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Novel neplanocin A derivatives have been identified as potent and selective inhibitors of hepatitis B virus (HBV) replication in vitro. These include (1S,2R,5R)-5-(5-bromo-4-methyl-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol (AR-II-04-26) and (1S,2R,5R)-5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-(hydroxylmethyl)cyclopent-3-ene-1,2-diol (MK-III-02-03). The 50% effective concentrations of AR-II-04-26 and MK-III-02-03 were 0.77 ± 0.23 and 0.83 ± 0.36 μM in HepG2.2.15.7 cells, respectively. These compounds reduced intracellular HBV RNA levels in HepG2.2.15.7 cells and infected primary human hepatocytes. Accordingly, they could reduce HBs and HBe antigen production in the culture supernatants, which was not observed with clinically approved anti-HBV nucleosides and nucleotides (reverse transcriptase inhibitors). The neplanocin A derivatives also inhibited HBV RNA derived from cccDNA. In addition, unlike neplanocin A itself, the compounds did not inhibit S-adenosyl-l-homocysteine hydrolase activity. Thus, it appears that the mechanism of action of AR-II-04-26 and MK-III-02-03 differs from that of the clinically approved anti-HBV agents. Although their exact mechanism (target molecule) remains to be elucidated, the novel neplanocin A derivatives are considered promising candidate drugs for inhibition of HBV replication.

Modified carbocyclic nucleosides (4a–g) constituting 7-deazapurine, 4′-methyl, exocyclic double bond and 2′,3′-hydroxy were synthesized. NOE and X-ray studies of 4c confirmed the α-configuration of 4′-methyl. The anti-HBV assay demonstrated 4e (IC(50) = 3.4 μM) without notable cytotoxicity (CC(50) = 87.5 μM) as a promising lead for future exploration.

The current antiretroviral therapy cannot cure the patients infected with human immunodeficiency virus type 1 (HIV-1) due to the existence of latently infected cells capable of virus production from harboring proviral DNA. MazF is an ACA nucleotide sequence-specific endoribonuclease derived from Escherichia coli. The conditional expression of MazF by binding of HIV-1 Tat to the promoter region of a MazF-expression vector has previously been shown to selectively inhibit HIV-1 replication in acutely infected cells. The expression of MazF significantly suppressed tumor necrosis factor (TNF)-α-induced HIV-1 production and viral RNA expression in the HIV-1 latently infected cell line OM-10.1 transduced with the MazF-expression vector (OM-10.1/MFR). Moreover, the viability of OM-10.1/MFR cells decreased with increasing concentrations of TNF-α, whereas such decrease was not observed for HL-60 cells transduced with the MazF-expression vector (HL-60/MFR), the uninfected parental cell line of OM-10.1. TNF-α increased the expression of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase in OM-10.1/MFR cells, indicating that the cell death was caused by the induction of apoptosis. TNF-α-induced expression of MazF mRNA was detected in OM-10.1/MFR but not HL-60/MFR cells, suggesting that TNF-α-induced apoptosis of latently infected cells was due to the expression of MazF. Thus, the anti-HIV-1 gene therapy using the MazF-expression vector may have potential for the cure of HIV-1 infection in combination with suitable latency reversing agents through reducing the size of latently infected cells without viral reactivation.

Galectin-3 (Gal-3) is involved in many biological processes and pathogenesis of diseases in part through nuclear factor (NF)-κB activation. We demonstrated that Gal-3 expression was significantly induced by tumor necrosis factor (TNF)-α or phorbol 12-myristate 13-acetate in OM-10.1 and ACH-2 cells, which are considered as a model of HIV-1 latently infected cells. The expression of Gal-3 was also associated with their viral production. However, the induction of Gal-3 by TNF-α was not observed in their uninfected parental cells. Knockdown of Gal-3 resulted in the suppression of NF-κB activation and HIV-1 replication in the latently infected cells. The expression level of Gal-3 was highly correlated with that of HIV-1 Tat in the latently infected cells stimulated with TNF-α. Furthermore, colocalization and possible interaction of Gal-3 and Tat were observed in the stimulated cells. These results suggent that Gal-3 expression is closely correlated with HIV-1 expression in latently infected cells through NF-κB activation and the interaction with Tat.

Background/aim Adult T-cell leukemia (ATL) is a hematological malignancy caused by infection with human T-cell leukemia virus type 1 (HTLV-1). Chemotherapy, antibody therapy, and bone marrow transplantation are used to treat this disease, however, median survival time has not been significantly improved. Our aim was to develop and evaluate a novel antibody-drug conjugate (ADC) with regards to cell cytotoxicity and target specificity. Materials and methods In this study, we have constructed a novel ADC, which is composed of an anti-CD70 single chain Fv-Fc antibody conjugated with the anticancer agent emtansine using a novel antibody modification method. Cell cytotoxicity and target specificity were assessed using a cell proliferation assay. Results The anti-CD70 ADC selectively killed HTLV-1-infected cells and ATL cells without affecting other cells. Conclusion The anti-CD70 ADC offers some chemotherapeutic potential for the treatment of ATL.

We report a case of a dialysis patient with severe aortic stenosis(AS) along with bilateral pheochromocytomas. A 52-year-old man presented with syncope and was diagnosed with severe AS. Although aortic valve replacement(AVR) was scheduled, bilateral pheochromocytomas were found during preoperative examination. There was a high possibility of developing hemodynamical crisis during AVR, and we planned to perform adrenalectomy prior to AVR. To avoid circulatory collapse just after adrenalectomy, balloon aortic valvuloplasty (BAV) was performed beforehand. Two weeks after the adrenalectomy, AVR was performed in a stable condition.

Chronic hepatitis B virus (HBV) infection is currently treated with nucleoside/nucleotides analogs. They are potent inhibitors of HBV DNA polymerase, which also functions as reverse transcriptase. Although nucleoside/nucleotide analogs efficiently suppress HBV replication in liver cells, they cannot eradicate HBV DNA from liver cells and cure the disease. Therefore, it is still mandatory to identify and develop effective inhibitors that target a step other than reverse transcription in the viral replication cycle. HBV capsid assembly is a critical step for viral replication and an attractive target for inhibition of HBV replication. We conducted in silico screening of compounds expected to bind to the HBV capsid dimer-dimer interaction site. The selected compounds were further examined for their anti-HBV activity in vitro. Among the test compounds, novel pyrimidotriazine derivatives were found to be selective inhibitors of HBV replication in HepG2.2.15.7 cells. Among the compounds, 2-[(2,3-dichlorophenyl)amino]-4-(4-tert-butylphenyl)-8-methyl-4H,9H-pyrimido[1,2-a][1,3,5]triazin-6-one was the most active against HBV replication. Studies on its mechanism of action revealed that the compound interfered with HBV capsid assembly determined by a cell-free capsid assembly system. Thus, the pyrimidotriazine derivatives are considered to be potential leads for novel HBV capsid assembly inhibitors.

Background: Hepatitis C virus (HCV) infection became curable because of the development of direct acting antivirals (DAAs). However, the high cost of DAAs has greatly impeded their potential impact on the treatment of HCV infection. As a result, hepatitis C will continue to cause substantial morbidity, and mortality among chronically infected individuals in low and middle income countries. Thus, urgent need exists for developing cheaper drugs available to hepatitis C patients in these countries. Materials and Methods: Alpha-zam, an indigenous herbal formulation from Nigella sativa seed, was examined for its anti-HCV activity and cytotoxicity in genotype 1b HCV replicon cells. The antiviral activity was determined by luciferase expression and viral RNA synthesis, while the cytotoxicity was assessed by viable cell number and glyceraldehyde-3-phosphate dehydrogenase RNA synthesis in the replicon cells. Results: Alpha-zam was found to be a selective inhibitor of HCV replication. The 50% effective dilution and 50% cytotoxic dilution of Alpha-zam were 761- and < 100-fold, respectively, in the subgenomic replicon cells LucNeo#2. Its selective inhibition of HCV was also confirmed by HCV RNA levels in LucNeo#2 and in the full-genome HCV replicon cells NNC#2 using real-time reverse transcriptase polymerase chain reaction. Furthermore, the anti-HCV activity of Alpha-zam was not due to the induction of interferon. Conclusion: Alpha-zam selectively inhibits HCV replication and therefore has potential for a novel antiviral agent against HCV infection.

The potential antiviral activity of aristeromycin type of derivatives (I) is limited by associated toxicity due to its possible 5'-O-phosphorylation and S-adenosyl-l-homocysteine hydrolase (SAHase) inhibitory activity. Aristeromycin structure has major pharmacophoric motif as 5'-OH and adenosine base, which may have significant role in enzyme binding followed by activity and or toxicity. Thus, the structural optimization to alter this major motif by replacing with its bioisostere and changing the 5'-O conformation through stereochemistry reversal was of interest. Thus, the inverted stereochemistry at 4'-position coupled with bioisostere of adenosine base in the target compounds (6-7) to access antiviral potential. The stereoselective formation of a key stereoisomer (2a) was achieved exclusively from neplanocin sugar (1a) by reduction in a single step. The novel target molecules (6-7) were synthesized in 4 steps with 55-62% yield. Compound 6 was analyzed by single crystal X-ray diffraction, which confirms the stereoselective formation of α-analogs with highly puckered cyclopentane ring and 2'-endo conformation. The compound 6 shown significant anti-hepatitis B virus activity of 6.5μM with CC50>100μM and yielded a promising lead with novel structural feature.

The present study includes the exploration of new possible nucleoside mimetics based on 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine carbocyclic nucleosides (4a-g), which were synthesized by 10-15 synthetic steps and characterized adequately. We report the anti-HCV activities and cytotoxicities of 4a-g. Compound 4a was analyzed by single crystal X-ray diffraction which showed some puckering in the cyclopentene ring with a 2'-endo conformation and anti-base disposition (χ = -125.7°).

Ebola virus disease is a severe disease caused by highly pathogenic Ebolaviruses. Although it shows a high mortality rate in humans, currently there is no licensed therapeutic. During the recent epidemic in West Africa, it was demonstrated that administration of antimalarial medication containing amodiaquine significantly lowered mortality rate of patients infected with the virus. Here, in order to improve its antiviral activity, a series of amodiaquine derivatives were synthesized and tested for Ebola virus infection. We found that multiple compounds were more potent than amodiaquine. The structure-activity relationship analysis revealed that the two independent parts, which are the alkyl chains extending from the aminomethyl group and a halogen bonded to the quinoline ring, were keys for enhancing antiviral potency without increasing toxicity. When these modifications were combined, the antiviral efficacy could be further improved with the selectivity indexes being over 10-times higher than amodiaquine. Mechanistic evaluation demonstrated that the potent derivatives blocked host cell entry of Ebola virus, like the parental amodiaquine. Taken together, our work identified novel potent amodiaquine derivatives, which will aid in further development of effective antiviral therapeutics.

Background The novel phenanthridinone derivative HA-719 has recently been identified as a highly potent and selective inhibitor of hepatitis C virus replication. To elucidate its mechanism of inhibition, we have isolated and analyzed a clone of hepatitis C virus replicon cells resistant to HA-719. Methods To isolate HA-719-resistant replicon cells, Huh-7 cells containing subgenomic hepatitis C virus replicons (genotype 1b) with a luciferase reporter (LucNeo#2) were cultured in the presence of G418 and escalating concentrations of HA-719. After several passages, total RNA was extracted from the growing cells, and Huh-7 cells were transfected with the extracted RNA. Limiting dilution of the transfected cells was performed to obtain an HA-719-resistant clone. Results The 50% effective concentration (EC50) of HA-719 for hepatitis C virus replication was 0.058 ± 0.012 µM in LucNeo#2 cells. The replicon cells capable of growing in the presence of G418 and 3 µM HA-719 were obtained after 18 passages (72 days). The HA-719-resistant clone LucNeo719R showed 98.3-fold resistant to the compound (EC50 = 5.66 ± 0.92 µM), but the clone had no cross-resistance to telaprevir (NS3 inhibitor), daclatasvir (NS5A inhibitor), and VX-222 (NS5B inhibitor). The sequence analysis for the wild-type and LucNeo719R identified 3, 2 and 7 mutations in NS3/4 A, NS4B, and NS5A, respectively, but no mutations in NS5B. Conclusion None of the amino acid mutations in the resistant clone corresponds to those reported to confer drug-resistance to current anti-hepatitis C virus agents, suggesting that the target of HA-719 for hepatitis C virus inhibition differs from those of the existing agents.

Aims Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease. SFTS is epidemic in Asia, and its fatality rate is around 30% in Japan. The causative virus severe fever with thrombocytopenia syndrome virus (SFTSV) is a phlebovirus of the family Phenuiviridae (the order Bunyavirales). Although effective treatments are required, there are no antiviral agents currently approved for clinical use. Ribavirin and favipiravir were examined for their anti-SFTSV activity and found to be selective inhibitors of SFTSV replication in vitro. However, their activity was not sufficient. Therefore, it is mandatory to identify novel compounds active against SFTSV. To this end, we have established a safe and rapid assay system for screening selective inhibitors of SFTSV. Methods The virus was isolated from SFTS patients treated in Kagoshima University Hospital. Vero cells were infected with SFTSV and incubated in the presence of various concentrations of test compounds. After three days, the cells were examined for their intracellular viral RNA levels by real-time reverse transcription-PCR without extracting viral RNA. The cytotoxicity of test compounds was determined by a tetrazolium dye method. Results Among the test compounds, the antimalarial agent amodiaquine was identified as a selective inhibitor of SFTSV replication. Its 50% effective concentration (EC50) and cytotoxic concentration (CC50) were 19.1 ± 5.1 and >100 µM, respectively. The EC50 value of amodiaquine was comparable to those of ribavirin and favipiravir. Conclusion Amodiaquine is considered to be a promising lead of novel anti-SFTSV agents, and evaluating the anti-SFTSV activity of its derivatives is in progress.

Purpose: To achieve good outcomes during aortic surgery with circulatory arrest, a secure and non-bleeding anastomosis must be achieved rapidly to ensure brain protection. We report our initial experiences with a modified Branched Graft Inverting (BGI) technique using an inserter under mild hypothermia. We aimed to reduce the surgical duration and to prevent unnecessary damage to the fragile aorta. Methods: We retrospectively reviewed patients with type A acute aortic dissection (AAD) who underwent distal anastomosis via the modified BGI technique using an inserter between January 2012 and March 2013. Open distal anastomosis was performed under mild hypothermia with right hemisphere perfusion from the right axillary artery. Results: Eight patients were enrolled. There was no mortality. Circulatory arrest time was reproducibly 20.3 ± 1.9 min, which was sufficient to complete non-bleeding distal anastomoses. The average rectal temperature during circulatory arrest was 26.5℃ ± 1.9℃. All patients were extubated the day after the operation without any neurological deficit. Conclusion: The modified BGI technique employing an inserter and mild hypothermia offered easy, secure, and reproducible distal anastomosis for ascending aortic replacement for type A acute aortic dissection. Our outcomes were favorable and support further development of this technique.

Cepharanthine (CEP) is a biscoclaurine amphipathic alkaloid isolated from the plant Stephania cepharantha Hayata. Although the effects of CEP on several types of cells have been investigated, those on dendritic cells (DCs) are poorly understood.To investigate the effect of CEP on the induction of apoptosis in murine DCs.The induction of Annexin V/propidium iodide-positive cells and permeability of mitochondrial membrane potential were evaluated in DCs treated with CEP. Cell-associated caspase activity and DNA fragmentation were analyzed by Dual Sensor: MitoCasp™ and agarose gel electrophoresis, respectively.The number of dead cells was increased by CEP treatment at concentrations more than 10 μg/ml. Flow cytometric analysis revealed that the cell death was found to be apoptosis, CEP treatment reduced mitochondrial membrane potential and upregulated the level of cleaved caspases, including caspase-9 and caspase-3/7, in a dose-dependent fashion. Furthermore, DNA fragmentation was observed in CEP-treated DCs.CEP is capable of inducing apoptosis and may be a potential agent against DC-mediated and allergic diseases.

症例1は78歳女性，1984年に生体弁で僧帽弁置換を施行しているが，生体弁機能不全のため1997年にMosaic弁29 mmで僧帽弁再置換術が施行された．その後2005年より労作時呼吸苦が出現，心雑音も聞かれた．エコーでMRが進行しており，再々手術を施行した．摘出したMosaic弁は，一つのcommissureがステントポストからはずれる，commissural dehiscenceの状態になっており，周囲の石灰化も伴っていた．症例2は70歳男性で，1986年に生体弁で僧帽弁置換，1997年にやはり生体弁機能不全にて，Mosaic 29 mmで再置換を行った．2005年より新たな心雑音を認め，重度のMRを生じていたため，再々手術を行った．摘出した弁は，ステント付近の弁尖に亀裂が生じ，これによりMRを生じていた．Mosaic弁は第3世代の生体弁として，良好な中長期成績が報告されているブタ弁であるが，今回の2症例については，いずれもわずか7年余りで，構造的劣化のため再手術となった．明らかな原因は不明であるが，年齢から予想される生体弁の寿命よりもかなり短い期間での再手術となったものであり，生体弁の選択時には留意すべき事実であると考えられた．

血管型ベーチェット病はベーチェット病の中で副症状として血管病変を示す疾患である．血管病変は動脈瘤形成，動脈閉塞，静脈閉塞など多彩で，特に動脈瘤の場合は瘤破裂や治療後の再発を認めることから予後不良と言われている．しかしながらベーチェット病の診断基準は臨床症状であるため，原因不明の病態として認識され，放置されてしまう可能性がある．今回我々は多彩な仮性動脈瘤を契機に診断に至った血管型ベーチェット病の2症例を経験したので報告する．症例1は69歳男性，左大腿仮性動脈瘤に対し自家静脈patch術を施行した．その1年後に右深大腿仮性動脈瘤を認め，同動脈結紮術を施行した．症例2は51歳男性，左浅大腿仮性動脈瘤に対して大伏在静脈をinterpositionした．

Graphical abstract, On the basis of our previous study on antiviral agents against the severe acute respiratory syndrome (SARS) coronavirus, a series of nucleoside analogues whose 5′-hydroxyl groups are masked by various protective groups such as carboxylate, sulfonate, and ether were synthesized and evaluated to develop novel anti-hepatitis C virus (HCV) agents. Among these, several 5′-O-masked analogues of 6-chloropurine-2′-deoxyriboside (e.g., 5′-O-benzoyl, 5′-O-p-methoxybenzoyl, and 5′-O-benzyl analogues) were found to exhibit effective anti-HCV activity. In particular, the 5′-O-benzoyl analogue exhibited the highest potency with an EC50 of 6.1 μM in a cell-based HCV replicon assay. Since the 5′-O-unmasked analogue (i.e., 6-chloropurine-2′-deoxyriboside) was not sufficiently potent (EC50 = 47.2 μM), masking of the 5′-hydroxyl group seems to be an effective method for the development of anti-HCV agents. Presently, we hypothesize two roles for the 5′-O-masked analogues: One is the role as an anti-HCV agent by itself, and the other is as a prodrug of its 5′-O-demasked (deprotected) derivative.

Background A new series of 1-aromatic methyl-substituted 3-(3,5-dimethylbenzyl)uracil and N-3,5-dimethylbenzyl-substituted urea derivatives were synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Methods A series of new 6-azido and 6-amino derivatives of 1-substituted-3-(3,5-dimethylbenzyl)uracils were synthesized using our previously reported method, and three acyclic derivatives were synthesized from urea. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicities of the compounds were evaluated using the viability of mock-infected cells. Results Some of these compounds showed good-to-moderate activities against HIV-1 with half maximal effective concentration (EC50) values in the submicromolar or subnanomolar range. Compared with emivirine, compound 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil showed significant anti-HIV-1 activity with an EC50 value of 10 nM and a high selectivity index of 1923. Preliminary structure–activity relationship studies and molecular modeling analyses were carried out to explore the major interactions between HIV-1 reverse transcriptase and the potent inhibitor 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil; these results may be important for further development of this class of compounds as anti-HIV-1 agents. Conclusion The excellent activity of 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil (EC50: 0.010 ± 0.006 µM, SI: >1923) may serve as the basis for conducting further investigations on the behavior of this class of compounds against drug-resistant mutants.

FIT-039 has recently been identified as a novel cyclin-dependent kinase 9 inhibitor with potent antiviral activity against a broad spectrum of DNA viruses, such as herpes simplex virus type 1 (HSV-1) and human cytomegaloviruses. In this study, FIT-039 was examined for its inhibitory effect on human immunodeficiency virus type 1 (HIV-1) replication in chronically infected cells. Its 50% effective concentration was 1.4-2.1μM, irrespective of the cells used for antiviral assays, while its 50% cytotoxic concentration was >20μM, indicating that FIT-039 is a selective inhibitor of HIV-1 replication. FIT-039 also inhibited HIV-1 RNA expression in a dose-dependent fashion. Since previous studies demonstrated that FIT-039 exhibited antiviral efficacy without noticeable adverse effects in HSV-1-infected mice, the compound should be further investigated for its clinical potential against HIV-1 infection.

Background The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an attractive target for the development of drugs used in the treatment of HIV-1 infection and acquired immune deficiency syndrome (AIDS). We have continued the search for novel anti-HIV-1 agents using the structure–activity relationships of the successful 1,3-disubstituted and 1,3,6-trisubstituted uracil-type HIV-1 RT inhibitors. Methods A series of new triazine analogs were synthesized using an established method. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicity of the compounds was evaluated by assessing the viability of mock-infected cells. Results Some of the compounds showed good-to-moderate activities against HIV-1, with half-maximal effective concentrations (EC50) in the submicromolar range. In particular, a dihydro-1-(4-aminobenzyl)triazine analog showed satisfactory anti-HIV-1 activity with an EC50 of 0.110 µM and a selectivity index (SI) of 909. Furthermore, molecular modeling analyses were performed to explore the major interactions between HIV-1 RT and potent inhibitors. These results may be important for further development of this class of compounds as anti-HIV-1 agents. Conclusion The satisfactory anti-HIV-1 activity of triazine analogs may serve as the basis for further investigations of the behavior of this class of compounds against drug-resistant mutants.

Background Exercise intolerance of the hand after harvest of the radial artery is not well understood, although mild reductions of blood flow to the hand are reported. To ascertain its prevalence, patient symptoms implying potential exercise intolerance were evaluated by measuring transcutaneous oxygen pressure of the hand during grip exercise. For ascertaining predictive values, we verified ulnar flow reserve measured by Doppler ultrasonography before the harvest of radial artery. Methods Forty patients whose radial artery was harvested for coronary bypass graft, were interviewed and tested 1 year after operation, and their preoperative ultrasonographic data compared. Results Five patients (12.5%) had mild symptoms implying exercise intolerance. Exercise tests revealed severe decreases in tissue oxygenation in 7 patients (17.5%), but in accordance with symptoms ( p = 0.0018). Tissue oxygenation in the operated hand was lower than in the nonoperated even in asymptomatic patients ( p = 0.0011). Preoperative Doppler echography revealed that ulnar arteries of symptomatic patients were smaller ( p = 0.0019) and carried lower blood flows during manual compression of the radial artery ( p = 0.0004) compared with those of asymptomatic patients. Smaller ulnar arteries (less than 1.4 mm/m 2 ) with poor flow reserves (less than 60 mL · min −1 · m −2 during radial compression) appear to indicate risks for exercise intolerance ( p = 0.0004). Conclusions More than 10% of patients after harvest of radial arteries had mild symptoms implying exercise-intolerance, which accorded with abnormal tissue oxygenation during grip exercise. Work habits of patients should be considered in radial harvest decisions, especially if preoperative Doppler echography indicates lower flow reserves for the ulnar artery.

The following paper describes patch closure (bovine pericardial sheet) of an ostium primum atrial septal defect and mitral valve repair (sutured mitral valve cleft + autologous pericardial annuloplasty + Alfieri’s method) in a 50-year-old man. He had been perfectly well until he was brought to the emergency room because of acute heart failure. Chest radiography revealed right-side heart enlargement. Electrocardiography indicated atrial flutter. Echocardiography revealed a large ostium primum atrial septal defect and moderate mitral regurgitation. The pulmonary-to-systemic blood flow ratio was 3.24. First, cardiologists performed catheter ablation of the cavotricuspid isthmus for atrial flutter. We performed patch closure of an ostium primum atrial septal defect and mitral valve repair after the patient’s heart failure was under control. The patient was discharged 13 days postoperatively in a satisfactory condition without any critical complications.

Objectives: Despite steady improvements, surgery for aortic arch diseas, including the distal arch, continues to result in high rates of morbidity and mortality. We have performed aortic arch repair using a transaortic stented graft implantation into the descending aorta in 8 patients who had true aortic arch aneurysms, and here have reviewed the efficacy and problems from this procedure.Methods: Six patients underwent transaortic stented graft implantation into the descending aorta with bypass to the arch vessels. The other two underwent stented graft implantation into the descending aorta with replacement of the ascending aorta and aortic arch. One patient had a ruptured aneurysm.Results: Each operation was performed via a median sternotomy without left thoracotomy. There was no new postoperative occurrence of left recurrent laryngeal nerve palsy. All the five patients without perioperative neurological complication could be extubated within 24 h after surgery. In each case, postoperative enhanced computed tomography scans showed successful thromboexclusion of the aneurysm. There was no endocleak and no graft migration. One patient suffered cerebral injury. Spinal cord injury occurred in 2 patients, and this serious complication may have been caused by prolonged ischemia in the lower body and the long stented graft.Conclusions: This surgical strategy was effective for arch aneurysm and produced less damage than a conventional procedure to the postoperative respiratory function, while the operative technique need to be improved to decrease the frequency of brain and spinal cord injury.

腹部大動脈瘤(AAA),虚血性心疾患(CAD)両疾患26例に外科的治療を行った.平均年齢72.6±3.7歳,男性21例,女性5例,AAAの平均最大径は58.0±12.7mmであった.11例は一期的手術を,15例は二期的手術を行った.一期的手術群では4例でon pump CABGを,high risk症例3例を含む7例でoff pump CABGを行った.手術死亡はなく,術後急性腎不全,肺炎,呼吸不全を認めた.二期的手術群にも手術死亡なく,1例に急性腎不全を認めた.待機中のAAA破裂はないが,巨大瘤症例2例で切迫破裂により緊急手術を行った.全身状態良好例の一期的手術の治療成績は良好であり,積極的な施行が望ましいと思われた.High risk症例においても,AAA治療に緊急を要する例などでは,off pump CABGを用いた一期的手術は可能と思われた.

A 68-year-old man presented at the outpatient clinic with epigastric discomfort. He had suffered a myocardial infarction 10 years previously. Chest radiography and computed tomography showed a giant calcified aneurysm in the left ventricle. Electrocardiography indicated atrial fibrillation. Echocardiography showed moderate mitral regurgitation and enlarged left atrium. End-diastolic volume and ejection fraction were 164 ml and 31%, respectively. Coronary angiography revealed total occlusion of the left anterior descending artery and diffuse stenosis of the right coronary artery. Aneurysmectomy, mitral annuloplasty, maze procedure, and coronary artery bypass were performed. The patient was discharged 16 days postoperatively in a satisfactory condition without complications.

Objective To determine the incidence, etiology, prognosis, and treatment of vocal cord paralysis (VCP) after surgery for thoracic aortic aneurysm (TAA). Study design Retrospective study performed between 1989 and 1995. Setting Academic, tertiary care, referral medical center. Patients Seventy-one TAA patients underwent surgery at the Kameda Medical Center between 1989 and 1995. Results Sixty-two of 71 patients were examined postoperatively for voice quality. Twenty patients (32%) had hoarseness develop caused by VCP, as confirmed by laryngoscopy. The left recurrent laryngeal nerve had been sacrificed in 1 patient during surgery, but it was preserved in the remaining 19 patients. Unilateral left VCP was noted in 19 patients, and bilateral VCP occurred in 1 patient. The incidence of VCP was higher in those patients who underwent surgery for type I aneurysms (9 of 14 patients, 64%). In 16 of the 19 patients (84%) who received follow-up for > 6 months, vocal cord movement did not return to normal. Surgery to improve voice quality, arytenoid adduction in five patients and intracordal injection in two patients, was performed with success. Conclusions Our results indicate that surgery for TAA is associated with a relatively high incidence of VCP. VCP occurred despite preservation of the recurrent laryngeal nerve, and the paralysis did not show a spontaneous recovery even 6 months after surgery.

Purpose Duodenal obstruction caused by aneurysmal dilatation of the abdominal aorta is a rare clinical entity that is traditionally treated by open aneurysm repair, aneurysmorrhaphy, and duodenal release. We present here the case of aortoduodenal syndrome treated by endovascular therapy. Case Report A 73-year-old man diagnosed simultaneously with sigmoidovesical fistula and an abdominal aortic aneurysm (AAA) underwent resection of the sigmoid colon followed by colostomy. On postoperative day 34, the patient experienced nausea and vomiting. Computed tomography revealed the AAA causing duodenal obstruction by direct compression. We chose endovascular therapy for treating the AAA rather than graft replacement because of the risk of infection by the colostomy orifice. Postoperatively, the patient reacquired the ability to eat. However, postoperative computed tomography revealed that the diameter of the AAA had not changed. Conclusions We considered that the decreased intra-aneurysmal pressure caused a release of duodenal obstruction.

Adult T-cell leukemia (ATL) is caused by infection with human T-cell leukemia virus type-1 (HTLV-1). The tetrahydrotetramethylnaphthalene derivative TMNAA has recently been identified as a selective inhibitor of HTLV-1-infected T-cell lines and adult T-cell leukemia (ATL) cells but not of uninfected T-cell lines and peripheral blood mononuclear cells (PBMCs). In the present study, more than 100 derivatives of TMNAA were synthesized and examined for their inhibitory effects on the proliferation of various T-cell lines and PBMCs. Among the compounds, MN417 is a more potent inhibitor of ATL cells than TMNAA. This compound is a novel phenanthridinone derivative with the tetrahydrotetramethylnaphthalene structure. Interestingly, PN-H and MN314-B, which are also phenanthridinone derivatives but do not have the tetrahydrotetramethylnaphthalene structure, could not distinguish between HTLV-1-infected and uninfected T-cell lines in terms of their anti-proliferative activity. These results suggest that the tetrahydrotetramethylnaphthalene structure is required for the selective inhibition of HTLV-1-infected cells.

The crystalline quality of GaAs and Ge heteroepitaxial films with microscopic charge imbalance and balance at heterointerfaces, grown on vicinal Si(1 1 0) substrates by molecular-beam epitaxy, has been characterized using X-ray diffraction and atomic force microscopy. Effects of microscopic charge balance and imbalance on the initial growth process have been investigated by comparing crystalline properties, such as surface roughness, residual strain, spread of the distribution of atomic interplanar spacing and spread due to mosaic structure, of GaAs films with those of Ge films. On a (1 1 0) substrate miscut 6° towards the [0 0 1] direction, the off-angles of GaAs and Ge films decreased by 0.8° towards the [0 0 1] direction, compared with off-angles of the respective substrates. This reflects an initial step-flow-like growth mode. The crystalline quality of GaAs films on Si(1 1 0) tilted towards [0 0 1] was improved by relaxing the microscopic charge imbalance through a well-controlled initial growth process, such as step-flow-like growth. However, increasing the off-angle does not always improve the crystalline quality of Ge films on vicinal Si(1 1 0), in spite of a microscopically balanced charge at the interface. Moreover, in Ge films on vicinal Si(1 1 0), the strong compressive strain is generated near step edges of the substrate, which is not sufficiently relieved by the thermal tensile strain generated during the cooling process after the growth. Good control of the initial growth process, by means of some relaxation process of microscopic charge imbalance and strain, or charge balance at the heterointerface, was found to be important for improving the crystalline quality of heteroepitaxial films on Si substrates.

An 84-year-old man was transferred to the emergency department for the treatment of shock. His upper body was swollen. Hematoma from the ruptured brachiocephalic artery aneurysm was compressing and obstructing the superior vena cava (SVC). A stent graft was deployed from the brachiocephalic artery to the right common carotid artery, and the proximal right subclavian artery was coil embolized. On postoperative day 5, when his neck swelling subsided and tracheal stenosis seemed resolved, the patient was extubated and the subsequent recovery was uneventful. He was discharged from the hospital on postoperative day 24. Although the stent grafting does not directly decompress the SVC by removing aneurysm and hematoma, it seems to be the treatment option for the morbid patients.

Twelve oxopyranyl-based compounds like (I) are synthesized in three steps from kojic acid in relatively good yields and investigated for their cytotoxicity and anti-HCV activity in subgenomic HCV replicon cells.

Aggressive forms of adult T-cell leukemia (ATL) respond poorly to conventional anticancer chemotherapy, and new lead compounds are required for the development of drugs to treat this fatal disease. Recently, we developed ATL cell-selective proliferation inhibitors based on a tetrahydrotetramethylnaphthalene (TMN) skeleton 1, and here we report the design and synthesis of silicon analogs of TMN derivatives. Among them, compound 13 showed the most potent growth-inhibitory activity towards the ATL cell line S1T, though its selectivity for S1T over the non-ATL cell line MOLT-4 was only moderate. This result, as well as computational studies, suggests that sila-substitution (C/Si exchange) is useful for structure optimization of these inhibitors.

Poly(γ-glutamic acid) (γ-PGA) nanoparticles (NPs) carrying antigens have been shown to induce potent antigen-specific immune responses. However, in vivo delivery of γ-PGA NPs to dendritic cells (DCs), a key regulator of immune responses, still remains unclear. In this study, γ-PGA NPs were examined for their uptake by DCs and subsequent migration from the skin to the regional lymph nodes (LNs) in mice. After subcutaneous injection of fluorescein 5-isothiocyanate (FITC)-labeled NPs or FITC-ovalbumin (OVA)-carrying NPs (FITC-OVA-NPs), DCs migrated from the skin to the LNs and maturated, resulting in the upregulation of the costimulatory molecules CD80 and CD86 and the chemokine receptor CCR7. However, the migrated DCs were not detected in the spleen. FITC-OVA-NPs were found to be taken up by skin-derived CD103+ DCs, and the processed antigen peptides were cross-presented by the major histocompatibility complex (MHC) class I molecule of DCs. Furthermore, significant activation of antigen-specific CD8+ T cells was observed in mice immunized with OVA-carrying NPs (OVA-NPs) but not with OVA alone or OVA with an aluminum adjuvant. The antigen-specific CD8+ T cells were induced within 7 days after immunization with OVA-NPs. Thus, γ-PGA NPs carrying various antigens may have great potential as an antigen-delivery system and vaccine adjuvant in vivo.

The tetrahydrotetramethylnaphthalene derivative TMNAA has recently been identified as a selective inhibitor of human T-lymphotropic virus type 1 (HTLV-1)-infected T-cell lines and adult T-cell leukemia (ATL) cells but not of uninfected T-cell lines and peripheral blood mononuclear cells (PBMCs). Although the target molecule of TMNAA is still unknown, it does not inhibit nuclear factor-κB (NF-κB) activity. Therefore, TMNAA was examined for its inhibitory effect on the cell proliferation in combination with the NF-κB inhibitor cepharanthine. Synergism was observed for the combination, in inhibiting the proliferation of HTLV-1-infected T-cell lines. Although TMNAA alone did not induce the apoptosis of HTLV-1-infected T-cell lines, it strongly enhanced their apoptosis induced by cepharanthine. Thus, TMNAA may have potential as a therapeutic agent against ATL either alone or in combination with cepharanthine, which is clinically used as an anti-inflammatory drug in Japan.

Open heart surgery in patients with liver cirrhosis is considered to be very risky, but the predictors of poor outcomes in such cases have not been established. We report the perioperative results of open heart surgery in patients with liver cirrhosis in our hospital. We reviewed the results of 13 cases in 12 patients with liver cirrhosis who underwent open heart surgery between January 2001 and December 2010. The Child-Turcotte-Pugh classification, the model for end-stage liver disease score, EuroSCORE, and perioperative data were used to identify risk factors for morbidity and mortality retrospectively. Ten patients had postoperative complications. Significant differences in morbidity were evident for Child-Turcotte-Pugh class, cardiopulmonary bypass time, and crossclamp time. Two patients died of liver failure, one at 40 days and the other at 2 years after surgery. Statistically significant differences in liver-related mortality were evident in the model for end-stage liver disease scores and serum cholinesterase levels. We concluded that a high Child-Turcotte-Pugh class was associated with increased morbidity. Cardiopulmonary bypass and crossclamp times were also related to high morbidity, while high model for end-stage liver disease scores and low serum cholinesterase levels predicted liver-related mortality.

A 52-year-old man was referred to our clinic because of chronic heart failure. A Levine 3/6 diastolic heart murmur was audible at the apex. Chest radiography showed an enlarged left ventricle. Transthoracic echocardiography showed moderately severe aortic regurgitation. Left ventricular end-diastolic/systolic diameter and ejection fraction were 75/59 mm and 41 %, respectively. Preoperative transesophageal 3-dimensional echocardiography revealed a quadricuspid aortic valve whose cusps were of almost equal size. Aortic valve replacement was performed via upper partial sternotomy.

Adult T-cell leukemia (ATL) is caused by infection with human T-lymphotropic virus type 1 (HTLV-1). A novel tetramethylnaphthalene derivative, TMNAA, selectively inhibited the proliferation of various HTLV-1-infected cells, including ATL cell lines and peripheral blood mononuclear cells (PBMCs) from ATL patients. In contrast, the proliferation of uninfected cell lines and PBMCs from healthy donors was hardly affected by the compound. Cell-cycle analysis revealed that TMNAA increased the population of the G0/G1 phase and reduced that of the S phase in HTLV-1-infected cells. TMNAA was found to suppress the phosphorylation of retinoblastoma protein and the expression of cyclin-dependent kinase 4 in HTLV-1-infected cells. Furthermore, the inhibition of cell proliferation was partially annihilated by removing the compound. These results indicate that TMNAA exerts selective inhibition of HTLV-1-infected cells through a novel mechanism, presumably modulating cell cycle regulatory proteins associated with the G0/G1 phase.

Dendritic cells (DCs) are specialized antigen presenting cells that connect innate and adaptive immunity. DCs are considered as a major target for controlling excessive immune responses. In this study, the effect of cepharanthine (CEP), a biscoclaurine alkaloid isolated from Stephania cepharantha Hayata, on murine DCs was examined in vitro. CEP inhibited antigen uptake by DCs at a concentration between 1 and 5 μg/ml. Although CEP did not inhibit the expression of costimulatory molecules and major histocompatibility complex (MHC) class I in DCs, the compound inhibited lipopolysaccharide (LPS)-induced DC maturation determined by the expression of costimulatory molecules and MHC class I. In addition, CEP could reduce the production of interleukin-6 and tumor necrosis factor-α in LPS-stimulated DCs. DCs treated with CEP were found to be a poor stimulator of allogeneic T cell proliferation and interferon-γ production from the cells. These results suggest that CEP may have great potential as an immunoregulatory agent against various autoimmune diseases and allergy.

The efficacy of using composite arterial Y-grafts in off-pump coronary artery bypass has not been established. We assessed graft patency, long-term clinical outcomes, and the indications for composite arterial Y-grafting by reviewing 53 patients who underwent primary isolated elective off-pump coronary artery bypass with composite arterial Y-grafts between January 2002 and December 2008. Coronary angiography or 64-slice multidetector computed tomographic coronary angiography was used to assess graft patency. Follow-up raged from 18 to 97 months. The rates of mortality, graft failure, and recurrence of ischemic heart disease were 0%, 22.6%, and 13.2%, respectively. Only 4 (7.5%) patients required additional procedures (percutaneous coronary interventions or repeat surgery) because of graft failure. A significantly higher rate of graft failure was evident when one end of the composite graft was anastomosed to a 75% stenosed branch of a native coronary artery and the other end to a branch with >90% stenosis. The long-term patency of composite arterial Y-grafts in off-pump coronary artery bypass requires proper judgment of the indications.