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Background: The CHA2DS2-VASc score has been widely used to predict stroke in patients with atrial fibrillation (AF). Recently, it was reported that the CHA2DS2-VASc score helps predict cardiovascular disease (CVD) or all-cause mortality in patients with or without AF. However, few reports have examined the association between this score and mortality in hemodialysis (HD) patients. Methods: We analyzed 557 consecutive patients who initiated HD at our facilities between February 2005 and October 2017. The CHA2DS2-VASc score was calculated at the time of initiation of HD. Patients were then categorized into three groups according to their CHA2DS2-VASc scores: 0–1 (low), 2–3 (intermediate), and 4–9 (high). Multivariate Cox proportional hazards analysis was used to assess independent risk factors for 3-year all-cause mortality. Results: During the 3-year follow-up period, 153 (27.5%) patients died (cardiovascular death: n = 88). According to multivariate analysis, serum albumin (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.43–0.85, p = 0.003), creatinine (HR 0.91, 95% CI 0.84–0.99, p = 0.049), and CHA2DS2-VASc score (HR 1.33, 95% CI 1.20–1.46, p < 0.001) were associated with 3-year all-cause mortality. Compared with patients in the low CHA2DS2-VASc score group, those in the intermediate- and high-score groups had a higher risk for all-cause and CVD mortality (all-cause mortality: HR 1.77, 95% CI 1.23–2.55, p = 0.002 and HR 2.94, 95% CI 1.90–4.53, p < 0.001, respectively; CVD mortality: HR 1.82, 95% CI 1.27–2.59, p = 0.001 and HR 2.85, 95% CI 1.88–4.31, p < 0.001, respectively). Conclusion: The CHA2DS2-VASc score is a valuable predictor of 3-year all-cause and CVD mortality in incident HD patients.

β2-Microglobulin (β2-MG) and α1-microglobulin (α1-MG) have molecular weights of 11,800 and 33,000 Da, respectively. We studied the α1-MG and β2-MG reduction ratios (RRs) and survival in patients on predilution online haemodiafiltration (Pre-OL-HDF).Participants were 247 Pre-OL-HDF patients. α1-MG and β2-MG RRs were assessed at baseline. Kaplan-Meier survival and Cox proportional hazard analyses were used.In 247 patients, the median age was 67 (56-73) years, the dialysis duration was 77 (46-150) months, and the diabetes prevalence was 47.4%. Twenty-two patients died over the 450-day study period. The mortality cut-off values using receiver-operating characteristic curves for the α1-MG and β2-MG RRs were 20% and 80%, respectively. Survival rates were significantly (p 0.05) higher in patients with α1-MG RRs ≥20% (n = 134) compared with patients with α1-MG RRs20% (n = 113) and in patients with β2-MG RRs ≥80% (n = 87) compared with patients with β2-MG RRs80% (n = 160). Cox models adjusting for diabetes and dialysis duration showed that α1-MG RR, β2-MG RR, and pre- and postdialysis β2-MG were risk factors for all-cause mortality; however, after additional adjustment for age, sex, and serum albumin, only β2-MG RR and pre- and postdialysis β2-MG were significant predictors of mortality (p 0.05). α1-MG RRs were significantly correlated with β2-MG RRs (ρ = 0.73, p 0.0001) and serum albumin levels (ρ = 0.13, p 0.05).In patients on Pre-OL-HDF, α1-MG RRs ≥20% and β2-MG RRs ≥80% were associated with better survival, β2-MG RR ≥80% and pre-and postdialysis β2-MG levels were significant predictors of all-cause mortality, and α1-MG RR ≥20% may predict mortality.

We have been developing the SOI pixel detector ``INTPIX'' for space use and general purpose applications such as the residual stress measurement of a rail and high energy physics experiments. INTPIX is a monolithic pixel detector composed of a high-resistivity Si sensor, a SiO2 insulator, and CMOS pixel circuits utilizing Silicon-On-Insulator (SOI) technology. We have considered the possibility of using INTPIX to observe X-ray polarization in space. When the semiconductor detector is used in space, it is subject to radiation damage resulting from high-energy protons. Therefore, it is necessary to investigate whether INTPIX has high radiation tolerance for use in space. The INTPIX8 was irradiated with 6 MeV protons up to a total dose of 2 krad at HIMAC, National Institute of Quantum Science in Japan, and evaluated the degradation of the performance, such as energy resolution and non-uniformity of gain and readout noise between pixels. After 500 rad irradiation, which is the typical lifetime of an X-ray astronomy satellite, the degradation of energy resolution at 14.4 keV is less than 10%, and the non-uniformity of readout noise and gain between pixels is constant within 0.1%., 7 pages, 8 figures, published in proceedings for SPIE Astronomical Telescopes + Instrumentation in 2022

Objective A high coronary artery calcification score (CACS) may be associated with high mortality in patients undergoing hemodialysis (HD). Recently, effects of iron on vascular smooth muscle cell calcification have been described. We aimed to investigate the relationships between iron, CACS, and mortality in HD patients. Methods We studied 173 consecutive patients who were undergoing maintenance HD. Laboratory data and Agatston’s CACS were obtained at baseline for two groups of patients: those with CACS ≥400 (n = 109) and those with CACS

We have been developing the monolithic active pixel detector "XRPIX" onboard the future X-ray astronomical satellite "FORCE". XRPIX is composed of CMOS pixel circuits, SiO2 insulator, and Si sensor by utilizing the silicon-on-insulator (SOI) technology. When the semiconductor detector is operated in orbit, it suffers from radiation damage due to X-rays emitted from the celestial objects as well as cosmic rays. From previous studies, positive charges trapped in the SiO2 insulator are known to cause the degradation of the detector performance. To improve the radiation hardness, we developed XRPIX equipped with Double-SOI (D-SOI) structure, introducing an additional silicon layer in the SiO2 insulator. This structure is aimed at compensating for the effect of the trapped positive charges. Although the radiation hardness to cosmic rays of the D-SOI detectors has been evaluated, the radiation effect due to the X-ray irradiation has not been evaluated. Then, we conduct an X-ray irradiation experiment using an X-ray generator with a total dose of 10 krad at the SiO2 insulator, equivalent to 7 years in orbit. As a result of this experiment, the energy resolution in full-width half maximum for the 5.9 keV X-ray degrades by 17.8 $\pm$ 2.8% and the dark current increases by 89 $\pm$ 13%. We also investigate the physical mechanism of the increase in the dark current due to X-ray irradiation using TCAD simulation. It is found that the increase in the dark current can be explained by the increase in the interface state density at the Si/SiO2 interface., 15 pages, 12 figures, accepted for publication in Journal of Astronomical Telescopes, Instruments, and Systems

AIM Assess the association and predictive value of geriatric nutritional risk index (GNRI), body composition, and bone mineral density (BMD) in haemodialysis (HD) patients. METHODS Laboratory data, body composition parameters measured via body composition monitor, and radius, lumbar spine, femoral neck BMD measured using dual energy X-ray absorptiometry were assessed in all subjects on HD or online haemodiafiltration (HDF) at baseline. Regression analysis for GNRI, Cox proportional hazard analyses and comparison of multiple receiver operating characteristic (ROC) curves were performed. RESULTS Among all 264 patients, age was 65 ± 12 years and dialysis vintage was 79 (39-144) months. GNRI tertile (T)1, T2, and T3 were 88 (85-91), 94 (93-95), and 98 (97-101), respectively. Patients in GNRI T1 had lower fat tissue index (FTI), lean tissue index, and femoral neck, lumbar spine, and distal mid-third radius BMD, but higher overhydration/extracellular fluid than patients in GNRI T2 or T3 (P

Background Primary coenzyme Q10 (CoQ10) deficiency of genetic origin is one of a few treatable focal segmental glomerulosclerosis (FSGS). Renal morphologic evidence for COQ8B mutation and CoQ10 deficiencies of other gene mutations is assessed using electron microscopy with marked increase of abnormal-shaped mitochondria in podocytes. However, light microscopic morphologic features of deficiencies other than FSGS have not been reported. Case presentation A 30-year-old woman was admitted to our hospital because proteinuria was found during four consecutive medical checkups. She had no medical history or family history of proteinuria and severe renal dysfunction. The swollen podocytes were stained to the same extent as mitochondria-rich proximal tubular cells under both Masson’s trichrome and hematoxylin-eosin staining, whereas no mitochondrial abnormalities were detected under the first electron microscopic views. As proteinuria and estimated glomerular filtration rate (eGFR) deteriorated after pregnancy, we reevaluated the additional electron microscopic views and detected mitochondrial abnormalities. Genetic testing revealed COQ8B mutation (c.532C > T, p.R178W); therefore, we diagnosed COQ8B nephropathy. CoQ10 supplementation improved proteinuria and stopped eGFR reduction. Conclusions This is the first report of granular swollen podocytes due to mitochondrial diseases detected under light microscopy. We propose that this finding can be the clue for the diagnosis of both COQ8B nephropathy and the other CoQ10 deficiencies.

The effect of convection volume (CV) in patients on pre-dilution online haemodiafiltration (Pre-OL-HDF) was evaluated.We conducted a retrospective, cross-sectional study in 126 patients on Pre-OL-HDF. Dialysis conditions, laboratory data, and same day post-dialysis body composition measurements using bioimpedance spectroscopy were assessed. Patients were divided into two groups according to their CV: ≥ median value and median value. Linear regression analyses for reduction ratios (RRs) of β2-microglobulin and α1-microglobulin, and body composition, were conducted.Age, dialysis vintage, and CVs of the study patients were 64 ± 12 years, 81 (48-154) months, and 43.2 (38.5-55.9) L/session, respectively. The higher CV (≥ 43 L/session) group (n = 66) had significantly higher RRs of β2-microglobulin and α1-microglobulin, lean tissue index, body cell mass index, total body water (TBW), extracellular water (ECW), and intracellular water (ICW) compared with the lower CV ( 43 L/session) group (n = 60, p .01). Serum albumin and fat tissue index were not significantly different between the groups. CV/ECW, CV/TBW, and CV/ICW but not un-adjusted CV, were significant determinants for β2-microglobulin and α1-microglobulin RRs (p .05). Lean tissue and body cell mass indexes, but not the fat tissue index, showed significant associations with CV, and RRs of β2-microglobulin and α1-microglobulin (p kb.05).Among patients on Pre-OL-HDF, higher values in the lean tissue index and body cell mass index were observed in those with higher CV versus lower CV, and CV adjusted to body water may be useful to prescribe individualized conditions for Pre-OL-HDF.

The CHA2DS2-VASc score has been widely used to predict stroke in patients with atrial fibrillation (AF). Recently, it was reported that the CHA2DS2-VASc score helps predict cardiovascular disease (CVD) or all-cause mortality in patients with or without AF. However, few reports have examined the association between this score and mortality in hemodialysis (HD) patients.We analyzed 557 consecutive patients who initiated HD at our facilities between February 2005 and October 2017. The CHA2DS2-VASc score was calculated at the time of initiation of HD. Patients were then categorized into three groups according to their CHA2DS2-VASc scores: 0-1 (low), 2-3 (intermediate), and 4-9 (high). Multivariate Cox proportional hazards analysis was used to assess independent risk factors for 3-year all-cause mortality.During the 3-year follow-up period, 153 (27.5%) patients died (cardiovascular death: n = 88). According to multivariate analysis, serum albumin (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.43-0.85, p = 0.003), creatinine (HR 0.91, 95% CI 0.84-0.99, p = 0.049), and CHA2DS2-VASc score (HR 1.33, 95% CI 1.20-1.46, p0.001) were associated with 3-year all-cause mortality. Compared with patients in the low CHA2DS2-VASc score group, those in the intermediate- and high-score groups had a higher risk for all-cause and CVD mortality (all-cause mortality: HR 1.77, 95% CI 1.23-2.55, p = 0.002 and HR 2.94, 95% CI 1.90-4.53, p0.001, respectively; CVD mortality: HR 1.82, 95% CI 1.27-2.59, p = 0.001 and HR 2.85, 95% CI 1.88-4.31, p0.001, respectively).The CHA2DS2-VASc score is a valuable predictor of 3-year all-cause and CVD mortality in incident HD patients.

Klotho is an antiaging protein reported to suppress transforming growth factor-β1 (TGF-β1) signaling. Aging kidneys are characterized by interstitial fibrosis, accumulation of cell cycle-arrested cells, and increased levels of oxidative stress. TGF-β1 signaling is involved in these processes. In this study, we investigated whether klotho overexpression improves these features in the kidneys of aging mice and examined the inhibitory effect of klotho on signaling molecules related to transforming growth of TGF-β1. Klotho transgenic (KLTG) and wild-type (WT) mice were used, and 8-wk-old and 24-mo-old mice were defined as young and aging, respectively. We found that klotho expression was decreased in aging WT mice, but it was maintained in aging KLTG mice. Klotho overexpression improved the survival of 24-mo-old mice. Although the serum Ca

A few previous clinical studies have shown that chloride (Cl) contributes to the progression and development of hypertension or proteinuria. Therefore, we aimed to determine whether hyperchloremia is associated with hypertension or proteinuria in patients with chronic kidney disease (CKD) and to define the relationships between the reduction in serum Cl concentration associated with CKD treatment and improvements in hypertension and/or proteinuria.We performed a retrospective observational study of new or referred patients with CKD who had hyperchloremia, moderate proteinuria, renal dysfunction, and hypertension. Patients taking medication for metabolic acidosis or with a history of dialysis were excluded. The participants' systolic and diastolic blood pressure (BP), serum sodium (Na) and Cl concentrations, and urinary protein (UP) concentration were measured at baseline and after 1 month of CKD treatment.Fifty-one patients with CKD were included in the study. Their serum Cl concentration independently correlated with sBP and UP at baseline (P = 0.022 and P = 0.033, respectively). After 1 month's CKD treatment, their serum Na and Cl concentrations, sBP, and UP were significantly lower. The change in sBP during the month (ΔsBP) correlated with the change in serum Cl (ΔCl) (P = 0.012) but not with the change in serum Na. Multivariate analysis showed that ΔsBP was independently associated with ΔCl (P = 0.029).Hyperchloremia is an independent predictor of hypertension and proteinuria for patients with CKD.

Thrombotic microangiopathies include hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Measurement of plasma levels of “a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13” (ADAMTS13) activity can distinguish HUS from TTP. Reduced plasma ADAMTS13 activity (

In this letter, we developed divide-and-conquer-based self-consistent-field methods with a finite-temperature (FT) scheme, denoted as FT-DC-SCF. The FT scheme can approximately involve the static correlation effect observed in bond-breaking reactions, double bond rotations, diradicals, and conjugated polymers within small additional computational costs. Test calculations of polyene, water cluster, diamond, graphene, magnesium oxide, and titanium demonstrate the high accuracy and efficiency of the developed FT-DC-SCF method. Furthermore, FT-DC-SCF was applied to the singlet-triplet energy gap and double bond rotation.

Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs’ therapeutic effects. In this study, we investigated whether pretreatment with IFN-γ could potentiate the anti-fibrotic ability of MSCs in rats with ischemia–reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-γ strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-γ treatment. In addition, conditioned medium obtained from IFN-γ-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-β1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 in conditioned medium obtained from IFN-γ-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ. Administration of MSCs treated with IFN-γ might represent a promising therapy to prevent the progression of renal fibrosis.

Hypoxia is a common pathway to the progression of end-stage kidney disease. Retinoic acid-inducible gene I (RIG-I) encodes an RNA helicase that recognizes viruses including SARS-CoV2, which is responsible for the production of interferon (IFN)-α/β to prevent the spread of viral infection. Recently, RIG-I activation was found under hypoxic conditions, and klotho deficiency was shown to intensify the activation of RIG-I in mouse brains. However, the roles of these functions in renal inflammation remain elusive. Here, for in vitro study, the expression of RIG-I and IFN-α/β was examined in normal rat kidney (NRK)-52E cells incubated under hypoxic conditions (1% O2). Next, siRNA targeting RIG-I or scramble siRNA was transfected into NRK52E cells to examine the expression of RIG-I and IFN-α/β under hypoxic conditions. We also investigated the expression levels of RIG-I and IFN-α/β in 33 human kidney biopsy samples diagnosed with IgA nephropathy. For in vivo study, we induced renal hypoxia by clamping the renal artery for 10 min in wild-type mice (WT mice) and Klotho-knockout mice (Kl−/− mice). Incubation under hypoxic conditions increased the expression of RIG-I and IFN-α/β in NRK52E cells. Their upregulation was inhibited in NRK52E cells transfected with siRNA targeting RIG-I. In patients with IgA nephropathy, immunohistochemical staining of renal biopsy samples revealed that the expression of RIG-I was correlated with that of IFN-α/β (r = 0.57, PP−/− mice. These findings suggest that hypoxia induces the expression of IFN-α/β through the upregulation of RIG-I, and that klotho deficiency intensifies this hypoxia-induced expression in kidneys.

This study aimed to investigate whether a combined estimation of the geriatric nutritional risk index (GNRI) and the modified creatinine index (mCI) provides synergistic information for mortality in patients treated by chronic hemodialysis. We analyzed 499 patients on hemodialysis for five years. We set each cut-off value as the high (≥92) and low (

Background Nephropathy in patients with thymic diseases such as thymoma and myasthenia gravis (MG) is rare and has been described mostly as isolated case reports. Here we evaluate a series of kidney biopsies from patients with thymoma and/or MG from a single institution in order to better define the spectrum and relative frequencies of thymic disease–associated nephropathies. Methods We conducted a retrospective case series study of 32 462 native kidney biopsies from January 2005 through December 2019 at Cedars-Sinai Medical Center, Los Angeles, CA, USA. Results Twenty-four biopsy specimens (0.07%) from patients with a history of thymoma and/or MG were identified. Two patients had repeat biopsies. The most common pathologic diagnosis that could be immunologically attributed to thymic disease was minimal change disease (MCD; 45%), followed by tubulointerstitial nephritis (TIN; 14%), immune complex (IC)-mediated glomerulonephritis (9%), membranous nephropathy (5%) and immunoglobulin A (IgA) nephropathy (5%). Interestingly, 50% of the MCD and 67% of TIN cases concomitantly showed mild IgG-dominant IC deposition in mesangial areas and/or in tubular basement membranes. In the two patients with repeat biopsies, mild mesangial IC deposition developed in the MCD patient but disappeared in the TIN patient with the second biopsy. Pathologic diagnoses unlikely related to the underlying thymic disease were diabetic glomerulosclerosis (9%), acute tubular necrosis (9%) and monoclonal Ig deposition disease (5%). Conclusions Thymic disease is associated with a wide spectrum of kidney diseases affecting the glomerular and tubulointerstitial compartments, often with low-grade IC deposition. These findings suggest a role of immunologic dysregulation in the pathogenesis of thymic disease–associated nephropathy.

Background:Mesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes may require a substantial period of time, leading to a delayed onset of MSCs therapeutic effects. Here, we investigatedwhetherpretreatment with IFN-γ potentiates the anti-fibrotic and anti-inflammatory activities of MSCs in an injured kidney. Methods:MSCs with or without IFN-γ treatment were injected into rats after ischemia-reperfusion injury (IRI) or unilateral ureter obstruction (UUO) to evaluate the therapeutic effect of IFN-γ-treated MSCs. In addition, we used conditioned medium obtained from IFN-γ-treated MSCs to investigate fibrotic change in cultured cells induced by transforming growth factor-β1 and phenotypic change of macrophages using THP-1 monocytes.Results:Administration of MSCs treated with IFN-γ strongly ameliorated renal fibrosis and inflammation in rat IRI and UUO models compared with that of untreated MSCs. In vitro experiments demonstrated that IFN-γ treatment enhanced the anti-fibrotic effects of MSCs by inhibiting the transforming growth factor-β1/Smad signaling pathway. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 induced polarization of immunosuppressive CD163-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ.Conclusions:Administration of MSCs treated with IFN-γ may represent a promising therapy to prevent the progression of renal fibrosis.

Recently, in addition to epithelial sodium channel alpha-subunit (αENaC), the thiazide-sensitive sodium-chloride cotransporter (NCC) and pendrin, also known as sodium-independent chloride/iodide transporter, were reported to be activated by aldosterone. Here, we investigated whether chloride (Cl−) is responsible for hypertension, inflammation, and renal damage in aldosterone-infused rats. Following left nephrectomy, 8-wk-old male Sprague-Dawley rats were allocated into four groups: 1) drinking 1.0% sodium chloride solution with aldosterone infusion (Aldo/NaCl rats); 2) drinking 1.44% sodium bicarbonate solution with aldosterone infusion (Aldo/NaHCO3 rats); 3) drinking distilled water with aldosterone infusion (Aldo/water rats); and 4) drinking distilled water without aldosterone infusion (sham rats). Additionally, heminephrectomized rats with aldosterone infusion were fed a 0.26% NaCl diet (control); 8.0% NaCl diet (high-Na/high-Cl); or a 4.0% NaCl 6.67% sodium citrate diet (high-Na/half-Cl). Last, Aldo/NaCl rats were treated with or without hydrochlorothiazide. Blood pressure in the Aldo/NaCl rats was significantly higher than in the Aldo/NaHCO3 rats, which was associated with the increased expression of NCC. Expression of markers of inflammation (CD3, CD68, interleukin-17A) and fibrosis (α-smooth muscle actin, collagen 1) were also increased in Aldo/NaCl rats. Similarly, aldosterone-infused rats fed a high-Na/half-Cl diet had lower blood pressure than those fed a high-Na/high-Cl diet, with a reduction of phosphorylated NCC, but not αENaC and pendrin. NCC inhibition with hydrochlorothiazide attenuated interleukin-17A protein expression along with the phosphorylation of NCC in Aldo/NaCl rats. These findings suggest that NCC-mediated Cl− uptake plays important roles in the development of aldosterone-induced hypertension and renal injury.

NH3 synthesis on Ru, Os, and Rh nanoparticle catalysts was investigated using density functional theory calculations. The Ru and Os nanoparticles exhibited similar shapes, while that of Rh differed significantly. For all metal species, step sites appeared at nanoparticle diameters (d) >2–4 nm. The calculated activation barriers (Ea) were small at step sites, and Ru and Os step sites exhibited similar Ea values despite the former having a higher turnover frequency. This is likely due to the surface coverage of vacant sites being higher on Ru. Although the increase in NH3 synthesis rate at d = 2–4 nm was common to Ru, Os, and Rh, the reaction rates decreased in the order: Ru > Os > Rh. Our results show that Ea values, surface vacant sites, and the number of step sites are important factors for NH3 synthesis. The Ru nanoparticles exhibited high activity due to satisfying all three factors.

[BACKGROUND AND HYPOTHESIS] Soybean isoflavones have been shown to reduce the risk of cerebral infarction in humans according to epidemiological studies. However, whether intake of miso can reduce the incidence of stroke in animal models remains unknown. In this study, we investigated the effects of soybean paste (miso) in an animal model of stroke. [METHODS] Stroke-prone spontaneously hypertensive rats (SHRSP) were fed a miso diet (normal diet 90%, miso 10%; final NaCl content 2.8%), a high salt diet (normal diet and NaCl 2.5%; final NaCl content 2.8%), or a low salt diet (normal diet; final NaCl content 0.3%). [RESULTS] Kaplan–Meier survival curves revealed a significantly lower survival rate in the high salt group compared to the miso group (P = 0.002) and the low salt group (P ≤ 0.001). Large hemorrhagic macules were found in the cerebrum in the high salt group, whereas none were found in the other 2 groups. There were also fewer histological and immunohistochemical changes in the brain and kidneys in the miso group compared to the high salt group. [CONCLUSION] Our results suggest that miso may have protective effects against stroke despite its high salt content., This work was supported by a grant-in-aid from the Central Miso Institute, Tokyo, Japan

Albuminuria and estimated glomerular filtration rate (eGFR) are clinically measured to evaluate the severity of chronic kidney disease (CKD). The aim of our study was to clarify the association between clinical parameters, including albuminuria and eGFR, and the risk of incident CKD in a nondiabetic population with normal range of albuminuria and eGFR. A 10-year follow-up, retrospective cohort study involving 317 Japanese men (mean age, 42 years) with eGFR ≥ 90 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR)

BackgroundLow-grade albuminuria has been considered a predictor of cardiovascular mortality. We investigated the relationship between high-normal albuminuria and subclinical atherosclerosis in non-diabetic men with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2.MethodsIn this cross-sectional study, 1,756 men with eGFR ≥60 mL/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) ResultsMedian UACR was 4.8 mg/g (interquartile range, 3.6-6.9 mg/g). Compared with subjects with low-normal UACR (ConclusionsOur results indicate that high-normal albuminuria is associated with both carotid IMT and plaque formation in the non-diabetic male population with eGFR ≥60 mL/min/1.73 m2.

Renal fibrosis is a common pathological feature of the progression of chronic kidney disease. Although valproic acid (VPA) has been recently shown to induce autophagy, the effect of VPA-induced autophagy on renal fibrosis remains unknown. We, therefore, investigated whether VPA-induced autophagy suppresses renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO). Male C57BL/6 mice were divided into five groups (n = 8 per group): (1) sham group; (2) vehicle group; (3) VPA-treated group; (4) 3-methyladenine (3-MA; autophagy inhibitor)-treated group; and (5) VPA plus 3-MA-treated group. Mice underwent UUO and the kidneys were studied after 5 days. We also investigated the effect of VPA-induced autophagy on α-smooth muscle actin (α-SMA) in transforming growth factor (TGF)-β1-stimulated rat kidney fibroblasts and epithelial cells. VPA attenuated renal fibrosis and induced autophagy in UUO mice, while 3-MA increased renal fibrosis and suppressed autophagy. In addition, the anti-fibrotic effect of VPA was diminished by 3-MA in UUO mice. In rat kidney fibroblasts and epithelial cells, VPA suppressed TGF-β1-stimulated α-SMA expression and induced autophagy. In contrast, 3-MA enhanced α-SMA expression while inhibiting autophagy. Furthermore, the combined use of VPA and 3-MA treatments increased the expression of α-SMA compared with VPA treatment alone in TGF-β1-stimulated rat kidney fibroblasts and epithelial cells, which was accompanied by the inhibition of autophagy. These findings suggest that VPA may be a candidate drug for the treatment of renal fibrosis through the induction of autophagy.

TGF-β1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain–containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-β1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-β1 neutralizing antibody. TGF-β1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P

In this study, we developed a time-dependent density-functional theory (TDDFT) with a finite-temperature (FT) scheme, denoted as FT-TDDFT. We introduced the concept of fractional occupation numbers for random phase approximation equation and evaluated the excited-state electronic entropy terms with excited-state occupation number. The orbital occupation numbers for the excited state were evaluated from the change in the ground-state electron configuration with excitation and deexcitation coefficients. Furthermore, we extended the FT formulation to the time-dependent density-functional tight-binding (TDDFTB) method for larger systems, denoted as FT-TDDFTB. Numerical assessment for the FT-(TD)DFT method showed smooth potential curves for double-bond rotation of ethylene in both ground and excited states. Excited-state calculations based on the FT-TDDFTB method were applied to the uniform π-stacking columns composed of trioxotriangulene, possessing neutral radicals in strong correlation systems.

Renal function declines with aging and is pathologically characterized by chronic inflammation and fibrosis. Renal senescence is induced not only by aging but also by various stimuli, including ischemia reperfusion injury. Recently, the accumulation of p16INK4a-positive cells in the kidney has been considered a molecular feature of renal senescence, with the p16INK4a gene reportedly regulated by mixed-lineage leukemia 1 (MLL1)/WD-40 repeat protein 5 (WDR5)-mediated histone 3 lysine 4 trimethylation (H3K4me3). Here, we determined whether inhibition of MLL1/WDR5 activity attenuates renal senescence, inflammation, and fibrosis in mice with ischemia reperfusion injury and in cultured rat renal fibroblasts. MM-102 or OICR-9429, both MLL1/WDR5 protein–protein interaction inhibitors, and small interfering RNA (siRNA) for MLL1 or WDR5 suppressed the expression of p16INK4a in mice with ischemia reperfusion injury, accompanied by downregulation of H3K4me3 expression. MM-102 attenuated renal fibrosis and inflammation in the kidney of mice with ischemia reperfusion injury. Moreover, in vitro study showed that transforming growth factor-β1 induced the expression of MLL1, WDR5, H3K4me3, and p16INK4a. Finally, chromatin immunoprecipitation identified the p16INK4a promoter at an H3K4me3 site in renal fibroblasts. Thus, our findings show that H3K4me3 inhibition ameliorates ischemia reperfusion-induced renal senescence along with fibrosis and inflammation.

Recently, in addition to epithelial sodium channel alpha-subunit (αENaC), the thiazide-sensitive sodium-chloride cotransporter (NCC) and pendrin, also known as sodium-independent chloride/iodide transporter, were reported to be activated by aldosterone. Here, we investigated whether chloride (Cl

High glucose (HG) induces production of transforming growth factor-beta1 (TGF-β1), but the mechanism remains elusive. The aim of this study was to determine the gene(s) involved in HG-induced TGF-β1 production in human peritoneal mesothelial cells (HPMCs). Microarray analysis was performed following a 3-h preincubation of HPMCs in 4 or 0.1 % glucose medium. Transcriptional genes were selected using Gene Ontology analysis for biological processes, including regulation of transcription and DNA-dependent. The effects of small interfering RNA (siRNA) treatments on the up-regulation of TGF-β1 mRNA were assessed by quantitative real-time polymerase chain reaction (qPCR). Finally, enzyme-linked immunosorbent assay (ELISA) was performed to determine which gene(s) contribute to the production of TGF-β1 protein in the medium. Microarray analysis revealed that the expression of 51 genes increased by more than 3-fold. Gene ontology analysis identified 13 genes for further study. qPCR confirmed mRNA amplification for 9 of the 13 genes. Furthermore, HG-induced up-regulation of TGF-β1 mRNA was attenuated by the siRNA of 4 genes: MDS1 and EVI1 complex locus (MECOM), FBJ murine osteosarcoma viral oncogene homolog B (FOSB), FBJ murine osteosarcoma viral oncogene homolog (FOS) and activating transcription factor 3 (ATF3). ELISA showed that siRNA treatment of FOS, but not MECOM, FOSB or ATF3, suppressed the increase of TGF-β1 protein in the medium. FOS is a downstream effector of HG stimulation in HPMCs that contributes to TGF-β1 production, suggesting that blocking FOS expression may be a therapeutic target for peritoneal fibrosis.

Chronic kidney disease patients share clinical and pathological features with the general aging population. Increased oxidative DNA damage, accumulation of cell cycle-arrested cells and decreased Klotho expression are assumed to be age-related factors that are reportedly linked to kidney disease. This study sought to determine the association between these age-related factors and renal damage in patients with IgA nephropathy (IgAN). We performed a cross-sectional analysis of 71 patients who were diagnosed with IgAN by renal biopsy. Expression of 8-hydroxydeoxyguanosine (8-OHdG, a marker of oxidative DNA damage), p16 (a marker of cell cycle-arrest) and Klotho (an anti-aging protein) were evaluated by immunohistochemical staining of renal biopsy samples. We correlated the changes in expression of these markers with Lee’s pathologic grades and the Oxford classification. We also investigated the independent association between these markers and interstitial fibrosis using multiple linear regression analysis. 8-OHdG and p16 increased but Klotho decreased with progression of pathologic grade. Expression of 8-OHdG and p16 increased with the deterioration of mesangial hypercellularity and segmental glomerulosclerosis. In addition, p16 increased but Klotho decreased with progression of tubular atrophy/interstitial fibrosis. In univariate regression analysis, age, body mass index, systolic blood pressure, urinary protein excretion and expression of 8-OHdG, p16 and Klotho showed significant correlations with interstitial fibrosis. Multivariable regression analyses revealed that aging, increased renal expression of p16 and decreased expression of Klotho were independently correlated with interstitial fibrosis. The age-related factors might play important roles in the development of IgAN.

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that have regenerative capability and exert paracrine actions on damaged tissues. Since peritoneal fibrosis is a serious complication of peritoneal dialysis, we tested whether MSCs suppress this using a chlorhexidine gluconate model in rats. Although MSCs isolated from green fluorescent protein–positive rats were detected for only 3 days following their injection, immunohistochemical staining showed that MSCs suppressed the expression of mesenchymal cells, their effects on the deposition of extracellular matrix proteins, and the infiltration of macrophages for 14 days. Moreover, MSCs reduced the functional impairment of the peritoneal membrane. Cocultures of MSCs and human peritoneal mesothelial cells using a Transwell system indicated that the beneficial effects of MSCs on the glucose-induced upregulation of transforming growth factor-β1(TGF-β1) and fibronectin mRNA expression in the human cells were likely due to paracrine actions. Preincubation in MSC-conditioned medium suppressed TGF-β1-induced epithelial-to-mesenchymal transition, α-smooth muscle actin, and the decrease in zonula occludens-1 in cultured human peritoneal mesothelial cells. Although bone morphogenic protein 7 was not detected, MSCs secreted hepatocyte growth factor and a neutralizing antibody to this inhibited TGF-β1 signaling. Thus, our findings imply that MSCs ameliorate experimental peritoneal fibrosis by suppressing inflammation and TGF-β1 signaling in a paracrine manner.

Deubiquitinating enzymes (DUBs) remove ubiquitin from their substrates and, together with ubiquitin ligases, play an important role in the regulation of protein expression. Although transforming growth factor (TGF)-β1-Smad signaling is a central pathway of renal fibrosis, the role of DUBs in the expression of TGF-β receptors and Smads during the development of renal fibrosis remains unknown. In this study, we investigated whether PR-619, a pan-DUB inhibitor, suppresses fibrosis in mice with unilateral ureteral obstruction (UUO) and TGF-β1-stimulated normal rat kidney (NRK)-49F cells, a rat renal fibroblast cell line. Either the vehicle (dimethyl sulfoxide) or PR-619 (100 μg) was intraperitoneally administered to mice after UUO induction once a day for 7 days. Administration of PR-619 attenuated renal fibrosis with downregulation of mesenchymal markers, extracellular matrix proteins, matrix metalloproteinases, apoptosis, macrophage infiltration, and the TGF-β1 mRNA level in UUO mice. Although type I TGF-β receptor (TGF-βRI), Smad2, Smad3, and Smad4 protein expression levels were markedly increased in mice with UUO, administration of PR-619 suppressed only Smad4 expression but not TGF-βRI, Smad2, or Smad3 expression. PR-619 also had an inhibitory effect on TGF-β1-induced α-smooth muscle actin expression and reduced Smad4 levels in NRK-49F cells. Our results indicate that PR-619 ameliorates renal fibrosis, which is accompanied by the reduction of Smad4 expression., This work was supported by JSPS KAKENHI Grant Number JP16K09618 (https://www.jsps.go.jp/j-grantsinaid/).

We report a 55-year-old right-handed man who presented with topographical disorientation following left retrosplenial hemorrhage. His directional information about familiar places, encoded by previous navigation, was severely impaired, and he could not learn the direction to new places in large-scale spaces beyond the range of visual surveillance. By contrast, he had no difficulties with directional information encoded in a tabletop manner: he could locate major cities or countries on a map, and he also could memorize the spatial relationship of objects in a room. Six months after the ictus, when he had recovered from his directional disorientation, a functional magnetic resonance imaging (fMRI) study of mental navigation demonstrated prominent activation in the retrosplenial area along the right parieto-occipital sulcus and the circumference of the injured area on the left side. The present study, together with previous investigations including clinical case reports, functional neuroimaging, and anatomical and physiological studies on monkeys, suggests that the 'sense of direction' in a large-scale locomotor environment is subserved by the visual area along the parieto-occipital sulcus, and that bilateral deterioration of this function causes directional disorientation.