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A 70-year-old man with severe interstitial pneumonia attributed to limited cutaneous systemic sclerosis was referred to our institution because of worsening dyspnea. High-resolution computed tomography did not show considerable progression compared with previous images, whereas transthoracic echocardiography showed severe right ventricular dysfunction. Oxygen saturation was decreased to 84% at room air. A blood test showed an increase in the plasma brain natriuretic peptide level (289.4 pg/mL). Right heart catheterization (RHC) showed a remarkably high mean pulmonary arterial pressure (mPAP) of 48 mmHg at room air. A vaso reactivity test using inhaled nitric oxide showed improvement of mPAP, pulmonary vascular resistance (PVR), and partial pressure of arterial oxygen. These findings suggested that the patient responded to pulmonary hypertension (PH)-targeted drugs. We then prescribed tadalafil 10 mg and inhaled iloprost 5 µg six times daily. Three weeks after initiating PH-targeted drugs, RHC indicated hemodynamic improvement similar to hemodynamic changes in the vaso reactivity test (mPAP: 28 mmHg; PVR: 4.2 W.U.). He was discharged with improved symptoms. Inhaled nitric oxide during RHC might be helpful to consider the treatment strategy when patients have PH comorbid systemic sclerosis and severe interstitial lung disease.

研究グループは、TAVI施術者に対する基本チェックリストによるフレイルの評価が経カテーテル大動脈弁留置術(TAVI)後3年の総死亡の予測因子として有用であることを明らかにしました。本研究成果により、基本チェックリストがフレイルを簡便かつ客観的に評価し、適切な治療方針の決定に役立つと期待できます。フレイルの指標とTAVIとの関連性はこれまでに報告されていますが、それらの指標は検査を多く要するものや、簡便であっても客観性に欠けるものがあります。今回、本研究グループは、2016年1月から2020年12月に本学医学部附属病院でTAVIを施行した280例を対象とし、従来のフレイルの指標に加えて基本チェックリストによるフレイルの評価を行いました。その結果、基本チェックリストにより算出したフレイルの指標は、従来のフレイルの指標と比較し同等であり、生存時間分析でTAVI後3年の死亡の独立した因子であることが分かりました。また、基本チェックリストの総スコア(25点満点)で3群に分類して解析したところ、フレイル群(13～25点)でTAVI後3年の死亡が有意に高いことが分かりました。, Background: Frailty is a major risk factor for death and disability following transcatheter aortic valve implantation (TAVI). The Kihon checklist (KCL) is a simple self-reporting yes/no survey consisting of 25 questions and is used as a screening tool to identify frailty in the primary care setting. No clinical studies have focused on frailty calculated by the KCL in the TAVI cohort. We investigated the 3-year prognostic impact of frailty evaluated by the KCL in patients who underwent TAVI. ......

Background The presence of functional tricuspid regurgitation (TR) is associated with mortality and morbidity. Although uniform management with a tricuspid annuloplasty ring is currently considered as a standard surgical procedure, high rates of residual TR despite annuloplasty are reported. Therefore, the identification of the TR mechanisms would be necessary to provide personalized treatment for each TR patient. Methods This study population consisted of 106 patients with mitral regurgitation (MR) who were scheduled for procedure. Transthoracic and transesophageal echocardiography were performed prior to mitral valve intervention. We performed three-dimensional quantitative assessment including tricuspid annular (TA) area and the distance between the three commissures of tricuspid valve. Results Significant TR, which is defined as moderate or greater TR, was detected in 23 (22%). TA area (P

Inhibiting apical sodium-dependent bile acid transporter (ASBT) has been identified as a potential strategy to reduce plasma cholesterol levels. Thus, in this study, we aimed to identify polyphenols that inhibited ASBT activity and to elucidate their mechanism. ASBT is responsible for most of the taurocholic acid (TC) uptake in Caco-2 cells. Of the 39 polyphenols examined, theaflavin (TF)-3-gallate (TF2A) and theaflavin-3'-gallate (TF2B) have been found to significantly reduce TC uptake in Caco-2 cells to 37.4 ± 2.8 and 33.8 ± 4.0%, respectively, of that in the untreated cells. The results from the TC uptake assay using N-acetylcysteine suggested that the inhibitory effect of TF2A and TF2B was attributed to the oxidization of their benzotropolone rings and their covalent bonding with ASBT's cysteine. TC uptake was reduced in the COS-7 cells expressing recombinant ASBT whose cysteine residues were mutated to alanine. Finally, the substrate concentration-dependent TC uptake assay showed that TFs competitively inhibited TC uptake.

The authors investigated the kinematic characteristics of the standing long jump in preschool children. Sixty 4-year-old children (boys: 30 and girls: 30) and sixty 5-year-old children (boys: 30 and girls: 30) participated in the present study. The authors focused on three differences in kinematics: between 4- and 5-year-old children, between boys and girls, and between high and low jumping performance groups at the same age. The kinematic data included the maximum flexions of the knee and hip before takeoff, at takeoff, and on landing; angular displacement of the upper body; takeoff speeds in horizontal and vertical directions; and takeoff angle of the greater trochanter. Anthropometric variables and kinematic data were separately analyzed with factors of age, sex, and group. The authors also performed multiple regression analysis to identify predictors of the jump distance. The movement speed of the greater trochanter in a horizontal direction, the maximum flexion angle of the hip before takeoff, and the hip angle on landing were identified as significant predictors of the jump distance among young children. These findings suggest that knowing how to use the hip and awareness of the horizontal direction are key factors to improve the long jump distance in young children.

Luciferases have been widely utilized as sensitive reporters to monitor gene expression and protein-protein interactions. Compared to firefly luciferase (Fluc), a recently developed luciferase, Nanoluciferase (NanoLuc or Nluc), has several superior properties such as a smaller size and stronger luminescence activity. We compared the reporter properties of Nluc and Fluc in rice (Oryza sativa). In both plant-based two-hybrid and split luc complementation (SLC) assays, Nluc activity was detected with higher sensitivity and specificity than that with Fluc. To apply Nluc to research involving the photoperiodic regulation of flowering, we made a knock-in rice plant in which the Nluc coding region was inserted in-frame with the OsMADS15 gene, a target of the rice florigen Hd3a. Strong Nluc activity in response to Hd3a, and in response to change in day length, was detected in rice protoplasts and in a single shoot apical meristem, respectively. Our results indicate that Nluc assay systems will be powerful tools to monitor gene expression and protein-protein interaction in plant research.

We investigated the relationship between basketball free-throw accuracy and anthropometry, physical fitness tests, and performance variables among 16 collegiate female basketball players. Each participant performed 20 basketball free throws. Anthropometric measures were height and weight; physical fitness tests were sit-and-reach, back strength, and grip strengths; other basketball performance variables were the phases of the pre-shoot routine: (a) time taken, (b) minimum angle when taking the ball back, (c) angle at ball release, (d) angular displacement during the forward arm swing, and (e) angular velocity at ball release on the elbow, shoulder, hip, knee, and ankle. We analyzed the correlation between free-throw accuracy and data on anthropometry and physical fitness, the time period and variability of the pre-shot routine, and kinematic data. There were negative correlations between free-throw accuracy and mean pre-shot time, and variability of the pre-shot time, indicating that participants with a shorter and less variable pre-shot time showed a higher free-throw accuracy. Angular displacement of the shoulder during the forward swing and angular velocity of the knee at ball release showed positive correlations with free-throw accuracy. There was also a negative correlation between free-throw accuracy and variability of angular displacement during the forward swing at the elbow, indicating that participants with smaller variability of angular displacement of the elbow showed higher free-throw accuracy. Some performance variables, including routine duration, angular displacement of the shoulder and elbow, and angular velocity of the knee, were related to free-throw accuracy.

Aims To investigate the ability of the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria and ARC-HBR score to predict 2-year bleeding and mortality in patients undergoing transcatheter aortic valve replacement (TAVR). Methods and results We enrolled 2514 patients who underwent successful TAVR during 2013–17. In this study, we used the ARC-HBR score for further HBR-risk stratification, and the ARC-HBR score was calculated as follows: each major criterion was 2 points and each minor criterion was 1 point. The impact of the ARC-HBR criteria and increasing ARC-HBR score on the incidence of moderate/severe bleeding events, mortality, and ischaemic stroke in the first 2 years were evaluated. We used survival classification and regression tree (CART) analysis for 2-year moderate or severe bleeding events, and patients were statistically classified into HBR low- (ARC-HBR score ≤1), intermediate- (ARC-HBR score = 2–4), or high-risk (ARC-HBR score ≥5) groups, and 91.4% were at HBR (ARC-HBR score ≥2). The rates of 2-year moderate/severe bleeding events and all-cause mortality were higher in the ARC-HBR group and highest in the HBR high-risk group. An increased HBR score was significantly associated with moderate/severe bleeding events [hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.07–1.31; P = 0.001] and all-cause mortality (adjusted HR 1.24, 95% CI 1.17–1.32; P < 0.001). Conclusions The ARC-HBR criteria identify patients at HBR after TAVR; an increased ARC-HBR score is associated with 2-year moderate/severe bleeding events and mortality.

We investigated the relationship between the free-throw accuracy and performance variables among fourteen elite male wheelchair basketball players. Participants performed 20 basketball free-throws. Basketball performance variables were the phases of the pre-shoot routine: (a) time taken, (b) minimum angle when taking the ball back, (c) angle at ball release, (d) angular displacement during the forward arm swing, and (e) angular velocity at ball release on the elbow, shoulder, and hip. A significant negative correlation was observed between the free-throw accuracy and mean pre-shot time, suggesting that participants with a shorter pre-shot time showed a higher free-throw accuracy. In addition, a significant negative correlation was found between the free-throw accuracy and variability of angular velocity of the hip at the time of ball release, indicating that the consistency of hip movement is an important factor in free-throw accuracy. In contrast, there were no relationship between the free-throw accuracy and player’s classification point defined as International Wheelchair Basketball Federation, and experience of wheelchair basketball. These data suggest that the routine duration and trunk movement are related to free-throw accuracy in wheelchair basketball.

AimsAcute decompensated heart failure (ADHF) can occur early after transcatheter aortic valve implantation (TAVI), but the risk factors or mechanisms associated with it have not been fully determined. This hypothesis-generating study aimed to investigate the clinical indices associated with the development of ADHF within 72 hours after TAVI and to improve procedural approaches for TAVI.Method and resultsIn this single-centre hypothesis generating prospective observational study, we enrolled 156 consecutive patients with severe aortic stenosis who underwent TAVI between January 2016 and February 2018 at our institution. We set the primary endpoint as the new development of ADHF within 72 hours after TAVI, and clinical indices associated with it were evaluated using a multivariable logistic model. The median age of the patients was 83 (quartile range 80–86) years, 48 (30.8%) were men and the median Society of Thoracic Surgery-Predicted Risk of Mortality was 7.1 (range 5.2–10.4). Mitral stenosis (MS), defined as mean transmitral valve pressure gradient ≥5 mm Hg, was present in 15 (9.6%) patients. After TAVI, the invasive mean transaortic valve pressure gradient (mAVPG) decreased from 48 (36–66) to 7 (5–11) mm Hg, and 12 (7.7%) patients developed ADHF within 72 hours after TAVI. Multivariable logistic regression analysis showed that MS (adjusted OR, 14.227; 95% CI 2.654 to 86.698; p=0.002) and greater decreases in mAVPG (1.038; 1.003 to 1.080; p=0.044) were associated with ADHF.ConclusionsMS and drastic improvement of mAVPG were associated with new development of ADHF within 72 hours after TAVI.

Background Recently, there are some reports that hypo-attenuated leaflet thickening (HALT) following transcatheter aortic valve implantation (TAVI) is incidentally detected by multi-slice computed tomography. It is believed that valve thrombosis causes HALT, because oral anticoagulation therapy (OAC) is effective for HALT regression. Furthermore, it is reported that d-dimer level increases in patients with HALT, and might be a key biomarker to detect HALT. Purpose We sought to investigate the predictors related to increased d-dimer level at 6 months after follow-up TAVI. Methods We enrolled 124 consecutive patients who underwent successful TAVI between 2016 and 2018. Study patients were classified into two groups according to antithrombotic therapy resume (OAC therapy or anti-platelet therapy).We set the primary endpoint as the d-dimer levels at 6 months after TAVI. To evaluate the risks of the primary endpoint, we employed a multivariable linear regression model, setting the primary endpoint as an objective variable and patient and clinical backgrounds as explanatory variables. Furthermore, we set the secondary endpoint as one-year bleeding event. Results The median age of patients was 83 years old (quartile 80-87). Patients who had taken OAC at 6 months follow-up after TAVI were 29.8%. The median d-dimer level at 6 months after TAVI was 1.3 (1.0-2.2) µg/ml, and OAC group had statistically lower d-dimer level at 6 months follow-up than those in non-OAC group (p = 0.020). Uni-variable liner regression model demonstrated that increased d-dimer level at follow-up had significant relationship with large effective orifice area (EOA) (p = 0.002) and low left ventricular ejection fraction (LVEF) (p = 0.048) after TAVI. Furthermore, large EOA (p = 0.003) and OAC therapy (p = 0.027) were independently associated with increased d-dimer level in multivariate analysis. Kaplan-Meier estimates revealed that there were no significant difference regarding one-year bleeding event between OAC group and non-OAC group (long-rank p = 0.167). Conclusions This study suggests that large EOA after TAVI is associated with increased d-dimer levels at 6 months after TAVI, and OAC therapy might have a potential to decrease d-dimer level after TAVI without increase of bleeding events. Abstract P107 Figure: One-year bleeding event

Background Little evidence is available regarding the risk of peri-procedural stroke detected by diffusion-weighted magnetic resonance imaging (DW-MRI) after transcatheter aortic valve implantation (TAVI). Our purpose was to evaluate stroke risk after TAVI using DW-MRI by enrolling consecutive patients who underwent transfemoral TAVI and post-procedural DW-MRI. Methods We prospectively enrolled 113 consecutive patients who underwent transfemoral TAVI and post-procedural DW-MRI. We used balloon-expandable valves as first-line therapy and selected self-expandable valves only for patients with narrow sinotubular junctions or annuli. We set the primary endpoint as the number of high intensity areas (HIA) detected by DW-MRI regardless of the size of the area. To evaluate the risks of the primary endpoint, we employed a multivariable linear regression model, setting the primary endpoint as an objective variable and patient and clinical backgrounds as explanatory variables. In addition, the relationship between valve type and the number of HIAs on DW-MRI was also confirmed by the propensity score matching analysis to evaluate the robustness of the result, using a multivariable linear regression model with the protocol described in the previous manuscript. Shortly, the propensity score was calculated with a logistic regression model by setting the treatment as the response variable and baseline characteristics and procedural information that were significantly different between 2 groups (balloon expandable and self-expandable) as explanatory variables, which included age, estimated glomerular filtration rate, oversizing rate, and BAV before THV deployment. Results Median patient age was 84 years, and 36.3% were men. Ninety-three patients underwent balloon-expandable TAVI and 20 underwent self-expandable TAVI. Symptomatic stroke occurred in 6 (5.3%) whereas asymptomatic stroke occurred in 59 (52.2%) patients. The incidence of symptomatic and total stroke was higher in patients who underwent self-expandable TAVI than those who underwent balloon-expandable TAVI (30.0% vs 0.0%, p Conclusions Self-expandable valves were associated with increased numbers of HIA on DW-MRI after TAVI in patients with severe aortic stenosis.

Cardio-ankle vascular index (CAVI) has been recognized as a useful indicator to assess the arterial stiffness and atherosclerosis. Some reports show that the higher CAVI values predict the worse prognosis in patients with cardiovascular disease. Although it is already reported that ankle-brachial

Mastication enhances brain function and mental health, but little is known about the molecular mechanisms underlying the effects of mastication on neural development in early childhood. Therefore, we analysed the gene expression in juvenile neural circuits in rats fed with a soft or chow diet immediately after weaning. We observed that the gene expression patterns in the thalamus varied depending on the diet. Furthermore, gene ontology analysis revealed that two terms were significantly enhanced: chemical synaptic transmission and positive regulation of dendritic spine morphogenesis. With respect to chemical synaptic transmission, glutamate decarboxylase and GABA receptors were upregulated in the chow diet group. The related genes, including vesicular GABA transporter, were also upregulated, suggesting that mastication activates GABAergic signalling. With respect to dendritic spine morphogenesis, Ingenuity Pathway Analysis predicted fewer extension of neurites and neurons and fewer number of branches in the chow diet group. The numbers of spines in the ventral posterolateral and posteromedial regions were significantly decreased. These results suggest that mastication in the early developing period upregulates GABAergic signalling genes, with a decrease of spines in the thalamus.

We examined whether calcium alginate (Ca-Alg) reduces blood cholesterol levels in rats fed a high-cholesterol diet. First, we examined taurocholate adsorption in vitro by various types of sodium alginate (Na-Alg). High molecular-weight, guluronic acid-rich Na-Alg showed the greatest adsorption of taurocholate, and therefore the corresponding Ca-Alg was chosen for the in vivo study. Rats were fed a high-cholesterol diet or a Ca-Alg-containing diet for 2 weeks. Body weight and diet intake were measured, and the general condition of the animals was monitored during this period. After 14 d, the plasma concentration of cholesterol, portal plasma concentration of bile acid, and bile acid in feces were measured. The plasma concentration of cholesterol was significantly reduced in rats fed a 2% Ca-Alg-containing diet. Furthermore, the portal concentration of bile acid was significantly lowered in the 2% Ca-Alg group. A tendency for a Ca-Alg concentration-dependent increase in fecal excretion of bile acid was also seen, although it was not statistically significant. While several changes in biochemical parameters and histopathological findings were observed, all the values remained within the physiological range. These results indicate that Ca-Alg is effective in reducing plasma cholesterol. A possible mechanism would be enhanced fecal excretion of bile acid due to reduced intestinal reabsorption, which in turn might stimulate bile acid synthesis from cholesterol in the liver, leading to a decrease in plasma cholesterol.

Niemann–Pick C1-Like 1 (NPC1L1) mediates cholesterol absorption, and ezetimibe is a potent NPC1L1 inhibitor applicable for medication of hypercholesterolemia. Epidemiological studies demonstrated that consumption of polyphenols correlates with a decreased risk for atherosclerosis due to their antioxidant effect. This activity can hardly be attributable to the antioxidant activity only, and we hypothesized that polyphenols inhibit intestinal transport of cholesterol. We elucidated the kinetic parameters of intestinal cholesterol absorption, screened several polyphenols for their ability to specifically inhibit intestinal cholesterol absorption, and determined the inhibitory effects of selected flavonoids in vitro and in vivo. The concentration-dependent uptake of cholesterol by Caco-2 cells obeyed a monophasic saturation process. This indicates the involvement of an active-passive transport, i.e., NPC1L1. Parameters of cholesterol uptake by Caco-2 cells were as follows: J max, K t, and K d were 6.89±2.96 19.03±11.58 µM, and 0.11±0.02 pmol/min/mg protein, respectively. Luteolin and quercetin inhibited cholesterol absorption by Caco-2 cells and human embryonic kidney 293T cells expressing NPC1L1. When preincubated Caco-2 cells with luteolin and quercetin before the assay, cholesterol uptake significantly decreased. The inhibitory effects of these flavonoids were maintained for up to 120 min. The level of inhibition and irreversible effects were similar to that of ezetimibe. Serum cholesterol levels significantly decreased more in rats fed both cholesterol and luteolin (or quercetin), than in those observed in the cholesterol feeding group. As quercetin induced a significant decrease in the levels of NPC1L1 mRNA in Caco-2 cells, the in vivo inhibitory effect may be due to the expression of NPC1L1. These results suggest that luteolin and quercetin reduce high blood cholesterol levels by specifically inhibiting intestinal cholesterol absorption mediated by NPC1L1.

A stereoselective assay for the determination of tolperisone enantiomers in plasma by high performance liquid chromatography was developed. Calibration curves obtained for the enantiomers were linear over plasma concentrations of 0.1-3.0 micrograms/ml with a detection limit of 20 ng/ml. Following intravenous bolus administration of 10 mg/kg of racemic tolperisone to rats, stereoselective disposition of tolperisone enantiomers was observed, and plasma concentrations were significantly higher for l-tolperisone than for d-tolperisone at 5, 15 and 30 min after administration. When either enantiomer was administered alone to rats, both enantiomers were found in plasma, indicating that a mutual chiral inversion occurs in the body.

We investigated the distribution and stability of pirarubicin in human blood obtained from 12 healthy volunteers. The distribution of pirarubicin into blood cells showed marked temperature- and concentration-dependencies and the Arrhenius plot for pirarubicin uptake in blood was biphasic. Therefore, pirarubicin appears to be taken up into blood cells by a carrier-mediated system. Pirarubicin was mainly enzymatically metabolized to pirarubicinol in blood cells, but pirarubicin was not metabolized into doxorubicin in either blood or plasma. On the other hand, in plasma, pirarubicin was degraded to unknown inactive compounds instead of pirarubicinol. It is therefore suggested that blood cells serve to protect against the degradation of pirarubicin into inactive compounds in blood. Accordingly, when the monitoring of pirarubicin and its active metabolites is carried out in patients, both blood and plasma must be frozen immediately after blood collection.