2015年日本胃肠病学会非酒精性脂肪性肝病/非酒精性脂肪性肝炎的循证医学临床治疗指南

目前非酒精性脂肪性肝病（NAFLD）是世界范围内工业化国家中慢性肝病最常见的原因,并且已经成为西方国家以及许多亚洲国家的严重公共健康问题。在NAFLD的疾病谱中,非酒精性脂肪性肝炎（NASH）是疾病的进展形式,可发展至肝硬化,并且会增加发生肝细胞癌（HCC）的风险。大部分NAFLD/NASH是代谢综合征的肝脏表现,这提示NAFLD/NASH在全身动脉粥样硬化疾病的发病过程中亦发挥重要作用。

酒精性肝病的发病机理和新的治疗靶点

酒精性肝病是世界范围内慢性肝病的一个主要原因,但是其发病机制尚不完全清楚,因此缺少靶向治疗的方法。总结了最近一些阐述酒精性肝病发病机制和诊断的研究,并且讨论了酒精性肝炎的几个新的治疗靶点。认为迫切须要将这些靶点转化为酒精性肝病患者的治疗方法。

Elevated Linoleic Acid (A Pro-Inflammatory PUFA) and Liver Injury in a Treatment Naive HIV-HCV Co-Infected Alcohol Dependent Patient

HIV and HCV co-infection is a unique disease condition, and medical management of such condition is difficult due to severity and systemic complications. Added with heavy alcohol drinking, risk of liver injury increases due to several pro-inflammatory responses that subsequently get involved with alcohol metabolism. Elevated levels of fatty acids have been reported both in viral infections as well as alcoholic liver disease though such investigations have not addressed the adverse event with dual viral infection of HIV and HCV along with heavy drinking. This case report of a patient with excessive alcohol drinking and first time diagnosis of HIV and HCV dual infection, elaborating concurrent alteration in Linoleic Acid (LA) levels and pro-inflammatory shift in ω-6/ω-3 ratio along with the elevations in liver injury markers. Elevated LA has been recently studied extensively for its role in alcoholic liver disease;and in the present case, we also found it to be clinically relevant to liver injury.

Analysis of fMRI Single Subject Data in the Fourier Domain Acquired Using a Multiple Input Stimulus Experimental Design

Analysis of functional MRI (fMRI) blood oxygenation level dependent (BOLD) data is typically carried out in the time domain where the data has a high temporal correlation. These analyses usually employ parametric models of the hemodynamic response function (HRF) where either pre-whitening of the data is attempted or autoregressive (AR) models are employed to model the noise. Statistical analysis then proceeds via regression of the convolution of the HRF with the input stimuli. This approach has limitations when considering that the time series collected are embedded in a brain image in which the AR model order may vary and pre-whitening techniques may be insufficient for handling faster sampling times. However fMRI data can be analyzed in the Fourier domain where the assumptions made as to the structure of the noise can be less restrictive and hypothesis tests are straightforward for single subject analysis, especially useful in a clinical setting. This allows for experiments that can have both fast temporal sampling and event-related designs where stimuli can be closely spaced in time. Equally important, statistical analysis in the Fourier domain focuses on hypothesis tests based on nonparametric estimates of the hemodynamic transfer function (HRF in the frequency domain). This is especially important for experimental designs involving multiple states (drug or stimulus induced) that may alter the form of the response function. In this context a univariate general linear model in the Fourier domain has been applied to analyze BOLD data sampled at a rate of 400 ms from an experiment that used a two-way ANOVA design for the deterministic stimulus inputs with inter-stimulus time intervals chosen from Poisson distributions of equal intensity.

Abuse-related effects of synthetic cathinones：importance of DAT/SERT relationships

OBJECTIVE Wide spread abuse of synthetic cathinones found in bath salts preparations has resulted in regulation of some cathinones internationally.Chemists skirt these laws by altering the chemical structures of first-generation cathinones(ie,MDPV,methylone,and mephedrone),resulting in second-generation cathinones(eg,α-PVP,α-PPP,MDPPP,and MDPBP).Although MDPV is a more effective reinforcer than cocaine,little is known about the reinforcing effectiveness of secondgeneration cathinones.To test the hypothesis that synthetic cathinones with higher selectivity for DAT relative to SERT are more effective reinforcers.METHODS Monoamine transporter inhibition was determined using synaptosomes prepared from rat brains.The relative reinforcing effectiveness of intravenously self-administered MDPV,MDPBP,MDPPP,α-PVP,α-PPP,and cocaine were directly compared through evaluations of (1)dose-response curves under a progressive ratio(PR)schedule of reinforcement and (2)demand curves obtained for each drug in male Sprague-Dawley rats.RESULTS Rank order selectivity for DAT/SERT wasα-PVP>MDPV>α-PPP≈MDPBP>MDPPP>cocaine.Comparisons of the maximum number of infusions obtained under a PR schedule of reinforcement(α-PVP>MDPV>α-PPP>MDPBP≈MDPPP>cocaine)and the essential value obtained for each drug in demand analyses(α-PVP>MDPV>α-PPP≈MDPBP≈MDPPP>cocaine)suggest relative reinforcing effectiveness is related to DAT/SERT selectivity.CONCLUSION These data provide evidence that DAT/SERT selectivity accounts for select synthetic cathinones functioning as more effective reinforcers than cocaine and may predict the abuse-related effects of novel synthetic cathinones in humans.

Hydrodynamic Gene Delivery of Interleukin-22 Protects the Mouse Liver from Concanavalin A-, Carbon Tetrachloride-,and Fas Ligand-Induced Injury via Activation of STAT3

Interleukin-22 (IL-22) is a recently identified T cell-derived cytokine whose biological significance remains obscure.Previously,we have shown that IL-22 plays a protective role in T cell-mediated hepatitis induced by Concanavalin A (Con A),acting as a survival factor for hepatocytes.In the present paper,we demonstrate that hydrodynamic gene delivery of IL-22 cDNA driven either by a liver-specific albumin promoter or a human cytomegalovirus (CMV) promoter results in IL-22 protein expression,STAT3 activation,and expression of several anti-apoptotic proteins,including Bcl-xL,Bcl-2,and Mcl-1 in the liver.Immunohistochemical analysis reveals that IL-22 protein expression is mainly detected in the cytoplasm of hepatocytes.Overexpression of IL-22 by hydrodynamic gene delivery significantly protects against liver injury,necrosis,and apoptosis induced by administration of Con A,carbon tetrachloride (CCl_4),or the Fas agonist Jo-2 mAb.Western blot analyses show that overexpression of IL-22 significantly enhances activation of STAT3 and expression of Bcl-xL,Bcl-2, and Mcl-1 proteins in liver injury induced by Con A.In conclusion,hydrodynamic gene delivery of IL-22 protects against liver injury induced by a variety of toxins,suggesting the therapeutic potential of IL-22 in treating human liver disease.Cellular & Molecular Immunology.2004;1(1):43-49.

Basic liver immunology

The liver is the largest solid organ in the body and has many unique immunological properties, including induction of immune tolerance, strong innate immunity, poor adaptive immune response versus overreactive autoimmunity and hematopoiesis in the fetal liver. Thus, the liver has been proposed as ＇an immunological organ＇. Although the primary functions of the liver are not traditionally considered to be immunological, the liver also performs many essential immune tasks. For example, hepatocytes are responsible for the production of 80-90% of the circulating innate immunity proteins in the body,