Total Synthesis of (±)-N-Methyldibromoisophakellin and N-Methylugibohlin via Net [3+2] Cycloguanidinylations Employing 2-Amido-1,3-Diamino-Allyl Cations.

A concise total synthesis of (±)-N-methyldibromoisophakellin, a member of the monomeric pyrrole-aminoimidazole alkaloid family isolated from the marine sponge Stylissa carbica, was achieved via a net [3+2] cycloaddition to install the cyclic guanidine. This ring annulation employs a 2-amido-1,3-aminoallyl cation obtained under oxidative conditions from variously N-substituted guanidines which in one instance led to isolation of a tetracycle bearing a carbinolamine center through subsequent benzylic oxidation. Finally, the serendipitous formation of a unique, related alkenyl guanidine, N-methylugibohlin, achieved via ring opening of cyclic guanidine under acidic conditions suggests that ugibohlin may be an artifact of isolation.

Effects of endoscopic injection sclerotherapy for esophagogastric varices on portal hemodynamics and liver function.

OBJECTIVES: To identify patients suitable for endoscopic injection sclerotherapy (EIS) by evaluating their portal hemodynamics and liver function. METHODS: We selected 58 patients with esophagogastric varices (EGV) and liver cirrhosis (LC) related to either hepatitis C virus (C) (n = 19), hepatitis B virus (n = 2), alcohol (AL) (n = 20), C + AL (n = 6), non-alcoholic steatohepatitis (n = 6), others (n = 3), or non-LC (n = 2). All patients underwent EIS. We measured their portal venous tissue blood flow (PVTBF) and hepatic arterial tissue blood flow (HATBF) using xenon computed tomography before and after EIS. We classified them into increased group and decreased group according to the PVTBF to identify the predictors that contribute to PVTBF increase post-EIS. RESULTS: Low value of indocyanine green retention at 15 min (ICG-R15), the absence of paraesophageal veins, and low baseline PVTBF/HATBF (P/A) ratio predicted increased PVTBF in the multivariate logistic analysis (odds ratio (OR) 10.46, p = 0.0391; OR 12.45, p = 0.0088; OR 13.57, p = 0.0073). The protein synthetic ability improved 1 year post-EIS in increased group. Cox proportional hazards regression identified alcohol drinking (hazard ratio; 3.67, p = 0.0261) as an independent predictor of EGV recurrence. CONCLUSIONS: Patients with low ICG-R15, low P/A ratio, and the absence of paraesophageal veins were probable predictors of PVTBF improvement post-EIS. In addition, the improvement of hepatic hemodynamics likely enhanced liver function following EIS.

High-Q Milligram-Scale Monolithic Pendulum for Quantum-Limited Gravity Measurements.

We present the development of a high-Q monolithic silica pendulum weighing 7 milligram. The measured Q value for the pendulum mode at 2.2 Hz was 2.0×10^{6}. To the best of our knowledge this is the lowest dissipative milligram-scale mechanical oscillator to date. By employing this suspension system, the optomechanical displacement sensor for gravity measurements we recently reported in Matsumoto et al. [Phys. Rev. Lett. 122, 071101 (2019)PRLTAO0031-900710.1103/PhysRevLett.122.071101] can be improved to realize quantum-noise-limited sensing at several hundred hertz. In combination with the optical spring effect, the amount of intrinsic dissipation measured in the pendulum mode is enough to satisfy requirements for measurement-based quantum control of a massive pendulum confined in an optical potential. This paves the way for not only testing dark matter via quantum-limited force sensors, but also Newtonian interaction in quantum regimes, namely, between two milligram-scale oscillators in quantum states, as well as improving the sensitivity of gravitational-wave detectors.

Evaluation of 8-week glecaprevir/pibrentasvir treatment in direct-acting antiviral-naïve noncirrhotic HCV genotype 1 and 2infected patients in a real-world setting in Japan.

Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)-infected patients who are direct-acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real-world experience with 8-week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8-week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention-to-treat population and 99.3% (526/530) in the per-protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8-week treatment with G/P, none had baseline polymorphisms or treatment-emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment-emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug-related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA-naïve noncirrhotic genotype 1 or 2 patients in a real-world clinical setting in Japan.

Demonstration of Displacement Sensing of a mg-Scale Pendulum for mm- and mg-Scale Gravity Measurements.

Gravity generated by large masses has been observed using a variety of probes from atomic interferometers to torsional balances. However, gravitational coupling between small masses has never been observed so far. Here, we demonstrate sensitive displacement sensing of the Brownian motion of an optically trapped 7 mg pendulum motion whose natural quality factor is increased to 10^{8} through dissipation dilution. The sensitivity for an integration time of one second corresponds to the displacement generated in a millimeter-scale gravitational experiment between the probe and a 100 mg source mass, whose position is modulated at the pendulum mechanical resonant frequency. Development of such a sensitive displacement sensor using a milligram-scale device will pave the way for a new class of experiments where gravitational coupling between small masses in quantum regimes can be achieved.

Diagnostic Ability of Endoscopic Bile Cytology Using a Newly Designed Biliary Scraper for Biliary Strictures.

BACKGROUND: A new device with metallic wires for scrape cytology was developed. AIMS: To compare the diagnostic performance of scrape cytology and conventional cytology during endoscopic retrograde cholangiopancreatography for biliary strictures. METHODS: A total of 420 cases with biliary stricture underwent transpapillary bile cytology. Among them, there are 79 cases with scrape cytology using the new device (scrape group) and 341 cases with conventional cytology (control group). Seventy-two and 174 cases underwent biliary biopsy at the same time as bile cytology in the scrape and control group, respectively. RESULTS: The sensitivity for malignancy of bile cytology in the scrape and control group was 41.2% [pancreatic cancer (PC): 23.1%, biliary cancer (BC): 52.5%] and 27.1% (PC: 16.3%, BC: 38.0%), respectively (P = 0.023). When analyzed PC and BC, respectively, there was no significant difference between the two groups. In the both groups, the sensitivity was significantly higher for BC than PC. In the scrape group, there was no difference in the sensitivity between cytology and biopsy [39.7% (PC: 17.4%, BC: 55.3%)], but in the control group, a significantly lower sensitivity was observed with cytology than biopsy (36.4% (PC: 19.7%, BC: 50.0%)) (P = 0.046). When analyzed PC and BC, respectively, there was no significant difference between cytology and biopsy. The sensitivity of combined cytology and biopsy was 55.6% (PC: 30.4%, BC: 71.1%) in the scrape group and 47.0% (PC: 24.6%, BC: 64.3%) in the control group. CONCLUSION: Scrape bile cytology for biliary strictures may be superior to conventional cytology.

Efficacy of ledipasvir/sofosbuvir with or without ribavirin for 12 weeks in genotype 1b HCV patients previously treated with a nonstructural protein 5A inhibitor-containing regimen.

AIM: The therapeutic benefit of adding ribavirin (RBV) to 12 weeks of ledipasvir/sofosbuvir (LDV/SOF) for patients who experienced failure of a previous nonstructural protein (NS) 5A inhibitor-containing regimen is unclear. METHODS: A total of 29 genotype 1b HCV patients who had failed prior daclatasvir (DCV) plus asunaprevir (ASV) treatment were retreated for 12 weeks of LDV/SOF, with or without RBV. Antiviral efficacy and predictive factors associating with a sustained virological response at 24 weeks (SVR24) were evaluated retrospectively. RESULTS: SVR24 was achieved in 67% (10/15) of patients who received LDV/SOF with, and 64% (9/14) without, RBV. The SVR24 rates were 80% in patients with, and 58% without, mild fibrosis (FIB-4 < 3.25). The SVR24 rate was lower with unfavorable IL28B rs8099917 SNP genotypes; specifically, the TT, TG and GG had SVR24 rates of 78%, 50% and 40%. The SVR24 rate was lower with a poor response to prior DCV plus ASV, where relapse, viral breakthrough and no response had SVR24 rates 71%, 58% and 0%. The SVR24 rate was lower with the number of NS5A resistance-associated substitutions (RAS), where 2, 3, 4 and 5 RAS had SVR24 rates of 78%, 67%, 50% and 0%. A patient with an NS5A-P32 deletion, which shows resistance to next-generation NS5A inhibitors, was retreated with LDV/SOF with RBV and achieved SVR24. CONCLUSIONS: The addition of RBV to 12 weeks of LDV/SOF has little therapeutic benefit when retreating patients in whom a prior NS5A inhibitor-containing regimen had failed.

Serum monomeric laminin-γ2 as a novel biomarker for hepatocellular carcinoma.

The diagnosis of hepatocellular carcinoma (HCC) in the early stages is important for successful clinical management. Laminin (Ln)-γ2 expression has been reported in various types of malignant carcinomas. We recently developed a highly sensitive method to measure serum monomeric Ln-γ2 levels using a fully automated chemiluminescent immunoassay (CLIA). Using our CLIA, we evaluated its diagnostic value in sera from patients with chronic liver disease (CLD) and patients with hepatocellular carcinoma (HCC). Serum alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were also examined in these subjects. Median levels of Ln-γ2 were significantly higher in patients with HCC (173.2 pg/mL; range: 39.5-986 pg/mL) compared with patients with CLD (76.7 pg/mL; range: 38.7-215.9 pg/mL) and with healthy volunteers (41.1 pg/mL; range: 10.9-79.0 pg/mL). The optimal cutoff value for Ln-γ2 that allowed us to distinguish between HCC and nonmalignant CLD was 116.6 pg/mL. Elevated Ln-γ2 levels were observed in 0% of healthy volunteers, 17% of patients with CLD, and 63% of patients with HCC. The positivity rate in patients with HCC for the combination of Ln-γ2 and DCP was 89.5%, which was better than that for either of the two markers alone (63% and 68%, respectively). Among patients with early-stage HCC (T1 or T2), the positivity rates for monomeric Ln-γ2, AFP and DCP were 61%, 39% and 57%, respectively. Serum Ln-γ2 may be a potential biomarker for HCC surveillance. The combination of Ln-γ2 and DCP may be more sensitive for laboratory diagnosis of HCC than the combination of AFP and DCP.

Impact of resistance-associated variant dominancy on treatment in patients with HCV genotype 1b receiving daclatasvir/asunaprevir.

Sustained virological responses (SVR) by daclatasvir (DCV) and asunaprevir (ASV) therapy for genotype 1b hepatitis C virus (HCV) infected patients has been significantly affected by pre-existence of Y93 H resistance-associated variants (RAVs) in the non-structural protein 5A (NS5A) region. The aim of this study was to elucidate the dominancy of naturally occurring RAVs in viral quasispecies on treatment outcomes in patients with HCV. In total, 138 patients were prospectively selected from 152 patients treated with DCV and ASV, where evaluation of treatment outcomes at 12 weeks post-treatment was possible. Pre-treatment RAVs in the non-structural protein 3 and NS5A regions were detected by polymerase chain reaction (PCR)-Invader assays, and the ratio of Y93H RAVs in viral quasispecies was measured by quantitative PCR-Invader assay. Among 25 patients detected the Y93H RAV, the Y93H ratio was 1-25% in 5 patients, 26-75% in 7 patients, and ≥76% in 13 patients. Overall, SVR at 12 weeks after the completion of treatment (SVR12) was 91% (125/138), and those with Y93H ratios of <1%, 1-25%, 26-75%, and ≥76% were 99%, 100%, 71%, and 23%, respectively. Thus, the SVR12 decreased as the HCV Y93H ratio increased (P < 0.0001). The dominancy of pre-treatment RAVs of DCV and ASV affected its treatment outcomes, suggesting that evaluating the dominancy of HCV RAVs could be required for every other direct-acting antiviral agent treatments. J. Med. Virol. 89:99-105, 2017. © 2016 Wiley Periodicals, Inc.

Optical levitation of a mirror for reaching the standard quantum limit.

We propose a new method to optically levitate a macroscopic mirror with two vertical Fabry-Pérot cavities linearly aligned. This configuration gives the simplest possible optical levitation in which the number of laser beams used is the minimum of two. We demonstrate that reaching the standard quantum limit (SQL) of a displacement measurement with our system is feasible with current technology. The cavity geometry and the levitated mirror parameters are designed to ensure that the Brownian vibration of the mirror surface is smaller than the SQL. Our scheme provides a promising tool for testing macroscopic quantum mechanics.

Involvement of superoxide generated by NADPH oxidase in the shedding of procoagulant vesicles from human monocytic cells exposed to bupivacaine.

It is known that a variety of sized procoagulant vesicles that express tissue factor are released from several types of cells including monocytes by mechanisms related to the induction of apoptosis, while it has not yet been evaluated whether superoxide is involved in the production of such vesicles. Here, we report that a local anesthetic bupivacaine induces apoptosis in human monocytic cells THP-1 within a short observation period, where the shedding of procoagulant vesicles is associated. The property as procoagulant vesicles was evaluated using flow cytometry by the binding of FITC-conjugated fibrinogen to vesicles in the presence of fresh frozen plasma and the suppression of this binding by heparin. Bupivacaine (1 mg/ml) increased the apoptotic cells and procoagulant vesicles. LY294002 (100 µM), that inhibits the recruiting of intracellular component of NADPH oxidase to construct the activated form of this enzyme complex, or superoxide dismutase (1500 unit/ml) suppressed bupivacaine-provoked induction of apoptosis and the increase of procoagulant vesicles. We suggest that this simple experimental system is useful to explore the molecular mechanisms of action of superoxide in the shedding of procoagulant vesicles from human monocytic cells.

Fusobacterium nucleatum detected simultaneously in a pyogenic liver abscess and advanced sigmoid colon cancer.

Fusobacterium nucleatum is an invasive, adherent, and pro-inflammatory anaerobic bacterium involved in various infections and colorectal cancer. We report a case with pyogenic liver abscess, diagnosed with advanced sigmoid colon cancer, in whom F. nucleatum was simultaneously detected. In this patient, F. nucleatum was systematically analyzed using the molecular biological techniques of metagenome analysis, conventional PCR, and microbial fluorescence in situ hybridization.

Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus.

The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully.

[Detection of early gastric cancer facilitated by surveillance for a pyogenic liver abscess caused by Streptococcus intermedius].

We report a case of early gastric cancer that was detected during surveillance of a pyogenic liver abscess caused by Streptococcus intermedius, an oral microbiota. Treatment with proton pump inhibitors can result in the alteration of gastric bacterial flora by altering intragastric acidity. This can place immunocompromised patients, such as those with diabetes mellitus and the elderly, at an increased risk for disease of the upper gastrointestinal tract to be a route of bacterial transmission. In this case, the patient developed a pyogenic liver abscess.

Optically trapped mirror for reaching the standard quantum limit.

The preparation of a mechanical oscillator driven by quantum back-action is a fundamental requirement to reach the standard quantum limit (SQL) for force measurement, in optomechanical systems. However, thermal fluctuating force generally dominates a disturbance on the oscillator. In the macroscopic scale, an optical linear cavity including a suspended mirror has been used for the weak force measurement, such as gravitational-wave detectors. This configuration has the advantages of reducing the dissipation of the pendulum (i.e., suspension thermal noise) due to a gravitational dilution by using a thin wire, and of increasing the circulating laser power. However, the use of the thin wire is weak for an optical torsional anti-spring effect in the cavity, due to the low mechanical restoring force of the wire. Thus, there is the trade-off between the stability of the system and the sensitivity. Here, we describe using a triangular optical cavity to overcome this limitation for reaching the SQL. The triangular cavity can provide a sensitive and stable system, because it can optically trap the mirror's motion of the yaw, through an optical positive torsional spring effect. To show this, we demonstrate a measurement of the torsional spring effect caused by radiation pressure forces.

A novel endoscopic papillectomy after a pancreatic stent placement above the pancreatic duct orifice: inside pancreatic stenting papillectomy.

BACKGROUND: Although pancreatic stenting is recommended for the prevention of postprocedure pancreatitis during endoscopic papillectomy (EP), in some patients it is technically difficult to perform postprocedure insertion of a pancreatic stent after endoscopic resection. GOALS: This study assessed the feasibility of a novel EP for the purpose of reliable post-EP pancreatic stenting. STUDY: We conducted a prospective pilot study involving 10 consecutive patients with tumor of the major duodenal papilla. We developed a novel pancreatic stent, which is attached to a suture, and devised a method by which the stent is first placed at an upstream migration into the major pancreatic duct above the orifice before resection and then placed at an appropriate location after endoscopic resection by pulling the suture attached to the stent [inside pancreatic stenting papillectomy (IPSP)]. RESULTS: The pancreatic stent was successfully placed at an upstream migration into the pancreatic duct above the orifice in 9 of the 10 patients. For the 9 patients with successful pancreatic stent placement, IPSP was performed. Although the suture was cut in 1 patient, pancreatic stents could be placed appropriately across the orifice by pulling the suture in all patients. Although bleeding occurred in 3 patients, there was no pos-procedure pancreatitis. CONCLUSIONS: IPSP is a practicable method allowing reliable post-EP pancreatic stenting and can contribute to pancreatitis prevention. However, larger studies need to be performed before its use can be recommended.

Evaluation of hepatic tissue blood flow using xenon computed tomography with fibrosis progression in nonalcoholic fatty liver disease: comparison with chronic hepatitis C.

AIMS: The present study evaluated the utility of xenon computed tomography (Xe-CT) as a noninvasive diagnostic procedure for the measurement of hepatic tissue blood flow (TBF) in patients with nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C (CH-C). METHODS: Xe-CT was performed in 93 patients with NAFLD and in 109 patients with CH-C. Subjects were classified into one of three groups, based on fibrosis stage: group 1, no bridging fibrosis; group 2, bridging fibrosis; and group 3, liver cirrhosis. Correlations between hepatic TBFs in each fibrosis stage were examined. RESULTS: In group 1, portal venous TBF (PVTBF), hepatic arterial (HATBF), and total hepatic TBF (THTBF) were significantly lower in patients with in nonalcoholic steatohepatitis (NASH) than in those with CH-C (p < 0.001, p < 0.05, p < 0.001, respectively). In group 2, PVTBF and THTBF were significantly lower in patients with in NASH than in those with CH-C (p < 0.001, p < 0.05, respectively). In group 3, hepatic TBFs were not significantly different when comparing patients with NASH and those with CH-C. CONCLUSIONS: PVTBF decreased due to fat infiltration. Therefore, hemodynamic changes occur relatively earlier in NAFLD than in CH-C. Patients with NASH should be monitored carefully for portal hypertensive complications in the early fibrosis stage.

Two cases of rupture of esophagogastric varices during the course of oxaliplatin-based chemotherapy for colorectal cancer.

Some cases of portal hypertension developing during the course of oxaliplatin-based chemotherapy have been reported. However, there have been no reports of rupture of esophagogastric varices (EGV) in Japan. We present two cases of rupture of EGV during the course of oxaliplatin-based chemotherapy. One case was treated via balloon-occluded retrograde transvenous obliteration, and the other case was treated by using endoscopic variceal ligation and endoscopic injection sclerotherapy. On the basis of our results, we recommend careful monitoring for the occurrence of EGV during the course of oxaliplatin-based chemotherapy.

New limit on Lorentz violation using a double-pass optical ring cavity.

A search for Lorentz violation in electrodynamics was performed by measuring the resonant frequency difference between two counterpropagating directions of an optical ring cavity. Our cavity contains a dielectric element, which makes our cavity sensitive to the violation. The laser frequency is stabilized to the counterclockwise resonance of the cavity, and the transmitted light is reflected back into the cavity for resonant frequency comparison with the clockwise resonance. This double-pass configuration enables a null experiment and gives high common mode rejection of environmental disturbances. We found no evidence for odd-parity anisotropy at the level of δc/c ≲ 10(-14). Within the framework of the standard model extension, our result put more than 5 times better limits on three odd-parity parameters κ(o+)(JK) and a 12 times better limit on the scalar parameter κ(tr) compared with the previous best limits.

Serum peptides, represented by complement 3f des-arginine, are useful for prediction of the response to pegylated interferon-α plus ribavirin in patients with chronic hepatitis C.

AIM: Biomarkers predicting sustained virological response (SVR) to pegylated interferon-α plus ribavirin (PEG IFN-α/RBV) were investigated. METHODS: Peptides in pretreatment sera from 107 patients with hepatitis C virus (HCV) genotype 1 were comprehensively analyzed by mass spectrometry. Ion intensity of the peptides was used to generate discriminant models between the responders who achieved SVR (R) and the non-responders (NR) to PEG IFN-α/RBV. RESULTS: In total, 107 peptides were detected in a training set (n = 23). A discriminant model using a peptide, complement 3f des-arginine (C3f-dR), showed sensitivity of 35% and specificity of 94% for SVR prediction in a testing set (n = 68). In all the R and NR (n = 96), an area under the receiver-operator curve (AUROC) of 0.64 in the C3f-dR model was increased to 0.78 by addition of platelet (PLT) counts (C3f-dR/PLT model). Another model using the 107 peptides (AUROC, 0.77) also showed higher AUROC (0.79) by addition of hemoglobin (Hb), body mass index (BMI) and age (107P/Hb/BMI/Age model). The sensitivity and specificity of the C3f-dR/PLT model were 59% and 88%, and those of the 107P/Hb/BMI/Age model were 70% and 92%, respectively. The C3f-dR/PLT model showed high AUROC (0.82), similar to that of interleukin-28B rs8099917 genotype analysis (0.86) in the 45 tested patients. Prediction by the combination of the C3f-dR/PLT model, the 107P/Hb/BMI/Age model and the rs8099917 genotype analysis was accurate in 44 out of the 45 patients (AUROC, 0.95). CONCLUSION: Serum peptides, especially C3f-dR, would be useful predictors for SVR to PEG IFN-α/RBV. The complements may be involved in the HCV elimination.