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Hepatocellular carcinoma (HCC) is the strongest independent predictor of mortality in non-alcoholic steatohepatitis (NASH)-related cirrhosis. The effects and mechanisms of combination of sodium-dependent glucose cotransporter inhibitor and canagliflozin (CA) and dipeptidyl peptidase-4 inhibitor and teneligliptin (TE) on non-diabetic NASH progression were examined. CA and TE suppressed choline-deficient, L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. CA alone or with TE significantly decreased proinflammatory cytokine expression. CA and TE significantly attenuated hepatic lipid peroxidation. In vitro studies showed that TE alone or with CA inhibited cell proliferation and TGF-&beta, 1 and &alpha, 1 (I)-procollagen mRNA expression in Ac-HSCs. CA+TE inhibited liver fibrogenesis by attenuating hepatic lipid peroxidation and inflammation and by inhibiting Ac-HSC proliferation with concomitant attenuation of hepatic lipid peroxidation. Moreover, CA+TE suppressed in vivo angiogenesis and oxidative DNA damage. CA or CA+TE inhibited HCC cells and human umbilical vein endothelial cell (HUVEC) proliferation. CA+TE suppressed vascular endothelial growth factor expression and promoted increased E-cadherin expression in HUVECs. CA+TE potentially exerts synergistic effects on hepatocarcinogenesis prevention by suppressing HCC cell proliferation and angiogenesis and concomitantly reducing oxidative stress and by inhibiting angiogenesis with attenuation of oxidative stress. CA+TE showed chemopreventive effects on NASH progression compared with single agent in non-diabetic rat model of NASH, concurrent with Ac-HSC and HCC cell proliferation, angiogenesis oxidative stress, and inflammation. Both agents are widely, safely used in clinical practice, combined treatment may represent a potential strategy against NASH.

Aim Proton pump inhibitors (PPIs) are frequently prescribed in patients with cirrhosis, but this therapy entails potential complications. We aimed to investigate the influence of PPI use on intestinal permeability in patients with cirrhosis. Methods We recruited 228 patients with cirrhosis and divided them into four groups. Group (Gp)1 comprised patients receiving a PPI with concurrent neomycin (NEO) (PPI-NEO group, n = 14 [6.1%]), Gp2 and Gp3 comprised those receiving either PPI or NEO (PPI group, n = 91 [39.9%]; and NEO group, n = 11 [4.4%]), and Gp4 comprised those receiving neither of these medications (control group; n = 112 [49.1%]). We assessed the intestinal permeability by measuring endotoxin activity (EA) using a luminol chemiluminescence method. Results Endotoxin activity levels were significantly higher in patients with Child B cirrhosis than in those with Child A cirrhosis, but we found no significant differences in EA levels between patients with Child C cirrhosis and those with either Child A or B cirrhosis. We observed no significant differences in EA levels among groups 1-4. Patients without antibiotic exposure (n = 203), comprising 91 patients on PPI therapy (Gp2) and 112 no-PPI-therapy controls (Gp4), were subdivided according to Child-Pugh (CP) classification. We found no significant differences in EA levels between Gp2 and Gp4 in either CP class. Conclusion Our results suggest that PPI usage does not have a significant impact on serum levels of gut-derived endotoxins, which are already elevated because of the increased intestinal permeability in patients with cirrhosis.

Co-Mo bimetallic nanoparticles (NPs) with various compositions were prepared on a CeO2 support (Co-Mo/CeO2) by sodium naphthalenide driven reduction. The Co-Mo/CeO2 catalyst exhibits much higher activity for ammonia synthesis than monometallic catalysts such as Co/CeO2 and Mo/CeO2, and the optimum activity is obtained at Co:Mo = 4:6. X-ray absorption fine structure (XAFS) analyses reveal that Co3Mo3N NPs are formed after ammonia synthesis reaction. Nitrogen temperature programmed desorption (N2-TPD) measurements indicate that the Co-Mo/CeO2 catalyst possesses a large number of nitrogen adsorption sites with an intermediate nitrogen adsorption energy between that of Co and Mo. Furthermore, nitrogen vacancy sites, which are active sites for N2 dissociation, are more easily formed on the Co-Mo/CeO2 catalyst than on bulk-type Co3Mo3N. As a consequence, the turnover frequency of the Co-Mo/CeO2 catalyst is much higher than that of bulk-type Co3Mo3N and is comparable to that of the efficient Ru/CeO2 catalyst.

Radiofrequency ablation (RFA) is recommended in Japan for patients with hepatocellular carcinomas (HCCs) one to three in number and ≤3 cm in size. The arfa® and VIVA® RFA systems are widely used for patients with HCC and this retrospective observational study aims to compare their performances. The study included 365 patients with HCCs one to three in number and ≤3 cm in size who underwent RFA using the arfa® system (arfa® group) or the VIVA® system (VIVA® group). The total bilirubin (T-Bil) level after RFA was higher in the arfa® group than in the VIVA® group. With a 3-cm electrode needle, the longest diameter (Dmax) and the shortest diameter were analyzed and found to be greater in the arfa® group than in the VIVA® group. Furthermore, Dmax with the 2.5-cm electrode needle was greater in the arfa® group than in the VIVA® group. Statistically significant differences in the ablation area and in the T-Bil value after RFA were observed between the groups; however, these differences are not considered clinical problems because the difference in the ablation area was only slight and the Child–Pugh score was the same between the groups. Thus, hepatologists can use either of the RFA systems based on their preference.

Equol is a metabolite of daidzein, a major soybean isoflavone with estrogenic and antioxidant activities. As the production of equol depends on the presence of certain members of the intestinal microflora, not all individuals can produce equol. We examined the relationship between NASH histological features and equol production. In an animal model, obese OLETF rats were intraperitoneally injected with a porcine serum to augment liver fibrogenesis. Equol-rich soy product, SE5-OH was orally administered during the experimental period. Treatment with SE5-OH markedly attenuated the development of liver fibrosis and expression of alpha-smooth muscle actin. In clinical research, 38 NAFLD patients (13 men and 25 women) were included. The degree of fibrosis and ballooning in equol-nonproducers was significantly higher than in equol-producers in women. The percentage of nonproducers with NAFLD activity score (NAS) ≥ 5 was significantly higher than that of producers. None of the histological features were significantly different between nonproducers and producers in men. Decision tree analysis identified predictors for NAS ≥ 5 in women. The status of equol production was the strongest predictor, followed by fasting glucose. Since equol can be noninvasively detected in urine, it can be applied as a screening tool for the progression of NASH in women.

The presence of bridging fibrosis predicts survival of primary biliary cholangitis (PBC). This study aimed to compare serum parameters for the estimation of liver fibrosis and prediction of clinical outcomes in PBC. Out of 392 patients with PBC, 102 who underwent liver biopsy and in whom fibrosis indices, platelet count, hyaluronic acid, type IV collagen 7 second domain, procollagen type III amino-terminal peptide, tissue inhibitor of metalloproteinases 1, Mac-2 binding protein glycosylation isomer, N-terminal type III collagen propeptide levels; fibrosis index based on 4 factors, aspartate aminotransferase-to-platelet ratio index, and enhanced liver fibrosis (ELF) score were determined, were included. The correlation of histological stages based on both Scheuer and Nakanuma classifications with fibrosis indices was investigated. The Nakanuma system comprises grading for liver fibrosis and bile duct loss. Diagnostic performances of 10 fibrosis indices were evaluated to identify patients with poor prognosis. Moreover, correlations of those with PBC clinical manifestation and survival were also investigated. Enhances liver fibrosis (ELF) score had the highest correlation coefficient for liver fibrosis evaluated according to either the Scheuer or Nakanuma classification among 10 serum fibrosis indices. It also had the highest diagnostic performance in estimating Scheuer stage III and Nakanuma fibrosis score 2, both of which represent portal-bridging fibrosis. Patients with an ELF score of ≥10.0 had shorter survival and presented more frequently clinical complications than those with an ELF score of

The gaze of others is known to be a particularly common cause of social anxiety. In the current study, we measured event-related potentials (ERPs) during gaze perception among people with or without high socially anxious tendencies (HSA). The experimental stimuli were grayscale images of the eye region of a face, showing direct or averted eye gaze (leftward gaze or rightward gaze) or closed eyes. We found that negative ERPs at a right occipito-temporal site (N170) and positive ERPs at the fronto-central region (P2) were evoked by eye gaze stimuli. While the N170 was not affected by socially anxious tendencies, the amplitude of the P2 was significantly greater in the HSA group than in the low socially anxious tendencies (LSA) group. Furthermore, P2 latency showed a significant interaction between groups and conditions: the HSA group exhibited shorter P2 latencies in response to direct gaze than averted gaze, while the LSA group did not. These results indicate that the neural processing of eye gaze is strongly influenced by socially anxious tendencies. In particular, the attentional processing of direct gaze is more prominent in individuals with HSA tendencies.

Internationally, Japan ranks very low in the number of women in political leadership roles. Since the 1990s, the number of women serving in the national and local legislative assemblies has increased, and since 2000, the number of women serving as governors or mayors has also gradually increased. In particular, the number of female mayors has grown significantly in recent years. This article attempts to clarify the reasons for the increase in female mayors by examining the careers of women elected since the early 21st century and four case studies that illuminate various pathways to power for female mayors. We suggest that Japan’s gender-segregated employment practices have inadvertently created a new pathway to local power for women, from housewife to civil society leaders, and ultimately to local politician. We consider issues such as supply and demand, and other background environmental factors that affect women’s candidacy within mayoral elections. Furthermore, through four case studies, we show that three of four women capitalized on their ‘outsider’ profiles in their mayoral elections through critiques of the previous mayors’ management. Moreover, all of the women made campaign promises on the expansion of care services and the realization of local fiscal responsibility.

Inflammation and oxidative stress contribute to the progression of nonalcoholic steatohepatitis (NASH)...

Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). Lusutrombopag, an oral thrombopoietin receptor agonist, is used to reduce the risk of hemorrhage in patients with thrombocytopenia who are undergoing invasive procedures. Platelet transfusion was the standard treatment for thrombocytopenia; however, multiple platelet transfusions lead to the production of antiplatelet antibody. The effect of giving lusutrombopag three times or more has not been previously reported. In this study, we investigated the effect of lusutrombopag readministration in patients with thrombocytopenia.This study included 14 patients (total, 24 readministrations) who received lusutrombopag two times or more. Changes in platelet counts were evaluated. Treatment response was defined as an increased platelet count of ≥20 000/μL after lusutrombopag treatment.Lusutrombopag was given twice in nine patients, three times in three patients, five times in one patient, and six times in one patient. An elevated platelet count of20 000/μL was noted in only one of the 24 readministrations. There were no postoperative hemorrhagic complications, and no patient had an increased platelet count of200 000/μL. One patient had a portal venous mural thrombus; however, he was asymptomatic, and the thrombus resolved after anticoagulant treatment, without recurrence. The comparison between the first, second, and third or more treatments showed there was no significant difference in platelet increase.Repeated treatment of lusutrombopag is effective for CLD patients with thrombocytopenia. Moreover, three or more treatments with lusutrombopag showed equal effect compared with one and two treatments with the medication.

BackgroundTo investigate the von Willebrand factor to ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma (HCC) in cirrhosis.MethodsSerum levels of alpha-fetoprotein, des-γ-carboxy prothrombin,Lens culinarisagglutinin-reactive fraction of alpha-fetoprotein (alpha-fetoprotein-L3%), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2, as well as the plasma levels of von Willebrand factor antigen (von Willebrand factor: Ag) and ADAMTS13 activity (ADAMTS13:AC), were evaluated in 41 cirrhotic patients with HCC undergoing radiofrequency ablation and in 20 cirrhotic patients without HCC. The diagnostic accuracy of each biomarker was evaluated using the receiver operating characteristic curve analysis.ResultsThe von Willebrand factor: Ag and von Willebrand factor: Ag/ADAMTS13:AC ratios were significantly higher in cirrhotic patients with HCC than in those without HCC (p p ConclusionsThe von Willebrand factor: Ag/ADAMTS13:AC ratio can potentially serve as a novel biomarker for early diagnosis of HCC in cirrhotic patients.

3D object detection is becoming increasingly significant for emerging autonomous vehicles. Safety decision making and motion planning depend highly on the result of 3D object detection. Recent 3D detection models are optimized for cars, cyclists and pedestrians with multiple models. This is not desirable because multiple models require significant resources, which are also used for other algorithms, such as localization or object tracking. We present SECOND-DX for providing multi-class support for 3D object detection with only a single model and it enables the detection of all three classes of 3D objects scanned using LiDAR sensors in real time. We conducted experiments involving the KITTI 3D object dataset to show that SECOND-DX is more accuracy overall evaluation metrics without compromising execution speed when compared with algorithms extended to support multi-class detection with a single model. Additionally, SECOND-DX can detect pedestrian classes comparable with that of current models that are optimized to support only cyclists and pedestrians.

Coating is one of the most useful techniques for corrosion protection of metallic materials, however, if coating is damaged, local corrosion will occur. It is important to repair the damaged area of coating soon, however it needs much cost. From these, our research group develop the coating with self-healing property, called by self-healing coating. In this coating capsules containing healing-agent of coating are dispersed. If the coating is damaged, capsules will be broken at the same time. The healing-agent containing in capsules will flow out. The healing-agent reacts with the water vapor in the air to form a healing-structure and cover the damaged area of coating. The capsules contained healing-agent are produced as follows. First, the prepolymer, this is precursor of shell of capsules, drip into the aqueous solution dissolved glycerol, it hardly dissolves in the aqueous solution since the prepolymer is the oil phase. A mixture of oil droplets dispersed in the aqueous solution is formed. When this mixture is agitated with high speed, the oil droplets become micro spheres and emulsion forms. Furthermore, the reaction between prepolymer and glycerol occurs only at this interface between oil phase and water phase, spherical shaped capsules contained a healing-agent in a polyurethane shell can be produced. From our previous study, the coating with these spherical capsules has a self-healing property, because healing-structure could be observed at the damaged area of coating, but this structure covered damaged area, incompletely. It is necessary to improve self-healing property of coating. From the self-healing mechanism of the coating, the self-healing property of the coating will be strongly depended on the amount of healing-agent flowing to the damaged area. Therefore, we start the development of the coating with capsules with other shape such as fiber shape are dispersed in order to develop an advanced self-healing coating with higher healing property. Considering the procedure of capsule formation, the shape of capsules can be controlled by the agitation speed and viscosity of prepolymer solution. The shape of capsules will be related to the amount of healing-agent flow from capsules to the damaged area of coating, when coating is damaged. e.g. more amount of healing-agent will flow from fiber shaped capsules than that from spherical shaped capsules, because fiber capsules will be arranged horizontally to the metal substrate due to the flow during the formation of coating, and the more capsules will be broken, when vertical damage was formed in the coating. In this paper, the shape of capsules produced from prepolymer solution with high viscosity and self-healing property of coating dispersed with these capsules were discussed. The procedure synthesizing capsules is follows. The prepolymer prepared by reaction between TDI and glycerol in cyclohexanone as a solvent under 75 ℃, 600 rpm. In order to increase the prepolymer concentration and viscosity of solution, the heat treatment of prepolymer solution were performed under 140 ℃, 8 min. After heat treatment, IPDI as a healing-agent, and xylene as inhibiter solidification inside of capsules were added. First, this prepolymer solution drip into the sodium dodecyl sulfate and glycerol aqueous solution with low agitation speed (200 rpm). The prepolymer solution was not dissolved in the aqueous solution and small oil droplets were dispersed in the aqueous solution. The shape of some of droplets will be changed from spherical to long spheroidal or fiber by agitation of solution. Furthermore, the shell formation reaction take place only at the interface between oil and water phases, the spherical, spheroidal and fiber shaped capsules could be formed. For comparison, the capsules produced under high agitation speed (600 rpm) and those from prepolymer solution without heat treatment were also prepared. These capsules were observed by a scanning electron microscope SEM. Fig. 1-a show the shape of capsules prepared from prepolymer solution without heat treatment under high agitation speed, 600 rpm. From this image, only spherical with 20 - 60 µm of diameter can be observed. The shape of capsules from same prepolymer under low agitation speed, 200 rpm, also only spherical however the size of capsules is bit larger, the maximum diameter is about 80 µm, as shown in Fig. 1-b. The shape of the capsule the produced from prepolymer with heat treatment with high agitation speed, shown in Fig. 1-c, are similar to that without heat treatment. In contrast to these, the capsules produced from prepolymer with heat treatment under low agitation speed have some kinds of shape, such as spherical, spheroidal and long fiber. The coating dispersed with these shaped capsules will be also discussed. Figure 1

Al and Al alloys are used for many purposes, e.g. automobiles, heat exchanger, electronics, because of their good properties such as lightness, high heat conductivity, good processability, hardness, and so on. However, corrosion protection of these materials are not so high, corrosion of Al, such as pitting corrosion and atmospheric corrosion, will occur during operation. From this, some kinds of surface treatments are needed for improvement of corrosion protection of Al used for long-term. A polymeric coating is one of popular technique to improve the corrosion protection of substrate metal. However, corrosion protection of substrate covered by polymeric coating will easily lose by mechanical damage of the coating, leading to exposure of substrate metal to surroundings and to the local corrosion of substrate under damaged area of coating. From above, new surface treatment techniques for Al substrate to keep high corrosion protection, even the surface was damaged, are developed in our research group. This is a coating, with self-healing property by dispersion of micro-capsules containing the healing agent of coating. When the coating is damaged, the healing agent flow out to the damaged area of coating and react with water vapor to form the self-healing structure and this can be covered to the damaged area of coating. However, the procedure of synthesis of micro-capsule containing healing agent is too complex and yield of this is too low to synthesize the capsules with low cost. From above, we start to develop the new type of self-healing coating. This coating can be formed on Al alloy anodized. As you know by anodic oxidation of Al alloy, electrochemically in some kind of acidic solution, porous type of anodic oxide film can be formed on Al alloy, which have many small pores arranged regularity. Pores of porous film are used as a container of healing agent of coating. Firstly, the pores in porous film formed on Al alloy were filled by healing agent. And then, this sample was covered by polyurethane coating. If this coating was damaged, mechanically, healing agent contained in pores of porous film, flow out to the damaged area and reaction with water to form polyurea as a self-healing structure and cover to the exposed Al substrate. In this study, healing property of this type of self-healing coating is investigated by observation of the surface of specimen with scratchin. #1050 Al alloy (size : 20 mm × 20 mm × 1.5 mmt) were electro-polished in CH3COOH / HClO4solution. And then anodic oxide films were formed on pretreated specimens by anodizing in (COOH)2 solution with a constant current density of 200 Am-2 for 1 hr. The anodized specimens immersed in IPDI for 100 min with ultrasonic bath, in order to promote that IPDI soln. to penetrate to pores of the porous film. After wiping the surface of the specimen by soft tissue, then a mixed solution of ethylene glycol and prepolymer of polyurethane coating was purged to specimen surface and leave for 24 h to form the polyurethane coating on anodized Al alloy surface. The prepolymer was synthesized by using the mixture of TDI, glycerol and cyclohexanone. Mixture was agitated under 600 rpm of stirring rate for 24 h. In order to remove the water dissolved in this mixture, the first 1 h of agitation, the mixture was bubbled by passing pure N2 gas. During the agitation, TDI reacts with glycerol to form the precursor of polyurethane. After specimen damaged by scratching with 7 N of load and ageing, corrosion protection of damaged Al alloy specimens with polyurethane coating were evaluated by immersion tests. The coated specimens were immersed to CuSO4 / KCl solution kept at room temperature for 1 day. After the immersion tests, to remove the coating, the specimens were immersed to the coating remover solution. And then, specimens were immersed to H3PO4 / K2CrO4 solution. Surfaces after immersion tests and removing of surface layer were observed by scanning electron microscopy (SEM). From the SEM observation for damaged specimen covered with porous film and normal coating, as shown in Fig. 1-a, sharp and deep scar can be seen at the canter of image of specimen surface. The scar can be seen on the image of damaged specimen with self-healing coating on anodized specimen, however, unique structure also can be observed at the bottom of scar, shown in Fig .1-b. This structure may be formed by the reaction between water in air and IPDI contained in the pore of porous film on Al alloy, thus, this coating has a self-healing property. Figure 1

Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload., 博士（医学）・甲第779号・令和3年3月15日, © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

It is unclear whether the link between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) is mediated by common risk factors. We aimed to elucidate the association between NAFLD and CKD using propensity score (PS)-matched analysis. We assessed 3725 Japanese individuals, excluding those with hepatitis B or C infection and men and women who consumed &gt, 30 and &gt, 20 g/day of alcohol, respectively. Of these, we enrolled 1097 Japanese subjects with NAFLD diagnosed by ultrasonography and 1097 PS-matched subjects without NAFLD. The prevalence of CKD was higher in subjects with NAFLD than in those without NAFLD before PS matching, but there was no significant difference between these groups in terms of CKD prevalence after PS matching. There was no difference in the prevalence of CKD between those with and without NAFLD in the subgroup analyses. Logistic regression analysis demonstrated that obesity, hypertension, and hyperuricemia were independent predictors of CKD, but NAFLD was not independently associated with CKD. In subjects with NAFLD, obesity, hypertension, and hyperuricemia were independent predictors of CKD. Thus, the link between NAFLD and CKD may be mediated by common risk factors. We recommend screening for CKD when patients with NAFLD have the aforementioned comorbidities.

Depth completion, which interpolates dense depth maps based on sparse inputs acquired from 3D LiDAR sensors, enhances perception capabilities of autonomous driving using object detection and 3D mapping. Recent studies on depth completion have leveraged deep learning approaches applying traditional convolutional neural networks to prediction of invisible information in sparse and irregular inputs. Due to the lack of local and global structures such as object boundary cues, however, the predicted information results in unstructured and noisy depth maps. This paper presents a supervised depth completion method using an adversarial network based only on sparse inputs. In the presented method, a fully convolutional depth completion network, along with the adversarial network, is designed to find and correct inconsistencies between ground truth distributions and the resulting depth maps interpolated by the depth completion network. This leads to more realistic and structured depth images without compromising runtime performance of inference. Experimental results based on the KITTI depth completion benchmark show that the presented adversarial network method achieves about 60% improvements for the accuracy of inference and increases the rate of convergence during training.

Aim The roles of hepatic progenitor cells (HPCs) in regeneration of a diseased liver are unclear. Hepatic stellate cells (HSCs) contribute to liver fibrosis but are also a component of the HPC niche. Hepatic progenitor cells expand along with HSC activation and liver fibrosis. However, little is known about the interplay of liver fibrosis and HPC-mediated liver regeneration. This study aimed to investigate HSCs and HPCs in liver regeneration. Methods Liver injury in mice was induced with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, and HPC expansion and fibrosis were assessed. An angiotensin II type 1 receptor blocker (ARB) was administered to assess its effect on fibrosis and regeneration. Results Treatment with ARB attenuated fibrosis and expansion of α-smooth muscle actin-positive activated HSCs as indicated by increased liver weight and Ki-67-positive hepatocytes. Immunohistochemical staining suggested that HPC differentiation was shifted toward hepatocytes (HCs) when ARB treatment decreased HPC encapsulation by HSCs and extracellular matrix. Conditioned medium produced by culturing the human HSC LX-2 line strongly augmented differentiation to biliary epithelial cells (BECs) but inhibited that to HCs. Activated HSCs expressed Jagged1, a NOTCH ligand, which plays a central role in differentiation of HPCs toward BECs. Conclusions Hepatic stellate cells, the HPC niche cells, control differentiation of HPCs, directing them toward BECs rather than HCs in a diseased liver model. Antifibrosis treatment with an ARB preferentially redirects HPC differentiation toward HCs by blocking the NOTCH pathway in the HPC niche, resulting in more efficient HPC-mediated liver regeneration.

Depression is a major reason for interferon (IFN) therapy cessation. IFN-free direct-acting antiviral (DAA) therapy for depression is not well-documented. Thus, four different IFN-free regimens were assessed in genotype-1 hepatitis C virus (HCV) patients with depression. Overall, 287 HCV genotype-1 patients who received combination therapies with IFN-free DAAs of daclatasvir/asunaprevir (DCV/ASV) (n=84), sofosbuvir/ledipasvir (SOF/LDV) (n=95), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) (n=74), and elbasvir/grazoprevir (EBR/GZR) (n=34) were included. Treatment-induced depression as a complication of HCV therapy in IFN-free DAA regimens was assessed. The severity of depression was evaluated using the Beck Depression Inventory-II (BDI-II) questionnaire. It was demonstrated that all four DAA regimens achieved similar high efficacy in Japanese patients with HCV genotype-1 infection. Moreover, in seven patients with depression who received the 24-week DCV/ASV treatment regimen, the BDI-II scores significantly increased at week 4 as compared with pretreatment values; furthermore, they decreased below baseline at week 12 despite the rapid decline of serum HCV levels after the initiation of DCV/ASV therapy. The BDI-II scores gradually decreased during therapy in the remaining 77 DCV/ASV-treated patients without depression. The BDI-II scores showed a significant decrease from baseline to the end of treatment with 12-week regimens, including SOF/LDV and EBR/GZR. The 12-week DAA regimen of SOF/LDV and EBR/GZR can be safely used with high efficacy in patients with genotype-1 HCV infection, including those with depression.

Proton pump inhibitors (PPIs) are frequently prescribed in patients with cirrhosis, but this therapy entails potential complications. We aimed to investigate the influence of PPI use on intestinal permeability in patients with cirrhosis.We recruited 228 patients with cirrhosis and divided them into four groups. Group (Gp)1 comprised patients receiving a PPI with concurrent neomycin (NEO) (PPI-NEO group, n = 14 [6.1%]), Gp2 and Gp3 comprised those receiving either PPI or NEO (PPI group, n = 91 [39.9%]; and NEO group, n = 11 [4.4%]), and Gp4 comprised those receiving neither of these medications (control group; n = 112 [49.1%]). We assessed the intestinal permeability by measuring endotoxin activity (EA) using a luminol chemiluminescence method.Endotoxin activity levels were significantly higher in patients with Child B cirrhosis than in those with Child A cirrhosis, but we found no significant differences in EA levels between patients with Child C cirrhosis and those with either Child A or B cirrhosis. We observed no significant differences in EA levels among groups 1-4. Patients without antibiotic exposure (n = 203), comprising 91 patients on PPI therapy (Gp2) and 112 no-PPI-therapy controls (Gp4), were subdivided according to Child-Pugh (CP) classification. We found no significant differences in EA levels between Gp2 and Gp4 in either CP class.Our results suggest that PPI usage does not have a significant impact on serum levels of gut-derived endotoxins, which are already elevated because of the increased intestinal permeability in patients with cirrhosis.

Several noninvasive biomarkers are available for diagnosing liver fibrosis stage and predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis and liver cirrhosis. However, these biomarkers are not sufficiently accurate. Recently, von Willebrand factor (VWF) has been related to angiogenesis and apoptosis. Furthermore, VWF is associated with hepatic spare ability and HCC.We aimed to determine whether VWF is a potential biomarker for liver fibrosis and HCC development.Two hundred and twelve patients with chronic hepatitis B and C were recruited. VWF antigen (VWF: Ag) levels in each patient were determined via enzyme-linked immunosorbent assay. Univariable and multivariable analyses were used to determine the risk factor of HCC.The VWF: Ag levels were higher in patients with severe liver fibrosis stage and/or HCC development than in those without. The area under the curve of VWF: Ag for diagnosis of severe liver fibrosis stage was 0.721. Multivariable analysis showed that only VWF: Ag was a predictive biomarker for HCC development.VWF: Ag is related to liver fibrosis and may be useful for predicting HCC development. VWF is a potentially useful biomarker to diagnose severe liver fibrosis and predict HCC development.

Social anxiety disorder is a common psychiatric disorder. The gaze of others is known to frequently induce social anxiety. We conducted a gaze detection experiment to examine the effects of social anxiety on autonomic response, namely heart rate (HR) response. We used the maximum HR deceleration between 0 s and 3 s after stimulus onset as an indicator of emotional stress. Participants were assigned to a high social anxiety (HSA) or low social anxiety (LSA) group on the basis of cut-off scores indicative of clinical levels of stress as per the Japanese version of the Liebowitz Social Anxiety Scale (LSAS-J). Our results showed that HR deceleration was greater for the HSA compared with the LSA group. Moreover, the higher the LSAS-J score was, the greater the increase was in HR deceleration (correlation coefficient rs = 0.52, p < 0.01). Our results suggest that the eye gaze of others can be processed as a threat in individuals with a high tendency towards social anxiety.

The farnesoid X receptor (FXR) agonist, a bile acid-activated nuclear receptor, has been shown to improve the histologic features of nonalcoholic steatohepatitis (NASH); however, a satisfactory effect on hepatic fibrosis has not been achieved. We aimed to investigate the combined effect of FXR agonist and angiotensin II type 1 receptor blocker on hepatic fibrogenesis in rat models of NASH. For 8 weeks, two rat models of NASH were developed. Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered intraperitoneal injections of 1 mL/kg pig serum (PS) twice a week, whereas Fischer-344 rats were fed a choline-deficient, L-amino acid-defined diet (CDAA). The in vitro and in vivo effects of an FXR agonist (INT747) and an angiotensin II type 1 receptor blocker (losartan) on hepatic fibrogenesis were evaluated. In PS-administered OLETF rats, INT747 and losartan had potent inhibitory effects on hepatic fibrogenesis with suppression of hepatic stellate cell (HSC) activation and expression of transforming growth factor β1 and toll-like receptor 4. INT747 decreased intestinal permeability by ameliorating zonula occuludens-1 disruption, whereas losartan directly suppressed activated-HSC (Ac-HSC) regulation. The in vitro inhibitory effects of INT747 and losartan on messenger RNA expressions of transforming growth factor β1, toll-like receptor 4, and myeloid differentiation factor 88 and phosphorylation of nuclear factor-κB and mothers against decapentaplegic homolog 3 in Ac-HSC were almost in parallel. Losartan directly inhibited the regulation of Ac-HSC. Likewise, INT747 in combination with losartan was beneficial on hepatic fibrogenesis in rats fed with CDAA diet. The therapeutic effects of these agents were almost comparable between PS-administered OLETF and CDAA-treated rats. Conclusion: INT747 and losartan synergistically suppressed hepatic fibrogenesis by reversing gut barrier dysfunction and inhibiting Ac-HSC proliferation. Combined therapy may represent a promising novel approach for NASH. (Hepatology Communications 2017;1:928-945).

The optimal management of microcystic lymphatic malformations (LMs) in children has not been established. We describe how we used the Ligasure™ Vessel Sealing System (LVSS) to achieve partial resection of refractory microcystic LMs in a 1-year-old boy. The child was admitted in respiratory distress caused by infection and swelling of cervical LMs. The LMs had been diagnosed prenatally, but had not decreased in size despite three treatments with OK-432 sclerotherapy. We performed direct dissection of the microcystic LMs using the LVSS with minimal intraoperative blood loss or lymphatic leakage. The LMs were resected as completely as possible without damage to the jugular vein or major nerves. His postoperative course was uneventful. Histological examination revealed complete sealing of the lymphovascular channels with obliterated lumens. Resection using the LVSS is effective and easy to perform for partial resection of microcystic LMs. We recommend the combination of initial OK-432 injection therapy and subsequent partial resection using the LVSS for refractory microcystic LMs.

Intrahepatic bile duct (IHBD) stones are one of the most complicated morbidities that occur after Roux-en-Y hepaticojejunostomy (RYH); however, the optimal therapeutic approach is controversial.Double-balloon enteroscopy (DBE) has been widely and frequently performed even in pediatric patients. We herein report the successful management of IHBD stones by biliary lithotripsy using DBE after RYH for a choledochal cyst (CC). DBE has made it possible to perform endoscopic therapeutic intervention, including balloon dilatation of an anastomotic stricture and removal of IHBD stones, without any major complications.DBE is a less invasive and safe treatment method for IHBD stones in pediatric patients, which is capable of reaching the bilioenteric anastomosis after RYH for CC.

Aim Assisted reproductive technology (ART) has increased the incidences of multiple gestations and low birth weights, which frequently warrant pediatric surgery. ART may have also increased the rate of birth defects. In this study, we aimed to determine whether infants conceived after ART required neonatal surgery more frequently compared with naturally conceived infants. Material and Methods Our study population comprised 1891 infants (160 ART (+) and 1731 ART (−)) who were admitted to our neonatal intensive care unit during a 5-year period (January 2006–December 2010); of these, 198 infants (9 ART (+) and 189 ART (−)), with diseases requiring surgery, were referred to pediatric surgeons (consultation cases). We examined the following: (i) factors potentially increasing the requirement for surgery; (ii) frequency of birth defects; and (iii) maternal factors that may increase the need for surgery. Results A significantly higher incidence of multiple gestation and low birth weight was observed in the ART (+) group than the ART (−) group. However, ART did not yield a higher rate of surgery and birth defects: overall, the rate of surgery was 4% (7/160) in the ART (+) group and 8% (143/1731) in the ART (−) group. Of 198 consultation cases, the percentage of infants actually requiring surgery was approximately the same in the ART (+) group (7/9 [78%]) and the ART (−) group (143/189 [76%]). Conclusion Infants conceived after ART comprised a small proportion of neonatal surgery cases, and did not require surgery more frequently.

Background Although complete excision is the standard treatment for pyriform sinus fistula (PSF), it has recently been suggested that chemocauterization via the internal orifice of the fistula could be an effective non-invasive treatment for the condition. The present report describes the details of our experience with and the efficacy of endoscopic chemocauterization for pediatric PSF. Method Between January 2010 and June 2015, four patients were diagnosed with PSF and scheduled to undergo endoscopic chemocauterization. Under general anesthesia, trichloroacetic acid (TCA) solution was endoscopically injected through the opening of the fistula using a fine plastic tube. Esophagogram was obtained at 3 weeks after the procedure to search for recurrence. Complete closure of the fistula was confirmed on endoscopy at 2–3 months after chemocauterization. Results Two of the four patients were treated once, and the remaining patients required further chemocauterization procedures. No recurrence developed in any patient after it had been confirmed that the fistula's internal orifice had been obliterated. Some transient complications, such as sore throat, nausea or temporary vocal fold paresis, occurred. Conclusion Chemocauterization with TCA seems to be a useful first-choice treatment for PSF.

Novel azolate-type ionic liquids (ILs), alkyltributylphosphonium benzimidazolates (alkyl chain: methyl, butyl, and octyl), were prepared by neutralization of the corresponding alkyltributylphosphon...

Nonoperative management is acceptable treatment for minor pancreatic injuries. However, management of major pancreatic duct injury in children remains controversial. We present our experience in treating isolated pancreatic duct injury. We describe the cases of three male patients treated for complete pancreatic duct disruption in the past 5 years at our institution. We performed pancreatic duct repair to avoid distal pancreatectomy and to maintain normal pancreatic function. All patients underwent enhanced computed tomography and endoscopic retrograde cholangiopancreatography in the early period. The injuries were classified as grade III according to the American Association for the Surgery of Trauma classification. In two cases, we performed end-to-end anastomosis of the pancreatic duct during the delayed period. In the third case, we placed a stent across the disruption to the distal pancreatic duct. The patients’ postoperative courses were uneventful, and the average hospitalization was 25.6 days after the procedure. At a median follow-up of 36 months (range 14–54 months), all patients remain asymptomatic, with normal pancreatic function, but with persistent distal pancreatic duct dilatation. We suggest that distal pancreatectomy should not be routinely performed in patients with isolated pancreatic duct injury.

Neonates with congenital tracheal stenosis (CTS) sometimes develop respiratory distress and may be difficult to intubate. We used balloon tracheoplasty with a rigid bronchoscope for emergency airway management in neonates with symptomatic CTS. Herein, we describe the balloon tracheoplasty procedure and the early outcomes following its use as the initial treatment of neonatal symptomatic CTS. We performed a retrospective analysis of five neonates with CTS who were initially treated with balloon tracheoplasty at our institution from January 2010 to December 2013. Five patients with a mean birthweight of 2,117 g were treated during the study period. Of these, four developed respiratory distress after birth, and all patients had difficult intubations. In all five patients, definitive diagnosis of CTS was made by rigid bronchoscopy and 3-dimensional reconstruction scan. A total of nine balloon dilatations were performed in five patients. Following balloon tracheoplasty, two patients were extubated, one was extubated after resection and end-to-end anastomosis following initial balloon dilatation, and one remained hospitalized with tracheostomy for tracheomalacia. The remaining patient died from tracheal bleeding associated with congenital heart disease. Although our sample size was small, balloon tracheoplasty is a potentially effective initial treatment for selected cases with neonatal symptomatic CTS.

Introduction: Limited data exist comparing the efficacy and safety of bumetanide- or metolazone-based diuretic regimens to furosemide in acute heart failure (HF). Our purpose was to evaluate the comparative effect on urine output (UO) and renal function between these regimens. Methods: A retrospective study of hospitalized HF patients treated with continuous infusion furosemide (CIF), combination furosemide plus metolazone (F + M), or continuous infusion bumetanide (CIB). Primary end points were between regimen comparisons for change in mean hourly UO versus baseline and incidence of worsening renal function. Results: Data on 242 patients with acute HF (age 58 ± 12 years, 63% male, left ventricular ejection fraction 38% ± 17%) were analyzed (160 CIF, 42 F + M, 40 CIB). The mean duration of diuretic regimens was 41 ± 32 hours. Compared to baseline, all regimens increased mean hourly UO ( P < .0001 for all), with greater increases with F + M (109 ± 171 mL) and CIB (90 ± 90 mL) compared to CIF (48 ± 103 mL; P = .009). Incidence of worsening renal function was not different between regimens; however, blood urea nitrogen (BUN) tended to increase more with F + M (4.4 ± 9.8 mg/dL) and CIB (4.3 ± 9.7 mg/dL) than CIF (1.8 ± 10.8 mg/dL), P = .09. The incidence of hyponatremia was higher with F + M and CIB. Differences in UO, BUN, and hyponatremia were retained in the subgroup analysis limited to patients with baseline serum creatinine Conclusion: Compared to CIF, F + M or CIB was associated with greater increases in UO. No difference in the incidence of worsening renal function was found; however, electrolyte abnormalities may be more prevalent when furosemide is combined with metolazone or when bumetanide is used. These therapeutic differences warrant prospective study.

Double-balloon enteroscopy (DBE) is a useful and feasible modality for evaluating small intestinal lesions, even in children. DBE makes it possible to perform biopsy, diagnosis, polypectomy and endoscopic therapies including hemostasis, tattooing and clipping of the small intestinal lesions. However, endoscopic procedures in the small intestines of children are more difficult than in adults, because the intestinal wall is thin and the lumen is narrow. A novel hybrid treatment was developed using DBE for small bowel lesions combined with transumbilical minimal incision surgery. This hybrid treatment is safe, effective, provides excellent cosmetic results and can be used as an alternative for traditional open laparotomy or endoscopic surgery.

A mesenchymal hamartoma of the chest wall is a rare benign tumor. Each case has a different clinical course as well as different radiological imaging findings, and various histopathological diagnoses. In addition, mesenchymal hamartoma is sometimes mistaken for a malignant tumor. This report presents a neonatal case of mesenchymal hamartoma of the bilateral chest wall.

A mixture of tetra-n-butylphosphonium benzimidazolate and benzimidazole is readily prepared as a proton conductive liquid having thermal stability up to 300 °C.

Serum retinol-binding protein (RBP4) is secreted by liver and adipocytes and is implicated in systemic insulin resistance in rodents and humans. RBP4 normally binds to the larger transthyretin (TTR) homotetramer, forming a protein complex that reduces renal clearance of RBP4. To determine whether alterations in RBP4-TTR binding contribute to elevated plasma RBP4 levels in insulin-resistant states, we investigated RBP4-TTR interactions in leptin-deficient ob/ob mice and high-fat-fed obese mice (HFD). Gel filtration chromatography of plasma showed that 88–94% of RBP4 is contained within the RBP4-TTR complex in ob/ob and lean mice. Coimmunoprecipitation with an RBP4 antibody brought down stoichiometrically equal amounts of TTR and RBP4, indicating that TTR was not more saturated with RBP4 in ob/ob mice than in controls. However, plasma TTR levels were elevated approximately fourfold in ob/ob mice vs. controls. RBP4 injected intravenously in lean mice cleared rapidly, whereas the t1/2for disappearance was approximately twofold longer in ob/ob plasma. Urinary fractional excretion of RBP4 was reduced in ob/ob mice, consistent with increased retention. In HFD mice, plasma TTR levels and clearance of injected RBP4 were similar to chow-fed controls. Hepatic TTR mRNA levels were elevated approximately twofold in ob/ob but not in HFD mice. Since elevated circulating RBP4 causes insulin resistance and glucose intolerance in mice, these findings suggest that increased TTR or alterations in RBP4-TTR binding may contribute to insulin resistance by stabilizing RBP4 at higher steady-state concentrations in circulation. Lowering TTR levels or interfering with RBP4-TTR binding may enhance insulin sensitivity in obesity and type 2 diabetes.

The purpose of this study is clarification of crystallization behaviors of linear polymers in spin-coating film-forming processes on the molecular scale by time-resolved measurements of grazing-incidence small-angle and wide-angle X-ray scattering (GISAXS and GIWAXS: GISWAXS) measurements using synchrotron radiation. A sample used in this study was a commercially-available poly(3-hydroxybutyrate) (P3HB) (Sigma-Aldrich, Mw=437,000, Mw/Mn=1.67, Tg= 276 K) which was a biobased and biocompatible polyester. By spin-coating at rotational speeds of 1000 – 4000 rpm with using 0.49, 1.0, and 2.1wt% chloroform solutions of the P3HB, P3HB thin films with thicknesses of ca. 30 –600 nm were formed on silicon substrates. In these spin-coating processes at 296K, GISAXS and GIWAXS patterns from the sample on the substrate were simultaneously detected at BL45XU of SPring-8 (Hyogo, Japan). At the beginning of spin-coating, an isotropic scattering pattern from the solution was observed. Next, anisotropic Bragg reflections from oriented orthorhombic crystals of P3HB appeared and increased in intensity for several tens seconds. This indicated that P3HB chains crystallized as chloroform evaporated from the sample. It was also found that P3HB orthorhombic crystal having edge-on orientation was preferentially formed in thinner films. When the rotational speed of the substrate increased, the apparent induction period of crystallization slightly increased and the crystal growth rate decreased. This implied that the chain mobility of P3HB for crystallization might reduce due to a reduction in quantity of the solvent molecules and an increase in magnitude of the centrifugal force. These results obtained in this research would be important knowledge to improve film processing technologies for biobased polymeric materials.

Growth hormone (GH) and prolactin (PRL) binding to their receptors, which belong to the cytokine receptor superfamily, activate Janus kinase (JAK) 2 tyrosine kinase, thereby leading to their biological actions. We recently showed that GH mainly stimulated tyrosine phosphorylation of epidermal growth factor receptor and its association with Grb2, and concomitantly stimulated mitogen-activated protein kinase activity in liver, a major target tissue. Using specific antibodies, we now show that GH was also able to induce tyrosine phosphorylation of insulin receptor substrate (IRS)-1/IRS-2 in liver. In addition, the major tyrosine-phosphorylated protein in anti-p85 phosphatidylinositol 3-kinase (PI3-kinase) immunoprecipitate from liver of wild-type mice was IRS-1, and IRS-2 in IRS-1 deficient mice, but not epidermal growth factor receptor. These data suggest that tyrosine phosphorylation of IRS-1 may be a major mechanism for GH-induced PI3-kinase activation in physiological target organ of GH, liver. We also show that PRL was able to induce tyrosine phosphorylation of both IRS-1 and IRS-2 in COS cells transiently transfected with PRLR and in CHO-PRLR cells. Moreover, we show that tyrosine phosphorylation of IRS-3 was induced by both GH and PRL in COS cells transiently transfected with IRS-3 and their cognate receptors. By using the JAK2-deficient cell lines or by expressing a dominant negative JAK2 mutant, we show that JAK2 is required for the GH- and PRL-dependent tyrosine phosphorylation of IRS-1, -2, and -3. Finally, a specific PI3-kinase inhibitor, wortmannin, completely blocked the anti-lipolytic effect of GH in 3T3 L1 adipocytes. Taken together, the role of IRS-1, -2, and -3 in GH and PRL signalings appears to be phosphorylated by JAK2, thereby providing docking sites for p85 PI3-kinase and activating PI3-kinase and its downstream biological effects.

Tetra-n-butylphosphonium benzimidazolate ([P4444][BzIm]) was prepared by mixing equimolar amounts of tetra-n-butylphosphonium hydroxide ([P4444][OH]) and neutral benzimidazole (BzIm). This salt had a melting point (Tm) of 55 °C and good thermal stability up to 300 °C. The equimolar mixture had ionic conductivity of 1.3 × 10−4 S cm−1 at 60 °C. Unequimolar mixing of these components gave rise either to hydroxide ions or proton conductive materials, depending on the mixing ratio. Addition of excess [P4444][OH] to benzimidazole (molar ratio of benzimidazole:[P4444][OH] = 1 : 2) led to good ionic conductivity (1.3 × 10−3 S cm−1 at 60 °C); this is attributed not only to [P4444] cations and [BzIm] anions but also hydroxide anions. Mixtures containing excess benzimidazole were expected to be proton conductors. As an example, the mixture with molar ratio benzimidazole : [P4444][OH] of 3 : 2 had ionic conductivity of 4.1 × 10−4 S cm−1 at 60 °C and a decomposition temperature (Td) above 300 °C. This conductivity was higher than the value expected from the Tg and other physicochemical properties of [P4444][BzIm], suggesting the contribution of proton conduction. Proton conduction was further confirmed by chronoamperometric measurement using electrochemical cells equipped with platinum electrodes.