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Objectives: The aim of this study was to establish a minimally invasive and simple screening test for detection of pancreatic ductal adenocarcinoma (PDAC) using duodenal juice (DJ)., Methods: Duodenal juice was collected prospectively before endoscopic retrograde cholangiopancreatography in 46 patients. A protease inhibitor was not added to the samples collected during the initial 2.5 minutes but was added in the latter 2.5 minutes. Thereafter, secretin was administered intravenously, and DJ was subsequently collected for additional 10 minutes. The sensitivities of carcinoembryonic antigen (CEA), S100 calcium-binding protein P (S100P), and interleukin 8 in DJ and pancreatic juice were assessed., Results: There were 30 patients with PDAC and 16 with benign lesions. It was possible to collect an adequate amount of DJ without secretin administration. In the PDAC group, CEA concentrations in DJ were significantly higher than those in the benign group, even without the use of a protease inhibitor. S100P levels in DJ in the PDAC group were significantly higher than those in the benign group in the presence of the protease inhibitor., Conclusions: Duodenal juice collection during routine upper endoscopy and assessments of CEA and S100P in DJ might become a useful screening test for detection of PDAC.

Background: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is often found with distinct pancreatic ductal adenocarcinoma (PDAC) in the same pancreas. The aim of this study was to clarify whether endoscopic retrograde pancreatography (ERP) would be useful for the early detection of concomitant PDACs in patients with IPMNs., Methods: Medical records of 179 patients who were histologically confirmed to have IPMNs after resection between 1987 and 2011 were reviewed. The patients having concomitant PDACs were selected, and the diagnostic abilities to detect concomitant PDACs of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS), and ERP were compared between early (stages 0-I according to Japanese General Rules for Pancreatic Cancer) and advanced (stages II-IV) PDACs., Results: A total of 23 PDACs developed synchronously or metachronously in 20 patients, and the prevalence of PDACs concomitant with IPMNs was 11.2 % (20/179). Sensitivities of CT (16 vs. 87 %), MRI (29 vs. 93 %), and EUS (29 vs. 92 %) in the early group were significantly lower than those in the advanced group (p < 0.01). On the other hand, the sensitivity of ERP in the early group was as high as that in the advanced group (86 vs. 82 %, respectively, p > 0.99). Among 7 early PDACs, 3 were diagnosed only by ERP., Conclusions: ERP has an important role in the early diagnosis of distinct PDACs in patients with IPMNs. Further investigation is necessary to clarify the indication and the timing of ERP during management of IPMNs in term of early detection of concomitant PDACs.

Background/aims: Although adjuvant chemotherapy (AC) using gemcitabine improves the prognosis of patients with resectable pancreatic cancer, the effect of gemcitabine AC on the prognosis of patients with borderline resectable pancreatic cancer is not clear., Methodology: We analyzed the prognosis of patients with pancreatic cancer who underwent curative pancreatoduodenectomy or total pancreatectomy in combination with portal/superior mesenteric vein resection (PVR) [PVR (+) group] or without PVR [PVR(-) group]., Results: MST of the PVR (+) group was significantly shorter than that of the PVR(-) group (p=0.017). In contrast, when we focused on the patients with gemcitabine AC, there was no significant difference in MST between the PVR (+) and the PVR (-) groups (p=0.247). Furthermore, we compared MST of two subgroups in the PVR (+) group depending on gemcitabine AC status. In the PVR (+) group, MST of the patients with gemcitabine AC was significantly longer than that without gemcitabine AC (p=0.003). This was also true for the patients with pancreatic cancer which had histologically proven invasion to portal/superior mesenteric vein (PV/SMV) (p=0.001)., Conclusions: The prognosis of patients with pancreatic cancer invading PV/SMV can be improved by combination therapy with PVR and gemcitabine adjuvant chemotherapy.

Proper protein folding in the endoplasmic reticulum (ER) is vital in all eukaryotes. When misfolded proteins accumulate in the ER lumen, the transmembrane kinase/endoribonuclease Ire1 initiates splicing of HAC1 mRNA to generate the bZIP transcription factor Hac1, which subsequently activates its target genes to increase the protein-folding capacity of the ER. This cellular machinery, called the unfolded protein response (UPR), is believed to be an evolutionarily conserved mechanism in eukaryotes. In this study, we comprehensively characterized mutant phenotypes of IRE1 and other related genes in the human fungal pathogen Candida glabrata. Unexpectedly, Ire1 was required for the ER stress response independently of Hac1 in this fungus. C. glabrata Ire1 did not cleave mRNAs encoding Hac1 and other bZIP transcription factors identified in the C. glabrata genome. Microarray analysis revealed that the transcriptional response to ER stress is not mediated by Ire1, but instead is dependent largely on calcineurin signaling and partially on the Slt2 MAPK pathway. The loss of Ire1 alone did not confer increased antifungal susceptibility in C. glabrata contrary to UPR-defective mutants in other fungi. Taken together, our results suggest that the canonical Ire1-Hac1 UPR is not conserved in C. glabrata. It is known in metazoans that active Ire1 nonspecifically cleaves and degrades a subset of ER-localized mRNAs to reduce the ER load. Intriguingly, this cellular response could occur in an Ire1 nuclease-dependent fashion in C. glabrata. We also uncovered the attenuated virulence of the C. glabrata Δire1 mutant in a mouse model of disseminated candidiasis. This study has unveiled the unique evolution of ER stress response mechanisms in C. glabrata.

Background: Cardiac troponin is a specific biomarker for cardiomyocyte necrosis in acute coronary syndromes. Troponin release from the coronary circulation remains to be determined because of the lower sensitivity of the conventional assay. We sought to determine basal and angina-induced troponin release using a highly sensitive troponin assay., Methods and Results: The cardiac troponin T levels in serum sampled from the peripheral vein (PV), the aortic root (AO), and the coronary sinus (CS) were measured in 105 consecutive stable patients with coronary risk factor(s) and suspected coronary artery disease (CAD) and in 33 patients without CAD who underwent an acetylcholine provocation test. At baseline, there was a significant increase in the troponin levels from AO [9.0 (6.4, 13.1) pg/mL for median (25(th), 75(th) percentiles)] to CS [10.3 (7.3, 15.5) pg/mL, p<0.001] in 96 (91.4%) patients and the difference was 1.1 (0.4, 2.1) pg/mL, which reflected basal transcardiac troponin release (TTR). TTR was positively correlated with PV levels (r = 0.22, p = 0.03). Male sex, left ventricular hypertrophy determined by echocardiography, T-wave inversion, and CAD correlated with elevated TTR defined as above: median, 1.1 pg/mL. A significant increase in TTR was noted in 17 patients with coronary spasms [0.6 (0.2, 1.2) pg/mL, p<0.01] but not in 16 patients without spasms [0.0 (-0.5, 0.9) pg/mL, p = 0.73] after the acetylcholine provocation., Conclusion: Basal TTR in the coronary circulation was observed in most of the patients with suspected CAD and risk factor(s). This sensitive assay detected myocardial ischemia-induced increases in TTR caused by coronary spasms.

Pediococcus lolii NGRI 0510Q(T) was isolated from ryegrass silage produced on Ishigaki Island, Okinawa Prefecture, Japan. Here we present a draft genome sequence for this strain, consisting of 103 contigs for a total of 2,047,078 bp, 2,154 predicted coding sequences, and a G+C content of 42.1%.

Aim: The purpose of this study was to evaluate the feasibility and advantages of extensive distal pancreatectomy (ExDP)., Patients and Methods: We retrospectively analyzed our experience in 24 patients, who underwent ExDP or total pancreatectomy (TP) for the treatment of pancreatic cancer (22 patients) or benign tumor (two patients)., Results: ExDP was associated with less blood loss (p=0.0189), shorter operative times (p=0.024), lower rates of worsening of diabetes mellitus (p<0.0001), and shorter hospital stays (p=0.0009) than TP. ExDP also had a lower complication rate than TP (1/11 cases versus 4/13 cases), but this was not a significant difference. There was no difference in the curative resection rate for pancreatic cancer between the two procedures (p=0.685)., Conclusion: ExDP is a feasible and function-preserving operation for the treatment of pancreatic tumors in the body of the pancreas near the portal vein.

Background: Angina without significant stenosis, or nonobstructive coronary artery disease, attracts clinical attention. Microvascular coronary artery spasm (microvascular CAS) can cause nonobstructive coronary artery disease. We investigated the clinical features of microvascular CAS and the therapeutic efficacy of calcium channel blockers., Methods and Results: Three hundred seventy consecutive, stable patients with suspected angina presenting nonobstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test, with simultaneous measurements of transcardiac lactate production and of changes in the quantitative coronary blood flow. We diagnosed microvascular CAS according to lactate production and a decrease in coronary blood flow without epicardial vasospasm during the acetylcholine provocation test. We prospectively followed up the patients with calcium channel blockers for microvascular coronary artery disease. We identified 50 patients with microvascular CAS who demonstrated significant impairment of the endothelium-dependent vascular response, which was assessed by coronary blood flow during the acetylcholine provocation test. Administration of isosorbide dinitrate normalized the abnormal coronary flow pattern in the patients with microvascular CAS. Multivariate logistic regression analysis indicated that female sex, a lower body mass index, minor-borderline ischemic electrocardiogram findings at rest, limited-baseline diastolic-to-systolic velocity ratio, and attenuated adenosine triphosphate-induced coronary flow reserve were independently correlated with the presence of microvascular CAS. Receiver-operating characteristics curve analysis revealed that the aforementioned 5-variable model showed good correlation with the presence of microvascular CAS (area under the curve: 0.820). No patients with microvascular CAS treated with calcium channel blockers developed cardiovascular events over 47.8±27.5 months., Conclusions: Microvascular CAS causes distinctive clinical features and endothelial dysfunction that are important to recognize as nonobstructive coronary artery disease so that optimal care with calcium channel blockers can be provided., Clinical Trial Registration: URL: www.umin.ac.jp/ctr. Unique identifier: UMIN000003839.

Objectives: Branch duct intraductal papillary mucinous neoplasms of the pancreas (BD-IPMNs) often are composed of multifocal lesions. We aimed to clarify the clinicopathologic features of multifocal BD-IPMNs., Methods: Medical records of 211 patients with BD-IPMNs (169 solitary and 42 multifocal) were retrospectively analyzed. We compared the pathological grade of resected IPMNs and the resulting clinical course between solitary and multifocal BD-IPMNs., Results: Sixty-nine patients (54 with solitary and 15 with multifocal BD-IPMNs) underwent pancreatectomy, and of these patients, 62 exhibited at least 1 malignant predictor. There was no significant difference in the prevalence of malignancy in the resected BD-IPMNs between the 2 groups. In the remaining 142 patients who exhibited no malignant predictors, both groups demonstrated no differences in morphologic changes of BD-IPMNs. Seventeen distinct ductal carcinomas were identified in both groups, and there was no difference in the prevalence of ductal carcinoma between the 2 groups. Moreover, there was no significant difference in the disease-specific survival rate between the 2 groups., Conclusions: In patients with multifocal BD-IPMNs, resection is only warranted for lesions that exhibit malignancy predictors; moreover, closer attention to the potential presence or development of distinct ductal carcinoma in patients with multifocal and solitary BD-IPMNs is warranted.

The sporulation inhibitory gene spi in the pock-forming conjugative plasmid pSA1.1 of Streptomyces azureus was introduced into cells via a high or low copy number vector to examine the effect of gene dosage on the growth of Streptomyces lividans TK24 as a host. In transformants carrying a high spi copy number, nutrient mycelial growth was inhibited, as was morphological differentiation from substrate mycelium to aerial mycelium on solid media. The degree of inhibition depended on the spi gene dosage, but the presence of pSA1.1 imp genes, which encode negative repressor proteins for spi, relieved the inhibition. Confocal images of Spi tagged with enhanced green fluorescent protein in cells on solid media revealed that spi expression was initiated at the time of elongation of substrate mycelium, that its expression increased dramatically at septation in aerial hyphae, and that the expression was maximal during prespore formation. Expression of spi covered the whole of the hyphae, and the level of expression at the tip of the hyphae during prespore formation was about sixfold greater than during substrate mycelial growth and threefold greater than during aerial mycelial growth. Thus, localized expression of spi at particular times may inhibit sporulation until triggering imp expression to repress its inhibitory effects.

Background: A dilated orifice of the duodenal papilla found during screening endoscopy or ERCP is well-known as one of the specific findings of intraductal papillary mucinous neoplasm (IPMN). However, its clinical significance is still unclear., Objective: To assess the diagnostic significance of a dilated orifice of the duodenal papilla and evaluate whether this could be a factor predictive of malignancy or a subtype of IPMN., Design: Retrospective study., Setting: University hospital., Patients: This study involved 149 patients who underwent pancreatectomy for IPMN between January 1987 and June 2011., Intervention: ERCP., Main Outcome Measurements: The rate of malignant and intestinal type IPMNs in patients with and without papillary dilation., Results: A dilated orifice of the duodenal papilla was significantly associated with intestinal type IPMN (P < .001), but this finding could not predict the malignant grade of IPMN (P = .13). Multivariate analysis revealed that a dilated orifice was a significant factor for predicting intestinal type in both main duct (P = .01) and branch duct IPMNs (P < .001)., Limitations: The validity of the definition of papillary dilation, selection bias, and a retrospective study., Conclusion: A dilated orifice of the duodenal papilla could be a significant factor for predicting intestinal type IPMN. This may lead to better clinical management of patients with IPMN., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Background: The hedgehog (Hh) signaling pathway is aberrantly activated in many cancers. Overproduction of sonic hedgehog (Shh), a ligand in the Hh pathway, increases Hh signaling activity by inhibiting Patched-1 (Ptch1), a suppressive receptor in the Hh pathway. The purpose of this study was to establish a novel strategy for treating pancreatic cancer and other Hh-dependent cancers through control of the tumor-suppressive function of Ptch1., Methods: We synthesized seven interacting peptides to the amino-acid sequence of the Ptch1 docking site for Shh. Human pancreatic cancer cell lines (AsPC-1, SUIT2) were cultured in the presence or absence of the peptides. Cell proliferation was assessed by cell counting and by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The activity of the Hh pathway was estimated by real-time polymerase chain reaction of the target gene product Gli1. To confirm their anti-tumor activity in vivo, the effect of the peptides in a mouse model of pancreatic cancer was determined. Finally, the Hh signaling activity of the xenograft was examined., Results: Three of the interacting peptides to Ptch1 suppressed the proliferation of the two pancreatic cancer cell lines and decreased the expression of Gli1, both in vitro and in vivo., Conclusions: This study suggests that interacting peptides to Ptch1 may be a new tool for controlling the Hh-dependent growth of pancreatic cancer.

Background: The number of patients undergoing non-cardiac surgery has been increasing. Thus, the reduction of cardiac events is important during the perioperative period. The prevalence of Japanese patients with coronary vasospasm is higher as compared with Western countries. The present study reported the role of coronary vasospasm in the perioperative period in a Japanese university hospital., Methods and Results: A total of 77,745 consecutive patients who underwent non-cardiac surgery in Kumamoto University Hospital between April 2003 and March 2010 were retrospectively examined. Forty-two cases in which patients underwent coronary catheterization due to cardiovascular events in the perioperative period were reviewed, and data were collected on the type of surgery, urgency of surgery, cardiac risk factors, previous history and the cardiology consultation. The Revised Cardiac Risk Index (RCRI) was also calculated. A total of 18 patients were diagnosed as having definite vasospastic angina. In the definite vasospastic angina group, 9 patients had cardiovascular events intraoperatively. Six patients were in the group undergoing high-risk surgery. The RCRI score in the definite vasospastic angina group was 0.5±0.6 (mean±SEM), and only 2 patients had a preoperative consultation with a cardiologist., Conclusions: Coronary vasospasm is not often encountered, but it can be a cause of cardiac trouble in the perioperative period. It should be taken into consideration at the time of planning of operation in Japanese patients even if they apparently have low cardiac risk.

Background: International consensus guidelines for the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas provide several factors that can be used to predict which IPMNs will become malignant.The sensitivity of each factor's predictive accuracy, however, is relatively low, making it difficult to determine the appropriate treatment in individual cases. The aim of this study was to investigate whether increasing the number of predictive factors might augment the sensitivity of the established guidelines to detect malignant IPMNs., Methods: The medical records of 138 patients with IPMNs resected at our institution were reviewed. Possible malignant predictors were analyzed by univariate and multivariate analysis, and the effects of the number of factors and the predictive score of the pathologic results were examined. The cutoff points for the number of predictors to discriminate between malignant and nonmalignant IPMNs were established by constructing receiver operating characteristic curves., Results: A predictive analysis could not be carried out for the main duct IPMNs because of the high prevalence of malignancy and the small number of significant predictors associated with them. For malignant branch duct IPMNs, however, we identified 4 predictive factors that helped determine the correct diagnosis as follows: (1) the presence of a cyst ≥30 mm in diameter; (2) the presence of mural nodules; (3) a history of acute pancreatitis; and (4) atypical results of pancreatic juice cytology. An increase in the number of these factors significantly affected the sensitivity to predict malignancy. The area under the curve for the number of predictors for malignant branch duct IPMNs was 0.856, and the sensitivity and specificity were 96% and 71%, respectively, when the cutoff point was set at 2. The predictive scoring system also showed the same values of sensitivity and specificity for the number of factors., Conclusion: Patients with branch duct IPMNs who have 2 or more of the 4 predictive factors described above should undergo standard pancreatectomy with lymph node dissection, whereas patients who present with 0 or 1 predictive factor can be treated by minimal pancreatectomy without nodal dissection or by careful observation without resection. All patients with main duct IPMNs, therefore, should be treated with resection as suspected malignancies., (Copyright © 2012 Mosby, Inc. All rights reserved.)

The serine-threonine-specific protein phosphatase calcineurin is a key mediator of various stress responses in fungi. Herein, we characterized functions of the endogenous regulators of calcineurin (RCNs), Rcn1 and Rcn2, in the pathogenic fungus Candida glabrata. Rcn1 exerted both inhibitory and stimulatory effects on calcineurin signaling, but Rcn2 displayed only inhibitory activity. Phenotypic analyses of C. glabrata strains lacking either RCNs, calcineurin, or both revealed that calcineurin requires Rcn1, but not Rcn2, for antifungal tolerance in C. glabrata., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

We report a case of undifferentiated colon cancer treated with FOLFIRI therapy. A 69-year-old male had suffered from descending colon cancer. He underwent a left hemicolectomy with D3 dissection. Histopathologically, the tumor was undifferentiated carcinoma, and the cytology of ascites was positive. Peritoneal disseminations occurred soon after surgery, and these tumors did not respond to FOLFOX4 therapy. FOLFIRI therapy was employed, and it reduced the size of these tumors once. However, the therapy failed to control the tumor progression 2 months later. Although we started bevacizumab and S-1, the patient died 11 months after the operation. The present case demonstrates the efficacy of FOLFIRI therapy for undifferentiated colon cancer.

Tako-tsubo cardiomyopathy is characterized by transient left ventricular contractile dysfunction. The precise etiology of tako-tsubo cardiomyopathy remains to be elucidated. We performed coronary angiography in two patients with tako-tsubo cardiomyopathy and evaluated the coronary microcirculation by digital subtraction angiography (DSA). In the acute phase of tako-tsubo cardiomyopathy, coronary DSA demonstrated severely reduced perfusion in the apex. Follow-up DSA showed the restoration of normal myocardial perfusion in the apex. Coronary DSA can simultaneously depict the coronary vessels and myocardial perfusion abnormalities. Furthermore, DSA can also show the relationship between the perfusion territory of the coronary arteries and the region of impaired myocardial perfusion. This technique might support the central role of microcirculation disturbance in tako-tsubo cardiomyopathy.

Aim: We sought to evaluate the feasibility of the lateral approach for laparoscopic splenic vessel-preserving distal pancreatectomy (LA-SVPDP)., Background: Complete preservation of the splenic vessels is an ideal outcome in spleen-preserving distal pancreatectomy (SPDP). However, the preservation of the vessels is challenging in laparoscopic surgery because the splenic vein is often embedded in the pancreatic parenchyma. Herein we have described LA-SVPDP, the most feasible method for laparoscopic SPDP, and the outcome of our initial experience., Patients: Twenty-three patients underwent laparoscopic SPDP. Before we adopted LA-SVPDP, 8 patients underwent the Warshaw method and 6 underwent SVPDP. After the adoption of LA-SVPDP, 8 patients underwent LA-SVPDP and 1 donor underwent the Warshaw method., Results: None of patients undergoing LA-SVPDP required conversion to an open operation, whereas 2 patients undergoing the other procedures were converted to open operations. Five out of 8 patients who underwent the Warshaw method showed engorgement of the gastric veins, revealed by computed tomography. However, only 1 of the 5 patients showed mild gastric varices on endoscopy., Conclusion: Although the Warshaw method is acceptable with a low incidence of gastric varices in our analysis, SVPDP is a feasible approach for SPDP. Our LA-SVPDP technique may contribute to safer and easier SVPDP in laparoscopic surgery., (Copyright © 2011 Mosby, Inc. All rights reserved.)

In the pathogenic fungus Candida glabrata, the YPS1 gene, which encodes a glycosylphosphatidylinositol-linked aspartyl protease, is required for cell wall integrity and virulence. Although the expression of YPS1 has been studied in Saccharomyces cerevisiae, the transcriptional regulation of this gene in C. glabrata is not well understood. Here, we report that C. glabrata Yps1 is required for cell growth at elevated temperatures, and that the heat-induced expression of YPS1 is regulated predominantly by the calcineurin-Crz1 pathway and partially by the Slt2 MAPK pathway. Although a total of 11 YPS genes are present in the C. glabrata genome, the loss of transcriptional induction in a calcineurin mutant was observed only for YPS1. The results of a YPS1 promoter-lacZ reporter assay using a series of constructs with mutated promoter elements indicated that the transcription factor Crz1 binds to multiple sites in the promoter region of YPS1. To date, as none of the putative Crz1 targets in C. glabrata have been characterized using a Δcrz1 mutant, monitoring the expression of YPS1 represents an effective method for measuring the activity of the calcineurin-Crz1 signaling pathway in this fungus., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Background: Hypercholesterolemia is a risk factor for coronary artery disease and closely linked to unstable plaque. Hypoadiponectinemia is frequently observed in patients with metabolic syndrome complicated with macroangiopathy and predicts poor clinical outcome. Spectral analysis of intravascular ultrasonography radiofrequency (IVUS-Virtual Histology [VH]) allows quantitative analysis of plaque composition. The purpose of this study was to verify the effects of low-density lipoprotein (LDL) cholesterol level on plaque morphology, and test the hypothesis that adiponectin influences coronary plaque volume and composition., Methods: Preintervention IVUS-VH using a continuous pullback was performed in 92 coronary vessels in 92 patients with coronary artery disease. The morphological distribution of plaque was evaluated prospectively in a 60-mm segment of coronary vessels containing the culprit lesion., Results: Serum LDL cholesterol levels correlated positively with necrotic core volume (r = 0.217, P = 0.037) and percent necrotic core tissue (r = 0.308, P = 0.003), while plasma adiponectin levels correlated negatively with plaque volume (r = -0.297, P = 0.004) and necrotic core volume (r = -0.306, P = 0.003). Multiple regression analyses showed close association between necrotic core volume and statin-use (β = -21.68, P = 0.004) and adiponectin levels (β = -31.25, P = 0.038), and that percent necrotic core tissue was influenced by statin-use (β = -4.595, P = 0.026) and LDL cholesterol levels (β = 0.092, P = 0.031)., Conclusions: Adiponectin is closely linked to coronary plaque volume. Hypercholesterolemia and hypoadiponectinemia correlate with necrotic core lesions and may contribute to increased risk of coronary plaque vulnerability. Statins can affectively prevent necrotic core plaque formation associated with hypercholesterolemia and hypoadiponectinemia., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study investigated the clinical significance of plasma pentraxin 3 (PTX3) levels in patients with heart failure with normal ejection fraction (HFNEF) and whether PTX3 is produced from coronary circulation., Background: Pentraxin 3 is a novel inflammatory marker and a member of pentraxin superfamily including C-reactive protein (CRP). The relationship between inflammatory markers and HFNEF remains unclear., Methods: We measured peripheral blood levels of PTX3, high-sensitivity CRP, tumor necrosis factor-alpha, and interleukin-6 in 323 patients comprising 82 HFNEF, 70 heart failure (HF) with reduced EF, and 171 non-HF patients. Levels of PTX3 were also measured at the aortic root and the coronary sinus in 75 patients., Results: The levels of PTX3, tumor necrosis factor-alpha, and interleukin-6, but not high-sensitivity CRP, were significantly higher in HFNEF patients than in non-HF patients. Multivariate logistic regression analysis identified only high levels of PTX3 as the independent inflammatory marker correlated with the presence of HFNEF in patients with normal left ventricular (LV) EF (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.11 to 1.98, p < 0.01) and with the presence of left ventricular diastolic dysfunction (LVDD) in non-HF patients (OR: 1.23, 95% CI: 1.02 to 1.50, p < 0.05). Levels of PTX3 at the coronary sinus were significantly higher than at the aortic root in HFNEF patients (p < 0.05) and in non-HF patients with LVDD (p < 0.01), but not different in non-HF patients without LVDD (p = 0.33)., Conclusions: Pentraxin 3 is significantly elevated in HFNEF patients and produced in the coronary circulation in patients with LVDD. Pentraxin 3, but not high-sensitivity CRP, is an independent inflammatory marker correlated with the presence of LVDD and HFNEF. (The Clinical Significance of Plasma Pentraxin 3 levels for Patients with Diastolic Heart Failure; UMIN000002170)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: The Impact of Nicorandil in Angina (IONA) trial demonstrated that the use of nicorandil, an anti-anginal drug, reduced future cardiovascular events in patients with stable angina. We hypothesized that nicorandil has beneficial effects on coronary arterial plaque characteristics and atherosclerogenesis., Methods and Results: Preintervention intravascular ultrasound-virtual histology was performed prospectively in 65 consecutive patients with stable angina pectoris. There were no differences in coronary risk factors between the nicorandil (n = 16) and non-nicorandil (n = 49) groups. However, the nicorandil group demonstrated a larger %fibrous tissue (68 ± 10 vs. 62 ± 11%, P = 0.049) and a smaller %necrotic core tissue (11 ± 7 vs. 16 ± 10%, P = 0.049) compared with the non-nicorandil group. Multiple regression analysis showed that %necrotic core tissue (P = 0.045) was negatively and %fibrous tissue (P = 0.026) was positively associated with the use of nicorandil independent of statin use. We also analyzed the effect of nicorandil on atherosclerotic lesion formation in a mouse model of atherosclerosis. Lipid profiles were unaffected, but the area of atherosclerotic lesion and plaque necrosis were significantly reduced following 8-week nicorandil treatment in ApoE-deficient mice fed an atherogenic diet. Nicorandil significantly reduced the expression levels of endoplasmic reticulum stress markers, C/EBP homologous protein (CHOP) and glucose regulated protein/BiP (GRP78) in atherosclerotic lesions. Nicorandil significantly attenuated tunicamycin-induced CHOP upregulation in cultured THP-1 macrophages., Conclusions: Nicorandil exerts its anti-atherogenic effect by mechanisms different from those of statins. Long-term nicorandil treatment is a potentially suitable second-line prevention therapy for patients with coronary artery disease., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The Cica Fungi Test Candida is a novel immunoassay test that is used in Japan to detect Candida mannan antigens. A total of 130 samples from 89 cases in which the β-D-glucan assay (MK method) was positive were collected between July 2007 and August 2008 at Nagasaki University Hospital, and the Cica Fungi Test Candida and Cand-Tec were performed. Diagnosis of candidemia was based on a positive culture for Candida spp. from blood or other sterile clinical specimens. A total of 19 samples from 16 cases with candidemia, and 111 samples from 73 cases without microbiological evidence of candidemia, were obtained. The sensitivity and specificity of the Cica Fungi Test and Cand-Tec were 63.2 and 95.5%, and 52.6 and 50.5%, respectively. The Cica Fungi Test showed significantly higher specificity than Cand-Tec (P<0.01). The β-D-glucan assay values were significantly higher in the candidemia samples than in the non-candidemia samples (P=0.0003), a result that was well correlated with the Cica Fungi Test (P=0.0005). The Cica Fungi Test was thus found to be more reliable and specific than Cand-Tec, and the combined evaluation with the β-D-glucan assay was more efficient for diagnosis of candidemia.

Aim: Increased coronary plaque burden, which could be involved in the pathogenesis of atherothrombotic events, is difficult to evaluate in the three major coronary arteries. The purpose of this study was to quantify coronary plaque volume using 64-slice computed tomography (CT)., Methods: We measured coronary plaque volume with our new protocol in 23 consecutive patients (48% men; 66 ± 11 years old) who underwent cardiac CT for suspicion of coronary artery disease and had noncalcified plaques. We counted the total pixel volume of noncalcified plaques in the three major coronary arteries., Results: The coronary plaque volume was 1.29 ± 0.56 cm(3) in the right coronary artery, 1.29 ± 0.42cm(3) in the left main coronary artery and left anterior descending artery, and 0.88 ± 0.32 cm(3) in the left circumflex artery. The total coronary plaque burden (TCPB) was 3.45 ± 1.02 cm(3)/patient and had a positive correlation with waist circumference (r =0.44, p < 0.05) and insulin resistance (r = 0.46, p < 0.05). TCPB was significantly greater in men (3.89 ± 1.07 cm(3) vs. 3.06 ± 0.82 cm(3) in women, p < 0.05), patients with diabetes or impaired glucose tolerance (3.77 ± 0.94 cm(3) vs. 2.86 ± 0.92 cm(3) in non-diabetics, p < 0.05), and patients with metabolic syndrome (3.91 ± 0.95 cm(3) vs. 3.03 ± 0.91 cm(3) in patients without metabolic syndrome, p < 0.05)., Conclusions: Cardiac CT can provide a noninvasive assessment of TCPB, which was significantly associated with metabolic syndrome and its components. Measuring TCPB by CT could be an important strategy for identifying high-risk patients with suspected coronary artery disease.

Objectives: We sought to assess the association between inflammation in pericardial fat (PF) and coronary artery disease (CAD) by pathological examination and clinical evaluation with cardiac computed tomography (CT)., Background: Inflammation of adipose tissue is involved in cardio-metabolic disorders and shows high density in CT., Methods: We quantified, by immunohistochemical means, the PF inflammation in 39 autopsy cases by counting leukocyte common antigen (LCA)-positive cells. We then measured the CT density of PF in 39 patients with acute coronary syndromes and 69 patients suspected of CAD., Results: Pericoronary PF had significantly more LCA-positive cells in CAD autopsy cases (n=21) than non-CAD cases (n=18) (44 ± 21 vs. 24 ± 22 cells/mm(2), p=0.006). The CT density of PF around culprit lesions was significantly higher than non-culprit lesions in patients with acute coronary syndromes (-72 ± 11 vs. -82 ± 14 HU, p=0.002), which may reflect PF inflammation. Among patients suspected of CAD, the pericardial CT density gradient (PDG; difference in CT density between pericoronary PF and PF apart from coronary arteries) was significantly greater in CAD patients (n=30) than non-CAD patients (n=39) (22 ± 16 vs. 16 ± 10 HU, p=0.046). Multiple logistic regression analysis demonstrated that the PF inflammation index (PFI; PDG × PF volume, which could be the integrated index of inflammatory activity and abundance of PF) was significantly associated with the presence of CAD (odds ratio [95% confidence interval]; 1.234 [1.012-1.503] per 1000 HU cm(3), p=0.037) independent of other metabolic risk factors such as hypertension, dyslipidemia, and diabetes., Conclusions: Active inflammation in PF correlates with CAD. PF inflammation may be involved in pathogenesis of CAD., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Vacuum-assisted closure (VAC) therapy is increasingly applied for patients with wound dehiscence or mediastinitis caused by surgical site infection (SSI) after open-heart surgery. We have used wall suction for such cases in the past. But this method was an obstacle for improvement of the quality of life (QOL) of the patient. Since the S-B Vac is portable, this equipment may allow wound healing without decreasing QOL. Here, we report a case in which VAC therapy was performed using the S-B Vac.

Background: Doppler imaging of ophthalmic artery (OA), the first major branch of the internal carotid artery, provides anatomical advantages due to the vertical angle to the body surface and absence of ultrasonic obstacles. It was hypothesized that the Doppler waveform indices of OA correlate with severity of systemic atherosclerosis., Methods and Results: The study subjects were 180 patients who underwent cardiac catheterization and OA Doppler imaging (90 patients with coronary artery disease (CAD) and 90 control patients). The ratio of stroke volume to pulse pressure, an index of arterial compliance, was closely associated with the ratio of systolic to diastolic mean velocity (Sm/Dm) in OA. The level of Sm/Dm increased in proportion with the increase in number of stenosed coronary arteries (0-vessel disease 2.1+/-0.3, 1-vessel disease 2.3+/-0.3, multi-vessel disease 2.6+/-0.5, P<0.0001). The Sm/Dm level in OA correlated positively with age, pulse pressure, pulse wave velocity, resistive index and pulsatility index in OA. The best Sm/Dm cut-off to predict CAD was 2.3, and patients with Sm/Dm >2.3 had 8.0-fold risk for CAD., Conclusions: The waveform indices of OA are clinically useful for evaluating the severity of CAD and may help explain the missing link between OA circulation and systemic arterial compliance.

The Slt2 mitogen-activated protein kinase pathway plays a major role in maintaining fungal cell wall integrity. In this study, we investigated the effects of SLT2 deletion and overexpression on drug susceptibility and virulence in the opportunistic fungal pathogen Candida glabrata. While the Deltaslt2 strain showed decreased tolerance to elevated temperature and cell wall-damaging agents, the SLT2-overexpressing strain exhibited increased tolerance to these stresses. A mutant lacking Rlm1, a transcription factor downstream of Slt2, displayed a cell wall-associated phenotype intermediate to that of the Deltaslt2 strain. When RLM1 was overexpressed, micafungin tolerance was increased in the wild-type strain and partial restoration of the drug tolerance was observed in the Deltaslt2 background. It was also demonstrated that echinocandin-class antifungals were more effective against C. glabrata under acidic conditions or when used concurrently with the chitin synthesis inhibitor nikkomycin Z. Finally, in a mouse model of disseminated candidiasis, the deletion and overexpression of C. glabrata SLT2 resulted in mild decreases and increases, respectively, in the CFUs from murine organs compared with the wild-type strain. These fundamental data will help in further understanding the mechanisms of cell wall stress response in C. glabrata and developing more effective treatments using echinocandin antifungals in clinical settings.

Background: The involvement of the human platelet antigen (HPA)-15 system in neonatal alloimmune thrombocytopenia (NAIT) has been reported in various populations, but not in the Japanese population. In Japan, the mixed passive hemagglutination assay (MPHA) is used for detection of HPA alloantibodies. However, most of the reported cases of HPA-15 incompatibility are based on the monoclonal antibody immobilization of platelet antigen (MAIPA) assay or immunoprecipitation; thus there is a possibility that HPA-15 alloantibodies are not efficiently detected by the MPHA, and currently, the causative antibody is not detectable in approximately half of the suspected NAIT cases in Japan., Study Design and Methods: We examined the sera of mothers from NAIT cases, previously with undetected HPA antibodies by MPHA, using the MAIPA technique. Sera from 90 mothers of suspected NAIT were tested by MAIPA for the presence of anti-HPA-15 alloantibodies., Results: Anti-HPA-15b was detected in one case. This case was a mother in the first pregnancy diagnosed as hydatid mole-coexisting fetus, and the baby was born with suspected NAIT. The familial analysis revealed compatibility of HPA-15 genotype between the mother and the baby (both HPA-15a/a), but incompatibility with the paternal one (HPA-15a/b). The hydatid mole's tissue was genotyped as HPA-15b positive. Besides anti-HPA-15b, maternal sera contain strong HLA Class I antibody, Conclusions: Here we reported the first case of anti-HPA-15 in Japan. Alloimmunization against the hydatid mole seems to be responsible for the production of HPA-15b alloantibody. This antibody, however, did not apparently involve in the development of NAIT of the newborn, the coexisting anti-HLA Class I being the possible cause.

Objectives: We investigated the utility of digital reactive hyperemia peripheral arterial tonometry (RH-PAT) in predicting ischemic heart disease (IHD), including obstructive coronary artery disease (CAD) and nonobstructive coronary artery disease (NOCAD), in women., Background: IHD is the leading cause of mortality, and its pathogenesis is diverse in women. Fingertip RH-PAT is a new device that provides noninvasive, automatic, and quantitative evaluation of endothelial dysfunction., Methods: RH-PAT was measured using Endo-PAT2000 (Itamar Medical, Caesarea, Israel) before cardiac catheterization in 140 stable women scheduled for hospitalization to examine chest pain. NOCAD was diagnosed by angiography with measurement of coronary blood flow and cardiac lactate production during intracoronary acetylcholine provocation test and cardiac scintigraphy with stress tests., Results: Sixty-eight women (49%) had obstructive CAD and 42 women (30%) had NOCAD. RH-PAT indexes were significantly attenuated in both obstructive CAD and NOCAD as compared with non-IHD (n = 30) (obstructive CAD: median 1.57, interquartile range [IQR] 1.42 to 1.76; NOCAD: median 1.58, IQR 1.41 to 1.78; non-IHD: median 2.15, IQR 1.85 to 2.48, p < 0.001). By multivariate logistic regression analysis, only RH-PAT index was significantly associated with IHD, including obstructive CAD and NOCAD (odds ratio 0.51; 95% confidence interval: 0.38 to 0.68; p < 0.001). In receiver-operating characteristic analysis, RH-PAT index was a significant predictor of IHD (area under the curve 0.86; p < 0.001). Furthermore, only RH-PAT was useful for the prediction of NOCAD after excluding obstructive CAD (area under the curve 0.85; p < 0.001; RH-PAT index of <1.82 had 81% sensitivity and 80% specificity)., Conclusions: RH-PAT indexes were significantly attenuated in women with IHD. Digital RH-PAT can predict patients with IHD, especially NOCAD before angiography. RH-PAT is potentially useful for identifying high-risk women for IHD. (Endothelial Dysfunction and Coronary Artery Spasm; NCT00619294)., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to examine the association of pericardial fat with the presence of coronary plaques., Background: Waist circumference, reflecting abdominal obesity, is a risk factor of metabolic syndrome and coronary artery disease (CAD). Adipose tissue secretes many factors implicated in atherogenesis, however, the role of pericardial fat (ectopic visceral fat around coronary arteries) in the pathogenesis of CAD is not clear., Methods: We measured total pericardial fat volume (PFV) and determined presence and characteristics of coronary plaques using 64-slice computed tomography in 171 consecutive patients suspected of CAD (101 men; mean age, 66+/-11 years, +/-SD)., Results: PFV correlated with age (p<0.05), body mass index (p<0.05), waist circumference (p<0.01), and high-density lipoprotein cholesterol (p<0.01) by multivariate regression analysis. PFV was significantly larger in patients with coronary plaques, even nonstenotic or noncalcified ones, than those without plaques (any plaques, n=123; 201+/-71cm(3), nonstenotic plaques, n=51; 192+/-63, noncalcified plaques, n=32; 196+/-56 vs. no plaque, n=48; 144+/-45, p<0.001, respectively). Multivariate backward logistic regression analysis demonstrated that PFV, but not waist circumference, significantly associated with the presence of any coronary plaques (odds ratio [OR]; 2.876, 95% confidence interval [95% CI]; 1.614-5.125, p<0.001), nonstenotic plaques confirmed by coronary angiography (OR; 3.423, 95% CI; 1.764-6.642, p<0.001), and noncalcified plaques (OR; 3.316, 95% CI; 1.435-7.661, p<0.01)., Conclusions: PFV correlated significantly with the presence of nonstenotic and noncalcified coronary plaques assessed by multislice computed tomography. Pericardial fat is more highly associated with early development of CAD than simple anthropometric measures of abdominal obesity., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

A Candida glabrata calcineurin mutant exhibited increased susceptibility to both azole antifungal and cell wall-damaging agents and was also attenuated in virulence. Although a mutant lacking the downstream transcription factor Crz1 displayed a cell wall-associated phenotype intermediate to that of the calcineurin mutant and was modestly attenuated in virulence, it did not show increased azole susceptibility. These results suggest that calcineurin regulates both Crz1-dependent and -independent pathways depending on the type of stress.

Background: Renin-angiotensin-aldosterone system (RAAS) inhibitors are currently indispensable for the treatment of heart failure. It is well known that hyperkalemia is likely to occur in renal failure; however, it has not yet been clarified how the serum potassium concentration changes as heart failure progresses. Currently, the cardio-renal decompensation syndrome holds that the serum potassium concentration is altered similarly by both heart failure and renal failure; however, there are no definitive reports on this. In order to use RAAS inhibitors more safely and effectively in heart failure, it is necessary to understand the factors affecting serum potassium concentration in the clinical setting., Methods and Results: We examined the clinical factors affecting serum potassium concentration in 1035 consecutive patients with cardiovascular disease who were hospitalized in our institution. Multiple regression analysis showed that the independent factors associated with an elevated serum potassium concentration were renal insufficiency evaluated by estimated glomerular filtration rate (eGFR) (P<0.0001), diabetes mellitus evaluated by HbA(1c) (P=0.0005) and the use of RAAS inhibitors (P=0.0010). The independent factors associated with a decreased serum potassium concentration were mean blood pressure (P<0.0001), heart failure evaluated by log BNP (P=0.0164) and the use of diuretics (P=0.0232)., Conclusions: The serum potassium concentration decreases with the severity of heart failure if renal function is preserved. From the perspective of potassium homeostasis, we could use the RAAS inhibitors more aggressively in patients with heart failure who do not have renal failure., (Copyright (c) 2008 Elsevier Ireland Ltd. All rights reserved.)

Background: Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the pathogenesis of acute coronary syndrome. We have recently demonstrated that the administration of edaravone before reperfusion attenuated reperfusion injury in patients with acute myocardial infarction (AMI)., Methods: Plasma MCP-1 levels were measured in 45 consecutive patients with AMI (edaravone group, n=25; control group, n=20). In the edaravone group, 30 mg edaravone was intravenously infused just before reperfusion. Plasma samples were obtained before and at 24h, 3, 5, 7, and 14 days after reperfusion. Cardiovascular events were defined as cardiac death, subacute thrombosis, or fatal arrhythmia. Heart failure requiring rehospitalization was evaluated at 12 months after reperfusion., Results: Plasma MCP-1 levels were not different between the two groups before reperfusion. Compared with the placebo group, the edaravone group had statistically lower maximum creatine kinase-MB levels (218±31 IU/l versus 145±21 IU/l, p<0.05) and plasma MCP-1 levels on day 3 after reperfusion (873±118 pg/ml versus 516±66 pg/ml, p<0.05). Heart failure requiring rehospitalization occurred in four patients in the control group, but did not occur in the edaravone group (p<0.05). At 12 months after reperfusion, left ventricular ejection fraction was statistically higher in the edaravone group than in the control group (62±2% versus 54±3%, p<0.05)., Conclusion: Edaravone suppressed plasma MCP-1, improved left ventricular ejection fraction, and reduced rehospitalization due to heart failure. Suppression of plasma MCP-1 level by edaravone might induce better prognosis for AMI patients.

Various oxidative stress markers have been measured to evaluate the status of heart failure (HF). However, the relationships between these markers and the aetiology of HF have not been fully investigated. This study compared 8-hydroxy-2'-deoxyguanosine (8-OHdG) and biopyrrins levels in patients with ischemic and non-ischemic HF. Study subjects were divided into a coronary artery disease (CAD) group (n=70), a non-CAD group (n=61) and a control group (n=33). In the CAD group, 8-OHdG and biopyrrins levels increased with the severity of the New York Heart Association (NYHA) functional class and log BNP levels correlated with 8-OHdG and biopyrrins levels. However, non-CAD patients with NYHA class III/IV had significantly lower 8-OHdG levels than CAD patients with NYHA class III/IV and the levels did not correlate with log BNP levels. In the CAD group, 8-OHdG levels reflected the severity of atherosclerosis. These results indicate that the properties of oxidative stress markers should be carefully taken into consideration for the assessment of HF status.

A 76-year-old woman with a diagnosis of dilated-phase hypertrophic cardiomyopathy was admitted to our hospital for exacerbation of congestive heart failure. After admission, she developed cardiac arrest and the electrocardiogram showed pulseless electrical activity. Cardiopulmonary resuscitation was started immediately; however, return of spontaneous circulation was achieved 56 min after cardiopulmonary arrest. Therapeutic hypothermia was considered as an adjunct therapy, together with intensive treatment. The target temperature of 33.0 °C was achieved 10 h after cardiopulmonary arrest. Core temperature was maintained between 33.0 and 35.0 °C for 72 h with no cardiac arrhythmia detected during this period. Re-warming was initiated at a rate of 1 °C/day. On day 6, the core temperature returned to 37 °C and recovery of consciousness was achieved on day 9. No impairment of neurological function was noted. She had no heart failure-related symptoms and B-type natriuretic peptide level decreased from 4174 pg/mL on admission to 450 pg/mL at discharge. Therapeutic hypothermia may be a promising post-resuscitation therapy for comatose survivors of in-hospital cardiac arrest with non-ventricular fibrillation leading to improvement in neurological outcome.

A 64-year-old man presented with chronic cough. Chest CT revealed a nodular shadow with cavitation in the right S6. Seven months after his first examination, the nodular shadow had gradually increased, so flexible fiberoptic bronchoscopy was performed. The results of bronchial brushing and aspiration cytology were negative, however, gram-stained smear of the bronchial aspirate revealed many gram-positive rods with branching filamentous hyphae and culture of the bronchial aspirate was positive for the Actinomyces species. On a diagnosis of pulmonary actinomycosis, 1500 mg of oral amoxicillin was initiated. After 4 months of treatment, the right S6 nodule size was unchanged and the level of CYFRA in serum was elevated. Therefore, video-assisted thoracic surgery (VATS) was performed. A histological examination of the resected tumor showed papillary and acinar adenocarcinoma. The common radiological features in patients with pulmonary actinomycosis are nodules, mass formation and cavitation. Pulmonary actinomycosis requires differentiation from lung cancer. Although lung cancer with coexisting pulmonary actinomycosis is rare, clinicians should take into consideration the fact that lung cancer and pulmonary actinomycosis can co-exist in the same patient.

We report a long-term survival case of primary cardiac lymphoma with reversible ventricular tachycardia (VT) and complete atrioventricular block (C-AVB). A 65-year-old man with VT was treated by oral amiodarone administration. Later, a dual-chamber pacemaker was implanted because of C-AVB. Then, he was readmitted, as he complained of fever and chest pain. Echocardiography showed an enlarged cardiac mass and thus an open-chest biopsy was performed. He was then diagnosed with primary cardiac lymphoma. The chemotherapy and radiotherapy resulted in the disappearance of the mass. Complete remission has been maintained for 8 years after the therapy, and no VT or C-AVB has been detected.

Background: Undiagnosed diabetes mellitus (DM) and impaired glucose tolerance (IGT) have important health consequences., Methods and Results: To examine the prevalence of undiagnosed glucose intolerance, oral glucose tolerance tests were administered to 1,142 consecutively enrolled middle-aged subjects (age range 40-55 years; 914 men, mean 50.7 years; 228 women, mean 49.4 years) who worked in a company and underwent a health check in 2006. No subject had a history of glucose intolerance. Fasting glucose levels increased with age in both men and women, with the levels being higher in men than women at every age. Glucose intolerance was more common in men compared with women (fasting glucose 100.1 +/-19.7 vs 92.9 +/-9.6, P<0.01; 1-h 170.7 +/-52.1 vs 139.7 +/-11.6, P<0.01; 2-h 136.0 +/-50.1 vs 119.8 +/-31.5 mg/dl, P<0.01). The prevalence of IGT and DM was also higher in men than in women (IGT: 24.1 vs 16.7, P<0.01; diabetes 10.7 vs 1.4%, P<0.01)., Conclusions: Fasting glucose levels increased with age in both men and women, with levels being higher in men than in women at every age. The prevalences of undiagnosed IGT and type 2 DM were also higher in men than in women.

Background: The precise nature of the upper turnaround part of atrioventricular nodal reentrant tachycardia (AVNRT) is not entirely understood., Methods: In nine patients with AVNRT accompanied by variable ventriculoatrial (VA) conduction block, we examined the electrophysiologic characteristics of its upper common pathway., Results: Tachycardia was induced by atrial burst and/or extrastimulus followed by atrial-His jump, and the earliest atrial electrogram was observed at the His bundle site in all patients. Twelve incidents of VA block: Wenckebach VA block (n = 7), 2:1 VA block (n = 4), and intermittent (n = 1) were observed. In two of seven Wenckebach VA block, the retrograde earliest atrial activation site shifted from the His bundle site to coronary sinus ostium just before VA block. Prolongation of His-His interval occurred during VA block in 11 of 12 incidents. After isoproterenol administration, 1:1 VA conduction resumed in all patients. Catheter ablation at the right inferoparaseptum eliminated antegrade slow pathway conduction and rendered AVNRT noninducible in all patients., Conclusion: Selective elimination of the slow pathway conduction at the inferoparaseptal right atrium may suggest that the subatrial tissue linking the retrograde fast and antegrade slow pathways forms the upper common pathway in AVNRT with VA block.

Background and Aims: Juvenile haemochromatosis (JH) is an autosomal recessive iron disorder characterized by the early onset of secondary cardiomyopathy. The candidate modifier genes are hemojuvelin (HJV) and hepcidin antimicrobial peptide (HAMP). In the Japanese population, the prevalence of JH is quite low. The influence of HJV mutation on the JH phenotype is still unclear., Methods and Results: We searched for possible mutations in a Japanese family with 2 members who were JH patients with severe heart failure. To search for possible variants in the HJV and HAMP genes, we performed direct sequencing in the family members. A homozygous nonsense mutation in exon 4 of HJV (Q312X) was identified in the JH patients and their mother. Three individuals in the family were heterozygous for this mutation. Subsequently, we evaluated the frequency of Q312X mutation in a large population (n=361) without heart failure, using allele-specific real-time PCR assay. No Q312X mutation was detected in this population. In the patients with the homozygous HJV mutation, iron loading revealed high serum ferritin concentration with accompanying elevated transferrin iron saturation. In contrast, ferritin levels were within the normal range in individuals with the heterozygous mutation., Conclusions: We found a nonsense mutation in the HJV gene. This mutation elevates ferritin levels and leads to JH associated with severe cardiomyopathy.

Objective: To compare patient-weight-adjusted and fixed iodine-dose protocols at coronary computed tomography angiography (CTA) using a 64-detector scanner and computer-assisted bolus tracking., Materials and Methods: Approval from our institutional review board and patient prior informed consent were obtained before entering 60 patients with suspected coronary disease in this study. The patients were randomly assigned to one of 2 protocols. In the fixed iodine-dose protocol, they received a fixed dose of 80 mL Iopamidol-370; the injection duration was 20 seconds. In the weight-adjusted iodine-dose protocol, the dose was tailored to the patient body weight; this group received 1.0 mL/kg and the injection duration was shorter, ie, 15 seconds. Imaging was on a 64-detector CT scanner using a computer-assisted bolus tracking technique. A radiologist blinded to the protocol used measured the Hounsfield density number of the large vessels and coronary arteries. CT attenuation in the aortic root was compared in patients whose weight was less than 58 kg (group 1) or 58 kg or more (group 2). The standard deviation (SD) of CT attenuation in the aortic root and the myocardium was compared with evaluate image noise. Using a 3-point scale, 2 radiologists independently evaluated beam-hardening artifacts and coronary enhancement. Statistical analysis was with the two-tailed Student t test and the Mann-Whitney U test., Results: There was no significant difference between the protocols with respect to CT attenuation of the ascending aorta and coronary arteries. Under the fixed-iodine-dose protocol, mean CT attenuation in the aortic root was 421.3 +/- 51.5 Hounsfield unit (HU) in the lighter-, and 397.2 +/- 42.3 HU in the heavier weight group, respectively; the difference was statistically significant (P = 0.03). Under the weight-adjusted iodine-dose protocol, these values were 407.6 +/- 85.1 and 409.2 +/- 47.9 HU, respectively and the difference was not statistically significant (P = 0.17). The SD of the ascending aorta and myocardium was significantly higher for the fixed- than the weight-adjusted iodine-dose protocol. The mean visual score for beam-hardening artifacts was significantly lower in the weight-adjusted- than the fixed-iodine-dose protocol (P < 0.01), however, there was no significant difference in the enhancement of the coronary arteries (P = 0.82)., Conclusion: At 64-detector CTA of the heart, the patient weight-tailored dose protocol with the 15-second injection duration yielded significantly better image quality than the fixed-dose, 20-second injection duration protocol.

The prevalence of anemia in patients with heart failure (HF) increases according to disease severity as a consequence of renal insufficiency, cytokine production, plasma volume expansion, and/or malnutrition. B-type natriuretic peptide (BNP) has been recognized as a biochemical marker of ventricular dysfunction. The aim of this study was to evaluate the clinical significance of anemia in HF patients and furthermore, to investigate whether a significant correlation exists between anemia, BNP, and poor clinical outcomes in HF patients. We studied 185 consecutive HF patients. We assessed the occurrence of major adverse cardiac events (MACE) post hospital discharge. Anemia was defined as Hb concentrations <12.9 g/dl in men and <11.3 g/dl in women, respectively. Kaplan-Meier analysis revealed that anemia and high BNP levels (>259 pg/ml) were significantly associated with the occurrence of MACE. Multiple logistic analysis revealed that the most predictive independent risk factor for the occurrence of MACE was high BNP levels, followed by anemia (relative risk [RR] = 2.803 and 2.241, respectively). We divided the patients with or without anemia and high or low BNP levels into four groups according to their respective Hb and BNP levels. The hazard ratio for MACE in the group with anemia and high BNP levels was 10.3 in comparison to the group without anemia and with low BNP levels (P = 0.0002). Both anemia and high plasma levels of BNP are significantly and independently associated with the occurrence of MACE in HF patients; furthermore, the synergistic effect of anemia combined with high BNP levels significantly predicts an enhanced risk for MACE.

Mycobacterium malmoense is a very rare pathogen of pulmonary infectious disease in Japan. We encountered a case of M. malmoense infectious lung disease which could be cured by surgical operation without chemotherapy. M. malmoense strains were isolated in both the bronchial washing lavage and the removed lung specimen, and it were identified using 16S rRNA gene and rpoB gene sequencing. This case might indicate that pulmonary infectious disease caused by a rare non-tuberculous mycobacteria pathogen should be positively considered to be treated surgically as an initial therapy when the patient's condition is admissive, and also indicated the importance of identification of the causative pathogen from surgical specimens. In addition, this was the second report of M. malmoense infectious disease, and the first case of surgical treatment case of M. malmoense lung disease in Japan, as far as we could determine.

Introduction: Increased plasma levels of von Willebrand factor (VWF) have been reported in acute myocardial infarction (AMI). Recently, we showed reduced activity of a VWF-cleaving protease (ADAMTS13) in AMI patients. However, there is no information as to whether ADAMTS13 affects the pathogenesis of unstable angina (UA). Thus, the purpose of this study was to examine changes in plasma VWF and ADAMTS13 levels in UA patients., Materials and Methods: Plasma VWF and ADAMTS13 levels (mU/ml) were measured in 45 patients with UA, 55 with stable exertional angina (SEA) and 47 with chest pain syndrome (CPS) at the time of coronary angiography. Levels were also measured in 15 UA patients after 6 months of follow-up., Results: VWF antigen levels (mU/ml) increased significantly in UA patients compared with SEA or CPS (2129.3+/-739.5, 1571.8+/-494.2 and 1569.5+/-487.0, respectively; P < 0.0001 in UA vs. SEA or CPS). ADAMTS13 antigen levels (mU/ml) were significantly lower in UA patients than SEA or CPS (737.3+/-149.5, 875.3+/-229.0 and 867.7+/-195.5, respectively; P < 0.01 in UA vs. SEA or CPS). Furthermore, there was a significant inverse correlation between VWF and ADAMTS13 antigen levels (r = -0.302, P = 0.0002). The antigen levels at 6 months of follow-up were not different compared to the acute phase in the 15 UA patients that had repeated blood sampling., Conclusions: These findings suggest that there is prolonged thrombogenicity in UA patients represented as an imbalance between VWF and ADAMTS13 activity.

Endothelial dysfunction precedes the development of clinical atherosclerosis. A decrease in endothelium-derived nitric oxide activity shows impaired vasodilator function and causes arterial intimal hyperplasia or thickening. Others and we have reported the close relation of endothelial function in brachial artery and coronary artery. To compare the flow-mediated endothelium-dependent vasodilation (FMD) in brachial artery and the intima+media area in coronary artery, we measured brachial artery vasodilator response following transient occlusion with high resolution ultrasound transducer and intima+media area in coronary arteries with intravascular ultrasound in 25 patients with normal coronary angiograms (age 61.6+/-8.7 years old, men 14 and women 11). FMD was measured at least 7 days after the cessation of all vasodilators. The mean FMD of 25 patients was 3.83+/-2.38%, the mean intima+media area in coronary arteries of 25 patients was 39.9+/-15.5% of total vessel wall. FMD has a close negative relation with the largest percent intima+media area (r=-0.77, p<0.01). Especially, the patients whose FMD was less than 3.83% had larger percent intima+media area than those whose FMD was 3.83% or more (48.7+/-10.7% versus 30.3+/-14.2%, p<0.01). There is an intima+media thickening even in the patients who had normal coronary angiograms, and that the percent intima+media area correlated with FMD. The measurement of FMD is useful for screening the coronary artery intima+media thickening noninvasively. The pathogenesis of acute coronary syndrome has been reported to be the plaque rupture even in the patients with normal coronary angiograms. Thus, we must pay much attention in the patients with impaired FMD even in the normal coronary angiograms.

Objective: Coronary spasm plays an important role in the pathogenesis of variant angina and also ischemic heart diseases in general, and it is more likely to occur in angiographically normal coronary arteries than in stenotic coronary arteries. We previously found a -786T/C polymorphism in the 5'-flanking region of the endothelial nitric oxide synthase (eNOS) gene and reported that this polymorphism is associated with coronary spasm. We report on an investigation of the genetic factor(s) associated with coronary spasm utilizing a genome-wide case-control study., Methods and Results: We recruited 411 consecutive Japanese women (201 with coronary spasm; 210 controls) who were all underwent an acetylcholine provocation test. For single nucleotide polymorphism analysis (SNP), 116,204 SNPs were genotyped for 100 women (50 with coronary spasm; 50 controls) utilizing the Affymetrix GeneChip 100 K Set. Case-control studies were performed with 311 women (151 with coronary spasm; 160 controls) using the 10 lowest permutation P value SNPs from the initial SNP analysis. Finally, we discovered SNP rs10498345, a genetic marker for coronary spasm in Japanese women (Odds ratio=0.43, P=9.48x10(-7)). Haplotype analysis showed that haplotype H2, the only haplotype containing the protective A allele at SNP rs10498345, was most strongly associated with coronary spasm (permutation P value <1x10(-4)). SNP rs10498345 was strongly associated with the vasoconstrictor response to acetylcholine. Northern blot analysis revealed a novel 4.7 kb RNA transcript, which lacked poly (A), nearby SNP rs10498345., Conclusions: SNP rs10498345 was strongly associated with coronary spasm in Japanese women utilizing genome-wide SNP analysis.

Von Willebrand factor (VWF), a cofactor in platelet adhesion and aggregation, increases hemostasis and thrombosis. Recently, a metalloprotease that cleaves VWF multimers has been identified, namely ADAMTS13. The aim of this study was to investigate the relation between serial changes in plasma VWF and ADAMTS13 and the prognosis after acute myocardial infarction (AMI). We measured serial changes of plasma VWF and ADAMTS13 antigen levels in 92 patients with AMI and 40 control subjects. VWF levels were significantly higher in patients with AMI compared with controls (p <0.01) on admission, peaked 3 days after admission, and remained high for 14 days. In contrast, on admission, ADAMTS13 levels were significantly lower in patients with AMI compared with controls (p <0.0001), with minimum antigen levels reached after 3 days, and remained lower for 14 days. The ratio of VWF/ADAMTS13 antigen levels was higher in patients with AMI compared with controls throughout the time course. Cox hazards analysis revealed that the early increase of VWF and VWF/ADAMTS13 ratio levels and the early decrease of ADAMTS13 levels were significant predictors of future thrombotic events during the 1-year follow-up period. Kaplan-Meier analysis demonstrated that patients with major decreases of ADAMTS13 levels and high increases of VWF/ADAMTS13 levels had significantly greater probabilities for development of thrombotic events (p = 0.0104 and 0.0209, respectively). In conclusion, these findings suggest that monitoring the changes of VWF and ADAMTS13 antigen levels in the early phase might be valuable for predicting and preventing thrombosis during 1-year follow-up in patients with AMI.