that compounds that have the potential to both inhibit ABCG2 and target the pathways activated in cancers would lead to further enhancements in the tumoricidal activity of conventional chemotherapeutics, especially those that are ABCG2 substrates. ABCG2 inhibition was assessed by determining a compound's capability of enhancing the intracellular accumulation of the specific ABCG2 substrate, pheophorbide a. With this robust assay, we performed a high-throughput screen using a library containing ～12,000 bioactive compounds, including FDA-approved drugs. A number of compounds that were previously unreported as ABCG2 inhibitors were identified. Among these was a kinase inhibitor (KI) that inhibited ABCG2 activity with an IC50 < 1 μM. To determine if this KI directly interacted with ABCG2, a membrane protein cellular thermal shift assay (CETSA) was performed. The CETSA studies demonstrated that our inhibitor stabilized and increased the melting temperature of ABCG2, suggesting direct binding of the KI to ABCG2. By using various combinations of the conventional cancer chemotherapeutic drug, mitoxantrone and the KI, an in vitro screen of murine myeloid leukemic cells revealed synergistic cell killing. Based on such promising preliminary results, these studies will be extended to in vivo studies which, may lead to a therapeutic approach that improves treatment response for cancers expressing ABCG2.

This work was supported by NIH and by the ALSAC.

References:

1) Fukuda Y et al. Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis JCI Insight. 2017;2(15):e92409

2) Morfouace M, Cheepala S, Jackson S, Albert YP, Kawauchi D, Shelat A, Fukuda Y, Sorrentino B, Schuetz JD*, Roussel MF*. (*co-corresponding authors) ABCG2 transporter expression impacts Group3 Medulloblastoma response to chemotherapy. Cancer Res Sep 15;75(18):3879-89, 2015

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教室におけるSt. Medical弁(以下、SJM弁)の遠隔成績を検討した。1980年1月より1990年4月までの期間のSJM弁による弁置換術122例を対象とした。大動脈弁置換術(AVR郡)26例、僧帽弁置換術(MVR)郡)75例、大動脈弁僧帽弁両弁置換術(DVR郡)21例であり、早期死亡はAVR郡、MVR郡、DVR郡でそれぞれ23.1%、8.0%、4.8%、であった。早期死亡を除く遠隔期追跡率は99.2%、追跡期間は425患者・年であり、遠隔期生存率は術後8年で各郡それぞれ81±13%、93±3%、63±26%であった。遠隔期合併症は血栓塞栓症2例の他、血栓弁、脳出血、paravalvular leakがそれぞれ1例ずつであり、術後10年における合併症非発生率は89±7%であった。以上より、教室におけるSJM弁置換術の遠隔成績は優秀であった。

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St. Medical(SJM)弁による弁置換術218例の5年間の遠隔成績を中心に検討した。術後30日以内の早期死亡率は10.6%, 晩期死亡率は9.7%であった。早期死を含めた術後5年目の累積生存率は79.2%であった。累積追跡期間454.5年, 平均2.1年の間の血栓塞栓症(TE)の発生率は2.6/100患者・年, prosthetic valve endocarditis(PVE)の発生率は0.7/100患者・年であった。primary mechanical failureはみられなかったが, 血栓弁1例, paravalvular leakage 1例を認めた。弁自体に起因すると思われる高度溶血が5例みられ, 弁に関係した合併症の発生率は4.8/100患者・年であった。術後の血行動態, 耐久性はほぼ満足しうるものであったが, TEの予防のため術後早期からの厳重な抗凝固療法が不可欠で, PVE, 溶血などに注意した厳重なfollow-upが必要と考えられた。

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症例は47歳女性.肺動脈弁閉鎖不全,冠状動脈肺動脈瘻にて肺動脈弁置換(SJM25A) および瘻閉鎖を施行した.術後約14日目頃から収縮期および拡張期雑音を聴取するようになり,弁透視で弁葉の動きが制限されていることが判明した.弁葉の可動制限の経時的変化などから血栓弁による人工弁機能不全と診断し,救急手術準備下でカテーテルによる血栓除去術を試みた.結局バーマンカテーテルの先端を弁葉の横に置き,バルーンパンピングを繰り返すことによって弁の動きが改善した.操作直前,直後にウロキナーゼ60万単位を肺動脈内に投与し,以後1週間にわたり連日30万単位のウロキナーゼを点滴静注した.ウロキナーゼ投与後の弁透視で弁葉の動きは完全に回復し,元気に退院した.右心系の血栓弁には,救急手術準備下にバルーンカテーテルによる血栓除去術とウロキナーゼ大量療法を試みる価値があると思われる.

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