Publications by authors named "Hiromi Suzuki"

138 Publications

Evaluating the long-term effect of space radiation on the reproductive normality of mammalian sperm preserved on the International Space Station.

Sci Adv 2021 Jun 11;7(24). Epub 2021 Jun 11.

Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400-8510, Japan.

Space radiation may cause DNA damage to cells and concern for the inheritance of mutations in offspring after deep space exploration. However, there is no way to study the long-term effects of space radiation using biological materials. Here, we developed a method to evaluate the biological effect of space radiation and examined the reproductive potential of mouse freeze-dried spermatozoa stored on the International Space Station (ISS) for the longest period in biological research. The space radiation did not affect sperm DNA or fertility after preservation on ISS, and many genetically normal offspring were obtained without reducing the success rate compared to the ground-preserved control. The results of ground x-ray experiments showed that sperm can be stored for more than 200 years in space. These results suggest that the effect of deep space radiation on mammalian reproduction can be evaluated using spermatozoa, even without being monitored by astronauts in Gateway.
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http://dx.doi.org/10.1126/sciadv.abg5554DOI Listing
June 2021

Secretion of signal peptides via extracellular vesicles.

Biochem Biophys Res Commun 2021 Jun 5;560:21-26. Epub 2021 May 5.

Department of Brain Function, Division of Stress Adaptation and Protection, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan; Department of Molecular Pharmacokinetics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 464-8601, Japan.

Signal peptides (SPs) consist of short peptide sequences present at the N-terminal of newly synthesizing proteins and act as a zip code for the translocation of the proteins to the endoplasmic reticulum (ER). It was thought that the SPs are intracellularly degraded after translocation to the ER; however, recent studies showed cleaved SPs have diverse roles for controlling cell functions in auto- and/or intercellular manners. In addition, it still remains obscure how SP fragments translocate away from the site where they are produced. Extracellular vesicles (EV) are important for intercellular communication and can transport functional molecules to specific cells. In this study, we show that SPs are involved in EV from T-REx AspALP cells that were transfected with a human APP SP-inducible expression vector. There was no difference in the average particle size or particle concentration of EV collected from T-REx AspALP cells and T-REx Mock cells. When the SP content in the EV was examined by mass spectrometry, the C-terminal fragment of APP SP was identified in the exosomes (SEV) of T-REx AspALP cells. In our preparation of SEV fractions, no ER-specific proteins were detected; therefore, SPs may be included in SEV but not in the debris of degraded ER. This is the first indication that SPs are secreted from cells via EV.
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http://dx.doi.org/10.1016/j.bbrc.2021.04.073DOI Listing
June 2021

Quality of Life and Mental Health Status of Japanese Older People Living in Chiang Mai, Thailand.

Geriatrics (Basel) 2021 Mar 30;6(2). Epub 2021 Mar 30.

Department of Public Health, Kawasaki Medical School, Kurashiki 701-0192, Japan.

This study aimed to establish the quality of life and mental health status among older Japanese people living in Chiang Mai, Thailand. We conducted a questionnaire survey among Japanese retired people aged 50 years or over who had been living in Thailand. The questionnaire covered socio-demographic variables including health status and ability to communicate in Thai. We measured mental health status using the Japanese version of the General Health Questionnaire-28 (GHQ-28) and quality of life using the Japanese version of EuroQOL-5D-3L. We explored the factors associated with poor mental health and quality of life using logistic regression analysis. In total, 96 (89.7%)participants provided complete responses. Overall, quality of life was generally good, although those with one or more chronic diseases reported significantly lower quality of life. Having one or more chronic diseases and being aged 70-79 were significantly associated with poorer mental health. In total, 21 (21.8%) respondents had a possible neurosis, which was defined as a total GHQ-28 score of more than 6. The logistic regression analysis showed a significant association between possible neurosis and the presence of chronic diseases (adjusted odds ratio: 11.7 1). Quality of life among older Japanese people living in Chiang Mai was generally good, but there was a high level of possible neurosis, especially among those with one or more chronic diseases.
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http://dx.doi.org/10.3390/geriatrics6020035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103260PMC
March 2021

Combination of the NanoSuit method and gold/platinum particle-based lateral flow assay for quantitative and highly sensitive diagnosis using a desktop scanning electron microscope.

J Pharm Biomed Anal 2021 Mar 26;196:113924. Epub 2021 Jan 26.

Institute for NanoSuit Research, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan. Electronic address:

Owing to its simplicity and low cost, the lateral flow assay (LFA) is one of the most commonly used point-of-care diagnostic techniques, despite its low sensitivity and poor quantification. Here, we report a newly developed LFA-NanoSuit method (LNSM) combined with a desktop scanning electron microscope (SEM) for the direct observation of immunocomplexes labeled with a colloidal metal instead of signal enhancement strategies, such as using color, electrochemical signals, silver enhancement, magnetic properties, luminescent, and surface-enhanced Raman spectroscopy (SERS). The proposed LNSM suppresses cellulose deformity, thereby allowing the acquisition of high-resolution images of gold/platinum-labeled immunocomplexed pathogens such as influenza A, without conductive treatment as in conventional SEM. Electron microscopy-based diagnosis of influenza A exhibited 94 % clinical sensitivity (29/31; 95 % confidence interval [CI]: 79.3-98.2 %) and 100 % clinical specificity (95 % CI: 98.1-100 %), which was more sensitive (71.4 %) than visual detection (14.3 %), especially in the lower influenza A-RNA copy number group. The detection ability of our method was nearly comparable to that of real-time reverse transcription-PCR. This is the first report on the diagnosis of clinical diseases using LFA equipped with a desktop SEM. This simple and highly sensitive quantitative analysis method involving LFA can be used to diagnose various diseases in humans and livestock, including highly infectious diseases such as COVID-19.
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http://dx.doi.org/10.1016/j.jpba.2021.113924DOI Listing
March 2021

A 52-week randomized controlled trial of ipragliflozin or sitagliptin in type 2 diabetes combined with metformin: The N-ISM study.

Diabetes Obes Metab 2021 Mar 8;23(3):811-821. Epub 2021 Jan 8.

Department of Internal Medicine, Niigata University Faculty of Medicine, Niigata, Japan.

Aim: To compare the long-term efficacy of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors as second-line drugs after metformin for patients not at high risk of atherosclerotic cardiovascular disease (ASCVD).

Materials And Methods: In a 52-week randomized open-label trial, we compared ipragliflozin and sitagliptin in Japanese patients diagnosed with type 2 diabetes, without prior ASCVD and treated with metformin. The primary endpoint was a glycated haemoglobin (HbA1c) reduction of ≥0.5% (5.5 mmol/mol) without weight gain at 52 weeks.

Results: Of a total of 111 patients (mean age 59.2 years, mean body mass index [BMI] 26.6 kg/m , 61.3% men), 54 patients received ipragliflozin and 57 received sitagliptin. After 52 weeks, achievement of the primary endpoint was not significantly different (37.0% and 40.3%; P = 0.72). HbA1c reduction rate at 24 weeks was greater for sitagliptin (56.1%) than for ipragliflozin (31.5%; P = 0.01). From 24 to 52 weeks, the HbA1c reduction with sitagliptin was attenuated, with no significant difference in HbA1c reduction after 52 weeks between sitagliptin (54.4%) and ipragliflozin (38.9%; P = 0.10). Improvements in BMI, C-peptide and high-density lipoprotein cholesterol were greater with ipragliflozin than with sitagliptin. Adverse events occurred in 17 patients with ipragliflozin and in 10 patients with sitagliptin (P = 0.11).

Conclusion: The HbA1c-lowering effect at 24 weeks was greater with sitagliptin than with ipragliflozin, but with no difference in efficacy related to HbA1c and body weight at 52 weeks. However, some ASCVD risk factors improved with ipragliflozin.
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http://dx.doi.org/10.1111/dom.14288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898334PMC
March 2021

Relationship between Plantar Pressure and Sensory Disturbance in Patients with Hansen's Disease-Preliminary Research and Review of the Literature.

Sensors (Basel) 2020 Dec 6;20(23). Epub 2020 Dec 6.

Department of Dermatology, National Sanatorium Tamazenshoen, Higashi-Murayama, Tokyo 189-0002, Japan.

Orthoses and insoles are among the primary treatments and prevention methods of refractory plantar ulcers in patients with Hansen's disease. While dynamic plantar pressure and tactile sensory disturbance are the critical pathological factors, few studies have investigated whether a relationship exists between these two factors. In this study, dynamic pressure measured using F-scan system and tactile sensory threshold evaluated with monofilament testing were determined for 12 areas of 20 feet in patients with chronic Hansen's disease. The correlation between these two factors was calculated for each foot, for each clinical category of the foot (0-IV) and across all feet. A significant correlation was found between dynamic pressure and tactile sensation in Category II feet ( = 8, = 0.016, r = 0.246, Spearman's rank test). In contrast, no significant correlation was detected for the entire foot or within the subgroups for the remainder of the clinical categories. However, the clinical manifestation of lesion areas showed high variability: (1) pressure concentrated, sensation lost; (2) margin of pressure concentration, sensation lost; (3) pressure concentrated, sensation severely disturbed but not lost; and (4) tip of the toe. These results may indicate that, even though there was a weak relationship between dynamic pressure and tactile sensation, it is important to assess both, in addition to the basics of orthotic treatment in patients with Hansen's disease presenting with refractory plantar ulceration.
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http://dx.doi.org/10.3390/s20236976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730212PMC
December 2020

The NRT1/PTR FAMILY protein NPF7.3/NRT1.5 is an indole-3-butyric acid transporter involved in root gravitropism.

Proc Natl Acad Sci U S A 2020 12 20;117(49):31500-31509. Epub 2020 Nov 20.

RIKEN Center for Sustainable Resource Science, Kanagawa 230-0045, Japan;

Active membrane transport of plant hormones and their related compounds is an essential process that determines the distribution of the compounds within plant tissues and, hence, regulates various physiological events. Here, we report that the NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER FAMILY 7.3 (NPF7.3) protein functions as a transporter of indole-3-butyric acid (IBA), a precursor of the major endogenous auxin indole-3-acetic acid (IAA). When expressed in yeast, NPF7.3 mediated cellular IBA uptake. Loss-of-function mutants showed defective root gravitropism with reduced IBA levels and auxin responses. Nevertheless, the phenotype was restored by exogenous application of IAA but not by IBA treatment. was expressed in pericycle cells and the root tip region including root cap cells of primary roots where the IBA-to-IAA conversion occurs. Our findings indicate that NPF7.3-mediated IBA uptake into specific cells is required for the generation of appropriate auxin gradients within root tissues.
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http://dx.doi.org/10.1073/pnas.2013305117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733822PMC
December 2020

Changes and Variations in Death Due to Senility in Japan.

Healthcare (Basel) 2020 Oct 30;8(4). Epub 2020 Oct 30.

Faculty of Social Studies, Shikokugakuin University, Zentsuji City 765-0013, Japan.

Objective: The proportion of elderly individuals (≥65 years old) in Japan has markedly increased. However, the definition of senility in Japan is controversial. The aim of the present study was to investigate changes and variations in the number of deaths due to senility in Japan.

Methods: Information on the number of deaths due to senility between 1995 and 2018 as well as other major causes of death was obtained from the Statistics Bureau of Japan official website. Changes and variations in the number of deaths due to senility were compared with other major causes of death in Japan. The relationships between the number of deaths due to senility and socioeconomic factors were also examined in an ecological study.

Results: The number of deaths due to senility was 35.7 ± 23.2/one hundred thousand people/year during the observation period and has continued to increase. A change point was identified in 2004 by a Jointpoint regression analysis. Variations in the number of deaths due to senility, which were evaluated by a coefficient of variation, were significantly greater than those due to other major causes of death, i.e., malignant neoplasm, heart diseases, cerebrovascular diseases, and pneumonia. The number of elderly individuals (≥65 years old) (%) and medical bills per elderly subject (≥75 years old) correlated with the number of deaths due to senility.

Conclusion: The number of deaths due to senility has been increasing, particularly since 2004. However, variations in the number of deaths due to senility were observed among all prefectures in Japan.
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http://dx.doi.org/10.3390/healthcare8040443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712013PMC
October 2020

Peripheral benzodiazepine receptor/18 kDa translocator protein positron emission tomography imaging in a rat model of acute brain injury.

Ann Nucl Med 2021 Jan 28;35(1):8-16. Epub 2020 Sep 28.

Department of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

Objective: The activation of microglia in various brain pathologies is accompanied by an increase in the expression of peripheral benzodiazepine receptor/18 kDa translocator protein (PBR/TSPO). However, whether activated microglia have a neuroprotective or neurotoxic effect on neurons in the brain is yet to be determined. In this study, we investigated the ability of the novel PBR/TSPO ligand FEPPA to detect activated microglia in an animal model of primary neurotoxic microglia activation.

Methods: [F] FEPPA positron emission tomography (PET) imaging was performed before and after intraperitoneal administration of lipopolysaccharide (LPS) (LPS group) or saline (control group) in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease. Images were compared between these groups. After imaging, the brains were collected, and the activated microglia at the disease sites were analyzed by the expression of inflammatory cytokines and immunohistochemistry staining. These results were then comparatively examined with those obtained by PET imaging.

Results: In the unilateral 6-OHDA lesion rat model, the PBR/TSPO PET signal was significantly increased in the LPS group compared with the saline group. As the increased signal was observed 4 h after the injection, we considered it an acute response to brain injury. In the post-imaging pathological examination, activated microglia were found to be abundant at the site where strong signals were detected, and the expression of the inflammatory cytokines TNF-α and IL-1β was increased. Intraperitoneal LPS administration further increased the expression of inflammatory cytokines, and the PBR/TSPO PET signal increased concurrently. The increase in inflammatory cytokine expression correlated with enhanced signal intensity.

Conclusions: PET signal enhancement by PBR/TSPO at the site of brain injury correlated with the activation of microglia and production of inflammatory cytokines. Furthermore, because FEPPA enables the detection of neurotoxic microglia on PET images, we successfully constructed a novel PET detection system that can monitor neurodegenerative diseases.
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http://dx.doi.org/10.1007/s12149-020-01530-2DOI Listing
January 2021

Seasonal Changes in Continuous Sedentary Behavior in Community-Dwelling Japanese Adults: A Pilot Study.

Medicines (Basel) 2020 Aug 25;7(9). Epub 2020 Aug 25.

The Faculty of Social Studies, Shikokugakuin University, Zentsuji, Kagawa 765-8505, Japan.

Sedentary behavior (SB) is associated with adverse health outcomes. The aim of this study was to clarify seasonal changes in SB including continuous SB (CSB) in community-dwelling Japanese adults. In this secondary analysis, a total of 65 community-dwelling Japanese adults (7 men and 58 women, 69 (50-78) years) were enrolled. SB (%), including CSB (≥30 min) as well as physical activity, were evaluated using a tri-accelerometer. The differences in these parameters between baseline (summer) and follow-up (winter) were examined. %CSB and %SB at baseline were 20.5 (4.0-60.9) and 54.0 ± 11.5, respectively. CSB was significantly increased (6.6%), and SB was also increased (5.1%) at follow-up compared with baseline. In addition, there were positive relationships between changes in CSB and SB, and body weight and body mass index. These results suggest that there were significant seasonal changes in CSB and SB in community-dwelling Japanese adults.
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http://dx.doi.org/10.3390/medicines7090048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555823PMC
August 2020

Relationship among psychological distress, food dependence, and the time discount rate: a pilot mediation analysis.

Psychol Health Med 2020 Aug 7:1-8. Epub 2020 Aug 7.

Department of Hygiene, Faculty of Medicine, Kagawa University, Miki, Kagawa Japan.

Psychological distress (PD) was shown to be associated with food dependence and higher time discount rate; however, few studies have clarified the relationship among these three variables. To clarify whether time discount rate mediated a relationship between food dependence and PD. In this study, the subjects were 91. We evaluated food dependence scores and time discount rate using self-administered questionnaires as well as PD using K6 questionnaires. Simple correlation and mediation analyses were performed by Structural Equation Modelling (SEM) to clarify relationships among PD, food dependence, and time discount rate. By SEM, a significant relationship was found between food dependence and K6 scores (standardized coefficient (β)=0.341, p=0.001). Moreover, a significant correlation was found between food dependence scores and time discount rate (β=0.345, p=0.001) as well as between time discount rate and K6 scores (β=0.419, p<0.001). By having time discount rate as a parameter, the correlation coefficients between food dependence and K6 scores varied between 0.341 (p=0.001) and 0.197 (p=0.045). After bootstrapping, 0 was not included in the 99% confidence interval [0.013, 0.139]. Time discount rate may mediate the relationship between food dependence and PD. To improve PD, food dependence as well as time discount rate should be reduced.
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http://dx.doi.org/10.1080/13548506.2020.1776888DOI Listing
August 2020

Endoscopic ultrasound-guided hepaticogastrostomy or hepaticojejunostomy without dilation using a stent with a thinner delivery system.

Endosc Int Open 2020 Aug 21;8(8):E1034-E1038. Epub 2020 Jul 21.

Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.

Use of endoscopic ultrasound-guided biliary drainage (EUS-BD) has recently increased. In EUS-BD, after puncturing the bile duct, dilation is performed and the stent is deployed. Due to adverse events (AEs) such as unexpected displacement of the guidewire, simplified procedures are required. Currently, stents with small-diameter delivery systems are being rapidly developed, expanding the possibilities for of EUS-BD without dilation. In this retrospective study, we aimed to evaluate the success rates and AEs in patients who underwent EUS-guided hepaticogastrostomy (EUS-HGS) or EUS-guided hepaticojejunostomy (EUS-HJS) without dilation. Six consecutive patients with malignant biliary obstruction and failed transpapillary BD underwent EUS-HGS or EUS-HJS without dilation, deploying a 6-mm fully-covered self-expandable metallic stent with a 6-Fr delivery system. The technical and clinical success rates were 100 %. There was one case each of stent migration and stent occlusion, and no other AEs were noted. EUS-HGS or EUS-HJS without dilation using a stent with a 6-Fr delivery system had high technical and clinical success rates; however, additional cases are required to validate the study findings.
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http://dx.doi.org/10.1055/a-1169-3749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373653PMC
August 2020

Scalp lymphangiosarcoma: A distinct skin manifestation of edematous erythema on face and scalp without subcutaneous hemorrhage or preceding condition of lymphedema.

J Dermatol 2020 Sep 16;47(9):e331-e333. Epub 2020 Jul 16.

Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

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http://dx.doi.org/10.1111/1346-8138.15482DOI Listing
September 2020

IVIG in childhood primary angiitis of the central nervous system: A case report.

Brain Dev 2020 Oct 1;42(9):675-679. Epub 2020 Jul 1.

Department of Neuroradiology, Tokyo Metropolitan Neurological Hospital, Japan.

Aggressive immunosuppressive therapies have been proposed to treat primary angiitis of the central nervous system (PACNS). Here, we report the first successfully stabilized case of childhood, small-vessel PACNS with intravenous immunoglobulin (IVIG) therapy. A 12-year-old boy was admitted to our hospital complaining of recurrent headaches and upper-left homonymous quadrantanopia, since the age of 11 years. Brain computed tomography scans revealed fine calcification in the right temporal and occipital lobes. Brain magnetic resonance imaging scans revealed white matter lesions, with gadolinium enhancement, which waxed, waned, and migrated for 1 year, without immunomodulatory therapies. A cerebrospinal fluid study showed pleocytosis (12 cells per µl). No clinical or serological findings suggested systemic inflammation or vasculitis. Brain angiography was unremarkable. Brain biopsy revealed thickened and hyalinized small vessels, with intramural infiltration of inflammatory cells, which confirmed the diagnosis of small-vessel PACNS. Because the patient developed surgical site infection following biopsy, the administration of monthly IVIG (2 g/kg) was prescribed, instead of immunosuppressive agents. After IVIG therapy, the patient remained stable, except for a single episode of mild radiological exacerbation at 16 months, which occurred when the IVIG interval was expanded. Oral prednisone was added and gradually tapered. At 50 months, his intellectual abilities and motor functions were normal, although he showed residual upper-left homonymous quadrantanopia and post-exercise headache. A temporary headache, associated with the immunoglobulin infusion, was resolved by slowing the infusion rate. PACNS should be treated aggressively to improve prognosis. However, when immunosuppressants are contraindicated, IVIG may be an alternative therapeutic option.
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http://dx.doi.org/10.1016/j.braindev.2020.06.007DOI Listing
October 2020

Decrease in blood donation rates in Japan: a time series analysis.

Rev Bras Epidemiol 2020 1;23:e200047. Epub 2020 Jun 1.

Department of Hygiene, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan.

Objective: To clarify that one of the causes for the decrease in blood donation (BD) rates was the introduction of the 400 ml BD program in 1986.

Method: BP rates were monitored over 48 years (1965-2012) and were divided into pre- and post-intervention periods prior to analysis. An interrupted time series analysis was performed using annual data on BD rates, and the impact of the 400 ml BD program was investigated.

Results: In a raw series, autoregressive integrated moving average analysis revealed a significant change in slope between the pre- and post-intervention periods in which the intervention factor was the 400 ml BD program. The parameters were as follows: intercept (initial value) = 0.315, confidence interval (CI) = (0.029, 0.601); slope (pre-intervention) = 0.316, CI = (0.293, 0.340); slope difference = -0.435, CI = (-0.462, -0.408); slope (post-intervention) = -0.119, CI = (-0.135, -0.103); all, p = 0.000; goodness-of-fit, R2 = 0.963. After adjusting for stationarity and autocorrelation, the parameters were as follows: intercept (initial value) = -0.699, CI = (-0.838, -0.560); slope (pre-intervention) = 0.136, CI = (0.085, 0.187); slope difference = -0.165, CI = (-0.247, -0.083); slope (post-intervention) = -0.029, CI = (-0.070, 0.012); all, p = 0.000 (except for slope (post-intervention), p = 0.170); goodness-of-fit, R2 = 0.930.

Conclusion: One of the causes for decrease in BD rates may be due to the introduction of the 400 ml BD program in Japan.
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http://dx.doi.org/10.1590/1980-549720200047DOI Listing
June 2020

Add-On Omalizumab for Inadequately Controlled Severe Pollinosis Despite Standard-of-Care: A Randomized Study.

J Allergy Clin Immunol Pract 2020 10 11;8(9):3130-3140.e2. Epub 2020 May 11.

Novartis Pharmaceuticals Corporation, East Hanover, NJ.

Background: Cedar pollinosis (CP), a common form of seasonal allergic rhinitis (AR), is a substantial medical problem in Japan due to its high prevalence and severe symptoms. Omalizumab (anti-IgE therapy) has previously proven to be effective in CP/AR, but no studies for inadequately controlled severe CP/AR despite standard-of-care (SoC) have been conducted.

Objective: To determine the efficacy of omalizumab added to SoC in patients with inadequately controlled severe CP in a randomized, double-blinded, placebo-controlled, phase III study.

Methods: Adult/adolescent patients with severe CP whose symptoms were inadequately controlled despite nasal corticosteroids plus 1 or more oral medications in the previous 2 seasons were randomized to receive omalizumab (n = 162) or placebo (n = 175). All patients received concomitant antihistamines and nasal corticosteroids as SoC. The primary endpoint was the mean nasal symptom score during the severe symptom period. Secondary endpoints included mean ocular symptom score, quality of life (QoL), and safety.

Results: The SoC + omalizumab treatment had statistically significantly and clinically important lower nasal (least squares mean difference, -1.03, P < .001) and ocular (-0.87, P < .001) symptom scores compared with SoC + placebo, respectively. Differences in scores for individual components of nasal and ocular symptoms were also statistically and clinically significant. SoC + omalizumab also improved QoL scores as overall and in all domains. No unexpected safety signals were observed.

Conclusions: In patients with severe CP, omalizumab added to SoC demonstrated consistent efficacy in improving symptoms and QoL, and was well tolerated. These results indicate that omalizumab could be a promising therapeutic option for severe CP/AR.
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http://dx.doi.org/10.1016/j.jaip.2020.04.068DOI Listing
October 2020

Hour-specific nomogram for transcutaneous Bilirubin in newborns in Myanmar.

Pediatr Int 2020 Sep 14;62(9):1049-1053. Epub 2020 Sep 14.

Department of Pediatrics, Faculty of Medicine, Kagawa University.

Background: Neonatal hyperbilirubinemia is a significant health problem in Myanmar, and the rate of kernicterus is also higher than in developed countries. Non-invasive methods for early detection and treatment of hyperbilirubinemia are urgently needed. In this study, we used transcutaneous bilirubin (TcB) measurements to develop an hour-specific TcB nomogram for the effective management of hyperbilirubinemia in Myanmar newborns.

Methods: The bilirubin levels of neonates born in Central Women Hospital in Yangon, Myanmar were measured three times a day within 72 h after birth using a transcutaneous bilirubinometer. An hour-specific TcB nomogram was created based on the data.

Results: Participants were 512 infants (287 boys, 225 girls) born in Central Women's Hospital in Yangon. The mean (±SD) gestational age was 38.4 ± 1.2 weeks; birthweight was 3078 ± 412 g. A total of 3,039 plots were obtained, and the TcB nomogram was created with smoothed percentile curves (97.5th, 50th, and 2.5th percentiles) for 0-72 h after birth.

Conclusions: An hour-specific TcB nomogram was successfully created to manage hyperbilirubinemia in Myanmar newborns.
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http://dx.doi.org/10.1111/ped.14251DOI Listing
September 2020

Inhibition of cellular inflammatory mediator production and amelioration of learning deficit in flies by deep sea Aspergillus-derived cyclopenin.

J Antibiot (Tokyo) 2020 09 24;73(9):622-629. Epub 2020 Mar 24.

Department of Molecular Target Medicine, Aichi Medical University School of Medicine, 480-1195, Nagakute, Japan.

In the course of screening lipopolysaccharide (LPS)-induced nitric oxide (NO) production inhibitors, two related benzodiazepine derivatives, cyclopenol and cyclopenin, were isolated from the extract of a deep marine-derived fungal strain, Aspergillus sp. SCSIOW2. Cyclopenol and cyclopenin inhibited the LPS-induced formation of NO and secretion of IL-6 in RAW264.7 cells at nontoxic concentrations. In terms of the mechanism underlying these effects, cyclopenol and cyclopenin were found to inhibit the upstream signal of NF-κB activation. These compounds also inhibited the expression of IL-1β, IL-6, and inducible nitric oxide synthase (iNOS) in mouse microglia cells, macrophages in the brain. In relation to the cause of Alzheimer's disease, amyloid-β-peptide is known to induce inflammation in the brain. Therefore, the present study investigated the ameliorative effects of these inhibitors on an in vivo Alzheimer's model using flies. Learning deficits were induced by the overexpression of amyloid-β42 in flies, and cyclopenin but not cyclopenol was found to rescue learning impairment. Therefore, novel anti-inflammatory activities of cyclopenin were identified, which may be useful as a candidate of anti-inflammatory agents for neurodegenerative diseases.
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http://dx.doi.org/10.1038/s41429-020-0302-9DOI Listing
September 2020

Examination of the Causality Relationship between Psychological Distress and Social Participation in Elderly People: A Pilot Study.

Acta Med Okayama 2020 Feb;74(1):59-63

Department of Hygiene, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan.

Few studies have considered the causal relationship between psychological distress and social participation in elderly people. Here we investigated this relationship based on an initial survey and a follow-up survey. In 2016, a survey was distributed to 86 participants. A follow-up survey of 80 of those participants was performed in 2017. We adopted the following variables: psychological distress and social participation as represented by the Kessler psychological distress scale and social participation scores, respectively. By using cross-lagged and synchronous effects models, we found that the 2016 Kessler psychological distress scale had a significant influence on the 2017 social participation scores (standardization factor=-0.221, p=0.020) and the 2017 Kessler psychological distress scale significantly influenced the 2017 social participation scores (standardization factor=-0.345, p=0.039). The results suggest that psychological distress may affect social participation one year later.
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http://dx.doi.org/10.18926/AMO/57954DOI Listing
February 2020

Relationship between Air Temperature Parameters and the Number of Deaths Stratified by Cause in Gifu Prefecture, Japan.

Healthcare (Basel) 2020 Feb 7;8(1). Epub 2020 Feb 7.

Faculty of Social Studies, Shikokugakuin University, Zentsuji city, Kagawa 765-0013, Japan.

Objective: It is well known that air temperature is closely related to health outcomes. We investigated the relationship between air temperature parameters and the number of deaths stratified by cause in Gifu prefecture, Japan.

Methods: The number of deaths stratified by cause in Gifu prefecture Japan between January 2007 and December 2016 was obtained from the official homepage of Gifu prefecture, Japan. Air temperature parameters (℃), i.e., the mean air temperature, mean of the highest air temperature, mean of the lowest air temperature, the highest air temperature, and the lowest air temperature during the same period in Gifu city were also obtained from the Japan Meteorological Agency official home page. The relationship between air temperature parameters and the number of deaths was evaluated in an ecological study.

Results: The number of deaths due to heart disease, cerebrovascular disease, pneumonia, accidents, or renal failure in January (coldest winter season in Japan) was the highest among the months. Simple correlation analysis also demonstrated a significant and negative relationship between air temperature parameters and the number of deaths due to heart disease, cerebrovascular disease, senility, pneumonia, accidents, and renal failure.

Conclusion: Lower air temperature may be associated with a higher number of deaths due to diseases in Gifu prefecture, Japan.
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http://dx.doi.org/10.3390/healthcare8010035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151071PMC
February 2020

Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects.

Sci Rep 2020 01 22;10(1):983. Epub 2020 Jan 22.

Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.

Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor-deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism-independent effects of anagliptin on NASH and HCC development.
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http://dx.doi.org/10.1038/s41598-020-57935-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976646PMC
January 2020

Novel Oxindole-Curcumin Hybrid Compound for Antioxidative Stress and Neuroprotection.

ACS Chem Neurosci 2020 01 18;11(1):76-85. Epub 2019 Dec 18.

NAGARAGAWA Research Center, API Co., Ltd. , Gifu 502-0071 , Japan.

Oxidative stress plays an important role in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The oxindole compound GIF-2165X-G1 is a hybrid molecule composed of the oxindole skeleton of the neuroprotective compound GIF-0726-r and the polyphenolic skeleton of the antioxidant curcumin. We previously reported that novel oxindole derivatives such as GIF-0726-r and GIF-2165X-G1 prevent endogenous oxidative stress-induced cell death in mouse hippocampal HT22 cells. In this study, we present a detailed investigation of the effect of GIF-2165X-G1 on endogenous oxidative stress in HT22 cells in comparison with GIF-0726-r and curcumin. GIF-2165X-G1 exhibited more potent neuroprotective activity than GIF-0726-r or curcumin and had less cytotoxicity than that observed with curcumin. Both GIF-0726-r and GIF-2165X-G1 were found to have ferrous ion chelating activity similar to that exhibited by curcumin. GIF-2165 X-G1 and curcumin induced comparable antioxidant response element transcriptional activity. Although the induction of heme oxygenase-1, an antioxidant response element-regulated gene product, was much stronger in curcumin-treated cells than in GIF-2165X-G1-treated cells, it turned out that the induction of heme oxygenase-1 is dispensable for neuroprotection. These results demonstrate that the introduction of the polyphenol skeleton of curcumin to the oxindole GIF-0726-r improves neuroprotective features. Furthermore, intrastriatal injection of GIF-2165X-G1 alleviated apomorphine-induced rotation and prevented dopaminergic neuronal loss in a 6-hydroxydopamine mouse model of Parkinson's diseases. Collectively, our novel findings indicate that the novel oxindole compound GIF-2165X-G1 serves to delay the progression of Parkinson's disease by suppressing oxidative stress.
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http://dx.doi.org/10.1021/acschemneuro.9b00619DOI Listing
January 2020

Rare manifestation of hypereosinophilic syndrome: Diffuse-type hair loss with massive perifollicular eosinophils.

J Dermatol 2020 Jan 11;47(1):61-63. Epub 2019 Nov 11.

Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

A 46-year-old woman consulted our hospital with diffuse alopecia and blood eosinophilia. Histological examination of the scalp revealed dense eosinophilic infiltration around the hair follicles and in the surrounding subcutis. Oral corticosteroid was effective to reduce hair loss and blood eosinophilia, but these conditions immediately relapsed after ending treatment. In addition to alopecia, she had diarrhea and colitis showing histological findings of dense eosinophilic infiltrations in the submucosa. We diagnosed hypereosinophilic syndrome based on hypereosinophilia of blood and tissue with clinical symptoms of alopecia and diarrhea. We suppose diffuse alopecia showing massive eosinophilic infiltration around the hair follicle is a rare symptom of hypereosinophilic syndrome.
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http://dx.doi.org/10.1111/1346-8138.15139DOI Listing
January 2020

"Active Guide" Brochure Reduces Sedentary Behavior of Elderly People: A Randomized Controlled Trial.

Acta Med Okayama 2019 Oct;73(5):427-432

Department of Hygiene, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan.

The aim of this study was to examine in a randomized controlled trial how much the sedentary behavior (sitting time) of community-dwelling elderly Japanese subjects decreased as a result of using the "Active Guide" brochure published by the Ministry of Health, Labour and Welfare (2013) and additional documents related to the benefits of reducing sedentary behavior. A total of 86 elderly people who participated in health-club activities for one year were randomly allocated to two groups. Subjects in the intervention group received explanations of the importance of physical activity using the "Active Guide" brochure (n=42) and additional documents, while subjects in the control group did not (n=44). Physical activity was measured using a triaxial accelerometer for two weeks at baseline and again after one year. After one year of intervention, the difference in the sedentary behavior rate from baseline was -2.2% for the intervention group (n=40) and +2.5% for controls (n=40) (Welch's t-test, p=0.007). Use of the "Active Guide" brochure and additional documents may reduce the sedentary behavior of community dwelling elderly people in Japan.
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http://dx.doi.org/10.18926/AMO/57373DOI Listing
October 2019

Relationship between Sedentary Behavior and All-cause Mortality in Japanese Chronic Hemodialysis Patients: A Prospective Cohort Study.

Acta Med Okayama 2019 Oct;73(5):419-425

Innoshima General Hospital, Onomichi, Hiroshima 722-2323, Japan.

We investigated the relationship between sedentary behavior and all-cause mortality in patients undergoing hemodialysis. A total of 71 patients (39 men, 32 women, aged 72.1±11.7 years) were enrolled in this longitudinal study. Their sedentary behavior was measured using a tri-accelerometer that provides relative values per daily wearing time. We classified the sedentary behavior time into 2 groups (under the median: short-sedentary behavior (SB) group; over the median: long-SB group) and compared the groups' clinical parameters. We compared the groups' survival rates by using Kaplan-Meier curves and the log-rank test, and we performed multivariate analyses by a Cox-proportional hazard model to evaluate the relationship between the sedentary behavior and the survival rate. Twenty patients (28.2%) died during the observation period. The survival rate of the short-SB group was significantly higher than that of the long-SB group. Sedentary behavior was thus an important factor for all-cause mortality even after adjusting for confounding factors by a Cox-proportional hazard model. Sedentary behavior is closely linked to all-cause mortality, especially total days and non-hemodialysis days, and reducing sedentary behavior may be beneficial to reduce the all-cause mortality of patients on chronic hemodialysis.
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http://dx.doi.org/10.18926/AMO/57372DOI Listing
October 2019

Transplantation of Mesenchymal Stem Cells Improves Amyloid-β Pathology by Modifying Microglial Function and Suppressing Oxidative Stress.

J Alzheimers Dis 2019 ;72(3):867-884

Department of Neurology, School of Medicine, Sapporo Medical University, Chuo-ku, Sapporo, Hokkaido, Japan.

Mesenchymal stem cells (MSC) are increasingly being studied as a source of cell therapy for neurodegenerative diseases, and several groups have reported their beneficial effects on Alzheimer's disease (AD). In this study using AD model mice (APdE9), we found that transplantation of MSC via the tail vein improved spatial memory in the Morris water maze test. Using electron paramagnetic resonance imaging to evaluate the in vivo redox state of the brain, we found that MSC transplantation suppressed oxidative stress in AD model mice. To elucidate how MSC treatment ameliorates oxidative stress, we focused on amyloid-β (Aβ) pathology and microglial function. MSC transplantation reduced Aβ deposition in the cortex and hippocampus. Transplantation of MSC also decreased Iba1-positive area in the cortex and reduced activated ameboid shaped microglia. On the other hand, MSC transplantation accelerated accumulation of microglia around Aβ deposits and prompted microglial Aβ uptake and clearance as shown by higher frequency of Aβ-containing microglia. MSC transplantation also increased CD14-positive microglia in vivo, which play a critical role in Aβ uptake. To confirm the effects of MSC on microglia, we co-cultured the mouse microglial cell line MG6 with MSC. Co-culture with MSC enhanced Aβ uptake by MG6 cells accompanied by upregulation of CD14 expression. Additionally, co-culture of MG6 cells with MSC induced microglial phenotype switching from M1 to M2 and suppressed production of proinflammatory cytokines. These data indicate that MSC treatment has the potential to ameliorate oxidative stress through modification of microglial functions, thereby improving Aβ pathology in AD model mice.
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http://dx.doi.org/10.3233/JAD-190817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918908PMC
November 2020

Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease.

Free Radic Biol Med 2019 12 16;145:20-32. Epub 2019 Sep 16.

Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, 060-8556, Japan. Electronic address:

Alzheimer's disease (AD) is a common neurodegenerative disease that progressively impairs memory and cognition. Deposition of amyloid-β (Aβ) peptides is the most important pathophysiological hallmark of AD. Oxidative stress induced by generation of reactive oxygen species (ROS) is a prominent phenomenon in AD and known to occur early in the course of AD. Several reports suggest a relationship between change in redox status and AD pathology including progressive Aβ deposition, glial cell activation, and inflammation. Galantamine is an acetylcholinesterase inhibitor and has been reported to have an oxidative stress inhibitory function. In the present study, galantamine was administered orally to AD model mice from before the appearance of Aβ plaques (preplaque phase), and in vivo change in redox status of the brain was measured using electron paramagnetic resonance (EPR) imaging. Administration of galantamine from the preplaque phase ameliorated memory decline in Morris water maze test and novel object recognition test. Monitoring of the redox status of the brain using EPR imaging showed that galantamine treatment improved the unbalanced redox state. Additionally, galantamine administration enhanced microglial function to promote Aβ clearance, reducing the Aβ-positive area in the cortex and amount of insoluble Aβ in the brain. In contrast, galantamine treatment from the preplaque phase suppressed the production of proinflammatory cytokines through neurotoxic microglial activity. Therefore, galantamine administration from the preplaque phase may have the potential of clinical application for the prevention of AD. In addition, our results demonstrate the usefulness of EPR imaging for speedy and quantitative evaluation of the efficacy of disease-modifying drugs for AD.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.09.014DOI Listing
December 2019

[Wilson's disease presenting as Asperger syndrome].

Rinsho Shinkeigaku 2019 Sep 30;59(9):589-591. Epub 2019 Aug 30.

Department of General Internal Medicine, Saiseikai Utsunomiya Hospital.

A 24-year-old man, who had been treated for 3 years as Asperger syndrome in adolescence due to behavioral disturbances, lack of social awareness and inability to socialize, was referred to our hospital shortly after tremors developed. On the basis of clinical features, laboratory findings and the brain MRI, a diagnosis of Wilson's disease (WD) was made. WD was further confirmed by genetic testing (the mutation of ATP7B gene). He was started with trientine hydrochloride 500 mg/day, and after 1 year of follow-up, his psychiatric symptoms have improved. Since psychiatric symptoms may precede the neurological symptoms, the possibility of WD should be always considered in the differential diagnosis of psychiatric disorders in young adults.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001245DOI Listing
September 2019

A Pilot Study of the Relationship between Diet and Mental Health in Community Dwelling Japanese Women.

Medicina (Kaunas) 2019 Aug 21;55(9). Epub 2019 Aug 21.

Department of Hygiene, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan.

: Diet is closely linked to mental health. The aim of this study was to explore the link between diet and mental health in community dwelling Japanese women. : A total of 89 community dwelling Japanese women, aged 66.8 ± 7.6 years, were enrolled in this cross-sectional study. Diet surveys were evaluated using the brief-type self-administered diet history questionnaire (BDHQ) and mental health was evaluated using the general health questionnaire-12 (GHQ) and clinical parameters. : The mean energy intake was 1806 ± 570 kcal and the GHQ score was 1.0 ± 1.4. Among nutrients, the n-6/n-3 fatty acid ratio was significantly correlated with the GHQ score (r = 0.269, = 0.011), and some micronutrients and vitamins were weakly or negatively correlated with the GHQ score. Among the food groups, fish and shellfish were negatively correlated with the GHQ scores. Multiple regression analysis demonstrated that the n-6/n-3 fatty acid ratio was the determinant factor for the GHQ score, even after adjusting for confounding factors. : These results suggest that a proper diet to reduce the n-6/n-3 fatty acid ratio may improve mental health in community dwelling Japanese women.
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http://dx.doi.org/10.3390/medicina55090513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780405PMC
August 2019