Improving performance and self-efficacy of novice nurses using hybrid simulation-based mastery learning.

AIM: Acute chest pain is a commonly encountered symptom in hospital medical/surgical units; however, almost half of nurses in their second year of clinical experience in our facility have reported struggling to care for acute chest pain patients. We developed, implemented, and examined the effectiveness of a simulation-based, mastery learning clinical nursing educational program to improve self-efficacy and performance in caring for patients with acute chest pain. METHODS: The study adopted a single-site, single-cohort design using simulation-based performance assessment and self-efficacy surveys on a convenience sample of 37 second-year clinical nurse participants in multi-stage hybrid mastery learning educational intervention using asynchronous e-learning, and hands-on simulation training and assessment with feedback on caring for chest pain patients. Performance assessments and self-efficacy surveys were administered pre-, post-, and 5 months post-intervention. RESULTS: Clinical performance on the post- and 5 months follow-up assessments were significantly higher than those for the pre-test (P < .0001). The self-efficacy scores for the post- and the 5 months follow-up assessments were significantly higher than the pre-course scores (P < .0001). Participants' self-efficacy perceptions were positively correlated with their performances at 5 months post-intervention. CONCLUSION: Performance and self-efficacy of novice nurses in caring for acute chest pain patients improved significantly with the multi-stage hybrid mastery learning educational intervention, with improvements retained 5 months post-intervention. The results suggest the applicability of simulation-based mastery learning in a clinical setting for novice nurses to attain specific skills, and raise their self-perception of competence to care for patients in acute settings.

Sarcoidosis with Splenic Involvement Diagnosed with Endoscopic Ultrasound-guided Fine-needle Aspiration.

Splenic sarcoidosis is often diagnosed by splenectomy or an ultrasound-guided splenic biopsy. However, splenectomy is invasive and costly, and a percutaneous biopsy is sometimes difficult. We herein report a case of splenic sarcoidosis diagnosed with endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). A 71-year-old man was referred to our hospital for abnormal shadows on a chest roentgenogram. Computed tomography showed multiple lesions in the spleen and pulmonary consolidations. Bronchoscopy revealed no definitive diagnosis. We therefore performed EUS-FNA for a splenic lesion that led to the diagnosis. This case suggests that EUS-FNA is useful in confirming the diagnosis of sarcoidosis with suspected splenic lesions.

Toll-like Receptor 4 on Macrophage Promotes the Development of Steatohepatitis-related Hepatocellular Carcinoma in Mice.

The role of Toll-like receptor (TLR) signaling has attracted much attention in the development of hepatic inflammation and hepatocellular carcinoma (HCC). We herein sought to determine the role of TLRs and responsible cells in steatohepatitis-related HCC. We used hepatocyte-specific Pten-deficient (Pten(Δ) (hep)) mice, which exhibit steatohepatitis followed by liver tumor formation, including HCC. We then generated Pten(Δ) (hep)/Tlr4(-/-) and Pten(Δ) (hep)/Tlr2(-/-) double-mutant mice and investigated the role of macrophages using reconstitution of bone marrow (BM)-derived cells, chemical depletion of macrophages, and isolated macrophages. Tlr4 but not Tlr2 deficiency in the Pten(Δ) (hep) mice suppressed tumor growth as well as hepatic inflammation. Gut sterilization by an antibiotic mixture reduced the portal LPS levels as well as tumor growth in the Pten(Δ) (hep) mice. Tumor growth was also decreased by reconstitution of BM-derived cells to Tlr4(-/-) BM cells. In addition, chemical depletion of macrophages significantly reduced tumor size and numbers. Macrophages expressing Ly6C were increased in number, which was associated with inflammation and tumor progression in the Pten(Δ) (hep) mice. Hepatic macrophages isolated from the Pten(Δ) (hep) mice abundantly expressed the Ly6C gene and produced much more IL-6 and TNFα in response to LPS. These proinflammatory cytokines induced the proliferation of HCC cells as well as oval cells, putative cancer progenitor cells. Indeed, putative cancer progenitor cells emerged before the development of macroscopic liver tumors and then increased in number under sustained inflammation. TLR4 on macrophages contributes to the development of steatohepatitis-related HCC in mice.

Efficacy of combined balloon-occluded retrograde transvenous obliteration and simultaneous endoscopic injection sclerotherapy.

OBJECTIVE: We evaluated the efficacy and safety of balloon-occluded retrograde transvenous obliteration (B-RTO) performed using absolute ethanol with iodized oil (ET+LPD) and simultaneous endoscopic injection sclerotherapy (EIS) with cyanoacrylate (CA) for gastric varices (GVs). METHODS: A total of 16 patients with endoscopically proven high-risk GVs treated using combined B-RTO with ET+LPD and EIS with CA between January 2007 and July 2012 were enrolled. RESULTS: Twelve cases included GVs involving both the cardia and fundus, two cases included fundal varices and two cases included cardiac varices. In terms of the form of GVs, 10 cases involved F2 lesions and six cases involved F3 lesions. The flow vein was the left gastric vein in 13 cases and the posterior gastric vein in three cases. The drainage route was a splenorenal shunt in all cases. The average dose of ET+LPD was 12.0 mL, while that of CA was 2.45 mL. All complications were transient, and no major complications occurred after the procedures. None of the patients experienced bleeding or recurrence of gastric varices after the combined B-RTO and EIS procedures during an average follow-up period of 38.3 months. CONCLUSION: Combined B-RTO with ET+LPD and simultaneous EIS with CA is considered to be an effective and safe procedure for treating GVs.

Successful treatment of hepatocellular carcinoma with lung metastasis using hepatic and bronchial artery infusion chemotherapy.

We herein report a case of hepatocellular carcinoma (HCC) with lung metastasis that was successfully treated with transcatheter arterial infusion chemotherapy via the hepatic and bronchial arteries. A 64-year-old man diagnosed with HCC in 2003 was treated with locoregional therapy followed by sorafenib for recurrent HCC. Tumor thrombosis and lung metastasis were noted in April 2012. We administered IA-call(®), a fine-powder formulation of cisplatin, via the hepatic and bronchial arteries. This therapy resulted in the disappearance of the lung metastases and a partial response to tumor thrombosis. The patient remained alive for 23 months after developing lung metastasis.

A chronic subdural hematoma in a patient receiving combination therapy with pegylated interferon alfa-2b and ribavirin for chronic hepatitis C.

A 70-year-old man who suffered from chronic hepatitis C was infected with HCV genotype 1 and exhibited a high viral load. He had hypertension and had consumed the equivalent of 50 g of ethanol per day. He was treated with pegylated interferon and ribavirin. After 51 weeks, he developed an unsteady gait while walking and demonstrated Barre's sign on the right foot and a headache. Contrast computed tomography showed a subdural hematoma with a mass effect. The patient was treated with drainage and aspiration surgery via a burr hole. Following the drainage procedure, there were no neurological sequelae. Treatment with pegylated interferon and ribavirin was discontinued. Fortunately, a sustained virological response was achieved.

Efficacy of contrast-enhanced ultrasonography in radiofrequency ablation for hepatocellular carcinoma.

OBJECTIVE: Local recurrence after radiofrequency ablation (RFA) is a major problem that needs to resolved to increase the survival rate of hepatocellular carcinoma (HCC). CE-US with Sonazoid(®), the second-generation contrast media, can detect smaller HCC lesions and the detection rate of ultrasonically unrecognized hypervascular HCC was improved by CE-US. The aim of the present study was to evaluate the role of CE-US with Sonazoid(®) in improving radicality and reducing local recurrence after RFA for HCC. PATIENTS AND METHODS: A total of 102 nodules treated by RFA at our hospital from January 2006 to October 2009 were enrolled: 31 nodules were treated without CE-US, since CE-US was not yet available (Group A), and 71 nodules were treated with a combination of RFA and CE-US with Sonazoid(®) (Group B). RESULTS: The clinical characteristics (sex, virus marker, Child-Pugh grade, with or without transcatheter arterial infusion chemotherapy with lipiodol, and T factor) did not differ significantly between group A and group B. Mean age was significantly older and tumor size was significantly larger in group B. Group B had significantly better radicality compared with group A. The non-local recurrence rate was significantly higher in group B as compared with group A. CONCLUSION: CE-US with Sonazoid(®) greatly helps to improve RFA efficacy in HCC treatment. We suggest that the ability of CE-US with Sonazoid(®) to detect an accurate area of HCC before RFA and to immediately detect a residual tumor during RFA might contribute to an increase of the radicality and reduction of local recurrence after RFA.

Epimorphin protects hepatocytes from oxidative stress by inhibiting mitochondrial injury.

BACKGROUND AND AIMS: Many investigations have demonstrated that cell injuries caused by generation of reactive oxygen species (ROS) is a common mechanism of various hepatic disorders. Recently, we have demonstrated that epimorphin, originally cloned as a mesenchymal protein, protects cultured intestinal epithelial cells from ROS. We therefore examine whether epimorphin protects primary cultured hepatocytes from ROS-induced cell injury. METHODS: We explored the cell viability and the intracellular ROS levels of purified murine hepatocytes after exposure to 0.5 mM H(2)O(2) with or without pretreatment of epimorphin. Then, we observed mitochondrial permeability transition (MPT) and depolarization using confocal microscopy to make clear the mechanism that epimorphin inhibited cell injuries after exposure to H(2)O(2). In addition, to clarify the signaling pathways related to cell survival, we carried out Western blotting analysis with phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) polyclonal antibody to evaluate the inhibition of JNK by epimorphin. Finally, we evaluated the cell viability in hepatocytes administered JNK inhibitor. RESULTS: Epimorphin protected primary cultured hepatocytes from H(2)O(2)-induced cell injuries independent of intracellular ROS levels. Epimorphin also inhibited onset of MPT, depolarization of the mitochondrial membrane potential, and eventually cell killing. The cell protective function of epimorphin after exposure to H(2)O(2) was not dependent on Akt signaling but on JNK signaling. CONCLUSION: Epimorphin can protect hepatocytes from MPT-dependent cell injury induced by ROS. Since hepatic disorders could be caused by MPT-dependent cell injuries with excessive ROS, epimorphin might open a new therapeutic avenue for hepatic disorders.

Skull metastasis from hepatocellular carcinoma with chronic hepatitis B.

A 56-year-old male visited our hospital for evaluation of an occipital mass. Contrast computed tomography showed hypervascular enhancement with osteolytic change in the skull and a huge enhanced mass in the liver. Magnetic resonance imaging showed bone metastasis in the thoracic vertebrae. Assays for hepatitis B surface antigen and hepatitis B core antibody were positive and his liver condition was Child-Pugh grade A. Our diagnosis was hepatocellular carcinoma (HCC) with skull and vertebrae metastases on chronic hepatitis B. He was treated with radiation therapy for bone metastases and transcatheter arterial chemoembolization for HCC. But he developed acute respiratory failure because of aspiration pneumonia, congestion and oedema with haemorrhage of the lungs and died. Dissection showed HCC with multiple bone metastases. The liver tumor was categorized as well-differentiated HCC, Edmondson classification I, trabecular type and pseudoglandular type. In the liver mild infiltration of lymphocytes was seen in Glisson's capsules which were significantly enlarged with well preserved limiting plates. Piecemeal necrosis was not obvious. No fibrosis was noted. An 8 cm × 7 cm × 3 cm metastatic lesion had formed in the left occipitotemporal part of the cranial bone. The lesion was osteolytic and showed invasion into the dura mater. Neither the subdural cavity nor the brain showed involvement from the metastatic tumor. However, skull metastasis from HCC is very rare and it affects the patient's prognosis and the quality of life. Therefore, it is very important to make an early diagnosis and carry out proper management of skull metastasis from HCC.

Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis.

AIM: Nonalcoholic fatty liver disease (NAFLD) is considered to be a public health problem worldwide. NAFLD is more prevalent in men than in women. Tamoxifen, a potent estrogen receptor antagonist, causes nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. Thus, there may be a sex difference that is dependent on estrogens in NAFLD and NASH. Hepatocyte-specific Pten-deficient mice exhibit hepatic lesions analogous to NASH and are considered to be a clinical model of NASH. We aimed to shed light on any sex differences in the hepatic lesions of Pten-deficient mice and the underlying mechanisms. METHODS: At 40 weeks, livers from male and female Pten-deficient mice were processed for measuring lipid content, genes expression analysis, and histological examination. Level of serum reactive oxygen species (ROS) was also determined. Seventy-six-week-old mice were used in tumor burden experiments. RESULTS: Hepatic steatosis, inflammation, and even carcinogenesis in Pten-deficient mice were attenuated in females compared to males. Attenuated fatty liver in females was ascribed to inactivation of sterol regulatory element binding protein-1c. Hepatic inflammation in females was suppressed via decreased ROS with increased antioxidant gene expression and decreased proinflammatory cytokine production. Anti-cancer effect in female mice was, at least in part, due to the significantly lower ratio of oleic to stearic acid in the liver. CONCLUSIONS: Hepatic lesions in Pten-deficient mice were attenuated in females compared to males, as were human NAFLD and NASH. Some of the underlying mechanisms in sex difference appeared to be due to the change of gene expression, dependent on estrogens.

Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice.

BACKGROUND/AIMS: Eicosapentaenoic acid (EPA) has been known as a reagent for improving lipid metabolism and inflammation. Hepatocyte-specific Pten-deficient mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). Therefore, we administered EPA to Pten-deficient mice to investigate the mechanisms of NASH. METHODS: Pten-deficient mice were assigned to a control group fed with a standard chow or an EPA group fed with a 5% EPA-supplemented standard chow. At 40 weeks, livers from each group were processed to measure triglyceride content, gene expression analysis, Western blotting analysis, and histological examination. Level of serum reactive oxygen species (ROS) was also determined. Forty- and 76-week-old mice were used in tumor burden experiments. RESULTS: EPA-ameliorated hepatic steatosis in Pten-deficient mice was based on decreased expression of AMPKalpha1-mediated SREBP-1c and increased PPARalpha expression. The EPA group exhibited less severe chronic hepatic inflammation compared to the control group, resulting from decreased ROS formation and a dramatically low ratio of arachidonic acid to EPA. Moreover, EPA inhibited development of hepatocellular carcinoma (HCC) in Pten-deficient mice based on an inhibition of MAPK activity and a low ratio of oleic to stealic acid, and a reduction in ROS formation. CONCLUSIONS: EPA ameliorated steatohepatitis and development of HCC in Pten-deficient mice.

Loss of Pten, a tumor suppressor, causes the strong inhibition of autophagy without affecting LC3 lipidation.

(1)Pten (phosphatase and tensin homolog deleted on chromosome ten), a tumor suppressor, is a phosphatase with a variety of substrate specificities. Its function as a negative regulator of the class I phosphatidyl-inositol 3-kinase/Akt pathway antagonizes insulin-dependent cell signaling. The targeted deletion of Pten in mouse liver leads to insulin hypersensitivity and the upregulation of the phosphatidyl-inositol 3-kinase/Akt signaling pathway. In this study, we investigated the effects of Pten deficiency on autophagy, a major cellular degradative system responsible for the turnover of cell constituents. The autophagic degradation of [(14)C-leucine-labeled proteins of hepatocytes isolated from Pten-deficient livers was strongly inhibited, compared with that of control hepatocytes. However, no significant difference was found in the levels of the Atg12-Atg5 conjugate and LC3-II, the lipidated form of LC3, an intrinsic autophagosomal membrane marker, between control and Pten-deficient livers. Electron microscopic analyses showed that numerous autophagic vacuoles (autophagosomes plus autolysosomes) were present in the livers of control mice that had been starved for 48 hours, whereas they were markedly reduced in Pten-deficient livers under the same conditions. In vivo administration of leupeptin to control livers caused the inhibition of autophagic proteolysis, resulting in the accumulation of autolysosomes. These autolysosomes could be separated as a denser autolysosomal fraction from other cell membranes by Percoll density gradient centrifugation. In leupeptin-administered mutant livers, however, the accumulation of denser autolysosomes was reduced substantially. Collectively, we conclude that enhanced insulin signaling in Pten deficiency suppresses autophagy at the formation and maturation steps of autophagosomes, without inhibiting ATG conjugation reactions.

Mao (Ephedra sinica Stapf) protects against D-galactosamine and lipopolysaccharide-induced hepatic failure.

Mao is one component of various traditional herbal medicines. We examined the effects of Mao on an acute liver failure model treated with d-galactosamine (GalN) and lipopolysaccharide (LPS). The lethality of mice administrated Mao with GalN/LPS was significantly decreased compared with that in mice without Mao. Hepatic apoptosis and inflammatory cell infiltration were slight in Mao-treated mice. Serum alanine aminotransferase (ALT) and total bilirubin (T.Bil) activity, tumor necrosis factor alpha (TNF-alpha) levels and caspase 8, 9, and 3 activity in the liver were significantly lower in mice administrated Mao. But, Serum interleukin-6 (IL-6), IL-10 levels and signal transducers and activators of transcription 3 (STAT3) activity in the liver were significantly higher in mice administrated Mao. To investigate the effect of STAT3, we used AG490, which selectively inhibits the activation of Janus kinase (JAK) family tyrosine kinase and inhibits the constitutive activation of STAT3. There was significant aggravation in hepatic apoptosis treated with Mao and AG490 compared with Mao alone. In conclusions, Mao significantly suppressed hepatic apoptosis by inhibition of TNF-alpha production and caspase activity. Furthermore, it is also suggested that Mao, which activates STAT3 induced by IL-6, may be a useful therapeutic tool for fulminant hepatic failure.

Epimorphin, a morphogenic protein, induces proteases in rodent hepatocytes through NF-kappaB.

BACKGROUND/AIMS: Epimorphin, expressed by hepatic stellate cells in the liver, directs normal morphogenesis in various organs. The aim of this study was to clarify the mechanism by which epimorphin functions as a morphogen in vitro. METHODS: Male Balb/c mice and Sprague-Dawley rats were used. First, we explored the relationship between epimorphin expression and distribution of protease-positive cells in carbon tetrachloride-induced acute liver injury. We then examined protease levels in cultured hepatocytes and signal transduction of epimorphin. Finally, we determined the requirement for proteases and NF-kappaB in spheroid formation induced by epimorphin. RESULTS: Epimorphin expression was enhanced in injured areas during late recovery phase, in which protease-positive hepatocytes were localized adjacent to epimorphin-expressing cells. In vitro, epimorphin induced matrix metalloproteinase (MMP) 9, MMP 3 and urokinase type plasminogen activator (uPA) in hepatocytes. NF-kappaB mediated these protease expressions in hepatocytes. These proteases were required for epimorphin-induced and Matrigel induced spheroid. An epimorphin-neutralizing antibody also blocked spheroid formation on Matrigel, which contained epimorphin. In addition, NF-kappaB activation was also required for spheroid formation. CONCLUSION: Epimorphin elicits hepatocyte spheroids by inducing proteases in rodent hepatocytes through NF-kappaB.

Non-alcoholic steatohepatitis and hepatocellular carcinoma: lessons from hepatocyte-specific phosphatase and tensin homolog (PTEN)-deficient mice.

Non-alcoholic steatohepatitis (NASH) is a term used to describe a spectrum of conditions characterized by histological findings of hepatic macrovesicular steatosis with inflammation in individuals who consume little or no alcohol. The NASH patients progress to liver cirrhosis and even hepatocellular carcinoma (HCC). Hepatocyte-specific phosphatase and tensin homolog (PTEN)-deficient mice (PTEN-deficient mice), which the authors had generated previously, showed massive hepatomegaly and steatohepatitis with triglyceride accumulation followed by liver fibrosis and HCC, a phenotype similar to human NASH. Therefore, it was shown that PTEN deficiency in hepatocytes could induce hepatic steatosis, inflammation, fibrosis and tumors and that PTEN-deficient mice were a useful animal model for not only the understanding of the pathogenesis of NASH but also the development of treatment for NASH.

Osler-Weber-Rendu disease with esophageal varices and hepatic nodular change.

A 72-year-old male visited our hospital for further evaluation of esophageal varices. Telangiectasias were present in the stomach. He had recurrent epistaxis, which was also confirmed in his family's medical history. We diagnosed this case as Osler-Weber-Rendu disease. He had concomitant with hepatic nodular change. Abdominal angiography showed arterio-portal (A-P) shunts, superior mesenteric artery (SMA)-superior mesenteric vein (SMV) shunt, extension of SMV, and dilated and meandering portal vein. Esophageal varices were treated by endoscopic variceral ligation (EVL) and argon plasma coagulation (APC) therapy for prophylaxis of bleeding.

Morphogenic protein epimorphin protects intestinal epithelial cells from oxidative stress by the activation of EGF receptor and MEK/ERK, PI3 kinase/Akt signals.

Epimorphin is a mesenchymal protein that regulates morphogenesis of epithelial cells. Our preliminary study suggested a novel function of epimorphin in enhancing survival of intestinal epithelial cells (IEC). Oxidative stress leads to cell injury and death and is suggested to be a key contributor to pathogenesis of inflammatory bowel disease. This study was conducted to determine whether epimorphin protects IEC from oxidative stress. Rat intestinal epithelial cell line IEC-6 was cultured with epimorphin (10 and 20 mug/ml), and the life span of IEC was assessed. The mean life span of IEC-6 cells was prolonged 1.9-fold (P < 0.0006) by treatment with epimorphin. We then examined the epimorphin signaling pathways. Epimorphin phosphorylated epidermal growth factor (EGF) receptor, activated the MEK/extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase and phosphatidylinositol 3 (PI3) kinase/Akt pathways, phosphorylated Bad, and induced Bcl-X(L) and survivin. Hydrogen peroxide (1 mM) induced cell death in 92% of IEC-6 cells, but epimorphin dramatically diminished (88.7%) cell death induced by hydrogen peroxide (P < 0.0001). This protective effect of epimorphin was significantly attenuated by inhibitors of MEK and PI3 kinase (P < 0.0001) or EGF receptor-neutralizing antibody (P = 0.0007). In wound assays, the number of migrated cells in the wound area decreased (72.5%) by treatment with 30 muM hydrogen peroxide, but epimorphin increased the number of migrated cells 3.18-fold (P < 0.0001). These results support a novel function of epimorphin in protecting IEC from oxidative stress. This anti-oxidative function of epimorphin is dramatic and is likely mediated by the activation of EGF receptors and the MEK/extracellular signal-regulated kinase and PI3 kinase/Akt signaling pathways and through the induction of anti-apoptotic factors.

Zinc L-carnosine protects against mucosal injury in portal hypertensive gastropathy through induction of heat shock protein 72.

BACKGROUND AND AIMS: Increased susceptibility to gastric mucosal injury is observed in portal hypertensive gastropathy (PHG). In this study, the effects of zinc L-carnosine, an anti-ulcer drug, were evaluated on expression of heat shock protein (hsp) 72 and cytoprotection in gastric mucosa in a rat model of PHG. METHODS: Portal hypertensive gastropathy with liver cirrhosis was induced by bile duct ligation for 4 weeks in male Sprague-Dawley rats. Expression of gastric mucosal hsp72 was evaluated by Western blotting at 6 h after intragastric administration of L-carnosine, zinc sulfate, or zinc L-carnosine. Blood was also collected for determination of serum zinc level. Mucosal protective abilities against hydrochloric acid (HCl) (0.6N) followed by pretreatment with L-carnosine, zinc sulfate or zinc L-carnosine were also studied. RESULTS: L-carnosine, zinc sulfate, and zinc L-carnosine induced hsp72 in gastric mucosa of rats with bile duct ligation. Zinc sulfate and zinc L-carnosine suppressed HCl-induced mucosal injury. However, L-carnosine could not suppress HCl-induced mucosal injury. Serum zinc levels were significantly elevated after zinc L-carnosine administration. Furthermore, pretreatment with zinc L-carnosine (30-300 mg/kg) increased the expression of hsp72 in gastric mucosa and prevented HCl-induced mucosal injury in rats with bile duct ligation in a dose-dependent manner. CONCLUSIONS: Zinc derivatives, especially zinc L-carnosine, protected portal hypertensive gastric mucosa with increased hsp72 expression in cirrhotic rats. It is postulated that zinc L-carnosine may be beneficial to the mucosal protection in PHG as a 'chaperone inducer'.

[Hepatocyte-specific Pten deficient mice].

Histological findings of hepatocyte-specific Pten deficient(Pten KO) mice livers were consistent with the criteria of human nonalcoholic steatohepatitis(NASH). Therefore, Pten KO mice are a powerful animal model of NASH. In Pten KO mice livers, steatosis develops based on the increased expression of genes that promote fatty acids synthesis. The increased expression of beta, oxidation-related genes accumulates oxidative stress in Pten KO mice livers resulting in hepatitis based on lipid hyperoxidation of hepatocytes membranes. Onset and exacerbation of hepatitis are also related to endotoxins derived from intestinal bacteria. Oxidative DNA damage, hyperproliferation of hepatocytes induced by the activation of Akt and ERK, and the increasement of malignant potential based on the change of fatty acids composition in the livers contribute to the development of hepatocellular carcinoma in Pten KO mice. Since it is considered that the mechanism to induce hepatic lesions in some NASH patients is the same as that in Pten KO mice, the investigation using Pten KO mice gives us clues to clarify the pathogenesis or develop effective therapy of NASH.