Five Prognostic Factors for Readmission in Patients Over 75 Years Old with Worsening Heart Failure

Heart failure （HF） is a common disease in elderly patients, particularly in those presenting as readmission for worsening HF. While recent studies have revealed mortality-associated factors in this population, little is known about prognostic factors associated with worsening HF. To investigate this clinical evidence gap in patients aged over 75 years, we retrospectively investigated 165 patients hospitalized for HF at Showa University Hospital, of whom 65 （39.4％） were readmitted for worsening HF. We extracted the candidate variables based on univariate analysis, and then elucidated the independent prognostic factors by multivariate analysis. Compared with non-readmitted patients, readmitted patients with worsening HF had lower left ventricular ejection fraction （LVEF） （39％ vs. 50％, P＝0.002） and body mass index （BMI） （19.9kg/m2 vs. 21.4kg/m2, P＝0.007）, higher levels of B-type natriuretic peptide （BNP） （478pg/ml vs. 198pg/ml, P＜0.001）, and heart rate （HR） （71.0 beats/min vs. 67.0 beats/min, P＝0.021） upon discharge during the primary admission. Multivariate logistic analysis identified LVEF ＜40％, BMI ＜21kg/m2, BNP ≥500pg/ml, Charlson score ≥3, and HR ≥70 beats/min upon initial discharge as independent prognostic factors. Based on these factors, readmission for worsening HF was more frequent in those with our proposed risk score of ≥3.0 than in those with a risk score ＜3.0 （P＜0.001）, and we suggested five prognostic factors for HF patients over 75 years old. Our proposed risk score combines these factors and might predict readmission for worsening HF in the elderly population

Risk of Drug-Induced Accidents and Injuries in Elderly Patients Treated with Specific Drugs Rather than Polypharmacy : Analyses of the Japanese Adverse Drug Event Report Database

One of the reasons the health care system requires long-term nursing care for elderly patients is the risk of falls and fractures. In this study, we sought to identify risk factors for drug-induced falls and fractures in elderly patients in Japan. Risk factors for drug-induced falls and fractures in the elderly were analyzed by searching for the Standardised Medical Dictionary for Regulatory Activities （MedDRA） query （SMQ） “accidents/injuries” in the Japanese Adverse Drug Event Report database （JADER）, as this SMQ was the most well suited for evaluating data on falls and fractures. For elderly patients in Japan, the risk factors for drug-induced accidents/injuries include age ≥ 70 years old, female sex, and treatment with specific drugs, but not polypharmacy. Among the risk factors with the 10 highest reporting odds ratios （RORs） were treatment with: anti-osteoporosis agents such as bisphosphonates （e.g., minodronic acid）, eldecalcitol and bazedoxifene; dementia therapeutic agents such as rivastigmine and memantine; antiparkinsonian agents such as entacapone and pramipexole; and neuropathic pain relievers such as pregabalin. Although various geriatric syndromes were generally caused by polypharmacy, it has been posited that individual medications such as those mentioned above have a more significant association with drug-induced accidents and injuries in the elderly than polypharmacy. These drugs should be used cautiously while considering drug interruption, dose reductions, and switching to alternative therapies with lower risks. An association between accidents/injuries and drugs targeting the central nervous system （such as hypnotics, sedatives, anxiolytics, and antidepressants） has previously been reported. However, in the present study, no elevated risks in association with triazolam, zopiclone, flunitrazepam, diazepam, rilmazafone, estazolam, etizolam, or paroxetine were detected. Using RORs for risk detection for drugs in the JADER database is accessible and useful, and enables sensitive risk detection

Title page Involvement of Human Organic Cation Transporter 1 (OCT1) in the Hepatic Uptake of YM155 Monobromide, 1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)- 4,9-dihydro-1H-naphtho[2,3-d]imidazolium Bromide, a Novel, Small Molecule Survivi

Abstract YM155 monobromide, 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide, which is a hydrophilic and cationic compound, exhibits anti-tumor activity in experimental human hormone refractory prostate carcinoma models. Urinary excretion was 18.3% to 28.6% of the dose in the clinical phase I study, and non-renal elimination may be explained by the biliary excretion of YM155 in its unchanged form. As the penetration through the sinusoidal membrane of the hepatocytes is the first step and an important part of biliary excretion, we evaluated the uptake o

Correlations between Oxidative Stress and Blood Lipids Are Stronger in Men than Women

Oxidative stress is one cause of atherosclerosis that makes it a lifestyle-related disease. Oxidized low-density lipoprotein （OxLDL） was previously found to be related to oxidative stress, measured using the diacron-reactive oxygen metabolites （d-ROMs） test and showed a negative correlation between biological antioxidant potential （BAP） test results and triglycerides （TG）. In addition, large gender differences exist among vascular disorders caused by arteriosclerosis. However, such gender differences and their correlation with oxidative stress and blood lipids have not been clarified. In this study, gender differences in correlations between oxidative stress and blood lipids as factors in the development of atherosclerosis was addressed. Subjects were 149 individuals who underwent medical examinations conducted in Ashikaga Teishin Clinic in Tochigi, Japan （98 males and 51 females）. A strong positive correlation was observed between d-ROMs test results and OxLDL in men （R＝0.480, P<0.0001）, but no correlation was seen in women. A strong negative correlation between BAP test results and TG was also noted in men （R＝−0.571, P<0.0001）, and a moderate negative correlation was detected in women （R＝−0.344, P＝0.0133）. A positive correlation between d-ROMs tests and OxLDL was seen in women under 50 years of age （R＝0.399, P＝0.0393）, but this correlation was not present in women who were 50 years of age or older （R＝−0.00656, P＝0.976）. Correlations between oxidative stress and OxLDL and between antioxidant potential and TG in men were more prominent than in women. This finding suggests that decreasing oxidative stress in the blood to prevent atherosclerosis is more important for men

Increase in Matrix Metalloproteinase-2 and 9 in the Liver of Nonalcoholic Steatohepatitis (NASH) Model Rats

Nonalcoholic steatohepatitis (NASH) is regarded as a hepatic manifestation of the metabolic syndrome which can progress to hepatic cirrhosis and hepatocellular carcinoma. It is thought that matrix metalloproteinases (MMPs) play an important role in hepatic fibrosis and we previously reported a correlation between oxidative stress and MMP-9 expression. However, the expression of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in the progression of NASH is unclear. In this study we used spontaneously hypertensive and hyperlipidemic rats (SHHR) fed a high-fat diet and 30% sucrose solution (HFDS) as a model for NASH, in order to clarify the relationships between oxidative stress, liver weight (LW), MMPs and TIMPs at various time-points in the progression of NASH. Male SHHR and Sprague-Dawley (SD) rats were divided into four groups: SHHR-normal diet (ND), SHHR-HFDS, SD-ND and SD-HFDS. Hepatic fibrosis was clearly increased at 13 months in SHHR-HFDS, resembpling NASH. LW and oxidative stress markers in plasma were increased in SHHR-HFDS compared to the other groups. Oxidative stress was correlated with LW in all rats. Expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 mRNA, measured by real-time polymerase chain reaction, was increased in the liver of SHHR-HFDS at 13 months. This study suggests that oxidative stress, MMPs and TIMPs may play an important role in the progression of NASH

Visceral Fat Accumulation is Associated with Oxidative Stress and Increased Matrix Metalloproteinase-9 Expression in Atherogenic Factor-overlapped Model Rats

Visceral fat accumulation in lifestyle-related diseases increases the risk of atherosclerosis. Matrix metalloproteinases (MMPs) play an important role in the progression of atherosclerosis. We examined atherogenic factor-overlapped model rats to clarify the relationships among visceral fat, oxidative stress, and MMPs. We used four groups of male, 11-month-old, spontaneously hypertensive hyperlipidemic rats (SHHRs) or Sprague-Dawley (SD) rats. Animals were fed either a diet of high fat and 30% sucrose solution (HFDS) or a normal diet (ND) ad libitum for 6 months. The visceral fat weight increased by approximately three fold in SHHR-HFDS compared to SHHR-ND. The oxidative stress marker in plasma and MMP-9 mRNA expression in white blood cells increased in SHHR-HFDS compared to the other groups. A correlation was determined between oxidative stress and visceral fat or MMP-9 mRNA in all rats. Lipid deposition and immunostaining of CD68 and MMP-9 were observed mainly in the intima of aorta in SHHR-HFDS, while tissue inhibitor of metalloproteinase-1 mRNA expression decreased in both SHHR groups. The findings suggested that increased oxidative stress due to the visceral fat accumulation induced MMP-9 expression and macrophage accumulation in the intima of aorta in lifestyle-related disease model rats

Quantification of (-)-epigallocatechin-3-gallate Inhibition of Migration and Invasion of Oral Squamous Cell Carcinoma Cell Lines Using Real-time Cell Analysis

Catechins found in green tea, in particular (−)-epigallocatechin-3-gallate (EGCG), have antitumor activity. The primary antitumor actions of catechins are anti-oxidative, anti-angiogenic, and anti-metastatic effects. Cell migration and invasion contribute to the metastatic potential of tumors. Real-time cell analysis (RTCA) measures cell migration and invasion in vitro. In the present study, using RTCA, we investigated whether the cell migration and invasion of oral squamous cell carcinomas (OSCCs) of the tongue and floor of the mouth were inhibited by EGCG. Studies were performed using the human SCC-4 and SAS cell lines, which are poorly differentiated OSCCs of the tongue, and the HO-1-u-1 cell line, an OSCC of the floor of the mouth. SCC-4 cells exhibited high cell migration and invasion compared with the SAS and HO-1-u-1 cells. EGCG was most effective in inhibiting the migration and invasion of SCC-4 cells, and inhibited OSCC cell invasion more strongly than it inhibited cell migration. EGCG inhibited the expression of matrix metalloproteinase (MMP)-2, MMP-9, and integrin α1 and β1 mRNA in the OSCC cell lines, particularly SCC-4 cells. The findings of the present study suggest that EGCG inhibits OSCC cell migration and invasion by inhibiting MMP-2, MMP-9, and integrin α1and β1 expression. Thus, EGCG may be a suitable agent or lead compound for the inhibition of OSCC metastasis

Role of Gremlins in the Aortic Arch of Spontaneously Hypertensive and Hyperlipidemic Rats

Atherosclerosis is a lifestyle-related disease that plays a major role in cardiovascular disease. Recently, we found that gene expression of Gremlin 2, an antagonist of bone morphogenetic protein (BMP), was significantly increased in the aorta of spontaneously hypertensive and hyperlipidemic rats (SHHRs) fed a high-fat, 30% sucrose solution diet (HFDS). However, the role of Gremlin 1 (Grem1) and Gremlin 2 (Grem2) in the aortic arch of rats under hypertensive, hyperlipidemic, and hyperglycemic conditions remains unclear. Therefore, in the present study we investigated the molecular role of Gremlins in the aorta of SHHRs. Four-month-old male Sprague-Dawley rats and SHHRs were fed a normal diet or the HFDS ad libitum for 4 months. Then, gene and protein expression was analyzed using quantitative polymerase chain reaction and western blotting, respectively. Grem1 and Grem2 protein expression was increased, whereas phosphorylated Smad1/5 protein expression was low, in the aorta of SHHRs fed the HFDS. In addition, the expression of the downstream gene targets of BMP, namely inhibitor of DNA binding 1 (Id1) and atonal homolog 8 (Atoh8), was decreased in aortas of SHHRs fed the HFDS. Furthermore, mRNA expression of Snail, α-smooth muscle actin (αSMA), and Fibronectin was increased in SHHRs fed the HFDS. These findings suggest that upregulation of Gremlins attenuates the activation of BMP signaling, which contributes to fibrogenesis of the aorta

Investigation of Cell Migration and Invasion Using Real-time Cell Analysis, as well as the Association with Matrix Metalloproteinase-9 in Oral Squamous Cell Carcinomas

The recently developed technology of real-time cell analysis (RTCA) was designed to analyze cell migration and invasion in vitro. In this study, we investigated these cellular factors in oral squamous cell carcinomas (OSCCs) of the tongue and floor of the mouth with RTCA. We also examined the associated matrix metalloproteinases (MMPs) and integrins. We used the cell lines SCC-4 and SAS, which are human poorly differentiated OSCCs from the tongue, and HO-1-u-1, which are human poorly differentiated OSCCs from the floor of the mouth. Using RTCA, cell migration was assessed on fibronectin–coated CIM-Plates, and invasion was assessed on fibronectin- and matrigel-coated CIM-Plates. SCC-4 cells demonstrated a high ability for cell migration and invasion compared with SAS and HO-1-u-1 cells. The SCC-4 cells also expressed high levels of MMP-9 and integrin α1 mRNA compared with SAS and HO-1-u-1 cells. The MMP inhibitor Marimastat blocked migration and invasion of all OSCCs. The findings suggest that MMP-9 is associated with cell migration and invasion in OSCCs, and indicate that RTCA will be useful for analyzing the metastatic capability of OSCCs and developing more effective new drugs for this disease

Quantification of (–)-Epigallocatechin-3-gallate Inhibition of Anaplastic Thyroid Cancer Cell Line Adhesion and Proliferation Using Real-time Cell Analysis

Anaplastic thyroid cancer (ATC) has a poor prognosis because of immediate metastasis. Several studies in humans and animals have suggested that the ingestion of green tea or its active ingredient (–)-epigallocatechin-3-gallate (EGCG) may decrease the risk of cancer. Using a recently developed real-time cell analysis (RTCA) system, we have shown previously that EGCG inhibits cell migration and the invasion of oral cavity cancers by suppressing matrix metalloproteinases. In the present study we used RTCA to investigate the effects of EGCG on cell adhesion to fibronectin-coated plates using three cancer cell lines: one ATC cell line (TCO-1) and two poorly differentiated oral squamous cell carcinomas (OSCCs) cell lines (SAS and HO-1-u-1; originating from the tongue and floor of the mouth, respectively). EGCG (50µM) inhibited the adhesion of all three cell lines. In addition to its effects on cell adhesion, 50µM EGCG inhibited the cell proliferation of TCO-1 cells. Furthermore, EGCG decreased αV integrin (ITGAV) mRNA levels in all three cell lines, suggesting that EGCG inhibits the cell adhesion and proliferation of OSCC and ATC cells via suppression of integrin expression. Therefore, EGCG represents a useful dietary constituent or a lead compound for counteracting metastasis of oral cavity cancers and thyroid cancers