Left Atrial Filling Time Index (LAFTI) Evaluated by 2D Speckle Tracking Echocardiography Predicts Poor Cardiac Prognosis in Patients with Heart Failure.

Left atrial (LA) dysfunction is known to be a more sensitive prognostic marker than left ventricular (LV) dysfunction in patients with heart failure (HF). Persistent LA overload increases LA stiffness which impairs LA relaxation. The aim of this study was to investigate whether LA filling time is associated with clinical outcomes in patients with HF. Two-dimensional speckle tracking echocardiography (2DSTE) was performed at discharge, to measure LA and LV strain in 179 HF patients admitted to our hospital. The LA filling time index (LAFTI) was defined as the time from onset of the R wave to the peak LA systolic strain divided by the R-R interval. All patients were prospectively followed with cardiac events including cardiac death and rehospitalization for HF. There were 64 cardiac events during a median follow-up period of 451 days. There were no significant differences in heart rate, severity of HF at discharge, etiology of HF, severity of mitral regurgitation, or LV global longitudinal strain between the cardiac event group and no cardiac event group. Patients with cardiac events had significantly higher levels of brain natriuretic peptide (BNP), ratio of the E wave to e' (E/e'), left atrial volume index (LAVI), and lower LAFTI than those without. Kaplan-Meier analysis showed that patients with lower LAFTI were associated with higher cardiac event rates. Multivariate Cox hazard analysis showed that LAFTI was independently associated with the cardiac events after adjustment for confounding factors. In conclusion, LAFTI is a feasible predictor for cardiac events in patients with HF.

Perfusion Balloon Is Useful for Preventing Obstruction of Left Main Coronary Artery During Transcatheter Aortic Valve Implantation.

The incidence of acute coronary obstruction during transcatheter aortic valve implantation (TAVI) is low (< 1.0%); however, it is associated with high mortality. An 83-year-old female with a history of chest pain and syncope was diagnosed with severe aortic stenosis. Computed tomography showed severely calcified aortic leaflets with a low left coronary ostial height of 7.8 mm, which indicates a high risk of coronary obstruction. TAVI was performed using the right femoral artery approach under general anesthesia. To prevent coronary obstruction and minimize coronary flow obstruction, coronary protection of the left main tract (LMT) via the left radial artery was established with a perfusion balloon. We crossed a 23 mm Sapien 3 transcatheter heart valve and settled it at an appropriate position on the aortic valve. After inflation of the perfusion balloon at the LMT, we started rapid ventricular pacing, and deployed the Sapien 3 using the KBI technique. Hemodynamics were stable and aortography showed excellent coronary flow with no stenosis of the LMT ostium. This strategy may serve as a useful method to prevent coronary obstruction and minimize coronary ischemia.

Metabolome Analysis Reveals Dermal Histamine Accumulation in Murine Dermatitis Provoked by Genetic Deletion of P-Glycoprotein and Breast Cancer Resistance Protein.

PURPOSE: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are xenobiotic transporters which pump out variety types of compounds, but information on their interaction with endogenous substrates in the skin is limited. The purpose of the present study was to clarify possible association of these transporters in dermal accumulation of inflammatory mediators. METHODS: Dermatitis model was constructed by repeated topical application of oxazolone in wild-type, and P-gp and BCRP gene triple knockout (Mdr1a/1b/Bcrp-/-) mice to observe difference in phenotype. Target metabolome analysis of 583 metabolites was performed using skin and plasma. RESULTS: Dermatitis and scratching behavior in dermatitis model of Mdr1a/1b/Bcrp-/- mice were more severe than wild-type mice, suggesting protective roles of these transporters. This hypothesis was supported by the metabolome analysis which revealed that concentration of histamine and other dermatitis-associated metabolites like urate and serotonin in the dermatitis skin, but not normal skin, of Mdr1a/1b/Bcrp-/- mice was higher than that of wild-type mice. Gene expression of P-gp and BCRP was reduced in oxazolone-treated skin and the skin of patients with atopic dermatitis or psoriasis. CONCLUSIONS: These results suggest possible association of these efflux transporters with dermal inflammatory mediators, and such association could be observed in the dermatitis skin.

Left atrial remodeling index is a feasible predictor of poor prognosis in patients with acute ischemic stroke.

Left atrial (LA) functional remodeling as well as LA structural remodeling are associated with incident LA appendage (LAA) thrombus formation. This study aimed to elucidate whether combined assessment of LA functional and structural remodeling can predict LAA dysfunction and recurrent cerebrovascular events in patients with acute ischemic stroke. We performed transthoracic and transesophageal echocardiography in 196 patients within 7 days after acute ischemic stroke. Peak systolic LA strain was evaluated using 2D speckle tracking imaging. We defined the ratio of LA peak systolic strain to LA volume index (LAVI) as the LA remodeling index (LARI). All patients were prospectively followed for recurrent cerebrovascular events. We divided patients into four groups according based on the LARI quartile. LAA dysfunction increased with decreasing LARI. In total, 52 recurrent cerebrovascular events were noted during the median follow-up period of 700 days. Patients with recurrent cerebrovascular events had lower LARI than those without recurrent events (0.50 ± 0.45 vs. 1.10 ± 0.95, P < 0.001). Kaplan-Meier analysis showed that patients with lower LARI were more susceptible to recurrent cerebrovascular events than those with higher LARI. Multivariate Cox proportional hazard regression analysis showed that LARI was an independent predictor of recurrent cerebrovascular events after adjustment for confounding factors. Net reclassification index improved with the addition of LARI to basic predictors. LARI is a novel feasible parameter for LAA dysfunction and can predict recurrent cerebrovascular events in patients with acute ischemic stroke.

Prolonged total atrial conduction time evaluated with tissue Doppler imaging predicts poor cardiac prognosis in patients with heart failure.

Prolonged total atrial conduction time is caused by atrial remodeling. Left atrial remodeling is associated with poor outcome in patients with heart failure (HF). This study aimed to investigate whether prolonged total atrial conduction time predicts poor prognosis in patients with HF. We performed transthoracic echocardiography in 100 patients (65 men; mean age 68 ± 13 years) who were hospitalized for HF. Total atrial conduction time was defined as the duration from P wave onset on electrocardiography to peak A' wave on tissue Doppler imaging (TDI) echocardiography (PA-TDI duration). There were 37 cardiac events (37%) during a median follow-up period of 414 days. The PATDI duration was significantly longer in patients with cardiac events than in those without (150 ± 18 ms vs 133 ± 19 ms; P < 0.05). There were no significant differences in left ventricular end-diastolic dimensions and ejection fractions between patients with and without cardiac events. Patients with HF were divided into 3 groups according to tertiles of the PA-TDI duration. Kaplan-Meier analysis showed that the highest tertile of PA-TDI duration was associated with the greatest risk among patients with HF. Multivariate Cox proportional hazard analysis showed that the PA-TDI duration was an independent predictor of cardiac events, leading to the conclusion that prolonged PA-TDI duration was a feasible predictor of cardiac prognosis in patients with HF.

Mechanisms of interleukin-10 induction in murine spleen and RAW264 cells by Latilactobacillus curvatus K4G4 isolated from fermented Brassica rapa L.

Lactic acid bacteria (LAB) are commonly used in fermented foods, and some LAB modulate the immune response. We aimed to investigate the mechanism by which LAB isolates from fermented Brassica rapa L. induce the production of anti-inflammatory interleukin (IL)-10 by the murine spleen and RAW264 cells. Spleen cells from BALB/c mice or the mouse macrophage cell line RAW264 were cultured with heat-killed LAB isolated from fermented B. rapa L., and the IL-10 level in the supernatant was measured. Latilactobacillus curvatus K4G4 provided the most potent IL-10 induction among 13 isolates. Cell wall components of K4G4 failed to induce IL-10, while treatment of the bacteria with RNase A under a high salt concentration altered K4G4 induction of IL-10 by spleen cells. In general, a low salt concentration diminished the IL-10 induction by all strains, including K4G4. In addition, chloroquine pretreatment and knock down of toll-like receptor 7 through small interfering RNA suppressed K4G4 induction of IL-10 production by RAW264 cells. Our results suggest that single-stranded RNA from K4G4 is involved, via endosomal toll-like receptor 7, in the induction of IL-10 production by macrophages. K4G4 is a promising candidate probiotic strain that modulates the immune response by inducing IL-10 from macrophages.

Involvement of the vagus nerve and hepatic gene expression in serum adiponectin concentrations in mice.

Several humoral factors, such as adiponectin and urate, have been suggested to affect metabolic syndromes. Previously, we reported a reduction in blood adiponectin concentrations after a high-fructose diet partially via the vagus nerve in rats. Although a lithogenic diet (LD), i.e., supplementation of a normal control diet (CT) with 0.6% cholesterol and 0.2% sodium cholate, reduced blood adiponectin concentrations, the involvement of the vagus nerve in this mechanism remains unclear. To estimate the involvement of the vagus nerve in the regulation of blood adiponectin concentrations using an LD, male imprinting control region mice that had been vagotomized (HVx) or only laparotomized (Sham) were administered a CT or an LD for 10 weeks. Serum adiponectin concentrations in the Sham-LD, HVx-CT, and HVx-LD groups were reduced by half compared with the Sham-CT group. The hepatic mRNA levels of fibroblast growth factor 21 (Fgf21), which reportedly stimulates adiponectin secretion from white adipose tissue, were lower in the LD groups compared with the CT groups. HepG2 hepatoma cells showed that various bile acids reduced the mRNA expression of FGF21. Moreover, the LD increased serum urate concentrations and reduced hepatic expressions of the acyl-CoA oxidase 1 (Acox1) mRNA and glucokinase, suggesting insufficient regeneration of ATP from AMP. In conclusion, serum adiponectin concentration may be regulated via the vagus nerve in normal mice, whereas a reduction of hepatic Fgf21 mRNA by bile acids may also lower serum adiponectin levels. Moreover, the LD may promote hepatic AMP accumulation and subsequently increase the serum urate concentration in mice.

Effect of potato ethanol residue on rat plasma cholesterol levels.

We investigated the cholesterol-lowering effect of a potato ethanol residue (PER). The plasma cholesterol levels excluding high-density lipoprotein cholesterol were lower in the rats given a PER-containing diet for 6 weeks than in the control group, whereas the fecal cholesterol levels were higher. These results suggest that PER partially reduced plasma cholesterol levels via excretion of cholesterol into the feces.

Japanese butterbur (Petasites japonicus) leaves increase hepatic oxidative stress in male rats.

We investigated the adverse effects of Japanese butterbur leaves (Petasites japonicus, Compositae) in male F344/DuCrj rats. The rats were fed a control diet or a treatment diet containing 5% butterbur leaf powder for 4 weeks. No differences were observed in body weight gain, food intake or feed efficiency between treatments, but relative liver weight in the butterbur group was significantly higher than that of the control group. In addition, thiobarbituric acid reactive substances (TBARs) and glutathione levels in the serum and liver of the butterbur group were higher than those of the control group. Hepatic glutathione reductase and glutathione S-transferase activities and mRNA expression in the butterbur leaf group were higher than in the control group. Furthermore, hepatic cytochrome 2E1 mRNA expression was higher than in the control group. In vitro, an acetone extract of the butterbur leaf powder showed the strongest increase in TBARs level in a hepatic homogenate through 4 d. Our findings suggest that feeding 5% butterbur leaf powder to rats can cause adverse effects by increasing oxidative stress.

Effects of feeding potato pulp on cholesterol metabolism and its association with cecal conditions in rats.

To clarify the functional properties of potato pulp (PP), a waste product resulting from extraction of starch from potatoes, we examined the effects of PP on cholesterol metabolism and cecal conditions in rats. Plasma total cholesterol (T-Chol) levels were lower in rats fed a PP-supplemented diet for four weeks than in those fed a control diet. Cecal pH was lowered due to an increase in the levels of cecal total short-chain fatty acids, especially butyrate, in the PP group compared to the control group. Furthermore, animals fed with the PP-supplemented diet showed increased cecal ratios of Lactobacillus and Clostridia and decreased cecal ratios of Bacteroides and Gammaproteobacteria with slightly negative and positive correlations with plasma T-Chol levels, respectively. In conclusion, ingestion of PP for four weeks is likely to improve both cecal conditions and cholesterol metabolism, suggesting that PP has prebiotic effects.

Bile acids induced hepatic lipid accumulation in mice by inhibiting mRNA expression of patatin-like phospholipase domain containing 3 and microsomal triglyceride transfer protein.

Preliminary studies have shown that a lithogenic diet (LG), which contains cholesterol and cholic acid, induces gallstones and hepatic lipid accumulation (HLA), and reduction of blood triglyceride in mice. We hypothesized that an LG induces HLA by diminishing hepatic triglyceride excretion; however, there is no clear understanding of the mechanism of LG-induced HLA. This study aimed to investigate transcript expression related to the synthesis, expenditure, and efflux of hepatic triglyceride, in mice fed an LG for 4 weeks. Results showed lower plasma concentrations of triglyceride in the LG group than in the control group, but no symptoms of hepatic injury were observed. Hepatic mRNA expressions of patatin-like phospholipase domain containing 3 (Pnpla3), microsomal triglyceride transfer protein (Mttp), and acyl-CoA oxidase 1 (Acox1) were also reduced in the LG group. Deoxycholic acid and lithocholic acid promoted intracellular lipid accumulation, reduced triglyceride concentration in media, and suppressed expression of PNPLA3 and MTTP in HepG2 human hepatoma cells. These findings suggest that deoxycholic acid and lithocholic acid promote HLA by inhibiting the expression of PNPLA3, ACOX1, and MTTP that are involved in lipid metabolism.

Candidates for area under the concentration-time curve (AUC)-guided dosing and risk reduction based on analyses of risk factors associated with nephrotoxicity in vancomycin-treated patients.

OBJECTIVES: Compared with vancomycin trough concentration (Cmin)-guided dosing, area under the concentration-time curve (AUC)-guided dosing is associated with decreased acute kidney injury (AKI). However, whether Cmin-guided or AUC-guided dosing should be used in patients other than those with serious MRSA infections remains uncertain. The purposes of this multicentre study were to identify risk factors for early- and late-phase vancomycin-induced AKI and to identify candidates for AUC-guided dosing, rather than Cmin-guided dosing, who require a more accurate dose titration to reduce the AKI risk. METHODS: A multivariate logistic regression analysis was applied to identify risk factors for AKI. Additionally, the cut­off day for AKI onset, cut-off Cmin for AKI, safe Cmin for reduced AKI risk and probability of AKI were calculated. RESULTS: In total, 8.4% (159/1882) of patients developed AKI. AKI occurred within the first 7 days of therapy (early phase) in the vast majority of patients. Significant risk factors for AKI during the early phase were identified as Cmin > 20 mg/L, ICU stay, concurrent diuretic or piperacillin/tazobactam use, and pre-existing renal dysfunction. A temporarily elevated Cmin (>15-20 mg/L) was not associated with a greater risk of AKI. In patients with risk factors, the cut-off Cmin for AKI and the estimated safe Cmin for reduced AKI risk were 18.8-21.0 mg/L and <11.7-13.5 mg/L, respectively. CONCLUSION: Patients with known AKI risk factors require a low target Cmin. The presence of several risk factors for AKI may indicate a need for more accurate dose titration using AUC-guided dosing.

Imaging findings at the donor site after iliac crest bone harvesting.

OBJECTIVE: Postoperative imaging after iliac crest bone harvesting is commonly performed, but has not been extensively reported in the literature. The objective of this analysis was to investigate the donor site after iliac crest graft harvesting. MATERIALS AND METHODS: Between January and December 2008, 3,450 patients underwent CT, which included the pelvis. Eighty-four patients were found whose iliac crests were harvested. The patient population consisted of 47 male and 37 female subjects ranging from 10 to 80 years old (mean 52.6 years) at the time of iliac bone harvesting. With the inclusion of prior examinations, 188 CT examinations, 17 MR imaging studies, and 19 bone scintigrams were analyzed at various time points after surgery. RESULTS: Computed tomography images demonstrated fluid collections, hematoma, and air at the donor site up to 1 month after bone harvesting. The air then disappeared. Fluid collection decreased in size by 4 months. Scar-like changes at the harvest site and irregular thick cortical bone were observed after 4 months. Later, CT and MR imaging demonstrated small scar-like lesions and cortical irregularities. CONCLUSION: The appearance of harvest site abnormalities depends on the time elapsed after surgery.

Effects of lipase, lipoxygenase, peroxidase and free fatty acids on volatile compound found in boiled buckwheat noodles.

BACKGROUND: Relationships between buckwheat (Fagopyrum esculentum Moench) flour lipase, lipoxygenase and peroxidase activity, along with levels of individual free fatty acids (FFAs) and levels of headspace volatile compounds of boiled buckwheat noodles, were investigated for 12 different buckwheat varieties. Enzyme activities and FFA levels in flour were correlated with their respective varietal arrays of boiled noodle headspace volatile compounds, measured by gas chromatography-mass spectrometry. RESULTS: The volatiles hexanal, tentative butanal, tentative 3-methylbutanal and tentative 2-methylbutanal showed significant positive correlation with one another, indicating that they may be generated through similar mechanisms. These important volatile components of buckwheat flavor were also positively correlated with lipase and/or peroxidase activity, indicating that enzymatic reactions are important in flavor generation in boiled buckwheat noodles. On the other hand, pentanal, which showed no significant correlation with any enzyme activity, showed a significant positive correlation to the levels of C18:2 and C18:3 FFAs, suggesting the existence of a 'non-enzymatic' and/or 'uncertain enzymatic pathway' for flavor generation in boiled buckwheat noodles. CONCLUSION: Lipase and peroxidase in buckwheat flour are important for flavor generation of boiled buckwheat noodles. This information is important for increasing desirable flavor of buckwheat products as well as for selecting varieties with improved flavor.

Colored potato extracts induce superoxide dismutase-2 mRNA via ERK1/2 pathway in HepG2 cells.

Rats fed a diet containing Shadow Queen (SQ), an anthocyanin-rich potato cultivar, previously showed an increase in the hepatic superoxide dismutase (SOD)-2 mRNA level. We investigated whether an extract of SQ would directly increase the hepatic SOD-2 mRNA level in HepG2 cells. Furthermore, we estimated the intracellular signaling pathway for the induction of SOD-2 mRNA expression. HepG2 cells were stimulated using extracts of four crops, including SQ, for 12 h; only extracts of colored potatoes induced SOD-2 mRNA expression significantly. This induction of SOD-2 mRNA expression was blocked by an inhibitor of the extracellular signal-related kinase (ERK) 1/2 pathway. Furthermore, an extract of SQ increased the phosphorylation of ERK1/2 after 15 or 30 min of stimulation. These data indicate that an extract of SQ directly induces hepatic SOD-2 mRNA expression via activation of ERK1/2 pathway in HepG2 cells.

Pharmacokinetics and Dialyzability of a Single Oral Dose of Amenamevir, an Anti-Herpes Drug, in Hemodialysis Patients.

INTRODUCTION: Amenamevir (ASP2151), a herpesvirus helicase-primase inhibitor, is currently used for the treatment of herpes zoster in Japan. Amenamevir is mainly metabolized in the liver, and urinary excretion of amenamevir is approximately 10% in healthy adults. The increase of systemic exposure in non-dialysis patients with severe renal impairment was much less than that associated with nucleoside antiviral agents. The aim of this study was to evaluate the pharmacokinetics and dialyzability of a single oral dose (400 mg) of amenamevir in hemodialysis patients. METHODS: This was a single-arm, open-label, multicenter clinical pharmacology study. Nine patients aged 20-80 years with end-stage kidney disease and undergoing maintenance hemodialysis three times weekly were enrolled. Pharmacokinetics and dialyzability were investigated by serial collection of blood samples until 48 h post-dose during the study. RESULTS: The maximum plasma concentration and time to reach maximum plasma concentration during 24 h post-dose were 1585 ng/mL and 6.2 h, respectively. The area under the plasma concentration-time curve (AUC) from time zero to 24 h was 23,890 ng h/mL. The median terminal elimination half-life within 24 h before, during, and after hemodialysis was 14.7, 15.2, and 12.4 h, respectively. The AUC in hemodialysis patients was approximately double that in healthy adults. This increase in AUC was much less than that reported in nucleoside antiviral agents. The hemodialysis clearance, elimination fraction percentage, and amount of amenamevir removed were 37.8 mL/min, 28.1%, and 132.0 µg, respectively. The amount of amenamevir removed by hemodialysis was minimal. None of the hemodialysis parameters were associated with serum albumin. This study revealed no clinically relevant safety concerns. CONCLUSION: There were no clinically relevant safety concerns when 400 mg of amenamevir was administered as a single dose to hemodialysis patients without dose adjustment and/or modification of the dosing schedule. TRIAL REGISTRATION: JapicCTI-184242.

Correction to: Pharmacokinetics and Dialyzability of a Single Oral Dose of Amenamevir, an Anti-Herpes Drug, in Hemodialysis Patients.

In the original article, there is incorrect text has published as "The hemodialysis clearance, elimination fraction percentage, and amount of amenamevir removed were 37.8 mL/min, 28.1%, and 132.0 µg, respectively".

Consumption of lycopene-rich tomatoes improved glucose homeostasis in rats via an increase in leptin levels.

The lycopene content of tomatoes is important because of its effects on vital physiological functions such as improvement of glucose tolerance and non-alcoholic fatty liver disease. To investigate the influence of the lycopene content of tomatoes on glucose tolerance and hepatic lipid content, homogenates of lycopene-rich (LR) or lycopene-free negative control (NC) tomato varieties were administrated to normal rats for 4 weeks. At the end of the experiment, an oral glucose tolerance test (OGTT) was performed. Rats were fed once and then dissected. According to the OGTT results, plasma glucose levels in the LR group were 10% and 9% lower at 15 min and 30 min, respectively, than those in the NC group, whereas plasma insulin levels did not differ between the groups at either time point. Upon dissection, plasma leptin levels in the LR group were higher than those in the NC group, while plasma adiponectin levels did not differ between groups. With the exception of retinol palmitate, no carotenoids were detected in the liver by HPLC analysis. Hepatic retinol palmitate levels and hepatic triacyl glyceride levels did not differ between the groups. We concluded that in normal rats, a lycopene-rich tomato variety improved glucose tolerance via an increase in plasma leptin levels that enhanced insulin sensitivity but did not affect carotenoid accumulation or lipid metabolism.

Effect of white wheat bread containing sugar beet fiber on serum lipids and hepatic mRNA in rats fed on a cholesterol-free diet.

We examined the effects of white wheat bread powder (BP) and white wheat bread powder containing sugar beet fiber (BBP) on serum cholesterol. The total cholesterol (-11%, -16%), HDL-cholesterol (-12%, -11%), non-HDL-cholesterol (-9%, -18%) and triacylglycerol (-44%, -58%) concentrations in the BP and BBP groups, respectively, were significantly different from those in the control group. The fecal excretion of neutral sterols in the BP and BBP groups and of acidic sterols in the BBP group was significantly higher than that in the control group. The hepatic cholesterol 7alpha-hydroxylase (CYP7A1) mRNA level in the BP and BBP groups was significantly higher than that in the control group. The cecal total short-chain fatty acid concentrations in the BBP group were significantly higher than those in the control group. These results indicate that the observed changes in serum lipid levels in the BP and BBP groups were due to the increased fecal lipid and CYP7A1 mRNA levels.

Yam contributes to improvement of glucose metabolism in rats.

To investigate whether yam improves glucose metabolism, yam-containing diets were given to Wistar rats. In a short-term experiment, fasted-rats were given 1.0 g of a control and 20% yam-containing diets. At 60 min after start of the feeding, glucose level in the yam diet group was lower or tended to be lower than that in the control diet. Insulin levels at 30 min and 60 min were significantly lower than those in the control group. In a long-term experiment, a normal diet (N) or 25% high fat diets with (Y) or without 15% yam powder (HF) were given to rats for 4 weeks. At 4 weeks, in an oral glucose tolerance test, the area under the curve (AUC) of plasma glucose level was higher in the HF group than that in the N group, whereas those in the Y groups did not differ from that in the N group. Glycosylated hemoglobin levels had similar tendency to the AUCs. Plasma leptin levels in the Y groups were significantly higher than that in the N group. In conclusion, yam may contribute to improvement of glucose metabolism. Additionally, we speculated that leptin level is possibly involved in the insulin-response to yam diets.