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While epidemiological and experimental studies have demonstrated kidney-protective effects of estrogen and female sex in adulthood, some epidemiological data showed deterioration of kidney function during puberty when estrogen production increases. However, molecular mechanisms explaining these conflicting phenomena remain unknown. Here, we showed that the pubertal sex hormone surge in female mice increases susceptibility to kidney ischemia reperfusion injury partly via downregulation of insulin-like growth factor 1 receptor (IGF-1R) expression in proximal tubules. Adult mice ovariectomized pre-pubertally (at postnatal day 21) showed strong tolerance to kidney ischemia, which was partly reversed by the administration of 17β-estradiol, while adult mice ovariectomized post-pubertally (at 8 weeks of age) were vulnerable to kidney ischemia. Kidney tubular IGF-1R protein expression decreased during postnatal growth but was highly expressed in adult mice ovariectomized pre-pubertally and in infant mice, which might be partly explained by different expression of an E3 ligase (MDM2) of IGF-1R. Mice deficient of Igf-1r in proximal tubules (iIGF-1RKO mice) during postnatal kidney growth showed increased susceptibility to ischemic injury. RNA-seq and western blotting analysis using proximal tubular cells from pre-pubertally ovariectomized iIGF-1RKO and control mice revealed altered expression of cell cycle-associated molecules such as cyclin D1. These results suggest that Igf-1r deletion during postnatal growth renders proximal tubular cells susceptible to ischemia possibly via altered cell cycle regulation. Thus, our findings provide evidence that exposure to pubertal sex hormones leads to increased susceptibility to kidney ischemia, which is partly mediated by modulation of IGF-1R signaling., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

ATP depletion plays a central role in the pathogenesis of kidney diseases. Recently, we reported spatiotemporal intracellular ATP dynamics during ischemia reperfusion (IR) using GO-ATeam2 mice systemically expressing an ATP biosensor. However, observation from the kidney surface did not allow visualization of deeper nephrons or accurate evaluation of ATP synthesis pathways. Here, we established a novel ATP imaging system using slice culture of GO-ATeam2 mouse kidneys, evaluated the ATP synthesis pathway, and analyzed intracellular ATP dynamics using an ex vivo IR-mimicking model and a cisplatin nephropathy model. Proximal tubules (PTs) were found to be strongly dependent on oxidative phosphorylation (OXPHOS) using the inhibitor oligomycin A, whereas podocytes relied on both OXPHOS and glycolysis using phloretin an active transport inhibitor of glucose. We also confirmed that an ex vivo IR-mimicking model could recapitulate ATP dynamics in vivo; ATP recovery in PTs after reoxygenation varied depending on anoxic time length, whereas ATP in distal tubules (DTs) recovered well even after long-term anoxia. After cisplatin administration, ATP levels in PTs decreased first, followed by a decrease in DTs. An organic cation transporter 2 inhibitor, cimetidine, suppressed cisplatin uptake in kidney slices, leading to better ATP recovery in PTs, but not in DTs. Finally, we confirmed that a mitochondria protection reagent (Mitochonic Acid 5) delayed the cisplatin-induced ATP decrease in PTs. Thus, our novel system may provide new insights into the energy dynamics and pathogenesis of kidney disease., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Although a prediction model is expected to identify individuals who are at a high risk of type 2 diabetes, the implementation status of prediction models has not been well examined. Our review indicates that the implementation of predictive models in practice remains low despite the increase in models being developed., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Objectives: Social distancing due to the coronavirus disease 2019 crisis can exacerbate inactivity in older adults. Novel approaches for older adults must be designed to improve their activity and maintain their health. This study examined the effect of nudge-based behavioral interventions on health-promoting activities in older adults in Japan., Design: Two-arm, participant-blinded randomized controlled trial., Setting and Participants: Japanese continuing care retirement community residents (n = 99, median age 82 years, 73% women) INTERVENTION: Two-step nudge-based behavioral intervention promoting tablet usage., Methods: We enrolled participants from an ongoing Internet of Things project in a retirement community in Japan. For the health promotion program, tablet computers were installed in a common area for participants to receive information about their health. The intervention group received a 1-time loss-emphasized nudge (first step), followed by asking questions about when they planned to use it again (second step). The control group used the tablet computers without being asked those questions. The main outcome was the participants' mean daily tablet activity every 4 weeks for the next 16 weeks., Results: Ninety-nine individuals were randomly assigned to the intervention or control group. The rate ratios for tablet use were significantly higher in the intervention group in the second and third periods. The subgroup analysis showed that these effects were largely attributable to men., Conclusions and Implications: Nudge-based interventions can be effective in promoting activities for older adults, especially older men. The finding of this study indicates a possible intervention to engage people who are socially isolated., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Erythropoietin (Epo) is produced by a subpopulation of resident fibroblasts in the healthy kidney. We have previously demonstrated that, during kidney fibrosis, kidney fibroblasts including Epo-producing cells transdifferentiate into myofibroblasts and lose their Epo-producing ability. However, it remains unclear whether Epo-producing cells survive and transform into myofibroblasts during fibrosis because previous studies did not specifically label Epo-producing cells in pathophysiological conditions. Here, we generated Epo CreERT2/+ mice, a novel mouse strain that enables labeling of Epo-producing cells at desired time points and examined the behaviors of Epo-producing cells under pathophysiological conditions. Lineage-labeled cells that were producing Epo when labeled were found to be a small subpopulation of fibroblasts located in the interstitium of the kidney, and their number increased during phlebotomy-induced anemia. Around half of lineage-labeled cells expressed Epo mRNA, and this percentage was maintained even 16 weeks after recombination, supporting the idea that a distinct subpopulation of cells with Epo-producing ability makes Epo repeatedly. During fibrosis caused by ureteral obstruction, Epo CreERT2/+ -labeled cells were found to transdifferentiate into myofibroblasts with concomitant loss of Epo-producing ability, and their numbers and the proportion among resident fibroblasts increased during fibrosis, indicating their high proliferative capacity. Finally, we confirmed that Epo CreERT2/+ -labeled cells that lost their Epo-producing ability during fibrosis regained their ability after kidney repair due to relief of the ureteral obstruction. Thus, our analyses have revealed previously unappreciated characteristic behaviors of Epo-producing cells, which had not been clearly distinguished from those of resident fibroblasts., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Here, we present a method for preparing vesicles by combining hydrothermal emulsification with solvent diffusion (SD). The sorbitan monolaurate/polyoxyethylene (20) sorbitan monolaurate (Span 20/Tween 20) system was used as the target lipid because these lipids are cheap and advantageous for the production scale. The water-in-oil (W/O) emulsion stabilized with lipids was formed under hydrothermal conditions (240 °C under 10 MPa), followed by mixing with water that included lipids to obtain a W/O-in-water (W/O/W) emulsion. The SD for the W/O/W emulsion as a subsequent process yielded vesicles. The optimal preparation conditions were 50:50 wt% Span 20/Tween 20 as a mixing ratio (final lipid concentration 12 mM), octanoic acid as an organic solvent, 240 °C for 4 min during the hydrothermal treatment, and 4 °C for 24 h in the SD process. The diameter of the vesicles obtained was at most 100 nm, which was comparable to that of the W/O/W emulsion before SD. This suggested that the W/O/W emulsion acted as a template for vesicle formation. The number density, diameter, and membrane properties of vesicles depend on the mixing ratio of the water/oil/lipid system. Specifically, the number density of vesicles was low relative to that of vesicles prepared by the conventional method., (Copyright © 2021. Published by Elsevier B.V.)

Tertiary lymphoid tissues (TLTs) are inducible ectopic lymphoid tissues in chronic inflammatory states and function as sites of priming local immune responses. We previously demonstrated that aged but not young mice exhibited multiple TLTs after acute kidney injury and that TLTs were also detected in human aged and diseased kidneys. However, the forms of progression and the implication for kidney injury remain unclear. To clarify this we analyzed surgically resected kidneys from aged patients with or without chronic kidney disease as well as kidneys resected for pyelonephritis, and classified TLTs into three distinct developmental stages based on the presence of follicular dendritic cells and germinal centers. In injury-induced murine TLT models, the stages advanced with the extent of kidney injury, and decreased with dexamethasone accompanied with improvement of renal function, fibrosis and inflammation. Kidneys from aged patients with chronic kidney disease consistently exhibited more frequent and advanced stages of TLTs than those without chronic kidney disease. Kidneys of patients with pyelonephritis exhibited more frequent TLTs with more advanced stages than aged kidneys. Additionally, TLTs in both cohorts shared similar locations and components, suggesting that TLT formation may not be a disease-specific phenomenon but rather a common pathological process. Thus, our findings provide the insights into biological features of TLT in the kidney and implicate TLT stage as a potential marker reflecting local injury and inflammation., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Excessive salt intake is widely known to be a cause of hypertension, cardiovascular events, and so on. However, simple tools for screening excessive salt intake are lacking., Objective: We aimed to develop a simple screening tool to identify community-dwelling adults with excessive salt intake., Methods: The present study involved participants who received health check-ups in Fukushima, Japan, in 2016 and 2017. We defined data from the 2016 check-up as the derivation set, and data from those who received check-ups in 2017 but not 2016 as the validation set. The outcome measure was excessive salt intake, defined as the estimated daily salt intake of 1 SD or more. Candidate predictors associated with the outcome were extracted using the Delphi method by an expert panel and narrowed down with clinical expertise and stepwise backward selection. The screening tool was developed using a coefficient-based multivariable scoring method and externally validated., Results: A total of 1101 participants were included in the derivation set and 249 in the validation set. At the conclusion of the deviation process, 8 predictors were selected and scored. The areas under the receiver operating characteristic curve for derivation and external validation were 0.70 (95% CI: 0.67, 0.74) and 0.71 (95% CI: 0.62, 0.80), respectively. The calibration slope and intercept for external validation were 1.16 and -0.03, respectively., Conclusion: We developed a screening tool to identify adults with excessive salt intake. By extracting groups with excessive salt intake, target populations needing intervention for salt reduction can be highlighted efficiently., (Copyright © The Author(s) 2020.)

Objectives: A discrepancy in self-reported and performance-based physical functioning levels is often observed among older adults. We investigated the association of discrepancy in self-reported and performance-based physical functioning levels with risk of future falls among community-dwelling older adults., Design: Prospective cohort study., Setting: Two communities in Fukushima Prefecture, Japan., Participants: 1379 older adults who took part in the yearly health checkup in both 2009 and 2010., Measures: The performance-based and self-reported physical functioning levels were evaluated by the Timed Up and Go test and the Short-Form 12 Health Survey (Japanese version) physical functioning subscale, respectively. We divided the participants into 4 groups based on the combinations of low or high performance-based and self-reported physical functioning groups, which were classified by age- and sex-specific reference values. The main outcome was the occurrence of any falls within the 1-year follow-up period, assessed using a self-reported questionnaire., Results: A total of 22% of the participants reported the occurrence of a fall during the follow-up period. In multivariable logistic regression analysis, the adjusted odds ratios of the high self-reported and low performance-based, low self-reported and high performance-based, and low self-reported and low performance-based physical functioning groups were 1.10 (95% confidence interval [CI], 0.67-1.82), 1.76 (95% CI, 1.17-2.66), and 1.80 (95% CI, 1.11-2.90), respectively, compared with the high self-reported and high performance-based physical functioning group., Conclusions: Our findings suggest that the discrepancy as high performance-based but low self-reported physical functioning level is associated with an increased risk of future falls in older adults aged 65-89 years. Clinicians should carefully assess older adults whose subjective perception of their physical functioning capacity is lower than those in similar age and sex groups, even if their actual physical functioning appears to be objectively high., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: The experimental studies suggested the hypothesis that the accumulation of advanced glycation end-products (AGEs) could induce hearing impairment. The purpose of this study is to examine the hypothesis among elderly people using an epidemiologic approach., Design: Cross-sectional study., Setting: Sukagawa City, Fukushima, Japan., Participants: A total of 270 residents aged 75 years or over without dementia, who participated in a health check-up conducted in 2015., Measurements: The exposure variable was AGEs, which was assessed using skin autofluorescence (AF) as a proxy measure. The primary outcome was moderate hearing impairment or worse, which was defined as a pure tone average of thresholds ≥41 decibel hearing level at 0.5, 1, 2, and 4 kHz in the better-hearing ear. The secondary outcome was the pure tone average of thresholds as a continuous variable. We estimated the odds ratio using a logistic regression model for the primary outcome and a general linear model for the mean difference in the pure tone average of thresholds for the secondary outcome. Both models were adjusted for relevant confounding factors: age, sex, smoking, diabetes, hypertension, and history of cerebrovascular diseases., Results: The median (interquartile range) AF was 2.2 (2.0, 2.5) arbitrary units (AU). Moderate hearing impairment was reported in 88 participants (32.6%). For the primary outcome, we found significant associations between moderate hearing impairment and AF (adjusted odds ratio per 1 AU, 2.60; 95% confidence interval 1.26-5.35). For the secondary outcome, we also found a significant association between a 1-AU increase in AF and increased pure tone average, with a difference (6.52 dB per 1 AU; 95% confidence interval 2.18-10.86) comparable in magnitude to the increase in pure tone average observed for a 6-year increase in age in our population., Conclusions: Our study indicated that high levels of AGEs were independently associated with hearing impairment. Modifying levels of AGEs may prevent hearing impairment., (Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Cancer is a major cause of death in patients undergoing haemodialysis. However, information about the actual clinical practice of chemotherapy for patients with cancer undergoing haemodialysis is lacking. We conducted a nationwide survey using questionnaires on the clinical practice of chemotherapy for such patients., Patients and Methods: The nationwide survey included patients undergoing haemodialysis who were subsequently diagnosed with cancer in 20 hospitals in Japan from January 2010 to December 2012. We reviewed their clinical data, including cancer at the following primary sites: kidney, colorectum, stomach, lung, liver, bladder, pancreas and breast. The questionnaires consisted of the following subjects: (1) patient characteristics; (2) regimen, dosage and timing of chemotherapy; and (3) clinical outcome., Results: Overall, 675 patients were registered and assessed for main primary cancer site involvement. Of 507 patients with primary site involvement, 74 patients (15%) received chemotherapy (44 as palliative chemotherapy and 30 as perioperative chemotherapy). The most commonly used cytotoxic drugs were fluoropyrimidine (15 patients), platinum (8 patients) and taxane (8 patients), and the dosage and timing of these drugs differed between institutions; however, the dosage of molecular targeted drugs (24 patients) and hormone therapy drugs (15 patients) was consistent. The median survival time of patients receiving palliative chemotherapy was 13.0 months (0.1-60.3 months). Three patients (6.8%) died from treatment-related causes and nine patients (20%) died of causes other than cancer. Of the 30 patients who received perioperative chemotherapy, 6 (20%) died of causes other than cancer within 3 years after the initiation of chemotherapy., Conclusion: Among the haemodialysis patients with cancer who received chemotherapy, the rates of mortality from causes other than cancer might be high for both palliative and perioperative chemotherapy. Indications for the use of chemotherapy in patients undergoing haemodialysis should be considered carefully., Competing Interests: Competing interests: MN has received honoraria from Daiichi Sankyo and Taiho Pharmaceutical. MasM has received research grants from Chugai, Kyowa Hakko Kirin, Takeda, Daiichi Sankyo, Astellas, Otsuka, Baxter, Teijin Pharma and Shionogi. TS has received research grants from Baxter, Astellas, Kyowa Hakko Kirin, Teijin Pharma and Takeda. EB has received research grants from Takeda, Chugai, Eli Lilly, Merck Serono, Shionogi and Taiho. He has also received honorarium from Eli Lilly. KT has received research grants from Kyowa Hakko Kirin, Chugai, Takeda, Kissei, Otsuka, Daiichi Sankyo and Torii. He has also received honoraria from Kyowa Hakko Kirin, Chugai and Sanofi. His institution has received funding from Baxter. AN has received research grant from Daiichi Sankyo. HY has received honoraria from Medicon, Taiho, Chugai, Yakult Honsha, Bristol-Myers Squibb, Takeda and Kyowa Hakko Kirin. MY has been on the advisory board of Astellas and received research grants from Astellas, Chugai, Daiichi Sankyo, Fuji Yakuhin, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Nippon Boehringer Ingelheim, Baxter, Takeda Pharmaceutical Company, Fuso Pharmaceutical Industries and Terumo Corporation. ManM has received research grant from Chugai, Yakult Honsha, Ono Pharmaceutical, Ayumi Pharmaceutical, Showa Yakuhin Kako, Shionogi, Taiho, Terumo and Nippon Zoki Pharmaceutical Corporations.

Introduction: Spinal immobilization has been indicated for all blunt trauma patients suspected of having cervical spine injury. However, for traumatic cardiac arrest (TCA) patients, rapid transportation without compromising potentially reversible causes is necessary. Our objective was to investigate the temporal trend of spinal immobilization for TCA patients and to examine the association between spinal immobilization and survival., Methods: We conducted a retrospective cohort study using the Japan Trauma Data Bank 2004-2015 registry data. Our study population consisted of adult blunt TCA patients encountered at the scene of a trauma. The primary outcome was the survival proportion at hospital discharge, and the secondary outcome was the proportion achieving return of spontaneous circulation (ROSC). We examined the association between spinal immobilization and these outcomes using a logistic regression model based on imputed data sets with the multiple imputation method to account for missing data., Results: Among 4313 patients who met the inclusion criteria, 3307 (76.7%) were immobilized. The proportion of patients that underwent spinal immobilization gradually decreased from 82.7% in 2004-2006 to 74.0% in 2013-2015. 1.0% of immobilized and 0.9% of non-immobilized patients had severe cervical spine injury. Spinal immobilization was significantly associated with lower survival at discharge (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.42 to 0.98) and ROSC by admission (OR, 0.48; 95%CI, 0.27 to 0.87). There was no significant sub-group difference of the association between spinal immobilization and survival at discharge by patients with or without cervical spine injury (p for interaction 0.73)., Conclusion: Spinal immobilization is widely used even for blunt TCA patients, even though it is associated with a lower rate of survival at discharge and ROSC by admission. According to these results, we suggest that spinal immobilization should not be routinely recommended for all blunt TCA patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: To assess the effect of blood type on survival outcomes and adverse events (AEs) in patients treated with tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC)., Materials and Methods: Patients who received TKIs as first-line therapy for mRCC between 2008 and 2015 at our hospital were included in the study (n = 136). Patients were divided into 2 groups based on their blood type as O and non-O. Survival outcomes and AEs were compared according to blood type. Cox regression models were used for univariate and multivariate survival analyses., Results: Of the 136 patients, 34 (25%) and 102 (75%) had O and non-O blood types, respectively. Blood type O was associated with an increased number of disease sites. There were no differences between the 2 groups with respect to other baseline characteristics. The progression-free survival in patients with O and non-O blood types was 12.1 and 11.6 months, respectively; the overall survival was 34.4 and 24.8 months, respectively. On univariate and multivariate analyses, the ABO blood type was not a significant prognostic factor for progression-free survival or overall survival. Furthermore, the incidences of serious AEs were similar in the 2 blood groups., Conclusions: ABO blood type was not associated with survival outcomes or incidences of serious AEs in mRCC patients treated with TKIs. However, blood type O may be associated with an increased number of disease sites., (Copyright © 2017. Published by Elsevier Inc.)

Objectives: To describe the registration of systematic review (SR) protocols and examine whether or not registration reduced the outcome reporting bias in high-impact journals., Study Design and Setting: We searched MEDLINE via PubMed to identify SRs of randomized controlled trials of interventions. We included SRs published between August 2009 and June 2015 in the 10 general and internal medicinal journals with the highest impact factors in 2013. We examined the proportion of SR protocol registration and investigated the relationship between registration and outcome reporting bias using multivariable logistic regression., Results: Among the 284 included reviews, 60 (21%) protocols were registered. The proportion of registration increased from 5.6% in 2009 to 27% in 2015 (P for trend <0.001). Protocol registration was not associated with outcome reporting bias (adjusted odds ratio [OR] 0.85, 95% confidence interval [CI] 0.39-1.86). The association between Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) adherence and protocol registration was not statistically significant (OR 1.09, 95% CI 0.59-2.01)., Conclusions: Six years after the launch of the PRISMA statement, the proportion of protocol registration in high-impact journals has increased some but remains low. The present study found no evidence suggesting that protocol registration reduced outcome reporting bias., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Sodium reduction is very important in preventing cardiovascular diseases, especially in regions with high salt intake such as Japan. One strategy for salt reduction is to raise consumer awareness of the need to reduce daily salt intake. We investigated whether cooking classes given to housewives focussing on salt reduction would influence not only their own consumption behaviour but also that of their family members., Study Design: Single-blinded, cluster randomized trial., Methods: We randomly assigned housewives to participate in cooking classes focussing on salt reduction (intervention group) or lectures about a healthy lifestyle (control group). The main outcome measure was the difference in estimated daily salt intake by spot urine sampling of housewives and their family members 2 months after intervention between the groups., Results: A total of 35 housewives and 33 family members were randomized. The mean daily salt intake was 10.00 (standard deviation [SD] 1.75) g/day in the control group (17 housewives and 15 family members) and 9.57 (SD 2.45) g/day in the intervention group (18 housewives and 18 family members) at baseline. Two months after the intervention, the mean salt intake was 10.30 (SD 1.78) g/day in the control group and 8.95 (SD 2.45) g/day in the intervention group. The mean difference was -1.19 g/day (95% confidence interval -2.29, -0.09; P = 0.034). A similar tendency was observed in the subgroups of housewives and family members., Conclusions: Our trial suggested that the effects of cooking classes focussing on salt reduction for housewives could be transferred to family members (UMIN-CTR: 000018870)., (Copyright © 2016 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Introduction: Falling is one of the most common and serious public health problems. It can cause injuries such as sprains and fractures, and hospitalization may be required for serious injuries. Patients with Parkinson's disease have a higher risk of falls, and urinary incontinence is a known risk factor for falls in the elderly. However, whether other urinary disturbances contribute to the risk of falling remains unclear. The purpose of this study was to identify the association between falls and urinary disturbances in Parkinson's disease., Methods: A prospective cohort study was conducted at a single institution with a 6-month observation period. Subjects were ambulatory patients with Parkinson's disease. Assessments included patient demographics, disease severity measured by the Hoehn and Yahr scale, and urinary disturbances measured using the overactive bladder symptom score (OABSS). Falls were reported using a self-documented fall record., Results: A total of 97 patients were included. Forty-four subjects experienced one or more falls during the observation period. The frequency of urination was not related to falling; however, mild urinary urgency, but not severe urinary urgency, increased the risk of falls by an odds ratio of 5.14 (95% confidence interval: 1.51-17.48). Mild urinary urgency was also associated with the time to the first fall and the frequency of falls. One third of falls occurred in the living room, and 13.8% of falls occurred on the way to/from the toilet., Conclusion: Falls in patients with Parkinson's disease might be associated with urinary urgency, but not with the frequency of urination., (Copyright © 2015 Elsevier B.V. All rights reserved.)