Background/Aims: PPARγ, farnesoid X receptor (FXR) and CYP7A1 are associated with solubility of bile. This study was performed to understand a mechanism and interactions of statin-induced PPARγ, PGC-1α and HNF-4α related to the statin-induced activation of FXR and CYP7A1, and verify whether the mevalonate pathway is involved in the mechanism. Methods: MTT assays were performed using cultured human Hep3B cells to determine the effect of atorvastatin on the cell proliferation. Expression levels of indicated proteins were measured using Western blotting assays by inhibiting the protein expression or not. Results: Atorvastatin increased expression of PPARγ, PGC-1α, HNF-4α, FXR, and CYP7A1 in Hep3B cells. PPARγ ligand of troglitazone upregulated the expression of PGC-1α, HNF-4α, FXR, and CYP7A1 in Hep3B cells. Silencing of PPARγ, PGC1α, and HNF4α using respective siRNA demonstrated that atorvastatin-induced FXR and CYP7A1 activation required sequential action of PPARγ /PGC-1α/HNF-4α. The silencing of PPARγ completely inhibited atorvastatin-induced PGC-1α expression, and the PGC1α silencing partially inhibited atorvastatin-induced PPARγ expression. The inhibition of HNF4α did not affect atorvastatin-induced PPARγ expression, but partially inhibited atorvastatin-induced PGC-1α expression. Besides, mevalonate completely reversed the effect of atorvastatin on PPARγ, PGC-1α, HNF-4α, FXR, and CYP7A1. Conclusions Atorvastatin induces FXR and CYP7A1 activation as a result of sequential action of PPARγ/PGC-1α/HNF-4α in human hepatocytes. We propose that atorvastatin enhances solubility of cholesterol in bile by simultaneously activating of FXR and CYP7A1.

BACKGROUND/AIMS: Statins act as antineoplastic agents through the inhibition of cell proliferation. This study sought to demonstrate the effects of statins on extrahepatic bile duct cancer cell apoptosis and to document the changes in protein expression involved in tumor growth and suppression. METHODS: Human extrahepatic bile duct cancer cells were cultured. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed to determine the effect of statins on cell proliferation. Apoptosis was measured by a cell death detection enzyme-linked immunosorbent assay and caspase-3 activity assay, and flow cytometry was used to determine the percentage of cells in each phase of the cell cycle. The protein expression of Bax, Bcl-2, insulin-like growth factor 1 (IGF-1) receptor, extracellular signal-regulated kinase 1/2 (ERK1/2), and Akt was measured by Western blot analysis. RESULTS: Simvastatin suppressed cell proliferation by inducing G1 phase cell cycle arrest in bile duct cancer cells. Furthermore, it induced apoptosis via caspase-3 activation, downregulated the expression of the Bcl-2 protein, and enhanced the expression of the Bax protein. Moreover, simvastatin suppressed the expression of the IGF-1 receptor and IGF-1-induced ERK/Akt activation. CONCLUSIONS: Simvastatin induces apoptosis in bile duct cancer cells, which suggests that it could be an antineoplastic agent for bile duct cancer.
Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Bile Duct Neoplasms/*drug therapy ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans ; Hypolipidemic Agents/*pharmacology ; Receptor, IGF Type 1/*drug effects ; Simvastatin/*pharmacology

BACKGROUND AND PURPOSE: Variant alleles of CYP2C9 and VKORC1 account for differences in anticoagulation response. We sought to establish a warfarin dosing formula for individualized target International Normalization Ratio of Prothrombin Times (INRs) using data from single nucleotide polymorphisms (SNPs) in VKORC1 and CYP2C9 in Korean patients. METHODS: Ischemic stroke patients displaying stable target INR for at least 3 months before enrollment were analyzed. Warfarin and vitamin K levels were measured to adjust for confounders. Phenotypes were defined using the 'warfarin response index' (WRI) defined as INR divided by the daily maintenance warfarin dose. We tested SNPs in CYP2C9 (3 sites: 430C>T (rs1799853), 1075A>C (rs1057910), 1076T>C) and VKORC1 (14 sites: 381C>T, 861C>A (rs17880887), 2653G>C, 3673A>G, 5496G>T, 5808T>G (r17882154), 6009C>T, 6484T>C (rs9934438), 6853C>T (rs17886369), 7566T>C, 8767G>C, 8814T>C, 9041G>A (rs17880624), and 9071G>T) using a standard sequencing method. Multivariate linear regression analysis was applied to establish the formula for warfarin dosage. RESULTS: All 204 patients had excellent drug compliance. The mean INR was 2.22 (+0.56) and mean daily maintenance dose of warfarin was 3.92 mg (+1.54). Patients with low WRI were younger (P<0.001) with high body mass index (P=0.003), high prevalence of wild-type CYP2C9 polymorphism (1075A>C, P<0.001), and six heterozygote SNPs in VRORC1 (P<0.001), which were tightly interlinked (381T>C, 3673G>A, 6484T>C, 6853C>G. 7566C>T, 9041G>A) (r2=1). Based on these data, a warfarin dosing formula was established. CONCLUSIONS: WRI is influenced by age, body mass index and SNPs in VKORC1 and CYP2C9 in Korean stroke patients. The obtained warfarin dosing formula may be clinically applicable.
Alleles ; Body Mass Index ; Compliance ; Genotype ; Heterozygote ; Humans ; International Normalized Ratio ; Linear Models ; Phenotype ; Polymorphism, Single Nucleotide ; Prevalence ; Prothrombin Time ; Stroke ; Vitamin K ; Warfarin

We report herein a case of subclavian steal syndrome due to occlusive disease in multiple branches of the aortic arch, which was successfully treated by axilloaxillary bypass and subclavian stent insertion. The hemodynamic changes were evaluated using duplex sonography and transcranial Doppler before and after each procedure. The waveform and parameters of blood flow revealed an objective improvement in cerebral perfusion. These findings correlated well with clinical outcome. Neurosonologic evaluation can provide objective evidence for improved hemodynamic status after treatment.
Aorta, Thoracic ; Hemodynamics ; Perfusion ; Stents ; Subclavian Steal Syndrome

We describe here a 57-year-old woman with a chronic-contained rupture of an internal iliac arterial aneurysm, and this was eroding the sacral neural foramen. Although an isolated internal iliac arterial aneurysm is known to be rare, the ruptured internal iliac arterial aneurysm was diagnosed based on the characteristic radiolgic findings with performing color Doppler ultrasound, MRI and multi-slice computed tomography. The ruptured aneurysm was successfully treated by coil embolization. Color Doppler US, MRI and multi-slice CT are useful for evaluating a mass of a vascular origin that involves the neural foramen.
Aneurysm ; Aneurysm, Ruptured ; Cytochrome P-450 CYP1A1 ; Embolization, Therapeutic ; Female ; Humans ; Middle Aged ; Rupture ; Spine

BACKGROUND: C677T single nucleotide polymorphism (SNP) of Methylentetrahydrofolate reductase (MTHFR) has been known to be associated with plasma homocysteine (Hcy) levels, which is an independent risk factor for stroke. However, recent large clinical trials did not show any benefits of Hcy lowering therapy with vitamins on the prevention of stroke. We hypothesized that the Hcy lowering effect by vitamins would be different according to the MTHFR C677T SNP types (CC, CT or TT), which may influence the benefits of vitamins by Hcy lowering on stroke prevention. METHODS: The authors retrospectively studied acute stroke patients with information of the genotype of MTHFR and serial levels of Hcy during a recent 4 year period (July 2002 - Dec 2005). Vitamins (folic acid 1 mg, and/or cobalamin 750 microgram and pyridoxine 75 mg) were prescribed to the patients whose basal plasma Hcy levels were above 12 umol/L. RESULTS: Among 172 patients, 68 patients took vitamins. The mean basal Hcy level was significantly higher in the TT type than the others, and was decreased by vitamin therapy. Distribution of homocysteine grading (normal, intermediate or high) in follow up was not significantly different according to these SNP types. CONCLUSIONS: The Hcy lowering effect by vitamins was not different by MTHFR genetic polymorphism. Considering the higher prevalence of certain gene types in stroke and our study results, genetic factors such as MTHFR polymorphism may play an important role on the development of stroke rather than the plasma Hcy levels.
Follow-Up Studies ; Genotype ; Homocysteine* ; Humans ; Oxidoreductases ; Plasma* ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide* ; Prevalence ; Pyridoxine ; Retrospective Studies ; Risk Factors ; Stroke* ; Vitamin B 12 ; Vitamins*

A pancreatic arteriovenous malformation (AVM) is a very rare disease entity that is usually asymptomatic; however, it may present with a massive gastrointestinal hemorrhage. Recent advances in cross-sectional imaging and the widespread availability of angiography have contributed to the diagnosis of this condition. A patient was transferred to our clinic due to unknown origin gastrointestinal bleeding and upper abdominal pain. Double balloon enteroscopy and duodenoscopy revealed a bleeding pancreatico-cholangio-duodenal fistula. We were able to diagnose an arteriovnous malformation with a pancreatico-cholangio-duodenal fistula by the use of angiography and from the post-operative pathological findings.
Abdominal Pain ; Angiography ; Arteriovenous Malformations* ; Diagnosis ; Double-Balloon Enteroscopy ; Duodenoscopy ; Fistula ; Gastrointestinal Hemorrhage ; Hemorrhage* ; Humans ; Pancreas ; Rare Diseases

Ictal spitting is an unusual manifestation that originates from the non-dominant hemisphere, but rarely from the dominant hemisphere. In the latter case, it has not been well defined as to whether symptomatogenic area for ictal spitting originates from the dominant hemisphere. We present a patient with ictal spitting. Intracranial EEG demonstrated a left hippocampal onset with propagation to the right hemisphere, and subsequent ictal spitting development. Even in dominant hemispheric seizures, the non-dominant hemisphere is a symptomatogenic area for ictal spitting.
Automatism* ; Electroencephalography ; Epilepsy, Temporal Lobe* ; Humans ; Seizures ; Temporal Lobe*

No abstract available.
Embolism, Air*

Dieulafoy's lesion is an unusual cause of gastrointestinal hemorrhage that results from the erosion of an abnormally large submucosal artery. In most cases, the lesion is encountered in the proximal stomach within 6 cm of the gastroesophageal junction. However, similar lesions have been reported in the antrum, duodenum, colon, and rectum. In particular, jejunal Dieulafoy's lesion Dieulafoy's lesion is an unusual cause of gastrointestinal hemorrhage that results from the erosion of an abnormally large submucosal artery. In most cases, the lesion is encountered in the proximal stomach within 6 cm of the gastroesophageal junction. However, similar lesions have been reported in the antrum, duodenum, colon, and rectum. In particular, jejunal Dieulafoy's lesion is extremely rare. We report a case of jejunal Dieulafoy's lesion with recurrent and massive bleeding, which was diagnosed and treated with the double-balloon enteroscopy.
Arteries ; Colon ; Double-Balloon Enteroscopy* ; Duodenum ; Esophagogastric Junction ; Gastrointestinal Hemorrhage ; Hemorrhage ; Jejunum* ; Rectum ; Stomach