Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model

BACKGROUND/AIMS: Adipose tissue produces a number of adipocytokines, including adiponectin, leptin, and tumor necrosis factor-alpha. Obesity, which is associated with low plasma adiponectin levels, is an independent risk factor for various liver diseases including nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the effects of adiponectin on the progression of NASH to cirrhosis and tumor formation using adiponectin-knockout (KO) mice. METHODS: Using a choline-deficient L-amino acid-defined (CDAA) diet-induced mouse NASH model, liver histology and oxidative stress markers were investigated in KO and wild-type (WT) mice. RESULTS: Hepatic steatosis was enhanced to a greater extent in KO mice, compared to WT mice after a 1-week CDAA diet. After 24 weeks, 6 out of 14 KO mice developed liver cirrhosis and hepatic tumors, whereas the 15 WT mice showed only simple steatosis. In KO mice, hepatic cytochrome P450 2E1 levels were upregulated, and markers of oxidative stress (thiobarbituric acid reactive substances, 8-hydroxydeoxyguanosine-positive cells) were significantly increased compared with WT mice. CONCLUSIONS: Our results indicate that lack of adiponectin enhances the progression of hepatic steatosis, fibrosis, and hepatic tumor formation in an animal model of NASH. Hypoadiponectinemia in obesity could be a risk factor for NASH-related hepatic tumor formation.     

Adenoassociated virus-mediated prostacyclin synthase expression prevents pulmonary arterial hypertension in rats

Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway of prostacyclin production. The therapeutic option of intravenous prostacyclin infusion in patients with pulmonary arterial hypertension is limited by the short half-life of the drug and life-threatening catheter-related complications. To develop a better delivery system for prostacyclin, we examined the feasibility of intramuscular injection of an adenoassociated virus (AAV) vector expressing PGIS for preventing monocrotaline-induced pulmonary arterial hypertension in rats. We developed an AAV serotype 1-based vector carrying a human PGIS gene (AAV-PGIS). AAV-PGIS or the control AAV vector expressing enhanced green fluorescent protein was injected into the anterior tibial muscles of 3-week-old male Wistar rats; this was followed by the monocrotaline administration at 7 weeks. Eight weeks after injecting the vector, the plasma levels of 6-keto-prostaglandin F(1alpha) increased in a vector dose-dependent manner. At this time point, the PGIS transduction (1x10(10) genome copies per body) significantly decreased mean pulmonary arterial pressure (33.9+/-2.4 versus 46.1+/-3.0 mm Hg; P<0.05), pulmonary vascular resistance (0.26+/-0.03 versus 0.41+/-0.03 mm Hg x mL(-1) x min(-1) x kg(-1); P<0.05), and medial thickness of the peripheral pulmonary artery (14.6+/-1.5% versus 23.5+/-0.5%; P<0.01) as compared with the controls. Furthermore, the PGIS-transduced rats demonstrated significantly improved survival rates as compared with the controls (100% versus 50%; P<0.05) at 8 weeks postmonocrotaline administration. An intramuscular injection of AAV-PGIS prevents monocrotaline-pulmonary arterial hypertension in rats and provides a new therapeutic alternative for preventing pulmonary arterial hypertension in humans.     

A Phase I/II study of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL

Nilotinib is a second-generation BCR-ABL kinase inhibitor with improved potency and selectivity compared to imatinib. A Phase I/II dose-escalation study was designed to evaluate the efficacy, safety, and pharmacokinetics of nilotinib in Japanese patients with imatinib-resistant or -intolerant Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL). A total of 34 patients were evaluated in this analysis and had a median duration of drug exposure of 293 (range 13–615) days. All 6 CML-CP patients without complete hematologic response (CHR) at baseline rapidly achieved CHR. A major cytogenetic response was achieved in 94% of patients with CML-CP, including a complete cytogenetic response in 69%. A major molecular response was achieved by 56%. These responses were also observed in patients with CML in advanced stages and Ph+ ALL. Non-hematologic adverse events were mostly mild to moderate. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 50 and 28% of patients, respectively. Overall, the results of this study suggest that nilotinib induced significant responses in imatinib-resistant or -intolerant patients with CML-CP and CML in advanced stages and Ph+ ALL. The results of this study confirmed the efficacy and safety of nilotinib in Japanese patients.     

Case of muscle abscess due to disseminated nocardiosis in a patient with autoimmune hemolytic anemia, and review of the published work

Although disseminated nocardiosis has been increasing with the expansion of immunosuppressive therapy and improvement in diagnostic methods, muscle abscess is a rare complication. There have been only nine case reports of muscle abscess due to Nocardia infection in the English-language published work. We present a case of muscle abscess with disseminated nocardiosis, and review the published work. The patient had been taking prednisolone at 20 mg a day for autoimmune hemolytic anemia for 14 years. She presented with erythema on her thigh resembling cellulitis. Computed tomography showed muscle abscess. The isolated organism was identified as Nocardia farcinica employing polymerase chain reaction and antibiotic sensitivity testing. The diagnosis of muscle abscess due to nocardiosis can be easily missed because there are no characteristic symptoms.     

Art and Parkinson’s disease: a dramatic change in an artist’s style as an initial symptom

In Parkinson's disease (PD), nonmotor symptoms manifest before motor symptoms. In this report, we present a remarkable case of a semiprofessional painter with PD whose painting style dramatically changed from abstract painting to realism before he developed motor, psychiatric, and autonomic nerve disorders. This case suggests that certain types of visual creativity may be impaired in the very early, presymptomatic stages of PD.