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It has been previously shown that the positional isomers of triacylglycerol (TAG) containing palmitic acid (P) and highly unsaturated fatty acids (HUFAs) such as DHA (D) and EPA (E) vary between fishes and marine mammals. However, it has not yet been understood why in marine mammals HUFAs are located only at the α position when two palmitic acid chains combine, and not in fishes. In order to gain further understanding of the biosynthetic pathways involved in the formation of these asymmetric TAGs, we investigated whether the HUFA in the TAG of marine mammals exists predominantly at the sn-1 or sn-3 position. We examined the TAG positional isomers and enantiomers in marine organisms in detail. As a result, while PDP and PEP were not detected, sn-PPD and sn-PPE were found in abundance in marine mammals. For fishes, on the other hand, PDP, PEP, sn-PPD, and sn-PPE were all identified. In the case of TAGs that contain two HUFAs and one palmitic acid, marine mammals were rich in DPD and EPE whereas fishes were rich in sn-PDD and sn-PEE.

Background: Several reports have identified that decline in renal function and presence of proteinuria are closely associated with incidence of atrial fibrillation (AF). However, it is still unclear whether these kidney-related markers are associated with the progression of AF from paroxysmal to persistent form., Methods and Results: Among the new patients who visited the Cardiovascular Institute Hospital between 2004 and 2010 (Shinken Database 2004-2010, n=15,227), both estimated glomerular filtration rate (eGFR) and proteinuria were measured in 1074 AF patients (paroxysmal/persistent 579/495, respectively), who were divided into tertiles of eGFR (the borderlines were 60.07 and 73.67 ml[min(-1)]1.73[m(-2)], respectively), and then further divided into the two categories with/without proteinuria. The average value of eGFR was lower (63.1 ml[min(-1)]1.73[m(-2)] vs. 68.8 ml[min(-1)]1.73[m(-2)], p<0.001) and the detection rate of proteinuria was higher (13.7% vs. 8.5%, p=0.006) in patients with persistent AF than in those with paroxysmal AF, respectively. In the multivariate analysis without parameters of echocardiography [left ventricular ejection fraction (LVEF) and left atrial dimension (LAD)], both eGFR and proteinuria were independently associated with persistent AF, but the association was abolished when the model included LAD and LVEF., Conclusions: In the present analysis with cross-sectional design, both eGFR and proteinuria were apparently linked to the persistent form of AF, but their role in the pathogenesis does not seem to exceed the atrial stretch and remodeling, represented by LAD and LVEF., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Tobacco smoking is a well-known risk factor for cardiovascular disease, but controversial results have been reported regarding its relationship with atrial fibrillation (AF). Moreover, no study on the relationship between smoking and AF has yet been undertaken in a Japanese context., Methods and Results: We used data from the Shinken Database 2004-2011 (men/women, n=10,714/6,803, respectively), which included all new patients attending the Cardiovascular Institute between June 2004 and March 2012. AF was diagnosed in 1,698 and 598 men and women, respectively. In men, smokers were more prevalent in the AF than in the non-AF group (54.5% vs. 44.7%), whereas in women the prevalence of smokers was similar between AF and non-AF groups (14.4% vs. 15.4%). This discrepancy between the sexes seems to derive from a characteristic distribution pattern of smoking habit in women. After adjustment for various cofactors, smoking was independently associated with AF (odds ratio 1.54; 95% confidence interval 1.35-1.75; P<0.001) without a significant interaction between sex categories (P=0.195)., Conclusions: Smoking was independently associated with AF without a significant interaction between sex categories among Japanese patients visiting a cardiovascular hospital. Further studies using a prospective cohort design are required to confirm a causal link between smoking and AF in Japanese patients.

The mortality and morbidity of patients with stable angina pectoris (SAP) after percutaneous coronary intervention (PCI) in Japan differ from those in Western countries, although Japanese data are limited. We selected from the Shinken Database a single-hospital-based cohort of Japanese patients (n = 15,227) who visited The Cardiovascular Institute between 2004 and 2010 to undergo PCI. We followed-up the patients after PCI. A major adverse cardiac event (MACE) was defined as composite endpoints including all-cause death, acute myocardial infarction (AMI), and target-lesion revascularization (TLR). This study included 747 SAP patients (median follow-up period, 1,000 ± 703 days). The all cause mortality rate in SAP was 1.3% at 1 year, 2.7% at 3 years, and 6.1% at 5 years. The AMI rate was 0.5% at 1 year, 1.1% at 3 years, and 3.0% at 5 years, and the MACE rate was 14.0% at 1 year, 17.6% at 3 years, and 25.6% at 5 years. Moreover, new lesion PCI and heart failure admission continued to occur beyond 1 year after PCI without attenuation of their annual incidences up to 5 years. Multivariate analysis showed that poor left ventricular ejection fraction, chronic kidney disease (CKD), and absence of statin treatment were independent predictors of all-cause death of SAP patients after PCI. The results of the present study revealed the characteristics and long-term outcomes of Japanese SAP patients after PCI. The results of the present study suggest cardiorenal interaction and statin treatment play important roles in the long-term outcomes of Japanese CAD patients treated by PCI.

Clenbuterol, a β₂-adrenergic agonist, increases the hypertrophy of skeletal muscle. Insulin-like growth factor (IGF) is reported to work as a potent positive regulator in the clenbuterol-induced hypertrophy of skeletal muscles. However, the precise regulatory mechanism for the hypertrophy of skeletal muscle induced by clenbuterol is unknown. Myostatin, a member of the TGFβ super family, is a negative regulator of muscle growth. The aim of the present study is to elucidate the function of myostatin and IGF in the hypertrophy of rat masseter muscle induced by clenbuterol. To investigate the function of myostatin and IGF in regulatory mechanism for the clenbuterol-induced hypertrophy of skeletal muscles, we analysed the expression of myostatin and phosphorylation levels of myostatin and IGF signaling components in the masseter muscle of rat to which clenbuterol was orally administered for 21 days. Hypertrophy of the rat masseter muscle was induced between 3 and 14 days of oral administration of clenbuterol and was terminated at 21 days. The expression of myostatin and the phosphorylation of smad2/3 were elevated at 21 days. The phosphorylation of IGF receptor 1 (IGFR1) and akt1 was elevated at 3 and 7 days. These results suggest that myostatin functions as a negative regulator in the later stages in the hypertrophy of rat masseter muscle induced by clenbuterol, whereas IGF works as a positive regulator in the earlier stages., (Copyright © 2012 John Wiley & Sons, Ltd.)

IgM antibodies have been known for decades to enhance humoral immune responses in an antigen-specific fashion. This enhancement has been thought to be dependent on complement activation by IgM-antigen complexes; however, recent genetic studies render this mechanism unlikely. Here, we describe a likely alternative explanation; mice lacking the recently identified Fc receptor for IgM (FcμR) on B cells produced significantly less antibody to protein antigen during both primary and memory responses. This immune deficiency was accompanied by impaired germinal center formation and decreased plasma and memory B-cell generation. FcμR did not affect steady-state B-cell survival but specifically enhanced the survival and proliferation induced by B-cell receptor cross-linking. Moreover, FcμR-deficient mice produced far more autoantibodies than control mice as they aged, suggesting that FcμR is also required for maintaining tolerance to self-antigens. Our results thus define a unique pathway mediated by the FcμR for regulating immunity and tolerance and suggest that IgM antibodies promote humoral immune responses to foreign antigen yet suppress autoantibody production through at least two pathways: complement activation and FcμR.

Risk stratification for heart failure (HF) in patients with atrial fibrillation (AF) has not been well established. The aim of this study was to identify the predictors of HF events in patients with AF, consequently developing a new risk-scoring system that stratifies the risk for HF events. In this prospective, single hospital-based cohort, all patients who presented from July 2004 to March 2010 were registered (Shinken Database 2004-2009). Follow-up was maintained by being linked to the medical records or by sending study documents of prognosis. Of the 13,228 patients in the Shinken Database 2004-2009, 1,942 patients with AF were identified. Of the patients with AF, HF events (hospitalization or death from HF) occurred in 147 patients (7.6%) during a mean follow-up period of 776 ± 623 days. After identifying the parameters that were independently associated with the incidence of HF events (coexistence of organic heart diseases, anemia [hemoglobin level <11 g/dl], renal dysfunction [estimated glomerular filtration rate <60 ml/min/m(2)], diabetes mellitus, and the use of diuretics), a new scoring system was developed, the H(2)ARDD score (heart diseases = 2 points, anemia = 1 point, renal dysfunction = 1 point, diabetes = 1 point, and diuretic use = 1 point; range 0 to 6 points). This scoring system discriminated the low- and high-risk populations well (incidence in patients scoring 0 and 6 points of 0.2% and 40.8% per patient-year, respectively) and showed high predictive ability (area under the curve 0.840, 95% confidence interval 0.803 to 0.876). In conclusion, the new H(2)ARDD score may help identify the population of patients with AF at high risk for HF events., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Excessive apoptosis and prolonged inflammation of alveolar cells are associated with the pathogenesis of pulmonary emphysema. We aimed to determine whether CD40 affects alveolar epithelial cells and endothelial cells, with regard to evoking apoptosis and inflammation. Mice were repeatedly treated with agonistic-anti CD40 antibody (Ab), with or without agonistic-anti Fas Ab, and evaluated for apoptosis and inflammation in lungs. Human pulmonary microvascular endothelial cells and alveolar epithelial cells were treated with agonistic anti-CD40 Ab and/or anti-Fas Ab to see their direct effect on apoptosis and secretion of proinflammatory molecules in vitro. Furthermore, plasma soluble CD40 ligand (sCD40L) level was evaluated in patients with chronic obstructive pulmonary disease (COPD). In mice, inhaling agonistic anti-CD40 Ab induced moderate alveolar enlargement. CD40 stimulation, in combination with anti-Fas Ab, induced significant emphysematous changes and increased alveolar cell apoptosis. CD40 stimulation also enhanced IFN-γ-mediated emphysematous changes, not via apoptosis induction, but via inflammation with lymphocyte accumulation. In vitro, Fas-mediated apoptosis was enhanced by CD40 stimulation and IFN-γ in endothelial cells and by CD40 stimulation in epithelial cells. CD40 stimulation induced secretion of CCR5 ligands in endothelial cells, enhanced with IFN-γ. Plasma sCD40L levels were significantly increased in patients with COPD, inversely correlating to the percentage of forced expiratory volume in 1 s and positively correlating to low attenuation area score by CT scan, regardless of smoking history. Collectively CD40 plays a contributing role in the development of pulmonary emphysema by sensitizing Fas-mediated apoptosis in alveolar cells and increasing the secretion of proinflammatory chemokines.

Aims: To validate Echo Particle Image Velocimetry (PIV) METHODS: High fidelity string and rotating phantoms moving with different speed patterns were imaged with different high-end ultrasound systems at varying insonation angles and frame rates. Images were analyzed for velocity and direction and for complex motion patterns of blood flow with dedicated software. Post-processing was done with MATLAB-based tools (Dflow, JUV, University Leuven)., Results: Velocity estimation was accurate up to a velocity of 42 cm/s (r = 0.99, p < 0.001, mean difference 0.4 ± 2 cm/s). Maximally detectable velocity, however, was strongly dependent on frame rate and insonation angle and reached 42 cm/s under optimal conditions. At higher velocities estimates became random. Direction estimates did depend less on velocity and were accurate in 80-90%. In-plane motion patterns were correctly identified with three ultrasound systems., Conclusion: Echo-PIV appears feasible. Velocity estimates are accurate, but the maximal detectable velocity depends strongly on acquisition parameters. Direction estimation works sufficiently, even at higher velocities. Echo-PIV appears to be a promising technical approach to investigate flow patterns by echocardiography.

Background: The presence of heart failure (HF) with preserved ejection fraction (HFPEF) is increasingly recognized. However, prognostic factors for HFPEF remain unclear., Methods and Results: The data were derived from Shinken Database 2004-2010, a prospective cohort study (n=15,227). We examined 301 consecutive HFPEF patients (New York Heart Association Class II or greater) and tracked them for an average 3.5 years. Cardiopulmonary exercise testing (CPX), blood exams, and ultrasound cardiogram (UCG) were performed at the first medical examination. Acute decompensated HF (ADHF) admission was observed in 19 patients (6.3%). CPX showed that the anaerobic threshold was lower (7.3±4.8mL/min/kg vs. 9.7±4.3mL/min/kg, p=0.02) and slope of the increase in ventilation to the increase in CO(2) output (VE-VCO(2) slope) was higher (40.6±8.5 vs. 34.6±7.9, p<0.01) in patients with ADHF admission than those without. Serum brain natriuretic peptide (BNP) tended to be higher and left atrial (LA) dimension was significantly greater (47.0±15.8mm vs. 41.0±9.9mm, p=0.01) in patients with ADHF admission than those without. Multivariate analysis showed that higher VE-VCO(2) slope and greater LA dimension were independent determinants of ADHF admission., Conclusion: An aggravated CPX parameter and LA dilatation were associated with ADHF admission in patients with symptomatic HFPEF, suggesting the prognostic role of cardiopulmonary dysfunction during exercise and LA remodeling in the pathogenesis of decompensated HF development in HFPEF., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Ozone depletion increases terrestrial solar ultraviolet B (UV-B; 280-315 nm) radiation, intensifying the risks plants face from DNA damage, especially covalent cyclobutane pyrimidine dimers (CPD). Without efficient repair, UV-B destroys genetic integrity, but plant breeding creates rice cultivars with more robust photolyase (PHR) DNA repair activity as an environmental adaptation. So improved strains of Oryza sativa (rice), the staple food for Asia, have expanded rice cultivation worldwide. Efficient light-driven PHR enzymes restore normal pyrimidines to UV-damaged DNA by using blue light via flavin adenine dinucleotide to break pyrimidine dimers. Eukaryotes duplicated the photolyase gene, producing PHRs that gained functions and adopted activities that are distinct from those of prokaryotic PHRs yet are incompletely understood. Many multicellular organisms have two types of PHR: (6-4) PHR, which structurally resembles bacterial CPD PHRs but recognizes different substrates, and Class II CPD PHR, which is remarkably dissimilar in sequence from bacterial PHRs despite their common substrate. To understand the enigmatic DNA repair mechanisms of PHRs in eukaryotic cells, we determined the first crystal structure of a eukaryotic Class II CPD PHR from the rice cultivar Sasanishiki. Our 1.7 Å resolution PHR structure reveals structure-activity relationships in Class II PHRs and tuning for enhanced UV tolerance in plants. Structural comparisons with prokaryotic Class I CPD PHRs identified differences in the binding site for UV-damaged DNA substrate. Convergent evolution of both flavin hydrogen bonding and a Trp electron transfer pathway establish these as critical functional features for PHRs. These results provide a paradigm for light-dependent DNA repair in higher organisms.

Angiogenic homeostasis is maintained by a balance between vascular endothelial growth factor (VEGF) and Notch signaling in endothelial cells (ECs). We screened for molecules that might mediate the coupling of VEGF signal transduction with down-regulation of Notch signaling, and identified B-cell chronic lymphocytic leukemia/lymphoma6-associated zinc finger protein (BAZF). BAZF was induced by VEGF-A in ECs to bind to the Notch signaling factor C-promoter binding factor 1 (CBF1), and to promote the degradation of CBF1 through polyubiquitination in a CBF1-cullin3 (CUL3) E3 ligase complex. BAZF disruption in vivo decreased endothelial tip cell number and filopodia protrusion, and markedly abrogated vascular plexus formation in the mouse retina, overlapping the retinal phenotype seen in response to Notch activation. Further, impaired angiogenesis and capillary remodeling were observed in skin-wounded BAZF(-/-) mice. We therefore propose that BAZF supports angiogenic sprouting via BAZF-CUL3-based polyubiquitination-dependent degradation of CBF1 to down-regulate Notch signaling.

Background: The characteristics and prognosis of patients with first-detected atrial fibrillation (AF) in Japan remain unclear., Methods and Results: First-detected AF patients without structural heart disease (n=289) were reviewed with regard to 2 symptom classifications (CCS-SAF and EHRA). In both classifications, asymptomatic patients comprised ≈40% of the patients, and patients in the most symptomatic class (≈6%) had peculiar characteristics and poor prognosis. In other symptomatic classes, symptoms affected the treatment strategy without a significant difference in the patients' backgrounds and prognosis., Conclusions: This is the first report to describe the distribution, characteristics and outcomes of first-detected AF patients according to symptom classifications.

Left ventricular outflow tract obstruction (LVOTO) is commonly observed in patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy (LVH). While some patients develop LVOTO at rest, it can also be provoked by physical exertion, and hence termed latent LVOTO (L-LVOTO). Recent reports demonstrated that L-LVOTO develops not only in LVH patients, but also in patients without LVH (non-LVH). However, the prevalence and clinical prognosis of non-LVH patients with L-LVOTO are not yet elucidated. In this study, we retrospectively investigated the echocardiographic features of patients with malignancy who underwent dobutamine stress echocardiography (DSE) to evaluate preoperative cardiac risk. One hundred ninety-nine patients were found not to have LVH or coronary artery disease. Among them, 106 patients exhibited L-LVOTO after DSE. We next compared the baseline echocardiographic features of L-LVOTO (+) patients with those of L-LVOTO (-) patients, and identified the left ventricular outflow tract (LVOT) ratio (systolic LVOT diameter/diastolic LVOT diameter) as a significant predictor of L-LVOTO. An LVOT ratio ≤ 0.83 was the best cutoff value to detect the presence of L-LVOTO, with a sensitivity of 81.1% and specificity of 80.6%. Overall, L-LVOTO was found to develop in almost half of non-LVH patients with malignancy. In addition, the baseline LVOT ratio was strongly related to the presence of L-LVOTO in non-LVH patients. Therefore, patients with dynamic LVOT narrowing may benefit from DSE to detect the presence of L-LVOTO.

Background: Although various kinds of cardiovascular risk factors have been reported to be associated with atrial fibrillation (AF), the relationship between serum uric acid level and AF has not been fully examined., Methods and Results: Data were collected from a single hospital-based cohort in the Shinken Database 2004-2008 (n=11,123), and consisted of serum uric acid level for 7,155 patients. The association between serum uric acid level and AF prevalence was evaluated on logistic regression. Uric acid significantly increased the crude AF prevalence in both men and women (both, P<0.001). The odds ratio (OR) and 95% confidence interval (95%CI) in the highest tertile compared with the lowest one were 3.368 (2.478-4.578) and 1.408 (1.169-1.695) in women and men, respectively. Uric acid was also significantly associated with other various cardiovascular risk factors for AF. Even after the multivariate model was adjusted using these variables, the effect of uric acid on AF was independent in women (OR, 1.888; 95%CI: 1.278-2.790), but not in men., Conclusions: Reflecting the composite of various cardiovascular risk factors, serum uric acid level was apparently associated with AF prevalence. The independent association in women might imply some sex-specific mechanisms. The results should be confirmed in prospective studies.

Background: The distribution of activated partial thromboplastin time (APTT) in nonvalvular atrial fibrillation (NVAF) patients under dabigatran therapy remains to be clarified., Methods and Results: The study population was 196 NVAF patients who were treated with dabigatran in 2011 (126 with 220 mg/day). The APTT values showed a wide distribution among the patients, especially in those with a reduced dose, who seemed to show a high value even in patients without contraindications., Conclusions: We found a wide distribution of APTT in NVAF patients under dabigatran treatment. High APTT might help screen for bleeding risks among patients under dabigatran, but requires future investigation.

Background: In Japan, the recent status of the mortality of atrial fibrillation (AF) patients is still unclear., Methods and Results: We used a single-hospital based cohort database in an urban city (Tokyo) in Japan, including all the new visitors from 2004 to 2009 (n=13,228). The non-adjusted death rates of AF patients for all-cause, stroke, and cardiovascular death were 1091, 97, and 727 per 100,000 patient-years, and the age-adjusted ones were 317 (95% CI, 316-318), 16 (95% CI, 16-16), and 238 (95% CI, 237-239), respectively. The age-adjusted relative risk of AF on all-cause mortality was 1.7 in the particular population., Conclusions: The present study provides the most recent data about the characteristics and the mortality of AF patients in Tokyo, thus serving as the basic information for finding problems to solve regarding Japanese AF patients., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Radiation exposure induces acute myeloid leukemia (AML) in humans and mice. Recent studies postulated that AML stem cells of spontaneous human AML arise from hematopoietic stem cells. However, other studies support the possibility that short-lived committed progenitors transform into AML stem cells, accompanied by a particular gene mutation. It remains unclear whether AML stem cells are present in radiation-induced AML, and information regarding AML-initiating cells is lacking. In this study, we identified and analyzed AML stem cells of mice with radiation-induced AML. The AML stem cells were identified by transplanting 100 bone marrow cells from mice with radiation-induced AML. We injected 100 cells of each of seven cell populations corresponding to different stages of hematopoietic cell differentiation and compared the latencies of AMLs induced in recipient mice. The identified radiation-induced AML stem cells frequently displayed similarities in both CD antigen and gene expression profiles with normal common myeloid progenitors. The number of common myeloid progenitor-like AML stem cells was significantly increased in mice with radiation-induced AML, but the progeny of common myeloid progenitors was decreased. In addition, analysis of radiation effects on the hematopoietic system showed that common myeloid progenitor cells were extremely radiosensitive and that their numbers remained at low levels for more than 2 months after radiation exposure. Our results suggest that murine radiation-induced AML stem cells arise from radiosensitive cells at a common myeloid progenitor stage.

Photocurrents of a ruthenium dye-TiO(2) system are enhanced by gold nanoparticles (100 or 40 nm diameter) embedded in TiO(2). As dye-particle spacing decreases to 10 nm, enhancement factor and intensity of localized electric fields at the TiO(2) surface increase. A further decrease in the spacing suppresses the enhancement.

Genetic polymorphisms have recently been found to be related to clinical outcome in septic patients. The present study investigated to evaluate the influence of genetic polymorphisms in Japanese septic patients on clinical outcome and whether use of genetic polymorphisms as predictors would enable more accurate prediction of outcome. Effects of 16 genetic polymorphisms related to pro-inflammatory mediators and conventional demographic/clinical parameters (age, sex, past medical history, and APACHE II score) on ICU mortality as well as disease severity during ICU stay were examined in the septic patients (n=123) admitted to the ICU between October 2001 and November 2007 by multivariable logistic regression analysis. ICU mortality was significantly associated with TNF -308GA, IL1β -31CT/TT, and APACHE II score. Receiver-operating characteristics (ROC) analysis demonstrated that, compared with APACHE II score alone (ROC-AUC=0.68), use of APACHE II score and two genetic parameters (TNF -308 and IL1β -31) enabled more accurate prediction of ICU mortality (ROC-AUC=0.80). Significant association of two genetic polymorphisms, TNF -308 and IL1β -31, with ICU mortality was observed in septic patients. In addition, combined use of these genetic parameters with APACHE II score may enable more accurate prediction of outcome in septic patients., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

CXCR4 expression is critical for localization of centroblasts in the dark zone of germinal centers (GCs), and centrocytes downregulate CXCR4 and thus leave the dark zone to reside in the light zone. However, mechanisms governing CXCR4 downregulation on centrocytes are not known. In this study, we show that the amount of intracellular CXCR4 in centroblasts was similar to that in centrocytes, suggesting differential control of CXCR4 protein expression in these GC B cells. Restimulation of activated B cells with IL-21, which is a major cytokine produced by T follicular helper cells, accelerated CXCR4 internalization by inducing endocytosis-related GRK6 expression. Although CXCR4 expression was downregulated on GC B cells by IL-21 stimulation, CXCR4(low) centrocytes developed in the spleens of IL-21R-deficient mice, suggesting other mechanisms for downregulation. The level of CD63 (which recruits CXCR4 to late endosome in CD4 T cells) in centrocytes was more than that in centroblasts and was strikingly elevated in activated Bcl6-deficient B cells. Bcl6, a transcriptional repressor, was detected on the chromatin of the CD63 gene in resting B cells, therefore CD63 is a molecular target of Bcl6. Downregulation of CD63 mRNA in activated Bcl6-deficient B cells by small interfering RNA upregulated CXCR4 expression on the B cells. Furthermore, addition of Bcl6 inhibitor to activated B cell cultures increased CD63 mRNA expression in (and downregulated CXCR4 expression on) those activated B cells. Thus, CXCR4 can be downregulated on activated B cells by IL-21-induced endocytosis and CD63-mediated endosomal recruitment, and these mechanisms may contribute to downregulation of CXCR4 on centrocytes.

Background: The effect of early statin initiation on secondary prevention remains uncertain in unselected Japanese populations with coronary artery disease (CAD)., Methods: We investigated the mortality and morbidity in CAD patients according to presence or absence of statins within 3 months after the diagnosis of CAD in the Shinken Database cohort study. The primary endpoint was all-cause mortality., Results: Data were available on 789 Japanese patients with CAD (male 78.8%). Among those, 351 patients (44.5%) received a statin. The mean (SD) baseline low-density lipoprotein (LDL)-cholesterol levels were 113.6 (35.7) mg/dL in the statin group and 113.6 (26.4) mg/dL in the non-statin group (p=0.992). Unadjusted 2-year survival in patients with or without statins was 98.4% and 92.1%, respectively (p<0.001). Among a prespecified subgroup of patients undergoing percutaneous coronary intervention (PCI) (n=238 with statins and n=183 without statins), a consistent effect of statins on 2-year survival was observed (98.5% and 90.9%, respectively, p<0.001). However, there was no significant difference in 2-year target lesion revascularization-free survival (77.9% in statins versus 73.7% in non-statins, respectively, p=0.298). The age- and gender-adjusted survival in the PCI subgroup was significantly higher in the statin group [hazard ratio (HR) 0.29, 95% confidence interval (CI) 0.095-0.913] compared to non-statin. Multivariate analysis showed statins significantly reduced mortality (HR 0.27, 95%CI 0.078-0.944), but not revascularization (HR 0.91, 95%CI 0.589-1.406)., Conclusions: This study suggested that statin therapy initiated early after the diagnosis of CAD can decrease the risk of fatal events in Japanese CAD patients., (Copyright © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Th2-type inflammation spontaneously shown in Bcl6-knockout (KO) mice is mainly caused by bone marrow (BM)-derived nonlymphoid cells. However, the function of dendritic cells (DCs) in Bcl6-KO mice has not been reported. We show in this article that the numbers of CD4(+) conventional DCs (cDCs) and CD8α(+) cDCs, but not of plasmacytoid DCs, were markedly reduced in the spleen of Bcl6-KO mice. Generation of cDCs from DC progenitors in BM cells was perturbed in the spleen of irradiated wild-type (WT) mice transferred with Bcl6-KO BM cells, indicating an intrinsic effect of Bcl6 in cDC precursors. Although cDC precursors were developed in a Bcl6-KO BM culture with Fms-like tyrosine kinase 3 ligand, the cDC precursors were more apoptotic than WT ones. Also p53, one of the molecular targets of Bcl6, was overexpressed in the precursors. The addition of a p53 inhibitor to Bcl6-KO BM culture protected apoptosis, suggesting that Bcl6 is required by cDC precursors for survival by controlling p53 expression. Furthermore, large numbers of T1/ST2(+) Th2 cells were naturally developed in the spleen of Bcl6-KO mice. Th2 skewing was accelerated in the culture of WT CD4 T cells stimulated with Ags and LPS-activated Bcl6-KO BM-derived DCs, which produced more IL-6 and less IL-12 than did WT DCs; the addition of anti-IL-6 Abs to the culture partially abrogated the Th2 skewing. These results suggest that Bcl6 is required in cDC precursors for survival and in activated DCs for modulating the cytokine profile.

The accumulation of perfluorooctanoic acid (PFOA) has been detected in wildlife, soil, and water. Further, 8:2 fluorotelomer alcohol (8:2 FTOH) is used for the industrial synthesis of other fluorotelomer compounds, surfactants, and polymeric materials; however, it was recently found to be a potential source of PFOA contamination in the environment. 1H,1H,2H,2H,8H,8H-perfluorododecanol (degradable telomer fluoroalcohol (DTFA)), which is a newly developed fluorotelomer, contains the -CH₂- group in the fluorinated carbon backbone, making it potentially degradable through biological reactions. In this study, we investigated the biodegradation of DTFA in a mixed bacterial culture obtained from activated sludge. Optimized quantitative liquid chromatography-mass spectrometry analysis of the predicted metabolites generated in the culture revealed accumulations of the transformation products from DTFA to 2H,2H,8H,8H-PFDoA and 2H,8H,8H-2-PFUDoA via multiple processes. Furthermore, the production of short fluorinated compounds, perfluorobutanoic acid, perfluoropentanoic acid, and perfluoropentanedioic acid, which are believed to have lower accumulation potential and toxicity toward organisms than PFOA, was determined.

Although CD40 signaling is required for activation and differentiation of B cells, including germinal center (GC) formation and generation of memory B cells, in vivo generation of CD40 signaling augments plasma cell differentiation but disrupts GCs. Thus, CD40 signaling is thought to direct B cells to extrafollicular plasma cell fate rather than GC formation. In this study, we analyzed CD40L transgenic (CD40LTg) mice that constitutively express CD40L on B cells. After immunization, activation of B cells, but not dendritic cells, was augmented, although dendritic cells can be activated by CD40 ligation. Bone marrow chimera carrying CD40LTg and nontransgenic B cells showed increased Ab production from transgenic, but not from coexisting nontransgenic, B cells, suggesting that CD40L on a B cell preferentially stimulates the same B cell through an autocrine pathway, thereby augmenting Ab production. Although GCs rapidly regressed after day 5 of immunization and failed to generate late-appearing high-affinity Ab, CD40LTg mice showed normal GC formation up to day 5, as well as normal generation of long-lived plasma cells and memory B cell responses. This observation suggests that CD40 signaling does not block GC formation or differentiation of GC B cells, but it inhibits sustained expansion of GC B cells and augments B cell differentiation.

Background: Isolated non-compaction of ventricular myocardium (INVM) is characterized by persistent embryonic myocardial morphology without other cardiac anomalies. Congestive heart failure, critical arrhythmias, and systemic thromboemboli are known as major manifestations during childhood. Recently it was reported that there are some patients who seem apparently healthy in adult INVM. Clinical characteristics including that for electrocardiograms (ECG) of adult INVM, however, are unknown for Japanese subjects., Methods and Results: From 24,082 patients who underwent echocardiography between June 2000 and June 2007, 187 patients (0.78%, 41.3+/-16.8 years, 122 male) were identified as having INVM according to the criteria proposed by Oechslin et al. Although fatal ventricular arrythmias and thromboembolic events occurred in 2 patients and in 1 patient, respectively, the rest had no severe cardiac complications. Normal ECG findings were found only in 24.6% of the patients. Most of the ECG abnormalities, however, were non-specific: ST-T changes in 35.2% and bundle branch block in 14.9%. Notably, Brugada-like ECG was frequently seen in the present Japanese INVM patients (3.2%). The incidence of these ECG findings was not dependent upon the extent of non-compaction., Conclusions: The prevalence and ECG findings of adult Japanese INVM patients in a hospital-based clinical practice have been identified.

For the mammalian olfactory epithelium to continually detect odorant, neuronal survival, apoptosis, and regeneration must be coordinated. Here, we showed that the proto-oncogene BCL6, which encodes a transcriptional repressor required for lymphocyte terminal differentiation, contributes to the survival of olfactory sensory neurons (OSNs). In the olfactory epithelia of the BCL6 null mutant mice, many OSNs were positive for both OMP and GAP43. The epithelium was relatively thinner, showing many apoptotic signals. These characters were phenotypically similar to those of the wild-type mice treated with nasal lectin irrigation, which acutely induces apoptosis of OSNs. Odorant receptors were expressed normally in the epithelia of the mutant mice, and their overall expression profile based on DNA microarray analyses was roughly similar to that of the apoptosis-induced olfactory epithelia of the wild-type mice. Experimental increase of BCL6 together with green fluorescent protein in OSNs using adenovirus-mediated gene transfer made the epifluorescence last longer than the control fluorescence without exogenous BCL6 after the nasal lectin irrigation, indicating that BCL6 made the infected neurons survive longer. We conclude that BCL6 plays an active role in the survival of OSNs as an anti-apoptotic factor and confers immature OSNs enough time to fully differentiate into mature ones.

A new mathematical method for estimating velocity vectors from color Doppler datasets is proposed to image blood flow dynamics; this method has been called echodynamography or vector flow mapping (VFM). In this method, the concept of stream function is exploited to expand a 2-D distribution of radial velocities in polar coordinates, observed with color Doppler, to a 2-D distribution of velocity vectors. This study was designed to validate VFM using 3-D numerical flow models. Velocity fields were reconstructed from the virtual color Doppler datasets derived from the models. VFM captured the gross features of flow structures and produced comparable images of the distribution of vorticity, which correlated significantly with the original field (for velocity magnitudes, standard error of estimate = 0.003 to 0.007 m/s; for vorticity, standard error of estimate = 0.35 to 2.01/s). VFM may be sensitive for depicting flow structures derived from color Doppler velocities with reasonable accuracy., (Copyright 2010 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Controlling osteoclastogenesis is critical to maintain physiological bone homeostasis and prevent skeletal disorders. Although signaling activating nuclear factor of activated T cells 1 (NFATc1), a transcription factor essential for osteoclastogenesis, has been intensively investigated, factors antagonistic to NFATc1 in osteoclasts have not been characterized. Here, we describe a novel pathway that maintains bone homeostasis via two transcriptional repressors, B cell lymphoma 6 (Bcl6) and B lymphocyte-induced maturation protein-1 (Blimp1). We show that Bcl6 directly targets 'osteoclastic' molecules such as NFATc1, cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP), all of which are targets of NFATc1. Bcl6-overexpression inhibited osteoclastogenesis in vitro, whereas Bcl6-deficient mice showed accelerated osteoclast differentiation and severe osteoporosis. We report that Bcl6 is a direct target of Blimp1 and that mice lacking Blimp1 in osteoclasts exhibit osteopetrosis caused by impaired osteoclastogenesis resulting from Bcl6 up-regulation. Indeed, mice doubly mutant in Blimp1 and Bcl6 in osteoclasts exhibited decreased bone mass with increased osteoclastogenesis relative to osteoclast-specific Blimp1-deficient mice. These results reveal a Blimp1-Bcl6-osteoclastic molecule axis, which critically regulates bone homeostasis by controlling osteoclastogenesis and may provide a molecular basis for novel therapeutic strategies.

The BTB-kelch protein Nd1-L acts as an actin cytoskeleton stabilizer expressed ubiquitously in mouse tissues. We examined the effect of Nd1-L on cancer cell invasion and metastasis. Over-expression of Nd1-L in murine colon carcinoma cell line Colon 26 and murine melanoma cell line B16 resulted in suppression of pulmonary and liver metastasis after inoculation of these cells to syngeneric mice and in increased survival in an animal model. On the other hand, knock down of Nd1-L by RNA interference promoted metastasis ability of these cells. Increased expression of Nd1-L inhibited migration and Matrigel invasion capacity of cancer cell lines in vitro. Thus, Nd1-L expression inversely correlated with invasive and metastasis capacity of cancer cells. Furthermore, increased expression of Nd1-L in NIH3T3 cells inhibited growth factor induced activation of Rho family small GTPases such as Rho, Rac and cdc42. These results suggest that Nd1-L is involved in invasion and metastasis of cancer cells by regulating the actin cytoskeleton and Rho family proteins.

Background: Several hospital-based investigations have reported that a high proportion of patients with heart failure (HF) have preserved left ventricular ejection fraction (LVEF). The purpose of this study was to determine the prevalence, prognosis, and predictors for mortality of Japanese HF patients with preserved versus reduced LVEF in a prospective cohort fashion., Methods and Results: Our hospital-based database including inpatients and also outpatients was used for analysis. Out of 4255 new patients, 597 patients (male/female 414/183, age 65.1+/-12.9 years) were diagnosed as having symptomatic HF at the initial visit. Among 589 HF patients undergoing echocardiography, 398 (67.6%) showed a preserved LVEF (>50%) and 191 (32.4%) had a reduced LVEF (< or =50%). Patients with preserved LVEF were older (p=0.004) and more likely to be female (p=0.002). During follow-up of an average 539 days, 34 cardiovascular deaths occurred, and patients with preserved LVEF showed a better prognosis than those with reduced LVEF (3.2% vs. 7.4% per year, p=0.0097). Multivariate Cox hazards analysis identified LVEF as an independent predictor in all HF patients. Also, separated group analysis showed that presence of chronic kidney disease was independently associated with poor prognosis irrespective of HF types., Conclusions: This prospective cohort study identified prevalence and prognosis of HF in Japanese in- and outpatients, where patients with preserved LVEF showed a better prognosis than those with reduced LVEF., (2009 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Mortality and morbidity after acute coronary syndrome (ACS) in Japan appear to be different from those in Western countries due to different social healthcare systems, races, geographical locations, and interventional procedures, although data are limited in Japan., Methods: With a hospital-based cohort study comprising all the new patients who had visited our hospital between 2004 and 2007 (n=6562), we identified all-cause mortality, the composite endpoint of cardiac death, non-fatal myocardial infarction (MI), or target vessel revascularization and the predictors., Results: Of the total, 293 patients were included with a discharge diagnosis of ACS (median follow-up of 24.5 months). Non-ST elevation-ACS (NSTE-ACS) (unstable angina and non-ST elevation MI) and ST elevation MI (STEMI) were observed in 165 (56.3%) and 128 (43.7%) patients, respectively. Percutaneous coronary intervention or coronary artery bypass graft surgery was performed in 72.7% and 14.5% of NSTE-ACS patients, respectively and in 82.8% and 10.2% of STEMI patients. The use of aspirin, ticlopidine, and beta-blockers for NSTE-ACS patients were 93.3%, 66.9%, and 38.0%, respectively, with corresponding rates of 96.0%, 75.4%, and 57.1% for STEMI patients. All-cause mortality rates in NSTE-ACS and STEMI were 1.8% and 5.5% at 30 days, respectively, and 6.3% and 12.9% at 2 years, with corresponding rates of 3.7% and 8.7% at 30 days, respectively, and 23.4% and 35.6% at 2 years for the composite endpoint. Multivariate analysis showed that predictors for mortality were older age (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.018-1.244) and estimated glomerular filtration rate value (HR 0.96, 95% CI 0.929-0.988) in NSTE-ACS, and older age (HR 1.10, 95% CI 1.011-1.119) and congestive heart failure on admission (HR 20.0, 95% CI 2.439-164.4) in STEMI., Conclusions: The present study identified long-term mortality, morbidity, and predictors of adverse events for Japanese patients with ACS., (2009 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Although recent studies have suggested that height and body mass index (BMI) independently affect the prevalence of atrial fibrillation (AF), their combined effects have not been fully examined in Japanese patients., Methods and Results: Patients without organic cardiac diseases, hypertension and diabetes mellitus were screened from a prospective, single hospital-based cohort of the Shinken Database 2004-2007 (n=4,719). Both height and BMI significantly increased the crude rate of AF prevalence and the effects were significant even after adjustment by age, sex and left atrial dimension. The relative risks (RRs) for AF in the height and BMI categories were 2.07 (95% confidence interval [CI] 1.70-2.52) and 1.78 (95%CI 1.46-2.17), respectively, in the highest tertile compared with the lowest tertile. The RRs in the highest combined tertile was high to 2.98 (95%CI 2.07-4.28) compared with the lowest combined tertile, an unignorable figure for AF prevalence in the future., Conclusions: Height and BMI synergistically affected the prevalence of AF in Japanese patients. With respect to the recent increase in body size of the Japanese population, the present study predicts that there will be more occurrences of AF than previously predicted. (Circ J 2010; 74: 66 - 70).

Murine Prickle1 and Prickle2 belong to the planar cell polarity genes. Prickle2 but not Prickle1 gene expression was induced in C1300 neuroblastoma cells during neurite-like process formation induced by retinoic acid (RA). Over-expression of Prickle1 or Prickle2 in C1300 cells induced striking neurite-like process formation in the absence of RA. Since Prickle binds to Dishevelled (Dvl) to induce its degradation in Drosophila, we examined the participation of Dvl protein in the neurite-like process formation of C1300 cells. Upon induction of the neurite-like process formation, the amount of Dvl1 protein decreased. Prickle1 and Prickle2 could associate with Dvl1 and over-expression of Prickle1 or Prickle2 resulted in the reduction of Dvl1 protein in C1300 cells. Furthermore, over-expression of Dvl1 in C1300 cells prevented the neurite-like process formation induced by Prickle1 or Prickle2 over-expression. Thus, Prickle1 and Prickle2 promote neurite-like process formation of C1300 cells via the Dvl1 dependent mechanism.

Accumulating evidence indicates that TBP (TATA-binding protein)-like protein (TLP) contributes to the regulation of stress-mediated cell cycle checkpoint and apoptotic pathways, although its physiological target genes have remained elusive. In the present study, we have demonstrated that human TAp63 is one of the direct transcriptional target genes of TLP. Enforced expression of TLP results in the transcriptional induction of the endogenous TAp63, but not of the other p53 family members such as TAp73 and p53. Consistent with these results, small interference RNA-mediated knockdown led to a significant down-regulation of the endogenous TAp63. Luciferase reporter assay and chromatin immunoprecipitation analysis revealed that the genomic region located at positions -487 to -29, where +1 represents the transcriptional initiation site of TAp63, is required for TLP-dependent transcriptional activation of TAp63 and also TLP is efficiently recruited onto this region. Additionally, cells treated with anti-cancer drug etoposide underwent apoptosis in association with the transcriptional enhancement of TAp63 in a p53-independent manner, and the knockdown of the endogenous TLP reduced etoposide-induced apoptosis through repression of TAp63 expression. Taken together, our present study identifies a TLP-TAp63 pathway that is further implicated in stress-induced apoptosis.

Objectives: To investigate the usefulness of analysis of single nucleotide polymorphism (SNP) using a newly developed DNA chip assay involving single base extension(SBE) and subsequent hybridization in cytokine-related genes in critical care patients., Design and Methods: Genotyping was performed in 76 ICU patients admitted to the ICU. First, the DNA samples from 58 patients were subjected to PCR and SBE conditioning for DNA. Second, another 18 patients were subjected to genotyping for SNPs in IL-6 -596G/A, -572C/G, -174G/C, TNF-alpha -308G/A, -238G/A, IL-1beta -511C/T and -31T/C by both TaqMan and DNA chip method, and by DNA direct sequencing prospectively., Results: First, PCR and SBE condition were established with initial sample sets, which were consistent with results by TaqMan method. Second, no difference was observed between two assay methods in prospective validation set., Conclusions: The genotyping assay using the new chip was developed and its usefulness was confirmed.

Prognosis of patients with heart failure (HF) remains unclear in Japan and should be determined in a prospective fashion. A prospective cohort of The Shinken Database comprised details on all of the new patients, including both inpatients and outpatients, who visited The Cardiovascular Institute Hospital in 2004-2005. HF patients were defined as those with symptomatic HF coexisting with structural heart diseases. Among 4,255 patients who visited our hospital, 597 patients (male/female 414/183, age 65.1 +/- 12.9 years, LVEF 56.2 +/- 18.0%) were diagnosed as presenting symptomatic HF. Ischemic heart disease was present in 305 (51.1%), valvular heart disease in 212 (35.5%), dilated cardiomyopathy in 59 (9.9%), hypertrophic cardiomyopathy in 24 (4.0%), hypertensive heart disease in 14 (2.3%), and others in 67 (11.2%). Hypertension, atrial fibrillation, and diabetes were observed in 35.3%, 27.4%, and 23.7%, respectively. During the mean follow-up period of 539 +/- 257 days, 40 deaths (5.0% per year) occurred, including 34 cardiovascular deaths (4.5% per year, NYHA class II: 1.0%, III: 11.3%, IV: 36.6% per year, respectively). The present study showed that the prognosis of Japanese patients with HF among moderate to severe severity was found to be similar to that of Western countries. Multiple Cox hazard analysis identified the presence of chronic kidney disease and NYHA class as independent predictors for cardiovascular death. This prospective cohort study identified the prevalence, prognosis, and risk factors in HF patients to provide a basis for therapeutic management in Japan.

Objective: A poor functioning dilated left ventricle with mitral regurgitation is the worst condition in chronic ischemic heart failure. Our 7-year experience in combined mitral valve and left ventricular reconstruction was evaluated., Materials and Methods: Among 246 patients having undergone a left ventriculoplasty for postinfarction left ventricular dysfunction in our experience, there were 76 patients with advanced heart failure due to dilated ischemic cardiomyopathy with mitral regurgitation (70 males and 6 females with a mean age of 60 years). All patients had NYHA class III (n = 41) or IV (n = 35) heart failure, including 26 patients (34%) with inotropic support before the operation. All patients had a mitral regurgitation of more than 2+ and 46 patients (61%) had 3+ or more. Mitral reconstruction (61 repairs, 15 replacements) and left ventriculoplasty (Dor 34, SAVE 36, PLV 6) were undergone in combination with CABG (74%)., Results: Operative mortality was 7.9% (5.0% in 60 elective and 18.8% in 16 emergency operations). The ejection fraction and cardiac index increased from 24.9 +/- 7.0% to 33.3 +/- 8.7%, and 2.0 +/- 0.4 l/min/m2 to 2.6 +/- 0.4 l/min/m2, respectively (p < 0.001). The endodiastolic and endosystolic volume indices, and diastolic dimension decreased from 165.9 +/- 43.2 ml/m2 to 121.2 +/- 31.1 ml/m2, 123.3 +/- 38.9 ml/m2 to 74.0 +/- 27.5 ml/m2, and 69.5 +/- 7.7 mm to 61.2 +/- 7.1 mm, respectively (p < 0.001). Late deaths were noted in 13 patients (17.1%), with 10 cardiac deaths. One- and 5-year survival rates were 80.2% and 67.7%, respectively. The mean NYHA class improved from 3.5 to 1.4 among the survivors. Multivariate analysis showed that patients with a mitral regurgitation of 3+ or more and preoperative endosystolic volume index were significant predictors for postoperative mortality. However, age, preoperative inotropes and pulmonary hypertension did not show any significant differences., Conclusion: Combined mitral and left ventricular reconstruction is effective in treating advanced heart failure with endstage ischemic cardiomyopathy associated with a dilated left ventricle and mitral regurgitation.

Many large-scale randomized control trials (RCTs) have been performed regarding treatment strategy in atrial fibrillation (AF) in Western countries and also in Japan. However, limited data are available concerning real-world relationships between the treatment strategy and prognosis of AF patients. Out of a prospective cohort of The Shinken Database 2004 (n = 2 412), 286 AF patients (male 205, 64.1 +/- 12.3 years, paroxysmal form 165) were retrospectively investigated. The percentage of AF patients under the rhythm control strategy was evaluated using the Kaplan-Meier method, which showed the cumulative proportion of rhythm control strategy was approximately 30% at the 90th day after the initial visit and 40.0% at 1 year. The average time to the first rhythm control strategy was 68.3 +/- 106.7 days. Those under rhythm control strategy were associated with fewer coexisting organic cardiac diseases, a younger age, and smaller left atrial dimension. Consequently, they showed very good prognosis (cumulative incidence rate of cardiovascular events at 1 year was 0.0%). Careful induction of rhythm control strategy, which was adopted in approximately 40% of the patients in the real world, was associated with fewer comorbidities and therefore might lead to better prognosis, although this does not mean the direct effects of rhythm control strategy.

Vascular Ehlers-Danlos syndrome is an inherited connective-tissue disorder causing arterial and gastrointestinal fragility and spontaneous rupture of the large arteries, uterus, or bowel. Among arterial dissections and ruptures, spontaneous coronary artery dissection is extremely rare in this disorder. The specific therapeutic strategy for this disorder and its complications has not yet been established. In this report, we describe a 33-year-old woman with all three coronary artery spontaneous dissections, resulting in cardiogenic shock and therapy-resistant ventricular fibrillation. We could successfully complete revascularization of all three coronary arteries and terminate the life-threatening arrhythmia. Biochemical findings finally revealed a point mutation in the COL3A1 gene, consistent with a diagnosis of vascular Ehlers-Danlos syndrome. To the best of our knowledge, this is the first case of vascular Ehlers-Danlos syndrome causing all three coronary artery spontaneous dissections. Our case also suggests that, from vascular fragility even if it is spontaneous coronary dissection, physicians always consider connective-tissue disorders as a differential diagnosis at an early stage even though that would be a first complication, and percutaneous coronary intervention with stenting using intravascular ultrasound could be a strategic option for even repeated and fatal spontaneous coronary artery dissections in vascular Ehlers-Danlos syndrome.

Persistent cloaca (PC) is a rare abnormality characterized by a direct communication between the gastrointestinal, urinary and genital structures. We report a case of PC presenting with persistent massive fetal ascites. Postpartum examination demonstrated a long and narrow common channel of PC. Fetal ascites is caused by urinary drainage through the fallopian tubes into the abdominal cavity. Usually it occurs temporarily and disappears with the subsequent development of intrapelvic cysts. A long and narrow common channel of PC has been found to contribute to the persistent ascites., (Copyright (c) 2009 S. Karger AG, Basel.)

We compared the prognostic power of end-tidal CO(2) pressure (PETCO(2)) during exercise, an index of arterial CO(2) pressure, with those of established respiratory gas indexes during exercise testing in patients with left ventricular dysfunction. Seventy-eight consecutive patients with a left ventricular ejection fraction (LVEF)

Rationale: The IL-23-IL-17A-producing CD4(+) T-cell (Th17 cell) axis plays an important role in the development of chronic inflammatory diseases, including autoimmune diseases. However, the role of the IL-23-Th17 cell axis in the regulation of allergic airway inflammation is still largely unknown., Objectives: To determine the role of IL-23 and Th17 cells in allergic airway inflammation., Methods: We examined the effect of anti-IL-23 antibody on antigen-induced airway inflammation. We also investigated the effect of enforced expression of IL-23 on allergic airway inflammation by generating lung-specific IL-23 transgenic mice. Moreover, we examined the effect of adoptive transfer of antigen-specific Th17 cells on allergic airway inflammation., Measurements and Main Results: IL-23 mRNA was expressed in the lung of sensitized mice upon antigen inhalation, and the neutralization of IL-23 decreased antigen-induced eosinophil recruitment and Th2 cytokine production in the airways. The enforced expression of IL-23 in the airways significantly enhanced antigen-induced eosinophil and neutrophil recruitment into the airways; Th2 cytokine, IL-17A, and tumor necrosis factor (TNF)-alpha production in the airways; goblet cell hyperplasia; and airway hyperresponsiveness. Moreover, IL-23-mediated enhancement of antigen-induced Th2 cytokine production and eosinophil recruitment in the airways was still observed in the mice lacking IL-17A. Furthermore, although adoptive transfer of antigen-specific Th17 cells alone induced neutrophil but not eosinophil recruitment into the airways upon antigen inhalation, cotransfer of Th17 cells with Th2 cells significantly enhanced antigen-induced Th2-cell-mediated eosinophil recruitment into the airways and airway hyperresponsiveness., Conclusions: IL-23 and Th17 cells not only induce Th17-cell-mediated neutrophilic airway inflammation but also up-regulate Th2-cell-mediated eosinophilic airway inflammation.

Background: Recent investigations have demonstrated that cerebral oxyhemoglobin (O(2)Hb) decreases during exercise in patients with left ventricular dysfunction, reflecting a cerebral hypoxia. We sought to establish a prognostic value of decreased cerebral O(2)Hb during exercise in cardiac patients, and to compare it with those of indexes obtained from cardiopulmonary exercise testing (CPX)., Methods and Results: A total of 344 consecutive patients with coronary artery disease were enrolled in the study. All the patients performed CPX, during which cerebral O(2)Hb was continuously monitored using near-infrared spectroscopy. There were 13 cardiac deaths and 78 cardiovascular events during the prospective follow-up period of 1,231+/-538 days. The change of O(2)Hb measured at the forehead from rest to peak exercise (DeltaO(2)Hb) was significantly lower in non-survivors than in survivors (-1.5+/-3.3 vs 1.7+/-3.2 micromol/L, p=0.0004). By multivariate Cox proportional hazards analysis, DeltaO(2)Hb and left ventricular ejection fraction (LVEF) were found to be independent prognostic markers for cardiac deaths. The DeltaO(2)Hb, LVEF and peak oxygen uptake were found to be significant prognostic markers for cardiovascular events, mainly for heart failure worsening and sudden cardiac death., Conclusion: The present findings suggest that a decrease in cerebral O(2)Hb during exercise predicts future cardiovascular events in patients with coronary artery disease.

Background and Objective: Leucocytes, especially lymphocytes and neutrophils, as well as alveolar macrophages, that infiltrate into the lung are involved in the development of pulmonary fibrosis. However, the role of T helper (Th)2-type inflammation, mediated by Th2 cells and eosinophils, in fibrosis remains unknown. Transgenic mice deficient in the transcriptional repressor, Bcl6, display an attenuation of Th2 cytokine production. We studied the effects of Th2-type pulmonary inflammation on bleomycin-induced pulmonary fibrosis using Bcl6 transgenic mice., Methods: Bleomycin was administered to ovalbumin (OVA)-sensitized Bcl6 transgenic and wild-type mice by intratracheal instillation during sequential OVA antigen challenge. Concentrations of transforming growth factor-beta1 in the BAL fluid were measured 2 weeks after bleomycin administration. At the same time lung tissue was examined histopathologically, and homogenized to assess collagen levels and Th1/Th2 cytokine mRNA expression., Results: Although OVA-sensitized, bleomycin-treated Bcl6 transgenic mice had markedly lower numbers of eosinophils in both BAL and lung tissue compared with OVA-sensitized, bleomycin-treated wild-type mice, the development of pulmonary fibrosis in response to bleomycin was similar in Bcl6 transgenic mice and wild-type mice., Conclusion: These results suggest that Th2-dominant inflammation in the lung is not essential for the development of bleomycin-induced pulmonary fibrosis.

The immunoglobulin genes undergo a high frequency of point mutations at both C:G and A:T pairs in the germinal center (GC) B cells. This hypermutation process is initiated by the activation-induced cytidine deaminase (AID), which converts cytosine to uracil and generates a U:G lesion. Replication of this lesion, or its repair intermediate the abasic site, could introduce C:G mutations but the mechanisms leading to mutations at non-damaged A:T pairs remain elusive. Using a lacZ-transgenic system in which endogenous genome mutations can be detected with high sensitivity, we found that GC B cells exhibited a much higher ratio of A:T mutations as compared to naïve B, non-GC B, and cells of other tissues. This property does not require AID or active transcription of the target gene, and is dependent on DNA polymerase eta. These in vivo results demonstrate that GC B cells are unique in having an intrinsic propensity to generate A:T mutations during repair of endogenous DNA damage. These findings have important implications in understanding how AID, which can only target C:G base pairs, is able to induce the entire spectrum of mutations observed in immunoglobulin variable region genes in GC B cells.

Incremental exercise testing to a symptom-limited maximum has been used to measure the ratio of the increase in ventilation (V.E) to the increase in CO(2) output (V.CO(2)) during exercise (V.E/V.CO(2) slope), a valuable index reflecting the severity of the ventilation-perfusion mismatch in heart failure. Here we studied whether this same value for the slope of V.E/V.CO(2) could be determined from a short constant work-rate exercise test of moderate intensity. Twenty-three patients with a previous myocardial infarction underwent moderate-intensity (69+/-15 W) constant work-rate exercise for 6 min and an incremental work-rate exercise test to the max. The V.E/V.CO(2) slope was calculated from the incremental exercise test from the start of increasing the work-rate to the ventilatory compensation point. The V.E/V.CO(2) slope was similarly calculated from the start of constant work-rate exercise until the 4th minute, when V.E and V.CO(2) changed minimally. The V.E/V.CO(2) slope determined from incremental exercise was 33.8+/-5.9, ranging from 20.9 to 42.8. The slope obtained from constant work-rate exercise was 32.9+/-5.7. The V.E/V.CO(2) slopes obtained from the two exercise tests did not differ significantly. The slope obtained from constant work-rate exercise was significantly positively correlated with the slope obtained from the incremental exercise (r=0.84, p<0.0001). The V.E/V.CO(2) slope can be determined from constant work-rate exercise at a moderate intensity. This indicates that the relationship between ventilation and CO(2) output is consistent and independent of the mode of exercise testing.

Modulation of surface T cell antigen receptor (TCR) expression is an important mechanism for the regulation of immune responses and the prevention of T cell hyperactivation and autoimmunity. The TCR is rapidly internalized after antigen stimulation and then degraded in lysosomes. However, few of the molecules involved in this process have been identified. We demonstrate that the lysosomal protein LAPTM5 negatively regulated surface TCR expression by specifically interacting with the invariant signal-transducing CD3zeta chain and promoting its degradation without affecting other CD3 proteins, CD3epsilon, CD3delta, or CD3gamma. TCR downmodulation required the polyproline-tyrosine motifs and the ubiquitin-interacting motif of LAPTM5. LAPTM5 deficiency resulted in elevated TCR expression on both CD4(+)CD8(+) thymocytes and spleen T cells after CD3 stimulation, as well as enhanced T cell responses in vitro and in vivo. These results identify a lysosomal protein important for CD3zeta degradation and illustrate a unique mechanism for the control of surface TCR expression and T cell activation.