Publications by authors named "Shinsaku Fukuda"

138 Publications

Leptomeningeal and intraventricular myelomatosis manifesting an aggressive form of communicating hydrocephalus.

Neuropathology 2021 Jun 10;41(3):243-249. Epub 2021 May 10.

Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Leptomeningeal myelomatosis (LMM) is a fatal complication that occurs in < 1% of patients with multiple myeloma. Many patients with LMM present with neurologic symptoms referable to cranial neuropathies, while the manifestation of communicating hydrocephalus has been underrecognized. A Japanese man with Bence Jones protein-κ multiple myeloma developed fever and headache at age 54 years. He then became somnolent and went into a coma. Neuroimaging analyses identified rapidly progressive communicating hydrocephalus due to meningitis. He died 83 days after the onset of headache without any response to treatment at age 55 years. No symptoms or signs associated with cranial nerves were found during the course of illness. Postmortem examination revealed hydrocephalus and diffuse infiltration of myeloma cells into the subarachnoid space of the cerebrum, cerebellum, and brainstem. In addition, the interstitial tissue of the choroid plexuses was filled with myeloma cells. These myeloma cells were positive for CD156 and light chain κ. The Ki-67 labeling index in myeloma cells of the central nervous system (CNS) was 30-40%. Histopathological examination further revealed many myeloma cells on the surface of the lateral, third and fourth ventricles and at the area postrema of the medulla oblongata. Patients with LMM can develop an aggressive form of communicating hydrocephalus. Given that cerebrospinal fluid, produced by epithelial cells in the choroid plexuses of the ventricles, passes into the subarachnoid space through the third and fourth ventricles, myeloma cells may invade the CNS through the choroid plexuses.
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http://dx.doi.org/10.1111/neup.12728DOI Listing
June 2021

Risk of metastatic recurrence after endoscopic resection for esophageal squamous cell carcinoma invading into the muscularis mucosa or submucosa: a multicenter retrospective study.

J Gastroenterol 2021 Apr 21. Epub 2021 Apr 21.

National University Corporation Hirosaki University, Hirosaki, Japan.

Background: We aimed to elucidate the risk of metastatic recurrence after endoscopic resection (ER) without additional treatment for esophageal squamous cell carcinomas (ESCCs) with tumor invasion into the muscularis mucosa (pT1a-MM) or submucosa (T1b-SM).

Methods: We retrospectively enrolled patients with pT1a-MM/pT1b-SM ESCC after ER at 21 institutions in Japan between 2006 and 2017. We compared metastatic recurrence between patients with and without additional treatment, stratified into category A (pT1a-MM with negative lymphovascular invasion [LVI] and vertical margin [VM]), B (tumor invasion into the submucosa ≤ 200 µm [pT1b-SM1] with negative LVI and VM), and C (others). Subsequently, using multivariate Cox analysis, we evaluated risk factors for metastatic recurrence after ER without additional treatment.

Results: We enrolled 593 patients, and metastatic recurrence occurred in 38 patients. Metastatic recurrence after additional treatment was significantly lower than that after no additional treatment in category C (9.1% vs. 23.6% in 5 years, p = 0.001), whereas no significant difference was noted in categories A (0.0% vs. 2.6%) and B (0.0% vs. 4.3%). In patients without additional treatment after ER, risk factors for metastatic recurrence were lymphatic invasion (hazard ratio [HR], 5.61), positive VM (HR, 4.55), and tumor invasion into the submucosa > 200 μm (HR, 3.25), and, but near half of the patients with metastatic recurrence had no further recurrence after salvage treatment, resulting in excellent 5-year disease-specific survival in categories A (99.6%) and B (100.0%).

Conclusions: Closed follow-up with no additional treatment may be an acceptable option after ER in pT1a-MM/pT1b-SM1 ESCC with negative LVI and VM.
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http://dx.doi.org/10.1007/s00535-021-01787-yDOI Listing
April 2021

SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243.

Cancer Res 2021 Jun 16;81(11):3067-3078. Epub 2021 Apr 16.

Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Schlafen11 (SLFN11) inactivation occurs in approximately 50% of cancer cell lines and in a large fraction of patient tumor samples, which leads to chemoresistance. Therefore, new therapeutic approaches are needed to target -deficient cancers. To that effect, we conducted a drug screen with the NCATS mechanistic drug library of 1,978 compounds in isogenic -knockout (KO) and wild-type (WT) leukemia cell lines. Here we report that TAK-243, a first-in-class ubiquitin activating enzyme UBA1 inhibitor in clinical development, causes preferential cytotoxicity in -KO cells; this effect is associated with claspin-mediated DNA replication inhibition by CHK1 independently of ATR. Additional analyses showed that -KO cells exhibit consistently enhanced global protein ubiquitylation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and protein aggregation. TAK-243 suppressed global protein ubiquitylation and activated the UPR transducers PERK, phosphorylated eIF2α, phosphorylated IRE1, and ATF6 more effectively in -KO cells than in WT cells. Proteomic analysis using biotinylated mass spectrometry and RNAi screening also showed physical and functional interactions of SLFN11 with translation initiation complexes and protein folding machinery. These findings uncover a previously unknown function of SLFN11 as a regulator of protein quality control and attenuator of ER stress and UPR. Moreover, they suggest the potential value of TAK-243 in -deficient tumors. SIGNIFICANCE: This study uncovers that deficiency induces proteotoxic stress and sensitizes cancer cells to TAK-243, suggesting that profiling status can serve as a therapeutic biomarker for cancer therapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178208PMC
June 2021

Disseminated carcinomatosis of the bone marrow from rectal cancer: A case report.

Clin Case Rep 2021 Mar 18;9(3):1483-1489. Epub 2021 Jan 18.

Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Hirosaki Japan.

A 66-year-old man presented with worsening dyspnea. A colonoscopy revealed an elevated lesion at the rectosigmoid junction. The biopsy specimen and bone marrow aspiration demonstrated adenocarcinoma, leading to a diagnosis of disseminated carcinomatosis of the bone marrow. Because chemotherapy proved effective, he survived until 333 days after admission.
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http://dx.doi.org/10.1002/ccr3.3810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981614PMC
March 2021

Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity.

Intest Res 2021 Jan 22. Epub 2021 Jan 22.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Background/aims: Thiopurines are key drugs for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). Recently, NUDT15 polymorphism (R139C, c.415C > T) has been shown to be associated with thiopurineinduced adverse events in Asian populations. In patients with the C/T genotype, low-dose thiopurine treatment is recommended, but its long-term efficacy and tolerability remain unclear. This study aimed to uncover the long-term efficacy and appropriate dosage of thiopurine for IBD patients with the C/T genotype.

Methods: A total of 210 patients with IBD (103 UC and 107 CD) determined to have NUDT15 R139C variants were enrolled. Clinical data were retrospectively reviewed from medical records.

Results: Of 46 patients (21.9%) with the C/T genotype, 30 patients (65.2%) were treated with thiopurines. Three of whom (10.0%) discontinued thiopurine treatment due to adverse events and 27 of whom continued. The median maintenance dosage of 6-mercaptopurine was 0.25 mg/kg/day (range, 0.19-0.36 mg/kg/day), and 6-thioguanine nucleotides level was 230 (104-298) pmol/8 × 108 red blood cells. Cumulative thiopurine continuation rates for 120 months for patients with the C/C and C/T genotypes were not significantly different (P= 0.895). Cumulative non-relapse rates in the patients with UC treated with thiopurine monotherapy and surgery-free rates in CD patients treated with combination therapy (thiopurines and anti-tumor necrosis factor-α agents) for maintenance remission were not significantly different at 60 months (C/C vs. C/T, P= 0.339 and P= 0.422, respectively).

Conclusions: Low-dose thiopurine treatment is an effective and acceptable treatment for patients with C/T genotype.
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http://dx.doi.org/10.5217/ir.2020.00133DOI Listing
January 2021

Effective Endoscopic Closure of Cholecysto-duodenal and Transverse Colon Fistulas Due to Squamous Cell Carcinoma of the Gallbladder Using Polyglycolic Acid Sheets and a Covered Metal Stent.

Intern Med 2021 Jun 29;60(11):1723-1729. Epub 2020 Dec 29.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Japan.

An 81-year-old woman presented with abdominal distension and right hypochondrial pain. Abdominal contrast computed tomography and magnetic resonance imaging revealed an 11-cm gallbladder tumor. The patient was diagnosed with squamous cell carcinoma of the gallbladder by endoscopic ultrasound-guided fine-needle aspiration from the gastric antrum. Thereafter, the gallbladder tumor enlarged, and cholecysto-duodenal and transverse colon fistulas were formed. A covered metal stent was placed on the transverse colon, and polyglycolic acid sheets were injected into the duodenum to close the fistulas endoscopically. Endoscopic closure is less invasive than surgery and considered effective for patients with poor general health conditions.
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http://dx.doi.org/10.2169/internalmedicine.6384-20DOI Listing
June 2021

Tryptanthrin suppresses double-stranded RNA-induced CXCL10 expression via inhibiting the phosphorylation of STAT1 in human umbilical vein endothelial cells.

Mol Immunol 2021 01 28;129:32-38. Epub 2020 Nov 28.

Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.

Tryptanthrin is a bioactive component of indigo plants such as Polygonum tinctrorium and known to have an anti-inflammatory activity. The aim of this study was to investigate the effects of tryptanthrin on Toll-like receptor 3 (TLR3)-mediated cytokine and chemokine expression in human umbilical vein endothelial cells (HUVEC). Herein, we found that tryptanthrin suppressed the expression of CXCL10 in HUVEC upon stimulation with a TLR3 ligand polyinosinic-polycytidylic acid (poly IC). Tryptanthrin did not inhibit poly IC-induced activation of interferon regulatory factor 3 (IRF3) or the mRNA expression of interferon (IFN)-β, while it significantly suppressed the expression of RIG-I, MDA5, and classical IFN-stimulated genes (ISGs). Tryptanthrin attenuated the phosphorylation and nuclear translocation of STAT1 in HUVEC stimulated with not only poly IC but also recombinant IFN-β. These results suggested that tryptanthrin inhibited poly IC-induced expression of CXCL10 and ISGs via suppressing the activation of STAT1 in HUVEC. Our findings indicate that tryptanthrin may be useful for regulating TLR3-mediated vascular inflammation.
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http://dx.doi.org/10.1016/j.molimm.2020.11.003DOI Listing
January 2021

Guidelines for sedation in gastroenterological endoscopy (second edition).

Dig Endosc 2021 Jan 9;33(1):21-53. Epub 2020 Dec 9.

Japanese Gastroenterological Endoscopy Society, Tokyo, Japan.

Sedation in gastroenterological endoscopy has become an important medical option in routine clinical care. Here, the Japan Gastroenterological Endoscopy Society and the Japanese Society of Anesthesiologists together provide the revised "Guidelines for sedation in gastroenterological endoscopy" as a second edition to address on-site clinical questions and issues raised for safe examination and treatment using sedated endoscopy. Twenty clinical questions were determined and the strength of recommendation and evidence quality (strength) were expressed according to the "MINDS Manual for Guideline Development 2017." We were able to release up-to-date statements related to clinical questions and current issues relevant to sedation in gastroenterological endoscopy (henceforth, "endoscopy"). There are few reports from Japan in this field (e.g., meta-analyses), and many aspects have been based only on a specialist consensus. In the current scenario, benzodiazepine drugs primarily used for sedation during gastroenterological endoscopy are not approved by national health insurance in Japan, and investigations regarding expense-related disadvantages have not been conducted. Furthermore, including the perspective of beneficiaries (i.e., patients and citizens) during the creation of clinical guidelines should be considered. These guidelines are standardized based on up-to-date evidence quality (strength) and supports on-site clinical decision-making by patients and medical staff. Therefore, these guidelines need to be flexible with regard to the wishes, age, complications, and social conditions of the patient, as well as the conditions of the facility and discretion of the physician.
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http://dx.doi.org/10.1111/den.13882DOI Listing
January 2021

Cyclosporine protects from intestinal epithelial injury by modulating butyrate uptake via upregulation of membrane monocarboxylate transporter 1 levels.

Biochem Biophys Rep 2020 Dec 21;24:100811. Epub 2020 Oct 21.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Background And Aims: A relationship between treatment outcomes and intestinal microbiota in patients with inflammatory bowel diseases has been demonstrated. Cyclosporine treatment leads to rapid improvement in severe ulcerative colitis. We hypothesized that the potent effects of cyclosporine would be exerted through relationships between intestinal epithelial cells (IECs) and the host microbiota. The present study was designed to elucidate the effects of cyclosporine on monocarboxylate transporter 1 (MCT1) regulation and butyrate uptake by IECs.

Methods: Colitis was induced in C57BL6 mice via the administration of 4% dextran sulfate sodium in drinking water, following which body weights, colon lengths, and histological scores were evaluated. To examine the role of butyrate in the protective effects of cyclosporine, MCT1 inhibitor and an antibiotic cocktail was administered and tributyrin (TB; a prodrug of butyrate) was supplemented; MCT1 protein expression and acetylated histone 3 (AcH3) signals in IECs, as well as the MCT1-membrane fraction of Caco-2 cells, were evaluated. To explore butyrate uptake, as s butyrate derivatives, 3-bromopyruvic acid (3-BrPA) and 1-pyrenebutyric acid were used.

Results: Treatment with cyclosporine inhibited body weight loss and colon length shortening. However, treatment with MCT1 inhibitor and the antibiotic cocktail negated the efficacy of cyclosporine, whereas TB supplementation restored its protective effect. Furthermore, cyclosporine upregulated MCT1 expression in the membrane and the AcH3 signal in IECs, while also inducing higher anti-inflammatory cytokine production compared to that in the vehicle-treated mice. The transcription level of mRNA in IECs and Caco-2 cells did not increase with cyclosporine treatment; however, cyclosporine treatment increased membrane MCT1 expression in these cells and uptake of butyrate derivative.

Conclusion: Cyclosporine treatment modulates butyrate uptake via the post-transcriptional upregulation of membrane MCT1 levels in IECs.
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http://dx.doi.org/10.1016/j.bbrep.2020.100811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578528PMC
December 2020

Association between serum β-carotene-to-retinol ratio and severity of hepatic steatosis in non-alcoholic fatty liver disease in Japan: A cross-sectional study.

Nutrition 2020 Nov - Dec;79-80:110984. Epub 2020 Aug 28.

Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Objectives: Retinol and β-carotene have been reported to be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, clinical studies are limited. The aim of this study was to investigate the relationship between serum the ratio of β-carotene to retinol (SC/SR) and hepatic steatosis in NAFLD diagnosed by ultrasonography.

Methods: The participants were 606 Japanese adults who were enrolled in a health survey. Clinical profile, dietary nutrition intake, blood biochemistry, serum retinol, and carotenoids were analyzed. NAFLD was defined as fatty liver on ultrasonography in the absence of other causes of steatosis.

Results: Women had higher daily intake of α- and β-carotene, although there were no differences in daily retinol and carotenoid intake between participants with or without NAFLD in both men and women. Women had a higher SC/SR ratio than men regardless of the presence or absence of NAFLD, and the SC/SR ratio in women decreased with exacerbation of hepatic steatosis, whereas the SC/SR ratio in men did not change despite exacerbation of hepatic steatosis. After adjusting for confounding factors, the likelihood of NAFLD among participants in the highest quartile of SC/SR ratio decreased by two-thirds compared with participants in the lowest quartile (adjusted odds ratio, 0.64; 95% confidence interval, 0.21-1.92; P = 0.041). The SC/SR ratio was positively correlated with serum high-density lipoprotein cholesterol level, and negatively correlated with serum triacylglycerol level.

Conclusions: The SC/SR ratio was lower in NAFLD with sex differences, and was associated with the severity of hepatic steatosis and lipid profile. Future studies are needed to expand on these findings.
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http://dx.doi.org/10.1016/j.nut.2020.110984DOI Listing
August 2020

Anatomical classification of upper gastrointestinal organs under various image capture conditions using AlexNet.

Comput Biol Med 2020 09 7;124:103950. Epub 2020 Aug 7.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.

Background: Machine learning has led to several endoscopic studies about the automated localization of digestive lesions and prediction of cancer invasion depth. Training and validation dataset collection are required for a disease in each digestive organ under a similar image capture condition; this is the first step in system development. This data cleansing task in data collection causes a great burden among experienced endoscopists. Thus, this study classified upper gastrointestinal (GI) organ images obtained via routine esophagogastroduodenoscopy (EGD) into precise anatomical categories using AlexNet.

Method: In total, 85,246 raw upper GI endoscopic images from 441 patients with gastric cancer were collected retrospectively. The images were manually classified into 14 categories: 0) white-light (WL) stomach with indigo carmine (IC); 1) WL esophagus with iodine; 2) narrow-band (NB) esophagus; 3) NB stomach with IC; 4) NB stomach; 5) WL duodenum; 6) WL esophagus; 7) WL stomach; 8) NB oral-pharynx-larynx; 9) WL oral-pharynx-larynx; 10) WL scaling paper; 11) specimens; 12) WL muscle fibers during endoscopic submucosal dissection (ESD); and 13) others. AlexNet is a deep learning framework and was trained using 49,174 datasets and validated using 36,072 independent datasets.

Results: The accuracy rates of the training and validation dataset were 0.993 and 0.965, respectively.

Conclusions: A simple anatomical organ classifier using AlexNet was developed and found to be effective in data cleansing task for collection of EGD images. Moreover, it could be useful to both expert and non-expert endoscopists as well as engineers in retrospectively assessing upper GI images.
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http://dx.doi.org/10.1016/j.compbiomed.2020.103950DOI Listing
September 2020

Dynamic analysis of human small intestinal microbiota after an ingestion of fermented milk by small-intestinal fluid perfusion using an endoscopic retrograde bowel insertion technique.

Gut Microbes 2020 11 19;11(6):1662-1676. Epub 2020 Jun 19.

Laboratory of Gastroenterology and Hematology, Graduate School of Medicine, Hirosaki University , Aomori, Japan.

Probiotic products have been shown to have beneficial effects on human hosts, but what happens in the gastrointestinal tract after its ingestion remains unclear. Our aim was to investigate the changes within the small intestines after a single intake of a fermented milk product containing a probiotic. We have periodically collected the small-intestinal fluids from the terminal ileum of seven healthy subjects for up to 7 h after ingestion by small-intestinal fluid perfusion using an endoscopic retrograde bowel insertion technique. The bacterial composition of the terminal ileum clearly revealed that the ingested probiotics ( strain Shirota: LcS and strain Yakult: BbrY) occupied the ileal microbiota for several hours, temporarily representing over 90% of the ileal microbiota in several subjects. Cultivation of ileal fluids showed that under a dramatic pH changes before reaching the terminal ileum, a certain number of the ingested bacteria survived (8.2 ± 6.4% of LcS, 7.8 ± 11.0% of BbrY). This means that more than 1 billion LcS and BbrY cells reached the terminal ileum with their colony-forming ability intact. These results indicate that there is adequate opportunity for the ingested probiotics to continuously stimulate the host cells in the small intestines. Our data suggest that probiotic fermented milk intake affects intestinal microbes and the host, explaining part of the process from the intake of probiotics to the exertion of their beneficial effects on the host.
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http://dx.doi.org/10.1080/19490976.2020.1766942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524281PMC
November 2020

Clinical Questions and Answers on Gastrointestinal Endoscopy during the Novel Coronavirus Disease 2019 pandemic.

Dig Endosc 2020 Jul;32(5):651-657

Japan Gastroenterological Endoscopy Society, Tokyo, Japan.

Some situations may require endoscopy during the COVID-19 (Coronavirus Disease 2019) pandemic. Here, we describe the necessary precautions in the form of clinical questions and answers (Q&A) regarding the safe deployment of gastrointestinal endoscopy in such situations while protecting endoscopy staff and patients from infection. Non-urgent endoscopy should be postponed. The risk of infection in patients should be evaluated in advance by questionnaire and body temperature. The health of staff must be checked every day. Decisions to employ endoscopy should be based on the institutional conditions and aims of endoscopy. All endoscopic staff need to wear appropriate personal protective equipment (PPE). The endoscope and other devices should be cleaned and disinfected after procedures in accordance with the relevant guidelines. Optimal management of the endoscopy unit is required. Endoscopy for infected patients or those with suspected infection demands exceptional caution. When a patient who undergoes endoscopy is later found to have COVID-19, the members of staff involved are considered exposed to the virus and must not work for at least 14 days if their PPE is considered insufficient. When PPE resources are limited, some equipment may be used continuously throughout a shift as long as it is not contaminated. Details of the aforementioned protective measures are described.
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http://dx.doi.org/10.1111/den.13757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301013PMC
July 2020

Changed Amino Acids in NAFLD and Liver Fibrosis: A Large Cross-Sectional Study without Influence of Insulin Resistance.

Nutrients 2020 May 17;12(5). Epub 2020 May 17.

Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.

Altered amino acid levels have been found in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, it is not clear whether this alteration is due to altered hepatic metabolism or insulin resistance. The aim of this study was to clarify the association among amino acid levels, fatty liver, and liver fibrosis while eliminating the influence of insulin resistance. NAFLD and liver fibrosis were diagnosed using transient elastography and subjects were divided into three groups: normal, NAFLD, and liver fibrosis. To exclude the influence of insulin resistance, the subjects were matched using the homeostasis model assessment of insulin resistance (HOMA-IR). The amino acid serum levels were compared among the groups. Of 731 enrolled subjects, 251 and 33 were diagnosed with NAFLD and liver fibrosis. Although significant differences were observed among the groups in the serum levels of most amino acids, all but those of glutamate and glycine disappeared after matching for HOMA-IR. The multivariate logistic regression revealed that glutamate, glycine, and HOMA-IR were independent risk factors for liver fibrosis. The altered serum levels of most amino acids were associated with insulin resistance, while the increase in glutamate and the decrease in glycine levels were strongly associated not only with insulin resistance, but also with altered liver metabolism in patients with liver fibrosis.
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http://dx.doi.org/10.3390/nu12051450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284573PMC
May 2020

Gastrointestinal endoscopy in the era of the acute pandemic of coronavirus disease 2019: Recommendations by Japan Gastroenterological Endoscopy Society (Issued on April 9th, 2020).

Dig Endosc 2020 Jul 28;32(5):648-650. Epub 2020 May 28.

Japan Gastroenterological Endoscopy Society, Tokyo, Japan.

All gastrointestinal endoscopic procedures have a high risk of aerosol contamination of the coronavirus disease 2019 (COVID-19) to endoscopists, nurses, and healthcare assistants. Given the current pandemic situation of COVID-19, the Japan Gastroenterological Endoscopy Society issued the recommendation for gastrointestinal (GI) endoscopy based on the status of COVID-19 as of April 9, 2020, in Japan: (i) indications for GI endoscopy in the pandemic of COVID-19; (ii) practical protective equipment for medical personnel depending on the risk for COVID-19; (iii) preprocedural management, such as pharyngeal local anesthesia using lidocaine spray which has a potential to generate the aerosols; (iv) ideal settings of the endoscopy room including the numbers of the staff and the patients; (v) postprocedural management, such as undressing and follow-up of the patients, as well as the involved staff, were documented to fit the practical scenarios in GI endoscopy, with the available data in Japan and the world. We believe that certain measures will prevent further spread of COVID-19.
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http://dx.doi.org/10.1111/den.13703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267159PMC
July 2020

Association of Bone Metabolism with Fatty Liver Disease in the Elderly in Japan: A Community-based Study.

Intern Med 2020 May 26;59(10):1247-1256. Epub 2020 Feb 26.

Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Japan.

Objective With the aging of society, both osteoporosis and fatty liver disease (FLD) are becoming important issues. However, the relationship between osteoporosis and FLD remains controversial. We investigated the association between bone metabolism and FLD in a Japanese community in a cross-sectional study. Methods A total of 1,020 participants were enrolled in a health survey. FLD was diagnosed by ultrasonography. Bone metabolism was evaluated based on bone mineral density (BMD), which was assessed using dual-energy X-ray absorptiometry, and with the bone formation index (total type I procollagen N-terminal propeptide/bone-alkaline phosphatase ratio; P1NP/BAP ratio) and the bone resorption index (crosslinked N-telopeptide of type I collagen/tartrate-resistant acid phosphatase-5b ratio; NTx/TRACP-5b ratio) calculated from serum bone turnover markers. Results The BMD (percentage of the young adult mean) was the same level in both male and female participants with and without FLD. Both men and women showed an age-dependent decrease in their bone formation index and bone resorption index values. Men of ≥70 years of age and women of 60-69 years of age with FLD had significantly lower bone formation index values and higher bone resorption index values. However, similar findings were not seen in women of ≥70 years of age. Conclusion Although the BMD levels were the same, regardless of the presence or absence of FLD, elderly participants with FLD showed decreased bone formation and increased bone resorption, with sex differences. Because our results suggest that FLD in elderly individuals is detrimental for bone metabolism, and that it leads to bone loss and osteoporosis, further studies using a cohort population are warranted.
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http://dx.doi.org/10.2169/internalmedicine.3906-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303441PMC
May 2020

Expression, mutation, and methylation of cereblon-pathway genes at pre- and post-lenalidomide treatment in multiple myeloma.

Cancer Sci 2020 Apr 12;111(4):1333-1343. Epub 2020 Mar 12.

Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Cereblon (CRBN) is a target for immunomodulatory drugs. This study investigated the prognostic value of the expression of CRBN-pathway genes on the clinical relevance of lenalidomide (Len) treatment and evaluated the levels of CRBN-binding proteins and mutations in these genes after Len treatment. Forty-eight primary multiple myeloma cells were collected prior to treatment with Len and dexamethasone (Ld) and 25 paired samples were obtained post-Ld therapy. These tumor cells were used to determine the expression and mutated forms of the CRBN-pathway genes. Following normalization with CRBN levels, there was a significantly reduced IKZF1/CRBN ratio in samples that responded poorly to Ld therapy. Moreover, patients with low ratios of IKZF1/CRBN showed a significantly shorter progression-free survival (PFS) and overall survival (OS) than those with higher ratios. However, patients with high ratios of KPNA2/CRBN showed a significantly shorter PFS and OS than patients with lower ratios. Of the 25 paired samples analyzed, most samples showed a reduction in the expression of CRBN and an increase in IKZF1 gene expression. No mutations were observed in CRBN, IKZF1, or CUL4A genes in the post-Ld samples. In conclusion, a decreased expression of IKZF1 and increased expression of KPNA2 compared to that of CRBN mRNA predicts poor outcomes of Ld therapy.
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http://dx.doi.org/10.1111/cas.14352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156787PMC
April 2020

Case report of lanthanum deposition in the esophagus.

Clin J Gastroenterol 2020 Oct 23;13(5):683-687. Epub 2019 Dec 23.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.

A 69-year-old woman had received hemodialysis for chronic renal failure and was taking lanthanum carbonate since 63 years of age. She presented with appetite loss and nausea. We performed esophagogastroduodenoscopy, which revealed multiple longitudinal white plaques in the esophagus. Lesion biopsies showed lanthanum deposition, and lanthanum carbonate was found histologically by energy-dispersive X-ray spectroscopy. The plaques of this patient appeared like those of dabigatran-induced esophagitis, and may have occurred due to long-term contact of the esophageal epithelium with lanthanum carbonate because patient spent time in lying state. Although a few studies regarding lanthanum deposition in the stomach have been conducted, there are no reports on lanthanum deposition in the esophagus. This case suggests that the presence of longitudinal white plaques in the esophagus may indicate lanthanum deposition.
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http://dx.doi.org/10.1007/s12328-019-01085-4DOI Listing
October 2020

Diagnostic approach for patients with unidentified fever according to the classical criteria of fever of unknown origin in the field of autoimmune disorders.

Immunol Med 2019 Dec 1;42(4):176-184. Epub 2019 Dec 1.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Fever of unknown origin (FUO) is caused by various diseases, making differential diagnosis difficult. This study aimed to determine the clinical features of patients with FUO for use in daily medical practice. Medical records of patients who first visited our department for FUO between January 2008 and December 2017 were reviewed. We classified the diagnostic categories as infection, non-infectious inflammation, neoplasm, others, and unidentified through definitive diagnosis and compared the clinical characteristics of patients who fulfilled the criteria of classical FUO and those who did not. The most prevalent diseases in patients who fulfilled the criteria were adult-onset Still's disease, Behçet's disease (BD), and polymyalgia rheumatica, which do not have any specific image inspection or specific serological markers. BD and familial Mediterranean fever were most prevalent in patients who did not fulfill the criteria. All neoplasms fulfilled the criteria of classical FUO. The most useful diagnostic procedure was determined according to the criteria of each disease. The key factor that did not fulfill the criteria was periodic fever continuing for less than 3 weeks. When examining patients with FUO, we should strictly diagnose in accordance with the criteria of each disease and consider diseases that cause periodic fever.
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http://dx.doi.org/10.1080/25785826.2019.1696631DOI Listing
December 2019

Leptin/adiponectin ratio correlates with hepatic steatosis but not arterial stiffness in nonalcoholic fatty liver disease in Japanese population.

Cytokine 2020 02 27;126:154927. Epub 2019 Nov 27.

Department of Gastroenterology, Hirosaki University Graduate School of Medicine, Aomori, Japan.

Background And Aims: Cardiovascular disease (CVD) is a leading cause of mortality in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the relationship of leptin-to-adiponectin (L/A) ratio with hepatic steatosis and arterial stiffness in NAFLD.

Methods: The subjects were 871 Japanese adults who participated in a health survey. Dietary intake, body composition, lipid profile, serum interleukin-6 (IL-6), leptin, and adiponectin were analyzed. NAFLD was defined as fatty liver on ultrasonography in the absence of other causes of steatosis. Arterial stiffness was evaluated by the brachial-ankle pulse wave velocity (baPWV).

Results: The subjects with NAFLD had a greater body mass index (BMI) and body fat percentage (BFP); a higher intake of daily energy (kcal) and carbohydrates; and a higher prevalence of hypertension, diabetes, and hyperlipidemia. The subjects with NAFLD had higher serum leptin and lower serum adiponectin concentrations and a higher L/A ratio than subjects without NAFLD. The L/A ratio increased with increasing severity of steatosis. The L/A ratio showed positive correlations with BMI and BFP, and a negative correlation with age. Women had higher L/A ratio and BFP levels than men regardless of the presence or absence of NAFLD. There was a weak positive correlation between baPWV and severity of steatosis. BaPWV was strongly correlated with age, while no relation was found between baPWV and L/A ratio. IL-6 level was correlated with baPVW and age, while the correlation between Il and 6 level and L/A ratio was very weak. The L/A ratio was correlated with triglycerides and the ratio of total cholesterol to high-density lipoprotein-cholesterol.

Conclusion: L/A ratio and arterial stiffness were associated with the severity of steatosis, whereas there was no correlation between L/A ratio and arterial stiffness in NAFLD. These findings suggest that not only leptin and adiponectin but also other factors might be involved in the pathogenesis for atherosclerosis in NAFLD.
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http://dx.doi.org/10.1016/j.cyto.2019.154927DOI Listing
February 2020

Long-term maintenance of the mucosal healing induced by azacitidine therapy in a patient with intestinal Behçet's-like disease accompanied with myelodysplastic syndrome involving trisomy 8.

Immunol Med 2019 Sep 9;42(3):135-141. Epub 2019 Nov 9.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Myelodysplastic syndromes (MDSs) are a group of myeloid neoplasms characterized by blood cell deformation and dysfunction, and MDS with trisomy 8 is closely linked with intestinal Behçet's-like diseases. Intestinal Behçet's-like disease is refractory to conventional therapies, including prednisolone, immunomodulators, and anti-tumor necrosis factor α agents. Here, we describe a 56-year-old woman with intestinal Behçet's-like disease ascribed to MDS with trisomy 8 who had multiple intractable intestinal ulcers. She presented with periodic fever and abdominal pain. The genetic analysis showed a heterozygous E148Q mutation in the Mediterranean fever gene. The patient did not tolerate treatment with colchicine because of diarrhea; therefore, azacitidine therapy was initiated. One cycle of azacitidine therapy improved the multiple intestinal ulcers, and the periodic fever and abdominal pain gradually disappeared. After eight cycles of azacitidine therapy, ileocolonoscopy, histological assessment and capsule endoscopy revealed mucosal healing. Azacitidine therapy was continued, and mucosal healing was maintained for more than 2 years. This case suggests that azacitidine therapy which has immunoregulatory effects and epigenetic modulations, might control intestinal Behçet's-like disease associated with MDS involving trisomy 8.
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http://dx.doi.org/10.1080/25785826.2019.1687251DOI Listing
September 2019

Usefulness of serum opsonic activity measured by chemiluminescence method to assess the invasiveness of colorectal endoscopic mucosal dissection.

Free Radic Res 2020 Dec 29;54(11-12):810-817. Epub 2019 Oct 29.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Endoscopic sub-mucosal dissection (ESD) is considered as a low-invasive treatment for early-stage colorectal cancer, but the degree of invasiveness has not been well investigated. The aim of this study was to evaluate the physical stress due to colorectal ESD based on changes in serum opsonic activity (SOA). SOA was examined by measuring reactive oxygen species (ROS) produced by neutrophils using lucigenin-dependent chemiluminescence (LgCL) and luminol-dependent chemiluminescence (LmCL). Sixty-nine patients were enrolled into the study and examined SOA in the morning of the day of ESD, the next day, and at four days after ESD. The peak height (PH) and area under the curve (AUC) of LgCL showed no significant difference between the day and the next day, whereas the PH and AUC for LgCL were significantly higher four days after ESD than on the day of ESD ( < .05). In contrast, the PH and AUC of LmCL showed no significant changes during the ESD perioperative period. This difference suggests that SOA changes during the colorectal ESD perioperative period involved minor increases in the production of lower-toxicity ROS. This finding supports the position that ESD is a technique that does not generate a great deal of physical stress. On the other hand, a significant increase in SOA at four days after colorectal ESD suggests that care is needed with postoperative management even after the patient has started to eat meals again.
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http://dx.doi.org/10.1080/10715762.2019.1681590DOI Listing
December 2020

A case of celiac disease with type I enteropathy-associated T-cell lymphoma in a Japanese male patient.

Immunol Med 2019 Sep 11;42(3):142-147. Epub 2019 Oct 11.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

A 45-year-old Japanese male patient who was diagnosed with celiac disease (CeD) developed type I enteropathy-associated T-cell lymphoma (EATL). In 2013, the patient was admitted to our hospital with worsening of diarrhea and weight loss. Pathological examination of biopsy specimens from the duodenum and ileum led to a diagnosis of suspected EATL. A previous total colonoscopy (TCS) indicated villous atrophy in the terminal ileum. The patient was changed to a gluten-free diet, and the nutritional status gradually improved. In September 2014, he experienced acute right lower abdominal pain. He underwent urgent surgery, and a perforation was identified in the ileum. A diagnosis of type I EATL was made following histopathological examination. After eight courses of CHOP therapy, the patient entered complete remission. TCS and esophagogastroduodenoscopy with magnifying narrow-band imaging performed in 2015 identified villous regrowth in the distal ileum and duodenum. Capsule endoscopy also found villous regrowth in the entire small intestine. To our knowledge, this is the first case of type I EATL following CeD with villous atrophy before EATL occurrence in a Japanese HLA-DQ2 carrier. The possibility of type I EATL occurring after CeD should be recognized, although CeD is quite rare in Japan.
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http://dx.doi.org/10.1080/25785826.2019.1673031DOI Listing
September 2019

Significant decrease in Faecalibacterium among gut microbiota in nonalcoholic fatty liver disease: a large BMI- and sex-matched population study.

Hepatol Int 2019 Nov 12;13(6):748-756. Epub 2019 Sep 12.

Department of Gastroenterology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.

Background: Compositional changes of the gut microbiota are known to occur in patients with nonalcoholic fatty liver disease (NAFLD); however, the changes did not corroborate between the studies. We evaluated the gut microbiota between NAFLD and non-NAFLD participants, excluding the influence of obesity and sex in this study involving a large number of participants.

Methods: In total, 1148 adults participated in the health survey. NAFLD was defined as fatty liver by ultrasonography in the absence of other causes of steatosis. To exclude the influence of obesity and sex, NAFLD participants were matched to non-NAFLD participants based on BMI and sex. The relative abundance of each bacterial taxa in fecal samples was calculated using 16S ribosomal RNA amplification and was compared between NAFLD and non-NAFLD participants.

Results: There were 205 (23.5%) participants defined as having NAFLD. Before matching, there were significant differences in the relative abundance of more than 1% in two classes, two orders, three families, and three genera including Faecalibacterium between NAFLD and non-NAFLD participants. After matching, 153 matched pairs were obtained. In terms of the relative abundance of more than 1%, the relative abundance of two taxa, including the family Ruminococcaceae and the genus Faecalibacterium, was significantly lower in NAFLD participants than in non-NAFLD participants (p = 0.016 and p = 0.018).

Conclusions: The significant decrease in Faecalibacterium is a remarkable characteristic on BMI- and sex-matched analysis in NAFLD participants in a large study population. The decrease in Faecalibacterium is related to the pathogenesis of NAFLD.
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http://dx.doi.org/10.1007/s12072-019-09987-8DOI Listing
November 2019

Signet-ring Cell Carcinoma in Hyperplastic Polyp of the Stomach.

Intern Med 2019 Dec 28;58(24):3531-3535. Epub 2019 Aug 28.

Department of Internal Medicine, Kuroishi General Hospital, Japan.

Signet-ring cell carcinoma rarely occurs in gastric hyperplastic polyps, with only a few such cases reported. We treated a 76-year-old woman with a signet-ring cell carcinoma arising from a hyperplastic polyp. She had been diagnosed with a gastric hyperplastic polyp four years previously. A follow-up endoscopic examination revealed the lesion in the polyp. A biopsy showed signet-ring cell carcinoma. Hybrid endoscopic submucosal dissection with snaring and a histological examination revealed signet-ring cell carcinoma in a hyperplastic polyp. The polyp was completely excised, with no evidence of recurrence one year later. A hyperplastic polyp of the stomach may transform into adenocarcinoma of an undifferentiated type.
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http://dx.doi.org/10.2169/internalmedicine.2860-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949455PMC
December 2019

Melanoma Differentiation-Associated Gene 5 Positively Modulates TNF-α-Induced CXCL10 Expression in Cultured HuH-7 and HLE Cells.

Inflammation 2019 Dec;42(6):2095-2104

Department of Vascular Biology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.

The molecular mechanisms of innate immunity are closely associated with the development of non-alcoholic fatty liver disease (NAFLD). TNF-α is a key cytokine involved in the pathogenesis of metabolic inflammation like NAFLD. Melanoma differentiation-associated gene 5 (MDA5) is a member of the intracellular RNA helicase family proteins that play a pivotal role in an antiviral immune response. Previous studies have demonstrated that TNF-α induces the expression of MDA5 in some types of cells. However, the correlation between TNF-α and the expression of MDA5 in hepatocytes remains unknown. In the present study, we used two human hepatocellular carcinoma cell lines, HuH-7 and HLE, and examined the expression of MDA5 in these cells upon stimulation with TNF-α. The expression of MDA5 induced by TNF-α was analyzed by quantitative real-time RT-PCR and western blotting. Next, RNA interference against MDA5 was performed and the expressions of CXCL10 and STAT1 were examined. We found that the expression of MDA5 had increased upon stimulation with TNF-α in a concentration-dependent manner. Gene silencing against MDA5 suppressed the expression of TNF-α-induced CXCL10 in both cells. In HLE cells, gene silencing of MDA5 impaired STAT1 phosphorylation 24 h after stimulation with TNF-α. On the other hand, TNF-α-induced STAT1 phosphorylation was not detected in HuH-7 cells. These results indicated that MDA5 positively modulated the TNF-α-induced expression of CXCL10 in both STAT1-dependent and -independent manner and may be associated with metabolic inflammation in the liver.
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http://dx.doi.org/10.1007/s10753-019-01073-3DOI Listing
December 2019

Influence of Helicobacter pylori Infection and Atrophic Gastritis on the Gut Microbiota in a Japanese Population.

Digestion 2020 8;101(4):422-432. Epub 2019 Aug 8.

Aomori General Health Examination Center, Aomori, Japan.

Background: Although infection with Helicobacter pylori and subsequent atrophic gastritis modulate the gastric conditions, their relationship with the gut microbiota in -Japanese population has not been clearly characterized.

Methods: A cohort of 1,123 subjects who participated in a health survey was studied. Infection of H. pylori was defined by both serum antibody and stool antigen test. The presence and severity of atrophic gastritis were defined by serum levels of pepsinogens. The relative abundance of each bacterial species in fecal samples was calculated by using 16S ribosomal RNA amplification, and the composition ratios of bacterial taxa were evaluated using propensity score matching.

Results: The abundance of 3 orders, 4 families, and 4 genera was significantly higher in H. pylori-infected subjects than in noninfected subjects (false discovery rate [FDR] <0.05). In H. pylori-infected subjects with severe atrophic gastritis, the abundance of the class Bacilli, order Lactobacillales, family Streptococcaceae, and genus Streptococcus was significantly higher than that in H. pylori-infected subjects without atrophic gastritis (FDR < 0.05).

Conclusions: A significant increase in the relative abundance of several taxa was observed in gut microbiota of Japanese subjects with H. pylori infection. Among the subjects with severe atrophic gastritis, the increase in the genus Streptococcus is a remarkable characteristic.
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http://dx.doi.org/10.1159/000500634DOI Listing
April 2021

Lifestyle Factors Rather Than Helicobacter pylori Infection or Estradiol Level are Associated With Osteopenia in Japanese Men.

Am J Mens Health 2019 Mar-Apr;13(2):1557988319848219

1 Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Japan.

Although decreased calcium absorption, decreased bone formation, alcohol drinking, and smoking have been considered as causes of osteopenia in men, the cause is unknown in half of the cases. Many reports highlighted the association between Helicobacter pylori infection and osteoporosis, mainly in East Asia and Japan. To identify relevant factors of osteoporosis in men, we examined estrogen and calcium intakes and other lifestyle factors together with gastric mucosal atrophy caused by Helicobacter pylori infection. This study is a cross-sectional study design of 268 healthy men who underwent general medical examinations. Multivariate analysis was performed, with age, body mass index, smoking habit, drinking habit, exercise habit, estradiol level, calcium intake, and Helicobacter pylori infection and its associated gastric mucosal atrophy as the independent variables and the presence of osteopenia as the dependent variable. The adjusted odds ratio was 0.74 (95% Confidence Interval [0.29, 1.90], p = .531) and 1.31 (95% Confidence Interval [0.54, 3.21], p = .552), when Helicobacter pylori infection was positive without and with gastric mucosal atrophy, respectively. Helicobacter pylori infection and gastric mucosal atrophy were not significant factors. Low body mass index, smoking habit, and low calcium intake were significantly associated with decreased bone density. In conclusion, Helicobacter pylori infection was not a significant risk, whereas low body mass index, current smoking, and lower calcium intake had a significant influence on the development of osteopenia in men.
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http://dx.doi.org/10.1177/1557988319848219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498780PMC
May 2020

Influence of gastric endoscopic submucosal dissection on serum opsonic activity measured by chemiluminescence.

J Clin Biochem Nutr 2019 Mar 6;64(2):180-185. Epub 2019 Feb 6.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.

This study aimed to elucidate whether changes in serum opsonic activity measured by lucigenin-dependent chemiluminescence and luminol-dependent chemiluminescence are useful for estimating physical stress during the perioperative period of gastric endoscopic submucosal dissection. Serum opsonic activity in the peripheral blood of 87 patients was examined in the morning of the day of endoscopic submucosal dissection, the next day, and at 4 days after endoscopic submucosal dissection. Peak height and area under the curve for lucigenin-dependent chemiluminescence were 106.1 ± 22.7% and 102.0 ± 24.7% on the day of endoscopic submucosal dissection, which increased significantly to 113.6 ± 29.4% and 111.0 ± 29.1% on the next day (both <0.01), and 112.4 ± 27.0% and 110.0 ± 28.1% at 4 days after endoscopic submucosal dissection (both <0.01), respectively. In contrast, significant changes were not observed in peak height and area under the curve for luminol-dependent chemiluminescence during the perioperative period of endoscopic submucosal dissection. This difference suggests that serum opsonic activity during the perioperative period of gastric endoscopic submucosal dissection is associated with the production of substances with lower oxidizing potential. (The study of changes in neutrophil function and physical stress during the perioperative period of endoscopic operation: UMIN000034514).
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http://dx.doi.org/10.3164/jcbn.18-93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436044PMC
March 2019