Endotoxin-Induced L-Arginine Pathway Produces Nitric Oxide and Modulates the Ca2+-Activated K+ Channel in Cultured Human Dermal Papilla Cells

Endotoxin induces an enzyme that synthesizes nitric oxide (NO) from L-arginine (NO synthase) in vascular smooth muscle cells, macrophages, and fibroblasts, leading to the release of NO. We evaluated the release of NO and its intracellular action on the Ca2+-activated K+ channel (Kca channel) in cultured human dermal papilla cells by use of the electron paramagnetie response (EPR) spin trapping method and the patch clamp technique. In dermal papilla cells pretreated for 24h with endotoxin (1 μg/ml), application of 1mM L-arginine generated NO, although no measurable release of NO was observed in cells without endotoxin pretreatment, as determined by the EPR spin trapping method. With the patch clamp technique, we found that the Kca channel of dermal papilla cells had high conductance and was voltage dependent. In addition, after endotoxin pretreatment, the extracellular application of 100 μM L-arginine modulated the Kca channel in the cellattached patch confignrations. In inside-out patch configuration, however, NO produced by L-arginine itself did not modulate the Kca channel. This modulation of the Kca channel was suppressed by pretreatment with 100 μm Nω-nitro-L-arginine methyl ester, an inhibitor of inducible and constitutive NO synthases. Methylene blue, a blocker of guanylate cyclase, inhibited the L-arginine-induced activation of the Kca channel. These results indicate that the endotoxin-induced L-arginine pathway generates NO, which consequently modulates the Kca channel in cultured human dermal papilla cells by increasing of cyclic GMP-dependent phosphorylation

Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles

We have identified an unusual potential dual Akt/protein kinase B consensus phosphorylation motif in the protein Synip (RxKxRS97xS99). Surprisingly, serine 97 is not appreciably phosphorylated, whereas serine 99 is only a specific substrate for Akt2 but not Akt1 or Akt3. Although wild-type Synip (WT-Synip) undergoes an insulin-stimulated dissociation from Syntaxin4, the Synip serine 99 to phenylalanine mutant (S99F-Synip) is resistant to Akt2 phosphorylation and fails to display insulin-stimulated Syntaxin4 dissociation. Furthermore, overexpression of WT-Synip in 3T3L1 adipocytes had no effect on insulin-stimulated recruitment of glucose transporter 4 (GLUT4) to the plasma membrane, whereas overexpression of S99F-Synip functioned in a dominant-interfering manner by preventing insulin-stimulated GLUT4 recruitment and plasma membrane fusion. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip–Syntaxin4 interaction

Successful Treatment in a Case of Massive Hepatocellular Carcinoma with Paraneoplastic Syndrome

Paraneoplastic syndromes of hepatocellular carcinoma (HCC) are not uncommon. However, the prognosis is poor and follow-up and improvement of paraneoplastic syndromes with treatment have been reported rarely. We report a successful case in an aged man of a massive HCC with paraneoplastic syndrome, treated by combined intraarterial chemotherapy and hepatic resection. Paraneoplastic syndrome (erythrocytosis and hyperlipidemia) was monitored throughout the treatment and erythropoietin (EPO) mRNA also was analyzed in the resected liver. The hemoglobin level and serum levels of EPO and total cholesterol (T-cho) decreased dramatically with treatment, along with a decrease in serum levels of α-fetoprotein and protein induced by vitamin vitamin K absence II (PIVKA-II). Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) revealed that the residual cancer expressed EPO RNA but the nontumor tissue did not. This was a rare case of paraneoplastic syndrome of HCC that was treated successfully. This case indicates that paraneoplastic syndrome reflected tumor progression and that serum levels of both EPO and T-cho might be used as tumor markers

Delocalization of vortex in SmBa2Cu3O7−δ superconducting films with BaHfO3 nano-rods

Transport measurements revealed flux pinning properties and vortex phases in SmBa2Cu3O7−δ (Sm123) superconducting films with BaHfO3 nano-rods on LaAlO3 substrates. The films have large matching fields BΦ up to 9.9 T, nano-rod diameters of ∼6 nm, and a slight Tc degradation with Tc ∼ 91.8 K by using the low temperature growth technique. According to the transport results, a small critical exponent ∼4 indicates the presence of a Bose-glass phase in the films. Double peaks of the flux pinning force density are unexpectedly observed at high temperatures over 80 K, which is accompanied by steep drops of the crossover magnetic fields between the single vortex pinning and the collective pinning states. The drops are explained by the delocalization of the vortex where the vortex is pinned by many nano-rods in the single vortex pinning state. From the viewpoint of the vortex delocalization, we conclude that BΦ should be less than 11 T for applications at liquid nitrogen temperature

Excited States of Calogero-Sutherland Model and Singular Vectors of the WNW_N Algebra

Using the collective field method, we find a relation between the Jack symmetric polynomials, which describe the excited states of the Calogero-Sutherland model, and the singular vectors of the $W_N$ algebra. Based on this relation, we obtain their integral representations. We also give a direct algebraic method which leads to the same result, and integral representations of the skew-Jack polynomials.Comment: LaTeX, 29 pages, 2 figures, New sections for skew-Jack polynomial and example of singular vectors adde

Heart Disease, Other Circulatory Diseases, and Onset of Major Depression among Community Residents in Japan: Results of the World Mental Health Survey Japan 2002-2004

We examined whether selected circulatory diseases (heart disease, stroke, diabetes and hypertension) were associated with an increased risk of major depression in the Japanese community population. Face-to-face household surveys were carried out in 7 areas, and a total of 2,436 persons participated (overall response rate: 58.4%) from 2002 to 2004. The WHO Composite International Diagnostic Interview 3.0 was used to diagnose major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and additional interviews assessed the presence of circulatory diseases. Using data from a random subsample of the respondents (n=832), we conducted Cox proportional hazards models to calculate hazard ratios for the onset of major depression with comorbid circulatory diseases as a time-dependent covariate. Heart attack was significantly associated with the onset of major depression (hazard ratio [HR], 7.51 [95%Confidential Interval (CI), 1.36-41.45]) after adjusting for sex, birth cohort, smoking, alcohol intake, and education. Heart disease (HR, 2.12 [95% CI, 0.79-5.70]), diabetes (HR, 2.36 [95% CI, 0.42-13.34]) and hypertension (HR, 0.97 [95% CI, 0.37, 2.50]) were not significantly associated. There were no subjects who developed major depression after stroke. These results suggest that heart attack, and maybe also heart disease and diabetes, affect the onset of major depression.</p

Drug Repositioning for Cardiac Arrest

The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using “TargetMine,” a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the “survival discharge.” Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients