Publications by authors named "Takako Nakamura"

45 Publications

[Questionnaire Survey of Pharmacy Students regarding Long-term In-hospital Practical Training: 8 Years of Changes].

Yakugaku Zasshi 2021 ;141(5):731-742

Division of Pharmacy, Chiba University Hospital.

In 2010, the in-hospital practical training period for pharmacy students was extended from 4 to 11 weeks. We have conducted questionnaire surveys of these students every year with the aim of reviewing the quality of training by conduction of surveys and evaluations. However, it was not clear whether reviewing based on the questionnaire results improved student satisfaction with the in-hospital practical training. Therefore, the aim of this study was to verify the validity of reviewing based on the questionnaire results by analyzing the data accumulated during the long-term practical training. A questionnaire survey was conducted of 333 5th-year students upon completion of practical training at Chiba University Hospital from 2010 to 2017. Students self-evaluated their attitude toward practical training on a 6-point scale and their satisfaction level for each component of the practical training on a 5-point scale. The students were also allowed to share their feelings about hospital pharmacy work. Repeated review of the training content can facilitate communication with patients, which was lacking at the beginning of the training period. Improved communication led to higher-quality pharmacy practice and increased student satisfaction. Meanwhile, changes to work procedures may reduce student satisfaction unless the training strategy is reviewed accordingly. Because the work of hospital pharmacists is constantly changing, it is considered that the content of the practical training should be revised accordingly through continuous conduction of surveys and evaluations, thereby enabling optimal practical training.
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http://dx.doi.org/10.1248/yakushi.20-00203DOI Listing
January 2021

[Evaluation of the Usefulness of Postoperative Analgesic Solution Preparation by Pharmacists in the Surgical Department].

Yakugaku Zasshi 2021 ;141(3):403-413

Division of Pharmacy, Chiba University Hospital.

Pharmacists began preparing drug solutions intraoperatively for postoperative analgesia in the Department of Surgery at Chiba University Hospital from May 2014. To verify the usefulness of pharmacists preparing these drug solutions, we conducted a questionnaire survey among 51 anesthesiologists and received 44 responses (recovery rate 86.3%). Burden on the anesthesiologists was significantly reduced both temporally and mentally when the pharmacists prepared the drug solutions compared with when the anesthesiologists did (p<0.01). The anesthesiologists' degree of anxiety about sometimes having to prepare drug solutions alone without any confirmation was also significantly reduced when pharmacists prepared them (p<0.01), which implies the need for a double-check system. In addition, 88.6% of anesthesiologists said that they were reassured with preparations done by the pharmacists under a sterile environment using a clean bench. Overall, 88.6% of anesthesiologists responded that they were satisfied with the preparation of drug solutions by pharmacists. Based on the results of this survey, pharmacists' preparation of drug solutions for postoperative analgesia is considered to be useful in ensuring the quality and safety of medical care because it reduced anesthesiologists' work to prepare the drug solutions, allowing them to concentrate on anesthesia and related work, it established a double-check system between the two staff teams, and it was done under a sterile environment.
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http://dx.doi.org/10.1248/yakushi.20-00128DOI Listing
June 2021

Usability assessment of drug-linking laboratory data listed on prescriptions for outpatients of chiba university hospital.

Sci Rep 2021 01 18;11(1):1715. Epub 2021 Jan 18.

Division of Pharmacy, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku Chiba-shi, Chiba, 260-8677, Japan.

To evaluate the impact of pharmacotherapy on efficacy and safety by providing laboratory data information linked to medicines on outpatient prescriptions from the hospital to the community pharmacy. Beginning on October 28, 2014, standardized laboratory data and drug-linking laboratory data were included with outpatient prescriptions at our hospital. We have created a database of drug-linking laboratory data for all drugs that can be prescribed in Japan. We counted the number of prescription inquiries related to laboratory data from community pharmacies, including those leading to prescription changes. Before laboratory data were listed on outpatient prescriptions, 4 prescription inquiries from community pharmacies per year were related to laboratory data. After our hospital started to list laboratory data, this number rose to 643, 576, 563, and 847 in the first, second, third, and fourth year (P < .05). Of these, 132, 143, 152, and 224 inquiries resulted in prescription changes. Listing laboratory data on outpatient prescriptions avoided 153 contraindications and 84 exacerbations of adverse drug reactions in four years by a prescription inquiry that had never been done before. The efficacy and safety of pharmacotherapy can be improved by listing relevant laboratory data on outpatient prescriptions.
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http://dx.doi.org/10.1038/s41598-021-81344-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814059PMC
January 2021

Analysis of patients' request to switch from a generic drug to the original drug in external prescriptions.

J Pharm Health Care Sci 2020 Dec 4;6(1):27. Epub 2020 Dec 4.

Division of Pharmacy, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan.

Background: Generic drugs are heavily promoted in Japan. The aim of this retrospective single-center study was to clarify whether the frequency and reason that patients request a switch from a generic drug to the original drug differ according to therapeutic category and dosage form.

Methods: This study was performed at Chiba University Hospital. Prescription inquiries about 121 generic drugs from community pharmacies over a 3-year period (from July 2014 to June 2017) were analyzed.

Results: Approximately 30% of the requests were related to the efficacy, safety, and comfort of the generic drug. The most cited motive was "patient's desire with no reason given" at 44.5%. According to multiple logistic regression analysis, therapeutic categories and dosage forms were associated with the requests. The median request frequency differed according to therapeutic category and dosage form. The frequency was highest for "agents affecting the central nervous system" and "tablets and capsules", respectively. Among the therapeutic categories, "agents affecting the central nervous system" had the highest median number of requests related to "decreased effectiveness"; "cardiovascular agents" had the highest median number of requests related to "physician's instruction"; and "agents for the epidermis" had the highest median number of requests related to "uncomfortable to use". Among dosage forms, the odds ratio for patients' original drug request for "liniment and patch" was about 1.5 times that for "tablets and capsules". "Liniment and patch" had the highest median frequency of requests related to "decreased effectiveness", "uncomfortable to use", and "patient's desire with no reason given".

Conclusions: The request frequency and reason differed according to therapeutic category and dosage form. Pharmacists should advise each patient properly about the choice and switching of drug brands, taking into account the therapeutic category and dosage form, especially liniments and patches.
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http://dx.doi.org/10.1186/s40780-020-00180-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716439PMC
December 2020

Neoantigen prediction in human breast cancer using RNA sequencing data.

Cancer Sci 2021 Jan 29;112(1):465-475. Epub 2020 Nov 29.

Department of Breast and Endocrine Surgery, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

Neoantigens have attracted attention as biomarkers or therapeutic targets. However, accurate prediction of neoantigens is still challenging, especially in terms of its accuracy and cost. Variant detection using RNA sequencing (RNA-seq) data has been reported to be a low-accuracy but cost-effective tool, but the feasibility of RNA-seq data for neoantigen prediction has not been fully examined. In the present study, we used whole-exome sequencing (WES) and RNA-seq data of tumor and matched normal samples from six breast cancer patients to evaluate the utility of RNA-seq data instead of WES data in variant calling to detect neoantigen candidates. Somatic variants were called in three protocols using: (i) tumor and normal WES data (DNA method, Dm); (ii) tumor and normal RNA-seq data (RNA method, Rm); and (iii) combination of tumor RNA-seq and normal WES data (Combination method, Cm). We found that the Rm had both high false-positive and high false-negative rates because this method depended greatly on the expression status of normal transcripts. When we compared the results of Dm with those of Cm, only 14% of the neoantigen candidates detected in Dm were identified in Cm, but the majority of the missed candidates lacked coverage or variant allele reads in the tumor RNA. In contrast, about 70% of the neoepitope candidates with higher expression and rich mutant transcripts could be detected in Cm. Our results showed that Cm could be an efficient and a cost-effective approach to predict highly expressed neoantigens in tumor samples.
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http://dx.doi.org/10.1111/cas.14720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780012PMC
January 2021

Chemical and molecular bases of dome formation in human colorectal cancer cells mediated by sulphur compounds from Cucumis melo var. conomon.

FEBS Open Bio 2020 12 6;10(12):2640-2655. Epub 2020 Nov 6.

Laboratory of Plant Life Science and Technology, United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan.

Colorectal cancer was the third most commonly diagnosed malignant tumor and the fourth leading cause of cancer deaths worldwide in 2012. A human colorectal cancer cell line, RCM-1, was established from a colon cancer tissue diagnosed as a well-differentiated rectum adenocarcinoma. RCM-1 cells spontaneously form 'domes' (formerly designated 'ducts') resembling villiform structures. Two sulphur-containing compounds from Cucumis melo var. conomon (Katsura-uri, or Japanese pickling melon), referred to as 3-methylthiopropionic acid ethyl ester (MTPE) and methylthioacetic acid ethyl ester (MTAE), can induce the differentiation of the unorganized cell mass of an RCM-1 human colorectal cancer cell culture into a dome. However, the underlying molecular mechanisms of such dome formation have not been previously reported. Here, we performed a structure-activity relationship analysis, which indicated that methylthioacetic acid (MTA) was the lowest molecular weight compound with the most potent dome-inducing activity among 37 MTPE and MTAE analogues, and the methylthio group was essential for this activity. According to our microarray analysis, MTA resulted in down-regulation of 537 genes and up-regulation of 117 genes. Furthermore, MTA caused down-regulation of many genes involved in cell-cycle control, with the cyclin E2 (CCNE2) and cell division cycle 25A (CDC25A) genes being the most significantly reduced. Pharmacological analysis showed that the administration of two cell-cycle inhibitors for inactivating CDC25A phosphatase (NSC95397) and the cyclin E2/cyclin-dependent kinase 2 complex (purvalanol A) increased the dome number independently of MTA. Altogether, our results indicate that MTA is the minimum unit required to induce dome formation, with the down-regulation of CDC25A and possibly CCNE2 being important steps in this process.
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http://dx.doi.org/10.1002/2211-5463.13001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714076PMC
December 2020

Investigation on the Epoxidation of Piperitenone, and Structure-activity Relationships of Piperitenone Oxide for Differentiation-inducing Activity.

J Oleo Sci 2020 Aug 9;69(8):951-958. Epub 2020 Jul 9.

Department of Applied Biological Science, Tokyo University of Science.

Piperitenone oxide, a major chemical constituent of the essential oil of spearmint, Mentha spicata, induces differentiation in human colon cancer RCM-1 cells. In this study, piperitenone oxide and trans-piperitenone dioxide were prepared as racemic forms by epoxidation of piperitenone. The relative configuration between two epoxides in piperitenone dioxide was determined to be trans by H NMR analysis and nuclear Overhauser effect spectroscopy (NOESY) in conjunction with density functional theory (DFT) calculations. Optical resolution of (±)-piperitenone oxide by high-performance liquid chromatography (HPLC) using a chiral stationary phase (CSP) afforded both enantiomers with over 98% enantiomeric excess (ee). Evaluation of the differentiation-inducing activity of the synthetic compounds revealed that the epoxide at C-1 and C-6 in piperitenone oxide is important for the activity, and (+)-piperitenone oxide has stronger activity than (-)-piperitenone oxide. The results obtained in this study provide new information on the application of piperitenone oxide and spearmint for differentiation-inducing therapy. Furthermore, natural piperitenone oxide was isolated from M. spicata. The enantiomeric excess of the isolated natural piperitenone oxide was 66% ee. Epoxidation of piperitenone with hydrogen peroxide proceeded in a phosphate buffer under weak basic conditions to give (±)-piperitenone oxide. These results suggest that the nonenzymatic epoxidation of piperitenone, which causes a decrease in the enantiomeric excess of natural piperitenone oxide, is accompanied by an enzymatic epoxidation in the biosynthesis of piperitenone oxide.
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http://dx.doi.org/10.5650/jos.ess19278DOI Listing
August 2020

Contribution of Katsura-uri (Japan's Heirloom Pickling Melon, Cucumis melo var. conomon) at the Completely Ripe Stage to Diabetes Control.

J Nutr Sci Vitaminol (Tokyo) 2020 ;66(3):261-269

Graduate School of Life and Environmental Sciences, Kyoto Prefectural University.

The fruit of Katsura-uri (Japan's heirloom pickling melon, Cucumis melo var. conomon) possesses a fruity aroma and moderate sweetness. The fruit juice has potential to minimize human postprandial blood glucose levels. This study provides information regarding the health benefits of Katsura-uri and its utility in treating diabetes. The study methodology involved measuring the color and firmness of Katsura-uri fruit at five ripening stages, and quantitation of the aroma substances, proximate composition, and sugars. Significant changes were detected in the color, firmness, and level of aroma substances with ripening of Katsura-uri fruit, albeit with no major changes in proximate composition, with the exception of dietary fiber, and sugars. To determine the effects of Katsura-uri juice, the blood glucose levels of ten diabetic volunteers aged 46-75 y were monitored after its consumption, and compared with after consumption of muskmelon juice equivalent to the total weight of Katsura-uri juice. The blood glucose area under the curve level was significantly lower after consumption of Katsura-uri juice (16±5 h • mg/dL) than after consumption of muskmelon juice (55±17 h • mg/dL; p<0.05). The level of the glucose spike was also significantly lower after consumption of Katsura-uri juice (22±5 mg/dL) than after consumption of muskmelon juice (64±6 mg/dL; p<0.05). The completely ripe Katsura-uri fruit provides the best results for diabetic subjects, which is the first case of fruits sweetened with the addition of zero-calorie sweeteners.
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http://dx.doi.org/10.3177/jnsv.66.261DOI Listing
April 2021

Expression profiles of four / homologous genes encoding bHLH transcription factors in .

J Pestic Sci 2020 May;45(2):95-104

The United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima, Japan.

bHLH-type transcription factors-BRASSINOSTEROID INSENSITIVE 1-EMS-SUPPRESSOR 1 (BES1) and BRASSINAZOLE RESISTANT 1 (BZR1)-play key roles in brassinosteroid (BR) signaling. By contrast, the functions of the other four BES1/BZR1 homologs (BEH1-4) remain unknown. Here, we describe the detailed expression profiles of the / family genes. Their expressions were distinct regarding growth-stage dependence and organ specificity but exhibited some overlaps as well. Furthermore, their mRNA levels mostly remained unchanged responding to seven non-BR phytohormones. However, and were downregulated by brassinolide, suggesting a close association with the BR function. Additionally, was ubiquitously expressed throughout the life of the plant but displayed some expression preference. For instance, expression was limited to guard cells and the adjacent pavement cells in the leaf epidermis and was induced during growth progression in very young seedlings, suggesting that is specifically regulated in certain contexts, although it is almost constitutively controlled.
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http://dx.doi.org/10.1584/jpestics.D20-001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251199PMC
May 2020

High-Yield Production of the Major Birch Pollen Allergen Bet v 1 With Allergen Immunogenicity in .

Front Plant Sci 2020 2;11:344. Epub 2020 Apr 2.

Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.

Type I allergy is an immunological disorder triggered by allergens and causes significant health problems. The major allergen of birch pollen is Bet v 1, which belongs to the pathogen-related protein 10 (PR-10) family. Here, we established a rapid and robust method for the production of Bet v 1 in leaves, with binding activity to allergic patients' IgE. The Bet v 1 allergen was expressed in using a strong agroinfiltration-based transient protein expression system, which consists of a deconstructed geminiviral vector system with a double terminator. Five days post-infiltration, the allergen concentration in leaves was 1.2 mg/g of fresh mass, being this the maximum yield of Bet v 1 in plants reported up to now. A part of plant-derived Bet v 1 was glycosylated. Bet v 1 purified from or was used to carry out enzyme-linked immunoassays; both recombinant allergens were found to have comparable binding properties to the IgE of allergic patients. These results suggest that our plant expression system allows rapid and robust production of the allergen, which keeps the immunogenicity.
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http://dx.doi.org/10.3389/fpls.2020.00344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142267PMC
April 2020

Association of marked prolongation of prothrombin time-international normalized ratio with warfarin and endoscopic nasobiliary drainage for biliary fistula after left hemihepatectomy.

J Clin Pharm Ther 2020 Aug 24;45(4):815-818. Epub 2020 Mar 24.

Division of Pharmacy, Chiba University Hospital, Chiba-shi, Japan.

What Is Known And Objective: Vitamin K deficiency is known to cause impaired coagulation. We report a case of marked prolongation of the prothrombin time-international normalized ratio (PT-INR) associated with warfarin and vitamin K deficiency caused by endoscopic nasobiliary drainage (ENBD).

Case Presentation: Oral administration of warfarin was initiated in a 67-year-old man after left hemihepatectomy. He developed a biliary fistula after surgery that was treated by ENBD, which resulted in significant prolongation of the PT-INR.

What Is New And Conclusion: The effect of warfarin was enhanced in this patient due to reduced absorption of vitamin K as a result of external biliary drainage.
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http://dx.doi.org/10.1111/jcpt.13137DOI Listing
August 2020

Combined Treatment with Hydrophilic and Lipophilic Statins Improves Neurological Outcomes Following Experimental Cardiac Arrest in Mice.

Neurocrit Care 2020 08;33(1):64-72

Department of Anesthesiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan.

Background: Global ischemia due to cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) causes significant neuronal damage in vulnerable areas in the brain. Currently, a majority of patients eventually die after successful CPR due to neurological injury. Statins have pleiotropic effects including anti-inflammatory and/or antioxidant responses. These pleiotropic effects can have a beneficial role in the post-CPR phase. We tested whether two different types of statins, hydrophilic pravastatin and lipophilic simvastatin, attenuated neurological injury following CA/CPR. The efficacy of pravastatin and simvastatin combination treatment was also assessed.

Methods: Isoflurane-anesthetized adult male wild-type C57Bl/6 mice subjected to 8-min CA/CPR were randomized into four groups: control, 2 mg/kg pravastatin, 20 mg/kg simvastatin, or a combination of 3 mg/kg pravastatin and 10 mg/kg simvastatin. Neurobehavioral assessment and histological analyses were performed to assess overall general health condition and neuronal injury, respectively.

Results: Combination treatment with pravastatin and simvastatin significantly reduced neuronal injury in the striatum and hippocampus, reduced cerebral edema, and improved general health at 4 days after CA/CPR. Combination statin treatment upregulated endothelial nitric oxide synthase mRNA in the brain. Pravastatin alone, but not simvastatin alone, improved general health after CA/CPR. Pravastatin was less potent than simvastatin at reducing neuronal injury in the brain.

Conclusion: Combination treatment with two different types of statins at the correct dose may be a promising approach to neuroprotection following CA/CPR.
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http://dx.doi.org/10.1007/s12028-019-00862-wDOI Listing
August 2020

Multidrug use positively correlates with high-risk prescriptions in the Japanese elderly: a longitudinal study.

J Pharm Health Care Sci 2019 2;5:20. Epub 2019 Sep 2.

1Pharmacy of Chiba University Hospital, Chiba, Japan.

Background: There is a lack of evidence that multidrug use triggers adverse events. Therefore, the main purpose of this study was to clarify the relationship between the total number of drugs and number of high-risk prescriptions administered to Japanese elderly patients.

Methods: Using hospital electronic medical records (EMR), we evaluated the prescriptions of outpatients aged 65 years or older. We defined prescriptions of potentially inappropriate medications (PIMs) and overlapping prescription of drugs with the same mechanism of action (DSAs) as high-risk prescriptions. We analyzed the relationship among total number of drugs and high-risk prescriptions. In addition, we performed a secondary research to determine whether the hospitalization rate and concomitant medication contents differ depending on the high-risk prescriptions.

Results: Data for 13,630 outpatients were analyzed. A significant positive correlation between the numbers of total drugs and PIMs was found. The prescription frequency of individual PIMs rose as the total number of prescription drugs increased. The odds ratio (OR) of overlapping DSAs was significantly higher in patients using 5 or more drugs. In addition, there were significantly more prescriptions of laxatives among patients with overlapping prescriptions of anticholinergic drugs. The use of almost all PIMs was not an independent risk factor for hospitalization; instead, the number of PIMs was an independent risk factor for hospitalization [OR 1.18 (95% CI, 1.12-1.26)].

Conclusions: The number of PIMs and overlapping DSAs were high in patients receiving multidrug treatment. To avoid adverse events and hospitalization, it might be useful to review prescriptions and consider the number of PIMs and overlapping DSAs.
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http://dx.doi.org/10.1186/s40780-019-0150-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717964PMC
September 2019

Lymphangiography and Post-lymphangiographic Multidetector CT for Preclinical Lymphatic Interventions in a Rabbit Model.

Cardiovasc Intervent Radiol 2019 Mar 20;42(3):448-454. Epub 2018 Nov 20.

Department of Radiology, Tokai University Hachioji Hospital, Tokai University School of Medicine, 1838 Ishikawa-machi, Hachioji, Tokyo, 192-0032, Japan.

Purpose: To describe the feasibility of lymphangiography and the visibility of the lymphatic system using post-lymphangiographic multidetector CT (MDCT) for preclinical lymphatic interventions in a rabbit model.

Materials And Methods: Lymphangiography via the popliteal lymph node or vessel after surgical exposure was performed, using six healthy female Japanese White rabbits. Lipiodol was manually injected for lymphangiography. Post-lymphangiographic MDCT examinations were performed in all rabbits. The dataset images were subjected to image processing analysis utilizing the three-dimensional maximum intensity projection technique. Three reviewers evaluated the degree of depiction of the lymphatic system using a four-point visual score (1, poor; 2, fair; 3, good; 4, excellent). The distance between the body surface and cisterna chyli was measured on post-lymphangiographic MDCT axial image.

Results: Lymphangiography was successfully performed in all rabbits. The popliteal lymph node was detectable in 90%. The visualization of lymphatic system via the popliteal node was achieved in 89%. Mean visual scores of > 3.0 were realized by the right femoral lymphatic vessel, left femoral lymphatic vessel, left iliac lymphatic vessel, left lumbar lymphatic trunks and cisterna chyli, whereas mean visual scores of < 3.0 were yielded by the right iliac lymphatic vessel, right lumbar lymphatic trunks and thoracic duct. The distance between the body surface and cisterna chyli on post-lymphangiographic MDCT axial images was 4.33 ± 0.14 cm.

Conclusion: Lymphangiography is feasible, and the visibility of the lymphatic system on post-lymphangiographic MDCT in a rabbit model provides enough information for interventional radiologists to perform preclinical lymphatic interventions.
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http://dx.doi.org/10.1007/s00270-018-2123-9DOI Listing
March 2019

DNA Methylation of Proximal PLAT Promoter in Chronic Rhinosinusitis With Nasal Polyps.

Am J Rhinol Allergy 2018 Sep 2;32(5):374-379. Epub 2018 Jul 2.

2 Division of Otorhinolaryngology and Head and Neck Surgery, Department of Sensory and Locomotor Medicine, Faculty of Medical Science, University of Fukui, Fukui, Japan.

Background Nasal polyps (NP) are characterized by pseudocysts derived from stromal tissue edema and cause persistent infections in patients with chronic rhinosinusitis (CRS). A low level of tissue-type plasminogen activator (gene name PLAT) is considered a cause of stromal tissue edema because of insufficient plasmin activation in NP; however, the mechanism regulating PLAT gene expression levels is still unclear. The epigenetic mechanism regulating the PLAT gene expression has been studied in other tissues. Objective We aimed to investigate the methylation levels in the proximal PLAT promoter and their effects on gene expression in NP tissue. Methods We investigated the methylation levels at 3 CpG sites in the proximal PLAT promoter regions (-618, -121, and -105 with respect to the transcription initiation site) by bisulfite pyrosequencing and their effects on the gene expression by quantitative real-time polymerase chain reaction (qPCR) in 20 paired samples of NP and inferior turbinate tissue (IT) from patients with CRS. Results The DNA methylation levels at all CpG sites were higher ( P < .01), and the PLAT expression was lower ( P < .001) in NP compared with IT. The methylation changes at the -618 site showed a negative correlation with the gene expression changes between NP and IT ( r = -.65, P < .01). Conclusions Hypermethylation of PLAT promoter may downregulate the gene expression in NP, leading to excessive fibrin deposition by aberrant coagulation cascade. DNA methylation of proximal PLAT promoter may contribute to NP growth and have a potential as a new therapeutic target.
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http://dx.doi.org/10.1177/1945892418782236DOI Listing
September 2018

Glibenclamide and Therapeutic Hypothermia Have Comparable Effect on Attenuating Global Cerebral Edema Following Experimental Cardiac Arrest.

Neurocrit Care 2018 08;29(1):119-127

Department of Anesthesiology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan.

Background: Cerebral edema is one of the major causes of mortality following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). A subunit of the sulfonylurea receptor 1-transient receptor potential M4 (Sur1-TRPM4) channel has been implicated in the pathogenesis of ischemia-evoked cerebral edema. In this study, we examined whether glibenclamide (GBC), a Sur1-TRPM4 channel inhibitor, attenuates cerebral edema following CA/CPR and further examined the efficacy of GBC combined with therapeutic hypothermia.

Methods: Isoflurane-anesthetized adult male wild-type C57Bl/6 mice subjected to 7-min CA/CPR were randomized into five groups: sham operation, control with normothermia, GBC with normothermia, control with hypothermia, and GBC with hypothermia. The primary outcome was to evaluate regional brain water content; the secondary outcome was to measure blood glucose level, Sur1-TRPM4 expression, and pro-inflammatory factor expression.

Results: Compared with normothermia, GBC treatment or hypothermia significantly attenuated brain water content in mice subjected to CA/CPR. GBC combined with hypothermia had no additional effects on attenuating cerebral edema. Pro-inflammatory factor messenger RNA expression (TNF-α and IL-6), NFκβ activation, and SUR1-TRPM4 levels were upregulated after CA/CPR. Compared with normothermia, hypothermia, but not GBC, partly suppressed these factors' expression.

Conclusions: GBC attenuated cerebral edema following CA/CPR by blocking Sur1-TRPM4 channels upregulated by CA insult. The effect of GBC was comparable with that of therapeutic hypothermia alone. These results suggest that GBC is an alternative approach for treating CA-evoked cerebral edema.
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http://dx.doi.org/10.1007/s12028-017-0479-3DOI Listing
August 2018

4-Methylthio-3-butenyl isothiocyanate (raphasatin) exerts chemopreventive effects against esophageal carcinogenesis in rats.

J Toxicol Pathol 2016 Oct 4;29(4):237-246. Epub 2016 Jul 4.

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.

To examine the effects of 4-methylthio-3-butenyl isothiocyanate on esophageal carcinogenesis, male 6-week-old F344 rats were subcutaneously injected with 0.5 mg/kg body weight -nitrosomethylbenzylamine three times per week for 5 weeks and fed a diet supplemented with 80 ppm 4-methylthio-3-butenyl isothiocyanate, equivalent to 6.05 mg/kg body weight/day for the initiation stage, 4.03 mg/kg body weight/day for the promotion stage, or 4.79 mg/kg body weight/day for all stages. Although the incidence of lesions was not affected by 4-methylthio-3-butenyl isothiocyanate treatment, the multiplicity of squamous cell papilloma in the esophagus was significantly decreased in rats in the 4-methylthio-3-butenyl isothiocyanate initiation stage group (1.13 ± 0.74), 4-methylthio-3-butenyl isothiocyanate promotion stage group (1.47 ± 0.99), and 4-methylthio-3-butenyl isothiocyanate all stage group (1.47 ± 1.13) as compared with rats treated with -nitrosomethylbenzylamine alone (3.00 ± 1.46). Immunohistochemical analysis revealed that 4-methylthio-3-butenyl isothiocyanate induced apoptosis, suppressed cell proliferation, and increased p21 expression when administered in the promotion phase. These modifying effects were not observed in the rats treated with 4-methylthio-3-butenyl isothiocyanate alone. Our results indicated that 4-methylthio-3-butenyl isothiocyanate may exert chemopreventive effects against -nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats.
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http://dx.doi.org/10.1293/tox.2016-0037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097966PMC
October 2016

Toxic effects of 4-methylthio-3-butenyl isothiocyanate (Raphasatin) in the rat urinary bladder without genotoxicity.

J Appl Toxicol 2017 04 15;37(4):485-494. Epub 2016 Sep 15.

Division of Pathology, National Institute of Health Sciences, Tokyo, 158-8501, Japan.

We recently reported that 4-methylthio-3-butenyl isothiocyanate (MTBITC) exerts chemopreventive effects on the rat esophageal carcinogenesis model at a low dose of 80 ppm in a diet. In contrast, some isothiocyanates (ITCs) have been reported to cause toxic effects, promotion activity, and/or carcinogenic potential in the urinary bladder of rats. In the present study, we investigated whether MTBITC had toxic effects in the urinary bladder similar to other ITCs, such as phenethyl ITC (PEITC). First, to examine the early toxicity of MTBITC, rats were fed a diet supplemented with 100, 300 or 1000 ppm MTBITC for 14 days. Treatment with 1000 ppm MTBITC caused increased organ weights and histopathological changes in the urinary bladder, producing lesions similar to those of 1000 ppm PEITC. In contrast, rats treated with 100 or 300 ppm MTBITC showed no signs of toxicity. Additionally, we performed in vivo genotoxicity studies to clarify whether MTBITC may exhibit a carcinogenic potential through a genotoxic mechanism in rats. Rats were treated with MTBITC for 3 days at doses of 10, 30 or 90 mg kg body weight by gavage, and comet assays in the urinary bladder and micronucleus assays in the bone marrow were performed. No genotoxic changes were observed after treatment with MTBITC at all doses. Overall, these results suggested that the effects of MTBITC in the rat urinary bladder are less than those of PEITC, but that MTBITC could have toxic effects through a nongenotoxic mechanism in the urinary bladder of rats at high doses. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/jat.3384DOI Listing
April 2017

Detection of a novel X-chromosomal short tandem repeat marker in Xq28 in four ethnic groups.

Leg Med (Tokyo) 2016 Mar 27;19:43-6. Epub 2016 Jan 27.

Department of Legal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.

DNA testing of X-chromosomal short tandem repeat (X-STR) polymorphisms has been the focus of attention in several studies, mainly due to its applicability in the investigation of complex kinship cases. Studies of X-STR in analyses of DNA sequences, population studies and DNA testing applications have been reported. We performed detection and population genetic study of a novel tetranucleotide X-STR locus in the present study. We identified a unique X-STR locus consisting of two tetranucleotides in Xq28. Although the STR is a simple tetranucleotide, its polymorphism was comparatively high [polymorphism information content (PIC)=0.7140] in Japanese subjects. In addition, the STR varied in structure among ethnic groups. We conclude that this locus will be useful for forensic DNA testing and anthropological studies.
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http://dx.doi.org/10.1016/j.legalmed.2016.01.010DOI Listing
March 2016

The significant effect of heterojunction quality on photoelectrochemical water splitting in bilayer photoelectrodes: Rb(x)WO3 thin films on RbLaNb2O7 layers.

Phys Chem Chem Phys 2014 Dec;16(48):26901-8

Advanced Manufacturing Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan.

We have prepared nearly perfect hexagonal m-plane-oriented RbxWO3 films on (010)-oriented RbLaNb2O7 layers. The prepared bilayer films showed Rb diffusion from the RbLaNb2O7 seed layers, and we obtained uniaxially oriented RbxWO3/Rb1-yLaNb2O7 photoanodes. The RbxWO3/Rb1-yLaNb2O7 bilayer photoanodes exhibited enhanced photoelectrochemical water splitting compared with the RbxWO3 and RbLaNb2O7 monolayer photoanodes. Furthermore, we clearly demonstrated that the high crystal quality of the heterojunction significantly enhanced water splitting. The photocurrent density of the nearly perfectly oriented RbxWO3/Rb1-yLaNb2O7 photoanode that we prepared was 9.4-fold that of an unoriented bilayer photoanode. This increase was attributed to the inhibition of photo-excited charge recombination and stimulated electron transfer derived from low grain-boundary resistance.
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http://dx.doi.org/10.1039/c4cp03917cDOI Listing
December 2014

Characterisation of cytoplasmic DNA complementary to non-retroviral RNA viruses in human cells.

Sci Rep 2014 May 30;4:5074. Epub 2014 May 30.

Department of Virology and Preventive Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, JAPAN.

The synthesis and subsequent genomic integration of DNA that is complementary to the genomes of non-retroviral RNA viruses are rarely observed. However, upon infection of various human cell lines and primary fibroblasts with the vesicular stomatitis virus (VSV), we detected DNA complementary to the VSV RNA. The VSV DNA was detected in the cytoplasm as single-stranded DNA fully complementary to the viral mRNA from the poly(A) region to the 7-methyl guanosine cap. The formation of this DNA was cell-dependent. Experimentally, we found that the transduction of cells that do not produce VSV DNA with the long interspersed nuclear element 1 and their infection with VSV could lead to the formation of VSV DNA. Viral DNA complementary to other RNA viruses was also detected in the respective infected human cells. Thus, the genetic information of the non-retroviral RNA virus genome can flow into the DNA of mammalian cells expressing LINE-1-like elements.
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http://dx.doi.org/10.1038/srep05074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038843PMC
May 2014

Concurrent urothelial carcinoma in the renal pelvis of an allograft kidney and native recipient bladder: evidence of donor origin.

Jpn J Clin Oncol 2014 Apr 3;44(4):366-9. Epub 2014 Mar 3.

*Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-8575, Japan.

A 44-year-old woman was admitted to the hospital for asymptomatic gross hematuria. At the age of 28, she underwent transplantation of a kidney from her father for end-stage renal disease secondary to rapidly progressive glomerulonephritis. She resumed peritoneal dialysis when the allograft kidney stopped functioning at the age of 42. Dialysis was continued for the next 2 years, when the hematuria occurred and she was readmitted. Radiologic evaluation and transurethral resection of the bladder tumor revealed a tumor of the renal pelvis of the allograft kidney (cT3N0M0) and multiple bladder tumors (cT1N0M0). Total cystectomy and allograft nephroureterectomy were performed. Histopathological examinations revealed high grade urothelial carcinoma in the renal pelvis of the allograft kidney (pT3) and native bladder (pT1). Fluorescence in situ hybridization of both specimens demonstrated that the renal pelvic tumors and bladder cancer possessed XY karyotypes. These results indicated that the urothelial carcinoma developed de novo in the renal pelvis of the allograft kidney and was implanted into the recipient's native bladder.
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http://dx.doi.org/10.1093/jjco/hyu015DOI Listing
April 2014

Photochemical modification of diamond powders with elemental sulfur and their surface-attachment behavior on gold surfaces.

Phys Chem Chem Phys 2009 Jan;11(4):730-4

National Institute of Advanced Industrial Science and Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8565, Japan.

A useful method of modifying the surface of diamond powder with sulfur-containing functionalities was developed by the photolysis of elemental sulfur. The introduction of sulfur-containing functional groups on the diamond surfaces was confirmed by X-ray photoelectron spectroscopy (XPS), diffuse reflectance Fourier transform infrared spectroscopy (DRIFT) and mass spectroscopy analyses. The sulfur-modified diamond powder attached to gold surfaces through sulfur-containing linkages. In brief, the exposure of the modified diamond powder to a gold colloid resulted in gold nanoparticles being attached to the diamond powder. The treatment of the modified diamond powder with thin gold film on a Si substrate resulted in the alignment of surface-attached diamond powder through sulfur linkages formed by self-assembly.
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http://dx.doi.org/10.1039/b814406kDOI Listing
January 2009

The preparation of Ag nanoparticle-modified single-walled carbon nanotubes and their antibacterial activity.

Biocontrol Sci 2009 Sep;14(3):133-8

Department of Chemistry, Tokyo Gakugei University, 4-1-1, Nukuikita-machi, Koganei, Tokyo 184-8501, Japan.

The sidewall modified single-walled carbon nanotubes (SWNTs) with amino-containing substituents were prepared using the radicals generated by the photolysis of acetonitrile. A subsequent treatment of modified SWNTs with the Ag colloid gave an attachment of Ag nanoparticles on the surface of SWNTs through the functionalized linkages. The Ag nanoparticle-modified SWNTs evaluated by antibacterial tests showed strong activities against Escherichia coli and Staphylococcus aureus. However, the use of Ag nanoparticle-modified SWNTs on simulated body fluid exhibited weaker antibacterial activity.
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http://dx.doi.org/10.4265/bio.14.133DOI Listing
September 2009

[Combined intrathecal morphine and bupivacaine for elective post-caesarean pain].

Masui 2009 Apr;58(4):416-21

Department of Anesthesia, Tokyo Metropolitan Toshima Hospital, Tokyo 173-0015.

Background: Intrathecal morphine is widely used for analgesia following cesarean section in Europe and North America. In Japan analgesic method of intrathecal morphine was admitted to the insurance adjustment and it is necessary to study optimal dose of the morphine.

Methods: We examined 72 parturients undergoing elective cesarean section under spinal anesthesia. Patients were randomly assigned to receive, in a double-blind fashion, either morphine 0.05 mg, morphine 0.1 mg, morphine 0.2 mg, or saline in 0.1 ml (control group) mixed with the bupivacaine for cesarean section. A patient-controlled analgesia (PCA) device for intravenous morphine provided free access to additional analgesics for 24 hr.

Results: Total amount of morphine during postoperative first 24 hrs using PCA was significantly higher in the control group than in 0.1 and 0.2 mg groups. There were no significant differences between the control group and the morphine groups with respect to nausea. The incidence of pruritus was significantly higher in 0.1 and 0.2 mg groups than in the control group. In one patient in 0.2 mg group, oxygen saturation decreased below 95% postoperatively, but it was improved by oxygen inhalation.

Conclusions: It is concluded that intrathecal morphine 0.1 mg gives effective analgesia with minimum side effects after cesarean section for the Japanese patients.
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April 2009

Metabolic interaction between ethanol, high-dose alprazolam and its two main metabolites using human liver microsomes in vitro.

J Forensic Leg Med 2007 Aug 26;14(6):348-51. Epub 2007 Mar 26.

Department of Legal Medicine, Institute of Community Medicine, University of Tsukuba, Ibaraki-ken, Japan.

Alprazolam is widely used as a short-acting antidepressant and anxiolytic agent and its effect appears at very low doses while ethanol is used as a social drug worldwide. Sometimes, toxic interactions occur following combined administration of these two drugs. In this study we have investigated the interaction between ethanol and high-dose alprazolam using human liver microsomes in vitro. The interaction effects between ethanol and alprazolam were examined by a mixed-function oxidation reaction using a human liver microsomal preparation. Alprazolam and its two main metabolites (alpha-hydroxyalprazolam: alpha-OH alprazolam, 4-hydroxyalprazolam: 4-OH alprazolam) were measured by HPLC/UV. The production of 4-OH alprazolam, one main metabolite of alprazolam, was weakly inhibited by higher dose of ethanol, but not alpha-OH alprazolam. These results using a human liver microsomal preparation show that the production of 4-OH alprazolam is weakly inhibited by ethanol but not alpha-OH alprazolam. Toxic levels may be reached by simultaneous administration of ethanol and high-dose alprazolam.
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http://dx.doi.org/10.1016/j.jflm.2006.11.004DOI Listing
August 2007

Simple and simultaneous determination for 12 phenothiazines in human serum by reversed-phase high-performance liquid chromatography.

J Chromatogr B Analyt Technol Biomed Life Sci 2007 Jul 13;854(1-2):116-20. Epub 2007 Apr 13.

Department of Legal Medicine, Institute of Community Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki-ken 305-8575, Japan.

A high-performance liquid chromatographic method has been developed for the simultaneous analysis of the 12 phenothiazines (chlorpromazine, fluphenazine, levomepromazine, perazine, perphenazine, prochlorperazine, profenamine, promethazine, propericiazine, thioproperazine, thioridazine and trifluoperazine) in human serum using HPLC/UV. The separation was achieved using a C(18) reversed-phase column (250 mm x 4.6 mm I.D., particle size 5 microm, Inersil ODS-SP). The mobile phase, consisting of acetonitrile-methanol-30 mM NaH(2)PO(4) (pH 5.6) (300:200:500, v/v/v), was delivered at a flow rate of 0.9 mL/min and UV detection was carried out at 250 nm. The recoveries of the 12 phenothiazines spiked into serum samples were 87.6-99.8%. Regression equations for the 12 phenothiazines showed excellent linearity, with detection limits of 3.2-5.5 ng/mL for serum. The inter-day and intra-day coefficients of variation for serum samples were commonly below 8.8%. The selectivity, accuracy and precision of this method are satisfactory for clinical and forensic purposes. This sensitive and selective method offers the opportunity for simultaneous screening and quantification of almost all phenothiazines available in Japan for the purposes of clinical and forensic applications.
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http://dx.doi.org/10.1016/j.jchromb.2007.04.004DOI Listing
July 2007

Geometric properties of covalently bonded DNA on single-crystalline diamond.

J Am Chem Soc 2006 Mar;128(12):3884-5

Diamond Research Center, AIST, Central 2, 1-1-1, Umezono, Tsukuba, Ibaraki 305-8568, Japan.

Diamond is a promising candidate for bioapplications. Properties of hybridized DNA arrays on single-crystalline diamond are studied on a microscopic level by atomic force microscopy (AFM) in buffer solutions. Compact DNA layers in a thickness of 76 A are resolved by optimizing phase and height contrast in AFM. The height shows some long-range (30 nm) undulations of +/-5 A due to tip and DNA interactions. The axis of double helix DNA is oriented at about 36 degrees with respect to the diamond surface. DNA molecules can be removed by contact-mode AFM with forces >45 nN, indicating stronger DNA bonding than on gold substrates.
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http://dx.doi.org/10.1021/ja058181yDOI Listing
March 2006

Simultaneous determination of three local anesthetic drugs from the pipecoloxylidide group in human serum by high-performance liquid chromatography.

J Chromatogr B Analyt Technol Biomed Life Sci 2006 Apr 9;834(1-2):213-6. Epub 2006 Mar 9.

Institute of Community Medicine, University of Tsukuba, Ibaraki-ken 305-8575, Japan.

A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous analysis of the local anesthetic amide drugs, bupivacaine, mepivacaine and ropivacaine, belonging to the pipecoloxylidide group using a C(18) reversed-phase column (150 x 4.6 mm I.D.) filled with 5-microm particles and attached to a UV detector. The mobile phase was composed of acetonitrile-methanol-30 mM NaH(2)PO(4) (pH 5.6) (100:100:300, v/v/v) and the flow rate was 1ml/min. The absorbance of the eluate was monitored at 210 nm. The retention times of the three compounds were: 4.6 min (mepivacaine), 9.7min (ropivacaine) and 16.4 min (bupivacaine). With this sample preparation method, good and consistent recoveries of the three compounds were obtained: 88-91% for mepivacaine, 87-89% for ropivacaine and 88-91% for bupivacaine. The limit of quantification for three compounds in human serum was 2 ng/ml for mepivacaine, 5 ng/ml for bupivacaine and ropivacaine. This method may be useful in clinical and forensic applications for the determination or identification of the local anesthetic drugs: bupivacaine, mepivacaine or ropivacaine.
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http://dx.doi.org/10.1016/j.jchromb.2006.02.034DOI Listing
April 2006
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