Embodied bidirectional simulation of a spiking cortico-basal ganglia-cerebellar-thalamic brain model and a mouse musculoskeletal body model distributed across computers including the supercomputer Fugaku.

Embodied simulation with a digital brain model and a realistic musculoskeletal body model provides a means to understand animal behavior and behavioral change. Such simulation can be too large and complex to conduct on a single computer, and so distributed simulation across multiple computers over the Internet is necessary. In this study, we report our joint effort on developing a spiking brain model and a mouse body model, connecting over the Internet, and conducting bidirectional simulation while synchronizing them. Specifically, the brain model consisted of multiple regions including secondary motor cortex, primary motor and somatosensory cortices, basal ganglia, cerebellum and thalamus, whereas the mouse body model, provided by the Neurorobotics Platform of the Human Brain Project, had a movable forelimb with three joints and six antagonistic muscles to act in a virtual environment. Those were simulated in a distributed manner across multiple computers including the supercomputer Fugaku, which is the flagship supercomputer in Japan, while communicating via Robot Operating System (ROS). To incorporate models written in C/C++ in the distributed simulation, we developed a C++ version of the rosbridge library from scratch, which has been released under an open source license. These results provide necessary tools for distributed embodied simulation, and demonstrate its possibility and usefulness toward understanding animal behavior and behavioral change.

Impact of metabolic disturbances and malnutrition-inflammation on 6-year mortality in Japanese patients undergoing hemodialysis.

Metabolic syndrome confers an increased risk of cardiovascular disease (CVD) in the general population. The relationship between adiponectins, and clinical outcomes in patients undergoing hemodialysis remains controversial. We investigated whether adiponectins, biomarkers of inflammation, nutrition status and clinical features predict the mortality of patients undergoing hemodialysis for 6 years. We measured baseline plasma total and high-molecular-weight (HMW) adiponectins, tumor necrosis factor (TNF)-α, serum high sensitivity C-reactive protein (hsCRP), and clinical characteristics including visceral fat area (VFA) and the Geriatric Nutritional Risk Index (GNRI) in 133 patients undergoing chronic hemodialysis. Forty-one of the 133 patients died during follow-up. The deceased patients were significantly older, had more prior CVD and diabetes, higher TNF-α and hsCRP levels but lower GNRI. VFA, and total and HMW adiponectin did not significantly differ between the two groups. TNF-α and hsCRP levels and GNRI score were significant for predicting all-cause and cardiovascular mortality in receiver operating curve analyses. When stratified by a GNRI score of 96, Cox proportional hazards analyses identified TNF-α as a significant predictor of all-cause mortality (hazard ratio [HR] 1.23; P = 0.038) and hsCRP as a significant predictor of all-cause and cardiovascular mortality (HR, 2.32, P = 0.003; HR 2.30, P = 0.012, respectively) after adjusting for age, sex, diabetes mellitus, and prior CVD, only in malnourished patients. These results demonstrate that malnutrition and the inflammatory markers TNF-α and hsCRP, but not metabolic markers, including VFA and adiponectins have a significant impact on 6-year all-cause and cardiovascular mortality in Japanese patients undergoing hemodialysis.

Retrospective comparison of the efficacy of tonsillectomy with and without steroid-pulse therapy in IgA nephropathy patients.

OBJECTIVE: Tonsillectomy and steroid-pulse (TSP) therapy have been proposed as a curative treatment for immunoglobulin A nephropathy (IgAN) in Japan. However, we sometimes encounter patients who reject steroid-pulse therapy because of concerns about the side effects of corticosteroids. Here, we examined the efficacy of TSP therapy and tonsillectomy alone for IgAN with urinary abnormalities. METHODS: Data on 40 IgAN patients diagnosed by renal biopsies, who presented glomerular hematuria and proteinuria at baseline and underwent bilateral palatine tonsillectomy, were analyzed retrospectively. Twenty of them underwent TSP therapy (TSP group), and 20 underwent tonsillectomy alone (T group). We examined associations between therapies, changes in urinary findings and renal function, and subsequent clinical remission (CR), defined as negative proteinuria and urinary erythrocytes of less than 5/high-power field. RESULTS: TSP group showed a significant decrease in proteinuria and hematuria earlier than T group. The rates of CR were significantly higher in TSP group compared with T group on the final observation period (75% vs. 45%, p<0.05). There was a significant difference between CR group and non-CR group only in the rate of receiving TSP therapy. CONCLUSION: TSP therapy significantly increased the probability of CR compared with tonsillectomy alone in IgAN patients with urinary abnormalities.

A patient with Dent disease and features of Bartter syndrome caused by a novel mutation of CLCN5.

UNLABELLED: Dent disease is an X-linked tubulopathy mainly caused by inactivating mutations of CLCN5. Features of Bartter syndrome such as hypokalemic metabolic alkalosis are rarely observed in patients with Dent disease. We report a Japanese male patient with Dent disease who also manifested features of Bartter syndrome. At the age of 3 years, he was diagnosed with Dent disease based on low molecular weight proteinuria and hypercalciuria. One year later, he was found to have features of Bartter syndrome, i.e., hypokalemia and metabolic alkalosis, and high levels of plasma renin activity and aldosterone with a normal blood pressure. Despite medical interventions, he developed chronic kidney disease stage 3 at the age of 21 years. To investigate the molecular basis of his disease, CLCN5, KCNJ1, SLC12A1, and CLCkb were analyzed and a novel mutation (Y567X) in CLCN5 was identified. CONCLUSION: Hypokalemic metabolic alkalosis is a rare manifestation in Dent disease. It is speculated that Dent patients with features of Bartter syndrome are susceptible to progression to renal failure. To study this hypothesis, additional observations and long-term follow-up of such patients are necessary.

The balance of fetuin-A and osteoprotegerin is independently associated with diastolic dysfunction in hemodialysis patients.

Fetuin-A and osteoprotegerin (OPG) are arterial calcification regulators, which are related to cardiovascular survival in hemodialysis patients. We hypothesized that a balance of these calcification regulators might mediate the progression of left ventricular (LV) diastolic dysfunction in hemodialysis patients. We recruited 63 hemodialysis patients and measured their serum fetuin-A, OPG, arterial stiffness, aortic calcification and echocardiographic parameters, including the transmitral early diastolic velocity/tissue Doppler mitral annular early diastolic velocity ratio (E/E'), and analyzed the relationships between these variables. Fetuin-A levels were significantly and negatively correlated with the ankle-brachial pulse wave velocity (baPWV), aortic calcification score (AOCS), left atrial volume index (LAVI), LV mass index (LVMI) and E/E'. OPG levels and the ratio of OPG to fetuin-A levels were significantly and positively correlated with the baPWV, AOCS, LAVI and E/E'. A stepwise multiple regression analysis revealed that E/E' was independently correlated with fetuin-A levels (ß=-0.334, P=0.02), OPG levels (ß=0.367, P=0.01) and the ratio of OPG to fetuin-A (ß=0.295, P=0.04). Categorizing the patients according to their serum fetuin-A and OPG levels revealed that patients with low fetuin-A and high OPG levels had the highest LAVI, LVMI and E/E' values after adjusting for potential confounders. Serum fetuin-A levels negatively reflected, whereas OPG levels and the ratio of OPG to fetuin-A positively reflected an increase in vascular and ventricular stiffness, leading to the aggravation of diastolic dysfunction. Therefore, based on our results, the balance of the tissue calcification regulators fetuin-A and OPG could mediate the progression of LV diastolic dysfunction in hemodialysis patients.

Potential impact of renin-angiotensin system inhibitors and calcium channel blockers on plasma high-molecular-weight adiponectin levels in hemodialysis patients.

Although metabolic syndrome confers an increased risk of cardiovascular disease in the general population, little is known about the alteration of abdominal adiposity and its association with adipocytokines in hemodialysis patients. We investigated the plasma high-molecular-weight (HMW) adiponectin level and its relationship to visceral fat area (VFA) and various markers of atherosclerosis in hemodialysis patients. In a cross-sectional study, conventional cardiovascular risk factors, plasma total and HMW adiponectin, the number of components of the metabolic syndrome and, using computed tomography, the distribution of abdominal adiposity were assessed in 144 hemodialysis patients (90 men and 54 women; mean age, 60.7 years) and 30 age- and sex-matched patients with chronic kidney disease (CKD). Plasma HMW adiponectin levels in hemodialysis patients were significantly higher than those in patients with CKD, negatively associated with VFA and serum triglycerides and positively associated with plasma total adiponectin, as well as the HMW-to-total adiponectin ratio in men and women (all P < 0.05) in a simple regression analysis. In a multiple regression analysis, VFA was a significant determinant of HMW adiponectin in hemodialysis patients. Furthermore, after adjustment for classical risk factors, HMW adiponectin levels were significantly higher in patients undergoing treatment with renin-angiotensin system inhibitors or calcium channel blockers compared with patients not undergoing such treatment. This study shows that plasma HMW adiponectin levels were negatively associated with VFA and positively associated with treatment with blockade of the renin-angiotensin system and of the calcium channel. Therefore, these drugs might be effective for improving adipocytokine-related metabolic abnormalities in hemodialysis patients.

An oral adsorbent, AST-120, suppresses oxidative stress in uremic rats.

BACKGROUND: The production of reactive oxygen species (ROS) has been suggested to play an important role in the progression of chronic kidney disease (CKD). An oral adsorbent, AST-120, removes uremic toxins such as indoxyl sulfate (IS) and delays the progression of CKD, but the effect on ROS production is unknown. The present study aimed to determine whether AST-120 reduces oxidative stress in uremic rat kidneys using markers of ROS production such as acrolein and 8-hydroxy-2'-deoxyguanosine (8-OHdG). METHODS: Daily administration of AST-120 was started 6 weeks after 5/6 nephrectomy and continued for 18 weeks. The changes in metabolic data, serum and urine IS levels, urinary excretion of markers of oxidative stress, and renal histological findings were investigated in uremic rats with or without AST-120 treatment. RESULTS: In parallel with the increase in serum and urine IS, the serum creatinine, urinary protein and acrolein levels started to increase at 6 weeks, but urinary 8-OHdG remained unchanged and significantly increased at 18 weeks in uremic rats. AST-120 markedly and significantly attenuated increases in uremic toxins and oxidative stress levels as well as the histological changes in glomerular sclerosis, interstitial fibrosis, and the tubular staining of 8-OHdG. CONCLUSION: AST-120 suppressed the progression of CKD, at least in part, via attenuation of oxidative stress induced by uremic toxin.

[Secondary nephrotic syndrome due to cardiovascular disease].

Cardiovascular diseases ralely evoke nephrotic syndrome. Especially hypertensive renal disease (nephroscrelosis) and renovascular hypertension occasionally may lead to nephrotic syndrome. We reported a case of nephrotic syndrome with renovascular hypertension successfully treated with candesartan. In eldery patients cardiovascular diseases are appeared. It is very important for clinicians to detect the mechanism of nephrotic syndrome caused by cardiovascular diseases.

A case of nephrotic syndrome associated with renovascular hypertension successfully treated with candesartan.

A sixty eight-year-old man was referred to our hospital for evaluation of hypertension and hypokalemia. His chief complaints were fatigability and weakness of the lower extremities. Atrophy of the right kidney was noted on computed tomography. The laboratory findings demonstrated massive proteinuria, markedly elevated plasma renin activity, hypokalemia, and renal insufficiency. Angiography showed total occlusion of the right renal artery. The patient was diagnosed as having nephrotic syndrome associated with renovascular hypertension. Treatment with candesartan, an angiotensin-II-receptor blocker (ARB), controlled both hypertension and proteinuria satisfactorily without worsening of his renal function. This is the first report on the effect of ARB on nephrotic syndrome associated with renovascular hypertension. Based on the results, ARB can be considered a promising agent for the treatment of patients with renovascular hypertension with massive proteinuria and renal insufficiency.