Ability of NAD and Sirt1 to epigenetically suppress albuminuria.

The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.

Does 20 Hz Transcranial Alternating Current Stimulation over the Human Primary Motor Cortex Modulate Beta Rebound Following Voluntary Movement?

Beta frequency oscillations originating from the primary motor cortex increase in amplitude following the initiation of voluntary movement, a process termed beta rebound. The strength of beta rebound has been reported to predict the recovery of motor function following stroke, suggesting therapeutic applications of beta rebound modulation. The present study examined the effect of 20 Hz transcranial alternating current stimulation (tACS) on the beta rebound induced by self-paced voluntary movement. Electroencephalograms (EEGs) and electromyograms (EMGs) were recorded from 16 healthy adults during voluntary movements performed before and after active or sham tACS. There was no significant change in average beta rebound after active tACS. However, the beta rebound amplitude was significantly enhanced in a subset of participants, and the magnitude of the increase across all participants was negatively correlated with the difference between individual peak beta frequency and tACS frequency. Thus, matching the stimulus frequency of tACS with individual beta frequency may facilitate therapeutic enhancement for motor rehabilitation.

Movement of the stimulated finger in a Go/NoGo task enhances attention directed to that finger as evidenced by P300 amplitude modulation.

Somatosensory cues and the optimal allocation of attentional resources are critical for motor performance, but it is uncertain how movement of a body part modulates directed attention and the processing of somatosensory signals originating from that same body part. The current study measured motor reaction time (RT) and the P300 event-related potential during a required movement response to stimulation of the same body part in a Go/NoGo task under multiple response. In the Movement Condition, participants were instructed to extend their right index finger in response to mild electrical stimulation of the same finger (Go signal) or remain still when receiving electrical stimulation to the fifth right finger (NoGo signal). Movement RTs and P300 amplitudes and latencies were measured under varying Go signal 50% probabilities. In other trial blocks, participants were required to count Go signals but not respond with movement or to ignore all signals while engaged in an unrelated task. Mean RT in the Movement Condition was 234.5 ms. P300 response amplitudes at midline electrodes (Fz, Cz, Pz) were the largest in the Movement Condition. The P300 amplitude at parietal electrode site Pz was significantly greater during Movement Condition trials than during Count Condition trials. The increase in P300 amplitude during trials requiring movement of the same body part receiving somatosensory stimulation suggests that movement itself modulates the attentional resources allocated to that body part.

Effects of repetitive practice of motor tasks on somatosensory gating.

Introduction: During voluntary muscle contraction, the amplitude of the somatosensory evoked potential (SEP) is reduced by inhibiting sensory information from a peripheral nerve supplying the contracted muscle. This phenomenon is called "gating." We reported that participants with good motor skills indicated strong suppression of somatosensory information. The present study investigated the effects of motor performance improvement following repetitive practice on the SEP amplitude. Methods: The ball rotation task (BR task) was practiced by 15 healthy participants repetitively. SEPs were recorded before (pre) and after (post) repetitive practice. Results: The BR task performance was significantly improved and the required muscle activation to perform the task was significantly reduced after the repetitive practice. The degree of gating was not significant between pre and post- for the SEP amplitude. A significant correlation was found between changes in SEP amplitude from pre to post and performance improvement. Discussion: After repetitive practice, the degree of gating did not change, but the performance of the BR task improved, and the muscle activity required for the BR task decreased. These results suggest that repetitive practice does not change the degree of gating but changes the mechanism of gating. Furthermore, they indicate that suppression of the somatosensory area may play a role in improving task performance.

Event-Related Brain Potentials N140 and P300 during Somatosensory Go/NoGo Tasks Are Modulated by Movement Preparation.

The Go/NoGo task requires attention and sensory processing to distinguish a motor action cue or 'Go stimulus' from a 'NoGo stimulus' requiring no action, as well as motor preparation for a rapid Go stimulus response. The neural activity mediating these response phases can be examined non-invasively by measuring specific event-related brain potentials (ERPs) using electroencephalography. However, it is critical to determine how different task conditions, such as the relationship between attention site and movement site, influence ERPs and task performance. In this study, we compared attention-associated ERP components N140 and P300, the performance metrics reaction time (RT) and accuracy (%Error) and movement-related cortical potentials (MRCPs) between Go/NoGo task trials in which attention target and movement site were the same (right index finger movement in response to right index finger stimulation) or different (right index finger movement in response to fifth finger stimulation). In other Count trials, participants kept a running count of target stimuli presented but did not initiate a motor response. The N140 amplitudes at electrode site Cz were significantly larger in Movement trials than in Count trials regardless of the stimulation site-movement site condition. In contrast, the P300 amplitude at Cz was significantly smaller in Movement trials than in Count trials. The temporal windows of N140 and P300 overlapped with the MRCP. This superposition may influence N140 and P300 through summation, possibly independent of changes in attentional allocation.

The relationships between motor behavior and sensory gating in the ball rotation task.

During voluntary muscle contraction, sensory information induced by electrostimulation of the nerves supplying the contracting muscle is inhibited and the amplitude of the corresponding somatosensory evoked potential (SEP) decreases. This phenomenon is called "gating." The reduction of the SEP amplitude is reportedly significantly larger when task performance is high. However, the relationship between dexterous movement skills and gating remains unclear. In this study, we investigated through a ball rotation (BR) task how dexterous movement skills affect the SEP amplitudes. Thirty healthy subjects performed the BR task comprising the rotation of two wooden balls as quickly as possible. We estimated the median number of ball rotations for each participant and classified the participants into two (fast and slow) groups based on the results. Moreover, we recorded SEPs, while the subjects performed BR tasks or rested. SEP amplitude reduction (P45) was significantly larger in the fast than in the slow group. We also observed that the P45 amplitude during the BR task was attenuated even more so in the case of the participants with better dexterous movement skills. Our results suggest that the participants with better dexterous movement skills might display stronger somatosensory information suppression because of increasing the motor cortex activity and the afferent input during the BR task.

Effects of kinesthetic illusion induced by visual stimulation (KINVIS) therapy on patients with stroke in the subacute phase: a visual analysis based on paralysis severity.

We explored the effect of kinesthetic illusion induced by visual stimulation (KINVIS) therapy on motor function in patients with stroke during the subacute phase based on paralysis severity. The study was performed using an ABAB design (A1, B1, A2, B2; for 10 days each). KINVIS therapy was additionally administered in periods B1 and B2. Ten patients with stroke were classified according to severity. The improvement in upper limb motor function was higher after B1 and B2 than after A1 and A2 in the moderate group. The effect of KINVIS therapy increases the degree of improvement in motor function, especially in the moderate group.

The Effect of Pedaling at Different Cadence on Attentional Resources.

We investigated the relationship between attentional resources and pedaling cadence using electroencephalography (EEG) to measure P300 amplitudes and latencies. Twenty-five healthy volunteers performed the oddball task while pedaling on a stationary bike or relaxing (i.e., no pedaling). We set them four conditions, namely, (1) performing only the oddball task (i.e., control), (2) performing the oddball task while pedaling at optimal cadence (i.e., optimal), (3) performing the oddball task while pedaling faster than optimal cadence (i.e., fast), and (4) performing the oddball task while pedaling slower than optimal cadence (i.e., slow). P300 amplitudes at Cz and Pz electrodes under optimal, fast, and slow conditions were significantly lower than those under control conditions. P300 amplitudes at Pz under fast and slow conditions were significantly lower than those under the optimal condition. No significant changes in P300 latency at any electrode were observed under any condition. Our findings revealed that pedaling at non-optimal cadence results in less attention being paid to external stimuli compared with pedaling at optimal cadence.

TGF-ß1 is involved in senescence-related pathways in glomerular endothelial cells via p16 translocation and p21 induction.

p16 inhibits cyclin-dependent kinases and regulates senescence-mediated arrest as well as p21. Nuclear p16 promotes G1 cell cycle arrest and cellular senescence. In various glomerular diseases, nuclear p16 expression is associated with disease progression. Therefore, the location of p16 is important. However, the mechanism of p16 trafficking between the nucleus and cytoplasm is yet to be fully investigated. TGF-ß1, a major cytokine involved in the development of kidney diseases, can upregulate p21 expression. However, the relationship between TGF-ß1 and p16 is poorly understood. Here, we report the role of podocyte TGF-ß1 in regulating the p16 behavior in glomerular endothelial cells. We analyzed podocyte-specific TGF-ß1 overexpression mice. Although p16 was found in the nuclei of glomerular endothelial cells and led to endothelial cellular senescence, the expression of p16 did not increase in glomeruli. In cultured endothelial cells, TGF-ß1 induced nuclear translocation of p16 without increasing its expression. Among human glomerular diseases, p16 was detected in the nuclei of glomerular endothelial cells. In summary, we demonstrated the novel role of podocyte TGF-ß1 in managing p16 behavior and cellular senescence in glomeruli, which has clinical relevance for the progression of human glomerular diseases.

Effect of primary motor cortex excitability changes after quadripulse transcranial magnetic stimulation on kinesthetic sensitivity: A preliminary study.

Muscle spindles provide the greatest contribution to kinesthetic perception. Primary motor cortex (M1) excitability changes in parallel with the intensity of kinesthetic perception inputs from muscle spindles; M1 is therefore involved in kinesthetic perception. However, the causal relationship between changes in kinesthetic sensitivity and M1 excitability is unclear. The purpose of this study was to test whether artificially and sustainably modulated M1 excitability causes changes in kinesthetic sensitivity in healthy individuals. We evaluated motor evoked potentials (MEP) in Experiment 1 and joint motion detection thresholds (JMDT) in Experiment 2 before and after quadripulse transcranial magnetic stimulation (QPS). Nine healthy right-handed male volunteers were recruited. In each experiment, participants received QPS or sham stimulation (Sham) on separate days. MEP amplitude and JMDT were recorded before and at 0, 15, 30, 45, and 60 min after QPS and Sham. Our results showed that M1 excitability and kinesthetic sensitivity increased after QPS, whereas neither changed after Sham. In the five subjects who participated in both experiments, there was a significant moderate correlation between M1 excitability and kinesthetic sensitivity. Thus, the long-lasting change in kinesthetic sensitivity may be due to changes in M1 excitability. In addition, M1 may play a gain adjustment role in the neural pathways of muscle spindle input.

The ADVIA2120i parameter Revised %MICRO is a surrogate marker of schistocyte formation after hematopoietic stem cell transplantation.

Objectives : Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is an important early post-treatment condition. This study evaluated the Revised %MICRO, a parameter obtained from the ADVIA 2120i automated blood cell counter, as a surrogate marker of the schistocyte ratio. We hypothesized that individual differences between the %MICRO value and schistocyte ratio would remain constant. Design and Methods: EDTA-2K-treated peripheral blood samples were collected from 19 patients who underwent allogeneic HSCT from April 2014 to September 2018. First, the baseline difference, X, was calculated using a sample from the first day after HSCT as X = %MICRO (first day) - schistocyte ratio (first day). Next, the Revised %MICRO for each subsequent day was calculated as Revised %MICRO = %MICRO - X. We evaluated correlations of the schistocyte ratio with the calculated %MICRO and Revised %MICRO and the RBC fragment, RBC distribution width, %MICRO and Revised %MICRO data obtained from the ADVIA 2120i. Results : The mean schistocyte percentage and Revised %MICRO were both 0.4% ±â€…0.6. RBC fragments correlated weakly with the %MICRO and schistocyte ratio, respectively (r = 0.162 and r = 0.771, respectively), whereas the Revised %MICRO correlated strongly with the schistocyte ratio (r = 0.893). Conclusion : The Revised %MICRO appears to be a good surrogate of the schistocyte ratio in a clinical setting. J. Med. Invest. 67 : 250-254, August, 2020.

Clinical characteristics associated with 1-year tolvaptan efficacy in autosomal dominant polycystic kidney disease with a wide range of kidney functions.

Autosomal dominant polycystic kidney disease (ADPKD) develops into end-stage kidney disease by 65 years of age in an estimated 45%-70% of patients. Recent trials revealed that tolvaptan inhibits disease progression both in early-stage or late-stage ADPKD ; however, stratified analysis showed a difference of favorable factors correlated with tolvaptan efficacy between early-stage and late-stage ADPKD. Thus, we examined the efficacy of tolvaptan in ADPKD with a wide range of estimated glomerular filtration rates (eGFR). We enrolled 24 patients with eGFR 35.3 (28.0-65.5) ml / min / 1.73m2 and evaluated treatment effect as ΔΔeGFR (ml / min / 1.73m2 / year) or ΔΔtotal kidney volume (TKV) (% / year) that was calculated as post-treatment annual change - pre-treatment annual change. Pre ΔeGFR was significantly low in eGFR responders, defined as ΔΔeGFR > 0 ml / min / 1.73m2 / year. In eGFR responders, pre ΔeGFR, post ΔeGFR, eGFR, TKV, and proteinuria were significantly correlated with ΔΔeGFR. In TKV responders defined as ΔΔTKV > 5 % / year, we identified hypertension history, proteinuria, TKV, and post ΔTKV as significantly correlated factors with ΔΔTKV. In conclusion, pre ΔeGFR may be a predictive factor of therapeutic efficacy on kidney function. Tolvaptan may have greater efficacy in early-stage ADPKD with rapid GFR decline or with well-controlled blood pressure. J. Med. Invest. 67 : 315-320, August, 2020.

Effect of liraglutide on lipids in patients with type 2 diabetes: a pilot study.

The mechanism for the cholesterol-lowering effect of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) remains unknown in patients with type 2 diabetes. We evaluated the effect of liraglutide on serum lipid profiles, including cholesterol synthesis and absorption markers, during daily clinical practice in Japanese patients with type 2 diabetes. We enrolled 38 patients with type 2 diabetes mellitus who were not treated with a GLP-1 RA (≥20 years of age, HbA1c ≥6.5%). Liraglutide, a GLP-1 RA, was administered subcutaneously once a day for three months to these patients. Blood samples and body weights were collected at 0, 1, and 3 months. Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) at 1 month, and non-high-density lipoprotein cholesterol (non-HDL-C) and calculated TC at 1 and 3 months, were decreased, while the cholesterol synthesis and cholesterol absorption markers were unchanged by this treatment. In patients with LDL-C levels over 100 mg/dL, LDL-C, non-HDL-C, TC, and calculated TC levels were decreased significantly by the treatment at 1 and 3 months, and the cholesterol absorption marker, campesterol, was decreased at 3 months. The administration of liraglutide for 3 months decreased non-HDL-C and calculated TC significantly, while the cholesterol synthesis and absorption markers were not changed by this treatment.

Region-dependent bidirectional plasticity in M1 following quadripulse transcranial magnetic stimulation in the inferior parietal cortex.

BACKGROUND: The ability to manipulate the excitability of the network between the inferior parietal lobule (IPL) and primary motor cortex (M1) may have clinical value. OBJECTIVE: To investigate the possibility of inducing long-lasting changes in M1 excitability by applying quadripulse transcranial magnetic stimulation (QPS) to the IPL, and to ascertain stimulus condition- and site-dependent differences in the effects. METHODS: QPS was applied to M1, the primary somatosensory cortex (S1), the supramarginal gyrus (SMG) and angular gyrus (AG) IPL areas, with the inter-stimulus interval (ISI) in the train of pulses set to either 5 ms (QPS-5) or 50 ms (QPS-50). QPS was repeated at 0.2 Hz for 30 min, or not presented (sham condition). Excitability changes in the target site were examined by means of single-pulse transcranial magnetic stimulation (TMS). RESULTS: QPS-5 and QPS-50 at M1 increased and decreased M1 excitability, respectively. QPS at S1 induced no obvious change in M1 excitability. However, QPS at the SMG induced mainly suppressive effects in M1 for at least 30 min, regardless of the ISI length. Both QPS ISIs at the AG yielded significantly different MEP compared to those at the SMG. Thus, the direction of the plastic effect of QPS differed depending on the site, even under the same stimulation conditions. CONCLUSIONS: QPS at the IPL produced long-lasting changes in M1 excitability, which differed depending on the precise stimulation site within the IPL. These results raise the possibility of noninvasive induction of functional plasticity in M1 via input from the IPL.

Event-related desynchronization possibly discriminates the kinesthetic illusion induced by visual stimulation from movement observation.

Visual stimulation of a repetitive self-movement image can evoke kinesthetic illusion when a virtual body part is set over the actual body part (kinesthetic illusion induced by visual stimulation, KINVIS). KINVIS induces activity in cerebral network, similar to that produced during motor execution, and triggers motor imagery passively. This study sought to identify a biomarker of KINVIS using event-related desynchronization (ERD) to improve the application of KINVIS to brain-machine interface (BMI) therapy of patients with stroke with hemiparesis. We included healthy adults in whom KINVIS could be induced. Scalp electroencephalograms were recorded during the KINVIS condition, where KINVIS was induced using a self-movement image. The findings were compared to signals recorded during an observation (OB) condition where only the self-movement image was viewed. For the signal intensity of the α- and low ß-frequency bands, we calculated ERD during a movie period. The ERD of the α-frequency band in P3 and CP3 during KINVIS was significantly higher than that during OB. Furthermore, using the ERD of the α-frequency band recorded from FC3 and CP3, we could discriminate illusory perception with a 70% success rate. In this study, KINVIS could be detected using the ERD of the α-frequency band recorded from the posterior portion of the sensorimotor cortex. Furthermore, adding ERD recorded from FC3 to that recorded from CP3 may enable the objective discrimination of KINVIS from OB. When applying KINVIS in BMI therapy, the combination ERD of FC3 and CP3 will become a parameter for objectively judging the degree of kinesthetic perception achieved.

The utility and limitation of inferior vena cava diameter as a dry weight marker.

BACKGROUND: IVC diameter on expiration (IVCdexp) is measured by echocardiography routinely. It is used to estimate volume status and designated as a definitive marker for determining dry weight (DW) in patients undergoing hemodialysis (HD). METHODS: A cross-sectional study. Outpatients (n = 107), and inpatients (n = 35) undergoing HD were enrolled. IVCdexp was measured on non-dialysis days in outpatients and dialysis days before and after the dialysis session in inpatients. In outpatients, the relationship of IVCdexp with echocardiography findings and clinical characteristics was analyzed. IVCdexp was compared with the other DW markers as a predictive factor for intradialytic hypotension. In inpatients, IVCdexp was analyzed by dividing inpatients with or without fluid in extravascular space. RESULTS: IVCdexp ranged from 5.4 to 16.9 mm in outpatients who had optimal DW. IVCdexp could reflect on volume status, but not predictive for intradialytic hypotension and not suggestive of fluid in extravascular space. CONCLUSIONS: IVCdexp was a rough marker to estimate volume status and only useful in suggesting apparent hypervolemia or hypovolemia. We should know that the IVCdexp value is affected by a lotof factors and not a definitive marker for estimating practical DW. J. Med. Invest. 66 : 172-177, February, 2019.

Direct oral anticoagulant successfully used to treat an adult nephrotic patient complicated with portal vein thrombosis.

Thromboembolism is a major complication of nephrotic syndrome, with the renal vein being the most frequent site. However, the incidence of portal vein thrombosis (PVT) in patients with nephrotic syndrome is rare. We report a case of a relapsed steroid-dependent minimal change disease with incidental PVT. A 38-year-old man presented with anasarca. Elevated liver enzymes were discovered during routine blood testing within days after commencing treatment. Although drug-induced liver injuries are frequently observed with mild aminotransferase abnormality during therapy with steroid or immune-suppressive agents, imaging revealed a massive thrombus of the portal vein, which was treated by anticoagulant therapy with edoxaban. Treatment with anticoagulant therapy could normalize liver function. Two months after the initiation of treatment with edoxaban, the follow-up CT scan and ultrasound showed the disappearance of PVT. Our case suggests that much attention should be paid to PVT as a cause of liver enzyme elevation when treating patients with nephrotic syndrome.

Urinary Exosomal mRNA of WT1 as Diagnostic and Prognostic Biomarker for Diabetic Nephropathy.

Diabetic nephropathy (DN) is the major cause of end-stage renal failure and is associated with increased morbidity and mortality as compared to other causes of renal disease. Albuminuria is often the first clinical indicator of the presence of DN. However, albuminuria or proteinuria is a common symptom in patients with various renal disorders. Therefore, specific biomarkers for the diagnosis of DN are required. A primary hallmark of DN is the progressive damage and death of glomerular podocytes, resulting in the leaking of proteins into the urine. Urinary exosomes released by podocytes are microvesicles containing information of the originated cells. Podocyte-derived signal transduction factors (PDSTFs) are good candidates to assess podocyte injuries. The profile of PDSTFs in urinary exosomes from patients with DN is different from that from patients with minimal change nehrotic syndrome. In addition, PDSTFs molecules in exosomes were derived from primary murine podocytes under high glucose conditions. Among PDSTFs in urinary exosomes, Wilms tumor 1 (WT1) levels reflected damage of diabetic glomeruli in the patients. Urinary exosomal WT1 can predict the decline in eGFR for the following several years. In conclusion, urinary exosomal WT1 is a useful biomarker to improve risk stratification in patients with DN. J. Med. Invest. 65:208-215, August, 2018.

Urinary type IV collagen excretion is involved in the decline in estimated glomerular filtration rate in the Japanese general population without diabetes: A 5-year observational study.

Urinary type IV collagen (U-Col4) and albumin excretion is evaluated to monitor the development of diabetic kidney disease. However, U-Col4 excretion in the general population without diabetes has not yet been fully elucidated. In this study, 1067 participants without diabetes and with urinary albumin-creatinine ratio <300 mg/gCr (normo- or microalbuminuria) who underwent an annual health examination in 2004 were enrolled and observed for 5 years. They were divided according to the amount of U-Col4 or urinary albumin excreted. The decline in estimated glomerular filtration rate (eGFR) was calculated. In participants with eGFR ≥80 mL/min, abnormal U-Col4 excretion was indicated as a significant independent risk factor for 10% eGFR change per year, which is one of the prognostic factors for the development of end-stage kidney disease. Moreover, in contrast to urinary albumin excretion, U-Col4 excretion was not related to age or kidney function, suggesting that some individuals with abnormal U-Col4 excretion can have an independent hidden risk for the development of kidney dysfunction. In conclusion, it is important to measure U-Col4 excretion in the general population without diabetes to determine changes in renal features in every individual and help detect future complications such as diabetic kidney disease. If U-Col4 excretion is abnormal, kidney manifestation should be carefully followed up, even if the kidney function and urinalysis findings are normal.