Attenuation of ischemic liver injury by prostaglandin E<inf>1</inf> analogue, misoprostol, and prostaglandin I<inf>2</inf> analogue, OP-41483

Background: Prostaglandin has been reported to have protective effects against liver injury. Use of this agent in clinical settings, however, is limited because of drugrelated side effects. This study investigated whether misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2 analogue, which have fewer adverse effects with a longer half-life, attenuate ischemic liver damage. Study Design: Thirty beagle dogs underwent 2 hours of hepatic vascular exclusion using venovenous bypass. Misoprostol was administered intravenously for 30 minutes before ischemia and for 3 hours after reperfusion. OP-41483 was administered intraportally for 30 minutes before ischemia (2 μg/kg/min) and for 3 hours after reperfusion (0.5 μg/kg/min). Animals were divided into five groups: untreated control group (n = 10); high-dose misoprostol (total 100 μg/kg) group (MP-H, n = 5); middle-dose misoprostol (50 μg/kg) group (MP-M, n = 5); low-dose misoprostol (25 μg/kg) group (MP-L, n = 5); and OP-41483 group (OP, n = 5). Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology were analyzed. Results: Two-week animal survival rates were 30% in control, 60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments with prostaglandin analogues improved HTBF, and attenuated liver enzyme release, adenine nucleotrides degradation, and histologic abnormalities. In contrast to the MP-H animals that exhibited unstable cardiovascular systems, the MP- M, MP-L, and OP animals experienced only transient hypotension. Conclusions: These results indicate that misoprostol and OP-41483 prevent ischemic liver damage, although careful dose adjustment of misoprostol is required to obtain the best protection with minimal side effects

Statistical Mechanics of Nonlinear On-line Learning for Ensemble Teachers

We analyze the generalization performance of a student in a model composed of nonlinear perceptrons: a true teacher, ensemble teachers, and the student. We calculate the generalization error of the student analytically or numerically using statistical mechanics in the framework of on-line learning. We treat two well-known learning rules: Hebbian learning and perceptron learning. As a result, it is proven that the nonlinear model shows qualitatively different behaviors from the linear model. Moreover, it is clarified that Hebbian learning and perceptron learning show qualitatively different behaviors from each other. In Hebbian learning, we can analytically obtain the solutions. In this case, the generalization error monotonically decreases. The steady value of the generalization error is independent of the learning rate. The larger the number of teachers is and the more variety the ensemble teachers have, the smaller the generalization error is. In perceptron learning, we have to numerically obtain the solutions. In this case, the dynamical behaviors of the generalization error are non-monotonic. The smaller the learning rate is, the larger the number of teachers is; and the more variety the ensemble teachers have, the smaller the minimum value of the generalization error is.Comment: 13 pages, 9 figure

Simulation of Lattice Polymers with Multi-Self-Overlap Ensemble

A novel family of dynamical Monte Carlo algorithms for lattice polymers is proposed. Our central idea is to simulate an extended ensemble in which the self-avoiding condition is systematically weakened. The degree of the self-overlap is controlled in a similar manner as the multicanonical ensemble. As a consequence, the ensemble --the multi-self-overlap ensemble-- contains adequate portions of self-overlapping conformations as well as higher energy ones. It is shown that the multi-self-overlap ensemble algorithm reproduce correctly the canonical averages at finite temperatures of the HP model of lattice proteins. Moreover, it outperforms massively a standard multicanonical algorithm for a difficult example of a polymer with 8-stickers. Alternative algorithm based on exchange Monte Carlo method is also discussed.Comment: 5 Pages, 4 Postscript figures, uses epsf.st

Attenuation of ischemic liver injury by monoclonal anti-endothelin antibody, awETN40

Background: Enhanced production of endothelin-1 (ET1), vasoconstrictive 21 amino acids produced by endothelial cells during ischemia and after reperfusion of the liver, is known to cause sinusoidal constriction and microcirculatory disturbances, which lead to severe tissue damage. Using a 2- hour hepatic vascular exclusion model in dogs, we tested our hypothesis that neutralization of ET-1 by monoclonal anti-ET-1 and anti-ET-2 antibody (AwETN40) abates vascular dysfunction and ameliorates ischemia/reperfusion injury of the liver. Study Design: After skeletonization, the liver was made totally ischemic by cross-clamping the portal vein, the hepatic artery, and the vena cava (above and below the liver). Venovenous bypass was used to decompress splanchnic and inferior systemic congestion. AwETN40, 5 mg/kg, was administered intravenously 10 minutes before ischemia (treatment group, n = 5). Nontreated animals were used as controls (control group, n = 10). Animal survival, hepatic tissue blood flow, liver function tests; total bile acid, high-energy phosphate, ET-1 levels, and liver histopathology were studied. Results: Treatment with AwETN40 improved 2-week animal survival from 30% to 100%. Hepatic tissue blood flow after reperfusion was significantly higher in the treatment group. The treatment significantly attenuated liver enzyme release, total bile acid, and changes in adenine nucleotides. Immunoreactive ET-1 levels in the hepatic venous blood of the control group showed a significant increase and remained high for up to 24 hours after reperfusion. Histopathologic alterations were significantly lessened in the treatment group. Conclusions: These results indicate that ET-1 is involved in ischemia/reperfusion injury of the liver, which can be ameliorated by the monoclonal anti-ET-1 and antiET-2 antibody AwETN40

Superoxide dismutase analog (Tempol: 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl) treatment restores erectile function in diabetes-induced impotence.

We hypothesized that the administration of the superoxide dismutase (SOD) mimetic Tempol (4-hydroxy-2, 2, 6, 6-tetramethylpiperidine 1-oxyl) may reverse diabetes-induced erectile dysfunction. To test this hypothesis, reactive oxygen species-related genes (SOD1, SOD2, GP x 1, CAT, NOS2, NOS3) were tested, erectile functional studies and immunohistochemical analysis were carried out in diabetic rats treated with or without Tempol. Thirty Sprague-Dawley (3-4 months old) rats were divided into three groups (n=10 each), 20 with diabetes (diabetic control and Tempol treatment) and 10 healthy controls. At 12 weeks after the induction of diabetes by streptozotocin and Tempol treatment, all groups underwent in vivo cavernous nerve stimulation. Rat crura were harvested and the expression of antioxidative defense enzymes were examined by semi-quantitative reverse transcriptase PCR (RT-PCR). To confirm the RT-PCR results, we carried out immunohistochemistry (IHC) for catalase (CAT) and iNOS (NOS2). Nitration of tyrosine groups in proteins was also examined by IHC. Mean intracavernous pressure in the diabetic group was significantly lower than in the healthy controls (P &lt;0.001) and was reversed by Tempol treatment (P &lt;0.0108). NOS2 protein expression was significantly increased in diabetic animals compared with healthy controls and Tempol restored NOS2 protein level. Nitrotyrosine was also higher in diabetic animals and although Tempol treatment decreased its formation, it remained higher than that found in healthy controls. This study suggests that Tempol treatment increased erectile function through modulating oxidative stress-related genes in diabetic rats. This is the first report about the relationship between diabetes-induced erectile dysfunction and oxidative stress, and antioxidative therapy using the superoxide dismutase mimetic, Tempol, to restore erectile function

Deformation of Equilibrium Shape of a Vesicle Induced by Injected Flexible Polymers

Using field theoretic approach, we study equilibrium shape deformation of a vesicle induced by the presence of enclosed flexible polymers, which is a simple model of drug delivery system or endocytosis. To evaluate the total free energy of this system, it is necessary to calculate the bending elastic energy of the membrane, the conformation entropy of the polymers and their interactions. For this purpose, we combine phase field theory for the membrane and self-consistent field theory for the polymers. Simulations on this coupled model system for axiosymmetric shapes show a shape deformation of the vesicle induced by introducing polymers into it. We examined the dependence of the stability of the vesicle shape on the chain length of the polymers and the packing ratio of the vesicle. We present a simple model calculation that shows the relative stability of the prolate shape compared to the oblate shape.Comment: 5 pages, 3 figure

Genome Comparison and Phylogenetic Analysis of Orientia tsutsugamushi Strains

Orientia tsutsugamushi (OT) is an obligate intracellular bacterium belonging to the family Rickettsiaceae and is the causative agent of scrub typhus, or Tsutsugamushi disease. The complete genome sequences of two OT strains (Boryong and Ikeda) have recently been determined. In the present study, we performed a fine genome sequence comparison of these strains. Our results indicate that although the core gene set of the family Rickettsiaceae is highly conserved between the two strains, a common set of repetitive sequences have been explosively amplified in both genomes. These amplified repetitive sequences have induced extensive genome shuffling and duplications and deletions of many genes. On the basis of the results of the genome sequence comparison, we selected 11 housekeeping genes and carried out multilocus sequence analysis of OT strains using the nucleotide sequences of these genes. This analysis revealed for the first time the phylogenetic relationships of representative OT strains. Furthermore, the results suggest the presence of an OT lineage with higher potential for virulence, which may explain the clinical and epidemiological differences between ‘classic’ and ‘new’ types of Tsutsugamushi disease in Japan