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Vehicle routing applications are ubiquitous in the field of pick-up and delivery service. We focus on the vehicle routing problem with balanced pick-up called VRPBP which originates from the package pick-up service. The aim of the problem is not only to efficiently explore the shortest travel route but also to balance loads between depots and vehicles. These problems can be regarded as optimization problems, and recent developments in Ising machines, including quantum annealing machines, bring us a new opportunity to solve complex real-world optimization problems. In this paper, a two-phase method and a three-phase method using Ising machines are proposed for solving the VRPBP. As the applicability of current Ising machines is limited due to the small size of Ising spins and connectivities, we partition the complex problem into two or three sub-problems, and the key elements of each sub-problem are mapped onto quadratic unconstrained binary optimization (QUBO) models to fit in the structure of the Ising machines. We first compared the performances of the Ising machine on the standard TSP and CVRP datasets with a conventional state-of-the-art solver and three conventional methods. Then, we evaluated the performances of the proposed methods compared with five conventional method for solving the VRPBP. The results confirm the effectiveness of the two proposed methods in solving vehicle-routing-related optimization problems.

In a simple two-country Ricardian economy with public infrastructures, we consider a simultaneous and non-cooperate game between governments with respect to public infrastructure supply. Then it is shown that a country with larger (smaller) factor endowment exports a good whose production is more (less) dependent on public infrastructures, and both countries will gain from trade as long as factor endowment differs between countries. However, the following special features appear. (i) Any incompletely specialising country produces two goods at an inner point of the production possibility set. (ii) If factor endowment is the same between countries, the trading equilibrium is attained by the pattern of specialisation such that each country specialises in one good different from each other and both countries become better off. Which country specialises in which good is indeterminate. The result shows a typical case of symmetric breaking.JEL codes:F11, H41

Background This retrospective study aimed to demonstrate surgical operative approach of total pelvic exenteration combined with sacral resection with rectal cancer and elucidate the relationships between the level of sacral resection and short-term outcomes.Methods Twenty cases were selected. Data regarding sex, age, body mass index, neoadjuvant therapy, location of sacral resection (“Upper” or “Lower” relative to the level between the 3rd and 4th sacral segment), operative time, bleeding, and curability (R0/R1) were collected and compared to determine their association with complications exhibiting a Clavien-Dindo grade III.Results The complication rate was significantly higher for recurrent cancers (n = 10, 76.9%) than for primary cancers (n = 1, 14.3%) (P= .007), and for “Upper” resection (n = 8, 72.7%) than for “Lower” resection (n = 3, 33.3%) (P= .078). Significant differences were observed when complication rates for “Lower” and primary cancer resection (n = 3, .0%) were compared between “Upper” and recurrent cancers (n = 8, 100.0%) (P= .007).Conclusion In patients with recurrent rectal cancer, “Upper” sacral resection during total pelvic exenteration is associated with a high complication rate, highlighting the need for careful monitoring.

Purpose: The aim of this paper is to investigate whether a Nash equilibrium of a two-country trading economy is symmetry-breaking or not. Design/methodology/approach: The approach to tackle this topic is a theoretical treatment by the general equilibrium trade theory and game theory. Findings: If each government's domestic policy serving private production is diminishing to the private production scale, the Nash equilibrium is not symmetry-breaking. Originality/value: In the existing study of Chatterjee (2017), a similar result is derived by focusing on the properties of each country's GDP function. The authors, however, consider an economy where each country's PPF is strictly concave and show that the Nash equilibrium uniquely exists and this equilibrium is symmetry.

A novel series of non-amidine-based C1s inhibitors have been explored. Starting from high-throughput screening hit 3, isoquinoline was replaced with 1-aminophthalazine to enhance C1s inhibitory activity while exhibiting good selectivity against other serine proteases. We first disclose a crystal structure of a complex of C1s and a small-molecule inhibitor (4e), which guided structure-based optimization around the S2 and S3 sites to further enhance C1s inhibitory activity by over 300-fold. Improvement of membrane permeability by incorporation of fluorine at the 8-position of 1-aminophthalazine led to identification of (R)-8as a potent, selective, orally available, and brain-penetrable C1s inhibitor. (R)-8significantly inhibited membrane attack complex formation induced by human serum in a dose-dependent manner in an in vitro assay system, proving that selective C1s inhibition blocked the classical complement pathway effectively. As a result, (R)-8emerged as a valuable tool compound for both in vitro and in vivo assessment.

This study examines the macroeconomic effects of foreign aid and fiscal policy by employing a multi-sector growth model. Foreign aid may decrease the recipient country’s market activities by lowering its capital accumulation and shifting market labour and capital to the non-market sector. This market activity shifting can improve the recipient country’s foreign asset/debt position where real exchange rate plays a role. We examine fiscal policies’ long- and short-run impacts and the recipient country’s administration efficiency in handling aid. Efficiency improvements in the recipient country’s governance of foreign aid can lower its real exchange rate, thereby contribute to improving foreign asset/debt holdings. Although administration costs in foreign aid may cause losses, by raising both market and non-market goods consumption, foreign aid improves the welfare of the recipient country. Our numerical analysis demonstrates the comparative statics and comparative dynamics impacts of several fiscal policy experiments. We illustrate that capital and labour income’s taxation effects can be very different.

This study showcases the specific inspiration from Professor Kemp by focusing on one particular firm—ASML, a Dutch lithography company. It has become the only producerto launch a group of products, the extreme ultraviolet (EUV) systems for advanced integrated circuits (ICs). Such success is relatively new and is due to a single, unprecedented multi-year programme, Customer Co-investment Program CCIP), since 2012. This programme accelerated ASML’s development of EUV, which has marginalised the other two rivals and former market leaders, Nikon and Canon, that they can only compete in the less advanced DUV and i-line systems. The article explores a number of interrelated aspects about the selected case. It discusses how economic theories offer tools into the crux of the matter. It then reviews technical and historical facts to facilitate further understanding. Next, the article considers two main issues: Is the ASML’s claim that CCIP is necessary based on the financing requirement linked to the new technology true? And is the outcome good? The first question is analysed by four inter-related levels of information asymmetry, and the second is discussed at a broader level. Finally, the article explains how Kemp and Shimomura inspires the analysis here of the illustrative case of ASML.JEL Codes:D22, D23, D82, L22, L63

We construct and analyse a two-country general equilibrium model in which the home and foreign countries trade two final goods, and legal immigration is restricted. International trade is distorted via tariffs imposed by both countries. Foreign migrants attempt illegal entry to the home country but face a probability of detection and arrest by border patrol of the home country. We examine how stricter border patrol affects the level of illegal immigration, establish conditions under which stricter border patrol reduces successful illegal immigration and determine the welfare implications of this policy change. We also determine the effects on illegal immigration and the welfare of all agents when illegal immigrants increase remittances back to the source country.JEL Codes:F13, F16, F22.

This article revisits Kemp’s and Tran-Nam’s incorporation into trade theory the Gossenian theme that consumption takes time. We show how the substitutability between time-intensive household-produced consumption goods and time-saving commercially produced consumption goods (which save households’ consumption and production time) together with capital accumulation can lead to an increase in trash and international trade in trash. The applicability of the standard gains from trade theorems is shown to be compromised by the externalities associated with international trade in trash between North and South. Under some parameter values, South is better off under autarky than under free trade in trash and the gains from trade by North is not sufficient to compensate South’s loss from trade.JEL Codes:D13, F18, F13

The article attempts to consider the impact of a customs union formed between two small countries embedded in the global economy and trading in intermediates, in terms of a general equilibrium framework. It shows that with such a union both countries will gain, although there will be asymmetric effect on wage inequality. However, with higher capital stock the significance of the formation of customs union will be undermined. It also shows that perfect international capital mobility will lead to finite changes in the economy, shutting down the less capital intensive unskilled export sector in each country, which in turn makes the bilateral union irrelevant. Further tariff reduction will increase inequality in both countries. We have also considered the welfare effects of formation of customs union in the form of tariff cut and such a tariff reduction unequivocally improves welfare of the customs union irrespective of small country and large country assumptions, without any intra-union income transfer.JEL Codes:F02, F11, F55, F68

This paper studies the effects of immigration policy on the immigration of foreign medical workers on the welfare and income distribution of home medical workers and labourers. We set up a simple small open economy with two traded goods and non-traded medical care services. In the economy, there exists a constant rate of labourers who get ill health and must leave their jobs and thereby lose part of their income. But they can reduce the loss of working time and income by consuming medical services. There are two channels that consumption of the medical service affects the welfare of consumers: (i) consumption of medical service raises the state of health and increases utility, and (ii) consumption of medical service reduces the leave period of labourers and raises their wage income (labour supply-enhancing effect). We see that the above second effect makes the effective price of the medical service for the consumer lower than its market price and causes consumption bias towards the consumption of medical services. To introduce the above properties of consumption of medical service, we define the effective expenditure function of the labourers and examine its properties and conduct comparative static analyses.JEL codes:F13, F22

Background: Colorectal endoscopic submucosal dissection (ESD) remains demanding due to technical difficulties and high risk of perforation. Most of the reported traction methods are initiated after creating a mucosal flap, which is time consuming. To obtain a good visualization at the mucosal incision stage, we developed the early clip-with-line (ECL) method. This method was started immediately after injection of sodium hyaluronate solution into the submucosal layer. In this study, we evaluated the efficacy and the safety of the ECL method for colorectal ESD. Methods: We retrospectively analyzed all cases of colorectal ESDs (41 cases in total) performed from January 2017 to February 2019 in our institution. From January 2017 to August 2018, 27 of these cases were performed using conventional (non-ECL) ESDs, while from September 2018 onwards, the remaining 14 cases were performed using the ECL method. Retrospective comparison between the ECL group and the non-ECL group was conducted in terms of clinical characteristics, treatment outcomes, and adverse events. Results: There were no significant differences in clinical characteristics between two groups. Procedure time (median [range]) was significantly shorter in the ECL group than in the non-ECL group (66 [29–131] min vs 90 [30–410] min; P= 0.03). As for adverse events, no case of perforation occurred in the ECL group, whereas perforation was observed in 7.4% (2/27) cases in the non-ECL group (no significant difference). Conclusion: Early clip-with-line method for colorectal endoscopic submucosal dissection reduced procedure time.

Zinc (Zn) plays an important role in immune function. Several studies have identified an association between a Zn deficiency and infection. Infectious diseases are major complications of chronic kidney disease (CKD). We investigated whether serum Zn concentrations are associated with risk of infection in patients with advanced CKD.

Background:There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy. Methods:We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions. Results:Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5–15.2) and 6.7 months (95% CI, 5.6–7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6–3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5–4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1–6.5 months), 17.6%, and 41.2%, respectively. Conclusion:Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.

ROS are involved in the pathogenesis of bullous pemphigoid (BP), but this involvement has not been fully elucidated. In this study, to further elucidate the pathogenic role of ROS in BP, we examined the results of the diacron-reactive oxygen metabolite test and the biological antioxidant potential test for 16 patients with BP who visited our hospital before being treated with systemic corticosteroids. In the patients with BP, the average diacron-reactive oxygen metabolite levels, expressed in Carratelli units, were significantly reduced at 1 month of treatment (from 335.6 ± 40.3 Carratelli units to 224.7 ± 61.6 Carratelli units, P< .001). Bullous Pemphigoid Disease Area Index (erosions/blisters) scores correlated with diacron-reactive oxygen metabolite levels (r = 0.51), suggesting that those levels reflect the disease severity. We also performed staining of 3,5-dibromotyrosine in skin tissues. The 3,5-dibromotyrosine is expected to be a marker of tissue damage related to inflammation and allergies. The 3,5-dibromotyrosine was stained in infiltrated cells around the dermis, throughout the blister fluid, and at the basement membrane within the blister. It is considered that tissue destruction caused by the myeloperoxidase released from neutrophils and by eosinophil peroxidase released from eosinophils is involved in blister formation. The results suggest that ROS play a role in BP.

O-GlcNAcase (OGA) has received increasing attention as an attractive therapeutic target for tau-mediated neurodegenerative disorders; however, its role in these pathologies remains unclear. Therefore, potent chemical tools with favorable pharmacokinetic profiles are desirable to characterize this enzyme. Herein, we report the discovery of a potent and novel OGA inhibitor, compound 5i, comprising an aminopyrimidine scaffold, identified by virtual screening based on multiple methodologies combining structure-based and ligand-based approaches, followed by sequential optimization with a focus on ligand lipophilicity efficiency. This compound was observed to increase the level of O-GlcNAcylated protein in cells and display suitable pharmacokinetic properties and brain permeability. Crystallographic analysis revealed that the chemical series bind to OGA via characteristic hydrophobic interactions, which resulted in a high affinity for OGA with moderate lipophilicity. Compound 5icould serve as a useful chemical probe to help establish a proof-of-concept of OGA inhibition as a therapeutic target for the treatment of tauopathies.

Background and Aims:The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. Approach and Results:We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009–2012, n= 267; period 2: 2013–2016, n= 352; period 3: 2017–2019, n= 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p< 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p= 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p< 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. Conclusions:The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

Background:Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden. Aims:The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs. Methods:We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC. Results:Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC. Conclusions:Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.

Background:The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial. Methods:We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan. Results:Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7–6.9 for first line, 4.8 months; 95% CI 3.8–5.9 for second or later line, p= 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin – bilirubin scores. Conclusion:Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.

Dysferlinopathies, which are muscular diseases caused by mutations in the dysferlin gene, remain serious medical problems due to the lack of therapeutic agents. Herein, we report the design, synthesis, and structure–activity relationships of a 2,6-disubstituted 3H-imidazo[4,5-b]pyridine series, which was identified from the phenotypic screening of chemicals that increase the level of dysferlin in myocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs). Optimization studies with cell-based phenotypic assay led to the identification of a highly potent compound, 19, with dysferlin elevation effects at double-digit nanomolar concentrations. In addition, the molecular target of our chemical series was identified as tubulin, through a tubulin polymerization assay and a competitive binding assay using a photoaffinity labeling probe.

Chronic inflammation, which is often associated with high all-cause and cardiovascular mortality, is prevalent in patients with renal failure; however, the precise mechanisms remain unclear. High-salt intake was reported to induce lymphangiogenesis and autoimmune diseases via osmotic stimuli with accumulation of sodium or chloride. In addition, sodium was recently reported to be stored in the extremities of dialysis patients. We studied the effects and mechanisms of high salt loading on tissue and systemic inflammation in subtotal-nephrectomized mice (5/6Nx) and in cultured cells. Macrophage infiltration in the peritoneal wall (P<0.001), heart (P<0.05) and para-aortic tissues (P<0.001) was significantly higher in 5/6Nx with salt loading (5/6Nx/NaCl) than in 5/6Nx without salt loading (5/6Nx/Water); however, there were no significant differences in blood pressure and renal function between the groups. Tissue interleukin-6, monocyte chemotactic protein-1 (MCP-1), serum- and glucocorticoid-inducible kinase 1 (Sgk1) and tonicity-responsive enhancer binding protein (TonEBP) mRNA were significantly elevated in the peritoneal wall and heart with 5/6Nx/NaCl when compared with 5/6Nx/Water. Sodium was stored in the abdominal wall, exerting high-osmotic conditions. Reversal of salt loading reduced macrophage infiltration associated with decreased TonEBP in 5/6Nx/NaCl. Macrophage infiltration associated with fibrosis induced by salt loading was decreased in the 5/6Nx/NaCl/CC chemokine receptor 2 (CCR2, receptor of MCP-1)-deficient mice when compared with 5/6Nx/NaCl/Wild mice, suggesting that CCR2 is required for macrophage infiltration in 5/6Nx with NaCl loading. In cultured mesothelial cells and cardiomyocytes, culture media with high NaCl concentration induced MCP-1, Sgk1 and TonEBP mRNA, all of which were suppressed by TonEBP siRNA, indicating that both MCP-1 and Sgk1 are downstream of TonEBP. Our study indicates that high NaCl intake induces MCP-1 expression leading to macrophage infiltration via the TonEBP-MCP-1 pathway in 5/6Nx/NaCl mice, and that TonEBP has a central role in inflammation in patients with renal failure taking high salt.

Chronic inflammation, which is often associated with high all-cause and cardiovascular mortality, is prevalent in patients with renal failure; however, the precise mechanisms remain unclear. High-salt intake was reported to induce lymphangiogenesis and autoimmune diseases via osmotic stimuli with accumulation of sodium or chloride. In addition, sodium was recently reported to be stored in the extremities of dialysis patients. We studied the effects and mechanisms of high salt loading on tissue and systemic inflammation in subtotal-nephrectomized mice (5/6Nx) and in cultured cells. Macrophage infiltration in the peritoneal wall (P<0.001), heart (P<0.05) and para-aortic tissues (P<0.001) was significantly higher in 5/6Nx with salt loading (5/6Nx/NaCl) than in 5/6Nx without salt loading (5/6Nx/Water); however, there were no significant differences in blood pressure and renal function between the groups. Tissue interleukin-6, monocyte chemotactic protein-1 (MCP-1), serum- and glucocorticoid-inducible kinase 1 (Sgk1) and tonicity-responsive enhancer binding protein (TonEBP) mRNA were significantly elevated in the peritoneal wall and heart with 5/6Nx/NaCl when compared with 5/6Nx/Water. Sodium was stored in the abdominal wall, exerting high-osmotic conditions. Reversal of salt loading reduced macrophage infiltration associated with decreased TonEBP in 5/6Nx/NaCl. Macrophage infiltration associated with fibrosis induced by salt loading was decreased in the 5/6Nx/NaCl/CC chemokine receptor 2 (CCR2, receptor of MCP-1)-deficient mice when compared with 5/6Nx/NaCl/Wild mice, suggesting that CCR2 is required for macrophage infiltration in 5/6Nx with NaCl loading. In cultured mesothelial cells and cardiomyocytes, culture media with high NaCl concentration induced MCP-1, Sgk1 and TonEBP mRNA, all of which were suppressed by TonEBP siRNA, indicating that both MCP-1 and Sgk1 are downstream of TonEBP. Our study indicates that high NaCl intake induces MCP-1 expression leading to macrophage infiltration via the TonEBP-MCP-1 pathway in 5/6Nx/NaCl mice, and that TonEBP has a central role in inflammation in patients with renal failure taking high salt.

A 42-year-old woman with liver tumors was referred to our hospital. Her condition was complicated by Fanconi anemia, and she had undergone total laryngectomy 8 years ago. On admission, contrast-enhanced computed tomography revealed hypervascular tumors in the right hepatic lobe. Ultrasound-guided tumor biopsy revealed that the tumor comprised moderately differentiated hepatocellular carcinoma. Although the patient exhibited preserved liver function (Child-Pugh A), complete blood count revealed severe pancytopenia. Eventually, the tumor was successfully treated by transcatheter arterial embolization (TAE). Both platelet transfusion and systemic administration of antibiotics were performed. She was discharged 35 days after TAE.

Direct-acting antivirals with or without peginterferon a (PEG-IFN a) plus ribavirin are now available for the treatment of hepatitis C virus (HCV) infection. Direct-acting antivirals are potent inhibitors of HCV replication, but some of them occasionally possess serious adverse events. We experienced a 64-year-old female with chronic HCV genotype 1b infection who showed elevated alanine aminotransferase of 528 IU/l at week 9 after the commencement of treatment of simeprevir with PEG-IFN a-2a plus ribavirin. However, she achieved sustained virological response at week 24 after the end of treatment. In Japan, we also have to treat elderly patients infected with HCV and/or advanced hepatic fibrosis. Until an effective interferon-free regimen is established, direct-acting antivirals with PEG-IFN plus ribavirin may still play a role in the treatment for certain patients. To avoid serious results from adverse events, careful attention and follow-up will be needed in the treatment course of simeprevir with PEG-IFN plus ribavirin for chronic HCV infection.

Bleeding following endoscopic sphincterotomy (EST) is a rare but unavoidable complication of the procedure. We routinely perform local injection of hypertonic saline-epinephrine (HSE) for the treatment of post-EST bleeding. Any blood clot is removed only by irrigation with water after local injection of pure ethanol into the blood clot to cause crusting. We evaluated the usefulness of this treatment method.

Phosphorylation of Xenopus Slingshot phosphatase (XSSH) at multiple sites within the tail domain occurs just after germinal vesicle breakdown (GVBD) and is accompanied by dephosphorylation of ADF/cofilin (XAC). Injection of anti-XSSH antibody, which blocks full phosphorylation of XSSH after GVBD, inhibits meiotic spindle formation and XAC dephosphorylation.

AbstractIntracranial metastasis of hepatocellular carcinoma (HCC) is rare, but has an extremely poor prognosis. We report a case with successful surgical removal of intracranial metastasis of HCC. A 32-year-old man was admitted to our hospital with severe vomiting. He had been followed for liver cirrhosis due to hepatitis B virus infection and received a right hepatic trisectionectomy for HCC 1 year earlier. For the recurrence of HCC, sorafenib had been administered 6 months before admission. On admission, he exhibited consciousness disturbance, which gradually worsened. Two days later, both computed tomography and magnetic resonance imaging revealed an intra-axial tumor with perifocal edema and hemorrhage in the left frontal lobe. The tumor was successfully removed by craniotomy and pathological examination revealed that it was composed of moderately differentiated HCC cells. The day after surgical resection of the tumor, his consciousness returned to normal. Subsequently, he was treated with hepatic arterial infusion chemotherapy with 5-fluorouracil and cisplatin using an implanted port-catheter system. Surgical resection of intracranial metastasis of HCC would be important and meaningful in some cases.Copyright © 2013 S. Karger AG, Basel

AbstractA 75-year-old woman with abdominal pain and vomiting was admitted to our hospital. Colonoscopy showed an advanced colon cancer that encompassed the entire circumference of the descending colon’s lumen. The patient was diagnosed with occlusive ileus associated with the colon cancer. She had been watched for liver cirrhosis due to the hepatitis C virus and received radiofrequency ablation therapy for hepatocellular carcinoma (HCC) 6 years previously. Although she exhibited a gradual increase in serum levels of a-fetoprotein and PIVKA-II starting 2 years before admission, no tumors were detected in the liver by abdominal ultrasonography and computed tomography. On admission, contrast-enhanced computed tomography revealed not only the colon cancer but also a tumor adjacent to the cecum. Both tumors were successfully removed by surgery and a pathological analysis revealed that the cecum tumor was poorly-differentiated HCC. The serum levels of a-fetoprotein and PIVKA-II declined markedly after the operation and no masses considered as peritoneal metastasis have been detected to date. This is the first report of the simultaneous resection of disseminated HCC and colon cancer.Copyright © 2013 S. Karger AG, Basel

Diabetes mellitus is a major disease worldwide, and the prevalence of diabetes has risen significantly in the past several decades. Although one of the major complications of diabetic eyes is diabetic retinopathy (DR), corneal diseases can not only develop in diabetic patients but are also difficult to manage. Diabetic neurotrophic keratopathy is a component of diabetic polyneuropathy and is recognized to be the cause of the morbidity of the cornea in diabetic patients. In addition, corneal endothelial cell damage can cause disturbances in the management of proliferative DR before and after surgeries because of endothelial decompensation with bullous keratopathy. However, there have been only a limited number of studies that have focused on the importance of corneal diseases in diabetic patients. This review describes the pathophysiological roles of different factors that have been found to be causative factors of diabetic corneal keratopathy and endothelial cell dysfunction in diabetic patients. In addition, the clinical features of the corneal changes in diabetic patients and recent studies related to the development of therapies for the management of corneal diseases are presented.

The main purpose of this research is to propose and develop energy saving inverter controlled magnetic jack. It is an electromechanical load lifting machine which provides controlled linear motion to the load. The project is carried out as a result of increase demand for limited fossil energy. Energy saving of the system is achieved through the use of power electronic inverter connected to the induction motor with sensors installed in some part of the system. The regenerative energy of the system achieved through repulsion of the magnets and increase in thickness of the system coil housing is either saved in the system capacitor which could be re-used later or fed back to the mains. Results show that the system is efficient in energy saving and regeneration. A total of 35.99% energy is expected to be realized by the system at the end of the work. The work is also expected to open new door for researchers in this field.

JAXA (Japan Aerospace Exploration Agency) has been conducting a research project named SAVERH (Situation Awareness and Visual Enhancer for Rescue Helicopter) with Shimadzu Corporation and NEC from 2008. SAVERH aims at inventing a method of presenting suitable information to the pilot to support search and rescue missions. An integrated system comprising an HMD (Helmet-Mounted Display) and a FLIR (Forward Looking Infrared) sensor were installed in a JAXA research helicopter, and a series of flight tests was conducted to evaluate the benefit of presenting FLIR images on the HMD in night flight. Three pilots evaluated the display system during six night flights, considering terrain and position awareness. The tests showed that use of FLIR gave better route tracking performance, and the effectiveness of head-slaved FLIR on an approach task was shown by subjective pilot rating.