Publications by authors named "Noriko Suzuki"

141 Publications

Electromyographic evaluation of perioral muscle activities during facial expression and button-pull exercise.

J Oral Rehabil 2021 Nov 14;48(11):1226-1234. Epub 2021 Aug 14.

Oral Health Science Center, Tokyo Dental College, Chiyoda-ku, Japan.

Background: Muscle weakness negatively affects perioral muscles and quality of life. The button-pull exercise is used to teach lip closure (LC) and to strengthen muscles. However, how the muscles accomplish LC during button-pull and its training effect on each muscle are unknown.

Objectives: This study aimed to investigate the LC mechanism and the efficacy of perioral muscle training.

Methods: Electromyographic (EMG) activities were obtained from perioral muscles along with the lip closing force (LCF) and were normalised to the maximum LC activities. Correlations between muscle activities and LCF were assessed during LCF increment/decrement task. The effectiveness of training methods was evaluated during functional face tasks (FFT). The effects of button-pull on muscles were evaluated during static loadings with two sized buttons.

Results: The muscles were active during LC, and the amplitudes changed with the LCF. In FFT, the muscles were simultaneously active and the total activity was highest during the blowing task. In button-pull, maximum button-pulling forces (BPFs) were significantly larger with the large button (p = .0001). In the static loading task, muscle activities increased with increasing button load. However, the small button produced significantly greater EMG activity than the large button in most of the load (p < .005).

Conclusion: LC is accomplished by the cooperation of perioral muscles. In button-pull, a larger button requires a larger BPF, but a smaller button shows higher muscle activities. Face expression exercises compare favourably with button-pull. Forceful LC and blowing tasks may be effective and balanced training of the perioral muscles.
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http://dx.doi.org/10.1111/joor.13241DOI Listing
November 2021

Tissue N-Glycan Analysis Using LC-MS, MS/MS, and MS.

Authors:
Noriko Suzuki

Curr Protoc 2021 Jul;1(7):e200

Graduate School of Science and Technology, Niigata University, Niigata, Japan.

Tissue glycans usually contain various structures, from simple to highly complicated, in different quantities. N-Glycans are particularly heterogeneous, with up to pentaantennary structures, different branch sequences, and several isomeric structures. 2-Aminopyridine (PA) tagging on released N-glycans is useful for separating isomers and to quantitatively analyze both the major and minor glycan structures in tissues using reversed-phase liquid chromatography (LC)-mass spectrometry (MS) and MS/MS analysis. Because the structural differences of PA-N-glycans influence their retention on a reversed-phase C18 column, it is easy to deduce the core structure, including core Fuc and bisecting GlcNAc as well as the branching pattern of each PA-N-glycan, based on the results of elution position, full MS, and MS/MS analysis. If more detailed structural analysis is required, combining sequential exoglycosidase digestions, sialic acid linkage-specific alkylamidation (SALSA), and/or SALSA/permethylation is useful for determining glycosidic linkages of branches. This article includes detailed protocols for the preparation of N-glycans released from glycoproteins/glycopeptides by glycoamidase F or hydrazinolysis, PA-tagging of N-glycans, fractionation with anion-exchange chromatography, and chemical or enzymatic modifications of PA-N-glycans, as well as reversed-phase LC-MS, MS/MS, and MS analysis of PA-N-glycans from tissues. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Preparation of released N-glycans from tissue samples using glycoamidase F Alternate Protocol: Preparation of released N-glycans from tissue samples by hydrazinolysis Basic Protocol 2: PA-tagging of N-glycans and sample cleanup Support Protocol 1: Monitoring of PA-N-glycans using normal-phase HPLC Basic Protocol 3: Anion-exchange chromatography of PA-N-glycans Basic Protocol 4: Sequential exoglycosidase digestions Basic Protocol 5: Determination of Sia-linkages by SALSA Support Protocol 2: Cotton-HILIC solid-phase extraction to remove reagents for alkylamidation Basic Protocol 6: Sequential modifications of glycans with SALSA and permethylation Basic Protocol 7: LC-MS and MS/MS analysis of PA-N-glycans (before permethylation) Basic Protocol 8: LC-MS, MS/MS, and MS analysis of PA-N-glycans (after permethylation).
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http://dx.doi.org/10.1002/cpz1.200DOI Listing
July 2021

Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement.

Sci Rep 2021 07 15;11(1):14532. Epub 2021 Jul 15.

Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Kanagawa, 251-8555, Fujisawa, Japan.

Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma C) and 1017-fold (AUC ) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation.
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http://dx.doi.org/10.1038/s41598-021-93888-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282797PMC
July 2021

Ethnic comparison in takotsubo syndrome: novel insights from the International Takotsubo Registry.

Clin Res Cardiol 2021 May 19. Epub 2021 May 19.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes.

Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients.

Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients.

Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.

Trial Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01947621.
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http://dx.doi.org/10.1007/s00392-021-01857-4DOI Listing
May 2021

Toward robust N-glycomics of various tissue samples that may contain glycans with unknown or unexpected structures.

Sci Rep 2021 03 18;11(1):6334. Epub 2021 Mar 18.

Graduate School of Science and Technology, Niigata University, 8050 Ikarashi-nino-cho, Nishi-ku, Niigata, 950-2181, Japan.

Glycans in tissues are structurally diverse and usually include a large number of isomers that cannot be easily distinguished by mass spectrometry (MS). To address this issue, we developed a combined method that can efficiently separate and identify glycan isomers. First, we separated 2-aminopyridine (PA)-derivatized N-glycans from chicken colon by reversed-phase liquid chromatography (LC) and directly analyzed them by electrospray ionization (ESI)-MS and MS/MS to obtain an overview of the structural features of tissue glycans. Next, we deduced the structures of isomers based on their elution positions, full MS, and MS/MS data, before or after digestions with several exoglycosidases. In this method, the elution position differed greatly depending on the core structure and branching pattern, allowing multiantennary N-glycan structures to be easily distinguished. To further determine linkages of branch sequences, we modified PA-N-glycans with sialic acid linkage-specific alkylamidation and/or permethylation, and analyzed the products by LC-MS and multistage MS. We determined the relative abundances of core structures, branching patterns, and branch sequences of N-glycans from chicken colon, and confirmed presence of characteristic branch sequences such as Le, sialyl Le, sulfated LacNAc, LacNAc repeat, and LacdiNAc. The results demonstrated that our method is useful for comparing N-glycomes among various tissue samples.
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http://dx.doi.org/10.1038/s41598-021-84668-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973440PMC
March 2021

LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models.

Sci Adv 2021 Mar 12;7(11). Epub 2021 Mar 12.

Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1,2)-2-((cyclopropylmethyl)amino)cyclopropyl)--(tetrahydro-2-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.
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http://dx.doi.org/10.1126/sciadv.aba1187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954450PMC
March 2021

Endoscopic full thickness resection in the colo-rectum: outcomes from the UK Registry.

Eur J Gastroenterol Hepatol 2021 06;33(6):852-858

Department of Gastroenterology, University Hospital Southampton NHS Foundation Trust.

Background: Endoscopic full-thickness resection (eFTR) of the colon using the full-thickness resection device (FTRD) is a novel method for removing lesions involving, or tethered to, deeper layers of the colonic wall. The UK FTRD Registry collected data from multiple centres performing this procedure. We describe the technical feasibility, safety and early outcomes of this technique in the UK.

Methods: Data were collected and analysed on 68 patients who underwent eFTR at 11 UK centres from April 2015 to June 2019. Outcome measures were technical success, procedural time, specimen size, R0 resection, endoscopic clearance, and adverse events. Reported technical difficulties were collated.

Results: Indications for eFTR included non-lifting polyps (29 cases), T1 tumour resection (13), subepithelial tumour (9), and polyps at the appendix base or diverticulum (17). Target lesion resection was achieved in 60/68 (88.2%). Median specimen size was 21.7 mm (10-35 mm). Histologically confirmed R0 resection was achieved in 43/56 (76.8%) with full-thickness resection in 52/56 (92.9%). Technical difficulties occurred in 17/68 (25%) and complications in 3/68 (5.9%) patients.

Conclusion: eFTR is a useful technique with a high success rate in treating lesions not previously amenable to endoscopic therapy. Whilst technical difficulties may arise, complication rates are low and outcomes are acceptable, making eFTR a viable alternative to surgery for some specific lesions.
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http://dx.doi.org/10.1097/MEG.0000000000001987DOI Listing
June 2021

Water-assisted colonoscopy: an international modified Delphi review on definitions and practice recommendations.

Gastrointest Endosc 2021 06 16;93(6):1411-1420.e18. Epub 2020 Oct 16.

Division of Gastroenterology and Hepatology, Stanford University School of Medicine, VA Palo Alto, California, United States.

Background And Aims: Since 2008, a plethora of research studies has compared the efficacy of water-assisted (aided) colonoscopy (WAC) and underwater resection (UWR) of colorectal lesions with standard colonoscopy. We reviewed and graded the research evidence with potential clinical application. We conducted a modified Delphi consensus among experienced colonoscopists on definitions and practice of water immersion (WI), water exchange (WE), and UWR.

Methods: Major databases were searched to obtain research reports that could potentially shape clinical practice related to WAC and UWR. Pertinent references were graded (Grading of Recommendations, Assessment, Development and Evaluation). Extracted data supporting evidence-based statements were tabulated and provided to respondents. We received responses from 55 (85% surveyed) experienced colonoscopists (37 experts and 18 nonexperts in WAC) from 16 countries in 3 rounds. Voting was conducted anonymously in the second and third round, with ≥80% agreement defined as consensus. We aimed to obtain consensus in all statements.

Results: In the first and the second modified Delphi rounds, 20 proposed statements were decreased to 14 and then 11 statements. After the third round, the combined responses from all respondents depicted the consensus in 11 statements (S): definitions of WI (S1) and WE (S2), procedural features (S3-S5), impact on bowel cleanliness (S6), adenoma detection (S7), pain score (S8), and UWR (S9-S11).

Conclusions: The most important consensus statements are that WI and WE are not the same in implementation and outcomes. Because studies that could potentially shape clinical practice of WAC and UWR were chosen for review, this modified Delphi consensus supports recommendations for the use of WAC in clinical practice.
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http://dx.doi.org/10.1016/j.gie.2020.10.011DOI Listing
June 2021

Gastric adenomas and their management in familial adenomatous polyposis.

Endoscopy 2021 08 17;53(8):795-801. Epub 2020 Sep 17.

The Polyposis Registry, St. Mark's Hospital, London, United Kingdom.

Background: Patients with familial adenomatous polyposis (FAP) are at increased risk of developing gastric adenomas. There is limited understanding of their clinical course and no consensus on management. We reviewed the management of gastric adenomas in patients with FAP from two centers.

Methods: Patients with FAP and histologically confirmed gastric adenomas were identified between 1997 and 2018. Patient demographics, adenoma characteristics, and management/surveillance outcomes were collected.

Results: Of 726 patients with FAP, 104 (14 %; 49 female) were diagnosed with gastric adenomas at a median age of 47 years (range 19 - 80). The median size of gastric adenomas was 6 mm (range 1.5 - 50); 64 (62 %) patients had adenomas located distally to the incisura. Five patients (5 %) had gastric adenomas demonstrating high-grade dysplasia (HGD) on initial diagnosis, distributed equally within the stomach. The risk of HGD was associated with adenoma size ( = 0.04). Of adenomas > 20 mm, 33 % contained HGD. Two patients had gastric cancer at initial gastric adenoma diagnosis. A total of 63 patients (61 %) underwent endoscopic therapy for gastric adenomas. Complications occurred in three patients (5 %) and two (3 %) had recurrence, all following piecemeal resection of large (30 - 50 mm) lesions. Three patients were diagnosed with gastric cancer at median follow-up of 66 months (range 66 - 115) after initial diagnosis.

Conclusions: We observed gastric adenomas in 14 % of patients with FAP. Of these, 5 % contained HGD; risk of HGD correlated with adenoma size. Endoscopic resection was feasible, with few complications and low recurrence rates, but did not completely eliminate the cancer risk.
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http://dx.doi.org/10.1055/a-1265-2716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315898PMC
August 2021

COVID-19 and endoscopic management of superficial gastrointestinal neoplastic lesions: a multinational cross-sectional survey.

Endoscopy 2021 Feb 11;53(2):173-177. Epub 2020 Aug 11.

Department of Gastroenterology, Portuguese Oncology Institute of Porto, Porto, Portugal.

Introduction: We aimed to report the impact of the pandemic lockdown period on the treatment and prognosis of superficial gastrointestinal neoplastic lesions.

Methods: A survey was completed by 11 centers from four continents regarding postponements during the early lockdown period of the pandemic, and the same period in 2019.

Results: In 2020, 55 % of the scheduled procedures were deferred, which was 11 times higher than in 2019; the main reasons were directly related to COVID-19. In countries that were highly affected, this proportion rose to 76 % vs. 26 % in those where there was less impact. Despite the absolute reduction, the relative distribution in 2019 vs. 2020 was similar, the only exception being duodenal lesions (affected by a 92 % reduction in mucosectomies). Although it is expected that the majority of postponements will not affect the stage (based on the results from biopsies and/or endoscopic appearance), 3 % of delayed procedures will probably require surgery.

Conclusions: The lockdown period caused by the SARS-CoV-2 pandemic led to a substantial reduction in the number of endoscopic resections for neoplastic lesions. Nevertheless, based on clinical judgment, the planned median delay will not worsen the prognosis of the affected patients.
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http://dx.doi.org/10.1055/a-1237-5221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869031PMC
February 2021

Sequential modifications of glycans by linkage-specific alkylamidation of sialic acids and permethylation.

Anal Biochem 2020 10 31;606:113861. Epub 2020 Jul 31.

Graduate School of Science and Technology, Niigata University, Niigata, Japan. Electronic address:

Permethylation is useful for glycosidic linkage analysis, but is often accompanied by a large proportion of by-products, especially for glycans containing sialic acids (Sia). Unlike hydroxyl groups of glycans, which are converted to stable methyl ethers by permethylation, the carboxylic acids on Sia are converted to methyl esters, which are easily reversible to carboxylate under alkaline conditions. To overcome this problem, we used linkage-specific alkylamidation to protect Sia prior to the permethylation. This method not only decreased the levels of by-products, but also enabled us to distinguish isomers of α2,3- and α2,6-Sia while simultaneously determining other glycosidic linkages.
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http://dx.doi.org/10.1016/j.ab.2020.113861DOI Listing
October 2020

Systematic review with meta-analysis: IBD-associated colonic dysplasia prognosis in the videoendoscopic era (1990 to present).

Aliment Pharmacol Ther 2020 07 20;52(1):5-19. Epub 2020 May 20.

St Mark's Hospital, Harrow, UK.

Introduction: The prognosis of dysplasia in patients with IBD is largely determined from observational studies from the pre-videoendoscopic era (pre-1990s) that does not reflect recent advances in endoscopic imaging and resection.

Aims: To better understand the risk of synchronous colorectal cancer and metachronous advanced neoplasia (ie high-grade dysplasia or cancer) associated with dysplasia diagnosed in the videoendoscopic era, and to stratify risk according to a lesion's morphology, endoscopic resection status or whether it was incidentally detected on biopsy of macroscopically normal colonic mucosa (ie invisible).

Methods: A systematic search of original articles published between 1990 and February 2020 was performed. Eligible studies reported on incidence of advanced neoplasia at follow-up colectomy or colonoscopy for IBD-dysplasia patients. Quantitative and qualitative analyses were performed.

Results: Thirty-three studies were eligible for qualitative analysis (five for the meta-analysis). Pooled estimated proportions of incidental synchronous cancers found at colectomy performed for a pre-operative diagnosis of visible high-grade dysplasia, invisible high-grade dysplasia, visible low-grade dysplasia and invisible low-grade dysplasia were 13.7% (95% CI 0.0-54.1), 11.4% (95% CI 4.6-20.3), 2.7% (95% CI 0.0-7.1) and 2.4% (95% CI 0.0-8.5) respectively. The lowest incidences of metachronous advanced neoplasia, for dysplasia not managed with immediate colectomy but followed up with surveillance, tended to be reported by the studies where high definition imaging and/or chromoendoscopy was used and endoscopic resection of visible dysplasia was histologically confirmed.

Conclusions: The prognosis of IBD-dysplasia diagnosed in the videoendoscopic era appears to have been improved but the quality of evidence remains low. Larger, prospective studies are needed to guide management. PROSPERO registration no: CRD42019105736.
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http://dx.doi.org/10.1111/apt.15778DOI Listing
July 2020

Curriculum review: serrated lesions of the colorectum.

Frontline Gastroenterol 2020 5;11(3):243-248. Epub 2019 Jun 5.

Wolfson Unit for Endoscopy, St Mark's Hospital, London, UK.

Colorectal cancer (CRC) is the second leading cause of death from cancer in the UK. Sporadic CRC evolves by the cumulative effect of genetic and epigenetic alterations. Typically, over the course of several years, this leads to the transformation of normal colonic epithelium to benign adenomatous polyp, low-grade to high-grade dysplasia and finally cancer-the adenoma-carcinoma sequence. Over the last decade, the serrated neoplasia pathway which progresses by methylation of tumour suppressing genes has been increasingly recognised as an important alternative pathway accounting for up to 30% of CRC cases. Endoscopists should be aware of the unique features of serrated lesions so that their early detection, appropriate resection and surveillance interval can be optimised.
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http://dx.doi.org/10.1136/flgastro-2018-101153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223468PMC
June 2019

Blood group P1 antigen-bearing glycoproteins are functional but less efficient receptors of Shiga toxin than conventional glycolipid-based receptors.

J Biol Chem 2020 07 14;295(28):9490-9501. Epub 2020 May 14.

Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan

Shiga toxin (STx) is a virulence factor produced by enterohemorrhagic STx is taken up by mammalian host cells by binding to the glycosphingolipid (GSL) globotriaosylceramide (Gb3; Galα1-4Galβ1-4Glc-ceramide) and causes cell death after its retrograde membrane transport. However, the contribution of the hydrophobic portion of Gb3 (ceramide) to STx transport remains unclear. In pigeons, blood group P1 glycan antigens (Galα1-4Galβ1-4GlcNAc-) are expressed on glycoproteins that are synthesized by α1,4-galactosyltransferase 2 (pA4GalT2). To examine whether these glycoproteins can also function as STx receptors, here we constructed glycan-remodeled HeLa cell variants lacking Gb3 expression but instead expressing pA4GalT2-synthesized P1 glycan antigens on glycoproteins. We compared STx binding and sensitivity of these variants with those of the parental, Gb3-expressing HeLa cells. The glycan-remodeled cells bound STx1 via -glycans of glycoproteins and were sensitive to STx1 even without Gb3 expression, indicating that P1-containing glycoproteins also function as STx receptors. However, these variants were significantly less sensitive to STx than the parent cells. Fluorescence microscopy and correlative light EM revealed that the STx1 B subunit accumulates to lower levels in the Golgi apparatus after glycoprotein-mediated than after Gb3-mediated uptake but instead accumulates in vacuole-like structures probably derived from early endosomes. Furthermore, coexpression of Galα1-4Gal on both glycoproteins and GSLs reduced the sensitivity of cells to STx1 compared with those expressing Galα1-4Gal only on GSLs, probably because of competition for STx binding or internalization. We conclude that lipid-based receptors are much more effective in STx retrograde transport and mediate greater STx cytotoxicity than protein-based receptors.
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http://dx.doi.org/10.1074/jbc.RA120.013926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363145PMC
July 2020

Double-tunneling butterfly method for endoscopic submucosal dissection of extensive rectal neoplasms.

VideoGIE 2020 Feb 30;5(2):80-85. Epub 2020 Jan 30.

The Wolfson Unit for Endoscopy, St Mark's Hospital, London, United Kingdom.

Background And Aims: Endoscopic submucosal dissection (ESD) is the preferred technique for en bloc resection of superficial colorectal neoplasms. Resection of extensive lesions with ESD can be challenging, owing to loss of orientation in the submucosal space. In this case series, we describe the double-tunneling (DoT) butterfly method for ESD of extensive rectal neoplasms.

Methods: The key feature of the DoT butterfly method is the creation of 2 tunnels that are transformed into bilateral flaps, leaving a submucosal septum between them.

Results: Four rectal neoplasms measuring (maximum diameter) 7 cm, 8 cm, 9 cm, and 18 cm, respectively, were resected in 4 patients by use of the DoT butterfly method. The lesions included recurrent adenoma (n = 1) and dysplasia (n = 1) in longstanding ulcerative colitis. Curative R0 resection was confirmed in all 4 cases. Histologic examination showed tubular adenomas with low-grade dysplasia in 1 of 4 patients and focal high-grade dysplasia in 3 of 4 patients. One patient experienced postprocedural bleeding that required endoscopic reintervention.

Conclusion: The DoT butterfly method appears to be useful for the resection of extensive rectal neoplasms. A prospective study is required to assess whether these results can be reproduced in a large cohort of patients.
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http://dx.doi.org/10.1016/j.vgie.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004922PMC
February 2020

Feasibility and Safety of Endoscopic Submucosal Dissection for Recurrent Rectal Lesions that after Transanal Endoscopic Microsurgery: A Case Series.

Digestion 2021 5;102(3):446-452. Epub 2020 Feb 5.

Divison of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Kobe, Japan.

Objectives: Recently, several studies have demonstrated the usefulness of endoscopic submucosal dissection (ESD) for residual or locally recurrent colorectal lesions after endoscopic treatment. However, the feasibility of ESD for recurrent rectal lesions after transanal endoscopic microsurgery (TEM) has not been fully investigated. In this study, we evaluated the feasibility and safety of ESD for recurrent rectal lesions after TEM.

Methods: The treatment outcomes of 10 lesions in 9 patients, who underwent ESD between January 2006 and March 2018 for recurrent rectal lesions after transanal endoscopic microsurgery, were evaluated.

Results: All lesions were successfully resected en bloc, and the R0 resection rate was 90%. The median size of the resected specimens and lesions (range) was 44 mm (21-70) and 27.5 mm (5-60), respectively. The pathological diagnoses included 4 adenomas and 6 cancerous lesions. The cancerous lesions included 5 cases of mucosal cancer and 1 case of superficial submucosal invasive cancer (depth of submucosal invasion <1,000 μm from the muscularis mucosae). No adverse events occurred. There was no recurrence during the follow-up period.

Conclusions: ESD for recurrent rectal lesions after TEM by expert's hands appears to be safe and feasible.
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http://dx.doi.org/10.1159/000505619DOI Listing
August 2021

TAK-915, a phosphodiesterase 2A inhibitor, ameliorates the cognitive impairment associated with aging in rodent models.

Behav Brain Res 2019 12 12;376:112192. Epub 2019 Sep 12.

Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Japan. Electronic address:

Changes in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling are implicated in older people with dementia. Drugs that modulate the cAMP/cGMP levels in the brain might therefore provide new therapeutic options for the treatment of cognitive impairment in aging and elderly with dementia. Phosphodiesterase 2A (PDE2A), which is highly expressed in the forebrain, is one of the key phosphodiesterase enzymes that hydrolyze cAMP and cGMP. In this study, we investigated the effects of PDE2A inhibition on the cognitive functions associated with aging, such as spatial learning, episodic memory, and attention, in rats with a selective, brain penetrant PDE2A inhibitor, N-{(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915). Repeated treatment with TAK-915 (3 mg/kg/day, p.o. for 4 days) significantly reduced escape latency in aged rats in the Morris water maze task compared to the vehicle treatment. In the novel object recognition task, TAK-915 (1, 3, and 10 mg/kg, p.o.) dose-dependently attenuated the non-selective muscarinic antagonist scopolamine-induced memory deficits in rats. In addition, oral administration of TAK-915 at 10 mg/kg significantly improved the attentional performance in middle-aged, poorly performing rats in the 5-choice serial reaction time task. These findings suggest that PDE2A inhibition in the brain has the potential to ameliorate the age-related cognitive decline.
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http://dx.doi.org/10.1016/j.bbr.2019.112192DOI Listing
December 2019

Glycan diversity in the course of vertebrate evolution.

Authors:
Noriko Suzuki

Glycobiology 2019 08;29(9):625-644

Graduate School of Science and Technology, Niigata University, Niigata, Japan.

Vertebrates are estimated to have arisen over 500 million years ago in the Cambrian Period. Species that survived the Big Five extinction events at a global scale underwent repeated adaptive radiations along with habitat expansions from the sea to the land and sky. The development of the endoskeleton and neural tube enabled more complex body shapes. At the same time, vertebrates became suitable for the invasion and proliferation of foreign organisms. Adaptive immune systems were acquired for responses to a wide variety of pathogens, and more sophisticated systems developed during the evolution of mammals and birds. Vertebrate glycans consist of common core structures and various elongated structures, such as Neu5Gc, Galα1-3Gal, Galα1-4Gal, and Galβ1-4Gal epitopes, depending on the species. During species diversification, complex glycan structures were generated, maintained or lost. Whole-genome sequencing has revealed that vertebrates harbor numerous and even redundant glycosyltransferase genes. The production of various glycan structures is controlled at the genetic level in a species-specific manner. Because cell surface glycans are often targets of bacterial and viral infections, glycan structural diversity is presumed to be protective against infections. However, the maintenance of apparently redundant glycosyltransferase genes and investment in species-specific glycan structures, even in higher vertebrates with highly developed immune systems, are not well explained. This fact suggests that glycans play important roles in unknown biological processes.
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http://dx.doi.org/10.1093/glycob/cwz038DOI Listing
August 2019

Association of heart failure duration with clinical prognosis in advanced heart failure.

Clin Res Cardiol 2020 Mar 27;109(3):350-357. Epub 2019 Jun 27.

Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, 53105, Bonn, Germany.

Background: Little is known about the prognostic impact of heart failure (HF) duration in patients with advanced HF.

Methods: A total of 109 consecutive patients with advanced HF referred to the institutional heart transplant program between July 2014 and December 2017 were prospectively enrolled. The patients were divided into two groups according to the HF duration using a pre-specified cutoff (> 18 months, n = 38; ≤ 18 months, n = 71). The Cox proportional hazards model was generated to investigate the association between the HF duration and a 1-year composite endpoint (all-cause mortality, left ventricular assist device implantation, and hospitalization due to HF).

Results: Patients with a longer HF duration were older and had significantly lower blood pressure, and greater left ventricular volume compared with those with a shorter HF duration. The 1-year event-free survival rate was significantly lower in patients with a longer HF duration (49.1% vs. 80.0%, log-rank p < 0.001). After adjustment, a longer HF duration was independently associated with an increased risk for the composite endpoint (hazard ratio, 2.44; 95% confidence interval, 1.03-5.76; p = 0.04). Additionally, longer HF duration was independently associated with an increased wall motion score index and a decreased heart-to-mediastinum ratio of I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy (all associations, p < 0.05).

Conclusions: A longer HF duration is associated with an increased risk of adverse outcomes as well as more severe myocardial damage among patients with advanced HF.
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http://dx.doi.org/10.1007/s00392-019-01515-wDOI Listing
March 2020

Preclinical characterization of AMPA receptor potentiator TAK-137 as a therapeutic drug for schizophrenia.

Pharmacol Res Perspect 2019 06 9;7(3):e00479. Epub 2019 May 9.

Neuroscience Drug Discovery Unit, Research Takeda Pharmaceutical Company Limited Fujisawa Japan.

The downregulation of the glutamate system may be involved in positive, negative, and cognitive symptoms of schizophrenia. Through enhanced glutamate signaling, the activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, an ionotropic glutamate receptor, could be a new therapeutic strategy for schizophrenia. TAK-137 is a novel AMPA receptor potentiator with minimal agonistic activity; in this study, we used rodents and nonhuman primates to assess its potential as a drug for schizophrenia. At 10 mg kg p.o., TAK-137 partially inhibited methamphetamine-induced hyperlocomotion in rats, and at 3, 10, and 30 mg kg p.o., TAK-137 partially inhibited MK-801-induced hyperlocomotion in mice, suggesting weak effects on the positive symptoms of schizophrenia. At 0.1 and 0.3 mg kg p.o., TAK-137 significantly ameliorated MK-801-induced deficits in the social interaction of rats, demonstrating potential improvement of impaired social functioning, which is a negative symptom of schizophrenia. The effects of TAK-137 were evaluated on multiple cognitive domains-attention, working memory, and cognitive flexibility. TAK-137 enhanced attention in the five-choice serial reaction time task in rats at 0.2 mg kg p.o., and improved working memory both in rats and monkeys: 0.2 and 0.6 mg kg p.o. ameliorated MK-801-induced deficits in the radial arm maze test in rats, and 0.1 mg kg p.o. improved the performance of ketamine-treated monkeys in the delayed matching-to-sample task. At 0.1 and 1 mg kg p.o., TAK-137 improved the cognitive flexibility of subchronic phencyclidine-treated rats in the reversal learning test. Thus, TAK-137-type AMPA receptor potentiators with low intrinsic activity may offer new therapies for schizophrenia.
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http://dx.doi.org/10.1002/prp2.479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507438PMC
June 2019

Diagnostic abilities of 3T MRI for assessing mandibular invasion of squamous cell carcinoma in the oral cavity: comparison with 64-row multidetector CT.

Dentomaxillofac Radiol 2019 May 26;48(4):20180311. Epub 2019 Feb 26.

1 Department of Oral and Maxillofacial Radiology, Graduate School, Tokyo Medical and Dental University , Tokyo , Japan.

Objectives: To evaluate the diagnostic accuracies of 3T MRI in evaluating mandibular invasion of squamous cell carcinoma (SCC) in the oral cavity and to compare those with that of multidetector CT (MDCT).

Methods: 41 cases with oral SCC examined by both 3T MRI and MDCT prior to surgery were included in this study. Intravenous contrast medium was administered in all examinations. Images were evaluated for the presence or absence of mandibular invasion and mandibular canal involvement by the tumour. For MRI, both two-dimensional (2D) fast spin echo (FSE) and three-dimensional (3D) volumetric interpolated breath-hold examination (VIBE) images were used for the evaluation. For MDCT, dental CT cross-sectional images were rused. The results were correlated with histopathological findings, and sensitivity and specificity of each imaging technique were calculated.DMFR prrof.

Results: Histopathologically, 32 of 41 cases had mandibular invasion and 10 cases had mandibular canal involvement. For mandibular invasion, all three imaging techniques showed sensitivities of 100%. However, the specificities of 2D FSE (56%) and 3D VIBE (78%) were lower than that of MDCT (89%), although the differences were not significant. For mandibular canal involvement, whereas the sensitivities of all three imaging techniques were 100%, the specificities of 2D FSE, 3D VIBE and MDCT were 54, 62 and 85%, respectively. The specificity of 2D FSE was significantlylower than that of MDCT ( < 0.017).

Conclusions: In the evaluation of mandibular invasion, 3T MRI was not as accurate as MDCT. In particular, 2D FSE sequences showed significantly lower specificity than MDCT in evaluating the extent of mandibular invasion. The use of 3D VIBE sequence slightly improved the low specificity of 2D FSE sequences.
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http://dx.doi.org/10.1259/dmfr.20180311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592587PMC
May 2019

Quantitative LC-MS and MS/MS analysis of sialylated glycans modified by linkage-specific alkylamidation.

Anal Biochem 2019 02 20;567:117-127. Epub 2018 Nov 20.

Graduate School of Science and Technology, Niigata University, 8050 Ikarashi-nino-cho, Nishi-ku, Niigata, 950-2181, Japan; Faculty of Science, Niigata University, 8050 Ikarashi-nino-cho, Nishi-ku, Niigata, 950-2181, Japan.

Sialic acids (Sia) are involved in various biological and pathological processes, and are often found attached to non-reducing ends of glycans through either α2,3- or α2,6-linkages. To quantitatively analyze glycan structures with these linkage isoforms by liquid chromatography-mass spectrometry (LC-MS), we established a linkage-specific two-step alkylamidation method for N-glycans. Using this method, carboxyl groups of α2,3- and α2,6-linked Sia are derivatized with two kinds of alkylamines with different mass values in a linkage-specific manner, allowing products to be easily distinguished. The reaction efficiencies for di-, tri-, and tetra-sialyl PA-N-glycans were >94%, with few by-products. Mixtures of 2-aminopyridine (PA)-tagged N-glycans from human α1-acid glycoprotein were subjected to the method, and products were analyzed by LC-MS and MS/MS, and simultaneously monitored with a fluorescence detector. The relative content of Siaα2-3Gal and Siaα2-6Gal was estimated from the integrated fluorescence intensity of each peak. Moreover, MS/MS data clearly indicated characteristic B-ion fragments of N-glycan branches, such as the sialyl Le sequence, with Sia linkage-specific alkylamidation, suggesting that this method also provides useful information of branch sequences. We optimized the method with the aim of (1) enabling high-throughput analysis and (2) maximizing the analysis of glycans from various types of samples, including highly heterogeneous glycans.
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http://dx.doi.org/10.1016/j.ab.2018.11.014DOI Listing
February 2019

Preparation of a Molecular Library of Branched β-Glucan Oligosaccharides Derived from Laminarin.

J Appl Glycosci (1999) 2018 20;65(4):45-49. Epub 2018 Nov 20.

1 Department of Biology, Faculty of Science, Niigata University.

To study the structure of β-glucans, we developed a separation method and molecular library of β-glucan oligosaccharides. The oligosaccharides were prepared by partial acid hydrolysis from laminarin, which is a β-glucan of . They were labeled with the 2-aminopyridine fluorophore and separated to homogeneity by size-fractionation and reversed phase high-performance liquid chromatography (HPLC). Branching structures of all isomeric oligosaccharides from trimers to pentamers were determined, and a two-dimensional (2D)-HPLC map of the β-glucan oligosaccharides was made based on the data. Next, structural analysis of the longer β-glucan oligosaccharide was performed using the 2D-HPLC map. A branched decamer oligosaccharide was isolated from the β-glucan and cleaved to smaller oligosaccharides by partial acid hydrolysis. The structure of the longer oligosaccharide was successfully elucidated from the fragment structures determined by the 2D-HPLC map. The molecular library and the 2D-HPLC map described in this study will be useful for the structural analysis of β-glucans.
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http://dx.doi.org/10.5458/jag.jag.JAG-2018_004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056915PMC
November 2018

TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window.

Neuropsychopharmacology 2019 04 12;44(5):961-970. Epub 2018 Sep 12.

Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.

Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPA-R) is a promising strategy to treat psychiatric and neurological diseases if issues of bell-shaped response and narrow safety margin against seizure can be overcome. Here, we show that structural interference at Ser743 in AMPA-R is a key to lower the agonistic effect of AMPA-R potentiators containing dihydropyridothiadiazine 2,2-dioxides skeleton. With this structural insight, TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide, was discovered as a novel AMPA-R potentiator with a lower agonistic effect than an AMPA-R potentiator LY451646 ((R)-N-(2-(4'-cyanobiphenyl-4-yl)propyl)propane-2-sulfonamide) in rat primary neurons. TAK-137 induced brain-derived neurotrophic factor in neurons in rodents and potently improved cognition in both rats and monkeys. Compared to LY451646, TAK-137 had a wider safety margin against seizure in rats. TAK-137 enhanced neural progenitor proliferation over a broader range of doses in rodents. Thus, TAK-137 is a promising AMPA-R potentiator with potent procognitive effects and lower risks of bell-shaped response and seizure. These data may open the door for the development of AMPA-R potentiators as therapeutic drugs for psychiatric and neurological diseases.
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http://dx.doi.org/10.1038/s41386-018-0213-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461786PMC
April 2019

[Effects of Serum Sodium Concentrations on Nausea and Vomiting after Moderately Emetogenic Chemotherapy].

Yakugaku Zasshi 2018 ;138(8):1095-1101

Division of Pharmacy, Yamagata University Hospital.

 Chemotherapy-induced nausea and vomiting (CINV) is the most unbearable adverse effect of chemotherapy. The antiemesis guidelines of the National Comprehensive Cancer Network indicate that hyponatremia is a risk factor for CINV, although the relationship between the incidence of CINV and hyponatremia has not been sufficiently studied. This two-center prospective observational study evaluated whether low serum sodium concentrations were a risk factor for CINV. The study included 34 patients who were scheduled to receive first-line carboplatin- or oxaliplatin-based chemotherapy for gynecological or colorectal cancers. Patient diaries were used to record the daily incidences of CINV events during a 5-day period. The patients were divided based on the median serum sodium concentration into a low Na group (<141 mEq/L) and a high Na group (≥141 mEq/L). The incidences of delayed nausea were 27.8% in the high Na group and 62.5% in the low Na group (p=0.042), with complete control rates (no vomiting, rescue medication, or grade 2 nausea) of 77.8% and 43.8%, respectively (p=0.042). The time to complete control failure in each group was analyzed using the Kaplan-Meier method, which revealed a significantly shorter time in the low Na group (p=0.03). Therefore, these results indicate that low serum sodium concentrations may increase the risk of CINV.
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http://dx.doi.org/10.1248/yakushi.18-00009DOI Listing
August 2018

Isolation of an Egg-Adapted Influenza A(H3N2) Virus without Amino Acid Substitutions at the Antigenic Sites of Its Hemagglutinin.

Jpn J Infect Dis 2018 05 27;71(3):234-238. Epub 2018 Apr 27.

Influenza Virus Research Center, National Institute of Infectious Diseases.

Antigenic changes in the hemagglutinin protein of recent A(H3N2) viruses often arise when these viruses adapt to their egg host. By serial egg passages of a cell-propagated virus, we successfully isolated an egg-adapted influenza A(H3N2) virus, A/Saitama/103/2014, without amino acid substitutions at the antigenic sites of its hemagglutinin protein but with multiple substitutions in its neuraminidase protein. Antigenic analysis of this egg-adapted A/Saitama/103/2014 virus indicated that its antigenicity did not differ from that of the World Health Organization prototype cell-propagated vaccine virus: A/Hong Kong/4801/2014. Our results suggest that this strategy may facilitate egg-based vaccine production without antigenic alterations in hemagglutinin by egg adaptation.
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http://dx.doi.org/10.7883/yoken.JJID.2017.551DOI Listing
May 2018

The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis.

Gastrointest Endosc 2018 10 24;88(4):665-673. Epub 2018 Apr 24.

Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK; Division of Population Medicine, Cardiff University School of Medicine, Cardiff, UK.

Background And Aims: Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Almost all patients with FAP will develop duodenal adenomas, and 5% will develop cancer. The incidence of duodenal adenomas in MAP appears to be lower than in FAP, but the limited available data suggest a comparable increase in the relative risk and lifetime risk of duodenal cancer. Current surveillance recommendations, however, are the same for FAP and MAP, using the Spigelman score (incorporating polyp number, size, dysplasia, and histology) for risk stratification and determination of surveillance intervals. Previous studies have demonstrated a benefit of enhanced detection rates of adenomas by use of chromoendoscopy both in sporadic colorectal disease and in groups at high risk of colorectal cancer. We aimed to assess the effect of chromoendoscopy on duodenal adenoma detection, to determine the impact on Spigelman stage and to compare this in individuals with known pathogenic mutations in order to determine the difference in duodenal involvement between MAP and FAP.

Methods: A prospective study examined the impact of chromoendoscopy on the assessment of the duodenum in 51 consecutive patients with MAP and FAP in 2 academic centers in the United Kingdom (University Hospital Llandough, Cardiff, and St Mark's Hospital, London) from 2011 to 2014.

Results: Enhanced adenoma detection of 3 times the number of adenomas after chromoendoscopy was demonstrated in both MAP (P = .013) and FAP (P = .002), but did not affect adenoma size. In both conditions, there was a significant increase in Spigelman stage after chromoendoscopy compared with endoscopy without dye spray. Spigelman scores and overall adenoma detection was significantly lower in MAP compared with FAP.

Conclusions: Chromoendoscopy improved the diagnostic yield of anomas in MAP and FAP 3-fold, and in both MAP and FAP this resulted in a clinically significant upstaging in Spigelman score. Further studies are required to determine the impact of improved adenoma detection on the management and outcome of duodenal polyposis.
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http://dx.doi.org/10.1016/j.gie.2018.04.2347DOI Listing
October 2018

Factors associated with delayed bleeding after resection of large nonpedunculated colorectal polyps.

Endoscopy 2018 08 6;50(8):790-799. Epub 2018 Apr 6.

Wolfson Unit for Endoscopy, St Mark's Hospital and Academic Institute, London, United Kingdom.

Background: Delayed bleeding is the most common significant complication after piecemeal endoscopic mucosal resection (p-EMR) of large nonpedunculated colorectal polyps (NPCPs). Risk factors for delayed bleeding are incompletely defined. We aimed to determine risk factors for delayed bleeding following p-EMR.

Methods: Data were analyzed from a prospective tertiary center audit of patients with NPCPs ≥ 20 mm who underwent p-EMR between 2010 and 2012. Patient, polyp, and procedure-related data were collected. Four post p-EMR defect factors were evaluated for interobserver agreement and included in analysis. Delayed bleeding severity was reported in accordance with guidelines. Predictors of bleeding were identified.

Results: Delayed bleeding requiring hospitalization occurred after 22 of 330 procedures (6.7 %). A total of 11 patients required blood transfusion; of these, 4 underwent urgent colonoscopy, 1 underwent radiological embolization, and 1 required surgery. Interobserver agreement for identification of the four post p-EMR defect factors was moderate (kappa range 0.52 - 0.57). Factors associated with delayed bleeding were visible muscle fibers ( = 0.03) and the presence of a "cherry red spot" ( = 0.05) in the post p-EMR defect. Factors not associated with delayed bleeding were American Association of Anesthesiologists class, aspirin use, polyp size, site, and use of argon plasma coagulation.

Conclusions: Visible muscle fibers and the presence of a "cherry red spot" in the resection defect were associated with delayed bleeding after p-EMR. These findings suggest evaluation and photodocumentation of the post p-EMR defect is important and, when considered alongside other patient and procedural factors, may help to reduce the incidence and severity of delayed bleeding.
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http://dx.doi.org/10.1055/a-0577-3206DOI Listing
August 2018

Aortic stenosis is a risk factor for all-cause mortality in patients on dialysis: a multicenter prospective cohort analysis.

BMC Nephrol 2018 04 3;19(1):80. Epub 2018 Apr 3.

Department of Nephrology, Fujita Health University, Toyoake, Aichi, Japan.

Background: Aortic stenosis (AS) is common in patients on dialysis as well as in the general population. AS leads to difficulty with dialysis therapy because of unstable conditions such as intradialytic hypotension due to low cardiac output. However, the precise morbidity rates and risk factors of AS in patients on dialysis are unknown. Moreover, there are no large-scale observational studies regarding the association between AS in patients on dialysis and mortality. Therefore, we will investigate whether morbidity of AS in patients on dialysis is associated with mortality.

Methods: This is a multicenter prospective cohort analysis in the Tokai region of Japan. The 75 participating centers in this study will enroll approximately 2400 patients during 12 months, with or without AS. We started enrollment in July 2017 and will follow patents until June 2023. Transthoracic echocardiography will be performed to evaluate aortic valve. Parameters used for evaluation of aortic valve are mean pressure gradient between left ventricle and ascending aorta, aortic valve area, and maximum aortic jet velocity. We will diagnose AS using the criteria based on the 2014 American Heart Association/ American College of Cardiology Guideline. We will also perform transthoracic echocardiography at 12, 24, 36, 48, and 60 months. Survival prognosis and CV events will be determined at the end of June 2019, 2020, 2021, 2022, and 2023. Development of AS will be also evaluated as new onset or annual change in AS parameters. We will classify patients based on the presence or absence of AS and the stages of AS and will compare outcomes. Study outcomes will include the following: 1) all-cause mortality rates; 2) incidence of cardiovascular (CV) events; 3) CV-related mortality rates; 4) infection-related mortality rates; 5) new onset or development of AS.

Discussion: We will consider the following hypotheses in this study, among others: The prevalence of AS is higher in dialysis patients; new onset and development of AS are associated with factors that are specific for dialysis, such as hyperphosphatemia, hyperparathyroidism, and medication; and outcomes in AS patients are poorer than in patients without AS at baseline.

Trial Registration: UMIN000026756 , Registered March 29 2017.
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http://dx.doi.org/10.1186/s12882-018-0877-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883521PMC
April 2018
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