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Oxidative stress is now recognized to be an important therapeutic target in kidney diseases. However, there are currently no biomarkers that can be used clinically to diagnose renal oxidative stress.A rapid assay system for urinary thioredoxin 1, an oxidative stress-dependent biomarker of acute kidney injury (AKI), was developed as a chemiluminescence enzyme immunoassay and validated analytically and clinically.Analytic evaluation revealed that hemolytic hemoglobin caused measurements to be abnormally high, above the detectable range. However, urine sediment containing red blood cells did not affect the measurements. Assays using our proposed chemiluminescence enzyme immunoassay were completed within as little as 6 min, whereas a conventional ELISA 4 h. AciduriapH 6.0 led to a significant underestimation of thioredoxin 1 concentrations. However, the effects of aciduria were completely reversible with use of a buffer developed for pH adjustment. Urinary thioredoxin 1 was increased in patients with AKI, but was unaffected by extrarenal oxidative stress diseases, including hypoxemia and myocardial infarction, or by chronic kidney disease in which serum creatinine concentrations were comparable.These results suggest that the chemiluminescent enzyme immunoassay system for urinary thioredoxin 1 enables rapid and specific diagnosis of AKI associated with oxidative stress.

Aim The influence of angiotensin II receptor blockers (ARB) on licorice-induced pseudoaldosteronism remains unclear and the antihypertensive drug selection of prescribers, when they encounter hypokalemia and hypertension in licorice-treated patients, has not been surveyed. Methods We examined the occurrence of hypokalemia, concomitant drugs, and treatment for hypokalemia and hypertension in 42, 26 and 27 patients prescribed the licorice-containing traditional Japanese kampo medicines shakuyakukanzoto (SKT; containing 6 g licorice/day), rikkunshito (RKT; 1 g licorice/day), and goshajinkigan (GJG; without licorice), respectively. Results Seven (16.7%; P

In recent years, study on autonomous driving has been actively conducted. The model-based control is used as one of control methods of autonomous driving. The model-based control in automated driving requires simple and accurate vehicle model that can accurately represent the state of the vehicle and has low processing load on computer memory. Therefore, we represented the modeling error due to fluctuation of road and dynamic characteristics of the vehicle as the deviation of the front wheel steering angle of the kinematics bicycle model which is a simple model. We propose a method to adaptively identify the vehicle model while estimating the modeling error in real time using Neural Network. In this paper, we apply the vehicle model including modeling error to the model predictive control as an example of model-based control, and verify the usefulness of this study in simulation using CarSim.

Ethnopharmacological relevance The dried root of Rehmannia glutinosa (RR) is a crude drug used in traditional Japanese Kampo medicine and traditional Chinese medicine (TCM). Sometimes, the crude drug is subjected to additional processing before use. Aim of the study To determine the effects of steam processing and pretreatment with liquor of RR through historical investigation, analytical chemistry, and pharmacological experiments. Materials and methods We inspected TCM literature from the Later Han Dynasty to the present day. Dried RR steamed for 3, 6, 9, or 12 h (steamed RRs, SRRs), dried RR soaked in yellow rice wine (liquor) (liquor-RR), and dried RR steamed for 6 h pretreated with liquor (liquor-SRR) were prepared. These samples were extracted using boiling water, and the inducible effects of the extracts on granulocyte colony-stimulating factor (G-CSF) secretion in cultured enterocytes and the content of their marker compounds were evaluated by using HPLC. Results The effect of processing using both steaming and the pretreatment using liquor described in TCM literature over different eras was to enhance the warming effect and tonifying qi (energy) of RR. We found that SRR, processed by pretreatment with liquor, became mainstream since the Qing Dynasty. In SRR, stachyose content was decreased and fructose and manninotriose contents were increased with steaming time. However, the content of these compounds was not altered by pretreatment with liquor. RR extract induced G-CSF secretion in cultured enterocytes; moreover, the SRR extract steamed for more than 6 h had significantly stronger effects than that RR. Pretreatment with liquor did not cause any significant differences in the effects of RR or SRR. Conclusions The aim of processing for RR by both steaming and pretreatment with liquor in TCM literature over different eras was to enhance the tonifying effect on qi and its immunostimulatory effect. Although the effect of RR on the induction of G-CSF secretion in intestinal epithelial cells was enhanced by steaming, this enhancement was not enhanced by the pretreatment with liquor. These results provide scientific support for steaming, but could not elucidate a reason for pretreatment with liquor in TCM theory.

Oxidative stress and peritubular capillary (PTC) injury are involved in the progression of chronic kidney disease (CKD). We investigated protective effects of Shichimotsu-koka-To (SKT), a Japanese traditional Kampo prescription, against nephrosclerosis and hypertension on a CKD model due to irreversible nephritis. Six-week-old male Wistar rats were subjected to uninephrectomy, and to injection of rabbit anti-thymocyte serum. SKT treatment was continued for 15 weeks, blood pressure was measured, and then renal specimens were collected. PTC networks were detected by immunostaining for CD-31. And superoxide dismutase (SOD)-like activity in the tissue was evaluated. Blood pressure in the SKT group, as well as sham group, was significantly lower than with the vehicle. SKT markedly ameliorated renal function, which was evaluated with urea nitrogen clearance. Compared with the vehicle, SKT treatment lowered both the glomerular enlargement and hyper-cellularity by 80%, and decreased the extracellular matrix area by 75%. SKT treatment also suppressed tubular injury, and maintained PTC networks. Furthermore, SKT recovered SOD-like activity to the basal levels. These results suggest that SKT may be useful for the treatment of CKD during the progression to nephrosclerosis, through the mechanisms of anti-oxidative activity and maintenance of PTC networks.

Considering that fibrin deposition is observed in glomerulonephritis as well as in diabetic nephropathy, we performed studies to clarify the roles of the coagulation pathway and the active type of coagulation factor X (factor Xa) in the development of chronic kidney disease (CKD) using animal models. Factor Xa activates various cell types through protease-activated receptor 2 (PAR2). Several in vitro studies have demonstrated that PAR2 can mediate factor Xa signaling, but not thrombin signaling. Coagulation processes proceed together with the extracellular matrix (ECM) accumulation through factor V expression in rat Thy-1 nephritis. DX-9065a, a factor Xa inhibitor, suppresses this type of glomerulonephritis. The factor Xa inhibitor danaparoid ameliorated proteinuria, cellular proliferation, and fibrin deposition in lipopolysaccharide (LPS)-triggered activation of High IgA (HIGA) strain of ddY mice. Another factor Xa inhibitor, fondaparinux, suppressed urinary protein, glomerular hypertrophy, and connective tissue growth factor (CTGF), and ECM protein deposition together with angiogenesis in diabetic db/db mice. Finally, in the model of peritoneal fibrosis, fondaparinux treatment decreased the thickness of submesothelial fibrotic tissue and angiogenesis. In consideration of the results to potential human therapy, factor Xa regulation may be promising for the treatment of the aggravation in glomerulonephritis and of the early phase of diabetic nephropathy. In the near future, novel factor Xa inhibitors with the characteristics of oral administration and biliary elimination may appear in the clinical use for treatment of cardiovascular diseases.

Rapid amelioration of hypercholesterolemia in nephrotic syndrome (NS) using low density lipoprotein-apheresis (LDL-A) sometimes leads to NS remission, along with improvement of impaired biodefense system; however, the mechanism of how LDL-A affects NS is still unknown. We studied IFN-γ production under IL-12 stimulation for 24 h in whole blood from 30 NS patients, 31 non-NS patients, 35 healthy volunteers and another four persistent NS patients due to refractory focal segmental glomerulonephritis and minimal change type nephrotic syndrome. We compared IFN-γ production in whole blood and peripheral blood mononuclear cells (PBMC) from persistent NS patients before and after each of 14 LDL-A procedures. Finally, we studied the effect that persistent NS patients' serum before and after LDL-A had on IFN-γ production in healthy volunteers' PBMC. Whole blood IFN-γ production was significantly lower in NS patients compared with healthy volunteers or non-NS patients. In persistent NS, after LDL-A, IFN-γ production returned to normal levels. IFN-γ production in PBMC varied greatly among these patients and did not show consistent changes after LDL-A. Healthy volunteers PBMC incubated with persistent NS patients' serum obtained after LDLA showed higher IFN-γ production than before LDL-A. IFN-γ production in peripheral blood is impaired if a patient is in a nephrotic state. LDL-A might restore suppressed PBMC function in persistent NS patients, thereby ameliorating the nephrotic state, possibly through removing interfering serum factors.

Shichimotsukokato (SKT) is a Kampo formula, comprising astragalus root, phellodendron bark, rehmannia root, peony root, cnidium rhizome, Japanese angelica root, and uncaria hook. It is prescribed to hypertensive patients who complain of a sensation of a rush of blood to the head, shoulder stiffness, tinnitus, and dull headache. We investigated the effects of SKT on renal hypertension in Wistar rats subjected to a 5/6 nephrectomy (Nx). Systolic blood pressure (SBP) increased markedly after surgery and remained high in the Nx rats. Oral treatment of SKT extract at dosages of 0.75 and 1.5 g/kg/day (corresponding to 5- and 10-fold human dosages, respectively) caused a significant suppression of the increase in SBP in Nx rats. Plasma concentrations of nitric oxide (NO) were marginally lower and asymmetric dimethylarginine (ADMA) significantly higher in the Nx rats than in sham-operated rats. SKT administration caused a significant counteraction of these changes. Finally, we evaluated the levels of protein methyltransferase (PRMT), an enzyme that catalyzes the production of ADMA, and the levels of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme involved in the degradation of ADMA, in the remnant kidney. Neither Nx nor SKT treatment affected PRMT-1 or DDAH-1 levels. DDAH-2 levels were reduced significantly in the Nx rats compared with the sham-operated rats. SKT treatment significantly ameliorated this decrease in the DDAH-2 levels. It is considered that SKT reduced blood pressure in the renal hypertension rat model, mediated, at least partially, by the DDAH-ADMA-NO pathway.

The effects of the dye-adsorption solvent on the performances of the dye-sensitized solar cells (DSSCs) based on black dye have been investigated. The highest conversion efficiency (10.6 %) was obtained in the cases for which 1-PrOH and the mixed solvent of EtOH and tBuOH (3:1 v/v) were employed as dye-adsorption solvents. The optimized value for the dielectric constant of the dye-adsorption solvent was found to be around 20. The DSSCs that used MeOH as a dye-adsorption solvent showed inferior solar-cell performance relative to the DSSCs that used EtOH, 1-PrOH, 2-PrOH, and 1-BuOH. Photo- and electrochemical measurements of black dye both in solution and adsorbed onto the TiO(2) surface revealed that black dye aggregates at the TiO(2) surface during the adsorption process in the case for MeOH. Both the shorter electron lifetime in the TiO(2) photoelectrode and the greater resistance in the TiO(2)-dye-elecrolyte interface, attributed to the dye aggregation at the TiO(2) surface, cause the decrease in the solar-cell performance of the DSSC that used MeOH as a dye adsorption solvent.

An efficient critical control system design is proposed in this paper. The key idea is to decompose the design problem into two simpler design steps by the technique used in the classical loop transfer recovery method (LTR). The disturbance cancellation integral controller is used as a basic controller. Since the standard loop transfer recovery method cannot be applied to the disturbance cancellation controller, the nonstandard version recently found is used for the decomposition. Exogenous inputs with constraints both on the amplitude and rate of change are considered. The majorant approach is taken to obtain the analytical sufficient matching conditions. A numerical design example is presented to illustrate the effectiveness of the proposed design.

Background: The high IgA (HIGA) strain of ddY mice represents an inbred model of IgA nephropathy that shows mesangioproliferative glomerulonephritis with mesangial IgA deposition. In this study, aggravation of glomerulonephritis in HIGA mice through lipopolysaccharide (LPS)-triggered activation of coagulation was investigated. Methods: Twelve-week-old HIGA and BALB/c mice were intraperitoneally injected with LPS twice at an interval of 3 days, and kidney specimens were collected 7 days after the second LPS injection. In an intervention experiment, the factor Xa inhibitor danaparoid was injected intraperitoneally every day for 7 days after the first LPS injection. Results: LPS injection induced macrophage infiltration and cellular proliferation in the mesangium together with fibrin deposition and monocyte chemoattractant protein 1 mRNA expression, as well as antigen deposition of tissue factor, factor V, factor X, and protease-activated receptor 2. These phenomena were obvious in HIGA mice when compared to BALB/c mice. Interestingly, toll-like receptor 4 was intensely expressed in HIGA mice before LPS injection and subsequently decreased. Danaparoid treatment significantly ameliorated proteinuria, cellular proliferation, and fibrin deposition. Conclusions: The present data suggest that tissue factor and factor V induction by LPS may in part accelerate mesangioproliferative glomerulonephritis through activation of factor X and downstream proinflammatory and procoagulant mechanisms.

The performances of infrared-dye-sensitized solar cells fabricated using two novel cyanine dyes (light absorption edge: 900 nm) were investigated. The performance of the cell using NK6037 dye was superior to that using NK4432; hence, an intimate interaction between the dye and the TiO 2 photoelectrode via the functional group is essential for efficient electron injection. The efficiency reached 1.9% by optimizing the light-confining effect of the TiO 2 photoelectrode and TiO 2 film thickness, and reached 2.3% by adjusting the concentration of deoxycholic acid (DCA) in the dye solution. The roles of the dye and DCA were clarified by photochemical and electrochemical characterization.

Objective Fibrin deposition on the peritoneum has been frequently observed in peritoneal fibrosis induced by long-term peritoneal dialysis. The present study was conducted to clarify the contribution of factor Xa through tissue factor and factor V expression in peritoneal fibrosis. Methods Wistar rats were intraperitoneally injected with chlorhexidine gluconate (CG) every day. For the interventional study, the factor Xa inhibitor fondaparinux was subcutaneously administered. After 28 days of CG injection, peritoneal specimens were examined by immunohistochemical analyses and in situ hybridization. Results The peritoneal submesothelial compact zone was observed to be markedly thicker in the CG-injected groups than in the normal group, and that thickness was dose dependent. Immunohistochemical study revealed massive fibrin, fibronectin, and type IV collagen depositions in the CG-injected groups, which was markedly higher than that in the normal group. Macrophage infiltration and staining for tissue factor, factor V, factor X, and protease-activated receptor-2 were intense in the CG-injected groups and negative/trace in the normal group. Tissue factor and factor V mRNAs were abundant in cells in the thickened peritoneum. A double-labeling experiment revealed that tissue factor was observed mainly in macrophages, and factor V was abundantly distributed in the fibrotic tissue together with macrophages. Fondaparinux treatment decreased the thickness of submesothelial fibrotic tissue, and size and number of CD31-positive vessels. Conclusion These results suggest that expression of tissue factor and factor V in infiltrated macrophages, together with factor X deposition, may progress angiogenesis and accumulation of extracellular matrix components, partly via profibrotic and procoagulant mechanisms in the peritoneum after inflammatory stimulation.

It is well known that patients with chronic kidney disease, including diabetic nephropathy, often develop cardiovascular diseases. In case of radiographic procedures, reduced renal function may be deteriorated by the use of iodinated contrast medium (CM). This is known as CM-induced nephropathy. In this study, we have focused on the mechanisms of this type of injury in diabetic nephropathy and the preventive effects of serofendic acid.We evaluated the cytotoxicity of CM and high glucose on tubular epithelial cells using an LLC-PK1 cell line, and measured cell viability with an alamarBlue assay. We further evaluated superoxide production levels measured by dihydroethidium. We also examined the protective effects of serofendic acid on cytotoxicity with superoxide production of CM and high glucose.CM reduced cell numbers in a dose-dependent and time-dependent manner in LLC-PK1 cells. Furthermore, cytotoxicity of CM in diluted concentration was additively influenced by high glucose. CM and high glucose increased superoxide production, which was evaluated by the response to dihydroethidium, and was suppressed by serofendic acid. Cytotoxicity of CM, high glucose, and H(2)O(2) was suppressed by serofendic acid, as well as the suppression by N-acetylcysteine on CM toxicity. Interestingly, the recovery by serofendic acid in H(2)O(2)- and high glucose-induced cellular injury was to the basal level, in contrast with the partial recovery from CM-induced injury. Finally, serofendic acid suppressed CM-induced injury and high glucose-induced apoptosis.These results suggest that CM and high glucose induce cytotoxicity and oxidative stress in LLC-PK1 cells and that serofendic acid protects the injury probably from superoxide generation.

During transportation by ambulance, a patient is exposed to inertial acceleration when an ambulance decelerates or turns a corner. Such acceleration often gives a patient physical stress such as blood pressure variation or body sway, which causes strong pain, feeling of discomfort or sometimes critical damage for seriously injured persons. To reduce this undesirable effect of the acceleration, the authors developed the actively-controlled bed (ACB) which controls the posture of a stretcher in real time to reduce foot-to-head and lateral acceleration acting on a supine person. This paper describes development of the ACB, including control system design and performance evaluation. The control system is designed by Zakian’s framework, which comprises the principle of matching and the method of inequalities, so that the design specifications on the tracking error and the motor torque are satisfied. From the results of driving experiments and simulation, it is estimated that the ACB can reduce the acceleration acting on a patient by 65% in the foot-to-head direction and by 75% in the lateral direction.

ネフローゼ症候群に柴苓湯が奏効した2症例を経験した。症例1は5.2g/日の多量の蛋白尿を呈し，柴苓湯の単独投与を開始し，その後の入院精査にて腎生検による組織型は微小変化型であったが，尿蛋白は入院中に減少し続け，投与開始の2ヵ月後に0.3g/日に至った。外来治療に移行して2.0g/日に増加したものの，再び減少し完全寛解に至った。症例2は8年前にネフローゼ症候群を呈し腎生検で特発性膜性腎症と診断され，少量プレドニゾロン，免疫抑制薬，アンジオテンシン受容体拮抗薬等の併用にて寛解していたが，経過中，4.4g/日の蛋白尿を呈して再発し，柴苓湯の併用にて4週間後1.3g/日となり，その後寛解した。身体所見および漢方医学的所見として症例1は軽度の胸脇苦満を認め，症例2は中等度の浮腫とともに胸脇苦満も明瞭であった。今回の症例におけるすみやかな寛解経過から，考えうる柴苓湯の作用機序を考察し報告する。

A 65-year-old Japanese male developed renal dysfunction, showing proteinuria and marked urinary excretion of beta2-microglobulin. He had consumed approximately 100-200 g peanuts and 750-1,000 ml beer every day for two or three months. He had previously been treated for hypertension with an angiotensin-converting enzyme inhibitor, enalapril. He then visited his primary-care doctor with mild fever, and renal dysfunction with mild diabetes mellitus were diagnosed. He was referred to our hospital, and because no diabetic retinopathy was observed by ophthalmological tests, renal biopsy examination was performed to clarify renal dysfunction. Renal biopsy specimens showed intimal thickening in the small arteries and interstitial nephritis with a granulomatous lesion, accompanied by oxalate crystals under polarized light. Glomeruli were unremarkable without any immunoglobulin deposition, and nodular lesions. Because he daily consumed a large amount of peanuts, oxalate nephropathy due to excessive intake of peanuts was strongly suspected. This case revealed that unusual food habits, including nuts, can cause oxalate nephropathy, and that close examination by renal biopsy was useful for clarifying the etiology of the unknown renal damage.

Fibrin monomer and its derivatives in blood are found in an early stage of thrombosis. When they are produced in blood, they form complexes with fibrinogen, and they exist as soluble complexes named soluble fibrin (SF). As final insoluble products, cross-linked fibrin (XFb) is often observed in mesangial areas in active types of human glomerulonephritis. To clarify the mechanisms of mesangial SF production and its relationship to XFb deposition in IgA nephropathy (IgAN), an immunohistochemical study was conducted.Nineteen patients with IgAN were studied. XFb was detected in renal biopsy specimens using anti-d-dimer antibody combined with plasmin exposure. SF was detected with a monoclonal antibody (IF-43), and factor V was detected with a specific rabbit antibody. The relationships of SF staining to the disease activity index, XFb deposition, and factor V staining was evaluated.XFb, factor V, and SF were observed in the mesangium in 14, 11, and 8, respectively, of a total of 19 specimens. SF had frequent staining in the proliferating areas, showing a significant relationship to XFb or factor V (P0.05). Furthermore, XFb, factor V, and SF depositions were markedly correlated with disease activity (P0.001 in each case).These findings suggest that SF is formed in the mesangial area in active IgA nephropathy accompanied by mesangial proliferation, in particular, in its early stage.

Saliva is the first body fluid to encounter exogenous materials or gases such as cigarette smoke (CS). The aim of this study was to examine whether smoking affects oral peroxidase (OPO) reactivity to mental stress. The subjects were 39 non-smokers and 10 smokers. In the experiment, the Kraepelin psychodiagnostic test as a psychological stressor and saliva was sampled 30 min before, just before, immediately after, and 30 min after the beginning of the test. OPO reactivity to the test between smokers and non-smokers was measured in addition to uric acid concentration, flow rate, IgA, thiocyanate (SCN-) concentration, amylase activity as a salivary stress marker, and ultra-weak chemiluminescence (UCL) level, which is indicative of salivary antioxidative and antibacterial abilities. Moreover, we studied the effect of smoking on the response of salivary peroxidase (SPO) and myeloperoxidase (MPO) activity to mental stress, respectively. The results showed that the IgA concentration, amylase activity, SCN(- concentration, and UCL level are higher in the non-smoking group than smoking group and the IgA concentration and UCL level increased in the non-smokers significantly just after the Kraepelin test. The levels of SCN-) were higher in smokers than in non-smokers and OPO activity was greater in the non-smoking group in all sessions. Furthermore, only the non-smokers had significantly increased MPO activity just after the test. MPO may play a crucial role in the response to acute psychological stress besides inflammation, and CS suppresses this response significantly.

An application of the loop transfer recovery (LTR) technique to critical control systems design is proposed for non-minimum phase plants. The controller structure is chosen as the Davison type integral controller with the Kalman filter. First, a critical control system is designed on the assumption that the state of the minimum phase part of the plant can be used for the feedback. A quadratic performance index with tuning parameters is used for determining the partial state feedback gain matrix. Second, the Kalman filter gain matrix is determined such that the output feedback controller performs as in the partial state feedback controller. The formal partial loop recovery procedure using the Riccati equation is adopted for this purpose. The proposed design method requires much simpler numerical search than the conventional one-step approach. An illustrative design example is presented.

Saliva sampling has the advantage of being noninvasive and stress free. Based on a recent study, salivary ultraweak chemiluminescence (UCL) is a new biomarker of psychologic stress. However, it is not clear what causes changes in the UCL level and whether the change is biologically significant. We investigated the candidates for salivary UCL induced by psychological stressors and discuss the physiologic function of these candidates. Vol unteers completed a questionnaire and then performed the Kraepelin test. Saliva was sampled just before, immediately after, and 30 min after the stress exposure. The UCL of saliva significantly increased just after stress exposure (1.56-fold) and returned to prestress levels after 30 min. The concentration of secretory immunoglobulin Aa lso increased significantly and the change in both biomarkers was rapid. Similar significant changes were observed in salivary peroxidase activity an dt he concentration of thiocyanate (SCN − ). On the other hand, the levels of amylase activity did not significantly increase and the concentration of cortisol increased slowly. Moreover, in the reconstitution experiment, UCL was generated at the same level by a mixture of peroxidase and SCN − at physiologic concentrations. In conclusion, we determined that the Kraepelin test as a mental arithmetic task elicited a significant response in the body and this response can be calculated using salivary UCL. Furthermore, SCN − and peroxidase in the saliva play a key role in salivary UCL.

In emergency transportation by ambulance, a patient receives acceleration in various direction. Particularly, longitudinal or lateral acceleration in braking and curve driving causes patient's stress such as blood pressure variation in brain, vomiting or feeling of discomfort. To reduce such patient's stress, we developed the 2-degree-of-freedom (2 DOF) actively-controlled bed (ACB) that reduces the acceleration acting on a patient by controlling posture of the bed. This paper reports its structure, control scheme and control performance. The effect is examined by experiment in terms of cancellation rate of acceleration and ride quality. Using the actual driving data of ambulance, the cancellation rate of acceleration in emergency transportation is also estimated by simulation.