[Successful Atrial Plication in Improving Respiratory Failure due to Bilateral Giant Atria].

Giant atria may trigger respiratory failure, which often requires surgical intervention. We report a patient who presented with respiratory failure due to bilateral giant atria. The patient was a 75-year-old woman with rheumatic heart disease. She had undergone mitral valve replacement and tricuspid annuloplasty at another hospital 17 years ago but recently developed respiratory dysfunction. Compression to the lungs by enlarged atria was diagnosed as the main cause of respiratory dysfunction. Hence, the anterior-to-posterior left atrial wall was plicated by para-annular and superior-half plication, respectively, and the right atrial wall was excised into an ellipse shape. Tricuspid valvuloplasty was performed on four sets of eight artificial chordae with CV5 sutures and an annuloplasty ring. Respiratory failure was alleviated after the surgery.

Open surgical treatment of superior vena cava syndrome due to invasive thymoma.

Here we describe a case of open surgery for superior vena cava syndrome due to invasive thymoma. An 85-year-old woman presented with facial swelling and exertional dyspnea. Computed axial tomography revealed a thymoma in the mediastinum, extending to the superior vena cava, right atrium, and bilateral brachiocephalic veins. Endovascular therapy did not seem feasible because superior vena cava appeared totally occluded, and stenting could cause tumor embolism to the pulmonary arteries. Open surgery facilitated macroscopically complete and successful tumor resection. If long-term survival seems possible, open surgery could be a viable treatment option for superior vena cava syndrome that is ineligible for endovascular therapy.

A case of freestyle valve reoperation 23 years after the first operation.

We present a case of redo stentless valve operation in a 73-year-old man who underwent aortic valve replacement via the subcoronary approach with a freestyle aortic bioprosthesis 23 years ago at our institution. He was referred for surgery because an echocardiogram showed severe aortic regurgitation due to structural valve deterioration, and aortic valve replacement was planned. Severe circumferential calcification and adhesion were noted during the surgery between the freestyle and native roots. Redo-aortic valve replacement was successful despite the technical difficulty. In stentless valve reoperations following aortic valve replacement via the subcoronary method, the planning of valve-in-valve transcatheter aortic valve implantation and sutureless valve implantation may be a practical and safe strategy.

Novel Neplanocin A Derivatives as Selective Inhibitors of Hepatitis B Virus with a Unique Mechanism of Action.

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.

Induction of E. coli-derived endonuclease MazF suppresses HIV-1 production and causes apoptosis in latently infected cells.

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.

Novel Anti-CD70 Antibody Drug Conjugate for the Treatment of Adult T-Cell Leukemia (ATL).

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.

[Surgical Treatment of Aortic Stenosis Combined with Bilateral Pheochromocytomas in a Dialysis Patient].

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.

Pyrimidotriazine derivatives as selective inhibitors of HBV capsid assembly.

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.

Galectin-3 is involved in HIV-1 expression through NF-κB activation and associated with Tat in latently infected cells.

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.

Synthesis and anti-HBV activity of α-stereoisomer of aristeromycin based analogs.

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.

Synthesis and Anti-HCV Activity of 4-Methoxy-7H-Pyrrolo[2,3-d] Pyrimidine Carbocyclic Nucleosides.

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°).

Endovascular Treatment of Aortoduodenal Syndrome.

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.

Identification of Antiviral Agents Targeting Hepatitis B Virus Promoter from Extracts of Indonesian Marine Organisms by a Novel Cell-Based Screening Assay.

The current treatments of chronic hepatitis B (CHB) face a limited choice of vaccine, antibody and antiviral agents. The development of additional antiviral agents is still needed for improvement of CHB therapy. In this study, we established a screening system in order to identify compounds inhibiting the core promoter activity of hepatitis B virus (HBV). We prepared 80 extracts of marine organisms from the coral reefs of Indonesia and screened them by using this system. Eventually, two extracts showed high inhibitory activity (>95%) and low cytotoxicity (66% to 77%). Solvent fractionation, column chromatography and NMR analysis revealed that 3,5-dibromo-2-(2,4-dibromophenoxy)-phenol (compound 1) and 3,4,5-tribromo-2-(2,4-dibromophenoxy)-phenol (compound 2), which are classified as polybrominated diphenyl ethers (PBDEs), were identified as anti-HBV agents in the extracts. Compounds 1 and 2 inhibited HBV core promoter activity as well as HBV production from HepG2.2.15.7 cells in a dose-dependent manner. The EC50 values of compounds 1 and 2 were 0.23 and 0.80 µM, respectively, while selectivity indexes of compound 1 and 2 were 18.2 and 12.8, respectively. These results suggest that our cell-based HBV core promoter assay system is useful to determine anti-HBV compounds, and that two PBDE compounds are expected to be candidates of lead compounds for the development of anti-HBV drugs.

Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative.

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.

A novel tetramethylnaphthalene derivative selectively inhibits adult T-cell leukemia (ATL) cells in vitro.

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.

A case of superior vena cava syndrome caused by a ruptured brachiocephalic artery aneurysm.

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.

Organosilicon compounds as adult T-cell leukemia cell proliferation inhibitors.

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.

Valve replacement via upper partial sternotomy for quadricuspid aortic valve.

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.

Synergistic inhibition of HTLV-1-infected cell proliferation by combination of cepharanthine and a tetramethylnaphthalene derivative.

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.

Analysis of open heart surgery in patients with liver cirrhosis.

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.