Changes in estimated glomerular filtration rate before and after the first visit for atrial fibrillation.

BACKGROUND: Although the development of atrial fibrillation (AF) and the progression of chronic kidney disease are known to be interrelated, it remains unclear when and how renal function changes during the clinical course of AF. METHODS: This study retrospectively enrolled 131 patients who were able to collect data on estimated glomerular filtration rate (eGFR) at least five times during the 500 days before and 500 days after the first visit (baseline) of new-onset AF, respectively. To investigate the temporal relationship between the development of AF and the beginning of worsening renal function (WRF), a piecewise regression model was applied to the eGFR time series data. The time point at which the slopes of the two regression lines changed (inflection -point), the slope before and after the inflection-point (ß1 and ß2, respectively), and the difference in slope (Δß) were estimated. The presence of WRF was defined as having the inflection-point at which both Δß and ß2 were < - 0.0083 mL/min/1.73 m2/day (corresponding to 3.03 mL/min/1.73 m2/year), and the corresponding the inflection-point was defined as the beginning of WRF. RESULTS: WRF was detected in 54 (41.2%) patients. The beginning of WRF were distributed at various times, but most frequently (23 of 54 patients) within 100 days before and after baseline. The presence of WRF was not associated with age, heart failure, or baseline eGFR, but was associated with positive ß1 (odds ratio 30.5, 95% confidence interval 11.1-83.9, P < 0.01). CONCLUSION: In nearly half of AF patients with WRF, the beginning of WRF was observed within a few months before or after the first visit for AF. Patients with a positive eGFR slope before the onset of AF are more likely to develop WRF after the onset of AF, suggesting that potential kidney damage may be underlying.

Polymeric iron chelators for enhancing 5-aminolevulinic acid-induced photodynamic therapy.

5-Aminolevulinic acid (5-ALA) is an amino acid that can be metabolized into a photosensitizer, protoporphyrin IX (PpIX) selectively in a tumor cell, permitting minimally invasive photodynamic diagnosis/therapy. However, some malignant tumor cells have excess intracellular labile iron and facilitate the conversion of PpIX into heme, which compromises the therapeutic potency of 5-ALA. Here, we examined the potential of chelation of such unfavorable intratumoral labile iron in photodynamic therapy (PDT) with 5-ALA hydrochloride, using polymeric iron chelators that we recently developed. The polymeric iron chelator efficiently inactivated the intracellular labile iron in cultured cancer cells and importantly enhanced the accumulation of PpIX, thereby improving the cytotoxicity upon photoirradiation. Even in in vivo study with subcutaneous tumor models, the polymeric iron chelator augmented the intratumoral accumulation of PpIX and the PDT effect. This study suggests that our polymeric iron chelator could be a tool for boosting the effect of 5-ALA-induced PDT by modulating tumor microenvironment.

Effects of Microbial Metabolites of (-)-Epigallocatechin Gallate on Glucose Uptake in L6 Skeletal Muscle Cell and Glucose Tolerance in ICR Mice.

Glucose uptake ability into L6 skeletal muscle cell was examined with eleven kinds of ring fission metabolites of (-)-epigallocatechin gallate (EGCG) produced by intestinal bacteria. The metabolites 5-(3,5-dihydroxyphenyl)-γ-valerolactone (EGC-M5), 4-hydroxy-5-(3,4,5-trihydroxyphenyl)valeric acid (EGC-M6), 5-(3,4,5-trihydroxyphenyl)-γ-valerolactone (EGC-M7) and 5-(3-hydroxyphenyl)valeric acid (EGC-M11) have been found to promote uptake of glucose into L6 myotubes significantly. EGC-M5, which is one of the major ring fission metabolites of EGCG, was also found to have a promotive effect on glucose transporter 4 (GLUT4) translocation accompanied by phosphorylation of AMP-activated protein kinase (AMPK) signaling pathway in skeletal muscle both in vivo and in vitro. Furthermore, the effect of oral single dosage of EGC-M5 on glucose tolerance test with ICR mice was examined and significant suppression of hyperglycemia was observed. These data suggested that EGC-M5 has an antidiabetic effect in vivo.

Takotsubo cardiomyopathy in Guillain-Barré syndrome.

BACKGROUND AND PURPOSE: Takotsubo cardiomyopathy (TCM) is a serious autonomic complication of Guillain-Barré syndrome (GBS). However, the association between TCM and GBS has not been investigated in detail. We investigated the characteristics of GBS patients with TCM (GBS-TCM). METHODS: Clinical features and anti-ganglioside antibody between the GBS-TCM patients and 62 classical GBS patients without TCM as control patients were compared. RESULTS: Eight GBS-TCM patients were identified, in whom TCM was diagnosed at a mean of 6.5 [range 3-42] days after the onset of GBS. The age at onset of GBS was elder in the GBS-TCM patients than in the control GBS patients (76.5 [56-87] vs. 52 [20-88] years, p < 0.01). Notably, cranial nerve deficits, particularly in the lower cranial nerves, were observed in all GBS-TCM patients (100% vs. 41.9%, p < 0.01). Additionally, the GBS-TCM patients showed a higher GBS disability score at nadir (5 [4-5] vs. 4 [1-5], p < 0.01), and lower Medical Research Council sum scores at admission and nadir (37 [30-44] vs. 48 [12-60] at admission, p < 0.05, and 20 [12-44] vs. 40 [0-60] at nadir, p < 0.05, respectively). Mechanical ventilation was more frequently required in the GBS-TCM patients (62.5% vs. 11.3%, p < 0.01). Three GBS-TCM patients were positive for anti-ganglioside antibodies. CONCLUSIONS: TCM occurred at a relatively early phase of GBS. The characteristics of GBS-TCM were the elder, lower cranial nerve involvements, severe limb weakness, and respiratory failure.

A proposed interval for evaluation of renal function during anticoagulation therapy using direct oral anticoagulants in patients with atrial fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) have been used to prevent cardiogenic embolism in patients with atrial fibrillation (AF). No evidence has been established for the follow-up renal function evaluation intervals. We hypothesized that a proposed follow-up interval of renal function can be estimated by patient's baseline characteristics including creatinine clearance (CCr). METHODS: We conducted a single-center retrospective study at Kindai University Hospital from May 2011 to December 2017. Patients were screened and they were enrolled if baseline CCr of ≥50 mL/min. To provide a periodical synchronization for measurements of CCr in all patients, these were evaluated at four different time points (approximately at 3, 6, 9, and 12 months). Primary endpoint was defined as a CCr value of <50 mL/min during the follow-up period. We analyzed associations between the cumulative risk for renal endpoint and baseline characteristics by the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: Renal endpoint was associated with age (95% CI: 0.07 to 0.21, p<0.01), body weight (95% CI: -0.09 to -0.01, p<0.01), CCr (95% CI: -0.18 to -0.07, p<0.01), and CHA2DS2-VASc score (95% CI: 0.14 to 0.63, p<0.01). Combining baseline CCr of <60 mL/min and other risk factors, acceptable intervals for 5% risk levels were 78 days (age ≥75 years old), 100 days (CHA2DS2-VASc score of> 4 points), and 90 days (body weight <60kg), respectively. Under conditions of baseline CCr of <60 mL/min, age ≥75 years old, CHA2DS2-VASc score of> 4 points, or body weight <60 kg, an increased risk of renal endpoints is 4.85, 3.29, 1.24, 2.44 fold, respectively. CONCLUSIONS: We propose a risk-stratified follow-up interval for renal evaluation in patients with AF and DOACs therapy according to a combination of baseline CCr and other risk factors.

Dye-sensitized solar cells based on donor-π-acceptor fluorescent dyes with a pyridine ring as an electron-withdrawing-injecting anchoring group.

A new-type of donor-acceptor π-conjugated (D-π-A) fluorescent dyes NI3-NI8 with a pyridine ring as electron-withdrawing-injecting anchoring group have been developed and their photovoltaic performances in dye-sensitized solar cells (DSSCs) are investigated. The short-circuit photocurrent densities and solar energy-to-electricity conversion yields of DSSCs based on NI3-NI8 are greater than those for the conventional D-π-A dye sensitizers NI1 and NI2 with a carboxyl group as the electron-withdrawing anchoring group. The IR spectra of NI3-NI8 adsorbed on TiO(2) indicate the formation of coordinate bonds between the pyridine ring of dyes NI3-NI8 and the Lewis acid sites (exposed Ti(n+) cations) of the TiO(2) surface. This work demonstrates that the pyridine rings of D-π-A dye sensitizers that form a coordinate bond with the Lewis acid site of a TiO(2) surface are promising candidates as not only electron-withdrawing anchoring group but also electron-injecting group, rather than the carboxyl groups of the conventional D-π-A dye sensitizers that form an ester linkage with the Brønsted acid sites of the TiO(2) surface.

Detection of water in organic solvents by photo-induced electron transfer method.

A new class of fluorescence sensor for detection of water in organic solvents based on photo-induced electron transfer (PET) of anthracene coupled with an amino acid has been designed and developed.

A novel method to demonstrate thrombus formation of the left atrial appendage in patients with persistent atrial fibrillation by cardiac computed tomography.

BACKGROUND: Transesophageal echocardiography (TEE) is currently the gold standard technique for diagnosing left atrial appendage (LAA) thrombi. Cardiac computed tomography (CT) has been expected to become an alternative method to TEE; however, a reliable quantitative evaluation method has not been established. METHODS AND RESULTS: We enrolled 177 patients with persistent atrial fibrillation who underwent both cardiac CT and TEE before catheter ablation. The patients were classified into two groups according to the TEE results: the thrombus group (13 patients) and non-thrombus group (164 patients). The Hounsfield unit (HU) density at the proximal LAA (LAAp) and distal LAA (LAAd) was measured on cardiac CT images. The LAAd/LAAp HU ratio and standard deviation of HU density (HU-SD) at the LAAd were evaluated. We created an algorithm by decision tree analysis to predict LAA thrombus formation using the HU ratio and HU-SD. Definite absence of LAA thrombus (Category-I) was diagnosed for 139 patients by combining the first and second branching of the decision tree (Category-Ia: HU ratio of ≥0.26, Category-Ib: HU ratio of <0.26, HD-SD of ≥26.94). Definite presence of LAA thrombus (Category-Ⅱ) was diagnosed for 3 patients using the third branching of the decision tree (Category-Ⅱ: HU ratio of <0.26 and HU-SD of <13.85). Highly possibility of LAA thrombus (Category-III), but not definite, was diagnosed for the remaining 35 patients; therefore, these patients required diagnostic TEE. The diagnostic accuracy of this algorithm was 0.95. CONCLUSION: We have proposed a reliable algorithm to diagnose LAA thrombus formation using the HU ratio and HU-SD.

Impact of atrial fibrillation/flutter on outcomes of patients with implantable cardioverter defibrillators: A sub-analysis of the Nippon Storm study.

BACKGROUND: Implantable cardioverter-defibrillator and cardiac resynchronization therapy using a defibrillator (ICD/CRT-D) are established means of reducing mortality due to ventricular arrhythmia. Although atrial fibrillation/flutter (AF) is the most common cardiac arrhythmia in patients with heart disease, the impact of AF on the prognosis of patients with ICD/CRT-D remains controversial. METHODS AND RESULTS: We analyzed data from the Nippon Storm Study, a prospective observational study of 1570 patients that was conducted at 48 Japanese ICD centers. We allocated 1549 participants to AF and non-AF groups, compared their clinical data at the time of enrollment, and monitored the incidences of mortality, hospitalization, and appropriate and inappropriate ICD/CRT-D therapy during a median 28 months. When the AF (n = 257, 16.6%) and non-AF-(n = 1292, 83.4%) groups were compared, the AF group was older (67.7 vs. 61.4 years; p<0.0001), and had lower left ventricular ejection fraction (38.0 ± 17.0% vs. 43.5 ± 18.9%; p<0.0001). During follow up, mortality was significantly higher in the AF than the non-AF group (p<0.0001). In multivariate analysis, AF was significantly associated with all-cause mortality [p = 0.013; hazard ratio (HR)=1.62]. Inappropriate ICD/CRT-D therapy occurred in 40/257 patients (15.6%) and AF was associated with a higher prevalence of inappropriate ICD/CRT-D therapy (p<0.0001; HR=2.25). CONCLUSION: The presence of AF at ICD/CRT-D implantation carries subsequent independent risks of 1.62-fold for death and 2.25-fold for inappropriate therapy.

Epigallocatechin gallate induces GLUT4 translocation in skeletal muscle through both PI3K- and AMPK-dependent pathways.

Our previous report demonstrated that epigallocatechin gallate (EGCg) promotes translocation of glucose transporter 4 (GLUT4) in skeletal muscle. In this study, we investigated the molecular mechanism of GLUT4 translocation by EGCg at the physiological concentration range. In L6 cells, EGCg induced phosphorylation of phosphatidylinositide 3'-kinase (PI3K) and downstream protein kinase C (PKC) λ/ξ without affecting the phosphorylation of insulin receptor and Akt. EGCg-induced GLUT4 translocation was suppressed by RNA interference-mediated knockdown of PI3K and treatment with PKC inhibitor Go6983. Moreover, EGCg increased Rac1 activity and actin remodelling as downstream events of PKCλ/ξ. These results indicate that EGCg induced GLUT4 translocation through a PI3K-dependent pathway, but its mode of action differed from that of insulin. EGCg also induced GLUT4 translocation through a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent pathway. 67 kDa laminin receptor, which is a target molecule of EGCg, was not involved in EGCg-induced glucose uptake in L6 cells. The oral administration of EGCg suppressed postprandial hyperglycaemia accompanied by GLUT4 translocation through both PI3K- and AMPK-dependent pathways, and promoted glycogen accumulation in skeletal muscle of ICR mice. EGCg promotes GLUT4 translocation through both PI3K- and AMPK-dependent pathways and glycogen accumulation in skeletal muscle.

Caffeine-Stimulated Intestinal Epithelial Cells Suppress Lipid Accumulation in Adipocytes.

Caffeine is a methylxanthine derived from plant foods such as coffee beans and tea leaves, and has multiple biological activities against physiological response and several diseases. Although there are some reports about the direct effect of caffeine against anti-lipid accumulation in vitro, the effect of caffeine on lipid accumulation in adipocytes through stimulating intestinal epithelial cells is unknown. Since direct treatment with caffeine to 3T3-L1 cells did not affect lipid accumulation, we determined whether caffeine-stimulated intestinal epithelial Caco-2 cells influence the lipid accumulation in 3T3-L1 adipocytes. Caco-2 cells were cultured on a transwell insert with or without caffeine for 24 h. Subsequently, the basolateral component of the Caco-2 cell culture on the transwell was collected and termed caffeine-conditioning medium (CCM). When 3T3-L1 adipocytes were incubated with CCM, CCM decreased lipid accumulation and suppressed gene expression of proliferator activated receptor (PPAR) γ and CCAAT/enhancer binding protein (C/EBP) α in 3T3-L1 adipocytes. Furthermore, CCM decreased the expression of C/EBPß and C/EBPδ at the protein level, but not at the mRNA level. We observed that a proteasome inhibitor, MG132, inhibited CCM-caused down-expression of C/EBPß and C/EBPδ proteins, and that CCM promoted the ubiquitination level of C/EBPß and C/EBPδ proteins. Protein microarray analysis showed caffeine suppresses the secretion of inflammatory cytokines, interleukin-8 and plasminogen activator inhibitor-1 from Caco-2 cells. These results suggest that caffeine indirectly suppresses lipid accumulation in 3T3-L1 adipocytes through decreasing secretion of inflammatory cytokines from Caco-2 cells.

Fluorescence PET (photo-induced electron transfer) sensors for water based on anthracene-boronic acid ester.

Anthracene-boronic acid ester as a new class of fluorescence PET sensors for detection of a trace amount of water in organic solvents has been designed and developed.