Demonstration of intrahepatic accumulated microbubble on ultrasound represents the grade of hepatic fibrosis

OBJECTIVES: To examine the feasibility of perflubutane-based ultrasound for grading hepatic fibrosis. METHODS: This prospective study included 202 subjects; main study (controls:33, F0–1:35, F2:26, F3:23, cirrhosis:29) and subsequent study (controls:16, F0–1:7, F2:20, F3:7, cirrhosis:6). Diagnostic abilities for assessing fibrosis grade were compared between contrast findings and FIB4 (age × AST/[platelet count × ALT(0.5)]). RESULTS: High-power emission produced an intrahepatic band-like structure, and the three-layer appearance was less frequent and monolayer appearance was more frequent in cirrhosis than controls/chronic hepatitis (P < 0.0001). Intensity difference at 15-min phase showed most significant correlation with fibrosis grade (ρ = 0.79, P < 0.0001), and the best areas under the receiver operating characteristic curves are 0.88 for marked fibrosis, 0.95 for advanced fibrosis and 0.97 for cirrhosis, which were significantly higher than those of FIB4, 0.85 for marked fibrosis, 0.89 for advanced fibrosis and 0.90 for cirrhosis. Sensitivity, specificity and efficiency of the intensity difference were 88%, 72% and 81% for marked fibrosis, 85%, 91% and 89% for advanced fibrosis and 97%, 90% and 91% for cirrhosis, respectively. The subsequent study validated the main study results; significant correlation between the intensity difference and the fibrosis grade (ρ = 0.73–0.77, P < 0.0001). CONCLUSIONS: Perflubutane-based ultrasound accurately predicts the grade of hepatic fibrosis. KEY POINTS: • The behaviour of intrahepatic microbubbles depends on the severity of hepatic fibrosis. • Layer enhancement pattern simply represents the degree of chronic liver disease. • Parenchymal intensity change due to high-power emission predicts the hepatic fibrosis grade

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

金沢大学大学院自然科学研究科生理活性物質科学The effect of positional change of the carbonyl group of enamides on Bu3SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides. © 2008 Elsevier Ltd. All rights reserved

ラジカル環化反応の位置化学の制御と生理活性化合物合成への応用

金沢大学大学院自然科学研究科生理活性物質科学金沢大学薬学

Production of anti-Candida antibodies in mice with gut colonization of Candida albicans.

BACKGROUND: Production of antibodies that are specific for allergens is an important pathological process in inflammatory allergic diseases. These contain the antibodies against antigens of Candida albicans, one of the normal microbial flora in an intestinal tract. We studied the effects of the prednisolone administration on the production of anti-Candida antibodies in the gastrointestinally C. albicans-colonized mice. METHODS AND MATERIALS: BALB/c mice, treated with antibacterial antibiotics to decontaminate indigenous intestinal bacterial flora, were inoculated intragastrically with C. albicans. The mice, in which C. albicans grows intestinally, were administered prednisolone to induce temporary immunosuppression. The Candida growth in their intestinal tract and their antibody response to Candida were examined. RESULTS: Antibiotic treatment allowed establishment of C. albicans gastrointestinal colonization, but did not cause subsequent systemic dissemination of C. albicans in all the animals. When these animals received an additional treatment with prednisolone, they showed a significantly higher population of C. albicans in their feces than those of animals treated with antibiotics alone, and the organisms were recovered even from their kidney. This systemic dissemination by C. albicans appeared to be temporal, because all the mice survived without any symptoms for more than 2 months. Examination of the serum titers of total immunoglobulin (Ig)E antibodies and specific IgE and IgG antibodies against Candida antigens demonstrated that titers of total IgE increased, partially by day 14 and clearly at day 27, in prednisolone-treated Candida-colonized mice. Without prednisolone treatment, an increment of the serum titer was scarcely observed. By day 27, corresponding to the increase of total IgE, the anti-Candida IgE and IgG titer increased in mice of the prednisolone-treated group. CONCLUSION: Administration of prednisolone to Candida-colonized mice can induce production of the IgG, IgE antibodies against Candida antigens, perhaps through temporal systemic dissemination of Candida from the intestinal tract

Real-Time PCR-Based Analysis of the Human Bile MicroRNAome Identifies miR-9 as a Potential Diagnostic Biomarker for Biliary Tract Cancer

Biliary tract cancer (BTC) is often difficult to diagnose definitively, even through histological examination. MicroRNAs (miRNAs) regulate a variety of physiological processes. In recent years, it has been suggested that profiles for circulating miRNAs, as well as those for tissue miRNAs, have the potential to be used as diagnostic biomarkers for cancer. The aim of this study was to confirm the existence of miRNAs in human bile and to assess their potential as clinical biomarkers for BTC. We sampled bile from patients who underwent biliary drainage for biliary diseases such as BTC and choledocholithiasis. PCR-based miRNA detection and miRNA cloning were performed to identify bile miRNAs. Using high-throughput real-time PCR-based miRNA microarrays, the expression profiles of 667 miRNAs were compared in patients with malignant disease (n = 9) and age-matched patients with the benign disease choledocholithiasis (n = 9). We subsequently characterized bile miRNAs in terms of stability and localization. Through cloning and using PCR methods, we confirmed that miRNAs exist in bile. Differential analysis of bile miRNAs demonstrated that 10 of the 667 miRNAs were significantly more highly expressed in the malignant group than in the benign group at P<0.0005. Setting the specificity threshold to 100% showed that some miRNAs (miR-9, miR-302c*, miR-199a-3p and miR-222*) had a sensitivity level of 88.9%, and receiver-operating characteristic analysis demonstrated that miR-9 and miR-145* could be useful diagnostic markers for BTC. Moreover, we verified the long-term stability of miRNAs in bile, a characteristic that makes them suitable for diagnostic use in clinical settings. We also confirmed that bile miRNAs are localized to the malignant/benign biliary epithelia. These findings suggest that bile miRNAs could be informative biomarkers for hepatobiliary disease and that some miRNAs, particularly miR-9, may be helpful in the diagnosis and clinical management of BTC

The Effects of Exercise Training on Obesity-Induced Dysregulated Expression of Adipokines in White Adipose Tissue

Obesity is recognized as a risk factor for lifestyle-related diseases such as type 2 diabetes and cardiovascular disease. White adipose tissue (WAT) is not only a static storage site for energy; it is also a dynamic tissue that is actively involved in metabolic reactions and produces humoral factors, such as leptin and adiponectin, which are collectively referred to as adipokines. Additionally, because there is much evidence that obesity-induced inflammatory changes in WAT, which is caused by dysregulated expression of inflammation-related adipokines involving tumor necrosis factor-α and monocyte chemoattractant protein 1, contribute to the development of insulin resistance, WAT has attracted special attention as an organ that causes diabetes and other lifestyle-related diseases. Exercise training (TR) not only leads to a decrease in WAT mass but also attenuates obesity-induced dysregulated expression of the inflammation-related adipokines in WAT. Therefore, TR is widely used as a tool for preventing and improving lifestyle-related diseases. This review outlines the impact of TR on the expression and secretory response of adipokines in WAT

Intermolecular cycloaddition of ethyl glyoxylate O-tert- butyldimethylsilyloxime with alkenes

金沢大学大学院自然科学研究科生理活性物質科学金沢大学薬学部Ethyl glyoxylate O-tert-butyldimethylsilyloxime, on treatment with various alkenes in the presence of BF3·OEt2, generated a C-ethoxycarbonyl N-boranonitrone intermediate, which underwent intermolecular cycloaddition to afford 3-(ethoxycarbonyl)isoxazolidines in moderate to high yields. © Georg Thieme Verlag Stuttgart