Association between Vitamin D and Heart Failure Mortality in 10,974 Hospitalized Individuals.

A broad range of chronic conditions, including heart failure (HF), have been associated with vitamin D deficiency. Existing clinical trials involving vitamin D supplementation in chronic HF patients have been inconclusive. We sought to evaluate the outcomes of patients with vitamin D supplementation, compared with a matched cohort using real-world big data of HF hospitalization. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 93,692 patients who were first hospitalized with HF between April 2012 and March 2017 (mean age was 79 ± 12 years, and 52.2% were male). Propensity score (PS) was estimated with logistic regression model, with vitamin D supplementation as the dependent variable and clinically relevant covariates. On PS-matched analysis with 10,974 patients, patients with vitamin D supplementation had lower total in-hospital mortality (6.5 vs. 9.4%, odds ratio: 0.67, p < 0.001) and in-hospital mortality within 7 days and 30 days (0.9 vs. 2.5%, OR, 0.34, and 3.8 vs. 6.5%, OR: 0.56, both p < 0.001). In the sub-group analysis, mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker, and ß-blocker were not affected by vitamin D supplementation. Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in the propensity matched cohort. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful for determining targets of future randomized control trials.

Inhibition of Growth of Candida albicans by a Lysozyme-chitosan Conjugate, LYZOX and its Combination with Decanoic Acid.

A lysozyme-chitosan conjugate preparation (LYZOX), produced from egg white lysozyme and chitosan by Maillard reaction, is a commercial product developed as a cosmetic ingredient or food additive. Effects of LYZOX on in vitro growth of Candida albicans were examined. C. albicans cells were treated with LYZOX for 3 hrs, and then washed and cultured for an additional 16 hrs in modified RPMI1640 medium. Mycelial growth of C. albicans was clearly inhibited by more than 100 µg/ml of LYZOX in a concentration-dependent manner. On the other hand, corresponding concentration of chitosan or lysozyme or their mixture only scarcely showed clear inhibitory effect. Similarly, anti-Candida activity of the combination of LYZOX and decanoic acid, a middle-chain fatty acid, was also examined. Inhibitory activity of this combination against mycelial growth of C. albicans was very potent and appeared synergistic, since fractionated inhibitory concentration (FIC) index for 70% growth inhibition was calculated to be 0.20. Oral application of this combination improved the symptoms of Candida-infected-tongue in an experimental murine candidiasis model. On the basis of these results, the possible application of LYZOX as a new functional product with anti-candida activity was discussed.

Multimodality imaging of biatrial myxomas in an asymptomatic patient.

Myxomas are located in the left atrium in 75-80% of cases and almost always present with signs and symptoms of a thromboembolic event. Biatrial myxomas are rare, and their incidence is generally less than 2.5% of all myxomas. We herein present a case of biatrial myxomas as an incidental finding by echocardiography where the patient underwent surgery. Echocardiography continues to be the initial imaging modality for intracardiac masses. Cardiac magnetic resonance provides superior tissue characterization, particularly important in differentiating a myxoma from a thrombus. Appropriate use of these non-invasive imaging modalities may lead to a correct diagnosis and good outcome. .

[Recovery behavior for decreased self-esteem related to the level and stability of self-esteem].

This study examined the relationship between the level and stability of self-esteem and behavior engaged in to recover from decreased self-esteem. A preparatory study (N=137) investigated recovery behaviors for decreased self-esteem. The main study investigated the factor structure of recovery behavior (N=518) and its relationship with self-esteem (N=96). The results showed that four types of behaviors were used for recovery from decreased self-esteem: disclosure, seeking acceptance, engaging in a pastime, and introspection. People with high and stable self-esteem (HS) engaged in disclosure and a pastime; people with high and unstable self-esteem (HU) engaged in a pastime. People with low and stable self-esteem (LS) did not do anything; people with low and unstable self-esteem (LU) engaged in disclosure and seeking acceptance. Finally, the characteristics of each group and issue of the scale were discussed.

Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement.

Akt is critical in insulin-induced metabolism of glucose and lipids. To investigate functions induced by hepatic Akt activation, a constitutively active Akt, NH(2)-terminally myristoylation signal-attached Akt (myr-Akt), was overexpressed in the liver by injecting its adenovirus into mice. Hepatic myr-Akt overexpression resulted in a markedly hypoglycemic, hypoinsulinemic, and hypertriglyceridemic phenotype with fatty liver and hepatomegaly. To elucidate the sterol regulatory element binding protein (SREBP)-1c contribution to these phenotypic features, myr-Akt adenovirus was injected into SREBP-1 knockout mice. myr-Akt overexpression induced hypoglycemia and hepatomegaly with triglyceride accumulation in SREBP-1 knockout mice to a degree similar to that in normal mice, whereas myr-Akt-induced hypertriglyceridemia in knockout mice was milder than that in normal mice. The myr-Akt-induced changes in glucokinase, phosphofructokinase, glucose-6-phosphatase, and PEPCK expressions were not affected by knocking out SREBP-1, whereas stearoyl-CoA desaturase 1 induction was completely inhibited in knockout mice. Constitutively active SREBP-1-overexpressing mice had fatty livers without hepatomegaly, hypoglycemia, or hypertriglyceridemia. Hepatic acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and glucose-6-phosphate dehydrogenase expressions were significantly increased by overexpressing SREBP-1, whereas glucokinase, phospho-fructokinase, glucose-6-phosphatase, and PEPCK expressions were not or only slightly affected. Thus, SREBP-1 is not absolutely necessary for the hepatic Akt-mediated hypoglycemic effect. In contrast, myr-Akt-induced hypertriglyceridemia and hepatic triglyceride accumulation are mediated by both Akt-induced SREBP-1 expression and a mechanism involving fatty acid synthesis independent of SREBP-1.

Differing roles of Akt and serum- and glucocorticoid-regulated kinase in glucose metabolism, DNA synthesis, and oncogenic activity.

Serum- and glucocorticoid-regulated kinase (SGK) is a serine kinase that has a catalytic domain homologous to that of Akt, but lacks the pleckstrin homology domain present in Akt. Akt reportedly plays a key role in various cellular actions, including glucose transport, glycogen synthesis, DNA synthesis, anti-apoptotic activity, and cell proliferation. In this study, we attempted to reveal the different roles of SGK and Akt by overexpressing active mutants of Akt and SGK. We found that adenovirus-mediated overexpression of myristoylated (myr-) forms of Akt resulted in high glucose transport activity in 3T3-L1 adipocytes, phosphorylated glycogen synthase kinase-3 (GSK3) and enhanced glycogen synthase activity in hepatocytes, and the promotion of DNA synthesis in interleukin-3-dependent 32D cells. In addition, stable transfection of myr-Akt in NIH3T3 cells induced an oncogenic transformation in soft agar assays. The active mutant of SGK (D-SGK, substitution of Ser422 with Asp) and myr-SGK were shown to phosphorylate GSK3 and to enhance glycogen synthase activity in hepatocytes in a manner very similar to that observed for myr-Akt. However, despite the comparable degree of GSK3 phosphorylation between myr-Akt and d-SGK or myr-SGK, d-SGK and myr-SGK failed to enhance glucose transport activity in 3T3-L1 cells, DNA synthesis in 32D cells, and oncogenic transformation in NIH3T3 cells. Therefore, the different roles of SGK and Akt cannot be attributed to ability or inability to translocate to the membrane thorough the pleckstrin homology domain, but rather must be attributable to differences in the relatively narrow substrate specificities of these kinases. In addition, our observations strongly suggest that phosphorylation of GSK3 is either not involved in or not sufficient for GLUT4 translocation, DNA synthesis, or oncogenic transformation. Thus, the identification of substrates selectively phosphorylated by Akt, but by not SGK, may provide clues to clarifying the pathway leading from Akt activation to these cellular activities.

An abundant periplasmic protein of the denitrifying phototroph Rhodobacter sphaeroides f. sp. denitrificans is PstS, a component of an ABC phosphate transport system.

To understand a physiological role of an abundant 34-kDa periplasmic protein in the denitrifying phototroph Rhodobacter sphaeroides f. sp. denitrificans grown in a medium containing malate as the carbon source, the gene for the protein was isolated. The deduced amino acid sequence of the protein had a sequence similarity of 66.2% to that of PstS from Sinorhizobium meliloti. The downstream sequence of the Rhodobacter pstS contained five genes similar to pstCAB and phoUB, and its upstream sequence contained a putative regulatory sequence that is analogous to the Pho box involved in phosphate-limitation-induced gene expression in Escherichia coli. Both the amount of the PstS and the pstS promoter-driven expression of lacZ activity increased about two-fold in response to phosphate limitation. This is the first isolation of pst genes encoding proteins of an ABC phosphate transporter system from phototrophic bacteria.

Three mitogen-activated protein kinases inhibit insulin signaling by different mechanisms in 3T3-L1 adipocytes.

TNFalpha, which activates three different MAPKs [ERK, p38, and jun amino terminal kinase (JNK)], also induces insulin resistance. To better understand the respective roles of these three MAPK pathways in insulin signaling and their contribution to insulin resistance, constitutively active MAPK/ERK kinase (MEK)1, MAPK kinase (MKK6), and MKK7 mutants were overexpressed in 3T3-L1 adipocytes using an adenovirus-mediated transfection procedure. The MEK1 mutant, which activates ERK, markedly down-regulated expression of the insulin receptor (IR) and its major substrates, IRS-1 and IRS-2, mRNA and protein, and in turn reduced tyrosine phosphorylation of IR as well as IRS-1 and IRS-2 and their associated phosphatidyl inositol 3-kinase (PI3K) activity. The MKK6 mutant, which activates p38, moderately inhibited IRS-1 and IRS-2 expressions and IRS-1-associated PI3K activity without exerting a significant effect on the IR. Finally, the MKK7 mutant, which activates JNK, reduced tyrosine phosphorylation of IRS-1 and IRS-2 and IRS-associated PI3K activity without affecting expression of the IR, IRS-1, or IRS-2. In the context of our earlier report showing down-regulation of glucose transporter 4 by MEK1-ERK and MKK6/3-p38, the present findings suggest that chronic activation of ERK, p38, or JNK can induce insulin resistance by affecting glucose transporter expression and insulin signaling, though via distinctly different mechanisms. The contribution of ERK is, however, the strongest.

The role of short- and long-axis function in determining late diastolic left ventricular filling in patients with hypertension: assessment by pulsed Doppler tissue imaging.

Left ventricular (LV) wall motion velocity during atrial systole is mediated by both transmitral flow and LV myocardial compliance at end-diastole. LV wall distensibility along the long- and short-axis during atrial systole and late diastolic LV filling may vary according to the remodeling of LV morphology. We measured LV wall motion velocities along the long and short axes using pulsed Doppler tissue imaging in 127 patients with hypertension to evaluate the relationship between the hemodynamic changes and LV morphology and to determine the role of both long- and short-axis function in late diastolic LV filling. Participants were classified into 3 groups according to LV dimension and end-diastolic wall thickness determined by M-mode echocardiography: group A (n = 62) without LV dilation or hypertrophy, group B (n = 55) with LV hypertrophy, and group C (n = 10) with LV dilation and systolic dysfunction. The time constant of the LV pressure decay during isovolumic diastole and the LV end-diastolic pressure were longest and greatest, respectively, in group C, compared with groups B and A. There were no significant differences in active left atrial emptying volume during atrial contraction determined by computerized echocardiographic 3-dimensional reconstruction among patient and control groups. The peak atrial systolic motion velocity of the LV posterior wall along the long axis was significantly lower in groups B and C, particularly in the latter group, than in group A. The peak atrial systolic motion velocity of the LV posterior wall along the short axis was greatest in group B and was lowest in group C compared with the other groups, respectively. The peak atrial systolic motion velocity of the LV posterior wall was greater along the long axis than the short axis in group A, but was less than the short axis in group B. In conclusion, the long- and short-axis function of the LV wall during atrial systole varies in patients with hypertension according to the severity of hemodynamic and morphologic abnormalities. The degree of LV wall expansion along the short axis is an important factor resulting from the atrial kick, and a determinant of its effectiveness.

High-salt diet enhances insulin signaling and induces insulin resistance in Dahl salt-sensitive rats.

A high-salt diet, which is known to contribute to the pathogenesis of hypertension, is also reportedly associated with insulin resistance. We investigated the effects of a high-salt diet on insulin sensitivity and insulin signaling in salt-sensitive (Dahl-S) and salt resistant (Dahl-R) strains of the Dahl rat. Evaluation of hyperinsulinemic-euglycemic clamp studies and glucose uptake into the isolated soleus muscle revealed that salt loading (8% NaCl) for 4 weeks induced hypertension and significant insulin resistance in Dahl-S rats, whereas no significant effects were observed in Dahl-R rats. Despite the presence of insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol 3-kinase, and phosphorylation of Akt were all enhanced in Dahl-S rats fed a high-salt diet. The mechanism underlying this form of insulin resistance thus differs from that previously associated with obesity and dexamethasone and is likely due to the impairment of one or more metabolic steps situated downstream of phosphatidylinositol 3-kinase and Akt activation. Interestingly, supplementation of potassium (8% KCl) ameliorated the changes in insulin sensitivity in Dahl-S rats fed a high-salt diet; this was associated with a slight but significant decrease in blood pressure. Evidence presented suggest that there is an interdependent relationship between insulin sensitivity and salt sensitivity of blood pressure in Dahl-S rats, and it is suggested that supplementing the diet with potassium may exert a protective effect against both hypertension and insulin resistance in salt-sensitive individuals.

Humoral regulation of resistin expression in 3T3-L1 and mouse adipose cells.

Resistin is a hormone secreted by adipocytes that acts on skeletal muscle myocytes, hepatocytes, and adipocytes themselves, reducing their sensitivity to insulin. In the present study, we investigated how the expression of resistin is affected by glucose and by mediators known to affect insulin sensitivity, including insulin, dexamethasone, tumor necrosis factor-alpha (TNF-alpha), epinephrine, and somatropin. We found that resistin expression in 3T3-L1 adipocytes was significantly upregulated by high glucose concentrations and was suppressed by insulin. Dexamethasone increased expression of both resistin mRNA and protein 2.5- to 3.5-fold in 3T3-L1 adipocytes and by approximately 70% in white adipose tissue from mice. In contrast, treatment with troglitazone, a thiazolidinedione antihyperglycemic agent, or TNF-alpha suppressed resistin expression by approximately 80%. Epinephrine and somatropin were both moderately inhibitory, reducing expression of both the transcript and the protein by 30-50% in 3T3-L1 adipocytes. Taken together, these data make it clear that resistin expression is regulated by a variety of hormones and that cytokines are related to glucose metabolism. Furthermore, they suggest that these factors affect insulin sensitivity and fat tissue mass in part by altering the expression and eventual secretion of resistin from adipose cells.

Activation of AMPK is essential for AICAR-induced glucose uptake by skeletal muscle but not adipocytes.

5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) reportedly activates AMP-activated protein kinase (AMPK) and stimulates glucose uptake by skeletal muscle cells. In this study, we investigated the role of AMPK in AICAR-induced glucose uptake by 3T3-L1 adipocytes and rat soleus muscle cells by overexpressing wild-type and dominant negative forms of the AMPKalpha2 subunit by use of adenovirus-mediated gene transfer. Overexpression of the dominant negative mutant had no effect on AICAR-induced glucose transport in adipocytes, although AMPK activation was almost completely abolished. This suggests that AICAR-induced glucose uptake by 3T3-L1 adipocytes is independent of AMPK activation. By contrast, overexpression of the dominant negative AMPKalpha2 mutant in muscle markedly suppressed both AICAR-induced glucose uptake and AMPK activation, although insulin-induced uptake was unaffected. Overexpression of the wild-type AMPKalpha2 subunit significantly increased AMPK activity in muscle but did not enhance glucose uptake. Thus, although AMPK activation may not, by itself, be sufficient to increase glucose transport, it appears essential for AICAR-induced glucose uptake in muscle.

Assessment of the Systolic Left Ventricular Myocardial Velocity Profile and Gradient Using Tissue Doppler Imaging in Patients with Hypertrophic Cardiomyopathy.

To determine the systolic characteristics of the hypertrophied myocardium in patients with hypertrophic cardiomyopathy (HCM), we evaluated the left ventricular [left ventricle (LV)] myocardial velocity profile (MVP) and gradient obtained from tissue Doppler imaging (TDI). Transmural wall-motion velocities in the ventricular septum and LV posterior wall were recorded in 12 patients with asymmetric septal hypertrophy and 12 healthy volunteers, and their profiles and gradients were determined. The maximum systolic myocardial velocity gradient in the ventricular septum was significantly lower in the HCM group than in the control group (0.88 +/- 0.35 versus 2.24 +/- 0.41; P < 0.001), whereas the gradient in the LV posterior wall was only slightly lower in the HCM group than in the control group (2.69 +/- 0.82 versus 3.45 +/- 0.96). In the control group, the MVPs in the ventricular septum and LV posterior wall were closely linear, suggesting that the transmural velocity is uniform during systole. MVPs in the ventricular septum and LV posterior wall in the HCM group also were closely linear, whereas the distribution of velocities in the ventricular septum was fairly dispersed compared with the control group. The myocardial velocity gradient on the right ventricular side of the ventricular septum decreased or disappeared in the patients with HCM, suggesting a nonuniform distribution of velocities. In conclusion, the MVP and gradient obtained from TDI may represent new indices for evaluating regional LV contractile abnormality in patients with HCM.

Left Atrial Contribution to Left Ventricular Filling in Patients with Mitral Stenosis: Combined Analysis of Transmitral and Pulmonary Venous Flow Velocities.

We recorded transmitral and pulmonary venous flow velocities using transthoracic continuous-wave and transesophageal pulsed Doppler echocardiography, respectively, in 36 patients with mitral stenosis who were in sinus rhythm to investigate the left atrial contribution to left ventricular filling in mitral stenosis. The mitral valve area was determined by transthoracic two-dimensional short-axis echocardiography. Patients were classified as having mild stenosis (>/=1.5 cm(2), n = 17) or moderate stenosis (<1.5 cm(2), n = 19). The mean pulmonary capillary wedge pressure and left atrial maximal diameter were significantly larger, and left atrial volume change during atrial contraction was significantly smaller in the moderate group than in the mild group. The percent left atrial contribution to left ventricular filling, estimated from the transmitral flow velocity, the peak atrial systolic velocity, and the percent ratio of left atrial systolic regurgitation to left atrial filling, estimated from the pulmonary venous flow velocity, were significantly lower in the moderate group than in the mild group. The percent left atrial contribution to left ventricular filling, the peak atrial systolic velocity, and the percent ratio of left atrial systolic regurgitation to left atrial filling were positively correlated with the mitral valve area and negatively correlated with the mean pulmonary capillary wedge pressure. These results suggest that the left atrial contribution to left ventricular filling in patients with mitral stenosis in sinus rhythm decreases as the severity of valve stenosis increases, and that analysis of the atrial systolic waves of the transmitral and pulmonary venous flow velocities provides important information for evaluation of left atrial systolic performance in patients with mitral stenosis.

Transesophageal Pulsed Doppler Echocardiographic Study of Systolic Flow Velocity Patterns of the Pulmonary Vein in Patients with Atrial Fibrillation.

We recorded pulmonary venous flow velocity in 27 patients with atrial fibrillation using transesophageal pulsed Doppler echocardiography to investigate the cycle length-dependent characteristics and background of early systolic reversal and second systolic forward waves. The study group consisted of 15 patients with mitral stenosis, 5 patients with left atrial myxoma, and 7 patients without underlying organic heart disease; they were compared with 20 normal controls in sinus rhythm. The mean pulmonary capillary wedge pressure was significantly greater in patients with mitral stenosis and left atrial myxoma than in normal controls and in patients with isolated atrial fibrillation. The mean peak velocity of the early systolic reversal wave was also significantly greater in patients with mitral stenosis and left atrial myxoma than in patients with isolated atrial fibrillation. The mean peak velocity of the second systolic forward wave was significantly lower in patients with mitral stenosis and left atrial myxoma than in controls and in patients with isolated atrial fibrillation. The preceding RR interval had significant negative correlations with the peak early systolic reversal velocity, left atrial pressure during closure of the mitral valve, and peak V wave height of the pulmonary capillary wedge pressure in patients with mitral stenosis and left atrial myxoma. In the same patient groups, the preceding RR interval had significant positive correlations with the peak second systolic forward velocity and amplitudes of the mitral annular and interatrial septal motions during ventricular systole. The variations in the peak velocities of the early systolic reversal and second systolic forward waves with the preceding RR interval were smaller in patients with more severe mitral stenosis. In conclusion, early systolic reversal waves of the pulmonary venous flow velocity reflect left atrial pressure, and the second systolic forward waves reflect left atrial filling. Both velocities vary with disease conditions or preceding RR intervals in atrial fibrillation.