Faculty Profiles - WADA Jun

Papers - WADA Jun

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Impaired mental health status in patients with chronic kidney disease is associated with estimated glomerular filtration rate decline. Reviewed International journal

Yasuhiro Onishi, Haruhito A Uchida, Hidemi Takeuchi, Yuki Kakio, Hitoshi Sugiyama, Jun Wada, Noriaki Shimada, Hironobu Tokumasu, Masaki Fukushima, Kenichiro Asano

Nephrology (Carlton, Vic.) 24 ( 9 ) 926 - 932 2019.9

Language：English Publishing type：Research paper (scientific journal)

AIM: Deteriorated health-related quality of life (HRQOL) is associated with increased risk for death in both chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients; however, the impact of HRQOL on CKD progression is not well investigated. METHODS: We aimed to evaluate the association between HRQOL and CKD progression in Japanese patients with CKD. One hundred and three outpatients who visited the department of nephrology at our hospital (mean estimated glomerular filtration rate (eGFR); 32.1 ± 11.2 mL/min per 1.73 m2 ) between April 2007 and March 2012 were enrolled in this study. The primary outcome was 30% decline of eGFR or ESRD. We assessed HRQOL of all participants at baseline, including the physical component summary (PCS), the mental component summary (MCS) and the role/social component summary (RCS), using SF-36. Based on the baseline score of PCS, MCS and RCS, we divided all subjects into two groups by median. RESULTS: We studied 66 men (64.1%) and 37 women aged 61.7 ± 10.0 years old. During approximately 2.5 years of follow-up period, 59 patients (57.3%) reached 30% eGFR decline or ESRD. Cox regression analyses demonstrated that lower MCS score was significantly associated with CKD progression (hazard ratio (HR) = 1.83, 95% CI = 1.04-3.21, P = 0.035), but that lower PCS score and RCS score were not (HR = 0.70, 95% CI = 0.39-1.25, P = 0.223; HR = 0.95, 95% CI = 0.54-1.67, P = 0.854, respectively). CONCLUSION: We found that impaired mental health was associated with CKD progression. The evaluation of the mental health should be performed in the patients with CKD.

DOI： 10.1111/nep.13515

Renal tubular injury exacerbated by vasohibin-1 deficiency in a murine cisplatin-induced acute kidney injury model. Reviewed International journal

Satoshi Tanimura, Katsuyuki Tanabe, Hiromasa Miyake, Kana Masuda, Keigo Tsushida, Tomoyo Morioka, Hitoshi Sugiyama, Yasufumi Sato, Jun Wada

American journal of physiology. Renal physiology 317 ( 2 ) F264-F274 - F274 2019.8

Language：English Publishing type：Research paper (scientific journal)

Acute kidney injury (AKI) is frequently encountered in clinical practice, particularly secondarily to cardiovascular surgery and administration of nephrotoxic agents, and is increasingly recognized for initiating a transition to chronic kidney disease. Clarifying the pathogenesis of AKI could facilitate the development of novel preventive strategies, because the occurrence of hospital-acquired AKI is often anticipated. Vasohibin-1 (VASH1) was initially identified as an antiangiogenic factor derived from endothelial cells. VASH1 expression in endothelial cells has subsequently been reported to enhance cellular stress tolerance. Considering the importance of maintaining peritubular capillaries in preventing the progression of AKI, the present study aimed to examine whether VASH1 deletion is involved in the pathogenesis of cisplatin-induced AKI. For this, we injected male C57BL/6J wild-type (WT) and VASH1 heterozygous knockout (VASH1+/-) mice intraperitoneally with either 20 mg/kg cisplatin or vehicle solution. Seventy-two hours after cisplatin injection, increased serum creatinine concentrations and renal tubular injury accompanied by apoptosis and oxidative stress were more prominent in VASH1+/- mice than in WT mice. Cisplatin-induced peritubular capillary loss was also accelerated by VASH1 deficiency. Moreover, the increased expression of ICAM-1 in the peritubular capillaries of cisplatin-treated VASH1+/- mice was associated with a more marked infiltration of macrophages into the kidney. Taken together, VASH1 expression could have protective effects on cisplatin-induced AKI probably by maintaining the number and function of peritubular capillaries.

DOI： 10.1152/ajprenal.00045.2019

Development of Hypertrophic Pachymeningitis in a Patient With Antineutrophil Cytoplasmic Antibody-Negative Eosinophilic Granulomatosis With Polyangiitis. Reviewed International journal

Yasuhiro Nakano, Yoshia Miyawaki, Ken-Ei Sada, Yuriko Yamamura, Yuzuki Kano, Keigo Hayashi, Haruki Watanabe, Yoshinori Matsumoto, Tomoko Kawabata, Jun Wada

Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 25 ( 5 ) e61 2019.8

A Patient with Type 3 Autoimmune Polyglandular Syndrome who Developed Systemic Lupus Erythematosus 8 years after the Diagnosis of Autoimmune Hepatitis. Reviewed

Tomoyo Mifune-Morioka, Haruhito A Uchida, Kazuhiko Fukushima, Mayu Watanabe, Chihiro Ouchi, Koki Mise, Chieko Kawakita, Yuzuki Kano, Akifumi Onishi, Kishio Toma, Jun Eguchi, Nozomu Wada, Fusao Ikeda, Erika Sasaki, Yu Suganami, Masayuki Kishida, Hitoshi Sugiyama, Hiroyuki Okada, Jun Wada

Acta medica Okayama 73 ( 4 ) 367 - 372 2019.8

Language：English Publishing type：Research paper (scientific journal)

Eight years prior to her present admission, a 61-year-old Japanese woman was diagnosed with autoimmune hepatitis, slowly progressive insulin-dependent diabetes mellitus, and chronic thyroiditis; she had been treated with oral prednisolone (PSL). After she suddenly discontinued PSL, she newly developed systemic lupus erythematosus. A combination therapy of oral PSL and intravenous cyclophosphamide resulted in remission. She was finally diagnosed with autoimmune polyglandular syndrome (APS) type 3 (3A ,3B, 3D), complicated with four different autoimmune diseases. Since patients with type 3 APS may present many manifestations over a long period of time, they should be carefully monitored.

DOI： 10.18926/AMO/56940

Combination of Renal Angioplasty and Angiotensin-converting-enzyme Inhibitor Can Reduce Proteinuria in Patients with Bilateral Renal Artery Disease. Reviewed

Hironobu Toda, Haruhito Uchida, Kazufumi Nakamura, Hidemi Takeuchi, Masaru Kinomura, Koji Nakagawa, Atsuyuki Watanabe, Toru Miyoshi, Nobuhiro Nishii, Hiroshi Morita, Jun Wada, Hiroshi Ito

Internal medicine (Tokyo, Japan) 58 ( 13 ) 1917 - 1922 2019.7

Language：English Publishing type：Research paper (scientific journal)

Recent large clinical trials failed to show clear benefits of percutaneous transluminal renal angioplasty (PTRA) as compared with medical therapy on patients with renal artery stenosis. It was also reported that proteinuria is an adverse prognostic factor after PTRA, and PTRA is less effective in patients with overt proteinuria. From the renoprotective point of view, to reduce proteinuria after PTRA is an important therapeutic goal in patients with renal artery stenosis with overt proteinuria. We hereby describe two patients successfully treated by combination therapy with PTRA and administration of angiotensin-converting enzyme (ACE) inhibitor for bilateral renal artery disease with overt proteinuria.

DOI： 10.2169/internalmedicine.2076-18

Capnocytophaga canimorsus peritonitis diagnosed by mass spectrometry in a diabetic patient undergoing peritoneal dialysis: a case report. Reviewed International journal

Katsuyuki Tanabe, Shugo Okamoto, Sumie Hiramatsu Asano, Jun Wada

BMC nephrology 20 ( 1 ) 219 - 219 2019.6

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Bacterial peritonitis is a serious complication of patients undergoing peritoneal dialysis (PD). Although the identification of causative organisms and use of appropriate antibiotics are essential for treatment, rare and fastidious bacteria are sometimes difficult to detect by conventional biochemical assays. Capnocytophaga canimorsus is a fastidious and slow-growing bacterium that forms a part of the normal oral flora of dogs and cats and is extremely rare as a peritonitis-causing organism. This report demonstrates the usefulness of a mass spectrometry-based technique in identifying such a rare organism in PD-related peritonitis and discusses the diagnosis and treatment of C. canimorsus peritonitis. CASE PRESENTATION: A 49-year-old woman with type 2 diabetes mellitus underwent PD for two years. Repeated exit-site infections led to subcutaneous pathway diversion two months ago. She was hospitalized with fever and abdominal pain as well as cloudy dialysis effluent. Laboratory data revealed increased serum C-reactive protein level and white blood cell (WBC) count in the effluent. Her exit site had no sign of infection, leading to the diagnosis of PD-related peritonitis. Initial therapy with intraperitoneal ceftazidime immediately ameliorated her symptoms, and the WBC count in the effluent normalized in five days. Culture test results of the dialysis effluent on admission were negative with no information regarding the infection route. However, mass spectrometry (MALDI Biotyper, Bruker Daltonics) successfully obtained the specific spectral pattern for C. canimorsus. She had four cats in her house and was advised not to allow the cats in the room where the bag exchange took place. CONCLUSIONS: C. canimorsus is a rare cause of peritonitis in PD patients and is usually susceptible to intraperitoneal third-generation cephalosporins. This mass spectrometry-based bacterial identification method could provide more opportunities to identify uncommon causes and promote appropriate antibiotics therapy in PD-related peritonitis.

DOI： 10.1186/s12882-019-1415-x

Cavernous Transformation and Granulomatous Epididymis in Behçet Disease. Reviewed International journal

Yumi Motokura, Haruki Watanabe, Yuriko Yamamura, Yuzuki Kano, Yoshinori Matsumoto, Tomoko Kawabata, Ken-Ei Sada, Jun Wada

Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases 25 ( 4 ) 45 - 47 2019.6

Contrast-enhanced Computed Tomography-Guided Percutaneous Cryoablation of Renal Cell Carcinoma in a Renal Allograft: First Case in Asia. Reviewed

Ichiro Tsuboi, Motoo Araki, Hiroyasu Fujiwara, Toshihiro Iguchi, Takao Hiraki, Naoko Arichi, Kasumi Kawamura, Yuki Maruyama, Yosuke Mitsui, Takuya Sadahira, Risa Kubota, Shingo Nishimura, Tomoko Sako, Atsushi Takamoto, Koichiro Wada, Yasuyuki Kobayashi, Toyohiko Watanabe, Hiroyuki Yanai, Masashi Kitagawa, Katsuyuki Tanabe, Hitoshi Sugiyama, Jun Wada, Hiroaki Shiina, Susumu Kanazawa, Yasutomo Nasu

Acta medica Okayama 73 ( 3 ) 269 - 272 2019.6

Language：English

Nephron-sparing treatment should be offered whenever possible to avoid dialysis in allograph cases. Cryoablation is a new treatment option for treating small-sized renal cell cancer (RCCs). We report a case of RCC arising in a kidney allograft treated by cryoablation. To our knowledge, this is the first case in Asia of RCC in a renal allograft treated using cryoablation. Contrast-enhanced CT-guided percutaneous renal needle biopsy and cryoablation were used to identify the RCC, which could not be identified by other techniques. The postoperative course was uneventful. Contrast-enhanced CT also showed no recurrence or metastases at the 6-month follow-up.

DOI： 10.18926/AMO/56871

Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet. Reviewed

Tomonari Kimura, Kazufumi Nakamura, Toru Miyoshi, Masashi Yoshida, Kaoru Akazawa, Yukihiro Saito, Satoshi Akagi, Yuko Ohno, Megumi Kondo, Daiji Miura, Jun Wada, Hiroshi Ito

International heart journal 60 ( 3 ) 728 - 735 2019.5

Language：English Publishing type：Research paper (scientific journal)

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are drugs for diabetes and might prevent heart failure. In this study, we investigated the effects of tofogliflozin, an SGLT2 inhibitor, on cardiac hypertrophy and metabolism in hypertensive rats fed a high-fat diet. Dahl salt-sensitive (DS) rats, hypertensive model rats, and Dahl salt-resistant (DR) rats, non-hypertensive model rats, were fed a high-salt and high-fat diet containing tofogliflozin (0.005%) for 9 weeks to examine the effects of this drug on cardiac hypertrophy and metabolism. Tofogliflozin tended to suppress a rise of the systolic blood pressure, relative to the control, throughout the treatment period in both DR and DS rats, and significantly suppress a rise of the systolic blood pressure, relative to the control, at the 9th week in DS rats. Tofogliflozin reduced cardiac hypertrophy (heart weight/body weight) not only in DS rats but also in DR rats. Histological analysis showed that tofogliflozin significantly decreased cardiomyocyte hypertrophy and perivascular fibrosis in both DS and DR rats. Tofogliflozin significantly decreased the expression levels of genes related to cardiac hypertrophy (encoding for natriuretic peptides A and B and interleukin-6), and to cardiac fibrosis (encoding for transforming growth factor-β1 and collagen type IV), in DS rats. Recent studies have shown that hypertrophied and failing hearts shift to oxidizing ketone bodies as a significant fuel source. We also performed metabolome analysis for ventricular myocardial tissue. Tofogliflozin reduced 3-hydroxybutyrate, a ketone body, and significantly decreased the expression levels of β-hydroxybutyrate dehydrogenase 1 and 3-oxoacid CoA-transferase, which are related to ketone oxidization. In conclusion, tofogliflozin ameliorated cardiac hypertrophy and fibrosis along with reduction of ketone usage in myocardial tissue.

DOI： 10.1536/ihj.18-392

The clinical efficacy of angiotensin II type1 receptor blockers on inflammatory markers in patients with hypertension: a multicenter randomized-controlled trial; MUSCAT-3 study. Reviewed International journal

Ryoko Umebayashi, Haruhito A Uchida, Yuka Okuyama, Yuki Kakio, Yoshihisa Hanayama, Kenichi Shikata, Jun Wada

Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 24 ( 3 ) 255 - 261 2019.5

Language：English Publishing type：Research paper (scientific journal)

Purpose: The purpose of present study was to evaluate the clinical efficacy of irbesartan on the anti-inflammatory and anti-oxidative stress effect in patients with hypertension compared to other ARBs. Further, we assessed the effect of the ARBs on kidney function and urinary albumin excretion. Methods: Eighty-five outpatients with hypertension who took an ARB except irbesartan more than 3 months were assigned into two groups, one continued the same ARB and the other switched the ARB to irbesartan for 6 months. Results: Although blood pressures were equally controlled (continue group: 148 ± 2/79 ± 2 mmHg to 131 ± 2/74 ± 2 mmHg; switch group: 152 ± 2/81 ± 2 mmHg to 132 ± 2/74 ± 2 mmHg; p < 0.001 each), the inflammatory markers (hsCRP, PTX3, MCP-1) and oxidative stress marker (MDA-LDL) did not change after 6 months in both groups. Urinary albumin excretion was significantly reduced only in the switch group without renal function deterioration (switch group 292.4 ± 857.9 mg/gCr to 250.6 ± 906.5 mg/gCr, p = 0.012). Conclusion: These results provide knowledge of the characteristics of irbesartan, suggesting appropriate choice of ARBs in the treatment for hypertension should be considered.

DOI： 10.1080/1354750X.2018.1548033

Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease. Reviewed International journal

Koichi Kikuchi, Daisuke Saigusa, Yoshitomi Kanemitsu, Yotaro Matsumoto, Paxton Thanai, Naoto Suzuki, Koki Mise, Hiroaki Yamaguchi, Tomohiro Nakamura, Kei Asaji, Chikahisa Mukawa, Hiroki Tsukamoto, Toshihiro Sato, Yoshitsugu Oikawa, Tomoyuki Iwasaki, Yuji Oe, Tomoya Tsukimi, Noriko N Fukuda, Hsin-Jung Ho, Fumika Nanto-Hara, Jiro Ogura, Ritsumi Saito, Shizuko Nagao, Yusuke Ohsaki, Satoshi Shimada, Takehiro Suzuki, Takafumi Toyohara, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Yukako Akiyama, Mariko Ichijo, Tetsuro Matsuhashi, Akihiro Matsuo, Yoshiaki Ogata, Ching-Chin Yang, Chitose Suzuki, Matthew C Breeggemann, Jurgen Heymann, Miho Shimizu, Susumu Ogawa, Nobuyuki Takahashi, Takashi Suzuki, Yuji Owada, Shigeo Kure, Nariyasu Mano, Tomoyoshi Soga, Takashi Wada, Jeffrey B Kopp, Shinji Fukuda, Atsushi Hozawa, Masayuki Yamamoto, Sadayoshi Ito, Jun Wada, Yoshihisa Tomioka, Takaaki Abe

Nature communications 10 ( 1 ) 1835 - 1835 2019.4

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Communications

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.

DOI： 10.1038/s41467-019-09735-4

Parathyroid Lipoadenoma: A Pitfall in Preoperative Localization. Reviewed

Satoshi Fujisawa, Kenichi Inagaki, Jun Wada

Internal medicine (Tokyo, Japan) 58 ( 8 ) 1183 - 1184 2019.4

Exogenous Vasohibin-2 Exacerbates Angiotensin II-Induced Ascending Aortic Dilation in Mice. Reviewed

Michihiro Okuyama, Haruhito A Uchida, Yoshiko Hada, Yuki Kakio, Nozomu Otaka, Ryoko Umebayashi, Katsuyuki Tanabe, Yasuhiro Fujii, Shingo Kasahara, Venkateswaran Subramanian, Alan Daugherty, Yasufumi Sato, Jun Wada

Circulation reports 1 ( 4 ) 155 - 161 2019.4

Language：English Publishing type：Research paper (scientific journal)

Background: Chronic angiotensin II (AngII) infusion promotes ascending aortic dilation in C57BL/6J mice. Meanwhile, vasohibin-2 (VASH2) is an angiogenesis promoter in neovascularization under various pathologic conditions. The aim of this study was to investigate whether exogenous VASH2 influences chronic AngII-induced ascending aortic dilation. Methods and Results: Eight-ten-week-old male C57BL/6J mice were injected with adenovirus (Ad) expressing either VASH2 or LacZ. One week after the injection, mice were infused with either AngII or saline s.c. for 3 weeks. Mice were divided into 4 groups: AngII+VASH2, AngII+LacZ, saline+VASH2, and saline+LacZ. Overexpression of VASH2 significantly increased AngII-induced intimal areas as well as the external diameter of the ascending aorta. In addition, VASH2 overexpression promoted ascending aortic medial elastin fragmentation in AngII-infused mice, which was associated with increased matrix metalloproteinase activity and medial smooth muscle cell (SMC) apoptosis. On western blot analysis, accumulation of apoptotic signaling proteins, p21 and p53 was increased in the AngII+VASH2 group. Furthermore, transfection of human aortic SMC with Ad VASH2 increased p21 and p53 protein abundance upon AngII stimulation. Positive TUNEL staining was also detected in the same group of the human aortic SMC. Conclusions: Exogenous VASH2 exacerbates AngII-induced ascending aortic dilation in vivo, which is associated with increased medial apoptosis and elastin fragmentation.

DOI： 10.1253/circrep.CR-19-0008

The relationship between repeated measurement of casual and 24-h urinary sodium-to-potassium ratio in patients with chronic kidney disease. Reviewed International journal

Yuka Okuyama, Haruhito A Uchida, Toshiyuki Iwahori, Hiroyoshi Segawa, Ayako Kato, Hidemi Takeuchi, Yuki Kakio, Ryoko Umebayashi, Masashi Kitagawa, Hitoshi Sugiyama, Katsuyuki Miura, Hirotsugu Ueshima, Jun Wada

Journal of human hypertension 33 ( 4 ) 286 - 297 2019.4

Language：English Publishing type：Research paper (scientific journal)

This study aimed to clarify the relationship between repeated measurements of casual (spot) and 24-h urinary sodium-to-potassium (Na/K) ratios in patients with chronic kidney disease (CKD). A total of 61 inpatients with CKD, 31 in stage 1-3 (eGFR [estimated glomerular filtration rate] ≥ 30 ml/min/1.73 m2) and 30 in stage 4-5 (eGFR < 30 ml/min/1.73 m2), aged 20-85 consuming a low-sodium diet (NaCl [sodium chloride] 6 g/day) were recruited. Urinary Na, K, and Na/K ratios were measured in both casual urine samples and 2-day, 24 h urine samples, and then analyzed by correlation and Bland-Altman analyses. Mean 24-h urine Na/K ratio was higher in participants in stage 4-5 (5.1) than in participants in stage 1-3 (4.1) CKD. Casual urine Na/K ratio was strongly correlated with 2-day, 24-h urine Na/K ratio by sampling 4 casual urine specimens every morning and evening in participants in stage 1-3 (r = 0.69-0.78), but not in stage 4-5 (r = 0.12-0.19). The bias for mean Na/K ratio between 2-day, 24-h urine, and the 4 casual urine sampling ranged from -0.86 to 0.16 in participants in stage 1-3, and the quality of agreement for the mean of this casual urine sampling was similar to that of sampling 8 casual urine samples for estimating 2-day, 24-h values. Methods using repeated casual urine Na/K ratios may provide a reasonable estimation of 24-h urine Na/K ratio in normotensive and hypertensive as well as individuals with stage 1-3, but not stage 4-5 CKD.

DOI： 10.1038/s41371-018-0127-1

Orexin A modulates prolactin production by regulating BMP-4 activity in rat pituitary lactotorope cells. Reviewed International journal

Satoshi Fujisawa, Motoshi Komatsubara, Kanako Ogura-Ochi, Naoko Tsukamoto-Yamauchi, Kishio Toma, Kenichi Inagaki, Jun Wada, Fumio Otsuka

Peptides 113 35 - 40 2019.3

Language：English Publishing type：Research paper (scientific journal)

The impact of orexins on anterior pituitary function has yet to be clarified. We studied the effects of orexin A and its interaction with the bone morphogenetic protein (BMP) system on the regulatory role of prolactin synthesis using rat lactotrope GH3 cells expressing BMP-4. Orexin type 1 receptor (OX1R), but not type 2 receptor (OX2R), was predominantly expressed in GH3 cells. Orexin A suppressed forskolin-induced, but not basal, prolactin mRNA expression without reducing cAMP levels. Of note, orexin A suppressed BMP-4-induced prolactin mRNA and cAMP synthesis. Impairment of the effects of orexin by chemical inhibitors suggested involvement of the P38 pathway in the OX1R activity that suppresses BMP-4-induced PRL expression. Given that inhibition of BMP-receptor signaling reduced prolactin mRNA levels, endogenous BMP action is likely to be linked to the activation of prolactin synthesis by GH3 cells. Orexin A was revealed to suppress Smad1/5/9 phosphorylation and Id-1 transcription induced by BMP-4, which was restored in the presence of orexin-receptor antagonists, suggesting that the inhibitory effect of orexin A occurred via OX1R. Orexin A also reduced ALK-3 expression but increased inhibitory Smad6/7 expression, while BMP-4 treatment downregulated OX1R expression. These results indicated that orexin A plays an inhibitory role in prolactin production through suppression of endogenous BMP activity in GH3 cells, suggesting that a new functional role of the interaction between orexin and BMP-4 is modulation of prolactin levels in lactotrope cells.

DOI： 10.1016/j.peptides.2019.01.002

Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells. Reviewed International journal

Sumie Hiramatsu, Katsue S Watanabe, Sonia Zeggar, Yosuke Asano, Yoshia Miyawaki, Yuriko Yamamura, Eri Katsuyama, Takayuki Katsuyama, Haruki Watanabe, Mariko Takano-Narazaki, Yoshinori Matsumoto, Tomoko Kawabata, Ken-Ei Sada, Jun Wada

Scientific reports 9 ( 1 ) 3054 - 3054 2019.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Nature

Global DNA hypomethylation in CD4+ cells in systemic lupus erythematosus (SLE) was suggested to play a key role in the pathogenesis. To identify new methylation-sensitive genes, we integrated genome-wide DNA methylation and mRNA profiling data in CD4+ cells of MRL/lpr (MRL) and C57BL6/J (B6) mice. We identified Cathepsin E (Ctse), in which 13 methyl-CpGs within 583 bp region of intron 1 were hypomethylated, and Ctse mRNA upregulated in MRL compared with B6 mice. One of methyl-CpGs, mCGCG was 93.3 ± 2.05% methylated in B6 mice, while 80.0 ± 6.2% methylated and mutated to CGGG in MRL mice. Kaiso is known to bind to mCGCG and we hypothesized that it represses expression of Ctse in B6 mice. The binding of Kaiso to mCGCG site in B6 mice was reduced in MRL mice revealed by ChIP-PCR. EL4 cells treated with 5-azaC and/or Trichostatin A showed the suppression of binding of Kaiso to mCGCG motif by ChIP-PCR and the overexpression of Ctse was demonstrated by qPCR. Ctse gene silencing by siRNA in EL4 cells resulted in reduction of IL-10 secretion. The hypomethylation of mCGCG motif, reduced recruitment of Kaiso, and increased expression of Ctse and Il-10 in CD4+ cells may be involved in the pathogenesis of SLE.

DOI： 10.1038/s41598-019-38809-y

Effect of an enhanced recovery after surgery protocol in patients undergoing pancreaticoduodenectomy: A randomized controlled trial. Reviewed International journal

Kosei Takagi, Ryuichi Yoshida, Takahito Yagi, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Shiro Hinotsu, Takashi Matsusaki, Hiroshi Morimatsu, Jun Eguchi, Jun Wada, Masuo Senda, Toshiyoshi Fujiwara

Clinical nutrition (Edinburgh, Scotland) 38 ( 1 ) 174 - 181 2019.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND & AIMS: Evidence of the advantages of enhanced recovery after surgery (ERAS) protocols following pancreaticoduodenectomy (PD) is limited. The aim of this study was to examine the efficiency of ERAS protocols in patients following PD. METHODS: Between June 2014 and October 2016, patients undergoing PD were randomly assigned to receive ERAS protocols or standard care. The primary endpoint was the postoperative length of stay. Secondary endpoints included postoperative complications, postoperative quality-of-life (QoR-40J), readmission, and medical cost. RESULTS: Of 80 eligible patients, 74 were analyzed in intention-to-treat principles: 37 in the control group and 37 in the ERAS group. The mean length of stay in the ERAS group was significantly shorter than that in the control group (20.1 ± 5.4 vs 26.9 ± 13.5 days, P < 0.001). The ERAS group had a significantly lower percentage of postoperative complications (32.4% vs 56.8%, P = 0.034) and readmissions (0% vs 8.1%, P = 0.038). Quality-of-life was also significantly better in the ERAS group (184 ± 12.4 vs 177 ± 14.5, P = 0.022). The total medical cost was lower in the ERAS group, but not significantly ($25,445 ± 5065 vs $28,384 ± 9999, P = 0.085). CONCLUSIONS: The optimization of ERAS protocols in patients undergoing PD is safe and accelerates perioperative recovery and quality-of-life, thereby reducing the length of stay. Morbidity was significantly decreased in the ERAS group without compromising surgical outcome. REGISTRATION NUMBER: UMIN000014068.

DOI： 10.1016/j.clnu.2018.01.002

Risk factors for cytomegalovirus infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis. Reviewed International journal

Michiko Morishita, Ken-Ei Sada, Yoshinori Matsumoto, Keigo Hayashi, Yosuke Asano, Sumie Hiramatsu Asano, Keiji Ohashi, Yoshia Miyawaki, Eri Katsuyama, Haruki Watanabe, Tomoko Kawabata, Jun Wada

PloS one 14 ( 7 ) e0218705 2019

Language：English Publishing type：Research paper (scientific journal)

AIMS: Cytomegalovirus (CMV) infection under immunosuppression sometimes causes death. This study aimed to elucidate risk factors for CMV infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: Patients with AAV who underwent remission induction treatment at Okayama University Hospital between 2006 and 2016 were retrospectively analyzed. The primary outcome was the development of CMV infection within 3 months. RESULTS: Of the 111 patients, 13 (11.7%) patients developed CMV infection. Patients with CMV infection were older (p = 0.030) and had a higher body mass index (p = 0.029) in comparison to those without CMV infection. A higher proportion had a severe form (p = 0.001) and granulomatosis with polyangiitis (GPA) (p = 0.001), as well as a higher Birmingham Vasculitis Activity Score (p = 0.018) and C-reactive protein (p = 0.018) levels at baseline. Using logistic regression analysis, severe form and GPA were independent risk factors (odds ratio [OR] = 9.68, 95% confidence interval [CI] = 1.92-60.23, and OR = 7.46, 95% CI = 1.46-47.60, respectively). In addition, patients with CMV infection were more likely than those without infection to be glucocorticoid-related diabetes mellitus (p = 0.025). CONCLUSION: Our study highlights disease severity and subgroups of AAV as risk factors for CMV infection.

DOI： 10.1371/journal.pone.0218705

Report of health checkup system for chronic kidney disease in general population in Okayama city: effect of health guidance intervention on chronic kidney disease outcome. Reviewed International journal

Yuki Kakio, Haruhito A Uchida, Hidemi Takeuchi, Yuka Okuyama, Ryoko Umebayashi, Hiroyuki Watatani, Yohei Maeshima, Hitoshi Sugiyama, Jun Wada

International journal of nephrology and renovascular disease 12 143 - 152 2019

Language：English Publishing type：Research paper (scientific journal)

Background: From 2011, Okayama municipal government started the health checkup follow-up project to find those who were unaware of suffering chronic kidney disease and to prevent from aggravation of CKD stage. In this study, we aimed to evaluate the effect of 2 years' CKD-follow-up project regarding renal function and CKD risks. Patients and methods: Those who received a health checkup by the national health insurance in Okayama city in 2011 were recruited. The patients with lifestyle-related diseases or metabolic syndrome were excluded. Subjects who had an estimated glomerular filtration rate<50 mL/min/1.73 m2 or urinary protein positive by dipstick test were defined as compromised renal function group. They were recommended to visit a medical institution. Non-compromised renal function participants with two or more risks for CKD (hyperglycemia, higher blood pressure, dyslipidemia, hyperuricemia) were recommended to receive a health guidance (risk group). The change of renal function and CKD risks between 2011 and 2013 in each group was examined. Results: A total of 28,309 people received a health checkup in 2011. In compromised renal function group, 39.5% (96/243) of the subjects improved their CKD stages in 2013 regardless of the visit of medical institutions or the frequency of receiving health checkup. In risk group, 63.4% (260/410) of the subjects decreased their CKD risks in 2013 independent of the reception of health guidance. Conclusion: In both compromised renal function group and risk group, more than half of subjects kept their kidney function (217/243) and decreased the number of CKD risks (260/410) in 2 years' follow-up. Receiving a health checkup itself and notification of one's own health condition could exert a protective effect on kidney function.

DOI： 10.2147/IJNRD.S198781

Thrombocytosis as a prognostic factor in polymyalgia rheumatica: characteristics determined from cluster analysis. Reviewed International journal

Keigo Hayashi, Keiji Ohashi, Haruki Watanabe, Ken-Ei Sada, Kenta Shidahara, Yosuke Asano, Sumie Hiramatsu Asano, Yuriko Yamamura, Yoshia Miyawaki, Michiko Morishita, Yoshinori Matsumoto, Tomoko Kawabata, Jun Wada

Therapeutic advances in musculoskeletal disease 11 1759720X19864822 2019

Language：English Publishing type：Research paper (scientific journal)

Background: This study aimed to identify the clinical subgroups of polymyalgia rheumatica (PMR) using cluster analysis and compare the outcomes among the identified subgroups. Methods: We enrolled patients with PMR who were diagnosed at Okayama University Hospital, Japan between 2006 and 2017, met the 2012 European League Against Rheumatism/American College of Rheumatology provisional classification criteria for PMR, and were treated with glucocorticoids. Hierarchical cluster analysis using variables selected by principal component analysis was performed to identify the clusters. Subsequently, the outcomes among the identified clusters were compared in the study. The primary outcome was treatment response at 1 month after commencement of treatment. The secondary outcome was refractory clinical course, which was defined as the requirement of additional treatments or relapse during a 2-year observational period. Results: A total of 61 consecutive patients with PMR were enrolled in the study. Their mean age was 71 years, and 67% were female. Hierarchical cluster analysis revealed three distinct subgroups: cluster 1 (n = 14) was characterized by patients with thrombocytosis (all patients showed a platelet count of >45 × 10⁴/µl), cluster 2 (n = 38), by patients without peripheral arthritis, and cluster 3 (n = 9), by patients with peripheral arthritis. The patients in cluster 1 achieved treatment response less frequently than those in cluster 2 (14% versus 47%, p = 0.030). Refractory cases were more frequent in cluster 1 than in cluster 2; however, no significant difference was noted (71% versus 42%, p = 0.06). Conclusions: Thrombocytosis could predict the clinical course in patients with PMR.

DOI： 10.1177/1759720X19864822

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