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Objectives The Three-Factor-Eating Questionnaire (TFEQ) is an established instrument to assess eating behavior in terms of dietary restraint, disinhibition and hunger. Methods The aims of this study were to examine (1) the correlation between eating behavior and body mass index (BMI), (2) the correlation between eating behavior and masticatory performance in terms of bite size and eating speed, and (3) the effects of gender on these correlations in 56 healthy subjects (33 males [21.9 ± 2.8 years old] and 23 females [21.7 ± 2.2 years old]). Results We found a significant correlation between restraint and BMI only in females and between hunger and BMI only in males. However, disinhibition and BMI were significantly correlated in both males and females. We also found a significant correlation between bite size and hunger only in males and between eating speed and disinhibition in both males and females. Conclusions These findings underline the importance of gender-specific counselling and behavioral treatment of obesity.

Oral infections, particularly periodontitis, are a well-established risk factor for cardiovascular diseases, although the molecular mechanisms involved remain elusive. The aims of the present study were to investigate the effects of lipopolysaccharide derived from Porphyromonas gingivalis (PG-LPS) on cardiac function in mice, and to elucidate the underlying mechanisms. Mice (C57BL/6) were injected with PG-LPS (0.8 mg/kg/day) with or without an inhibitor of Toll-like receptor 4 (TLR4) signaling (TAK-242, 0.8 mg/kg/day) for 4 weeks. Left ventricular ejection function was significantly decreased at 1 week (from 67 ± 0.5 to 58 ± 1.2 %) and remained low at 4 weeks (57 ± 1.0 %). The number of apoptotic myocytes was increased (approximately 7.4-fold), the area of fibrosis was increased (approximately 3.3-fold) and the number of 8-hydroxydeoxyguanosine-positive myocytes, a sensitive indicator of oxidative DNA damage, was increased (approximately 7.6-fold) at 4 weeks in the heart of PG-LPS treated mice. However, levels of various serum pro-inflammatory cytokines in PG-LPS-treated mice were similar to those in control mice. The impairment of cardiac function in PG-LPS-treated mice appears to involve activation of TLR4-NADPH oxidase (NOX) 4 signaling, leading to abundant production of reactive oxygen species and Ca2+ leakage from sarcoplastic reticulumn induced by calmodulin kinase II (CaMKII)-mediated phosphorylation of phospholamban (at Thr-17) and ryanodine receptor 2 (at Ser-2448). Pharmacological inhibition of TLR4 with TAK-242 attenuated the changes in cardiac function in PG-LPS-treated mice. Our results indicate that TLR4-NOX4 signaling may be a new therapeutic target for treatment of cardiovascular diseases in patients with periodontitis.

Objective Periodontitis (PD) is a chronic inflammatory disease of tooth-supportive tissue. An association between PD and cardiovascular disease (CVD) has been established. Although PD is generally accepted as a risk factor for CVD, the existence of a relationship remains debatable. Possible mechanisms include the release of inflammatory mediators such as lipopolysaccharide (LPS), which may spread systemically and promote CVD. Methods To compare the effects of lipopolysaccharide derived from Porphylomonas gingivalis (PG-LPS) on cardiac muscle in mice, mice were treated for 1 week with/without PG-LPS at a dose equivalent to the circulating level in PD patients (0.8 mg/kg/day). Results Cardiac function in terms of left ventricular ejection function was significantly decreased at 1 week compared to that in the control (from 66 ± 0.5% to 57 ± 1.1%). Compared to the controls, the number of apoptotic myocytes and the area of fibrosis were significantly increased by approximately 2.7-fold and 14-fold, respectively. The impairment of cardiac function appeared to involve the activation of cAMP/PKA signaling and cAMP/calmodulin kinase II signaling (CaMKII), leading to cardiac fibrosis, myocyte apoptosis and heart failure. Conclusions Our results indicate that cAMP/PKA and cAMP/CaMKII signaling may be a new therapeutic target for the treatment of cardiovascular diseases in patients with periodontitis.

The aim of this study was to determine whether early mobilization was associated with rehospitalization among elderly heart failure patients. We measured the time from admission to mobilization and other clinical characteristics for 190 heart failure patients (mean age, 80.7 years). The primary outcome was heart failure rehospitalization. Kaplan-Meier survival curves were plotted and the hazard ratios for rehospitalization were determined using Cox proportional hazards regression models. During a median follow-up period of 750 days, 58 patients underwent rehospitalization. The time from admission to mobilization was significantly longer for these patients than for those who were not rehospitalized. Univariate and multivariate Cox proportional hazards analyses showed that the time from admission to mobilization was an independent predictor of rehospitalization, and receiver-operating characteristic analysis determined an optimal cutoff value of 3 days for differentiating the patients more likely to experience a subsequent cardiac event (sensitivity, 76%; specificity, 69%; area under the curve, 0.667). Kaplan-Meier survival curve analysis showed a significantly lower event rate in the ≤ 3-day group (p = 0.001, log-rank test). In conclusion, the time from admission to mobilization may be one of the strongest predictors of rehospitalization in elderly heart failure patients. Early mobilization within 3 days may be an initial target for the acute phase treatment of heart failure.

Introduction: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is often used to diagnose pancreatic tumors. In rare cases, preoperative EUS-FNA can be complicated by gastric wall implantation of pancreatic cancer. Case presentation: A 66-year-old woman with pancreatic tail cancer underwent evaluation by EUS-FNA, followed by distal pancreatectomy and splenectomy. Twelve months postoperatively, a submucosal tumor was detected at the posterior gastric wall, at the location where the EUS-FNA was performed, and a boring biopsy from the submucosal tumor showed an adenocarcinoma. Therefore, we performed partial gastrectomy. Immunostaining results of the resected specimen were identical to those of the resected pancreatic cancer. The patient was diagnosed as having gastric wall implantation of pancreatic cancer due to EUS-FNA. Conclusion: This case emphasizes the importance of monitoring the site of EUS-FNA for gastric wall implantation of pancreatic cancer, and boring biopsy is a useful diagnostic tool.

Although cardiac sarcoidosis is associated with poor prognosis, diagnosis of the disease is challenging and the sensitivity and specificity of diagnostic modalities are limited. This study was performed to evaluate the potential of serum microRNAs (miRNAs) as diagnostic biomarkers for cardiac sarcoidosis.We performed genome-wide expression profiling for 2565 miRNAs (Human-miRNA ver.21) using peripheral blood samples from 5 patients with cardiac sarcoidosis (61±9 years) and 3 healthy controls (54±7 years). From this screening study, we selected 12 miRNAs that were significantly related to cardiac sarcoidosis. Next, we performed real-time polymerase chain reaction (PCR) on blood samples from 15 new patients with cardiac sarcoidosis and 4 healthy controls to quantify the expression of these 12 miRNAs.In the screening study, 12 miRNAs were differentially expressed (p0.01) in all 5 patients with cardiac sarcoidosis, showing greater fold-change values (4 or0.25) compared with the expression in the 3 healthy controls. Analysis of the real-time PCR for blood samples from the other 15 patients and 4 controls using Mann-Whitney U tests revealed that the expression of miR-126 and miR-223 was significantly higher in the patients than in the healthy individuals. However, there were no differences in the expressions of miRNA-126 and miR-223 between patients with only cardiac lesions and those with extra-cardiac lesions.Our results demonstrate the potential of serum miR-126 and miR-223 as new-generation biomarkers for the differential diagnosis of cardiac sarcoidosis in patients with heart failure.

The study aimed to identify factors related to bone mineral density (BMD) among older patients with heart failure (HF). A total of 70 consecutive patients with HF aged 65 years or older who were admitted to an acute hospital due to worsening condition were enrolled before discharge. BMD of the femoral neck was evaluated using the DEXA method. Physical function, as well as echocardiographic and laboratory findings including biomarker of HF severity were collected. Bivariate and multiple regression analyses were employed to determine the association between BMD and the clinical variables. Bivariate analysis determined that age, grip strength, walking speed, serum albumin, and N-terminal pro B-type natriuretic peptide (NT-proBNP) were significantly correlated with BMD (P

Tooth loss or incorrect positioning causes occlusal disharmony. Furthermore, tooth loss and atrial fibrillation (AF) are both risk factors for ischemic stroke and coronary heart disease. Therefore, we hypothesized that occlusal disharmony-induced stress increases susceptibility to AF, and we designed the present study to test this idea in mice. Bite-opening (BO) was done by cementing a suitable appliance onto the mandibular incisor to cause occlusal disharmony by increasing the vertical height of occlusion by 0.7 mm for a period of 2 weeks. AF susceptibility, evaluated in terms of the duration of AF induced by transesophageal burst pacing, was significantly increased concomitantly with atrial remodeling, including fibrosis, myocyte apoptosis and oxidative DNA damage, in BO mice. The BO-induced atrial remodeling was associated with increased calmodulin kinase II-mediated ryanodine receptor 2 phosphorylation on serine 2814, as well as inhibition of Akt phosphorylation. However, co-treatment with propranolol, a non-selective β-blocker, ameliorated these changes in BO mice. These data suggest that improvement of occlusal disharmony by means of orthodontic treatment might be helpful in the treatment or prevention of AF.

Occlusal disharmony leads to morphological changes in the hippocampus and osteopenia of the lumbar vertebra and long bones in mice, and causes stress. Various types of stress are associated with increased incidence of cardiovascular disease, but the relationship between occlusal disharmony and cardiovascular disease remain poorly understood. Therefore, in this work, we examined the effects of occlusal disharmony on cardiac homeostasis in bite-opening (BO) mice, in which a 0.7 mm space was introduced by cementing a suitable applicance onto the mandibular incisior. We first examined the effects of BO on the level of serum corticosterone, a key biomarker for stress, and on heart rate variability at 14 days after BO treatment, compared with baseline. BO treatment increased serum corticosterone levels by approximately 3.6-fold and the low frequency/high frequency ratio, an index of sympathetic nervous activity, was significantly increased by approximately 4-fold by the BO treatment. We then examined the effects of BO treatment on cardiac homeostasis in mice treated or not treated with the non-selective β-blocker propranolol for 2 weeks. Cardiac function was significantly decreased in the BO group compared to the control group, but propranolol ameliorated the dysfunction. Cardiac fibrosis, myocyte apoptosis and myocyte oxidative DNA damage were significantly increased in the BO group, but propranolol blocked these changes. The BO-induced cardiac dysfunction was associated with increased phospholamban phosphorylation at threonine-17 and serine-16, as well as inhibition of Akt/mTOR signaling and autophagic flux. These data suggest that occlusal disharmony might affect cardiac homeostasis via alteration of the autonomic nervous system.

Sympathetic activation causes clinically important arrhythmias including atrial fibrillation (AF) and ventricular tachyarrhythmia. Although the usefulness of β-adrenergic receptor blockade therapy is widely accepted, its multiple critical side effects often prevent its initiation or continuation. The aim of this study is to determine the advantages of vidarabine, an adenylyl cyclase (AC)-targeted anti-sympathetic agent, as an alternative treatment for arrhythmia. We found that vidarabine, which we identified as a cardiac AC inhibitor, consistently shortens AF duration and reduces the incidence of sympathetic activation-induced ventricular arrhythmias. In atrial and ventricular myocytes, vidarabine inhibits adrenergic receptor stimulation-induced RyR2 phosphorylation, sarcoplasmic reticulum (SR) Ca2+ leakage, and spontaneous Ca2+ release from SR, the last of which has been considered as a potential arrhythmogenic trigger. Moreover, vidarabine also inhibits sympathetic activation-induced reactive oxygen species (ROS) production in cardiac myocytes. The pivotal role of vidarabine's inhibitory effect on ROS production with regard to its anti-arrhythmic property has also been implied in animal studies. In addition, as expected, vidarabine exerts an inhibitory effect on AC function, which is more potent in the heart than elsewhere. Indexes of cardiac function including ejection fraction and heart rate were not affected by a dosage of vidarabine sufficient to exert an anti-arrhythmic effect. These findings suggest that vidarabine inhibits catecholamine-induced AF or ventricular arrhythmia without deteriorating cardiac function in mice.

A spontaneous external biliary fistula is most commonly a cholecystocutaneous fistula secondary to acute cholecystitis. A fistula arising from an intrahepatic duct is extremely rare. An 87-year-old man presented with swelling of the epigastric region and right upper quadrant abdomen. He had a history of cholecystectomy and endoscopic sphincterotomy. After antibiotic treatment and surgical opening of both lesions, abdominal computed tomography demonstrated a soft tissue mass cephalad to the umbilicus. We excised the mass, and found it to be associated with a fistula through the linea alba. Fistulography showed an abscess cavity communicating with the intrahepatic duct in segment III. Histopathological examination of the mass showed an abscess without malignancy. The fistula closed spontaneously without laparotomy. In this case, the underlying pathology was considered to be associated with a subcapsular hepatic cyst in segment III.

Neuroleptic malignant syndrome (NMS) with characteristic symptoms is a potentially lethal reaction to antipsychotic drugs. Atypical NMS usually lacks major symptoms and frequently occurs after treatment using atypical antipsychotics, such as aripiprazole. A 64-year-old man developed aripiprazole-induced NMS after surgery, and our early recognition of the NMS was based on high creatine kinase levels and low serum iron levels. His characteristic symptoms (a fever, rigidity, and altered mental status) were only present for a few hours and were resolved by aripiprazole discontinuation and supportive care. Aripiprazole-induced NMS can present with brief but major symptoms, and clinicians may overlook this "brief" appearance of NMS.

Background: Little is known about physiological anticoagulation effects via antithrombin III (AT III) and protein C/S (PC/PS) in patients using new oral anticoagulants (NOACs). Methods: We evaluated 120 consecutive patients with non-valvular atrial fibrillation (AF) receiving NOACs. Patients were randomly divided into three groups: a dabigatran group (DG, N=40), a rivaroxaban group (RG, N=40) or an apixaban group (AG, N=40). A warfarin group (WG, N=40) was matched with NOAC groups for age, sex and type of AF during the same time period. Blood samples were obtained in pretreatment, trough and peak phases to measure the activity of physiological coagulation inhibitors, including AT III and PC/PS or thrombus formation markers such as D-dimer and thrombin–antithrombin complex (TAT). Results: D-dimer, TAT and AT III values for the NOAC groups were equivalent in the peak and trough phases. PC/PS activity in both phases was equally maintained in the pretreatment phase in the NOAC groups, while the activity in the WG was significantly suppressed in steady state. Moreover, no differences in trends for PC/PS activity were observed among NOAC groups. Conclusions: PC/PS activity was constant in both peak and trough phases in the patients on NOACs compared with activity of those on warfarin. In addition, there was no difference in the findings among NOACs.

Background It has been suggested that protein directly activated by cAMP (Epac), one of the downstream signaling molecules of β-adrenergic receptor (β-AR), may be an effective target for the treatment of arrhythmia. However, there have been no reports on the anti-arrhythmic effects or cardiac side-effects of Epac1 inhibitors in vivo. Methods and Results: In this study, the roles of Epac1 in the development of atrial and ventricular arrhythmias are examined. In addition, we examined the usefulness of CE3F4, an Epac1-selective inhibitor, in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca2+ leak, a major trigger of arrhythmias, and spontaneous SR Ca2+ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca2+ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects. Conclusions These findings indicated that Epac1 is involved in the development of atrial and ventricular arrhythmias. CE3F4, an Epac1-selective inhibitor, prevented atrial and ventricular arrhythmias in mice.

Aim Bladder ruptures are commonly misdiagnosed as gastrointestinal perforations or intestinal ischemia. If a diagnosis is made preoperatively, conservative treatment is a safe and effective option. We evaluated the validity of using the attenuation value of ascites, measured by non-contrast computed tomography (CT), to identify patients with bladder ruptures. Methods A retrospective search of our hospital database identified 7 patients with confirmed bladder ruptures between 2007 and 2013. We also enrolled 18 patients with gastrointestinal perforations and 10 patients with intestinal ischemia with detectable ascites on abdominal CT that had undergone emergency exploratory laparotomy between 2007 and 2013. Between-group comparisons of attenuation values of ascites as obtained by non-contrast CT were evaluated. Results All attenuation values were less than 10 Hounsfield units (HU) in bladder rupture patients. Moreover, the attenuation value of ascites in cases of bladder rupture (median, 5.7; range, 3.1–6.1) was significantly lower than in cases of gastrointestinal perforation (median, 14.7; range, 4.7–25.4) and intestinal ischemia (median, 13.3; range, 6.0–18.1) (P = 0.004 for both comparisons). Conclusion Bladder rupture mimics gastrointestinal perforation and intestinal ischemia with acute kidney injury. Therefore, the diagnosis of bladder rupture using the attenuation value of ascites on non-contrast CT is both useful and highly significant. We suggest that bladder rupture be considered in the differential diagnosis of patients presenting with acute abdominal pain and attenuation values of ascites of less than 10 Hounsfield units.

Background and aims Omentin, an adipocytokine secreted by visceral adipose tissue, protects against obesity-linked cardiovascular complications. However, little is known about its role in epicardial adipose tissue (EAT) and coronary artery disease (CAD). We investigated the expression of omentin in EAT from CAD subjects. Methods EAT, subcutaneous adipose tissue (SCAT), and plasma samples were collected from CAD (n = 15; 23.3 ± 3.1 kg/m 2 ) and non-CAD patients (n = 10; 20.8 ± 3.9 kg/m 2 ). Omentin mRNA expression was measured using real-time PCR, while plasma concentrations were measured using an ELISA. EAT volume was determined with 64-slice computed tomography. Results Omentin expression in EAT and EAT volume were higher in CAD patients compared with controls (2.49 ± 2.6 vs . 0.85 ± 0.3, p = 0.002 and 113 ± 58 ml vs . 92.4 ± 30 ml, p = 0.045, respectively). Omentin expression in SCAT was similar between CAD and control patients (1.37 ± 0.84 vs . 1.07 ± 0.55, p = 0.267). Plasma omentin levels were lower in CAD patients compared with controls (343 ± 158 ng/ml vs . 751 ± 579 ng/ml, p = 0.025), and were negatively associated with the expression of omentin in EAT, in patients with CAD (β = −0.78, p = 0.049). On the other hand, there was no association between omentin in EAT and clinical variables in patients with non-CAD. Conclusions Omentin expression increases in the EAT of non-obese CAD patients, despite a decrease in plasma levels, suggesting that omentin may play a role in the pathogenesis of CAD.

Type 5 adenylyl cyclase (AC5) plays an important role in the development of chronic catecholamine stress-induced heart failure and arrhythmia in mice. Epac (exchange protein activated by cAMP), which is directly activated by cAMP independent of protein kinase A, has been recently identified as a novel mediator of cAMP signaling in the heart. However, the role of Epac in AC5-mediated cardiac dysfunction and arrhythmias remains poorly understood. We therefore generated AC5 transgenic mice (AC5TG) with selective disruption of the Epac1 gene (AC5TG-Epac1KO), and compared their phenotypes with those of AC5TG after chronic isoproterenol (ISO) infusion. Decreased cardiac function as well as increased susceptibility to pacing-induced atrial fibrillation (AF) in response to ISO were significantly attenuated in AC5TG-Epac1KO mice, compared to AC5TG mice. Increased cardiac apoptosis and cardiac fibrosis were also concomitantly attenuated in AC5TG-Epac1KO mice compared to AC5TG mice. These findings indicate that Epac1 plays an important role in AC5-mediated cardiac dysfunction and AF susceptibility.

Albuminuria is the most widely evaluated marker of kidney damage. Many previous studies have demonstrated an association between the presence of albuminuria and increased cardiovascular events. However, there are limited data regarding the impact of albuminuria in patients requiring coronary revascularization. This study investigated whether the urinary albumin excretion rate could predict cardiovascular events in such a population. We enrolled 698 consecutive patients who underwent elective percutaneous coronary intervention. The baseline urinary albumin-to-creatinine ratio (ACR; mg/gCr) was measured and patients were divided into those with normoalbuminuria (ACR30 mg/gCr), microalbuminuria (ACR 30 to 300 mg/gCr), or macroalbuminuria (ACR300 mg/gCr). We collected data on the incidences of cardiac death and/or nonfatal myocardial infarction. We identified 389, 230, and 79 patients with normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively. During follow-up (median: 1,564 days), 41 events occurred. The event-free survival rate was 89% in patients with macroalbuminuria, 92% in those with microalbuminuria, and 97% in those with normoalbuminuria, respectively (log-rank test p = 0.002). After adjustment for conventional risk factors, Cox analysis revealed hazard ratios for cardiac death and/or nonfatal myocardial infarction were 2.56 (95% CI 1.23 to 5.32, p = 0.01) in those with microalbuminuria and 4.02 (95% CI 1.59 to 10.12, p = 0.003) in those with macroalbuminuria compared with those with normoalbuminuria. In conclusion, an elevated urinary albumin excretion rate independently predicted adverse cardiovascular outcomes, with a gradual risk increase that progressed from microalbuminuria to macroalbuminuria in patients undergoing elective percutaneous coronary intervention.

An 80-year-old man who had undergone distal gastrectomy and Billroth-II gastrojejunostomy 38 years previously, for a benign gastric ulcer, was diagnosed with remnant gastric cancer based on upper gastrointestinal endoscopy findings. He presented at our emergency department with acute-onset epigastric pain due to perforated remnant gastric cancer. Conservative medical management was selected, including nasogastric tube insertion, antibiotics, and proton pump inhibitors, because his peritonitis was limited to his epigastrium and his general condition was stable. Twenty-one days after the perforation occurred, curative total remnant gastrectomy and D2 lymphadenectomy were performed. Adhesion between the lateral segment of the liver and the dissected lesser curvature of the gastric remnant may have contributed to the peritonitis in this case, which was limited to the epigastrium. This is the first report of perforated remnant gastric cancer in which conservative treatment was effective prior to curative resection. The protocol reported here may be of use to other clinicians who may encounter this clinical entity in their practices.

Although multiple factors influence food bite size, the relationship between food bite size per mouthful and mandible or tongue size remains poorly understood. Here, we examined the correlations between food bite size and the lower dental arch size (an indicator of tongue size) in human subjects with good oral and general health, using fish sausage and bread as test foods. Notably, bite size of both foods was significantly positively correlated with the lower dental arch size, whereas masticatory performance (measured in terms of glucose extraction from a gummy jelly) showed no dependence on bite size. Further, bite size was significantly positively correlated with the body mass index. Our findings suggest that larger bite size is associated with larger tongue size, which might be a contributory factor to obesity.

Objective Uninterrupted oral warfarin strategy has become the standard protocol to prevent complications during catheter ablation (CA) for the treatment of atrial fibrillation (AF). However, little is known about the safety and efficacy of uninterrupted dabigatran therapy in patients undergoing CA for AF. Therefore, this study investigated the safety and efficacy of uninterrupted dabigatran therapy and compared the findings with those for uninterrupted warfarin therapy. Methods Bleeding and thromboembolic events during the periprocedural period were evaluated in 363 consecutive patients who underwent CA for AF at Nagoya University Hospital, and received uninterrupted dabigatran (n=173) or uninterrupted warfarin (n=190) for periprocedural anticoagulation. Results A total of 27 (7%) patients experienced either bleeding or thromboembolic complications. Major bleeding complications occurred in 2 (1%) patients in the dabigatran group (DG) and 2 (1%) patients in the warfarin group (WG). Eight (5%) patients in the DG and 9 (5%) patients in the WG experienced groin hematoma, a type of minor bleeding complication. Meanwhile, no patient in the DG and 1 (1%) in the WG developed cerebral ischemic stroke. Overall, there was no significant difference between the groups for any category. The activated partial thromboplastin time (APTT) independently predicted periprocedural complications in the DG. Conclusion Uninterrupted dabigatran therapy in CA for AF thus may be a safe and effective anticoagulant therapy, and appears to be closely similar to continuous warfarin; however, it is essential to pay close attention to the APTT values when using dabigatran during CA.

A 76-year-old previously healthy Japanese man experienced severe diarrhea (8,000 mL per day) after undergoing laparotomy for small bowel obstruction and was diagnosed with Clostridium difficile infection. Although he developed a maculopapular rash secondary to the systemic absorption of enteral vancomycin (VCM), the patient was successfully treated with the continuous administration of VCM through a long intestinal tube placed in the terminal ileum. This method ensured the reliable delivery of VCM to the colon, while the continuous administration maintained high fecal levels of the drug. This treatment approach is an effective minimally invasive option for patients with severe diarrhea.

Introduction Apixaban, a factor Xa (FXa) inhibitor, is a new oral anticoagulant for stroke prevention in atrial fibrillation (AF). However, little is known about its efficacy and safety as a periprocedural anticoagulant therapy for patients who had undergone catheter ablation (CA) for AF. Methods and Results We evaluated 342 consecutive patients who underwent CA for AF between April 2013 and March 2014 and received apixaban (n = 105) and warfarin (n = 237) for uninterrupted periprocedural anticoagulation. We retrospectively investigated the occurrence of bleeding and thromboembolic complications during the procedural period and compared them between the apixaban group (AG) and warfarin group (WG). Thromboembolic complications occurred in one (0.4%) patient in the WG. Major and minor bleeding complications occurred in one (1%) and four (4%) patients in the AG, and three (1%) and 12 (5%) patients in the WG. No significant difference in complications was observed between the AG and WG. Of importance, adverse event rates did not differ between the two groups after adjusting by a propensity score analysis. In preoperative tests of blood coagulation, there were significant differences in the prothrombin time, activated partial thromboplastin time, FXa activity, and prothrombin fragment 1 + 2 (F1+2) levels between the AG and WG. Conclusion The use of apixaban during the periprocedural period of AF ablation seemed as efficacious and safe as warfarin.

Background Diabetic retinopathy has been identified as a predictor of cardiovascular events and heart failure in patients with diabetes mellitus (DM). This study aimed to assess the impact of diabetic retinopathy on the incidence of late cardiac events following percutaneous coronary intervention. Methods We enrolled 88 consecutive DM patients who underwent elective percutaneous coronary intervention and whose ophthalmologic records were available. Patients were divided into 2 groups: those with diabetic retinopathy (DR+ group; n = 47), and those without diabetic retinopathy (DR− group; n = 41). We examined the incidence of major adverse cardiac events (MACE) including cardiac death, myocardial infarction, and acute heart failure requiring emergency admission over a period of up to 5 years. Results Patients in the DR+ group were likely to have a lower estimated glomerular filtration rate. Kaplan–Meier analysis showed that the event-free survival rates for all MACE, myocardial infarction, and heart failure were significantly lower in the DR+ group than in the DR− group (p = 0.002, p = 0.025, and p = 0.022, respectively). Multivariate Cox proportional hazards analysis indicated that the presence of DR was a significant predictor of MACE (hazard ratio: 8.7; 95% CI: 1.1–69.8, p = 0.042). Conclusion The presence of DR might be a useful predictor of late cardiac events following percutaneous coronary intervention.

Clopidogrel loading is a standard method to achieve rapid platelet inhibition and prevent thrombotic events. At the current time, little information is available to determine the effect of adjunctive cilostazol compared with clopidogrel loading.We retrospectively analyzed 212 patients undergoing primary percutaneous coronary intervention with drug-eluting stents for ST-segment elevation acute myocardial infarction. All patients were administered aspirin (100 mg once a day) and clopidogrel (75 mg once a day). The patients were divided into two groups according to the presence (loading group, n = 100) or absence (cilostazol group, n = 112) of clopidogrel loading (300 mg). Patients in the cilostazol group were administered adjunctive cilostazol (100 mg twice a day) in place of clopidogrel loading. Patient characteristics, medications, and 30-day clinical outcomes were examined.The mean duration of cilostazol administration in the cilostazol group was 6.2 ± 4.9 days from the time of primary coronary intervention. No significant difference was observed in major adverse cardiac events (cardiac death, definite stent thrombosis, and non-fatal myocardial infarction) between the loading group and the cilostazol group (9/100; 9.0 vs. 8/112; 7.1%, p = 0.62). Definite stent thrombosis was observed for two patients in the loading group and one patient in the cilostazol group. The occurrence ratio of bleeding events did not differ significantly between the two groups (9.0 vs. 5.4%, p = 0.30).There was no significant difference in the incidence of major adverse cardiac events between temporary adjunctive cilostazol treatment and clopidogrel loading in ST-segment elevation acute myocardial infarction patients. Our findings suggest one potential of cilostazol.

Background: Adult T-cell leukemia/lymphoma (ATL) is a refractory peripheral T-cell malignancy caused by human T-lymphotropic virus type 1 (HTLV-1) infection. Although only allogeneic hematopoietic stem cell transplantation (allo-HSCT) displaying the graft-vs. ATL (GvATL) can bring durable remission, allo-HSCT is largely ineligible for newly diagnosed ATL patients due to disease aggressiveness and advanced age-related conditions. Thus, a novel treatment with safety and efficacy instead of allo-HSCT still remains an unmet need, and a cellular immunotherapy using TCR or CAR gene-modified immune cells exerting GvATL could be such an option. However, to generate those effector cells from autologous T cells of heavily pre-treated ATL patients faces many obstacles. To circumvent those hurdles, an employment of unconventional allogeneic Vγ9/δ2-T cells which are potentially free from the risk of GVHD could provide greater treatment opportunity for ATL patients due to highly extended donor availability. Taking above, here, we have newly devised an adoptive immunotherapy using a novel HTLV-1 p40Tax-specific TCR gene-modified allogeneic Vγ9/δ2 T cells against ATL. Methods: After written informed conscent, we firstly established novel HLA-A24 restricted TCR-α/β genes from HTLV-1 P40Tax301-309 (SFHSLHLLF)/HLA-A24 tetramer-positive peripheral CD8+T-lymphocytes of ATL patinets in durable remission using a single cell cloning method. Then, we confirmed that T cells gene-modified with these TCR-α/β genes exerted the epitope-specific and HLA-A24-restricted responses. Next, in order to achieve highly stable expression of this TCR-α/β heterodimer on gene-modified Vγ9/δ2-T cells, we newly developed a retroviral vector co-expressing TCR-α/β and CD8 α/β genes using self-cleaving P2A and E2A peptides. Using this vector, allogeneic Vγ9/δ2-T cells from healthy donors numerously expanded with high purity in our novel culture system were subjected to gene-transfer to express relevant TCR α/β complex. Thereafter, we asssessed target-reactive cytokine production and cytocidal activity mediated by those gene-modified allogeneic Vγ9/δ2-T cells both in vitro and in vivo. Finally, we additionally assessed a potential risk of GVHD using intravenous administration of another TCR gene-modified Vγ9/δ2 T-cells in vivo. Results: To start with PBMCs from healthy donors, allogeneic Vγ9/δ2-T cells were stably multiplied greater than thousandfold with a quite high purity (≥95%) using our novel bisphosphonate derivative PTA (tetrakis-pivaloyloxymethyl2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate) combined with both 25 ng/ml of IL-7 and IL-15 in culture for 8 to 10 days. The stable expression of introduced TCR α/β heterodimer on Vγ9/δ2-T cells were successfully achieved by co-expression of CD8 α/β molecule. Those gene-modified Vγ9/δ2-T cells successfully recognized target peptide (SFHSLHLLF) in an HLA-A24 restricted fashion, and similarly demonstrated a cytocidal activity both in vitro and in vivo against HLA-A24 positive HTLV-1 infected cell lines (TL-Su and ILT#Hod), but not HLA-A24-negtive/Tax-positive cell line ILT#37 or HLA-A24-positve/Tax-negative cell line ATN-1. Furthermore, intravenously administered those TCR gene-modified Vγ9/δ2-T cells quickly and durably eradicated luciferase-gene modified TL-Su cells, but not ATN-1 cells in xenografted immunodeficient (NOG) mice, examined by in vivo imaging system. Finally, infused HLA-A2 restricted and NY-ESO-1 specific TCR (G50) gene-modified Vγ9/δ2-T cells exerted durable antitumor activity without causing GVHD using NOG mice xenografted with HLA-A2 positive melanoma cell line cells (NW-MEL-38). Conclusions: Our preclinical observations here obviously demonstrated the potential utility of TCR-α/β gene-modified allogeneic Vγ9/δ2-T cells for the treatment of ATL without causing GVHD. Further studies regarding biological behaviors of HTLV-1 Tax specific TCR-α/β gene-modified allogeneic Vγ9/δ2-T cells following target recognition in vivo are warranted, however, based on these lines of evidence and currently conducting assessments using clinical samples, we are planning to launch a novel clinical trial, particularly focusing on the applicability of HLA partially matched relative donors, as the source of gene-modified allogeneic Vγ9/δ2-T cells, which could highly extend the donor availability. Disclosures Fujiwara: BrightPath Biotherapeutics, Co.,Ltd.: Other: member of the department endowed by BrightPath Bio. Okumura:BrightPath Biotherapeutics, Co.,Ltd.: Other: member of the department endowed by BrightPth Bio.. Miyahara:BirghtPath Biotherapeutics, Co., Ltd.: Other: member of the department endowed by BrightPath Bio.. Wan:BrightPath Biotherapeutics, Co., Ltd.: Other: member of the department endowed by BrightPath Bio.. Tawara:Astellas Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Shiku:BrightPath Biotherapeutics, Co., Ltd.: Other: Chair of the department endowed by BrightPath Bio..

Case An 88-year-old woman presented with abdominal pain, massive ascites, and acute kidney injury. She was clinically hypervolemic and the computed tomography attenuation value of the ascites was near that of water. Subsequent abdominocentesis revealed ammonia-smelling ascites fluid, leading to a suspicion of urinary tract injury, and a conclusive diagnosis of spontaneous bladder rupture was achieved using cystography. Outcome The patient was managed conservatively with antibiotics, percutaneous drainage, and bladder catheter. As a result, she was discharged with normal renal function. Conclusion The diagnosis of bladder rupture is difficult, and is rarely confirmed in the absence of a diagnostic suspicion. This case indicates that ascitic fluid odor, patient volume status, and the computed tomography attenuation value of ascites are potential indicators of bladder rupture.

systematic review. Circulation 2008;118:1828–36. [28] Kandzari DE, Berger PB, Kastrati A, et al. Influence of treatment durationwith a 600mg dose of clopidogrel before percutaneous coronary revascularization. J Am Coll Cardiol 2004;44:2133–6. [29] Claeys MJ, Van der Planken MG, Bosmans JM, et al. Does pre-treatment with aspirin and loading dose clopidogrel obviate the need for glycoprotein IIb/IIIa antagonists duringelective coronary stenting?A focus onperi-proceduralmyonecrosis. EurHeart J 2005;26:567–75. [30] Heestermans AA, van Werkum JW, Taubert D, et al. Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction. Thromb Res 2008;122:776–81. [31] Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009;373:723–31. [32] CannonCP,HarringtonRA, James S, et al. Comparisonof ticagrelorwith clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010;375:283–93. [33] Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–30. [34] Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial. Am J Cardiol 2007;100:1364–9. [35] Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008;51:690–7. [36] Doyle BJ, Ting HH, Bell MR, et al. Major femoral bleeding complications after percutaneous coronary intervention: incidence, predictors, and impact on longterm survival among 17,901 patients treated at the Mayo Clinic from 1994 to 2005. JACC Cardiovasc Interv 2008;1:202–9.

High low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol (L/H) ratio is associated with progressions of coronary arteriosclerosis and chronic kidney disease. On the other hand, renal function markedly declined after acute myocardial infarction (AMI). The aims of the present study were (1) to identify what type of patients with AMI would have high L/H ratio at follow-up and (2) to evaluate whether decline in renal function after AMI had accelerated or not in patients with high L/H ratio. The 190 eligible AMI patients who underwent primary percutaneous coronary intervention (PCI) and received atorvastatin (10 mg) were divided into one of two groups according to the L/H ratio at 6-month follow-up: L/H >2 group (n = 81) or L/H ≤2 group (n = 109). The characteristics on admission in the two groups were examined. Furthermore, changes in serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) during 1- and 6-month follow-up were compared between the two groups. L/H >2 group were significantly younger and had greater body mass index (BMI) and worse lipid profile on admission compared with L/H ≤2 group. Percentage increase in sCr and percentage decrease in eGFR during 1-month follow-up in L/H >2 group tended to be greater than in L/H ≤2 group, and those during 6-month follow-up were significantly greater (16.5 ± 2.77 vs. 9.79 ± 2.23 %, p = 0.03 and 11.8 ± 1.93 vs. 2.75 ± 3.85 %, p = 0.04, respectively). In AMI patients undergoing primary PCI, those who were young and had large BMI and poor lipid profile on admission were likely to have a high L/H ratio at follow-up despite statin therapy. In addition, the decline in renal function after AMI had significantly accelerated in patients with high L/H ratio.

To determine if the increase in transient focal enhancement of the liver adjacent to the gallbladder seen on dynamic computed tomography (CT) is greater in gangrenous cholecystitis than in nongangrenous cholecystitis by determining the CT attenuation value.We retrospectively reviewed the medical records of 57 patients who underwent emergency cholecystectomy for acute cholecystitis and preoperative dynamic CT scans between March 2011 and April 2016. Based on the pathology findings, patients were assigned to a gangrenous group or a nongangrenous group. The CT attenuation ratio (AR) was defined as the ratio of the maximum CT attenuation value in the region of interest in segment 5 (liver parenchyma adjacent to the gallbladder) and that in the control region of interest in segment 8. The patient characteristics and CT findings were compared between the groups. The appropriate AR of the arterial phase (ARAP) cutoff value for a diagnosis of gangrenous cholecystitis was determined using receiver operating characteristic curve analysis.The ARAP was significantly higher in the gangrenous group than in the nongangrenous group (P.001); the area under the receiver operating characteristic curve was 0.849. The ARAP cutoff value of 1.46 had a sensitivity and specificity of 84.6% and 83.9%, respectively (odds ratio, 21.17; 95% confidence interval, 4.90-118.91), and ARAP ≥1.46 was significantly correlated with a diagnosis of gangrenous cholecystitis (P.001).The increase in transient focal enhancement of the liver adjacent to the gallbladder during the arterial phase of dynamic CT was greater in gangrenous cholecystitis than in nongangrenous cholecystitis.

We previously investigated the utility of μ-oxo N,N′- bis(salicylidene)ethylenediamine iron (Fe(Salen)) nanoparticles as a new anti-cancer agent for magnet-guided delivery with anti-cancer activity. Fe(Salen) nanoparticles should rapidly heat up in an alternating magnetic field (AMF) and we hypothesized that these single-drug nanoparticles would be effective for combined hyperthermia-chemotherapy. Conventional hyperthermic particles are usually made of iron oxide and thus cannot exhibit anti-cancer activity in the absence of an AMF. We found that Fe(Salen) nanoparticles induced apoptosis in cultured cancer cells and that AMF exposure enhanced the apoptotic effect. Therefore, we evaluated the combined three-fold strategy, i.e., chemotherapy with Fe(Salen) nanoparticles, magnetically guided delivery of the nanoparticles to the tumor and AMF-induced heating of the nanoparticles to induce local hyperthermia, in a rabbit model of tongue cancer. Intravenous administration of Fe(Salen) nanoparticles per se inhibited tumor growth before the other two modalities were applied. This inhibition was enhanced when a magnet was used to accumulate Fe(Salen) nanoparticles at the tongue. When an AMF was further applied (magnet-guided chemotherapy plus hyperthermia), the tumor masses were dramatically reduced. These results indicate that our strategy of combined hyperthermia-chemotherapy using Fe(Salen) nanoparticles specifically delivered with magnetic guidance represents a powerful new approach for cancer treatment.

Summary Background Recent studies have reported that concomitant use of clopidogrel with proton-pump inhibitors (PPIs) might decrease antiplatelet effects and increase the risk of adverse outcomes after coronary stenting. However, little is known about the difference between clopidogrel and ticlopidine in concomitant use with PPIs, especially within the Asian population. Methods We retrospectively analyzed 302 consecutive patients (248 males, mean age 66 ± 12 years) undergoing primary stenting for acute myocardial infarction from July 2006 to June 2010. PPIs were administered to 92% (278/302) of the patients. The patients were divided into two groups on the basis of clopidogrel (clopidogrel group, n = 187) or ticlopidine (ticlopidine group, n = 91) with PPI. Their characteristics, medications, and 30-day clinical outcomes were examined. Results There were no significant differences in 30-day major adverse cardiac events (cardiac death, non-fatal myocardial infarction, and definite stent thrombosis), bleeding events, and stroke between the two groups. The discontinuation of clopidogrel due to side effects was significantly less frequent than that of ticlopidine (1.1% vs 7.7%, p = 0.003, respectively). Conclusion Our findings suggest that concomitant use of clopidogrel with PPIs might be safer than ticlopidine with PPIs in patients undergoing primary stenting for acute myocardial infarction.

Despite numerous discoveries from genetically engineered mice, relatively few have been translated to the bedside, mainly because it is difficult to translate from genes to drugs. This investigation examines an antiviral drug, which also has an action to selectively inhibit type 5 adenylyl cyclase (AC5), a pharmaceutical correlate of the AC5 knockout (KO) model, which exhibits longevity and stress resistance. Our objective was to examine the extent to which pretreatment with this drug, adenine 9-β-d-arabinofuranoside (Ara-A), favorably ameliorates the development of heart failure (HF). Ara-A exhibited selective inhibition for AC5 compared with the other major cardiac AC isoform, AC6, i.e., it reduced AC activity significantly in AC5 transgenic (Tg) mice, but not in AC5KO mice and had little effect in either wild-type or AC6Tg mice. Permanent coronary artery occlusion for 3 wk in C57Bl/6 mice increased mortality and induced HF in survivors, as reflected by reduced cardiac function, while increasing cardiac fibrosis. The AC5 inhibitor Ara-A significantly improved all of these end points and also ameliorated chronic isoproterenol-induced cardiomyopathy. As with the AC5KO mice, Ara-A increased mitogen/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation. A MEK inhibitor abolished the beneficial effects of the AC5 inhibitor in the HF model, indicating the involvement of the downstream MEK-ERK pathway of AC5. Our data suggest that pharmacological AC5 inhibition may serve as a new therapeutic approach for HF.

Cellular reactive oxygen species (ROS) production is increased by both temperature and anticancer drugs. Antioxidants are known to suppress ROS production while cancer patients may take them as dietary supplement during chemotherapy and hyperthermic therapy. We examined changes in ROS production in prostate cancer cells in the presence of various anticancer drugs and antioxidants at different temperatures. ROS production was increased with temperature in cancer cells, but not in normal cells; this increase was potently inhibited by ascorbic acid. ROS production was also increased in the presence of some anticancer drugs, such as vinblastine, but not by others. Dietary antioxidant supplements, such as β-carotene, showed variable effects. Ascorbic acid potently inhibited ROS production, even in the presence of anticancer drugs, while β-carotene showed no inhibition. Accordingly, our results suggest that cancer patients should carefully choose antioxidants during their cancer chemotherapy and/or hyperthermic therapy.

Cytochrome P450 (CYP) represents a large family of enzymes that catalyze the oxidation of endogenous and exogenous compounds. The functions of CYP enzymes in the metabolism of xenobiotics have well been established in the liver. However, some CYP enzymes are highly expressed in the heart and catalyze arachidonic acid oxidation to a variety of eicosanoids, which attenuates ischemia-reperfusion injury of the heart. CYP-mediated cardioprotection is associated with activation of multiple pathways such as sarcolemmal and mitochondrial potassium channels, p42/p44 MAPK and PI3K-AKT signaling in cells. CYP enzymes also represent a significant source of reactive oxygen species (ROS) that may target cellular homeostatic mechanisms and mitochondria. CYP isoforms expressed in the heart are critical for generation of epoxyeicosatrienoic acids (EETs) and ROS. It has been demonstrated that CYP2J2 generates cardioprotective EETs, whereas another isozyme in the heart, CYP2C, generates EETs as well as detrimental ROS. Genetic polymorphisms of CYP2C or CYP2J2 have a pathologic impact on coronary artery diseases. Cardiac CYP enzymes can be involved in drug metabolism within the heart and influence pharmacologic efficacy. Metabolism mediated by CYP enzymes influences the survival of cardiomyocytes during ischemia, which is critical for treatment of human ischemic heart disease. In this review, we summarize current knowledge of this enzyme family and discuss the roles of CYP in ischemia-reperfusion injury of the heart.

Cyclic AMP (cAMP) is known to play a major role in regulating cardiac function. Difference in adenylyl cyclase (AC) isoforms is a potential mechanism by which the cAMP signal, a common second messenger signal, can be regulated in a tissue-specific manner. However, the physiological significance of expressing multiple AC isoforms in a tissue and how each specific isoform regulates the cAMP signal remains poorly understood. In a genetically engineered mouse model in which the expression of the type 5 AC is knocked out (AC5KO), we identified the attenuation of autonomic regulation and calcium-mediated inhibition of cardiac function. We also identified that disruption of type 5 AC preserves cardiac function in response to chronic pressure-overload and catecholamine stress, at least in part, through the inhibition of cardiac apoptosis, which plays a major role in the development of heart failure. The protection against both apoptosis and development of cardiac dysfunction induced by left ventricular pressure overload in AC5KO makes this molecule potentially important for developing future pharmacotherapy, where suppressing the activity of type 5 AC, and not the entire β-adrenergic signaling (β-AR) signaling pathway, may have an advantage over the current β-AR–blockade therapy in the treatment of heart failure. Keywords:: cardiac adenylyl cyclase, knockout mouse, autonomic nervous system, heart failure, longevity, cardiac disease

Colors of plinian pumices were measured by spectrocolorimetry, and their quantitative color parameters in the L*a*b* color space were determined. A series of heating experiments of obsidian was conducted to simulate the color-change processes of rhyolitic glasses. In these experiments, following three stages of color-change processes were observed. Stage I showed a rapid b* (yellowishness) increase associated with fast dehydration controlled by water diffusivity (D water). In stage II, a* (reddishness) increase was accompanied by Fe2+ decrease. Both a* increase and Fe2+ decrease can be simulated by a diffusion model. Obtained diffusivity D oxidation were about two orders of magnitude smaller than D water . The a*-value increase after the oxidation in stage III appeared to be quasi-linear with time, indicating the zeroth order reaction corresponding to the formation of hematite-like structures in rhyolitic glasses. The diffusion-limited a* increase model in stage II was applied to a natural plinian pumice fall unit to evaluate time periods of color-change processes through oxidation by air of fragmented rhyolitic materials.

Obesity is well known to be associated with a wide variety of illnesses, and is an increasing problem not only in developed countries but also in developing countries. It is well known that large bite size contributes to excess energy intake and obesity, whereas an increased number of chews before swallowing the food bolus is associated with suppression of obesity. However, the effect of food diameter on bite size per mouthful and on chewing behavior remains poorly understood. Here, we examined the effects of food diameter on bite size and chewing behavior using a masticatory counter during the mastication of stick-type biscuits having the same length (10 cm) and ingredients, but with four different diameters (3.0, 3.5, 4.0, and 8.0 mm). Bite length and bite weight per mouthful were similar among the 3.0, 3.5, and 4.0 mm groups. However, bite length in the 8.0 mm group was significantly smaller, whereas bite weight was significantly greater than in the 3.0/3.5 mm groups. Further, the number of chews gradually increased, whereas the number of chews per bite weight gradually decreased, with an increase of biscuit diameter. These results indicate that a smaller biscuit diameter is associated with a smaller bite weight per mouthful and a greater number of chews per bite weight. This is the first report to quantity the effect of food diameter on bite weight per mouthful and on chewing behavior; these results should be helpful in the design of effective, safe, and low-cost behavioral modification therapy to combat obesity.

Close monitoring of intraoperative activated clotting time (ACT) is crucial to prevent complications during the periprocedural period of atrial fibrillation (AF) ablation. However, little is known about the ACT in patients receiving new oral anticoagulant agents (NOACs).The purpose of this study was to evaluate change in the ACT among anticoagulant agents used during the periprocedural period of AF ablation.We examined 869 consecutive patients who underwent AF ablation between April 2012 and August 2014 and received NOACs (n = 499), including dabigatran, rivaroxaban, and apixaban, or warfarin (n = 370) for uninterrupted periprocedural anticoagulation. Changes in intraprocedural ACT were investigated among the anticoagulant agents. Furthermore, the incidence of periprocedural events was estimated.The average time in minutes required for achieving a target ACT300 seconds was significantly longer in the dabigatran group (DG) and apixaban group (AG) than in the warfarin group (WG) and rivaroxaban group (RG) (60 and 70 minutes vs 8 and 9 minutes, respectively; P.001). In addition, the proportion of patients who achieved the target ACT after initial heparin bolus was significantly lower in the DG and AG than in the WG and RG (36% and 26% vs 84% and 78%, respectively; P.001). Furthermore, the incidence of periprocedural complications was equivalent among the groups.The average time required to reach the target ACT was longer in the DG and AG than in the WG and RG.

Dehydration experiments on basaltic, andesitic and dacitic glasses with 1.1, 0.7 and 1.0 wt.% total water, respectively, were performed at 400–675 °C and 0.1 MPa. The dehydration rates were measured by in situ infrared (IR) spectroscopy and modeled by assuming the diffusion of one component water (total water). The diffusivities of total water in basalt and dacite were found to be linearly dependent on total water contents, but that in andesite was weakly dependent on or independent of total water contents at water content and temperature ranges of this study. The total water diffusivities in basalt and dacite were determined by assuming the linear-dependent diffusivity on total water contents and that in andesite was obtained by assuming the constant diffusivity. The obtained diffusivities of total water D (μm2/s) can be expressed by the following equations: D Basalt = C / C 0 ⁢ exp ⁡ [ ( 20.2 ± 2.1 ) − ( 166,000 ± 13,000 ) / R ⁢ T ] D Andesite = exp ⁡ [ ( 12.4 ± 1.4 ) − ( 138,000 ± 10,000 ) / R ⁢ T ] D Dacite = C / C 0 ⁢ exp ⁡ [ ( 13.9 ± 0.9 ) − ( 133,000 ± 6000 ) / R ⁢ T ] , where C is the total water contents in weight percent; C0, reference total water contents of 1.1 and 1.0 wt.% for basalt and dacite, respectively; and T, temperature in Kelvin. These equations cover the temperature ranges of 400–575, 500–675 and 500–675 °C, and the water content ranges of

Kawabe, J; Okumura, S; Lee, MC; Sadoshima, J; Ishikawa, Y, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 286(5), H1845-H1852, 2004. "Copyright 2004 by the American Physical Society." publisher, Mechanical stress contributes to vascular disease related to hypertension. Activation of ERK is key to mediating cellular proliferation and vascular remodeling in response to stretch stress. However, the mechanism by which stretch mediates ERK activation in the vascular tissue is still unclear. Caveolin, a major component of a flasklike invaginated caveolae, acts as an adaptor protein for an integrin-mediated signaling pathway. We found that cyclic stretch transiently induced translocation of caveolin from caveolae to noncaveolar membrane sites in vascular smooth muscle cells (VSMCs). This translocation of caveolin was determined by detergent solubility, sucrose gradient fractionation, and immunocytochemistry. Cyclic stretch induced ERK activation; the activity peaked at 5 min (the early phase), decreased gradually, but persisted up to 120 min (the late phase). Disruption of caveolae by methyl-β-cyclodextrin, decreasing the caveolar caveolin and accumulating the noncaveolar caveolin, enhanced ERK activation in both the early and late phases. When endogenous caveolins were downregulated, however, the late-phase ERK activation was subsided completely. Caveolin, which was translocated to noncaveolar sites in response to stretch, is associated with β_1-integrins as well as with Fyn and Shc, components required for ERK activation. Taken together, caveolin in caveolae may keep ERK inactive, but when caveolin is translocated to noncaveolar sites in response to stretch stress, caveolin mediates stretch-induced ERK activation through an association with β_1-integrins/Fyn/Shc. We suggest that stretch-induced translocation of caveolin to noncaveolar sites plays an important role in mediating stretch-induced ERK activation in VSMCs.

The dehydration rate of hydrous rhyolitic glasses at 475–875 °C was measured by in situ infrared (IR) spectroscopy in order to determine the diffusion coefficient of water in rhyolitic glasses. The IR spectra of glass thin sections were obtained at 90-s intervals during 90 min at high temperatures, and the change in absorbance at 3550 cm−1 corresponding to total water was monitored. The diffusion coefficients obtained from dehydration rates of the rhyolitic glasses are considered to be averaged value over the water-concentration profile in the sample. The averaged apparent diffusion coefficients increase with the initial total water content from 0.20 μm2 s−1 for 0.7 wt% to 0.37 μm2 s−1 for 2.8 wt% at 700 °C. The apparent activation energy for the diffusion of total water decreases with increasing initial water content from 112 ± 6 kJ mol−1 for 0.7 wt% to 60 ± 17 kJ mol−1 for 4.1 wt%. Assuming a linear relation between the diffusion coefficient of total water and the total water content, the diffusion coefficients at each initial total water content were also determined. The diffusion coefficients of total water at the water contents of 0.7 and 1.9 wt% and at 0.1 MPa were best fitted by ln D=[(12.9 ± 0.8) − (111 500 ± 6400)/RT] and ln D=[(10.6 ± 0.4) − (86 800 ± 2800)/RT], respectively, and are in agreement with previous data (D in μm2 s−1, T in K). The present in situ IR dehydration experiment is a rapid and effective method for the determination of water diffusivity at high temperatures.

The sympathetic nervous system is designed to respond to stress. Adenylyl cyclase (AC) is the keystone of sympathetic transmission, yet its role in response to acute overload in the heart or in the pathogenesis of heart failure is controversial. We examined the effects of pressure overload, induced by thoracic aortic banding, in mice in which type 5 AC, a major cardiac AC isoform, was disrupted ( AC5 – / – ). Left ventricular weight/tibial length ratio (LVW/TL) was not different between the WT and AC5 – / – at baseline and increased progressively and similarly in both groups at 1 and 3 wk after aortic banding. However, LV ejection fraction (LVEF) fell in WT at 3 wk after banding (from 70 ± 2.8 to 57 ± 3.9%, P < 0.05), and this decrease was associated with LV dilatation, indicating incipient cardiac failure. In contrast, AC5 – / – mice did not exhibit a fall in LVEF from 74 ± 2.2%. The number of apoptotic myocytes was similar at baseline, but it increased roughly 4-fold in WT at both 1 and 3 wk after banding, and significantly less, P < 0.05, in AC5 – / – . Importantly, the increase in apoptosis occurred before the decline in LVEF in WT. The protective mechanism seems to involve Bcl-2, which was up-regulated significantly more in AC5 – / – mice with pressure overload. Our findings suggest that limiting type 5 AC plays a protective role in response to pressure overload and the development of heart failure, potentially through limiting the incidence of myocardial apoptosis.

This study aimed to examine the association between body mass index (BMI) and prognosis in heart failure patients after cardiac resynchronization therapy-defibrillator (CRT-D) implantation.We retrospectively investigated 125 patients (33 overweight [BMI ≥25 kg/m(2)], 75 normal weight [BMI 18.5-24.9 kg/m(2)], and 17 underweight patients [BMI18.5 kg/m(2)]) who underwent CRT-D implantation. The clinical outcome endpoints were all-cause death and appropriate shock therapy.During the follow-up period (mean 3.1 ± 1.8 years), 23 patients died (1 [3.0 %] overweight, 17 [22.7 %] normal weight, and 5 [29.4 %] underweight patients), and appropriate shock events were observed in 14 patients (2 [6.1 %] overweight, 10 [13.3 %] normal weight, and 2 [11.8 %] underweight patients). All patients survived shock therapy. After adjusting for confounding factors, overweight patients had significantly fewer outcomes relating to all-cause death and appropriate shock events (hazard ratio 0.27, 95 % confidence interval 0.08-0.91, p = 0.034) than normal weight patients. However, the prognostic difference between overweight and normal weight patients could be diminished as a result of the successful shock therapies (p = 0.067). Additionally, prognosis did not differ between overweight and normal weight patients among the responders, but did differ among the non-responders. The underweight patients had a poorer prognosis after CRT-D implantation compared with the other groups.Although high BMI was associated with better outcomes among heart failure patients with CRT-D implantations, the difference in the prognosis between overweight and normal weight patients was reduced because of defibrillator therapy and the improvement in cardiac function provided by CRT-D implantation.

Signaling via heterotrimeric G-protein is involved in the development of human diseases including ischemia-reperfusion injury of the heart. We previously identified an ischemia-inducible G-protein activator, activator of G-protein signaling 8 (AGS8), which regulates Gβγ signaling and plays a key role in the hypoxia-induced apoptosis of cardiomyocytes. Here, we attempted to intervene in the AGS8-Gβγ signaling process and protect cardiomyocytes from hypoxia-induced apoptosis with a peptide that disrupted the AGS8-Gβγ interaction. Synthesized AGS8-peptides, with amino acid sequences based on those of the Gβγ-binding domain of AGS8, successfully inhibited the association of AGS8 with Gβγ. The AGS8-peptide effectively blocked hypoxia-induced apoptosis of cardiomyocytes, as determined by DNA end-labeling and an increase in cleaved caspase-3. AGS8-peptide also inhibited the change in localization/permeability of channel protein connexin 43, which was mediated by AGS8-Gβγ under hypoxia. Small compounds that inhibit a wide range of Gβγ signals caused deleterious effects in cardiomyocytes. In contrast, AGS8-peptide did not cause cell damage under normoxia, suggesting an advantage inherent in targeted disruption of the AGS8-Gβγ signaling pathway. These data indicate a pivotal role for the interaction of AGS8 with Gβγ in hypoxia-induced apoptosis of cardiomyocytes, and suggest that targeted disruption of the AGS8-Gβγ signal provides a novel approach for protecting the myocardium against ischemic injury.