Publications by authors named "Hiroshi Yamamoto"

844 Publications

Enhancing growth of mangrove seedlings in the environmentally extreme Arabian Gulf using treated sewage sludge.

Mar Pollut Bull 2021 Jun 11;170:112595. Epub 2021 Jun 11.

Water Research Center, New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates.

The response of mangrove (Avicennia marina) seedlings to treated (wet) sludge from a sewage treatment plant (STP) was tested in a randomized block design experiment at a tree nursery on Mubarraz Island in the Arabian Gulf. The growth response of seedlings to half-strength and full-strength STP sludge was monitored over 103 days and compared with the response to freshwater, seawater and half-strength seawater treatments. Sludge treatments resulted in significantly greater plant growth, leaf number, leaf biomass and root biomass than the other treatments did. The positive effect of STP sludge on seedling growth is attributed to enhanced levels of total nitrogen (8.9 ± 0.1 mg l) and total phosphorus (7.8 ± 0.2 mg l) in the sludge and its low salinity. These results suggest that sludge from sewage treatment plants may be beneficially used in mangrove nurseries and plantations in this arid region, where soils are nutrient-poor and fresh water is scarce.
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http://dx.doi.org/10.1016/j.marpolbul.2021.112595DOI Listing
June 2021

Toxicity assessment of typical polycyclic aromatic hydrocarbons to Daphnia magna and Hyalella azteca in water-only and sediment-water exposure systems.

Sci Total Environ 2021 Aug 17;784:147156. Epub 2021 Apr 17.

Department of Natural Environmental Studies, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8563, Japan; Center for Health and Environmental Risk Research, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki, 305-8506, Japan. Electronic address:

While the equilibrium partitioning (EqP) method has been demonstrated to effectively predict the adverse effects of nonionic organic chemicals in sediment on benthic organisms by sediment toxicity tests, only a limited number of studies have been performed both in water-only and whole-sediment toxicity tests using the same species and verified the validity of EqP-based toxicity assessment. To further examine the validity of the EqP method for application in a wide range of hydrophobicity, we conducted sorption/desorption experiments and both water-only and sediment toxicity tests using a popular aquatic crustacean species, Daphnia magna (48 h), and benthic species Hyalella azteca (96 h) for six typical polycyclic aromatic hydrocarbons (PAHs) with three to five rings and an amine derivative: anthracene, phenanthrene, fluoranthene, pyrene, benzo[a]pyrene, dibenzo[a,h]anthracene, and 1-aminopyrene. The linear sorption coefficient was determined and ranged from 2.7 × 10 (phenanthrene) and 1.2 × 10 L/kg (benzo[a]pyrene) highly depending on the hydrophobicity while the aqueous concentrations were stable after 24 h in the desorption test. As result of acute toxicity tests in the water-only exposure system, anthracene and dibenz[a,h]anthracene were found to be nontoxic to both species, while median effect/lethal concentrations (EC/LC) were determined as ranging from 0.66 (benzo[a]pyrene) to 330 μg/L (phenanthrene), and from 11 (1-aminopyrene) to 180 μg/L (phenanthrene) for D. magna and H. azteca, respectively. Among these compounds, three PAHs with three, four, and five rings each, and 1-aminopyrene were subjected to sediment-water toxicity tests. In the sediment-water tests, the LC of phenanthrene and pyrene was three to six times higher than that of the water-only tests for H. azteca while the EC was 1.1 to 2.0 times higher for D. magna. In contrast, the EC/LC of benzo[a]pyrene (BaP) in the sediment-water toxicity test was more than 5 times higher than that in the water-only test for both H. azteca and D. magna. The EC/LC values of 1-aminopyrene were similar in both the sediment-water and the water-only toxicity tests, ranging narrowly from 21 to 28 μg/L and 8.8 to 11 μg/L for D. magna and H. azteca, respectively. The EC/LC based on the body residue (ER/LR) was investigated for two of the representative PAHs, pyrene, and BaP. The ER/LR of pyrene in both species was 2.3 and 11 times higher in the water-only toxicity test for D. magna and H. azteca, respectively, while those of BaP in the sediment-water toxicity test were not calculated for the sediment-water toxicity tests, and the highest body concentration in the sediment-water tests was lower than the ER/LR in the water-only toxicity test. Although the experimental results were comparable with the predicted sediment toxicity values based on the EqP method for the selected PAHs in this study, there is a risk of phenanthrene and pyrene being slightly underestimated (1.4-1.9 fold for phenanthrene and 3.7-6.1 fold for pyrene) by the EqP method for H. azteca. These results reaffirm that the bioavailability of poorly water-soluble chemicals is important for sediment toxicity and that the exposure pathway should be further investigated to avoid under- and overestimation via the EqP method.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147156DOI Listing
August 2021

Ruptured type A aortic dissection with saddle pulmonary embolism-like appearance on computed tomography angiography.

J Card Surg 2021 May 30. Epub 2021 May 30.

Department of Cardiovascular surgery, Akita University Graduate School of Medicine, Akita, Japan.

We present a case of ruptured type A acute aortic dissection with pulmonary trunk compression by mediastinal hematoma. This condition mimicked a pulmonary embolism on the early arterial phase of computed tomography angiography, whereas the correct diagnosis was determined from the late arterial phase and unenhanced computed tomography. We highlight the importance of carefully interpreting triphasic computed tomography angiography to assess the status of aortic dissection.
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http://dx.doi.org/10.1111/jocs.15691DOI Listing
May 2021

Glucagon-like peptide 2 (GLP-2) in bovine colostrum and transition milk.

Heliyon 2021 May 15;7(5):e07046. Epub 2021 May 15.

Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, 878-0201, Japan.

Bovine colostrum contains growth factors, cytokines, hormones, and enzymes, which have important roles in stimulating gastrointestinal development of neonatal calves. In the present study, we measured the concentration of glucagon-like peptide 2 (GLP-2), one of the gut-derived peptides secreted from intestinal L-cells, in colostrum and transition milk of Japanese black cattle. All colostrum samples were collected within 24 h after calving (d 0) and transition milk was collected at 24, 48 and 72 h relative to the time at colostrum sampling (d 1, d 2 and d 3, respectively). Concentrations of GLP-2 in colostrum were 5.53 ± 1.07 ng/mL on average (range = 0.94-9.60 ng/mL) and decreased from d 0 to 3 ( < 0.01). Furthermore, concentrations of GLP-2 in colostrum and transition milk were quadratically decreased with the elapsed time from parturition until colostrum sampling (R = 0.48, < 0.01). Our results show for the first time that GLP-2 is present in bovine colostrum and transition milk and that concentrations decreased with elapsed time from parturition.
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http://dx.doi.org/10.1016/j.heliyon.2021.e07046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141762PMC
May 2021

Cooperation of chloroplast ascorbate peroxidases and proton gradient regulation 5 is critical for protecting Arabidopsis plants from photooxidative stress.

Plant J 2021 May 24. Epub 2021 May 24.

Graduate School of Natural Science and Technology, Shimane University, Nishikawatsu, Matsue, Shimane, Japan.

High-light (HL) stress enhances the production of H O from the photosynthetic electron transport chain in chloroplasts, potentially causing photooxidative damage. Although stromal and thylakoid membrane-bound ascorbate peroxidases (sAPX and tAPX, respectively) are major H O scavenging enzymes in chloroplasts, their knockout mutants do not exhibit a visible phenotype under HL stress. There are trans-thylakoid ∆pH-dependent mechanisms for controlling H O production from photosynthesis, such as thermal dissipation of light energy and down-regulation of electron transfer between photosystem II and I, which may compensate for the lack of APXs. To test this hypothesis, we focused on a proton gradient regulation 5 (pgr5) mutant, wherein both ∆pH-dependent mechanisms are impaired, and an Arabidopsis sapx tapx double mutant was crossed with the pgr5 single mutant. The sapx tapx pgr5 triple mutant exhibited extreme sensitivity to HL compared to its parental lines. This phenotype was consistent with cellular redox perturbations and enhanced expression of many oxidative stress-responsive genes. These findings demonstrate that the PGR5-dependent mechanisms compensate for chloroplast APXs and vice versa. An intriguing finding was that the failure of non-photochemical quenching (NPQ) induction in pgr5 (because of the limitation in ∆pH formation) was partially recovered in sapx tapx pgr5. Further genetic studies suggested that this recovery was dependent on the NADH dehydrogenase-like complex (NDH)-dependent pathway for cyclic electron flow around photosystem I. Together with data from the sapx tapx npq4 mutant, we discuss the interrelationship between APXs and ∆pH-dependent mechanisms under HL stress.
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http://dx.doi.org/10.1111/tpj.15352DOI Listing
May 2021

[Nivolumab‒Induced Severe Thrombocytopenia in a Patient with Advanced Gastric Cancer].

Gan To Kagaku Ryoho 2021 May;48(5):709-712

Dept. of Gastroenterology and Hepatology, Kurashiki Central Hospital.

Here, we report a case of severe thrombocytopenia induced by nivolumab. A 70‒year‒old woman with advanced gastric cancer was treated with nivolumab. After the first dose, she noticed an erythematous rash. During the second cycle, fever and purpura on the lower extremities were also noted. Laboratory examinations revealed severe thrombocytopenia of grade 4, mild hemolytic anemia, leukopenia, and coagulopathy. Immune‒related adverse events(irAE)were suspected, and we started 40 mg(0.7 mg/kg)prednisolone(PSL)per day. Her symptoms and laboratory data immediately improved. However, when we reduced the dose of PSL, she developed rash and thrombocytopenia again. We increased the dose of PSL to 40 mg, which was effective for improving these abnormalities. We then gradually reduced the PSL, paying attention to avoid a relapse of irAEs. We could not restart chemotherapy thereafter, and she died from progression of gastric cancer. As shown in this case, PSL is effective for immune‒related thrombocytopenia; however, determining how to reduce the dose of PSL and when to restart chemotherapy requires careful consideration.
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May 2021

Avoiding anticoagulation drugs for postoperative atrial fibrillation enabled successful conservative treatment of left atrial dissection: a case report.

Surg Case Rep 2021 May 12;7(1):120. Epub 2021 May 12.

Department of Cardiovascular Surgery, Akita University Graduate School of Medicine, Hondo 1-1-1, Akita, 010-8543, Japan.

Background: Left atrial dissection is a rare complication of cardiac surgery, most commonly associated with mitral valve surgery. Herein, we report on the successful conservative treatment of left atrial dissection while avoiding anticoagulation therapy.

Case Presentation: A 64-year-old man developed left atrial dissection during operation for acute type A aortic dissection, most likely due to retrograde cardioplegia cannulation. As there was no connection between the left atrial dissection cavity and the left atrium on enhanced computed tomography, we did not administer anticoagulants to prevent expansion of the left atrial dissection cavity. However, the patient developed atrial fibrillation, which was successfully managed by beta-blocker and amiodarone administration. Follow-up imaging showed gradual left atrial dissection reduction, and the patient was started on anticoagulation therapy.

Conclusion: We were able to resolve left atrial dissection by preventing the use of anticoagulation therapy in the acute stage by managing the atrial fibrillation with antiarrhythmic drugs.
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http://dx.doi.org/10.1186/s40792-021-01194-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116416PMC
May 2021

[Traction-assisted Negative Pressure Wound Therapy for Pediatric Poststernotomy Mediastinitis:Report of Two Cases].

Kyobu Geka 2021 Feb;74(2):121-124

Department of Cardiovascular Surgery, Akita University, Akita, Japan.

We herein report two cases of pediatric poststernotomy mediastinitis treated by traction-assisted negative pressure wound therapy (NPWT) with Zip Surgical Skin Closure (Zip), which is a non-invasive skin closure device. We used this device with NPWT in cases of pediatric poststernotomy mediastinitis to stabilize the sternum and reduce the natural retractive forces of the skin. The patients were two boys (two and three months old), with an onset of infection at 13 and eight postoperative days, respectively. The culture examination detected methicillin-susceptible Staphylococcus aureus in both cases. Traction-assisted NPWT with Zip was performed at-75 mmHg for 16 and 33 days, and the wounds healed completely. In conclusion, this modification was successfully applied to treat pediatric poststernotomy mediastinitis and may help reduce the duration of treatment.
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February 2021

Patient's age and D-dimer levels predict the prognosis in patients with TAFRO syndrome.

Int J Hematol 2021 Apr 30. Epub 2021 Apr 30.

Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa-ken, 920-0293, Japan.

Objectives: To identify prognostic factors for TAFRO syndrome, a rare inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly.

Methods: Data of patients with TAFRO syndrome were extracted from a Japanese patient registry. Patients were divided into groups according to the clinical and laboratory parameters at initial presentation. Cut-off values for the laboratory parameters were determined using receiver operating characteristic curve analysis and by clinical relevance. Patient survival was analyzed by the Kaplan-Meier method. Univariable analysis was performed using log-rank tests. Multivariable analyses were performed with the logistic regression model and the Cox proportional hazards model.

Results: We extracted the data of 83 patients with TAFRO syndrome from the registry. Univariable analysis identified several potential prognostic factors. Of these factors, age ≥60 years and D-dimer ≥18 μg/dL remained significant predictors of poor overall survival in the multivariable Cox proportional hazards model. Based on these results, we developed a simple prognostic scoring system for TAFRO syndrome (TS-PSS).

Conclusion: Patients in our cohort were stratified into low, intermediate, and high-risk groups by the TS-PSS. This system should be verified with independent patient cohorts in future studies.
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http://dx.doi.org/10.1007/s12185-021-03159-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085640PMC
April 2021

Efficacy and safety of nelfinavir in asymptomatic and mild COVID-19 patients: a structured summary of a study protocol for a multicenter, randomized controlled trial.

Trials 2021 Apr 28;22(1):309. Epub 2021 Apr 28.

Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan.

Objectives: The aim of this trial is to evaluate the antiviral efficacy, clinical efficacy, and safety of nelfinavir in patients with asymptomatic and mild COVID-19.

Trial Design: The study is designed as a multicenter, open-label, blinded outcome assessment, parallel group, investigator-initiated, exploratory, randomized (1:1 ratio) controlled clinical trial.

Participants: Asymptomatic and mild COVID-19 patients will be enrolled in 10 university and teaching hospitals in Japan. The inclusion and exclusion criteria are as follows: Inclusion criteria: (1) Japanese male or female patients aged ≥ 20 years (2) SARS-CoV-2 detected from a respiratory tract specimen (e.g., nasopharyngeal swab or saliva) using PCR, LAMP, or an antigen test within 3 days before obtaining the informed consent (3) Provide informed consent Exclusion criteria: (1) Symptoms developed ≥ 8 days prior to enrolment (2) SpO < 96 % (room air) (3) Any of the following screening criteria: a) ALT or AST ≥ 5 × upper limit of the reference range b) Child-Pugh class B or C c) Serum creatinine ≥ 2 × upper limit of the reference range and creatinine clearance < 30 mL/min (4) Poorly controlled diabetes (random blood glucose ≥ 200 mg/dL or HbA1c ≥ 7.0%, despite treatment) (5) Unsuitable serious complications based on the assessment of either the principal investigator or the sub-investigator (6) Hemophiliac or patients with a marked hemorrhagic tendency (7) Severe diarrhea (8) Hypersensitivity to the investigational drug (9) Breastfeeding or pregnancy (10) With childbearing potential and rejecting contraceptive methods during the study period from the initial administration of the investigational drug (11) Receiving rifampicin within the previous 2 weeks (12) Participated in other clinical trials and received drugs within the previous 12 weeks (13) Undergoing treatment for HIV infection (14) History of SARS-CoV-2 vaccination or wishes to be vaccinated against SARS-CoV-2 (15) Deemed inappropriate (for miscellaneous reasons) based on the assessment of either the principal investigator or the sub-investigator INTERVENTION AND COMPARATOR: Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be randomized to either the nelfinavir group or the symptomatic treatment group. The nelfinavir group will be administered 750 mg of nelfinavir orally, three times daily for 14 days (treatment period). However, if a participant tests negative on two consecutive PCR tests of saliva samples, administration of the investigational drug for that participant can be discontinued at the discretion of the investigators. The symptomatic treatment group will not be administered the investigational drug, but all other study procedures and conditions will be the same for both groups for the duration of the treatment period. After the treatment period of 14 days, each group will be followed up for 14 days (observational period).

Main Outcomes: The primary endpoint is the time to negative conversion of SARS-CoV-2. During the study period from Day 1 to Day 28, two consecutive negative PCR results of saliva samples will be considered as the negative conversion of the virus. The secondary efficacy endpoints are as follows: For patients with both asymptomatic and mild disease: area under the curve of viral load, half decay period of viral load, body temperature at each time point, all-cause mortality, incidence rate of pneumonia, percentage of patients with newly developed pneumonia, rate of oxygen administration, and the percentage of patients who require oxygen administration. For asymptomatic patients: incidence of symptomatic COVID-19, incidence of fever (≥ 37.0 °C for two consecutive days), incidence of cough For patients with mild disease: incidence of defervescence (< 37.0 °C), incidence of recovery from clinical symptoms, incidence of improvement of each symptom The secondary safety endpoints are adverse events and clinical examinations.

Randomization: Patients will be randomized to either the nelfinavir group or the symptomatic treatment group using the electric data capture system (1:1 ratio, dynamic allocation based on severity [asymptomatic], and age [< 60 years]).

Blinding (masking): Only the assessors of the primary outcome will be blinded (blinded outcome assessment).

Numbers To Be Randomized (sample Size): The sample size was determined based on our power analysis to reject the null hypothesis, S (t | z =1) = S (t | z = 0) where S is a survival function, t is time to negative conversion, and z denotes randomization group, by the log-rank test with a two-sided p value of 0.05. We estimated viral dynamic parameters by fitting a nonlinear mixed-effects model to reported viral load data, and simulated our primary endpoint from viral-load time-courses that were realized from sets of viral dynamics parameters sampled from the estimated probability distribution of the parameters (sample size: 2000; 1000 each for randomization group). From this estimation of the hazard ratio between the randomization groups for the event of negative conversion using this simulation dataset, the required number of events for rejecting our null hypothesis with a power of 0.80 felled 97.345 by plugging the estimated hazard ratio, 1.79, in Freedman's equation. Therefore, we decided the required number of randomizations to be 120 after consideration of the frequency of censoring and the anticipated rate of withdrawal caused by factors such as withdrawal of consent.

Trial Status: Protocol version 6.0 of February 12, 2021. Recruitment started on July 22, 2020 and is anticipated to be completed by March 31, 2022.

Trial Registration: This trial was registered in Japan Registry of Clinical Trials (jRCT) ( jRCT2071200023 ) on 21 July 21, 2020.

Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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http://dx.doi.org/10.1186/s13063-021-05282-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080096PMC
April 2021

Long-term survival of two patients with recurrent high-risk neuroblastoma.

Pediatr Int 2021 Apr 27. Epub 2021 Apr 27.

Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan.

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http://dx.doi.org/10.1111/ped.14489DOI Listing
April 2021

RAGE signaling antagonist suppresses mouse macrophage foam cell formation.

Biochem Biophys Res Commun 2021 May 1;555:74-80. Epub 2021 Apr 1.

Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan. Electronic address:

The engagement of the receptor for advanced glycation end-products (receptor for AGEs, RAGE) with diverse ligands could elicit chronic vascular inflammation, such as atherosclerosis. Binding of cytoplasmic tail RAGE (ctRAGE) to diaphanous-related formin 1 (Diaph1) is known to yield RAGE intracellular signal transduction and subsequent cellular responses. However, the effectiveness of an inhibitor of the ctRAGE/Diaph1 interaction in attenuating the development of atherosclerosis is unclear. In this study, using macrophages from Ager and Ager mice, we validated the effects of an inhibitor on AGEs-RAGE-induced foam cell formation. The inhibitor significantly suppressed AGEs-RAGE-evoked Rac1 activity, cell invasion, and uptake of oxidized low-density lipoprotein, as well as AGEs-induced NF-κB activation and upregulation of proinflammatory gene expression. Moreover, expression of Il-10, an anti-inflammatory gene, was restored by this antagonist. These findings suggest that the RAGE-Diaph1 inhibitor could be a potential therapeutic drug against RAGE-related diseases, such as chronic inflammation and atherosclerosis.
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http://dx.doi.org/10.1016/j.bbrc.2021.03.139DOI Listing
May 2021

Pregnancy-associated diabetes insipidus in Japan-a review based on quoting from the literatures reported during the period from 1982 to 2019.

Endocr J 2021 Apr 23;68(4):375-385. Epub 2021 Mar 23.

Komatsu University#, Komatsu 923-0921, Japan.

This Review Article overviews the literature on diabetes insipidus (DI) associated with pregnancy and labor in Japan published from 1982 to 2019. The total number of patients collected was 361, however, only one-third of these cases had detailed pathophysiologic information enabling us to identify the respective etiology and subtype. Pregnancy-associated DI can be divided into 3 etiologies, central (neurogenic) DI, nephrogenic DI, and excess vasopressinase-associated DI. Neurogenic DI has various causes: for example, DI associated with tumoral lesions in the pituitary and neighboring area, DI associated with Sheehan's syndrome and/or pituitary apoplexy, and DI associated with lymphocytic infundibuloneurohypophysitis (LINH, stalkitis). Nephrogenic DI results from defective response of the kidney to normal levels of vasopressin. However, the most interesting causal factor of pregnancy-associated DI is excess vasopressinase, caused either by excess production of vasopressinase by the placenta or defective clearance of vasopressinase by the liver. Hepatic complications resulting in pregnancy-associated DI include acute fatty liver of pregnancy (AFLP) and HELLP syndrome (syndrome of hemolysis, elevated liver enzymes, low platelets), as well as pre-existing or co-incidental hepatic diseases. A possible role of glucose uptake in putative stress-induced DI and the importance of correct diagnosis and treatment of pregnancy-associated DI, including use of 1-deamino 8-D arginine vasopressin, are also discussed.
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http://dx.doi.org/10.1507/endocrj.EJ20-0745DOI Listing
April 2021

Sources of variation in sediment toxicity of hydrophobic organic chemicals: Meta-analysis of 10-14-day spiked-sediment tests with Hyalella azteca and Chironomus dilutus.

Integr Environ Assess Manag 2021 Mar 19. Epub 2021 Mar 19.

Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Ibaraki, Japan.

Spiked-sediment toxicity tests with benthic organisms are routinely used to assess the potential ecological impact of sediment-associated hydrophobic organic contaminants. Although several sediment tests have been standardized, experimental factors such as spiking methods still vary between laboratories. To identify the experimental factors that affect the bioavailability of contaminants and account for the highest percentage of the variability of toxicity values (i.e., 50% lethal concentration; LC50), we performed a meta-analysis of published 10-14-day spiked-sediment toxicity tests with the standard test species Hyalella azteca and Chironomus dilutus. Analysis of 172 test records revealed that the variability of sediment LC50s for a given combination of chemical and test species was large. The mean coefficient of variation (CV) was 65%, even after organic carbon normalization, and was slightly larger than the CV in water-only tests (49%). Regression analyses revealed that the most important factor contributing to the variability of the sediment LC50s was sediment type (i.e., environmental or formulated sediment) and that use of formulated sediment (i.e., composed of peat, cellulose, or leaves as organic carbon source) tended to cause higher toxicity than use of environmental sediment. This might be caused by the difference in partitioning the coefficient of organic contaminants and the resulting difference in the bioavailability between sediment types. The effects of other factors, including aging periods and spiking methods, were insignificant or specific to certain chemicals. These discoveries facilitate refinement of the methodologies used in sediment toxicity testing and the correct interpretation of test results. Integr Environ Assess Manag 2021;00:1-11. © 2021 SETAC.
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http://dx.doi.org/10.1002/ieam.4413DOI Listing
March 2021

Prognostic value of the geriatric nutritional risk index among patients with previously treated advanced non-small cell lung cancer who subsequently underwent immunotherapy.

Thorac Cancer 2021 05 12;12(9):1366-1372. Epub 2021 Mar 12.

First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.

Background: The geriatric nutritional risk index (GNRI) is a simple and useful marker for predicting prognosis and treatment efficacy among patients with various cancers. However, to the best of our knowledge, there are no previous reports regarding the prognostic value of GNRI among patients with non-small cell lung cancer (NSCLC) who were treated with immune checkpoint inhibitors (ICIs).

Methods: We retrospectively evaluated 85 patients with previously treated advanced NSCLC who were administered ICIs at Shinshu University Hospital between February 2016 and October 2020. Progression-free survival (PFS) and overall survival (OS) were compared between groups with high (≥89.5) and low (<89.5) GNRI values. We used univariate and multivariate Cox regression analyses to identify prognostic factors that were associated with PFS and OS.

Results: The high and low GNRI groups included 61 and 24 patients, respectively. Relative to the low GNRI group, the high GNRI group had significantly longer median PFS (3.7 vs. 2.4 months, p = 0.041) and significantly longer median OS (14.2 vs. 6.1 months, p = 0.008). Multivariate analyses revealed that independent predictors of favorable OS were high GNRI, performance status of 0-1, and age of ≥70 years. The high GNRI group was significantly more likely to undergo subsequent therapy after immunotherapy (68.6 vs. 33.3%, p = 0.008).

Conclusions: The present study revealed that high GNRI was associated with good outcomes among patients with previously treated NSCLC who were treated with ICIs.
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http://dx.doi.org/10.1111/1759-7714.13909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088948PMC
May 2021

The role of discoidin domain receptor 2 in the renal dysfunction of alport syndrome mouse model.

Ren Fail 2021 Dec;43(1):510-519

Department of Molecular Medicine Graduate School of Pharmaceutical Sciences, Kumamoto, Japan.

Alport syndrome (AS) is a hereditary glomerular nephritis caused by mutation in one of the type IV collagen genes α3/α4/α5 that encode the heterotrimer COL4A3/4/5. Failure to form a heterotrimer due to mutation leads to the dysfunction of the glomerular basement membrane, and end-stage renal disease. Previous reports have suggested the involvement of the receptor tyrosine kinase discoidin domain receptor (DDR) 1 in the progression of AS pathology. However, due to the similarity between DDR1 and DDR2, the role of DDR2 in AS pathology is unclear. Here, we investigated the involvement of DDR2 in AS using the X-linked AS mouse model. Mice were treated subcutaneously with saline or antisense oligonucleotide (ASO; 5 mg/kg or 15 mg/kg per week) for 8 weeks. Renal function parameters and renal histology were analyzed, and the gene expressions of inflammatory cytokines were determined in renal tissues. The expression level of DDR2 was highly elevated in kidney tissues of AS mice. Knockdown of using -specific ASO decreased the expression. However, the DDR2 ASO treatment did not improve the proteinuria or decrease the BUN level. DDR2 ASO also did not significantly ameliorate the renal injury, inflammation and fibrosis in AS mice. These results showed that knockdown by ASO had no notable effect on the progression of AS indicating that DDR2 may not be critically involved in AS pathology. This finding may provide useful information and further understanding of the role of DDRs in AS.
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http://dx.doi.org/10.1080/0886022X.2021.1896548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971217PMC
December 2021

The Role of Immune-Related Adverse Events in Prognosis and Efficacy Prediction for Patients with Non-Small Cell Lung Cancer Treated with Immunotherapy: A Retrospective Clinical Analysis.

Oncology 2021 25;99(5):271-279. Epub 2021 Feb 25.

First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.

Purpose: The development of immune-related adverse events (irAEs) in patients undergoing immunotherapy has been reported to be a favorable prognostic factor in several studies. We aimed to examine the correlation between irAEs and prognosis in patients with non-small cell lung cancer (NSCLC) and further reveal the patient characteristics associated with response to immunotherapy among treatment responders who developed irAEs.

Methods: We retrospectively enrolled 80 patients with NSCLC who received immunotherapy at Shinshu University Hospital between February 2016 and February 2020. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and those without irAEs. We examined the prognostic factors associated with PFS and OS using univariate and multivariate Cox proportional-hazards models. We further analyzed the patients who developed irAEs by classifying them into responders and non-responders.

Results: Twenty-five patients developed irAEs. The median PFS and OS of the patients with irAEs were significantly longer than those of the patients without irAEs (6.8 vs. 1.9 months, p < 0.001, and 37.8 vs. 8.1 months, p < 0.001, respectively). Multivariate analysis associated with PFS and OS indicated that the development of irAEs was an independent favorable prognostic factor. Among the patients developing irAEs, the responder group had a significantly higher incidence of multiple irAEs than the non-responder group (41.7 vs. 0.0%, p = 0.009).

Conclusion: Our findings revealed that the development of irAEs was associated with clinical benefits in NSCLC patients who received immunotherapy. In particular, patients with multiple irAEs might have good prognoses.
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http://dx.doi.org/10.1159/000511999DOI Listing
May 2021

Regimen of 5-Fluorouracil and Cisplatin Increases the Incidence of Extravasation in Patients Undergoing Chemotherapy.

In Vivo 2021 Mar-Apr;35(2):1147-1150

Department of Pharmacy, National Hospital Organization Okayama Medical Centre, Okayama, Japan.

Background/aim: Extravasation associated with chemotherapy can induce localised injury, necrosis, and nerve damage, resulting in discontinued chemotherapy and impaired quality of life; however, risk factors for extravasation remain unclear. The present study aimed to identify chemotherapy regimen-associated factors related to extravasation.

Patients And Methods: Data on patient and chemotherapy protocol characteristics were extracted from our hospital's electronic database; the frequency of extravasation was compared among patients receiving different chemotherapy regimens.

Results: Twenty-two patients with extravasation undergoing chemotherapy during the study period were enrolled in the present study. Patients undergoing treatment with 5-fluorouracil and cisplatin were most likely to develop extravasation in the present study. All patients presenting with extravasation during treatment with 5-fluorouracil and cisplatin developed swelling and many (40%) developed erythema within the first two cycles of treatment.

Conclusion: Treatment with 5-fluorouracil combined with cisplatin increases the incidence of extravasation. Ensuring suitable vascular access and increasing awareness regarding the symptoms and timing of extravasation among patients and medical staff can improve extravasation prevention and diagnosis.
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http://dx.doi.org/10.21873/invivo.12361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045088PMC
June 2021

[Effects of Heart Rate on Myocardial Native T Value Acquired by 5s(3s)3s MOLLI Sequence].

Nihon Hoshasen Gijutsu Gakkai Zasshi 2021 ;77(2):172-181

Department of Radiology, Nihon University Hospital.

Quantitative evaluation of myocardial native T value by measuring modified Look-Locker inversion recovery (MOLLI) method is clinically useful and is used for follow-up of various myocardial diseases. The heart rate during the scan can vary even in the same subjects. Therefore, it is important to know the effects of the heart rate on the native T value of the myocardium. In this study, we evaluated the effect of the heart rate on the T value in the 5s (3s) 3s scheme, time control data collection period of the MOLLI method, using phantom experiments and experiments of healthy volunteers. The 5s (3s) 3s scheme of the MOLLI method is considered to have little dependence on the heart rate, but the T value still varied up to about 7% depending on the heart rate, and was underestimated up to 8% during low heart rate using phantom experiments.
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http://dx.doi.org/10.6009/jjrt.2021_JSRT_77.2.172DOI Listing
February 2021

Calcified Aortic Wall Removal for Dysphagia Aortica Caused by Chronic Traumatic Aortic Pseudoaneurysm.

Ann Vasc Surg 2021 Feb 5. Epub 2021 Feb 5.

Department of Cardiovascular surgery, Akita University Graduate School of Medicine, Akita, Japan.

In this study, we report a case of a 45-year-old man with dysphagia aortica secondary to chronic traumatic aortic pseudoaneurysm of the aortic isthmus. He had been involved in a motor vehicle accident 27 years earlier. Computed tomography demonstrated a severely calcified aortic pseudoaneurysm of the aortic isthmus that compressed the esophagus extrinsically. An invasive surgical procedure involving a graft replacement and removal of the calcified aortic wall released the esophageal compression and completely improved the patient's symptoms. To the best of our knowledge, a case of dysphagia aortica caused by calcified pseudoaneurysm has never been reported.
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http://dx.doi.org/10.1016/j.avsg.2021.01.088DOI Listing
February 2021

Primary mediastinal germ cell tumors - A retrospective analysis of >30 years of experience in a single institution.

Thorac Cancer 2021 03 27;12(6):807-813. Epub 2021 Jan 27.

Department of Thoracic Surgery, Shinshu University School of Medicine, Matsumoto, Japan.

Background: This study was performed to clarify the treatment outcome of patients with primary mediastinal germ cell tumors (PMGCTs), focusing on the clinical manifestations and management during definitive therapy and long-term follow-up.

Methods: In this study, we retrospectively reviewed the medical records of patients with PMGCTs treated at Shinshu University School of Medicine, and examined the clinical profiles and treatment outcomes of 22 patients (mean age of 29 years) with primary mediastinal GCTs treated at our hospital between 1983 and 2019.

Results: Five patients were diagnosed with pure seminoma and 17 had nonseminomatous GCT. A total of 21 patients were treated with cisplatin-based chemotherapy and 15 patients (68.2%) underwent thoracic surgery after chemotherapy. Although all cases of nonseminomatous GCT were negative for tumor markers after cisplatin-based chemotherapy, two cases showed variable GCT cells and two had somatic components (angiosarcoma and rhabdomyosarcoma) in resected specimens. Three relapsed soon after surgery. Growing teratoma syndrome developed during chemotherapy in four cases. Urgent thoracic surgery was performed in three patients, but one case was inoperable. The calculated 10-year overall survival rates were 100% in mediastinal seminoma and 64.7% in NSGCT. During follow-up, second non-GCT malignancies developed in three patients (colon cancer, 190 months; thyroid cancer, 260 months; non-small cell lung cancer, 250 months after the initial chemotherapy) and one patient with primary mediastinal seminoma was associated with multiple type I endocrine tumors.

Conclusions: Our experiences demonstrated that long-term survival and/or cure can be achieved with adequate chemotherapy followed by local surgical treatment even in patients with mediastinal GCTs. However, the clinical manifestations and biological behaviors during and/or after chemotherapy were complex and varied. In addition, the development of secondary malignancies should be taken into consideration for long-term follow-up. Clinicians should be aware of the various clinical features and secondary malignancies in primary mediastinal GCTs.
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http://dx.doi.org/10.1111/1759-7714.13859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952792PMC
March 2021

Upper gastrointestinal ischemia as a rare complication of paroxysmal nocturnal hemoglobinuria.

Clin Case Rep 2021 Jan 22;9(1):506-510. Epub 2020 Nov 22.

Department of Gastroenterology and Hepatology Kurashiki Central Hospital Kurashiki Japan.

When patients with PNH present with abdominal symptoms, thrombosis-induced gastrointestinal injury should be considered; computed tomography and esophagogastroduodenoscopy may help make the diagnosis of this potentially serious complication.
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http://dx.doi.org/10.1002/ccr3.3567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813057PMC
January 2021

Electric dipole induced bulk ferromagnetism in dimer Mott molecular compounds.

Sci Rep 2021 Jan 14;11(1):1332. Epub 2021 Jan 14.

RIKEN, Cluster for Pioneering Research (CPR), Wako, Saitama, 351-0198, Japan.

Magnetic properties of Mott-Hubbard systems are generally dominated by strong antiferromagnetic interactions produced by the Coulomb repulsion of electrons. Although theoretical possibility of a ferromagnetic ground state has been suggested by Nagaoka and Penn as single-hole doping in a Mott insulator, experimental realization has not been reported more than half century. We report the first experimental possibility of such ferromagnetism in a molecular Mott insulator with an extremely light and homogeneous hole-doping in π-electron layers induced by net polarization of counterions. A series of Ni(dmit) anion radical salts with organic cations, where dmit is 1,3-dithiole-2-thione-4,5-dithiolate can form bi-layer structure with polarized cation layers. Heat capacity, magnetization, and ESR measurements substantiated the formation of a bulk ferromagnetic state around 1.0 K with quite soft magnetization versus magnetic field (M-H) characteristics in (Et-4BrT)[Ni(dmit)] where Et-4BrT is ethyl-4-bromothiazolium. The variation of the magnitude of net polarizations by using the difference of counter cations revealed the systematic change of the ground state from antiferromagnetic one to ferromagnetic one. We also report emergence of metallic states through further doping and applying external pressures for this doping induced ferromagnetic state. The realization of ferromagnetic state in Nagaoka-Penn mechanism can paves a way for designing new molecules-based ferromagnets in future.
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http://dx.doi.org/10.1038/s41598-020-79262-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809364PMC
January 2021

Prediction of Long-Term Diabetes Remission After Metabolic Surgery in Obese East Asian Patients: a Comparison Between ABCD and IMS Scores.

Obes Surg 2021 Apr 7;31(4):1485-1495. Epub 2021 Jan 7.

Weight Loss and Metabolic Surgery Center, Yotsuya Medical Cube, Tokyo, Japan.

Purpose: Recently, more than 10 models have been developed to predict remission of type 2 diabetes mellitus (T2DM) after metabolic surgery. The ABCD score was compared to the individualized metabolic surgery (IMS) score in terms of prediction of T2DM remission, but which of the two scoring systems is better remains controversial.

Methods: Patient data from 463 obese East Asian patients who underwent laparoscopic Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or SG with duodenojejunal bypass (SG-DJB) as a primary operation and were followed for at least 3 years were retrospectively collected from 24 institutions. The correlation between the ABCD and IMS scoring systems and the discrimination power of the models was evaluated. The cut-off point for the IMS stage of T2DM severity was also revised to adjust the scoring system to obese East Asian patients.

Results: The two scoring systems were significantly well correlated. The IMS scoring system showed significant differences in T2DM remission rates between the procedures in the moderate stage, but the ABCD score showed no significant differences in each category. The discrimination power of the IMS score was comparable to that of the ABCD score at both 3 and 5 years. The revised IMS scoring system showed that SG-DJB had significantly higher T2DM remission rates in the moderate stage at 5 years than RYGB or SG.

Conclusion: IMS score may be comparable to ABCD score to predict T2DM remission in obese East Asian patients. The revised IMS scoring system may also select candidates for SG or SG-DJB.
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http://dx.doi.org/10.1007/s11695-020-05151-6DOI Listing
April 2021

Aquatic toxicity (Pre)screening strategy for structurally diverse chemicals: global or local classification tree models?

Ecotoxicol Environ Saf 2021 Jan 9;208:111738. Epub 2020 Dec 9.

Center for Health and Environmental Risk Research, National Institute for Environmental Studies (NIES), 16-2 Onogawa, Tsukuba 305-8506, Japan.

With an ever-increasing number of synthetic chemicals being manufactured, it is unrealistic to expect that they will all be subjected to comprehensive and effective risk assessment. A shift from conventional animal testing to computer-aided methods is therefore an important step towards advancing the environmental risk assessments of chemicals. The aims of this study are two-fold: firstly, it examines the relationships between structural and physicochemical features of a diverse set of organic chemicals, and their acute aquatic toxicity towards Daphnia magna and Oryzias latipes using a classification tree approach. Secondly, it compares the efficiency and accuracy of the predictions of two modeling schemes: local models that are inherently restricted to a smaller subset of structurally-related substances, and a global model that covers a wider chemical space and a number of modes of toxic action. The classification tree-based models differentiate the organic chemicals into either 'highly toxic' or 'low to non-toxic' classes, based on internal and external validation criteria. These mechanistically-driven models, which demonstrate good performance, reveal that the key factors driving acute aquatic toxicity are lipophilicity, electrophilic reactivity, molecular polarizability and size. A comparative analysis of the performance of the two modeling schemes indicates that the local models, trained on homogeneous data sets, are less error prone, and therefore superior to the global model. Although the global models showed worse performance metrics compared to the local ones, their applicability domain is much wider, thereby significantly increasing their usefulness in practical applications for regulatory purposes. This demonstrates their advantage over local models and shows they are an invaluable tool for modeling heterogeneous chemical data sets.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111738DOI Listing
January 2021

Protein Synthesis in the Developing Neocortex at Near-Atomic Resolution Reveals Ebp1-Mediated Neuronal Proteostasis at the 60S Tunnel Exit.

Mol Cell 2021 01 22;81(2):304-322.e16. Epub 2020 Dec 22.

Institute of Medical Physics and Biophysics, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany. Electronic address:

Protein synthesis must be finely tuned in the developing nervous system as the final essential step of gene expression. This study investigates the architecture of ribosomes from the neocortex during neurogenesis, revealing Ebp1 as a high-occupancy 60S peptide tunnel exit (TE) factor during protein synthesis at near-atomic resolution by cryoelectron microscopy (cryo-EM). Ribosome profiling demonstrated Ebp1-60S binding is highest during start codon initiation and N-terminal peptide elongation, regulating ribosome occupancy of these codons. Membrane-targeting domains emerging from the 60S tunnel, which recruit SRP/Sec61 to the shared binding site, displace Ebp1. Ebp1 is particularly abundant in the early-born neural stem cell (NSC) lineage and regulates neuronal morphology. Ebp1 especially impacts the synthesis of membrane-targeted cell adhesion molecules (CAMs), measured by pulsed stable isotope labeling by amino acids in cell culture (pSILAC)/bioorthogonal noncanonical amino acid tagging (BONCAT) mass spectrometry (MS). Therefore, Ebp1 is a central component of protein synthesis, and the ribosome TE is a focal point of gene expression control in the molecular specification of neuronal morphology during development.
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http://dx.doi.org/10.1016/j.molcel.2020.11.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163098PMC
January 2021

Direct Abdominal Aortic Access for Thoracic Endovascular Aortic Repair in a Patient with Severe Aortic and Arterial Calcification.

Ann Vasc Surg 2021 May 15;73:509.e21-509.e24. Epub 2021 Jan 15.

Department of Cardiovascular surgery, Akita University Graduate School of Medicine, Akita, Japan.

Aortic and arterial calcification is a complication of advanced atherosclerosis and is a critical intraoperative issue that can reduce the ability to achieve safe and adequate access for stent graft introduction. Different vascular access sites are used to deliver stent grafts when a standard transfemoral or iliac access is not feasible. We report a challenging case of a direct transabdominal aortic thoracic endovascular aortic repair for a thoracic aortic aneurysm complicated with severe aortic and arterial calcification, in which the noncalcified area of the infrarenal abdominal aorta was extremely limited. This may be a reasonable access site, especially for patients with severe aortic and arterial calcification.
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http://dx.doi.org/10.1016/j.avsg.2020.11.001DOI Listing
May 2021

An open-label continuation trial of sirolimus for tocilizumab-refractory idiopathic multicentric Castleman disease: Study protocol for an investigator-initiated, multicenter, open-label trial (SPIRIT compliant).

Medicine (Baltimore) 2020 Dec;99(50):e23291

Division of Advanced Preventive Medical Sciences, Department of Immunology and Rheumatology.

Background: Interleukin 6 (IL-6) inhibitors are the first-line treatment for idiopathic multicentric Castleman disease (iMCD); however, there is no established treatment for cases that are resistant to IL-6 inhibitors. Although sirolimus, a mammalian target of rapamycin inhibitor, has been suggested to be effective in patients with iMCD, the long-term safety and efficacy of sirolimus on individuals with IL-6 inhibitor-resistant iMCD have not been evaluated.

Methods/design: In this investigator-initiated, multicenter, open-label trial, the long-term safety of sirolimus will be evaluated in patients participating in a placebo-controlled, randomized, double-blind, parallel-group trial on tocilizumab (TCZ)-resistant iMCD. The study will be conducted in 7 centers in Japan. This trial will be promptly started after the evaluation and examination for 16 weeks in the preceding study. The trial will be completed by the time the drug is approved for iMCD treatment in Japan. The primary endpoint is the incidence of adverse events. The secondary endpoints include the following: the levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; physician global assessment (100-mm visual analog scale); patient global assessment (100-mm visual analog scale); and lymph node changes in subjects with lymphadenopathy.

Discussion: This clinical trial will provide evidence regarding the long-term safety of sirolimus as a potential novel therapeutic agent for patients with tocilizumab-resistant iMCD.

Trial Registration Number: jRCT2051200050.
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http://dx.doi.org/10.1097/MD.0000000000023291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738043PMC
December 2020