Publications by authors named "Hiromi Fukuda"

37 Publications

Novel Endoscopic Therapy for Gastric Varices Using Direct Forward-Viewing Endoscopic Ultrasonography.

Case Rep Gastroenterol 2021 Jan-Apr;15(1):28-34. Epub 2021 Jan 21.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan.

Gastric varices (GV) carry a high risk of massive hemorrhage because of potential rupture. To reduce the risk associated with GV, patients need to undergo hemostatic and preventive treatment. The objective of this retrospective study was to evaluate the usefulness of a new method, direct forward-viewing endoscopic ultrasonography (DFV-EUS) for the treatment of GV. We performed endoscopic injection sclerotherapy with histoacryl (EIS-HA) using DFV-EUS for GV in four patients. The paracentesis success rate was 75% (3/4). DFV-EUS has a significant advantage for the treatment of GV in that it can show physicians endoscopic and ultrasound views in real time during the delivery of the sclerosant into the GV. However, the proper use of the ultrasound view must be elucidated through further research for safer and more effective therapy. In the presence of distance between the mucosal surface and vascular lumen or when the blood flow site requires puncture as an additional treatment, DFV-EUS might be a good candidate for the treatment of GV. Altogether, EIS-HA with DFV-EUS might be a new therapeutic option for patients with GV.
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http://dx.doi.org/10.1159/000510132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879242PMC
January 2021

Elobixibat, an ileal bile acid transporter inhibitor, ameliorates non-alcoholic steatohepatitis in mice.

Hepatol Int 2021 Jan 4. Epub 2021 Jan 4.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, Fukuoka, 814-0180, Japan.

Background: Recent studies have suggested that several types of toxic bile acids (BAs) are involved in the pathogenesis of non-alcoholic steatohepatitis (NASH). In the present study, we aimed to determine whether elobixibat, an ileal bile acid transporter (IBAT) inhibitor, would ameliorate NASH in mice.

Methods: C57BL/6N mice were fed a methionine and choline-deficient (MCD) to induce NASH or standard diet as control for 8 weeks (n = 5 per group). The MCD diet-fed mice were administered elobixibat 5 days a week for 4 weeks by gavage (n = 5). The effects of the treatments on liver histopathology, proinflammatory cytokine concentrations, intestinal epithelial tight junctions, and the intestinal microbial composition were then assessed.

Results: In MCD-fed mice, hepatic fibrosis and inflammatory cell infiltration developed, and the serum aspartate transaminase activity and BA concentration were higher than the control. In addition, the proinflammatory cytokine concentrations were high in the liver and mesenteric lymph nodes (MLN), and the expression of intestinal epithelium tight junction proteins, claudin1, was increased. In the intestinal microbial composition, the abundance of the Lachnospiraceae and Ruminococcaeae were decreased, whereas that of the Enterobacteriaceae was increased. Treatment with elobixibat reduced the serum BA and increased the fecal BA concentration, and ameliorated the liver inflammation and fibrosis. It also reduced the expression of proinflammatory cytokines in the liver and MLNs, and transforming growth factor-β expression in the liver. Finally, elobixibat normalized intestinal tight junction protein level and the composition of the intestinal microbiota.

Conclusion: Elobixibat ameliorates NASH-related histopathology, reduces cytokine expression, and normalizes the intestinal microbial composition in MCD-fed mice, which suggests that it may represent a promising candidate for the therapy of NASH.
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http://dx.doi.org/10.1007/s12072-020-10107-0DOI Listing
January 2021

Hepatitis B virus core-related antigen is useful for surveillance of hepatocellular carcinoma recurrence in a patient with occult hepatitis B virus infection: Case report.

Clin Case Rep 2020 Dec 16;8(12):3032-3037. Epub 2020 Sep 16.

Department of Gastroenterology and Medicine Faculty of Medicine Fukuoka University Fukuoka Japan.

Serum HBV core-related antigen (HBcrAg) is useful for detecting HCC in patients with occult HBV infection. Surveillance for HCC is needed in patients who are positive for HBcrAg, even if they are negative for HBsAg and HBV DNA.
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http://dx.doi.org/10.1002/ccr3.3360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752430PMC
December 2020

Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy.

Neurol Genet 2020 Dec 19;6(6):e531. Epub 2020 Nov 19.

Department of Neurology (T.I., T.O., Y. Saitoh, S.O., Y.T.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Human Genetics (K.S., A.F., H.F., N. Miyake, T.M., N. Matsumoto), Yokohama City University Graduate School of Medicine, Kanagawa; Department of Pathology and Laboratory Medicine (T.S., Y. Saito), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (T.Y.), Iida Municipal Hospital, Shinshu University School of Medicine, Nagano; Department of Medicine (Neurology and Rheumatology) (Y.M., Y. Sekijima), Shinshu University School of Medicine, Nagano; and Department of Neurology and Stroke Medicine (H.F.), Yokohama City University, Japan.

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http://dx.doi.org/10.1212/NXG.0000000000000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713717PMC
December 2020

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Hum Mutat 2021 Jan 11;42(1):50-65. Epub 2020 Nov 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
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http://dx.doi.org/10.1002/humu.24129DOI Listing
January 2021

Irsogladine maleate alters expression of a tight junction protein in portal hypertensive gastropathy.

J Gastroenterol Hepatol 2020 Sep 14. Epub 2020 Sep 14.

Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Background And Aim: Portal hypertensive gastropathy (PHG) is characterized by noninflammatory edema and vasodilatation of the lamina propria of the mucosal epithelium. In addition, the alterations of intercellular junction proteins and dilatation of the endothelial gaps have been reported. In this study, we examined whether irsogladine maleate (IM), a gastric mucosal protective agent, has the potential to improve PHG by restoration of tight junctions (TJs).

Methods: Twenty-four patients with PHG were registered and randomly assigned into two groups: 12 patients in the IM-administration group and 12 patients in the non-administration group. In the administration group, IM (4 mg/day) was administered orally for 12 weeks. Gastric mucosa with a red color in patients with PHG were obtained endoscopically on the registration day and 12 weeks later. The endoscopic findings were evaluated, an immunohistochemical analysis of claudin-3 (a TJ protein) expression in gastric mucosal tissues by a laser microscope was performed, and claudin-3 expression was quantified by western blot analysis.

Results: Irsogladine maleate improved the degree of PHG in 2/12 patients endoscopically, in contrast to none of the 12 patients in the non-administration group. Immunohistochemical analysis showed that expression of claudin-3 increased in 8/12 patients in the IM-administration group and 2/12 patients in the non-administration group (P = 0.036). Western blot analysis revealed that the increase in claudin-3 after 12 weeks was significantly higher in the IM-administration group than in the non-administration group (P = 0.010).

Conclusions: The present pilot study suggested that IM might improve the gastric mucosa in PHG through restoration of TJ-protein claudin-3.
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http://dx.doi.org/10.1111/jgh.15259DOI Listing
September 2020

Exploratory Research on the Relationship between Human Gut Microbiota and Portal Hypertension.

Intern Med 2020 1;59(17):2089-2094. Epub 2020 Sep 1.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan.

Objective The relationship between gut microbiota and portal hypertension remains unclear. We investigated the characteristics of the gut microbiota in portal hypertension patients with esophago-gastric varices and liver cirrhosis. Methods Thirty-six patients (12 patients with portal hypertension, 12 healthy controls, and 12 non-cirrhosis patients) were enrolled in this university hospital study. Intestinal bacteria and statistical analyses were performed up to the genus level using the terminal restriction fragment length polymorphism method targeting 16S ribosomal RNA genes, with diversified regions characterizing each bacterium. Results Levels of Lactobacillales were significantly higher (p=0.045) and those of Clostridium cluster IV significantly lower (p=0.014) in patients with portal hypertension than in other patients. This Clostridium cluster contains many butanoic acid-producing strains, including Ruminococcace and Faecalibacterium prausnitzii. Clostridium cluster IX levels were also significantly lower (p=0.045) in portal hypertension patients than in other patients. There are many strains of Clostridium that produce propionic acid, and the effects on the host and the function of these bacterial species in the human intestine remain unknown. Regarding the Bifidobacterium genus, which is supposed to decrease as a result of cirrhosis, no significant decrease was observed in this study. Conclusion In the present study, we provided information on the characteristics of the gut microbiota of portal hypertension patients with esophago-gastric varices due to liver cirrhosis. In the future, we aim to develop probiotic treatments following further analyses that include the species level, such as the intestinal flora analysis method and next-generation sequencers.
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http://dx.doi.org/10.2169/internalmedicine.4628-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516306PMC
September 2020

Reduction in Tumor Stain at 2 Weeks after Treatment Initiation Is a Predictor of the Efficacy of Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma.

Oncology 2020 2;98(11):779-786. Epub 2020 Sep 2.

Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Background And Aims: Lenvatinib is an oral anticancer drug for patients with unresectable advanced hepatocellular carcinoma (HCC). We evaluated whether a reduction in tumor stain at 2 weeks after lenvatinib treatment in patients with unresectable HCC is a predictor of early treatment efficacy at 12 weeks.

Patients And Methods: Of the 23 patients who initiated lenvatinib treatment between April 2018 and January 2019, treatment efficacy was measured in 15 patients for more than 12 weeks after treatment. Changes in tumor stain, tumor size on contrast-enhanced computed tomography (CT), and serum levels of tumor markers were evaluated 2 weeks after lenvatinib treatment. Therapeutic efficacy was assessed by tumor stain and tumor size by contrast-enhanced CT within the first 12 weeks, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines.

Results: At 12 weeks, efficacy evaluation of 15 patients revealed that 11 of them experienced partial responses, for a response rate of 73.3%. In the first 2 weeks, 13 patients (86.7%) experienced a decreased tumor stain, including 10 responders (90.9%) and 3 non-responders (75.0%). All patients in the non-responder group had required a lenvatinib dose reduction due to adverse events within 12 weeks. On contrast-enhanced CT, the change rate of tumor stain to HCC at 2 weeks after treatment was <0.8 among 10 responders (90.9%) and 1 non-responder (25.0%; p = 0.033). No significant differences between responders and non-responders were observed with regard to most characteristics at baseline and at 2 weeks after treatment initiation. However, significant differences were observed between groups in the presence or absence of a dose suspension period, the presence or absence of lenvatinib dose reduction from the maximum value during the first 2 weeks, and decreased tumor stain at 2 weeks after treatment initiation.

Conclusion: Reduction in tumor stain at 2 weeks after lenvatinib treatment may be an early biomarker of efficacy at 12 weeks in patients with unresectable HCC.
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http://dx.doi.org/10.1159/000509005DOI Listing
November 2020

Horizontal Transmission of Hepatitis B Virus Genotype C Among Members of a Wrestling Club in Japan.

Am J Case Rep 2020 Aug 31;21:e925044. Epub 2020 Aug 31.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka City, Fukuoka, Japan.

BACKGROUND In adulthood, most cases of acute hepatitis B virus (HBV) infection are transmitted either by sexual contact or by contaminated needles, but there are other modes of transmission. We report on three cases of HBV infection among members of a wrestling club. CASE REPORT A 19-year-old male wrestling athlete was admitted with acute hepatitis B. Five months later, 2 other men, who were members of the same wrestling club, were diagnosed with HBV infection. The full-length sequences of the HBV DNA were identical in all three cases and classified as subgenotype C2 on phylogenetic analysis. This is the most common genotype found in Japan. No history of sexual or bleeding contact with acquaintances outside the club was noted in any of these cases. This suggests horizontal transmission within the wrestling club. CONCLUSIONS The possibility of HBV transmission through bleeding wounds and sweat is a concern in contact sports such as wrestling. Hence, hepatitis B vaccination is recommended for unvaccinated contact-sports players.
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http://dx.doi.org/10.12659/AJCR.925044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483542PMC
August 2020

The Efficacy and Therapeutic Outcome of Bipolar Radiofrequency Ablation for the Treatment for Hepatocellular Carcinoma in the Real-World Setting, Compared with Monopolar Radiofrequency Ablation Conducted during the Same Period.

Oncology 2020 14;98(12):859-868. Epub 2020 Aug 14.

Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Background: Several reports have suggested that the bipolar radiofrequency ablation (RFA) system is useful for the treatment of hepatocellular carcinoma (HCC). We evaluated the efficacy and safety of the bipolar RFA system for HCC treatment in the real-world setting.

Methods: A total of 155 patients with 224 HCC tumors were enrolled. First, we examined the characteristics and outcomes of two RFA systems, monopolar and bipolar. Second, we identified the factors associated with local tumor progression in 72 patients with 104 HCC tumors, who could be followed up for at least 3 months after treatment and had been treated with the bipolar RFA system.

Results: Of the baseline characteristics, tumor size and location were associated with the selection of the bipolar RFA system. A sufficient ablative zone margin (≥5 mm) was obtained by bipolar RFA in 81 of 94 (86.1%). The 1- and 2-year local tumor progression rates were 15.6 and 26.3%, respectively. An alpha-fetoprotein-L3 (AFP-L3) ratio >10% (HR: 7.64; 95% CI: 1.7-39.8, p = 0.007) and an insufficient ablative zone margin (<5 mm) (HR: 4.53; 95% CI: 1.02-20.3, p = 0.047) were related to local tumor progression in Cox regression analysis. Although severe adverse events were not observed in most cases, severe hepatic infarction occurred in 1 patient.

Conclusions: The bipolar RFA system is safe and effective for HCC treatment. Tumor localization within the liver is an important factor associated with bipolar RFA. Careful follow-up or reconsideration of treatment is necessary for cases with AFP-L3 ratio >10% or insufficient ablative zone margin (<5 mm), which were associated with local tumor progression.
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http://dx.doi.org/10.1159/000508921DOI Listing
December 2020

Unresectable Ectopic Hepatocellular Carcinoma Treated with Sorafenib.

Case Rep Gastroenterol 2020 Jan-Apr;14(1):226-233. Epub 2020 Apr 27.

Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Ectopic hepatocellular carcinoma (HCC) is a rare malignancy, which manifests similar morphology and immunohistochemistry to intrahepatic HCC. Herein, we report a case of ectopic HCC in a 73-year-old male. The patient presented to our hospital with gradually progressing right lower abdominal pain, and enhanced computed tomography revealed multiple nodules in the peritoneum without intrahepatic mass. A diagnostic laparoscopy was performed, and the final pathology result confirmed that it was HCC. Additional laboratory tests showed elevated serum alpha-fetoprotein and protein induced by vitamin K absence-II (PIVKA-II) levels, suggesting our diagnosis. The patient received sorafenib, a tyrosine kinase inhibitor (TKI), for unresectable ectopic HCC. However, the tumor progressed, and because of tarry stools and hemorrhagic anemia, sorafenib was ceased after 7 months of therapy. One month after the cessation of sorafenib, the PIVKA-II level increased abruptly, and the patient died 1 year after diagnosis. The effective treatment for unresectable ectopic HCC is still unknown. Additional cases should be accumulated to determine the effect of TKI on ectopic HCC.
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http://dx.doi.org/10.1159/000506929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204886PMC
April 2020

Two Cases of Hepatocellular Carcinoma Arising Over 20 Years after a Sustained Virologic Response Following Interferon Therapy for Chronic Hepatitis C.

Intern Med 2020 Aug 30;59(15):1855-1860. Epub 2020 Apr 30.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan.

The development of hepatocellular carcinoma (HCC) after a sustained virologic response (SVR) due to interferon (IFN) therapy for hepatitis C virus infection remains a serious problem. We herein report 2 cases of HCC that developed more than 20 years after SVR with IFN therapy for chronic hepatitis C. The patients were 89- and 72-year-old men with HCC that developed 24-25 years after an SVR with IFN therapy. These patients regularly underwent imaging examinations; therefore, the HCC was detected in the early stage, when it was still curable. Both cases suggest that long-term surveillance after an SVR is effective for the detection of HCC, and radical treatment is possible.
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http://dx.doi.org/10.2169/internalmedicine.4479-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474997PMC
August 2020

Hepatitis B Virus Reactivation after Receiving Cancer Chemotherapy under Administration of Leuprorelin Acetate.

Intern Med 2020 May 17;59(9):1163-1166. Epub 2020 Jan 17.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan.

An 88-year-old man was admitted for elevated liver enzyme levels. Nine years earlier, the patient had been diagnosed with diffuse large B-cell lymphoma (DLBCL) and undergone rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin, prednisone (R-CHOP) therapy. This patient previously had had a hepatitis B virus (HBV) infection before chemotherapy. After the chemotherapy, he was administered an luteinizing hormone-releasing hormone (LHRH) agonist for prostate cancer. We diagnosed him with HBV reactivation because of positive serum HBV-DNA. HBV reactivation can occur a long time after chemotherapy, particularly if another treatment with immunity-altering drugs is added. In such cases, additional surveillance may be required to detect HBV reactivation.
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http://dx.doi.org/10.2169/internalmedicine.3805-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270765PMC
May 2020

Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]Pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 2.

ChemMedChem 2019 12 7;14(24):2093-2101. Epub 2019 Nov 7.

Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.

We identified novel potent inhibitors of p38 mitogen-activated protein (MAP) kinase using a structure-based design strategy, beginning with lead compound, 3-(butan-2-yl)-6-(2,4-difluoroanilino)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1). To enhance the inhibitory activity of 1 against production of tumor necrosis factor-α (TNF-α) in human whole blood (hWB) cell assays, we designed and synthesized hybrid compounds in which the imidazo[4,5-b]pyridin-2-one core was successfully linked with the p-methylbenzamide fragment. Among the compounds evaluated, 3-(3-tert-butyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)-4-methyl-N-(1-methyl-1H-pyrazol-3-yl)benzamide (25) exhibited potent p38 inhibition, superior suppression of TNF-α production in hWB cells, and also significant in vivo efficacy in a rat model of collagen-induced arthritis (CIA). In this paper, we report the discovery of potent, selective, and orally bioavailable imidazo[4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors.
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http://dx.doi.org/10.1002/cmdc.201900373DOI Listing
December 2019

GGC Repeat Expansion of NOTCH2NLC in Adult Patients with Leukoencephalopathy.

Ann Neurol 2019 12 22;86(6):962-968. Epub 2019 Oct 22.

Department of Neurology and Stroke Medicine , Yokohama City University, Yokohama, Japan.

Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. In this study, we analyzed 101 Japanese patients with genetically unresolved adult leukoencephalopathy using whole-exome sequencing and repeat-primed polymerase chain reaction for detecting GGC expansion in NOTCH2NLC. NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease. We found 12 patients with GGC expansion in NOTCH2NLC as the most frequent cause of adult leukoencephalopathy followed by NOTCH3 variants in our cohort. Furthermore, we found 1 case with de novo GGC expansion, which might explain the underlying pathogenesis of sporadic cases. ANN NEUROL 2019;86:962-968.
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http://dx.doi.org/10.1002/ana.25586DOI Listing
December 2019

IL28B gene polymorphism is correlated with changes in low-density lipoprotein cholesterol levels after clearance of hepatitis C virus using direct-acting antiviral treatment.

J Gastroenterol Hepatol 2019 Nov 21;34(11):2019-2027. Epub 2019 Jun 21.

Department of Gastroenterology, Fukuoka University Faculty of Medicine, Fukuoka, Japan.

Background: Direct-acting antivirals (DAAs) rapidly clear hepatitis C virus (HCV), but the lipid dynamics after DAA treatment remain unknown. Low-density lipoprotein (LDL) cholesterolemia is the predicting factor for the onset and death of atherosclerotic cardiovascular diseases. Thus, in this study, we examined the frequency and risk of hyper-LDL cholesterolemia in HCV patients who achieved sustained virologic response (SVR) with DAA treatment.

Methods: A total of 121 patients with HCV genotype 1b, who achieved SVR with DAA treatment, were examined for serum levels of total cholesterol, LDL-cholesterol (LDL-C), high-density lipoprotein, and triglycerides from the start of treatment until 2 years after SVR (SVR-2y). ΔLDL-C was defined as the change in LDL-C levels from treatment initiation to SVR-2y. Hyper-LDL cholesterolemia was defined as ≥ 140 mg/dL LDL-C at SVR-2y. Stepwise multiple regression analysis was performed to determine whether ΔLDL-C and hyper-LDL cholesterolemia are associated with other factors, including viral kinetics.

Results: A total of 63, 3, and 55 patients were administered daclatasvir + asunaprevir, ombitasvir + paritaprevir + ritonavir, and ledipasvir + sofosbuvir, respectively. ΔLDL-C in patients with the IL28B (rs8099917) TG/GG genotype was significantly higher than in those with IL28B TT (27.3 ± 27.0 and 9.6 ± 27.3 mg/dL; P < 0.001). In addition, IL28B TG/GG was an independent risk factor for hyper-LDL cholesterolemia (odds ratio: 8.47; P < 0.001).

Conclusions: An IL28B polymorphism is associated with ΔLDL-C and hyper-LDL cholesterolemia after achieving SVR. Thus, lipid markers should be carefully monitored in patients who achieve SVR with DAA.
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http://dx.doi.org/10.1111/jgh.14741DOI Listing
November 2019

Structure-Based Design, Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 1.

ChemMedChem 2019 05 18;14(10):1022-1030. Epub 2019 Apr 18.

Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.

We identified a lead series of p38 mitogen-activated protein kinase inhibitors using a structure-based design strategy from high-throughput screening of hit compound 1. X-ray crystallography of 1 with the kinase showed an infrequent flip of the peptide bond between Met109 and Gly110, which was considered to lead to high kinase selectivity. Our structure-based design strategy was to conduct scaffold transformation of 1 with maintenance of hydrogen bond interactions with the flipped hinge backbone of the enzyme. In accordance with this strategy, we focused on scaffold transformation to identify imidazo[4,5-b]pyridin-2-one derivatives as potent inhibitors of the p38 MAP kinase. Of the compounds evaluated, 21 was found to be a potent inhibitor of the p38 MAP kinase, lipopolysaccharide-induced tumor necrosis factor-α (TNF-α) production in human monocytic leukemia cells, and TNF-α-induced production of interleukin-8 in human whole blood cells. Herein we describe the discovery of potent and orally bioavailable imidazo[4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors that suppressed cytokine production in a human whole blood cell-based assay.
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http://dx.doi.org/10.1002/cmdc.201900129DOI Listing
May 2019

Supporting elder persons in rural Japanese communities through preventive home visits by nursing students: A qualitative descriptive analysis of students' reports.

Public Health Nurs 2019 07 7;36(4):557-563. Epub 2019 Mar 7.

Oita University of Nursing and Health Sciences, Oita, Japan.

This article describes the evaluation of an innovative nursing education curriculum project, preventive home visiting practice, which began full implementation in 2015, in terms of students' learning outcomes. For the purpose of learning how elder persons live in community, all the 327 undergraduate nursing students, from freshmen to seniors, provided monthly or bi-monthly visits to home-dwelling elderly persons aged 75 or above in their home over 1 year period, in order to provide support for their independent living and to learn from them. The students' reports submitted at the end of the first academic year were qualitatively analyzed to evaluate what they learned. They acquired multiple perspectives for understanding elder persons, including a variety of individual and environmental aspects of wellness, prevention, and community life. They also acknowledged the importance of team practice through working and collaborating with different grade levels and generations. Overall, the observed learning contents were useful for future nursing education with elder persons and facilitating critical changes in nursing education systems to address the problems of aged society.
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http://dx.doi.org/10.1111/phn.12596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850435PMC
July 2019

Autoimmune Hepatitis with Concomitant Idiopathic Thrombocytopenic Purpura Diagnosed by Transjugular Liver Biopsy.

Case Reports Hepatol 2018 9;2018:5305691. Epub 2018 Dec 9.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan, Fukuoka 814-0180, Japan.

Patients with autoimmune hepatitis (AIH) may sometimes have concomitant idiopathic thrombocytopenic purpura (ITP). Severe thrombocytopenia in ITP interferes with percutaneous liver biopsy for pathological diagnosis of AIH. Here, we report a case of AIH with ITP in a 63-year-old woman. The patient presented to our hospital with liver dysfunction and thrombocytopenia. For histological examination, transjugular liver biopsy (TJLB) was performed, leading to a diagnosis of AIH. Corticosteroids treatment led to an improvement in her liver enzyme levels and platelet count. In conclusion, patients with AIH may sometimes have concomitant ITP. TJLB was effective for making the diagnosis of AIH with severe thrombocytopenia due to ITP.
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http://dx.doi.org/10.1155/2018/5305691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304620PMC
December 2018

Hepatocellular Carcinoma Arising in a Non-cirrhotic Liver with Secondary Hemochromatosis.

Intern Med 2019 Mar 19;58(5):661-665. Epub 2018 Nov 19.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Japan.

A 70-year-old man was admitted for treatment of a single liver nodule that was detected by contrast-enhanced computed tomography. Twenty years earlier, the patient had been diagnosed with myelodysplastic syndrome-refractory anemia and secondary hemochromatosis but had not received erythrocyte transfusions. The current histological, computed tomography, and magnetic resonance imaging findings revealed hepatocellular carcinoma (HCC) and non-cirrhotic liver hemochromatosis. The liver tumor was treated using radiofrequency ablation therapy. Secondary hemochromatosis may be a risk factor for HCC, even if the liver is not cirrhotic. In such cases, additional surveillance may be required to detect the development of HCC.
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http://dx.doi.org/10.2169/internalmedicine.0973-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443541PMC
March 2019

Endoscopic treatment or balloon-occluded retrograde transvenous obliteration is safe for patients with esophageal/gastric varices in Child-Pugh class C end-stage liver cirrhosis.

Clin Mol Hepatol 2019 06 9;25(2):183-189. Epub 2018 Nov 9.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan.

Background/aims: There is a controversy about the availability of invasive treatment for esophageal/gastric varices in patients with Child-Pugh class C (CP-C) end-stage liver cirrhosis (LC). We have evaluated the validity of invasive treatment with CP-C end-stage LC patients.

Methods: The study enrolled 51 patients with CP-C end-stage LC who had undergone invasive treatment. The treatment modalities included endoscopic variceal ligation in 22 patients, endoscopic injection sclerotherapy in 17 patients, and balloon-occluded retrograde transvenous obliteration (BRTO) in 12 patients. We have investigated the overall survival (OS) rates and risk factors that contributed to death within one year after treatment.

Results: The OS rate in all patients at one, three, and five years was 72.6%, 30.2%, and 15.1%, respectively. The OS rate in patients who received endoscopic treatment and the BRTO group at one, three, and five years was 67.6%, 28.2% and 14.1% and 90.0%, 36.0% and 18.0%, respectively. The average of Child-Pugh scores (CPS) from before treatment to one month after variceal treatment significantly improved from 10.53 to 10.02 (P=0.003). Three significant factors that contributed to death within one year after treatment included the presence of bleeding varices, high CPS (≥11), and high serum total bilirubin levels (≥4.0 mg/dL).

Conclusion: The study demonstrated that patients with a CPS of up to 10 and less than 4.0 mg/dL of serum total bilirubin levels may not have a negative impact on prognosis after invasive treatment for esophageal/gastric varices despite their CP-C end-stage LC.
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http://dx.doi.org/10.3350/cmh.2018.0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589850PMC
June 2019

Factors Attenuating Zinc Deficiency Improvement in Direct-Acting Antiviral Agent-Treated Chronic Hepatitis C Virus Infection.

Nutrients 2018 Nov 2;10(11). Epub 2018 Nov 2.

Department of Gastroenterology, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.

Zinc deficiency is frequently observed in chronic liver diseases. However, no studies have focused on the zinc status in chronic hepatitis C (HCV)-infected patients receiving direct-acting antiviral agents (DAAs). In this retrospective study, we assessed the serum zinc status in DAA-treated HCV patients with sustained virologic response for over two years (Zn-2y). Ninety-five patients were enrolled, whose baseline characteristics and blood parameters at DAA therapy initiation were collected. Baseline Zn < 65 µg/dL (odds ratio (OR) = 10.56, < 0.001) and baseline uric acid (UA) > 5.5 mg/dL (OR = 9.99, = 0.001) were independent risk factors for Zn-2y deficiency. A decision-tree algorithm classified low-baseline Zn and high-baseline UA as the first two variables, suggesting that baseline hypozincemia and hyperuricemia are prognosticators for long-term zinc deficiency. Baseline Zn was negatively correlated with the Fibrosis-4 (FIB-4) index, while baseline UA was significantly higher in habitual alcohol drinkers. In conclusion, serum zinc levels should be closely monitored, considering that zinc status improvement is related to liver fibrosis regression. Hyperuricemia indicates risks of developing metabolic disorders and subsequent zinc deficiency, for which an adjustment of personal lifestyle or dietary habits should be recommended clinically.
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http://dx.doi.org/10.3390/nu10111620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266757PMC
November 2018

Fitz-Hugh-Curtis syndrome in a man positive for Chlamydia trachomatis.

Clin J Gastroenterol 2018 Aug 7;11(4):338-342. Epub 2018 Feb 7.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan, Fukuoka, 814-0180, Japan.

Fitz-Hugh-Curtis syndrome (FHCS) is characterized by perihepatic and pelvic inflammation and occurs mostly in women of childbearing age. Here, we report a case of FHCS caused by Chlamydia trachomatis in a 50-year-old man. The patient presented to our hospital with right upper quadrant abdominal pain, and enhanced computed tomography revealed perihepatic and pelvic free fluid and early-phase hepatic capsular enhancement. A urine specimen was positive for Chlamydia trachomatis. The patient was diagnosed with FHCS due to Chlamydia trachomatis infection. In conclusion, FHCS cannot be excluded when men present with right upper quadrant abdominal pain without significant signs of biliary tract disease.
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http://dx.doi.org/10.1007/s12328-018-0829-5DOI Listing
August 2018

Disappearance of multiple hyperechoic liver nodules in sporadic porphyria cutanea tarda after treatment with ledipasvir/sofosbuvir for hepatitis C.

Clin J Gastroenterol 2017 Oct 7;10(5):459-463. Epub 2017 Sep 7.

Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, 7-45-1 Nanakuma, Jonan, Fukuoka, 814-0180, Japan.

Ultrasonography in a 60-year-old man with chronic hepatitis C (CHC) demonstrated multiple hyperechoic nodules. Radiological investigations did not reveal any signs of malignancy. However, magnetic resonance chemical shift imaging showed multiple focal fatty changes in the liver. Urinary levels of uroporphyrin and coproporphyrin were elevated, and we made a diagnosis of porphyria cutanea tarda. Direct-acting antivirals, ledipasvir/sofosbuvir, were initiated for CHC, which led to sustained viral response, resolution of the liver nodules, and normalization of urinary porphyrin. Hepatitis C virus infection can cause porphyria cutanea tarda with multiple hyperechoic liver nodules, which might be cured by direct-acting antivirals.
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http://dx.doi.org/10.1007/s12328-017-0772-xDOI Listing
October 2017

Neural tube defects: Risk factors and preventive measures.

Congenit Anom (Kyoto) 2017 Sep 28;57(5):150-156. Epub 2017 Jun 28.

Department of School Health Science, Aichi University of Education, Kariya, Japan.

For the last 25 years, it has been proven that the occurrence or recurrence of neural tube defects can be prevented with the administration of folic acid before and early pregnancy. At present, over 80 countries in the world, except Japan, have mandated the fortification of wheat flour and/or rice with folic acid, which has resulted in a significant reduction in the prevalence of neural tube defects. In 2000, the Japanese government recommended folic acid 400 μg daily for young women of childbearing age and women who are planning to conceive. In 2002, the government started to present information about the importance of folic acid in the development of fetuses in the Mother-Child Health Booklet annually. Despite these endeavors, the prevalence of neural tube defects has remained unchanged. We discuss the risk factors of neural tube defects and propose preventive measures to decrease the number of neonates with neural tube defects. We believe that the government should implement the fortification of staple food with folic acid very soon, which will eventually decrease not only the neonatal mortality and morbidity, but also the economic burden on our health care system.
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http://dx.doi.org/10.1111/cga.12227DOI Listing
September 2017

Survey on awareness of folic acid recognition and intake by female students.

Congenit Anom (Kyoto) 2017 Sep 23;57(5):166-170. Epub 2017 May 23.

Department of Urology, Atsuta Rehabilitation Hospital, Nagoya, Japan.

To reduce the risk of neural tube defects, studies have been conducted on female students of medical services, nutritional science, and nursery education that investigated the awareness of folic acid by using questionnaires. Many investigators have suggested the need to provide detailed information about the awareness of folic acid and knowledge about folic acid intake and neural tube defect risk reduction. The dietary habits of female students showed a positive correlation with their estimated folic acid intake, suggesting that improvements in dietary habits are associated with the consumption of folic acid. The importance of folic acid intake must be more aggressively promoted among female students. Thus, many learning opportunities should be provided for such students to help increase their folic acid intake.
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http://dx.doi.org/10.1111/cga.12224DOI Listing
September 2017

Effectiveness of community-based health services by nurse practitioners: protocol for a systematic review and meta-analysis.

BMJ Open 2015 Jun 23;5(6):e006670. Epub 2015 Jun 23.

Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Introduction: To realise universal health coverage in an ageing society, adequate provision of appropriately trained human resources is essential. The nurse practitioner (NP) is an autonomous and independent, advanced practice nurse capable of providing treatment and care that can be substituted for some aspects of a medical doctor's (MD's) role, especially in a community setting. Previous systematic reviews found higher levels of patient satisfaction with services provided by NPs than those provided by MDs. As non-communicable diseases become a major health burden requiring long-term healthcare in community settings, this systematic review aims to assess the equivalence of NP services to standard care provided by MDs, and to determine whether their practice is an effective alternative to that of MDs in community settings.

Methods And Analysis: Relevant randomised controlled trials (RCTs) and cluster RCTs will be searched in the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL and the British Nursing Index. We will assess patient and health system utilisation outcomes of interventions comparing treatment and care provided by NPs in community settings with that provided by MDs. Two authors will independently screen studies for inclusion, consulting with a third author where necessary to resolve discrepancies. The risk of bias of included studies will be assessed using the Cochrane Collaboration risk of bias tool, and quality of evidence using the GRADE approach. Meta-analysis of included studies will be conducted using fixed-effect or random-effects models depending on the degree of between-study heterogeneity. Results will be presented using risk ratios with 95% CI for dichotomous outcomes and standardised mean differences with 95% CI for continuous outcomes.

Ethics And Dissemination: This systematic review and meta-analysis protocol does not require ethical approval. We will disseminate the findings of this systematic review and meta-analysis via publications in peer-reviewed journals.

Trial Registration Number: PROSPEROCRD42014009627.
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http://dx.doi.org/10.1136/bmjopen-2014-006670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480018PMC
June 2015

Factors Affecting Professional Autonomy of Japanese Nurses Caring for Culturally and Linguistically Diverse Patients in a Hospital Setting in Japan.

J Transcult Nurs 2016 11 20;27(6):567-573. Epub 2015 May 20.

Oita University of Nursing and Health Sciences, Oita, Japan University of Tokyo, Tokyo, Japan.

Purpose: The study aimed to analyze the professional autonomy of Japanese nurses when caring for non-Japanese patients and to identify its contributing factors.

Method: A descriptive cross-sectional design was used. Participants included 238 clinical nurses working at 27 hospitals in Japan. The Intercultural Sensitivity Scale (Chen and Starosta), and the Scale for Professional Autonomy in Nursing (Kikuchi and Harada) were used to measure intercultural sensitivity and professional autonomy. Stepwise multiple regression analysis was used to identify the most significant factors affecting professional autonomy.

Results: Professional autonomy of Japanese nurses caring for non-Japanese patients was significantly lower than when caring for Japanese patients (142.84 vs. 172.85; p < .001). Contributing factors were intercultural sensitivity (p < .001), length of nurse experience (p < .05), and availability of interpretation service (p < .05).

Conclusion: Incorporating transcultural nursing content into training programs in schools and hospitals could enhance professional autonomy of Japanese nurses by promoting intercultural sensitivity.
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http://dx.doi.org/10.1177/1043659615587588DOI Listing
November 2016

C677T mutation in methylenetetrahydrofolate reductase gene and neural tube defects: should Japanese women undergo gene screening before pregnancy?

Congenit Anom (Kyoto) 2014 Feb;54(1):30-4

Department of Urology, Tsushima Rehabilitation Hospital, Tsushima, Japan.

We analyzed the role of maternal C677T mutation in methylenetetrahydrofolate reductase (MTHFR) gene on spina bifida development in newborns. A total of 115 mothers who had given birth to a spina bifida child (SB mothers) gave 10 mL of blood together with written informed consent. The genotype distribution of C677T mutation was assessed and compared with that of the 4517 control individuals. The prevalence of the homozygous genotype (TT) among SB mothers was not significantly different from that among the controls (odds ratio [OR] = 0.65; 95% confidence interval [CI] = 0.31-1.25; P = 0.182), suggesting that MTHFR 677TT genotype in Japan is not associated with spina bifida development in newborns. The T allele frequency was not increased in SB mothers (34.8%) as compared to that of the control individuals (38.2%). Further, the internationally reported association between the two groups was found to be similar in all 15 countries studied except the Netherlands, where the TT genotype was found to be a genetic risk factor for spina bifida. For the prevention of affected pregnancy every woman planning to conceive has to take folic acid supplements 400 μg a day and the government is asked to take action in implementing food fortification with folic acid in the near future. In conclusion, it is not necessary for Japanese women to undergo genetic screening C677T mutation of the MTHFR gene as a predictive marker for spina bifida prior to pregnancy, because the TT genotype is not a risk factor for having an affected infant.
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http://dx.doi.org/10.1111/cga.12026DOI Listing
February 2014