Y.M. Kim

Effects of Recombinant Adenovirus-Mediated Uncoupling Protein 2 Overexpression on Endothelial Function and Apoptosis

Increased oxidative stress in vascular cells plays a key role in the development of endothelial dysfunction and atherosclerosis. Uncoupling protein 2 (UCP2) is an important regulator of intracellular reactive oxygen species (ROS) production. This study was undertaken to test the hypothesis that, UCP2 functions as an inhibitor of the atherosclerotic process in endothelial cells. Adenovirus-mediated UCP2 (Ad-UCP2) overexpression led to a significant increase in endothelial nitric oxide synthase (eNOS) and decrease in endothelin-1 mRNA expression in human aortic endothelial cells (HAECs). Moreover, UCP2 inhibited the increase in ROS production and NF-&kgr;B activation, and apoptosis of HAECs induced by lysophophatidylcholine (LPC) and linoleic acid. LPC and linoleic acid caused mitochondrial calcium accumulation and transient mitochondrial membrane hyperpolarization, which was followed by depolarization. UCP2 overexpression prevented these processes. In isolated rat aorta, Ad-UCP2 infection markedly improved impaired vascular relaxation induced by LPC. The data collectively suggest that UCP2, functions as a physiologic regulator of ROS generation in endothelial cells. Thus, measures to increase UCP2 expression in vascular endothelial cells may aid in preventing the development and progression of atherosclerosis in patients with metabolic syndrome.

α-Lipoic Acid Prevents Endothelial Dysfunction in Obese Rats via Activation of AMP-Activated Protein Kinase

Objective—Lipid accumulation in vascular endothelial cells may play an important role in the pathogenesis of atherosclerosis in obese subjects. We showed previously that α-lipoic acid (ALA) activates AMP-activated protein kinase (AMPK) and reduces lipid accumulation in skeletal muscle of obese rats. Here, we investigated whether ALA improves endothelial dysfunction in obese rats by activating AMPK in endothelial cells. Methods and Results—Endothelium-dependent vascular relaxation was impaired, and the number of apoptotic endothelial cells was higher in the aorta of obese rats compared with control rats. In addition, triglyceride and lipid peroxide levels were higher, and NO synthesis was lower. Administration of ALA improved all of these abnormalities. AMPK activity was lower in aortic endothelium of obese rats, and ALA normalized it. Incubation of human aortic endothelial cells with ALA activated AMPK and protected cells from linoleic acid–induced apoptosis. Dominant-negative AMPK inhibited the antiapoptotic effects of ALA. Conclusions—Reduced AMPK activation may play an important role in the genesis of endothelial dysfunction in obese rats. ALA improves vascular dysfunction by normalizing lipid metabolism and activating AMPK in endothelial cells.

Dopamine transporter density is decreased in parkinsonian patients with a history of manganese exposure: What does it mean?

Manganese (Mn) exposure can cause parkinsonism. Pathological changes occur mostly in the pallidum and striatum. Two patients with a long history of occupational Mn exposure presented with Mn‐induced parkinsonism. In one patient, magnetic resonance imaging (MRI) showed findings consistent with Mn exposure, and Mn concentration was increased in the blood and urine. However, this patients clinical features were typical of idiopathic Parkinson disease (PD). Previous pathological and positron emission tomography studies indicate that striatal dopamine transporter density is normal in Mn‐induced parkinsonism, whereas it is decreased in PD. Therefore, we performed [123I]‐(1r)‐2β‐carboxymethoxy‐3β‐(4‐iodophenyl)tropane ([123I]‐β‐CIT) single‐photon emission computed tomography. Severe reduction of striatal β‐CIT binding was indicated, which is consistent with PD. We propose three interpretations: (1) the patients have PD, and Mn exposure is incidental; (2) Mn induces selective degeneration of presynaptic dopaminergic nerve terminals, thereby causing parkinsonism; or (3) Mn exposure acts as a risk of PD in these patients. Our results and careful review of previous studies indicate that the axiom that Mn causes parkinsonism by pallidal lesion may be over‐simplified; Mn exposure and parkinsonism may be more complex than previously thought. Further studies are required to elucidate the relationship between Mn and various forms of parkinsonism.

Fertility‐sparing laparoscopic radical trachelectomy for young women with early stage cervical cancer

Please cite this paper as: Kim J‐H, Park J‐Y, Kim D‐Y, Kim Y‐M, Kim Y‐T, Nam J‐H. Fertility‐sparing laparoscopic radical trachelectomy for young women with early stage cervical cancer. BJOG 2010;117:340–347.

Laparoscopic versus open radical hysterectomy in early-stage cervical cancer: long-term survival outcomes in a matched cohort study

BACKGROUND To compare the long-term survival outcomes between laparoscopic radical hysterectomy (LRH) and open radical hysterectomy (ORH). METHOD We matched patients with stage IA2 to IIA cervical cancer with known risk factors for recurrence who underwent ORH and LRH. RESULTS Compared with ORH (n = 263), LRH (n = 263) did not have higher risks of recurrence [hazard ratio (HR) = 1.28; 95% confidence interval (CI) 0.62-2.64] or death (HR = 1.46; 95% CI 0.62-3.43). Even in patients with tumors >2 cm in diameter, the risks of recurrence (HR = 0.82; 95% CI 0.31-2.16) or death (HR = 1.01; 95% CI 0.35-2.95) were not higher for LRH than for ORH. The LRH and ORH group had 5-year recurrence-free survival rates of 92.8% and 94.4%, respectively (P = 0.499). LRH resulted in significantly lower estimated blood loss (379.6 versus 541.1 ml, P < 0.001) and shorter postoperative hospital stay (12.5 versus 20.3 days, P < 0.001). Intraoperative complication rates were similar in the two groups (6.8% versus 5.7%, P = 0.711), but postoperative complication rate was lower in the LRH than in the ORH group (9.2% versus 21%, P < 0.001). CONCLUSION LRH is an oncologically safe alternative to ORH and was associated with fewer postoperative complication and earlier recovery.

Vaspin protects vascular endothelial cells against free fatty acid-induced apoptosis through a phosphatidylinositol 3-kinase/Akt pathway.

Vaspin, an adipocytokine recently identified in a rat model of type 2 diabetes, has been suggested to have an insulin-sensitizing effect. However, the exact mechanism underlying this action has not been fully elucidated. Furthermore, the specific function of vaspin is largely unknown, especially in vascular cells. We examined whether vaspin affects the insulin-signaling pathway in cultured endothelial cells and is capable of preventing free fatty acid (FFA)-induced apoptosis in endothelial cells through its insulin sensitizing effect, specifically, through its stimulatory effect on PI3-kinase/Akt signaling pathways. Vaspin significantly increased Akt phosphorylation and prevented the impairment of Akt phosphorylation by linoleic acid (LA) in insulin-stimulated endothelial cells, which effects were abolished by pretreatment with the PI3-kinase inhibitor, Wortmannin. Moreover, pretreatment with vaspin prevented LA-induced apoptosis in insulin-stimulated endothelial cells; this anti-apoptotic effect of vaspin was also eliminated by pretreatment with Wortmannin. The present study indicates that vaspin protects vascular endothelial cells from FFA-induced apoptosis through upregulation of the PI3-kinase/Akt signaling pathway. Our study is the first to demonstrate that vascular cells can be targets of vaspin. Our results further suggest that vaspin could have beneficial effects on the atherosclerosis.

Outcomes after radical hysterectomy in patients with early-stage adenocarcinoma of uterine cervix

Background:To determine the prognostic factors and treatment outcomes of patients with early-stage adenocarcinoma (AdCa) of uterine cervix who underwent radical hysterectomy (RH).Methods:Patients with early-stage squamous cell carcinoma (SCCa) of the uterine cervix who underwent RH were compared with patients with AdCa by multivariate analysis.Results:A total of 1218 patients were eligible, of which 996 (81.8%) had SCCa and 222 (18.2%) had AdCa. In multivariate analysis, parametrial involvement and lymph node metastasis were significant factors for both recurrence-free survival(RFS) and overall survival (OS) of patients with AdCa, whereas age, tumour size, parametrial involvement and lymph node metastasis were significant factors for both RFS and OS of patients with SCCa. After adjusting for significant prognostic factors, patients with AdCa had significantly poorer RFS (odds ratio (OR)=2.07, 95% confidence interval (CI)=1.37–3.12, P=0.001) and OS (OR=2.56, 95% CI=1.65–3.96, P<0.001) than patients with SCCa. Recurrence outside the pelvis was more frequent in AdCa than in those with SCCa (75 vs 57.8%, P=0.084).Conclusion(s):Although RH is still acceptable for treatment of patients with AdCa, a more effective systemic adjuvant therapy is required.

Peroxisome Proliferator-Activated Receptor-γ Coactivator 1-α Overexpression Prevents Endothelial Apoptosis by Increasing ATP/ADP Translocase Activity

Objective—Fatty acids increase reactive oxygen species generation and cell apoptosis in endothelial cells. The peroxisome proliferator-activated receptor-&ggr; coactivator 1-&agr; (PGC-1&agr;) is a transcriptional coactivator that increases mitochondrial biogenesis and fatty acid oxidation in various cells. This study was undertaken to investigate the possible preventive effect of PGC-1&agr; on endothelial apoptosis and its molecular mechanism. Methods and Results—Treatment with linoleic acid in cultured human aortic endothelial cells increased reactive oxygen species generation and cell apoptosis. These effects appeared to be mediated by increases in cytosolic fat metabolites, ie, fatty acyl CoA, diacylglycerol, and ceramide, and consequent decreases in ATP/ADP translocase activity of adenine nucleotide translocator. Adenoviral overexpression of PGC-1&agr; prevented linoleic acid-induced increases in reactive oxygen species generation and cell apoptosis in human aortic endothelial cells by increasing fatty acid oxidation, decreasing diacylglycerol and ceramide, and increasing ATP/ADP translocase activity. In isolated aorta, PGC-1&agr; overexpression prevented linoleic acid-induced decrease in endothelium-dependent vasorelaxation, and this effect was abolished by adenine nucleotide translocator1 shRNA. Conclusions—PGC-1&agr; regulates reactive oxygen species generation and apoptosis in endothelial cells by increasing fatty acid oxidation and enhancing ATP/ADP translocase activity. Measures to increase PGC-1&agr; expression or ATP/ADP translocase activity in vascular cells may aid in the prevention or treatment of atherosclerosis.

Clinical impact of positron emission tomography or positron emission tomography/computed tomography in the posttherapy surveillance of endometrial carcinoma: evaluation of 88 patients.

The objective of this study was to evaluate the validity and clinical impact of positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) using 18-fluoro-2-deoxy-D-glucose in the posttherapy surveillance of patients with endometrial carcinoma. Eighty-eight patients previously treated for histopathologically diagnosed endometrial adenocarcinoma underwent 99 PET or PET/CT scans at follow-up visits at Asan Medical Center, Seoul, Korea, between 2001 and 2007. The standard of reference for tumor recurrence consisted of histopathologic confirmation or follow-up information at least 6 months after PET or PET/CT. Of the 88 patients, 24 underwent PET (n= 11) and/or PET/CT (n= 14) scans due to suspected disease recurrence. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of PET and/or PET/CT in detecting recurrence in these patients were 100%, 83.3%, 96%, 95%, and 100%, respectively. Especially, PET/CT revealed true-positive findings in three patients with elevated tumor markers but negative CT findings. The remaining 64 patients underwent PET (n= 8) and/or PET/CT (n= 66) as part of routine posttherapy surveillance; these patients were asymptomatic, with no evidence of disease. The sensitivity, specificity, accuracy, PPV, and NPV of PET and/or PET/CT in detecting recurrence in these patients were all 100%. Clinical decisions on treatment were changed in 14 (21.9%) patients by introducing PET or PET/CT into their conventional posttherapy surveillance program. PET and/or PET/CT were highly effective in discriminating true recurrence in patients with suspected recurrence, highly sensitive in detecting recurrence in asymptomatic patients, and had impacts on clinical decisions in a considerable portion of patients.

Oleic acid induces endothelin-1 expression through activation of protein kinase C and NF-κB

This study investigated the effect of oleic acid on the expression levels of endothelin-1 (ET-1) and on the signaling pathways mediating it in human aortic endothelial cells (HAECs). ET-1 mRNA expression was significantly increased by oleic acid in a dose- and time-dependent manner. Elevation of ET-1 expression in response to oleic acid was inhibited by the protein kinase C (PKC) inhibitor, GF109203X, or the NF-κB inhibitor, pyrrolidine dithiocarbamate. In addition, both PKC and NF-κB activities were significantly increased by oleic acid. Immunoblot analysis revealed that conventional PKCs (PKC-α and -βII isoforms) were significantly increased in the membranous fractions of HAECs treated with oleic acid. PKC inhibitor completely abolished oleic acid-induced NF-κB activation, suggesting that PKC activation is upstream of NF-κB activation in oleic acid-induced ET-1 expression. These data suggest that elevated plasma oleic acid levels observed in obese, insulin-resistant subjects result in endothelial dysfunction, at least in part, through an increase in ET-1 expression.