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Papers - ITOH Hiroshi

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Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men

Yamaguchi Shintaro, Irie Junichiro, Mitsuishi Masanori, Uchino Yuichi, Nakaya Hideaki, Takemura Ryo, Inagaki Emi, Kosugi Shotaro, Okano Hideyuki, Yasui Masato, Tsubota Kazuo, Hayashi Kaori, Yoshino Jun, Itoh Hiroshi

Endocrine Journal (The Japan Endocrine Society) 71 ( 2 ) 153 - 169 2024

ISSN 09188959

Obesity and aging are major risk factors for several life-threatening diseases. Accumulating evidence from both rodents and humans suggests that the levels of nicotinamide adenine dinucleotide (NAD+), a regulator of many biological processes, declines in multiple organs and tissues with aging and obesity. Administration of an NAD+ intermediate, nicotinamide mononucleotide (NMN), replenishes intracellular NAD+ levels and mitigates aging- and obesity-associated derangements in animal models. In this human clinical study, we aimed to investigate the safety and effects of 8-week oral administration of NMN on biochemical, metabolic, ophthalmologic, and sleep quality parameters as well as on chronological alterations in NAD+ content in peripheral tissues. An 8-week, single-center, single-arm, open-label clinical trial was conducted. Eleven healthy, middle-aged Japanese men received two 125-mg NMN capsules once daily before breakfast. The 8-week NMN supplementation regimen was well-tolerated; NAD+ levels in peripheral blood mononuclear cells increased over the course of NMN administration. In participants with insulin oversecretion after oral glucose loading, NMN modestly attenuated postprandial hyperinsulinemia, a risk factor for coronary artery disease (n = 3). In conclusion, NMN overall safely and effectively boosted NAD+ biosynthesis in healthy, middle-aged Japanese men, showing its potential for alleviating postprandial hyperinsulinemia.

Clinical significance of serum urea-to-creatinine ratio in patients undergoing peritoneal dialysis.

Shun Tonomura, Kiyotaka Uchiyama, Takashin Nakayama, Ryunosuke Mitsuno, Daiki Kojima, Eriko Yoshida Hama, Tomoki Nagasaka, Erina Sugita Nishimura, Ei Kusahana, Rina Takahashi, Norifumi Yoshimoto, Shintaro Yamaguchi, Kohkichi Morimoto, Tadashi Yoshida, Kaori Hayashi, Takeshi Kanda, Naoki Washida, Hiroshi Itoh

Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 27 ( 6 ) 1103 - 1112 2023.12

ISSN 17449979

INTRODUCTION: We aimed to determine the correlation between the serum urea-to-creatinine ratio and residual kidney function (RKF) in patients undergoing peritoneal dialysis (PD), as well as its predictive value for PD-related outcomes. METHODS: This study included a cross-sectional study to assess the correlation between serum urea-to-creatinine ratio and RKF in 50 patients on PD and a retrospective cohort study to assess the association between serum urea-to-creatinine ratio and PD-related outcomes in 122 patients who initiated PD. RESULTS: Serum urea-to-creatinine ratios had significant positive correlations with renal Kt/V and creatinine clearance values (r = 0.60, p < 0.001 and r = 0.61, p < 0.001, respectively). Additionally, serum urea-to-creatinine ratio was significantly associated with a lower risk of transfer to hemodialysis or PD/hemodialysis hybrid therapy (hazard ratio: 0.84, 95% confidence interval: 0.75-0.95). CONCLUSION: The serum urea-to-creatinine ratio can be an indicator of RKF and a prognostic factor in patients undergoing PD.

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Comparison of the effects of angiotensin receptor-neprilysin inhibitors and thiazide diuretic/renin-angiotensin system inhibitor combination therapy in hypertensive patients: a retrospective cohort study.

Ryunosuke Mitsuno, Kiyotaka Uchiyama, Takashin Nakayama, Rina Takahashi, Norifumi Yoshimoto, Shintaro Yamaguchi, Naoki Washida, Takeshi Kanda, Kaori Hayashi, Hiroshi Itoh

Journal of human hypertension 37 ( 12 ) 1049 - 1055 2023.12

ISSN 09509240

Angiotensin receptor-neprilysin inhibitors (ARNIs) have been approved as antihypertensive agents in Japan, and thiazide diuretics (TZDs) are widely used concomitantly with renin-angiotensin system inhibitors (RASIs) for hypertension. This retrospective study included patients with hypertension who switched from RASI to ARNI therapy (ARNI group) and those who were prescribed TZDs with RASIs (TZD/RASI group). Drug-related changes in the estimated glomerular filtration rate (eGFR), blood pressure (BP), body weight (BW), serum electrolytes, uric acid (UA), and triglyceride levels were compared between the two groups. Overall, 70 participants (31 and 39 in the ARNI and TZD/RASI groups, respectively) were enrolled and observed for a median of 2 months. According to linear mixed models, compared with the TZD/RASI group, the ARNI group exhibited a significant change in mean eGFR of 3.71 mL/min/1.73 m2 [95% confidence interval (CI), 0.57-6.84; P = 0.02] from the time of switching drug to the next outpatient visit. Further, compared with the TZD/RASI group, the ARNI group exhibited significant changes in mean serum UA (-1.27; 95% CI, -1.66 to -0.88), sodium (1.22; 95% CI, 0.12 to -2.32), chloride (2.14; 95% CI, 0.75-3.52), and triglyceride (-52.1; 95% CI, -100.9 to -3.29) levels. Conversely, serum potassium levels, BW, and systolic and diastolic BP did not differ significantly between the two groups (P = 0.69, 0.44, 0.49, and 0.66, respectively). Compared with the combination therapy of TZD and RASI, ARNI therapy causes less renal dysfunction, hyperuricemia, and hypertriglyceridemia with fewer electrolyte abnormalities and no significant difference in antihypertensive effects.

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Dietary protein intake and all-cause mortality: results from The Kawasaki Aging and Wellbeing Project.

Hideaki Kurata, Shu Meguro, Yukiko Abe, Takashi Sasaki, Keiko Asakura, Yasumichi Arai, Hiroshi Itoh

BMC geriatrics 23 ( 1 ) 479 - 479 2023.12

BACKGROUND: Increased protein intake has been recommended to prevent sarcopenia/frailty, reports on the quantity and quality of protein intake needed and the associated prognosis, particularly in the aging population of Asia, are limited. In this study, we aimed to investigate the relationship between protein intake and mortality in Japanese individuals, aged 85 years and older. METHODS: The data were obtained from The Kawasaki Aging and Wellbeing Project, which is a prospective cohort study of older adults aged between 85 and 89 years with no physical disability at baseline. Of the 1,026 adults in the cohort, 833 were included in the analysis, after excluding those who had not completed a brief, self-administered diet history questionnaire or those who scored less than 24 on the Mini-Mental State Examination. The participants were grouped into quartiles based on protein intake: Q1 (protein < 14.7, %Energy), Q2 (14.7 ≤ protein < 16.7, %Energy), Q3 (16.7 ≤ protein < 19.1, %Energy), and Q4 (≥ 19.1, %Energy). Multivariate Cox proportional hazards models were utilized to evaluate the association between protein intake and all-cause mortality. Kaplan-Meier survival curves were employed to investigate the relationship between protein intake and all-cause mortality. RESULTS: The mean protein intake of our study population was 17.0% of total energy. Animal protein intake, particularly fish intake, increased significantly along with total protein intake. The study had an average observation period of 1,218 days and recorded 89 deaths. After adjusting for age, sex, skeletal muscle mass index, cardiovascular disease, cancer, education, and serum albumin levels, a lower risk of all-cause mortality was observed in the highest protein intake (Q4) group than in the lowest protein intake (Q1) group (hazard ratio: 0.44, 95% confidence interval: 0.22-0.90, p-value: 0.020). CONCLUSION: Protein intake is associated with a reduced risk of all-cause mortality in older adults (aged ≥ 85 years) who engage in independent activities of daily living. This association may impact all-cause mortality independent of muscle mass.

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Peritoneal dialysis-related peritonitis with encapsulated ascites due to Mycobacterium abscessus subsp. massilience and subsp. bolletii: a case series and literature review

Nagasaka T., Uchiyama K., Shirai R., Mitsuno R., Maruki T., Hama E.Y., Sugita E., Kusahana E., Sumura R., Nakayama T., Kinugasa S., Morimoto K., Ishibashi Y., Washida N., Itoh H.

Renal Replacement Therapy 9 ( 1 ) 2023.12

Background: As there is no established standard of care for non-tuberculous mycobacterium (NTM) peritoneal dialysis (PD)-related peritonitis, its treatments have to be case-dependent, which is often difficult. Additionally, several reported cases were accompanied by encapsulated ascites, adhesive ileus, and encapsulating peritoneal sclerosis, suggesting treatment difficulties. We report two cases of PD-related peritonitis with encapsulated ascites due to Mycobacterium abscessus subsp. massilience and subsp. bolletii. To the best of our knowledge, this is the first case series to report PD-related peritonitis caused by Mycobacterium abscessus subsp. bolletii. Case presentation: The first case is that of a 74-year-old male patient who started PD six years ago for end-stage renal failure due to diabetic nephropathy. In February 2021, he presented with signs of infection at the exit-site and swelling of the tunnel. Mycobacterium abscessus subsp. massilience was detected in the culture of the exit-site exudate; thus, he was diagnosed with tunnel infection (caused by NTM). Subsequently, fever, abdominal pain, and increased cell counts in the PD drainage fluid were observed, and he was judged to have NTM peritonitis. His general condition improved after PD catheter removal in addition to antimicrobial treatment and encapsulated ascites drainage. The second case is that of a 52-year-old man who commenced PD for end-stage renal failure due to nephrosclerosis 12 years ago. In May 2022, he was diagnosed with PD-related peritonitis based on signs of infection at the exit-site, encapsulated ascites on computed tomography, and a cloudy PD drainage fluid. Mycobacterium abscessus subsp. bolletii was detected in the culture of the exit-site exudate, which led to the diagnosis of NTM peritonitis. In addition to antimicrobial treatment, PD catheter removal and encapsulated ascites drainage were performed. The patient also had adhesive bowel obstruction due to peritonitis and required decompression therapy with the insertion of a gastric tube. Conclusions: PD catheter removal and encapsulated ascites drainage might have improved inflammation and treatment outcomes. Additionally, Mycobacterium abscessus might be prone to forming encapsulated cavities and/or intestinal adhesions; however, further accumulation of cases clarifying “subspecies” of Mycobacterium abscessus is necessary to confirm this hypothesis.

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Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection.

Takashin Nakayama, Tatsuhiko Azegami, Maki Kiso, Masaki Imai, Ryuta Uraki, Kaori Hayashi, Akihito Hishikawa, Norifumi Yoshimoto, Ran Nakamichi, Erina Sugita-Nishimura, Eriko Yoshida-Hama, Yoshihiro Kawaoka, Hiroshi Itoh

Scientific reports 13 ( 1 ) 3103 - 3103 2023.12

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.

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Efficacy and safety of a telemedicine system in subjects with gestational diabetes mellitus (TELEGLAM): Study protocol for a randomized controlled trial.

Kazuki Aoyama, Yuya Nakajima, Shu Meguro, Yasunori Sato, Rei Goto, Mariko Hida, Takeshi Arimitsu, Yoshifumi Kasuga, Mamoru Tanaka, Hiroshi Itoh

Heliyon 9 ( 11 ) e22504 2023.11

ISSN 24058440

BACKGROUND: Strict glycemic control is important to prevent perinatal complications in patients with gestational diabetes mellitus (GDM). Patients often require insulin injection, and frequent hospital visits are necessary to adjust the dose of insulin, which is considered burdensome for pregnant patients. Telemedicine may reduce the burden of hospital visits, and previous studies have reported its safety in GDM patients. This study aimed to evaluate the efficacy of telemedicine in GDM patients, focusing on patient satisfaction and health economic indicators. METHODS: This is a single-center, two-arm, randomized, open-label parallel-group study. Subjects will be selected from the patient population attending the Department of Endocrinology, Metabolism, and Nephrology, Keio University School of Medicine, Japan. Patients diagnosed with GDM by an oral glucose tolerance test (OGTT) by 29 weeks and 6 days of gestation who have undergone self-monitoring of blood glucose (SMBG) and insulin injection are eligible for inclusion. In the intervention group, telemedicine will be administered using the MeDaCa telemedicine system developed by the Medical Data Card, Inc., Tokyo, Japan. Subjects in the control group will be examined face-to-face every 2-3 weeks, as usual. We set health economic indicators and patient satisfaction as the primary endpoints, and will perform a cost-consequence analysis. Glycemic control indicators and perinatal outcomes will be evaluated as secondary endpoints. CONCLUSIONS: Eligible patients are currently being recruited. Recruitment will be completed when the expected number of patients are enrolled.

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N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) has potent anti-fibrotic and anti-inflammatory activity in a fibrotic kidney model: is it an old uremic toxin?

Norito Yoshimura, Katsutoshi Yamada, Takashi Ono, Mitsuru Notoya, Hideo Yukioka, Rina Takahashi, Shu Wakino, Takeshi Kanda, Hiroshi Itoh

Clinical and experimental nephrology 27 ( 11 ) 901 - 911 2023.11

ISSN 13421751

BACKGROUND: Uremic toxins accumulate in renal tissues and cells due to chronic kidney disease (CKD). Abnormalities in nicotinamide adenine dinucleotide (NAD +) metabolism lead to the progression of CKD. NAD + metabolites, such as N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) and N-methyl-4-pyridone-5-carboxamide (N-Me-4PY), have been recognized as uremic toxins. However, no reports have validated whether they are actually harmful to the body. Therefore, we focused on the structural similarity of these metabolites to the anti-fibrotic drug pirfenidone and evaluated their effects on renal fibrosis. METHODS: Each NAD + metabolite was treated with TGFβ1 to kidney fibroblasts or tubular epithelial cells, and quantitative RT-PCR and Western blot analysis were conducted. N-Me-2PY was orally administered to a ligated murine kidney fibrosis model (UUO) to evaluate its anti-fibrotic and toxic effects on the body. RESULTS: N-Me-2PY, N-Me-4PY, and nicotinamide N-oxide (NNO) inhibited TGFβ1-induced fibrosis and inflammatory gene expression in kidney fibroblasts. N-Me-2PY strongly suppressed the expression of types I and III collagen, αSMA, and IL-6. N-Me-2PY also suppressed TGFβ1-induced type I collagen and IL-6 expression in renal tubular epithelial cells. No toxic effect was observed with N-Me-2PY treatment, while attenuating renal fibrosis and tubular dilation in UUO mice. Suppression of various fibrosis- and inflammation-related genes was also observed. N-Me-2PY did not inhibit TGFβ1-induced Smad3 phosphorylation but inhibited Akt phosphorylation, suggesting that N-Me-2PY exerts anti-fibrotic and anti-inflammatory effects through Akt inhibition, similar to pirfenidone. CONCLUSIONS: NAD + metabolites, such as N-Me-2PY, are not uremic toxins but are potential therapeutic agents that have anti-fibrotic effects in CKD.

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Pediatric blood pressure category predicts longitudinal blood pressure change in adolescence and early adulthood.

Tatsuhiko Azegami, Keiko Uchida, Yasunori Sato, Ayano Murai-Takeda, Mikako Inokuchi, Hiroshi Itoh, Masaaki Mori

Pediatric research 94 ( 5 ) 1731 - 1737 2023.11

ISSN 00313998

BACKGROUND: Patterns of blood pressure (BP) change from early adolescence to young adulthood have not been well-described. The objective of this study was to examine the predictive value of pediatric BP classification on BP change and identify subpopulations with large BP increases during adolescence and early adulthood. METHODS: Baseline data were obtained from medical checkups of Japanese adolescents aged 12-13 years in 2009 or 2010 and subsequent BP values were followed for a 9-year period. Mixed-effects models were used to estimate the effects of baseline factors on subsequent BP changes. RESULTS: Hypertensive and elevated BP group consistently had higher BP values than normal BP group throughout the observation period. Multivariate mixed-effects model analyses revealed group-by-time interactions between systolic BP change and BP category in males and uric acid category in females, and between diastolic BP change and white blood cell count in males and obesity and high-density lipoprotein cholesterol in females; however, these factors had limited effects on the rate of BP increase, indicating that they are not suitable as clinical predictors of BP increase. CONCLUSIONS: Pediatric BP category predicted BP values, but there was no factor that identified subpopulations with large BP increases in adolescence and early adulthood. IMPACT: Blood pressure category in the American Academy of Pediatrics clinical practice guideline at age 12-13 years predicted subsequent blood pressure values during adolescence and early adulthood. No baseline factor that identified a subpopulation with large increase in blood pressure during adolescence and early adulthood in clinical practice was found. Our study contributes to the existing literature by demonstrating the usefulness of the American Academy of Pediatrics clinical practice guideline for blood pressure classification in a Japanese population.

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Proportion of early extubation and short-term outcomes after esophagectomy: a retrospective cohort study.

Hirano Y, Konishi T, Kaneko H, Itoh H, Matsuda S, Kawakubo H, Uda K, Matsui H, Fushimi K, Daiko H, Itano O, Yasunaga H, Kitagawa Y

International journal of surgery (London, England) 109 ( 10 ) 3097 - 3106 2023.10

ISSN 1743-9191

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Adipocyte NMNAT1 expression is essential for nuclear NAD+ biosynthesis but dispensable for regulating thermogenesis and whole-body energy metabolism.

Shintaro Yamaguchi, Daiki Kojima, Tooba Iqbal, Shotaro Kosugi, Michael P Franczyk, Nathan Qi, Yo Sasaki, Keisuke Yaku, Kenji Kaneko, Kenichiro Kinouchi, Hiroshi Itoh, Kaori Hayashi, Takashi Nakagawa, Jun Yoshino

Biochemical and biophysical research communications 674 162 - 169 2023.09

ISSN 0006291X

Nicotinamide adenine dinucleotide (NAD+) functions as an essential cofactor regulating a variety of biological processes. The purpose of the present study was to determine the role of nuclear NAD+ biosynthesis, mediated by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), in thermogenesis and whole-body energy metabolism. We first evaluated the relationship between NMNAT1 expression and thermogenic activity in brown adipose tissue (BAT), a key organ for non-shivering thermogenesis. We found that reduced BAT NMNAT1expression was associated with inactivation of thermogenic gene program induced by obesity and thermoneutrality. Next, we generated and characterized adiponectin-Cre-driven adipocyte-specific Nmnat1 knockout (ANMT1KO) mice. Loss of NMNAT1 markedly reduced nuclear NAD+ concentration by approximately 70% in BAT. Nonetheless, adipocyte-specific Nmnat1 deletion had no impact on thermogenic (rectal temperature, BAT temperature and whole-body oxygen consumption) responses to β-adrenergic ligand norepinephrine administration and acute cold exposure, adrenergic-mediated lipolytic activity, and metabolic responses to obesogenic high-fat diet feeding. In addition, loss of NMNAT1 did not affect nuclear lysine acetylation or thermogenic gene program in BAT. These results demonstrate that adipocyte NMNAT1 expression is required for maintaining nuclear NAD+ concentration, but not for regulating BAT thermogenesis or whole-body energy homeostasis.

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Associated factors and effects of comorbid atrial fibrillation in hypertensive patients due to primary aldosteronism

Sakaguchi S., Okamoto R., Inoue C., Akao M., Kamemura K., Kurihara I., Takeda Y., Ohno Y., Inagaki N., Rakugi H., Katabami T., Tsuiki M., Tanabe A., Tamura K., Fujita S., Yano Y., Dohi K., Abe M., Chiba Y., Fujii Y., Fujita M., Fukui M., Fukuoka T., Goto H., Hasegawa T., Hashimoto S., Haze T., Ichijo T., Itoh H., Iwamoto T., Izawa S., Kai T., Kawaguchi T., Kawamura T., Kawashima J., Kimura N., Kobayashi H., Matsuda F., Matsuda Y., Miyauchi S., Nakamura Y., Nishimoto K., Ogawa O., Ogawa Y., Ogo A., Okamura S., Okumura A., Otsuki M., Sakamoto R., Shimbo T., Sone M., Sugiyama T., Suzuki A., Suzuki T., Takahashi K., Takura T., Tanaka T., Wada N., Watanabe M., Watanabe T., Yamada M., Yamamoto K., Yamasaki T., Yanase T., Yoneda T., Yoshikawa Y., Yoshimoto T., Naruse M.

Journal of Human Hypertension 37 ( 9 ) 757 - 766 2023.09

ISSN 09509240

The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P < 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment.

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Longitudinal changes in pancreatic volume and pancreatic fat with weight gain in Japanese without diabetes: An analysis using health check-up data.

Maria Sunouchi, Jun Inaishi, Ryoko Shimizu-Hirota, Yoshifumi Saisho, Kaori Hayashi, Hiromasa Takaishi, Hiroshi Itoh

Metabolism open 19 100250 - 100250 2023.09

AIMS/INTRODUCTION: There have been few reports about the longitudinal changes in pancreas volume (PV) or pancreatic steatosis (PS) in response to obesity. In this longitudinal analysis using health check-up data, we explored changes in PV, PS and glucose metabolic indices that occurred after weight gain in Japanese without diabetes. MATERIALS/METHODS: Clinical data on 37 Japanese subjects with a ≥1 kg/m2 increase in body mass index between two health check-ups and without diabetes were collected. PV, pancreas attenuation (PA) and splenic attenuation (SA) were evaluated using computed tomography (CT) images. The pancreas area was outlined by hand in multiple images with slice thickness of 2 mm, and the PV was computed by summing these areas. PS was defined as the difference between SA and PA (SA-PA). Medical records were collected, including findings on immunoreactive insulin (IRI), homeostasis model assessment of insulin resistance (HOMA-R) and beta cell function (HOMA-β). Paired t-test and Spearman's correlation coefficient were used in the analyses. RESULTS: The median follow-up period was 21.1 months and the mean BMI was increased from 25.5 ± 3.3 kg/m2 to 27.0 ± 3.3 kg/m2. PV (53.5 ± 15.9 cm3 vs. 56.2 ± 16.4 cm3) and SA-PA (8.7 ± 9.1 HU vs. 13.6 ± 10.9 HU) increased significantly after weight gain (both, P < 0.001). There were significant increases of IRI and HOMA-R with the weight gain (both, P < 0.05), whereas HOMA-β exhibited only a nonsignificant trend of increase (55.4％ (41.5-65.5) vs. 56.8％ (46.2-83.7), P = 0.07). CONCLUSIONS: Both PV and PS were increased longitudinally with weight gain in Japanese without diabetes.

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Characterizing non-Markovian Quantum Process by Fast Bayesian Tomography

R. Y. Su, J. Y. Huang, N. Dumoulin. Stuyck, M. K. Feng, W. Gilbert, T. J. Evans, W. H. Lim, F. E. Hudson, K. W. Chan, W. Huang, Kohei M. Itoh, R. Harper, S. D. Bartlett, C. H. Yang, A. Laucht, A. Saraiva, T. Tanttu, A. S. Dzurak

2023.07

To push gate performance to levels beyond the thresholds for quantum error
correction, it is important to characterize the error sources occurring on
quantum gates. However, the characterization of non-Markovian error poses a
challenge to current quantum process tomography techniques. Fast Bayesian
Tomography (FBT) is a self-consistent gate set tomography protocol that can be
bootstrapped from earlier characterization knowledge and be updated in
real-time with arbitrary gate sequences. Here we demonstrate how FBT allows for
the characterization of key non-Markovian error processes. We introduce two
experimental protocols for FBT to diagnose the non-Markovian behavior of
two-qubit systems on silicon quantum dots. To increase the efficiency and
scalability of the experiment-analysis loop, we develop an online FBT software
stack. To reduce experiment cost and analysis time, we also introduce a native
readout method and warm boot strategy. Our results demonstrate that FBT is a
useful tool for probing non-Markovian errors that can be detrimental to the
ultimate realization of fault-tolerant operation on quantum computing.

Intermittent Fasting Sustainably Improves Glucose Tolerance in Normal Weight Male Mice Through Histone Hyperacetylation.

Sho Endo, Asuka Uto, Kazutoshi Miyashita, Masaaki Sato, Hiroyuki Inoue, Kentaro Fujii, Aika Hagiwara, Masaki Ryuzaki, Takuma Oshida, Kenichiro Kinouchi, Hiroshi Itoh

Journal of the Endocrine Society 7 ( 7 ) bvad082 2023.07

To explore the mechanism by which intermittent fasting (IF) exerts prolonged effects after discontinuation, we examined mice that had been subjected to 4 cycles of fasting for 72 hours and ad libitum feeding for 96 hours per week (72hIF), followed by 4 weeks of ad libitum feeding, focusing on expression of genes for lipid metabolism in the skeletal muscle and histone acetylation in the promoter region. The 72hIF regimen resulted in metabolic remodeling, characterized by enhanced lipid utilization and mitochondrial activation in the muscle. This long-term IF (72hIF) caused stronger metabolic effects than alternate day fasting (24hIF) wherein fasting and refeeding are repeated every 24 hours. Upregulation of lipid oxidation genes and an increase in oxygen utilization were sustained even at 4 weeks after discontinuation of 72hIF, associated with histone hyperacetylation of the promoter region of uncoupling protein 3 (Ucp3) and carnitine palmitoyl transferase 1b (Cpt1b) genes. An increase in leucine owing to fasting-induced muscle degradation was suggested to lead to the histone acetylation. These findings support the previously unappreciated notion that sustainable promotion of histone acetylation in lipid oxidation genes of the muscle and adipose tissues during and after IF may contribute to sustained metabolic effects of IF.

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Impact of Prophylactic Corticosteroid Use on In-hospital Mortality and Respiratory Failure After Esophagectomy for Esophageal Cancer: Nationwide Inpatient Data Study in Japan.

Hirano Y, Konishi T, Kaneko H, Itoh H, Matsuda S, Kawakubo H, Uda K, Matsui H, Fushimi K, Daiko H, Itano O, Yasunaga H, Kitagawa Y

Annals of surgery 277 ( 6 ) e1247 - e1253 2023.06

ISSN 0003-4932

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Mean annual intradialytic blood pressure decline and cardiovascular events in Japanese patients on maintenance hemodialysis.

Rina Takahashi, Kiyotaka Uchiyama, Naoki Washida, Keigo Shibagaki, Akane Yanai, Takashin Nakayama, Kengo Nagashima, Yasunori Sato, Takeshi Kanda, Hiroshi Itoh

Hypertension research : official journal of the Japanese Society of Hypertension 46 ( 6 ) 1536 - 1546 2023.06

ISSN 09169636

An intradialytic systolic blood pressure (SBP) decline, which defines intradialytic hypotension, may be associated with higher all-cause mortality. However, in Japanese patients on hemodialysis (HD), the association between intradialytic SBP decline and patient outcomes is unclear. This retrospective cohort study included 307 Japanese patients undergoing HD over 1 year in three dialysis clinics and evaluated the association between the mean annual intradialytic SBP decline (predialysis SBP-nadir intradialytic SBP) and clinical outcomes, including major adverse cardiovascular events (MACEs; cardiovascular death, nonfatal myocardial infarction or unstable angina, stroke, heart failure, and other severe cardiovascular events requiring hospitalization) by following up for 2 years. The mean annual intradialytic SBP decline was 24.2 (25-75th percentile, 18.3-35.0) mmHg. In the model fully adjusted for intradialytic SBP decline tertile group (T1, <20.4 mmHg; T2, 20.4 to <29.9 mmHg; T3, ≥29.9 mmHg), predialysis SBP, age, sex, HD vintage, Charlson comorbidity index, ultrafiltration rate, use of renin-angiotensin system inhibitors, corrected calcium, phosphorus, human atrial natriuretic peptide, geriatric nutritional risk index, normalized protein catabolism rate, C-reactive protein, hemoglobin, and use of pressor agents, Cox regression analyses showed that the hazard ratio (HR) was significantly higher for T3 than for T1 for MACEs (HR, 2.38; 95% confidence interval 1.12-5.09) and all-cause hospitalization (HR, 1.68; 95% confidence interval 1.03-2.74). Therefore, in Japanese patients on HD, a greater intradialytic SBP decline was associated with worse clinical outcomes. Further studies are warranted to investigate whether interventions to attenuate the intradialytic SBP decline will improve the prognosis of Japanese patients on HD.

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A systematic review and meta-analysis of the clinical impact of stopping renin-angiotensin system inhibitor in patients with chronic kidney disease.

Takashin Nakayama, Ryunosuke Mitsuno, Tatsuhiko Azegami, Yasunori Sato, Kaori Hayashi, Hiroshi Itoh

Hypertension research : official journal of the Japanese Society of Hypertension 46 ( 6 ) 1525 - 1535 2023.06

ISSN 09169636

Although renin-angiotensin system (RAS) inhibitors reduce the risk of cardiovascular diseases and end-stage kidney disease (ESKD) in chronic kidney disease (CKD) patients, they are often discontinued in clinical practice due to drug-related adverse events. However, limited evidence is available about the clinical impact of RAS inhibitor discontinuation in CKD patients. A comprehensive search of publications investigating the effect of discontinuing RAS inhibitors on clinical outcomes in CKD patients in PubMed, the Cochrane Library, and Web of Science was conducted (inception to November 7, 2022), and potentially relevant studies were searched by hand (through November 30, 2022). Two reviewers independently extracted data according to the PRISMA and MOOSE guidelines and assessed the quality of each study with risk-of-bias tools, RoB2 and ROBINS-I. The pooled hazard ratio (HR) for each outcome was integrated with a random-effect model. A total of 1 randomized clinical trial and 6 observational studies involving 248,963 patients were included in the systematic review. The meta-analysis of observational studies showed that discontinuation of RAS inhibitors was associated with a higher risk of all-cause mortality (HR, 1.41 [95% CI, 1.23-1.62]; I2 = 97%), ESKD (1.32 [95% CI, 1.10-1.57]; I2 = 94%) and MACE (1.20 [95% CI 1.15-1.25]; I2 = 38%), but not with hyperkalemia (0.79 [95% CI 0.55-1.15]; I2 = 90%). Overall risk of bias was moderate-to-serious, and quality of evidence (GRADE system) was low-to-very low. The present study suggests that CKD patients would benefit from continuing RAS inhibitors.

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A higher resting heart rate is associated with cardiovascular event risk in patients with type 2 diabetes mellitus without known cardiovascular disease.

Shota Ikeda, Keisuke Shinohara, Nobuyuki Enzan, Shouji Matsushima, Takeshi Tohyama, Kouta Funakoshi, Junji Kishimoto, Hiroshi Itoh, Issei Komuro, Hiroyuki Tsutsui

Hypertension research : official journal of the Japanese Society of Hypertension 46 ( 5 ) 1090 - 1099 2023.05

ISSN 09169636

A higher resting heart rate (RHR) is associated with an increased risk of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The aim of this study was to investigate the association between RHR and cardiovascular events in T2DM patients with diabetic retinopathy and without known cardiovascular disease. We analyzed the association between RHR and cardiovascular events, including coronary, cerebral, renal and vascular events or cardiovascular death in T2DM patients with retinopathy and hyperlipidemia without prior cardiovascular events who were enrolled in the EMPATHY study. Data from 4746 patients were analyzed. The median RHR was 76 bpm. Patients were divided into four groups based on their baseline RHR ( < 60, 60-69, 70-79, and ≥80 bpm). Patients with a higher RHR were more likely to be younger and had a higher body mass index, blood pressure value, HbA1c value, and estimated glomerular filtration rate and a lower B-type natriuretic peptide value; they also had a higher proportion of current smoking status, neuropathy, and nephropathy. After adjusting for confounders, including the aforementioned risk factors, a RHR of 70-79 bpm and a RHR ≥ 80 bpm were significantly associated with cardiovascular events (hazard ratio 1.50, 95% CI 1.03-2.20; and hazard ratio 1.62, 95% CI 1.11-2.36; respectively) compared to a RHR of 60-69 bpm. The analysis using restricted cubic splines indicated that the cardiovascular risk seemed to be similarly high when the RHR range was ≥70 bpm. In conclusion, in T2DM patients with diabetic retinopathy and without known cardiovascular disease, a high RHR, particularly ≥70 bpm, was associated with the risk of cardiovascular events compared to a RHR of 60-69 bpm. High resting heart rate (RHR), particularly ≥70 bpm, was associated with the risk of cardiovascular events compared to RHR 60-69 bpm in patients with type 2 diabetes mellitus (T2DM), diabetic retinopathy, and hyperlipidemia, but without known cardiovascular disease.

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DNA-damaged podocyte-CD8 T cell crosstalk exacerbates kidney injury by altering DNA methylation.

Ran Nakamichi, Akihito Hishikawa, Shunsuke Chikuma, Akihiko Yoshimura, Takashi Sasaki, Akinori Hashiguchi, Takaya Abe, Tomoko Tokuhara, Norifumi Yoshimoto, Erina Sugita Nishimura, Eriko Yoshida Hama, Tatsuhiko Azegami, Takashin Nakayama, Kaori Hayashi, Hiroshi Itoh

Cell reports 42 ( 4 ) 112302 - 112302 2023.04

Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8+ T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44high memory CD8+ T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8+ T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8+ T cells, which contribute to sustained renal injury in chronic kidney disease.

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