Publications by authors named "Akio Koyama"

100 Publications

Clinical outcomes and predictors of restenosis in patients with femoropopliteal artery disease treated using polymer-coated paclitaxel-eluting stents or drug-coated balloons.

Heart Vessels 2021 Sep 22. Epub 2021 Sep 22.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Both polymer-coated paclitaxel-eluting stents (PC-PESs) and drug-coated balloons (DCBs) are used in conjunction with endovascular therapy (EVT) for the treatment of peripheral artery disease (PAD). We aimed to identify the risk factors for the loss of patency following the use of PC-PES and DCB in a real clinical setting. We assessed the multi-center registry data of 151 lesions from 151 patients who underwent EVT for symptomatic PAD in the superficial femoral and proximal popliteal arteries using PC-PES or DCB. One-year primary patency (PP) and clinically driven target lesion revascularization (CD-TLR) were evaluated using Kaplan-Meier analysis. The predictive risk factors for 1-year outcomes were analyzed using the random survival forest method. PC-PES and DCB were used in 65 (43.0%) and 86 (57.0%) cases, respectively. There were no significant differences in 1-year PP or freedom from CD-TLR between PC-PES and DCB. PP occurred in 85.4% and 80.2% of cases in the PC-PES and DCB groups, respectively (log-rank p = 0.65), while freedom from CD-TLR was noted in 92.7% and 94.1% of cases in the PC-PES and DCB groups, respectively (log-rank p = 0.73). In order of importance, a Clinical Frailty Scale score ≥ 6, female sex, lower proximal vessel diameter, lower body mass index, and younger and older age were identified as predictive risk factors of restenosis in the PC-PES group. Peripheral artery calcification scoring system grade of ≥ 2, post-dissection pattern ≥ D, lower proximal and distal vessel diameter, and lesion length ≥ 100 mm were identified as predictive risk factors of restenosis, in order of importance, in the DCB group. Both PC-PES and DCB were associated with favorable clinical outcomes within 1 year in patients with femoropopliteal artery disease. Furthermore, several factors that could predict restenosis within 1 year following the use of each device were detected.
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http://dx.doi.org/10.1007/s00380-021-01941-9DOI Listing
September 2021

Zinc Deficiency and Clinical Outcome After Infrainguinal Bypass Grafting for Critical Limb Ischemia.

Circ Rep 2020 Feb 26;2(3):167-173. Epub 2020 Feb 26.

Division of Vascular Surgery, Departments of Surgery, Nagoya University Graduate School of Medicine Nagoya Japan.

The aim of this study was to identify a relationship between zinc (Zn) deficiency and clinical outcome in patients with critical limb ischemia (CLI). Forty-five limbs from 44 patients with CLI who underwent de novo infrainguinal bypass grafting (IBG) were retrospectively reviewed. The patients were divided into a Zn deficiency group (ZD group: Zn <60 µg/dL) and a Zn sufficiency group (ZS group: Zn ≥60 µg/dL). Graft patency, limb salvage (LS), amputation-free survival (AFS), and wound healing were compared between the groups. LS and AFS were examined to identify whether Zn deficiency was an independent predictor. The preoperative factors potentially predictive of Zn deficiency were also analyzed. Twenty-four limbs were categorized into the ZD group. Patients in the ZD group were more likely to have undergone hemodialysis (HD) and have lower serum albumin. The surgical procedures were not significantly different between the groups. Patency, LS, AFS, and complete wound healing rates were significantly lower in the ZD group. Zn deficiency was a negative predictor of LS. Age >75 years and HD were identified as predictors of Zn deficiency. Zn deficiency was associated with poor clinical outcome. Zn supplementation may improve clinical outcomes during IBG for CLI.
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http://dx.doi.org/10.1253/circrep.CR-20-0003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921358PMC
February 2020

Patterns in Psychiatrists' Prescription of Valproate for Female Patients of Childbearing Age With Bipolar Disorder in Japan: A Questionnaire Survey.

Front Psychiatry 2020 15;11:250. Epub 2020 Apr 15.

Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Accumulating evidence has shown that valproate has the greatest teratogenic potential for increasing the risk of major congenital malformations, such as neural tube defects, cleft palate, and neurodevelopmental disability. Although valproate is a pharmacological option for acute mania and is used as a stabilization drug for patients with bipolar disorder, some global guidelines state that valproate should not be used for girls or women of childbearing age with bipolar disorder. We investigated patterns in psychiatrists' prescription of valproate for bipolar female patients of childbearing age in Japan.

Methods: From March to May 2018, we conducted a questionnaire survey among psychiatrists from all prefectures in Japan on psychiatric practice as it relates to major depression and bipolar disorder throughout women's life. The questionnaire had two parts: (1) assessment of participating psychiatrists' backgrounds and attitudes toward patients and (2) their patterns of prescription of psychotropics for female patients with mood disorders across generations and periods of pregnancy. Each question item had four response options: "not at all," "rarely," "sometimes," and "frequently." We examined patterns of prescription for childbearing-aged women (late adolescence/young adulthood aged 18-24 years, childbearing-age, older adults aged 25-49 years) and pregnant women.

Results: In total, 571 psychiatrists (427 males, 123 females, and 21 unknowns) responded appropriately to the questionnaire, including 320 who examined at least one or more late adolescence/young adulthood bipolar women. Approximately 70% of psychiatrists answered that they frequently or sometimes prescribed valproate for bipolar women of childbearing age [late adolescence/young adulthood: not at all, = 23 (7.5%); rarely, = 69 (22.5%); sometimes, =116 (37.8%); and frequently, = 99 (32.2%); childbearing-age, older adults: not at all, = 13 (2.7%); rarely, = 67 (13.8%); sometimes, = 185 (38.1%); and frequently, = 220 (45.4%)]. The proportion of general hospital psychiatrists who answered "not at all" or "rarely" to the frequency of their valproate prescriptions was higher than that of psychiatrists working in other medical facilities ( (3) = 18.2, < 0.001).

Conclusion: Most psychiatrists frequently or sometimes prescribe valproate for women of childbearing age in Japan.
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http://dx.doi.org/10.3389/fpsyt.2020.00250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176044PMC
April 2020

A Century-Old Mystery Unveiled: Sekizaisou is a Natural Lignin Mutant.

Plant Physiol 2020 04 12;182(4):1821-1828. Epub 2020 Feb 12.

Graduate School of Bio-Applications and Systems Engineering, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan and Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan

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http://dx.doi.org/10.1104/pp.19.01467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140961PMC
April 2020

Association Between Preoperative Frailty and Mortality in Patients With Critical Limb Ischemia Following Infrainguinal Bypass Surgery - Usefulness of the Barthel Index.

Circ J 2017 12 23;82(1):267-274. Epub 2017 Aug 23.

Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine.

Background: Most patients with critical limb ischemia (CLI) exhibit severe comorbidities accompanied by frailty. This study assessed and risk-stratified mortality after infrainguinal bypass (IB) in CLI and investigated the effects of frailty.Methods and Results:The study retrospectively reviewed 107 consecutive CLI patients who had undergone de novo IB due to atherosclerotic disease. Data regarding patient age, comorbidities, laboratory data, and functional status were collected; functional status was evaluated using the Barthel index (BI) and nutritional status was evaluated using albumin concentrations and body mass index (BMI). Mean (±SD) BI and BMI were 75±16 and 22±4 kg/m, respectively. BI (hazard ratio [HR] 0.96; 95% confidence interval [CI] 0.94-0.99, P=0.004), BMI (HR 0.85; 95% CI 0.75-0.95, P=0.003), atrial fibrillation (AF; HR 5.31; 95% CI 2.12-13.30, P<0.001), and ejection fraction (EF; HR 0.94; 95% CI 0.91-0.98, P=0.003) were independent predictors of mortality. Patients were divided into 2 groups based on BI (BI >75, n=71; and BI <70, n=36). Survival after IB was significantly lower for the lower BI group (P<0.001, log-rank test). After propensity score matching, post-IB survival remained significantly lower in the lower BI group (P=0.02).

Conclusions: BI, BMI, AF, and EF were independently associated with all-cause mortality after IB for CLI. BI and BMI may be useful in identifying and optimizing treatment for high-risk frail patients.
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http://dx.doi.org/10.1253/circj.CJ-17-0369DOI Listing
December 2017

Long-term Comparison of Endovascular and Open Repair of Abdominal Aortic Aneurysms: Retrospective Analysis of Matched Cohorts with Propensity Score.

Ann Vasc Surg 2017 Aug 6;43:96-103. Epub 2017 Apr 6.

Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Although recent guidelines recommend endovascular aneurysm repair (EVAR) for robust younger patients, we have been limiting our indication to older patients or those who are physically frail. This study compares long-term outcomes of our series of abdominal aortic aneurysms (AAAs) treated with endovascular repair (ER) and open surgery (OS), using propensity score matching.

Methods: Between June 2007 and October 2014, 819 patients with infrarenal AAA underwent elective repair at our institution. Among them, 737 patients (386 ERs and 351 OSs) with over 1-year follow-up or any events (reintervention or mortality) were enrolled. Covariates for matching included age, sex, hypertension, coronary arterial disease, obstructive pulmonary disease, diabetes, stroke, malignancy, hemodialysis, ejection fraction, serum creatinine, and respiratory function.

Results: After propensity score matching, 157 pairs were selected. In the original cohort, overall survival at 5 years was 84.1% in ER and 89.3% in OS; the difference was significant (P = 0.019). The freedom-from-reintervention rates at 5 years were also significantly different, 81.8% in ER and 92.8% in OS (P = 0.007). In the matched cohort, age and comorbidities were similar both in ER and OS. The overall survival at 5 years was 85.4% and 90.1% in ER and OS, respectively; the difference was not significant (P = 0.242). The freedom-from-reintervention rates at 5 years were 81.1% in ER and 89.1% in OS; these were also not significantly different (P = 0.178).

Conclusions: Risk-adjusted comparisons revealed that long-term outcomes of ER and OS were comparable among our relatively frail patients in their age 70s. Our results failed to show the long-term advantage of EVAR in rather high-risk patients and provided no supportive evidence for our selection criteria.
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http://dx.doi.org/10.1016/j.avsg.2017.01.011DOI Listing
August 2017

Mizoribine therapy combined with steroids and mizoribine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome.

Clin Exp Nephrol 2017 Dec 25;21(6):961-970. Epub 2016 Oct 25.

Professor Emeritus, Juntendo University, Tokyo, Japan.

Background: We designed a prospective and randomized trial of mizoribine (MZR) therapy combined with prednisolone (PSL) for idiopathic membranous nephropathy (IMN) with steroid-resistant nephrotic syndrome (SRNS).

Methods: Patients with IMN were divided into 2 groups, and MZR combined with PSL was administered for 2 years. PSL was initially prescribed at 40 mg/day and tapered. MZR was given once-a-day at 150 mg and 3-times-a-day at 50 mg each to groups 1 and 2. Serum MZR concentrations from 0 to 4 h after administration were examined within one month of treatment. The concentration curve and peak serum level (C ) of MZR were estimated by the population pharmacokinetic (PPK) parameters of MZR.

Results: At 2 years, 10 of 19 patients (52.6 %) in group 1 and 7 of 18 patients (38.9 %) in group 2 achieved complete remission (CR). The time-to-remission curve using the Kaplan-Meier technique revealed an increase in the cumulative CR rate in group 1, but no significant difference between the groups. Meanwhile, there was a significant difference in C between groups 1 and 2 (mean ± SD: 1.20 ± 0.52 vs. 0.76 ± 0.39 μg/mL, p = 0.04), and C levels in CR cases were significantly higher than those in non-CR cases. Receiver operating characteristic analysis showed that C more than 1.1 µg/mL was necessary for CR in once-a-day administration.

Conclusion: Administration of MZR once a day is useful when combined with PSL for treatment of IMN with SRNS. In addition, it is important to assay the serum concentration of MZR and to determine C , and more than 1.1 µg/mL of C is necessary for CR.
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http://dx.doi.org/10.1007/s10157-016-1340-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698362PMC
December 2017

Effects of Applied Nitrogen Amounts on the Functional Components of Mulberry (Morus alba L.) Leaves.

J Agric Food Chem 2016 Sep 12;64(37):6923-9. Epub 2016 Sep 12.

Faculty of Life and Environmental Science, Shimane University , 1060 Nishikawatsu-cho, Matsue, Shimane 690-8504, Japan.

This study investigated the effects of applied nitrogen amounts on specific functional components in mulberry (Morus alba L.) leaves. The relationships between mineral elements and the functional components in mulberry leaves were examined using mulberry trees cultivated in different soil conditions in four cultured fields. Then, the relationships between the nitrogen levels and the leaf functional components were studied by culturing mulberry in plastic pots and experimental fields. In the common cultured fields, total nitrogen was negatively correlated with the chlorogenic acid content (R(2) = -0.48) and positively correlated with the 1-deoxynojirimycin content (R(2) = 0.60). Additionally, differences in nitrogen fertilizer application levels affected each functional component in mulberry leaves. For instance, with increased nitrogen levels, the chlorogenic acid and flavonol contents significantly decreased, but the 1-deoxynojirimycin content significantly increased. Selection of the optimal nitrogen application level is necessary to obtain the desired functional components from mulberry leaves.
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http://dx.doi.org/10.1021/acs.jafc.6b01922DOI Listing
September 2016

Temporal Changes in Post-Infectious Glomerulonephritis in Japan (1976-2009).

PLoS One 2016 10;11(6):e0157356. Epub 2016 Jun 10.

Department of Nephrology, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Background: The incidence of post-infectious glomerulonephritis (PIGN) in developed countries has decreased over the last 50 years. Here we identified the trends of the incidence of PIGN in Japan during the past four decades.

Methods: We explored the frequency, clinicopathological findings, and prognosis of PIGN based on 6,369 cases from the Renal Biopsy Database of our institute in the Kanto region of Japan, diagnosed histologically from 1976 to 2009.

Results: The numbers of PIGN cases were 131 (2.1%) in total, and 2.4%, 1.1%, 2.6% and 2.1% identified in the 1970s, 1980s, 1990s, and 2000s, respectively. Acute glomerulonephritis (AGN), including post-streptococcal glomerulonephritis (PSGN), accounted for almost all of the PIGN cases in the 1970s, but decreased to approx. 40%-50% since the 1990s. In the 1990s, Staphylococcus aureus infection-related nephritis (SARN) showed a rapid increase in rate, reaching 30%. The incidence of hepatitis C virus infection-associated GN (HCVGN) has increased since the 1990s. The average age at onset rose from 33 to 51 years over the study period. These transitions can be summarized as increases in SARN and HCVGN and decreases in PSGN and other types of AGN, since SARN and HCVGN have older onsets compared to PSGN and other AGN types. The clinicopathological features were marked for each PIGN. Regarding the prognosis, the renal death rates of both the SARN and HCVGN groups were significantly higher than those of other PIGN.

Conclusion: Based on our analysis of the Renal Biopsy Database, the incidence of PIGN in Japan reached its peak in the 1990s. The temporal changes in the incidence of PIGN reflected the trends in infectious diseases of each decade and the continual aging of the population, with a related higher susceptibility to infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902309PMC
July 2017

Effect of solar radiation on the functional components of mulberry (Morus alba L.) leaves.

J Sci Food Agric 2016 Aug 15;96(11):3915-21. Epub 2016 Feb 15.

Shimane University, 1060 Nishikawatsu-cho, Matsue, Shimane, 690-8504, Japan.

Background: The functional components of mulberry leaves have attracted the attention of the health food industry, and increasing their concentrations is an industry goal. This study investigated the effects of solar radiation, which may influence the production of flavonol and 1-deoxynojirimycin (DNJ) functional components in mulberry leaves, by comparing a greenhouse (poor solar radiation) and outdoor (rich solar radiation) setting.

Results: The level of flavonol in leaves cultivated in the greenhouse was markedly decreased when compared with those cultivated outdoors. In contrast, the DNJ content in greenhouse-cultivated plants was increased only slightly when compared with those cultivated outdoors. Interestingly, the flavonol content was markedly increased in the upper leaves of mulberry trees that were transferred from a greenhouse to the outdoors compared with those cultivated only in the outdoors.

Conclusion: Solar radiation conditions influence the synthesis of flavonol and DNJ, the functional components of mulberry leaves. Under high solar radiation, the flavonol level becomes very high but the DNJ level becomes slightly lower, suggesting that the impact of solar radiation is great on flavonol but small on DNJ synthesis. © 2016 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.7614DOI Listing
August 2016

Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial.

BMC Nephrol 2015 Oct 16;16:165. Epub 2015 Oct 16.

Astellas Pharma Inc., 2-5-1 Nihonbashi-honcho, Chuo-ku, Tokyo, 103-8411, Japan.

Background: Evidence increasingly points to the importance of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease (ESRD). Beraprost sodium (BPS) is an orally active prostacyclin (PGI2) analogue demonstrating prevention of the progression of chronic kidney disease (CKD) in various animal models by maintaining renal blood flow and attenuating renal ischemic condition.

Methods: This multicenter, randomized, double-blind, placebo-controlled, phase II trial was designed to determine the recommended dose of the sustained-release form of BPS (TRK-100STP 120 μg/day or 240 μg/day) in Japanese patients with CKD. TRK-100STP was administered to a total of 112 patients. The primary efficacy endpoint was the difference in the slope of the regression line of reciprocal of serum creatinine (1/SCr) over time, obtained by the least-squares method.

Results: Regarding the primary endpoint, statistical superiority of TRK-100STP 240 μg over placebo was not confirmed and so a recommended dose was not determined. Compared to placebo, however, the slope of regression line of 1/SCr, elevation of SCr and serum cystatin C during the treatment period revealed greater improvement at 120 μg, at both doses, and at 240 μg, respectively. In terms of safety, both TRK-100STP treatment groups were well tolerated.

Conclusions: Although the study failed to meet the primary endpoint, results indicate that TRK-100STP may potentially prevent the decline in renal function of CKD patients independent of blood pressure or urinary protein levels.

Trial Registration: NCT02480751. June 21, 2015.
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http://dx.doi.org/10.1186/s12882-015-0130-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608181PMC
October 2015

Dipeptidyl peptidase 4 inhibitor reduces intimal hyperplasia in rabbit autologous jugular vein graft under poor distal runoff.

J Vasc Surg 2016 05 2;63(5):1360-70. Epub 2015 Feb 2.

Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya City, Japan. Electronic address:

Background: Dipeptidyl peptidase 4 inhibitors are widely used in patients with type 2 diabetes mellitus to accomplish glycemic control through an increase in the blood glucagon-like peptide 1 (GLP-1) concentration. These agents also inhibit vascular inflammation (eg, in atherosclerosis). This study was undertaken to determine whether and how vildagliptin (a potent dipeptidyl peptidase 4 inhibitor) might reduce intimal hyperplasia in vein grafts.

Methods: Twelve rabbits were randomly divided into two groups; one group received vildagliptin orally (10 mg/kg/d; n = 6), whereas the control group (n = 6) did not. Vildagliptin administration was started 7 days before rabbits underwent interposition reversed autologous jugular vein grafting and ended at graft harvesting (28 days after the operation). Histochemical changes in the vascular wall were examined, as were changes in the acetylcholine-induced effects on the endothelial Ca(2+) concentration ([Ca(2+)]i) and endothelium-dependent relaxation.

Results: Under fasting conditions, vildagliptin increased the plasma GLP-1 concentration, without affecting plasma glucose or insulin. Acetylcholine induced endothelium-dependent relaxation only in the vildagliptin group, and this was blocked by the nitric oxide synthase inhibitor N(ω)-nitro-l-arginine. Acetylcholine did not modify the endothelial [Ca(2+)]i in either the control or vildagliptin group. Intimal hyperplasia was significantly less in the vildagliptin group (0.11 ± 0.02 mm, n = 5) than in the controls (0.31 ± 0.06 mm, n = 4; P < .01).

Conclusions: Vildagliptin increased the plasma GLP-1 concentration. It also enhanced acetylcholine-induced [Ca(2+)]i-independent endothelial nitric oxide release and reduced vein graft intimal hyperplasia, independently of any glycemic control action.
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http://dx.doi.org/10.1016/j.jvs.2014.12.048DOI Listing
May 2016

Significance of combined cyclosporine-prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial.

Clin Exp Nephrol 2014 Oct 23;18(5):784-94. Epub 2013 Dec 23.

General Medical Research Center, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan,

Background: Combined treatment with cyclosporine microemulsion preconcentrate (CyA MEPC) and steroids has been widely used for idiopathic membranous nephropathy (IMN) associated with steroid-resistant nephrotic syndrome (SRNS). Recent studies have shown that once-a-day and preprandial administration of CyA MEPC is more advantageous than the conventional twice-a-day administration in achieving the target blood CyA concentration at 2 h post dose (C2). We designed a randomized trial to compare these administrations.

Methods: IMN patients with SRNS (age 16-75 years) were divided prospectively and randomly into 2 groups. In group 1 (n = 23), 2-3 mg/kg body weight (BW) CyA MEPC was given orally once a day before breakfast. In group 2 (n = 25), 1.5 mg/kg BW CyA MEPC was given twice a day before meals. CyA + prednisolone was continued for 48 weeks.

Results: Group 1 showed a significantly higher cumulative complete remission (CR) rate (p = 0.0282), but not when incomplete remission 1 (ICR1; urine protein 0.3-1.0 g/day) was added (p = 0.314). Because a C2 of 600 ng/mL was determined as the best cut-off point, groups 1 and 2 were further divided into subgroups A (C2 ≥600 ng/mL) and B (C2 <600 ng/mL). Groups 1A and 2A revealed significantly higher cumulative remission (CR + ICR1) (p = 0.0069) and CR-alone (p = 0.0028) rates. On the other hand, 3 patients with high CyA levels (C2 >900 ng/mL) in Group 1A were withdrawn from the study because of complications.

Conclusion: CyA + prednisolone treatment is effective for IMN with associated SRNS at a C2 of ≥600 ng/mL. To achieve remission, preprandial once-a-day administration of CyA at 2-3 mg/kg BW may be the most appropriate option. However, we should adjust the dosage of CyA by therapeutic drug monitoring to avoid complications.
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http://dx.doi.org/10.1007/s10157-013-0925-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194018PMC
October 2014

Varietal differences in the flavonol content of mulberry (Morus spp.) leaves and genetic analysis of quercetin 3-(6-malonylglucoside) for component breeding.

J Agric Food Chem 2013 Sep 10;61(38):9140-7. Epub 2013 Sep 10.

Shimane Agricultural Technology Center , 2440 Ashiwata-cho, Izumo, Shimane 693-0035, Japan.

The varietal differences in the flavonol glycosides rutin, isoquercitrin, kaempferol 3-(6-rhamnosylglucoside), quercetin 3-(6-malonylglucoside), astragalin, quercetin 3-(6-acetylglucoside), and kaempferol 3-(6-malonylglucoside) contained in mulberry leaves were elucidated. This information was used for breeding mulberry cultivars with a high concentration of functional components. The flavonol content, composition, and proportion in leaves varied widely. 'Kobuchizawa 1' had the highest level of total flavonols (1819 mg/100 g of dry weight), 5 times higher than that of 'Mikurasima 15' (393 mg/100 g of dry weight). Quercetin 3-(6-malonylglucoside) was the most abundant flavonol, although it was not found in all cultivars. Quercetin 3-(6-acetylglucoside) was only found in 'Keguwa'. From the quercetin 3-(6-malonylglucoside) content in crossbred offspring, malonyltransferase, an enzyme involved in quercetin 3-(6-malonylglucoside) synthesis, was acquired according to Mendelian inheritance. An offspring with a higher quercetin 3-(6-malonylglucoside) level than both parents was obtained from the crossing. This suggested that crossbreeding was effective for acquiring cultivars with a higher content of quercetin 3-(6-malonylglucoside).
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http://dx.doi.org/10.1021/jf403136wDOI Listing
September 2013

Clinical findings on ANCA-associated renal vasculitis from the Japan RPGN registry obtained via a questionnaire survey.

Clin Exp Nephrol 2013 Oct 14;17(5):646-649. Epub 2012 Dec 14.

Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Renal involvement with significant organ damage is common in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). As a result, it is independently referred to ANCA-associated renal vasculitis. Clinically, ANCA-associated renal vasculitis is characterized by rapidly progressive glomerulonephritis. Pathologically, it is defined by pauci-immune type necrotizing and crescentic glomerulonephritis. According to previous reports from all over the world, the etiology, prevalence, and prognosis of RPGN including ANCA-associated renal vasculitis varies among races and periods. To elucidate the clinical characteristics of Japanese RPGN patients, a registry derived from a questionnaire survey was established in 1999 and maintained until 2006. As a result, 1,772 cases were collected, analyzed, and reported previously. In this mini-review, we outline the characteristic clinical findings of Japanese patients (Asian) with ANCA-associated renal vasculitis, based on the registry data.
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http://dx.doi.org/10.1007/s10157-012-0740-1DOI Listing
October 2013

Primary membranoproliferative glomerulonephritis on the decline: decreased rate from the 1970s to the 2000s in Japan.

Clin Exp Nephrol 2013 Apr 13;17(2):248-54. Epub 2012 Sep 13.

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

Background: A prolonged change in the rate of primary membranoproliferative glomerulonephritis (MPGN) was identified using a Japanese database of renal biopsies.

Methods: We retrospectively investigated 6,369 renal biopsies that were performed between 1976 and 2009. Primary MPGN patients were selected, and the clinical and pathological findings were examined. We also statistically analyzed the changing rate of the onset of primary MPGN according to each decade.

Results: Seventy-nine cases with primary MPGN (1.2 % of total biopsies) were diagnosed. The age of the patients ranged from 6-79 years (average 34.6 years). There were 24 children and 55 adults, including 37 male and 42 female patients. Thirty-six cases of primary MPGN (45.6 %) showed nephrotic syndrome-8 childhood and 28 adult cases. In the pathological classification of 44 samples using electron microscopy, 29 cases were MPGN type I, 1 case was MPGN type II, and 14 cases were MPGN type III. The secular change of the rate of primary MPGN onset showed a statistically significant reduction from the 1970s to the 2000s. The rate of primary MPGN onset in the child population also significantly decreased, but not in the adult population. Among the clinical parameters, disease severity and prognosis remained unchanged. Regarding treatment in recent years, steroid pulse therapy became more available but the administration of warfarin and anti-platelet drugs significantly decreased.

Conclusion: We concluded that the rate of total primary MPGN and that of pediatric patients with primary MPGN decreased.
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http://dx.doi.org/10.1007/s10157-012-0690-7DOI Listing
April 2013

ANCA-associated systemic vasculitis in Japan: clinical features and prognostic changes.

Clin Exp Nephrol 2012 Aug 18;16(4):580-8. Epub 2012 Feb 18.

Department of Nephrology, Faculty of Medicine, University of Tsukuba, 1-1-1 Ten-oudai, Tsukuba, Ibaraki 305-8575, Japan.

Background: This study was conducted to standardize treatment and determine patient and renal outcome in Japanese anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis/rapidly progressive glomerulonephritis (AAV/RPGN) patients, because the prognosis of AAV/RPGN patients in Japan had been poor compared with that of other countries.

Methods: The participants in this retrospective cohort study were 824 ANCA-positive RPGN patients, 705 of whom were only myeloperoxidase (MPO)-ANCA positive.

Results: Among the early-years cohort (group A; cases diagnosed between 1988 and 1998), patients frequently died due to opportunistic infection. Therefore, we recommended a reduced dose of prednisolone (oral prednisolone dose <0.8 mg/kg/day) with or without cyclophosphamide for initial treatment of Japanese RPGN patients. After this recommendation, 1-year survival of the patients improved: 75% in group A, 79% in group B (between 1999 and 2002), and 81% in group C (after 2003). During the entire observation period, average serum creatinine level at the start of treatment decreased, and improvement of 1-year renal survival was also found (72% in group A, 83% in group B, and 83% in group C), while the recurrence rate was significantly increased in group C (0.05/patient-year in group A, 0.07/patient-year in group B, and 0.13/patient-year in group C).

Conclusions: Oral prednisolone dose <0.8 mg/kg/day with or without cyclophosphamide as an initial treatment could improve patient survival in older Japanese AAV/RPGN patients. However, maintenance treatment avoiding relapse should be established to improve renal outcomes.
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http://dx.doi.org/10.1007/s10157-012-0598-2DOI Listing
August 2012

[Dr Leonor Michaelis and early days of Hokkaido University School of Medicine; episodes among three medical researchers in the roaring twenties].

Hokkaido Igaku Zasshi 2011 Aug;86(4-5):203-8

Laboratory of Environmental Biology/Department of Hygiene Hokkaido University School of Medicine, Sapporo 060-8638, Japan.

Little has been known about the personal history of Dr. Takaichi Mohri (Nakashima), the first professor of department of hygiene at Hokkaido University School of Medicine. We, therefore, have been inquiring academic backgrounds of Dr. Mohri for two decades. These inquiries show interesting episodes between Dr. Leonor Michaelis, one of the biggest names in enzymologists, and early days of this Medical School. In this article, we describe that at least two professors, Drs. Takaichi Mohri and Kaoru Ohguro, were in good acquaintances with Dr. Michaelis as follows; 1) the latter half of 1921, Dr. Ohguro visited a laboratory of Dr. Michaelis in Berlin, 2) from November 1922 to June 1923, Dr. Michaelis in Nagoya collaborated with Dr. Mohri in Sapporo, 3) Dr. Michaelis in Nagoya visited Dr. Ohguro's house and office in Sapporo at March 1925, and 4) at the same occasion, Dr. Michaelis made his lecture on biochemistry in Hokkaido University School of Medicine. Since Drs. Ohguro and Mohri were classmates of the University of Tokyo Faculty of Medicine, Dr. Ohguro could introduce Dr. Michaelis to Dr. Mohri who used to be a graduate student in department of biochemistry. As a result of relationships, Drs. Michaelis and Mohri published a paper entitled "Eine weitere Methode zur Bestimmung des isoelektrischen Punktes von Eiweisskoerpern und ihre Anwendung auf die Serumalbumine verschiedener Tiere" in Biochemische Zeitschrift, which was a part of Dr. Mohri's Ph.D. thesis.
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August 2011

[Examination of original plant of mulberry bark extract, a natural food additive, based on composition of the constituents].

Shokuhin Eiseigaku Zasshi 2011 ;52(4):258-64

National Institute of Health Sciences, Tokyo.

Mulberry bark extract, a natural food additive, is described as a "root bark extract from Morus bombycis" (Japanese name: Yamaguwa) in the Notice (1996) relating to existing food additives used in Japan. The results of analyses by LC/UV and LC/MS suggested that the Mulberry bark extract products that were tested were actually made from the root bark of Morus alba (Japanese name: Maguwa) or its hybrid species, because the compositions of the constituents in the products are more similar to those in the extracts of the dried root bark of M. alba and hybrid species that are cultivated in Japan than to those of M. bombycis. In addition, the constituents of the food additive products were different from those of the natural medicine Mori Cortex products ('Souhakuhi' in Japanese) made from the root bark of mulberry grown in China, and which is described as being derived from M. alba in the Japanese pharmacopoeia. These results were also corroborated by Principal Component Analysis using the peak areas of LC/MS analysis as explanatory variables. After this study, it was decided that Mulberry bark extract is one of the existing food additives that should be excluded from the list this year in Japan.
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http://dx.doi.org/10.3358/shokueishi.52.258DOI Listing
February 2012

Serum levels of BAFF and APRIL in myeloperoxidase anti-neutrophil cytoplasmic autoantibody-associated renal vasculitis: association with disease activity.

Nephron Clin Pract 2011 3;118(4):c339-45. Epub 2011 Feb 3.

Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Japan.

Background: A proliferation-inducing ligand (APRIL) and the B cell activation factor belonging to the tumor necrosis factor family (BAFF) have proven to be key factors in the selection and survival of B cells, and a higher concentration of BAFF has been shown to contribute to autoreactive B cell survival and elevated autoantibody production. Here, serum BAFF and APRIL levels were investigated to analyze their association with disease activity in myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated renal vasculitis.

Methods: APRIL and BAFF levels in serum obtained from 37 patients with MPO-ANCA-associated vasculitis were measured by ELISA. Samples were taken from active vasculitis patients, inactive vasculitis patients and inactive vasculitis patients with infectious complications.

Results: Although there was no difference in serum APRIL among the active vasculitis, inactive vasculitis and infectious complication patients, serum BAFF was higher in active vasculitis patients than in inactive vasculitis, infectious complication and control patients (for all, p < 0.001). There was no significant correlation between serum APRIL and ANCA titers, but there was a significant correlation between serum BAFF and ANCA titers (r = 0.465, p < 0.001).

Conclusion: Excessive BAFF production in MPO-ANCA-associated vasculitis may be one of the factors for autoimmune B cell tolerance, resulting in MPO-ANCA production.
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http://dx.doi.org/10.1159/000323393DOI Listing
May 2012

Methicillin-resistant Staphylococcus-aureus-associated glomerulonephritis on the decline: decreased incidence since the 1990s.

Clin Exp Nephrol 2011 Feb 13;15(1):184-6. Epub 2010 Nov 13.

We believe that bacterial-infection-associated glomerulonephritis (GN), so-called methicillin-resistant Staphylococcus aureus (MRSA)-GN, was exterminated in Japan. The control of bacterial infection is the most important part of infection-associated GN. In 1990s Japan, hospital-associated MRSA (HA-MRSA) caused MRSA-GN outbreaks. On the other hand, MRSA-GN incidence has been quite limited since 2000. This epidemiological transition suggests that antibacterial therapies and health programs for HA-MRSA infection in Japan were effective against MRSA-GN. Moreover, it appears that staphylococcal superantigens act in the pathogenesis of GN. The change of superantigen production might have influenced to the disappearance of MRSA-GN. If HA-MRSA-producing superantigen outbreaks occur in developing countries, our experience in Japan can provide guiding principles for preventing and eradicating GN.
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http://dx.doi.org/10.1007/s10157-010-0369-xDOI Listing
February 2011

Serum ratio of soluble triggering receptor expressed on myeloid cells-1 to creatinine is a useful marker of infectious complications in myeloperoxidase-antineutrophil cytoplasmic antibody-associated renal vasculitis.

Nephrol Dial Transplant 2011 Mar 13;26(3):868-74. Epub 2010 Aug 13.

Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki, Japan.

Background: The contribution of infections to the mortality of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients is important and should induce early and careful control of these events. However, the differentiation of infection from active vasculitis is often difficult. The usefulness of serum-soluble triggering receptor expressed on myeloid cells-1 (TREM-1) for detecting the presence of infectious complications regardless of disease activity was investigated.

Methods: Soluble TREM-1 in serum obtained from 41 patients with myeloperoxidase (MPO)-ANCA-associated vasculitis was measured by an enzyme-linked immunosorbent assay. Twenty-nine samples were from active vasculitis patients, 27 samples from inactive vasculitis patients without infection and 17 samples from inactive vasculitis patients with infectious complications. Serum-soluble TREM-1 was also measured in 10 patients with acute pyelonephritis and 30 patients with chronic kidney disease (CKD).

Results: There was a significant correlation between serum levels of soluble TREM-1 and serum creatinine levels among all patients (r = 0.554, P < 0.0001). The serum-soluble TREM-1/creatinine ratio was higher in inactive vasculitis patients with infectious complications than in active vasculitis, inactive vasculitis without infection and CKD patients (P = 0.0005, P < 0.0001 and P < 0.0001, respectively), but not significantly different to that in acute pyelonephritis patients. On receiver-operating-characteristic curve analysis, a lower-limit value of 9.40 ng/mg for this ratio had a sensitivity of 84.6% and a specificity of 90.8% in differentiating patients with infection from those without infection.

Conclusions: The serum ratio of soluble TREM-1 to creatinine may be a useful marker for detection of infectious complications in MPO-ANCA-associated vasculitis.
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http://dx.doi.org/10.1093/ndt/gfq506DOI Listing
March 2011

Successful pregnancy in a female patient with congenital chloride diarrhea (CLD) and renal impairment.

J Nephrol 2009 Nov-Dec;22(6):809-13

Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.

We report a successful case of pregnancy in a female patient with congenital chloride diarrhea (CLD) and reduced renal function due to interruption of treatment. CLD is an autosomal recessive disorder of intestinal electrolyte absorption caused by mutations in the solute carrier family 26, member 3 (SLC26A3) gene, and continuous production of watery diarrhea induces dehydration, metabolic alkalosis and many kinds of electrolyte disturbances in CLD patients. The patient in our case was a 24-year-old female CLD patient with moderate renal impairment; a renal biopsy specimen showed minimal glomerular changes, but tubulointerstitial damage by crystal formation, consistent with renal function data. One year after our initial examination and reinstitution of therapy, the patient got married and soon conceived. There were no major problems during the course of pregnancy, and the patient successfully delivered a healthy full-term infant vaginally. The symptoms and clinical course of the patient were particularly mild, and we discuss possible reasons for these observations from a perspective of genotype, phenotype and environmental conditions.
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February 2010

Analysis of T-cell receptor usage in myeloperoxidase--antineutrophil cytoplasmic antibody-associated renal vasculitis.

Clin Exp Nephrol 2010 Feb 7;14(1):36-42. Epub 2009 Oct 7.

Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Ibaraki, 300-0395, Japan,

Background: Bacterial superantigens produced by Staphylococcus aureus may be associated with the onset of proteinase-3 antineutrophil cytoplasmic antibody (PR3-ANCA)-associated vasculitis, including Wegener's granulomatosis. We investigated T-cell subsets to assess the superantigens present in patients with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis.

Methods: Peripheral-blood mononuclear cells (PBMC) obtained from 40 normal controls and ten patients with MPO-ANCA-associated vasculitis were stained with fluorescence-labeled monoclonal antibodies against T-cell markers, including 17 variable regions of T-cell receptor beta-chains (TCR-Vbeta) and were then analyzed using flow cytometry.

Results: Among PBMCs, the percentage of CD3(+) cells from patients with MPO-ANCA-associated vasculitis was significantly lower than that from normal controls, but there were no differences between the two groups in the percentage of CD19(+) cells or CD16(+) cells. Although there were no differences regarding the overall percentage of CD4(+) cells between the two groups, the percentage of CD4(+)CD45RO(+) cells in patients with MPO-ANCA-associated vasculitis was significantly higher than that in normal controls, and percentages of CD4(+)CD45RO(+)HLA-DR(+) and CD4(+)CD45RO(+)CD62L(low) cells in patients with MPO-ANCA-associated vasculitis were also significantly increased. There was no significant difference between the two groups in terms of the usage of the 17 different TCR-Vbeta regions.

Conclusion: There was no difference in bacterial superantigens between controls and MPO-ANCA-associated vasculitis patients because of the absence of specific usage of TCR-Vbeta regions. Given the elevated levels of memory T cells, conventional antigens rather than superantigens may be associated with the pathogenesis of MPO-ANCA-associated vasculitis.
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http://dx.doi.org/10.1007/s10157-009-0230-2DOI Listing
February 2010

A nationwide survey of rapidly progressive glomerulonephritis in Japan: etiology, prognosis and treatment diversity.

Clin Exp Nephrol 2009 Dec 17;13(6):633-50. Epub 2009 Jun 17.

Ibaraki Prefuctural University, Ami, Japan.

Background: The etiology, prevalence, and prognosis of rapidly progressive glomerulonephritis (RPGN) including renal vasculitis vary among races and periods.

Method: To improve the prognosis of Japanese RPGN patients, we conducted a nationwide survey of RPGN in the nephrology departments of 351 tertiary hospitals, and found 1772 patients with RPGN (Group A: diagnosed between 1989 and 1998, 884 cases; Group B: diagnosed between 1999 and 2001, 321 cases; and Group C: diagnosed between 2002 and 2007, 567 cases). ANCA subclasses, renal biopsy findings, treatment, outcome and cause of death were recorded.

Result: The most frequent primary disease was renal-limited vasculitis (RLV) (42.1%); the second was microscopic polyangiitis (MPA) (19.4%); the third was anti-GBM-associated RPGN (6.1%). MPO-ANCA was positive in 88.1% of RLV patients and 91.8% of MPA patients. The proportion of primary renal diseases of RPGN was constant during those periods. The most frequent cause of death was infectious complications. The serum creatinine at presentation and the initial dose of oral prednisolone decreased significantly in Groups B and C compared to Group A. However, both patient and renal survival rates improved significantly in Groups B and C (survival rate after six months in Group A: 79.2%, Group B: 80.1%, and Group C: 86.1%. Six-month renal survival in Group A: 73.3%, Group B: 81.3%, and Group C: 81.8%).

Conclusion: Early diagnosis was the most important factor for improving the prognosis of RPGN patients. To avoid early death due to opportunistic infection in older patients, a milder immunosuppressive treatment such as an initial oral prednisolone dose reduction with or without immunosuppressant is recommended.
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http://dx.doi.org/10.1007/s10157-009-0201-7DOI Listing
December 2009

In vivo imaging of renal redox status during azelnidipine treatment.

Hypertens Res 2008 Aug;31(8):1643-50

Center for Integrative Medicine, Tsukuba University of Technology, Tsukuba, Japan.

The effect of the calcium channel blocker azelnidipine on the redox status of a murine hypertension model was analyzed and imaged using in vivo low frequency electron paramagnetic resonance (EPR). A murine two kidney-one clip (2K1C) hypertension model was produced by a clipping of the right renal artery. The resulting hypertensive mice were treated with low-dose azelnidipine (1 mg/kg/d), with high-dose azelnidipine (3 mg/kg/d) or without azelnidipine (HT group). An EPR system equipped with a loop-gap resonator and an imaging system was employed. Redox status was evaluated as organ reducing activity measured by means of the decay rate (half-lives) of the spin probe 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (Carbamoyl-PROXYL). Four weeks after clipping the mice demonstrated hypertension as expected. After the additional 2 weeks of azelnidipine treatments, the Carbamoyl-PROXYL half-lives of the Low and High azelnidipine groups measured in the upper abdominal area were significantly shorter than those of the HT group, suggesting improvements in the reducing activity. The blood pressures of the three groups showed no significant differences at this time, and there was no correlation between the renal reducing activity and either blood pressure or serum creatinine values. EPR imaging studies revealed that the improvement in abdominal reducing activity was mainly recognized in the kidney but not in the liver. These results indicate that azelnidipine ameliorates renal redox status through an improvement in reducing activity independent of blood pressure control.
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http://dx.doi.org/10.1291/hypres.31.1643DOI Listing
August 2008

Renal pathology of ANCA-related vasculitis: proposal for standardization of pathological diagnosis in Japan.

Clin Exp Nephrol 2008 Aug 22;12(4):277-291. Epub 2008 Apr 22.

Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Background: In Japan, systematic evaluation of the histologic parameters of anti-neutrophil cytoplasmic autoantibodies (ANCA)-related vasculitis has been performed according to the Japanese classification by Shigematsu et al. However, this classification is quite different from that of the European Vasculitis Study Group (EUVAS) classification. Therefore, a histological common basis is needed to compare Japanese histological data with the international database.

Method: Histological parameters concerning glomerular, tubulointerstitial, and vascular lesions of ANCA-related vasculitis, which are indispensable for clinical management, were elucidated and defined by reviewing, utilizing the merits of, and amending the two scoring systems.

Results And Conclusion: A new comprehensive and standardized scoring system, by which histological quantitative assessment can provide evidence for therapy planning, has been developed for renal biopsy of Japanese ANCA-related vasculitis.
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http://dx.doi.org/10.1007/s10157-008-0052-7DOI Listing
August 2008
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