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Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2012年第19期18卷 2300-2308页

作者： Yoshihisa Takahashi Yurie Soejima Toshio Fukusato Department of Pathology Teikyo University School of MedicineTokyo 173-8605Japan

Nonalcoholic fatty liver disease(NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse.Nonalcoholic steatohepatitis(NASH),a severe form of NAFLD,can progress to liver cirrhosis and hepatocellular carcinoma.NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity,type 2 diabetes,and hyperlipemia.Animal models of NAFLD/NASH give crucial information,not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents.An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH.Animal models of NAFLD/NASH are divided into genetic,dietary,and combination models.In this paper,we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages.

关键词：动物模型脂肪肝酒精性肝炎肝疾病 NASH 代谢综合征 2型糖尿病

Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2015年第13期21卷 3777-3785页

作者： Yoshihisa Takahashi Keiichiro Sugimoto Hiroshi Inui Toshio Fukusato Department of Pathology Teikyo University School of MedicineTokyo 173-8605Japan Research and Development Center Nagaoka Perfumery Co. Ltd.IbarakiOsaka 567-0005Japan Center for Research and Development of Bioresources Osaka Prefecture UniversitySakaiOsaka 599-8570Japan Department of Clinical Nutrition College of Health and Human SciencesOsaka Prefecture UniversityHabikinoOsaka 583-8555Japan

Nonalcoholic fatty liver disease(NAFLD)/nonalcoholic steatohepatitis(NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers(thiazolidinediones) and antioxidants(vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.

关键词： Pharmacological therapy Nonalcoholic fatty liver d

Plexiform angiomyxoid myofi broblastic tumor of the stomach

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World Journal of Gastroenterology 2010年第23期16卷 2835-2840页

作者： Yoshihisa Takahashi Masako Suzuki Toshio Fukusato Department of Pathology Teikyo University School of Medicine Department of Pathology Sekishinkai Sayama Hospital

Plexiform angiomyxoid myofibroblastic tumor of the stomach is a unique mesenchymal tumor that we first described in 2007.The tumor is very rare,and to date,only 18 cases confirmed by immunohistochemistry have been reported in the literature.The patients' ages ranged from 7 to 75 years(mean,43 years),and the male-to-female ratio was approximately 1:1.Representative clinical symptoms are ulceration,associated upper gastrointestinal bleeding(hematemesis),and anemia.The tumors are located at the antrum in all cases,and grossly,the tumor is whitish to brownish or reddish,and forms a lobulated submucosal or transmural mass.Microscopically,the tumor is characterized by a plexiform growth pattern,the proliferation of cytologically bland spindle cells,and a myxoid stroma that is rich in small vessels and positive for Alcian blue stain.Immunohistochemically,the tumor cells are positive for α-smooth muscle actin and negative for KIT and CD34.Differential diagnoses include gastrointestinal stromal tumor and other mesenchymal tumors of the gastrointestinal tract.Some authors proposed that this tumor should be designated as "plexiform fibromyxoma",but this designation might cause confusion.The tumor is probably benign and thus far,neither recurrence nor metastasis has been reported.

关键词： Plexiform angiomyxoid myofibroblastic tumor Stomach Gastrointestinal stromal tumor Plexiform fibromyxoma Myofi broblast Fibroblast

Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2014年第42期20卷 15539-15548页

作者： Yoshihisa Takahashi Toshio Fukusato Department of Pathology Teikyo University School of Medicine

Nonalcoholic fatty liver disease(NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis(NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma(HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC(SH-HCC), showsfeatures that resemble non-neoplastic steatohepatitis,and is thought to be strongly associated with underlying NASH.In this report,we review the histopathological features of NAFLD/NASH.

关键词： Histopathology Nonalcoholic fatty liver dis-ease N

Adenomyoma of the small intestine

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World Journal of Gastrointestinal Pathophysiology 2011年第6期2卷 88-92页

作者： Yoshihisa Takahashi Toshio Fukusato Department of Pathology Teikyo University School of Medicine2-11-1 Kaga Itabashi-kuTokyo 173-8605Japan

Adenomyoma of the gastrointestinal tract is a rare benign tumor-like lesion.The small intestine is the second most frequent location,usually in the periampullary area,but the lesion also occurs in the jejunum and ileum.While adenomyoma of the Vaterian system is primarily diagnosed in adults,more than half of reported cases of jejunal and ileal adenomyoma have been diagnosed in pediatric patients.Adenomyoma of the periampullary area usually presents with biliary obstruction or abdominal pain,whereas jejunal and ileal adenomyoma usually presents with intussusception or is incidentally discovered during surgery or autopsy.Since endoscopic and radiological examination yields uncharacteristic findings,histopathological evaluation is important in adenomyoma diagnosis.Pathologically,adenomyoma consists of glandular structures of various sizes and interlacing smooth muscle bundles that surround the glandular elements.The pathogenesis of adenomyoma is generally considered to be either a form of hamartoma or a pancreatic heterotopia.Although limited resection is considered the most effective treatment,pancreaticoduodenectomy is often performed when the lesion occurs in the periampullary area due to preoperative misdiagnosis as a carcinoma.It is,therefore,important that clinicians and pathologists maintain current knowledge of the disease to avoid inaccurate diagnosis,which could lead to unnecessary surgery.

关键词： Adenomyoma Small intestine Biliary obstruction Intussusception Hamartoma Heterotopic pancreas

Russell body duodenitis in a patient with retroperitoneal metastasis of ureteral cancer

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World Journal of Gastroenterology 2013年第1期19卷 125-128页

作者： Yoshihisa Takahashi Seiichiro Shimizu Koji Uraushihara Toshio Fukusato Department of Pathology Teikyo University School of MedicineTokyo 173-8605Japan Department of Pathology Showa General HospitalTokyo 187-8510Japan Department of Gastrointestinal Medicine Showa General HospitalTokyo 187-8510Japan

Russell bodies are globular and eosinophilic inclusion bodies in the cytoplasm of mature plasma cells.Plasma cells whose cytoplasm is filled with Russell bodies are designated as Mott cells.Russell body duodenitis(RBD) is a unique form of chronic duodenitis that is characterized by infiltration of numerous Mott cells.RBD is very rare;only two cases have been reported to date.In this paper,we report a case of RBD in a patient with retroperitoneal metastasis of ureteral cancer.A 77-year-old man was admitted to our hospital complaining of appetite loss,vomiting,and upper abdominal distension.He had undergone left nephroureterectomy for ureteral cancer 4 years earlier.Upper digestive tract endoscopy revealed edema,stenosis,and punctate redness of the mucosa of the duodenum,and a biopsy was performed.Histological analysis showed that numerous Mott cells had infiltrated the lamina propria mucosae,and the condition was diagnosed as RBD.A mass lesion in the retroperitoneum adjacent to the duodenum was detected by abdominal computed tomography,and was diagnosed as metastatic urothelial carcinoma by biopsy.It is possible that chemokines produced by tumor cells caused RBD in this case.

关键词： Russell body Duodenitis Ureteral cancer Mott cells Plasma cells

Protein induced by vitamin K absence or antagonist Ⅱ-producing gastric cancer

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World Journal of Gastrointestinal Pathophysiology 2010年第4期1卷 129-136页

作者： Yoshihisa Takahashi Tohru Inoue Toshio Fukusato Department of Pathology Teikyo University School of Medicine Department of Pathology Tokyo Kousei-Nenkin Hospital

Protein induced by vitamin K absence or antagonist Ⅱ(PIVKA-Ⅱ) is a putative specific marker of hepatocellular carcinoma(HCC),but it may also be produced by asmall number of gastric cancers.To date,16 cases of PIVKA-Ⅱ-producing gastric cancer have been reported,2 of which were reported by us and all of which were identified in Japan.There are no symptoms specific to PIVKA-Ⅱ-producing gastric cancer,and the representative clinical symptoms are general fatigue,appetite loss,and upper abdominal pain.Serum alpha-feto-protein(AFP)levels are also increased in almost allcases.Liver metastasis is observed in approximately 80% of cases and portal vein tumor thrombus is ob-served in approximately 20% of cases.Differential diagnosis between metastatic liver tumor and HCC is often difficult.Grossly,almost all cases appear as advanced gastric cancer.Histologically,a hepatoid pattern is observed in many cases,in addition to a moderately to poorly differentiated adenocarcinoma component.The production of PIVKA-Ⅱ and AFP is usually confirmed using immunohistochemical staining.Treatment and prognosis largely depends on the existence of liver meta-stasis,and the prognosis of patients with liver metas-tasis is very poor.PIVKA-Ⅱ may be produced during the hepatocellular metaplasia of the tumor cells.

关键词： Protein induced by vitamin K absence or antagonist Ⅱ Gastric cancer Alpha-fetoprotein Hepato-cellular carcinoma Hepatoid carcinoma

Spontaneous regression of hepatic inflammatory pseudotumor with primary biliary cirrhosis:Case report and literature review

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World Journal of Gastroenterology 2006年第10期12卷 1645-1648页

作者： Hiroshi Koide Ken Sato Toshio Fukusato Kenji Kashiwabara Noriaki Sunaga Takafumi Tsuchiya Saeko Morino Naondo Sohara Satoru Kakizaki Hitoshi Takagi Masatomo Mori Department of Medicine and Molecular Science Gunma University Graduate School of Medicine MaebashiGunma 371-8511Japan Department of Pathology Teikyo University School of Medicine Itabashi-kuTokyo 173-8605Japan Clinical Pathology Gunma University Graduate School of Medicine MaebashiGunma 371-8511Japan

肝的煽动性的假肿瘤(IPT ) 是煽动性的房间渗入的增殖的纤维组织描绘的稀罕良性的非肿瘤的损害。IPT 的准确病原学仍然保持不清楚。尽管有全身的煽动性的混乱的 IPT 的协会很好被建立了，有胆管炎的一种特殊关系是显然稀罕的。我们与主... 详细信息

肝的煽动性的假肿瘤(IPT ) 是煽动性的房间渗入的增殖的纤维组织描绘的稀罕良性的非肿瘤的损害。IPT 的准确病原学仍然保持不清楚。尽管有全身的煽动性的混乱的 IPT 的协会很好被建立了，有胆管炎的一种特殊关系是显然稀罕的。我们与主要胆汁性肝硬变(PBC ) 报导肝的 IPT 的自发的回归的一个案例。迄今为止，仅仅有 PBC 的 IPT 的二个案例被报导了。在我们的情况中，然而， IPT 在有效治疗导致的 PBC 的胆管炎的改进的功课期间发展了，不同于二个以前报导的案例。我们的案例显示 IPT 的发展也不联系到胆管炎或亢奋的 gamma-globulinemia 的活动，自从我们的案例被证实当胆汁的酶和免疫球蛋白比承认上的相应价值高得多时，没有 IPT 的放射线学的联盟者。我们有二个以前报导的案例的案例的比较建议与 PBC 发生的 IPT 不代表一样的疾病实体或是为 PBC 的一个旁观者。

关键词：自行退化肝脏炎性假瘤胆硬化苯扎贝特

Reducing model biases is essential to projecting future climate variability

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National Science Review 2021年第10期8卷 136-137页

作者： toshio Yamagata Application Lab Japan Agency for Marine-Earth Science and Technology

Extreme El Ni?o events not only cause climate disasters leading to enormous socioeconomic losses, but also have devastating impacts on the world’s ecosystems [1,2]. A reliable projection of their frequency change in the future warmer climate is therefore very important for our sustainable development as well as disaster prevention [3].

关键词： EL-NINO OCEAN