Dronedarone hydrochloride enhances the bioactivity of endothelial progenitor cells via regulation of the AKT signaling pathway

Cardiovascular disease (CVD) and its complications are the leading cause of morbidity and mortality in the world. Because of the side effects and incomplete recovery from current therapy, stem cell therapy emerges as a potential therapy for CVD treatment, and endothelial progenitor cell (EPC) is one of the key stem cells used for therapeutic applications. The effect of this therapy required the expansion of EPC function. To enhance the EPC activation, proliferation, and angiogenesis using dronedarone hydrochloride (DH) is the purpose of this study. DH received approval for atrial fibrillation treatment and its cardiovascular protective effects were already reported. In this study, DH significantly increased EPC proliferation, tube formation, migration, and maintained EPCs surface marker expression. In addition, DH treatment up-regulated the phosphorylation of AKT and reduced the reactive oxygen species production. In summary, the cell priming by DH considerably improved the functional activity of EPCs, and the use of which might be a novel strategy for CVD treatment.

Dronedarone hydrochloride enhances the bioactivity of endothelial progenitor cells via regulation of the AKT signaling pathway

Cardiovascular disease (CVD) and its complications are the leading cause of morbidity and mortality in the world. Because of the side effects and incomplete recovery from current therapy, stem cell therapy emerges as a potential therapy for CVD treatment, and endothelial progenitor cell (EPC) is one of the key stem cells used for therapeutic applications. The effect of this therapy required the expansion of EPC function. To enhance the EPC activation, proliferation, and angiogenesis using dronedarone hydrochloride (DH) is the purpose of this study. DH received approval for atrial fibrillation treatment and its cardiovascular protective effects were already reported. In this study, DH significantly increased EPC proliferation, tube formation, migration, and maintained EPCs surface marker expression. In addition, DH treatment up-regulated the phosphorylation of AKT and reduced the reactive oxygen species production. In summary, the cell priming by DH considerably improved the functional activity of EPCs, and the use of which might be a novel strategy for CVD treatment.

Antifungal Activities of Streptomyces blastmyceticus Strain 12-6 Against Plant Pathogenic Fungi

Streptomyces blastmyceticus strain 12-6 was isolated from a forest soil sample of Cheonan area on the basis of strong antifungal activities against plant pathogenic fungi. Butanol extracts of the cultural filtrates were active against C. acutatum, C. coccodes, C. gloeosporioides, F. oxysporum, and T. roseum. Active fractions were prepared by thin layer chromatography using silica gel plate; 12-6-2 (R(f) 0.36), 12-6-3 (R(f) 0.44). Scanning electron microscopy showed that the active fractions caused a change in surface texture of fungal spores from smooth surface to wrinkled surface. The lethal effect on the spores of the active fractions varied from 56% to 100%. It was shown that the spores of C. acutatum were more sensitive to the antifungal fractions than the spores of F. oxysporum. Fluorescence staining using TOTO-1 indicated that the antifungal fractions could make the spores more sensitive to the fluorescence dye. Thus, it was suggested that antifungal agents prepared in this study exhibited the antifungal activity by damaging the plasma membrane of both fungal spores and hyphae. Identification of antifungal agents in the active fraction using GC-MS analysis revealed the presence of cyclo-(Leu-Pro) and 9-octadecenamide as major components that have already been known as antifungal substances.

Correction to: Engineered M13 Nanofiber Accelerates Ischemic Neovascularization by Enhancing Endothelial Progenitor Cells

There is a minor spelling error in the last of name of the 9th author in the originally published article.

Hypoxia-dependent mitochondrial fission regulates endothelial progenitor cell migration, invasion, and tube formation

Tumor undergo uncontrolled, excessive proliferation leads to hypoxic microenvironment. To fulfill their demand for nutrient, and oxygen, tumor angiogenesis is required. Endothelial progenitor cells (EPCs) have been known to the main source of angiogenesis because of their potential to differentiation into endothelial cells. Therefore, understanding the mechanism of EPC-mediated angiogenesis in hypoxia is critical for development of cancer therapy. Recently, mitochondrial dynamics has emerged as a critical mechanism for cellular function and differentiation under hypoxic conditions. However, the role of mitochondrial dynamics in hypoxia-induced angiogenesis remains to be elucidated. In this study, we demonstrated that hypoxia-induced mitochondrial fission accelerates EPCs bioactivities. We first investigated the effect of hypoxia on EPC-mediated angiogenesis. Cell migration, invasion, and tube formation was significantly increased under hypoxic conditions; expression of EPC surface markers was unchanged. And mitochondrial fission was induced by hypoxia time-dependent manner. We found that hypoxia-induced mitochondrial fission was triggered by dynamin-related protein Drp1, specifically, phosphorylated DRP1 at Ser637, a suppression marker for mitochondrial fission, was impaired in hypoxia time-dependent manner. To confirm the role of DRP1 in EPC-mediated angiogenesis, we analyzed cell bioactivities using Mdivi-1, a selective DRP1 inhibitor, and DRP1 siRNA. DRP1 silencing or Mdivi-1 treatment dramatically reduced cell migration, invasion, and tube formation in EPCs, but the expression of EPC surface markers was unchanged. In conclusion, we uncovered a novel role of mitochondrial fission in hypoxia-induced angiogenesis. Therefore, we suggest that specific modulation of DRP1-mediated mitochondrial dynamics may be a potential therapeutic strategy in EPC-mediated tumor angiogenesis.

Engineered M13 Nanofiber Accelerates Ischemic Neovascularization by Enhancing Endothelial Progenitor Cells

Dysfunction or loss of blood vessel causes several ischemic diseases. Although endothelial progenitor cells (EPCs) are a promising source for cell-based therapy, ischemia-induced pathophysiological condition limits the recovery rate by causing drastic cell death. To overcome this issue, we attempted to develop a cell-targeted peptide delivery and priming system to enhance EPCbased neovascularization using an engineered M13 bacteriophage harboring nanofibrous tubes displaying ∼ 2700 multiple functional motifs. The M13 nanofiber was modified by displaying RGD, which is an integrin-docking peptide, on the minor coat protein, and bymutilayering SDKPmotifs,which are the key active sites for thymosin b4, on themajor coat protein. The engineered M13 nanofiber dramatically enhanced ischemic neovascularization by activating intracellular and extracellular processes such as proliferation, migration, and tube formation in the EPCs. Furthermore, transplantation of the primed EPCs with the M13 nanofiber harboring RGD and SDKP facilitated functional recovery and neovascularization in a murine hindlimb ischemia model. Overall, this study demonstrates the effectiveness of theM13 nanofiber-based novel peptide deliveryandprimingstrategy inpromotingEPC bioactivity and neovessel regeneration. To our knowledge, this is first report onM13 nanofibers harboring dual functional motifs, the use of which might be a novel strategy for stem and progenitor cell therapy against cardiovascular ischemic diseases.

High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker

Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes.

Clinical Outcome of Treatment with Infliximab in Crohn's Disease: A Single-Center Experience / 대한소화기학회지

BACKGROUND/AIMS: Our aim was to assess the long-term data regarding efficacy and safety of infliximab (IFX) treatment for refractory Crohn's disease (CD) patients in our tertiary teaching hospital. METHODS: We have retrospectively analyzed the medical records of 89 CD patients who underwent IFX treatment between March 2003 and February 2011 at Kyung Hee University Hospital (Seoul, Korea). The primary outcome measurements were the rates of initial clinical response (CR) at 10 weeks after the 1st IFX infusion and sustained CR at the end of the follow-up. Overall adverse events related to IFX treatment were also evaluated. RESULTS: The mean (SD) follow-up period of eligible 80 patients was 33.7 (21.9) months. A total of 77 patients (96%) showed initial clinical response, but 8 patients showed loss of response to IFX during the follow-up. Finally, 59 patients (59/77, 76.6%) showed sustained CR at the end of the study. Logistic regression analyses showed that an initial CR at 10 weeks was the independent predictor associated with sustained CR (OR 22.286, 95% CI 2.742-132.717, p=0.001). Overall adverse events reported in 18 patients (18/80, 23.3%), including 3 serious infection (pulmonary tuberculosis and herpes zoster). CONCLUSIONS: Treatment with IFX was efficacious and relatively safe for refractory CD patients in Korea. An initial CR at 10 weeks was significantly associated with sustained CR.

A Case of Mixed Malaria Infection with Severe Hemolytic Anemia after Travel to Angola

In Korea, Plasmodium vivax (P. vivax) is the most common agent of malaria infection. However, as travel to regions where malaria is endemic increases, so do the numbers of Plasmodium falciparum and mixed infections. P. falciparum predominates, while P. vivax is rare in west-central Africa. We report on a case of mixed malaria infection with severe hemolytic anemia caused by P. falciparum and P. vivax in a 38-year-old man after traveling to Angola. A diagnosis of P. falciparum malaria was made by microscopic examination. However, both P. vivax and P. falciparum were detected by the polymerase chain reaction (PCR). As a radical cure P. vivax, the patient was treated with mefloquine, artemether, and primaquine. Both P. falciparum and P. vivax had disappeared from peripheral blood by admission day 4, however, low grade fever and headache persisted, and his hemoglobin and hematocrit levels were depleted. A peripheral blood smear was negative for both P. vivax and P. falciparum; however, a direct anti-globulin test and anti-nuclear antibody test were positive, suggesting immune hemolytic anemia. After conservative treatment, which included a transfusion with packed red blood cells (RBC), his symptoms and signs showed improvement and laboratory findings were normalized.

A Case of Cholangiocarcinoma and Colorectal Cancer Diagnosed Simultaneously in a Patient with Ulcerative Colitis and Concurrent Primary Sclerosing Cholangitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) accompanied by a risk to develop colorectal dysplasia and cancer. Primary sclerosing cholangitis (PSC) is strongly associated with UC and there are some distinguishing clinical features between UC patients with PSC (UC-PSC) and UC patients without PSC. The most important feature is that UC patients with concomitant PSC are at a significantly increased risk of developing colorectal dysplasia or cancer. Furthermore, it has been suggested that patients with UC and PSC are also at an increased risk of cholangiocarcinoma. We report a case of cholangiocarcinoma and colorectal cancer diagnosed simultaneously in a patient with UC and concurrent PSC. He was diagnosed with UC and PSC 13 years ago and had been treated irregularly. Surveillance colonoscopy and biopsies were performed and one of the biopsied specimen confirmed adenocarcinoma. He underwent abdominal computed tomography (CT) because of the abnormal liver function test and the CT showed cholangiocarcinoma. To the best of our knowledge, this is the first case report of a UC-PSC with cholangiocarcinoma and colorectal cancer at the same time in Korea.

A Case of Metastatic Adenocarcinoma of the Pleura from the Exocervix without Local Recurrence / 대한내과학회지

It is very rare for an exocervical adenocarcinoma to metastasize to the lung parenchyma and pleura. A 54-year-old woman was admitted with dyspnea and left pleural effusion on chest X-ray. She had a history of exocervical adenocarcinoma 3 years previously and was treated with hysterectomy, chemotherapy, and radiation therapy. Last year, she was diagnosed with a left vestibular schwannoma and underwent subtotal mass removal surgery. After admission, metastatic adenocarcinoma of the pleura was diagnosed by video-assisted thoracic surgery biopsy. We herein report the rare case of exocervical adenocarcinoma that presented as a metastatic lesion to the pleura 3 years after the initial diagnosis.

A Comparison of Clinical Characteristics between Medically-treated Patients and Surgically-treated Patients with Ischemic Colitis

BACKGROUND/AIMS: Ischemic colitis (IC) is usually a self-limiting disease. But, it can cause necrosis that requires urgent surgical treatment. We sought to evaluate clinical difference in IC patients between medical and surgical treatment groups, and to identify prognostic factors for adverse outcomes. METHODS: We conducted a retrospective analysis of clinical characteristics in patients with IC treated in Chonnam National University Hospital between May 2001 and April 2010. A total of 81 patients with IC were enrolled. We classified the patients into two groups-a medical treatment group and a surgical treatment group-and evaluated their clinical features, treatment outcomes and mortality. RESULTS: Absence of hematochezia, vomiting, abdominal tenderness, abdominal rebound tenderness, heart rate over 90 beats/min, systolic blood pressure less than 100 mm Hg, hyponatremia and increased LDH or serum creatinine level were observed more frequently in surgically-treated patients (p<0.05). Most cases in the medically-treated group resolved without complications (98.3%). But, about half of the cases (52.4%) of the surgically-treated group resolved and the mortality rate was 47.6%. CONCLUSIONS: In patients with ischemic colitis, several clinical factors are associated with surgical treatment. Although IC is often selflimited, our data suggests that special attention and aggressive therapy is warranted in treating these patients.

A Comparison of Clinical Characteristics between Medically-treated Patients and Surgically-treated Patients with Ischemic Colitis

BACKGROUND/AIMS: Ischemic colitis (IC) is usually a self-limiting disease. But, it can cause necrosis that requires urgent surgical treatment. We sought to evaluate clinical difference in IC patients between medical and surgical treatment groups, and to identify prognostic factors for adverse outcomes. METHODS: We conducted a retrospective analysis of clinical characteristics in patients with IC treated in Chonnam National University Hospital between May 2001 and April 2010. A total of 81 patients with IC were enrolled. We classified the patients into two groups-a medical treatment group and a surgical treatment group-and evaluated their clinical features, treatment outcomes and mortality. RESULTS: Absence of hematochezia, vomiting, abdominal tenderness, abdominal rebound tenderness, heart rate over 90 beats/min, systolic blood pressure less than 100 mm Hg, hyponatremia and increased LDH or serum creatinine level were observed more frequently in surgically-treated patients (p<0.05). Most cases in the medically-treated group resolved without complications (98.3%). But, about half of the cases (52.4%) of the surgically-treated group resolved and the mortality rate was 47.6%. CONCLUSIONS: In patients with ischemic colitis, several clinical factors are associated with surgical treatment. Although IC is often selflimited, our data suggests that special attention and aggressive therapy is warranted in treating these patients.

Three Cases of Central Nervous System Infection Caused by Multi-Drug-Resistant Acinetobacter baumannii / 대한내과학회지

In recent years, Acinetobacter baumannii has become an increasingly common nosocomial pathogen. It causes rare, but severe, central nervous system (CNS) infection, especially in patients undergoing neurosurgical procedures or with head trauma. Multi-drug-resistant A. baumannii (MDR-AB) has emerged as a pathogen causing CNS infection. We describe A. baumannii CNS infections seen during the last 5 years and focus on MDR-AB CNS infection. Seven patients were admitted to the neurosurgical intensive care unit with serious head injuries. Imipenem-susceptible A. baumannii was identified in all four cases seen from 2003 to 2006, whereas the three cases seen from 2007 to 2008 were MDR-AB CNS infections. Two cases of MDR-AB CNS infection were cured with intraventricular or intrathecal colistin without any side effects. Therefore, intraventricular or intrathecal colistin should be considered for MDR-AB CNS infection. Studies of the dose and duration of intraventricular and intrathecal administration are needed.

Effects of Statins on the Epicardial Fat Thickness in Patients with Coronary Artery Stenosis Underwent Percutaneous Coronary Intervention: Comparison of Atorvastatin with Simvastatin/Ezetimibe

BACKGROUND: Epicardial fat is a visceral thoracic fat and known to be related with presence of dyslipidemia and coronary arterial stenosis. We evaluated the effects and differences of statins on epicardial fat thickness (EFT) in patients underwent successful percutaneous coronary intervention (PCI). METHODS: In this retrospective cohort study, we enrolled consecutive patients underwent successful PCI and scheduled six to eight-months follow-up coronary angiography from March 2007 to June 2009. EFT was measured by echocardiography twice at the time of PCI and the follow-up coronary angiography. We included 145 patients (58 females; mean, 63.5 +/- 9.5 years). RESULTS: Of the 145 patients, 82 received 20 mg of atorvastatin (atorvastatin group) and 63 medicated with 10 mg of simvastatin with 10 mg of ezetimibe (simvastatin/ezetimibe group). With statin treatments, total cholesterol concentration (189.1 +/- 36.1 to 143.3 +/- 36.5 mg/dL, p < 0.001), triglycerides (143.5 +/- 65.5 to 124.9 +/- 63.1 mg/dL, p = 0.005), low density lipoprotein-cholesterol (117.4 +/- 32.5 to 76.8 +/- 30.9 mg/dL, p < 0.001) and EFT (4.08 +/- 1.37 to 3.76 +/- 1.29 mm, p < 0.001) were significantly decreased. Atorvastatin and simvastatin/ezetimibe showed similar improvements in the cholesterol profiles. However, atorvastatin decreased EFT more significantly than simvastatin/ezetimibe (EFT change 0.47 +/- 0.65 in the atorvastatin vs. 0.12 +/- 0.52 mm in the simvastatin/ezetimibe group; p = 0.001). CONCLUSION: In this study, the atorvastatin group showed significant reduction in EFT than in the simvastatin/ezetimibe group. This might be originated from the statin difference. More large, randomized study will be needed to evaluate this statin difference.

Prediction of Future Occurrence and Probability of Developing Breast Cancer over Lifespan in Korean Women / 한국유방암학회지

PURPOSE: Although female breast cancer remains relatively rare in Korea, its incidence and mortality have been rising quite rapidly. In this study, we estimated the probability of developing breast cancer, and examined the trend of its incidence using the proportion of cases with breast cancer among the total female cancer cases in the Korean Central Cancer Registry. METHODS: The probability of developing breast cancer was estimated for Korean women using a method based on the cumulative risk. The number of future breast cancer cases for the year 2020 was estimated by extrapolating the secular trend of the proportions of those with breast cancer between 1995 and 2002, using a logistic regression model. RESULTS: With an expected average life span of 84 years, Korean female has a 2.36% chance of developing breast cancer during her lifetime. The predicted expected age-adjusted proportions of breast cancer among the total female cancer cases were 19.5, 24.3, 29.9 and 36.1% for the years 2005, 2010, 2015 and 2020, respectively. The predicted expected crude proportions for the same years were 17.4, 19.7, 21.7 and 23.4%, respectively. The expected number of breast cancer cases to the 2020 would be 19,791, which is at least five times than that in 1996. CONCLUSION: Based on our results, female breast cancer in Korea will increase further and cumulative rate of breast cancer is highest at 40s and 50s. Lifestyle modification and prevention strategy especially for younger or high risk women might be essential to reduce breast cancer incidence.

Mortality Trends in Colorectal Cancer and Breast Cancer in Korea: Birth Cohort Effects? / 한국역학회지

PURPOSE: Cancer has been the leading cause of deaths since 1980s in Korea. Among them, colorectal cancer and breast cancer shows steadily increasing pattern, being the fourth and the fifth common site of cancer death in Korea, respectively. This analysis aimed to evaluate potential contribution of birth cohort effects to the recent increases in mortality of colorectal cancer and breast cancer since 1983 in Korea. METHODS: Mortality statistics on deaths of both cancers for the past 20 years of 1983~2002 were obtained from the National Statistical Office. The age-standardized mortality rates were calculated based on the census population of 1992 as a standard. RESULTS: Age-standardized mortality rate for colorectal cancer increased 4.7-fold in men and 3.6-fold in women, whereas 2.1-fold increase in breast cancer mortality during 1983~2002. Age-specific mortality rates for colorectal cancer were steadily increasing by age before 1991 in both genders. However, the mortality rates showed an exponentially increasing pattern for the age group of 70 and over during 1993~2001, which was more prominent in female. The birth cohort curves showed that there were 2- to 3-fold increases in the mortality rates of people who were born in 1931 for colorectal cancer compared to those of people who were born in 1921. Differences in mortality for breast cancer by birth cohort were 1.7-fold among age group of 45~49 and 50~54 between 1936 and 1946. CONCLUSIONS: This analysis suggests that recent increases in mortality of colorectal cancer and breast cancer could potentially be due to birth cohort effects, i.e. rapid changes in life-style in younger generation. The quantitative approach using age-period-cohort model should be pursued.

Total Laparoscopic Hysterectomy (TLH) : A Clinical Review of 300 Cases / 대한산부인과학회잡지

This clinical study was conducted to survey 300 cases of total laparoscopic hysterctomy (TLH) by the Department of Obstetrics and Gynecology of Boram Hospital in Ulsan, Korea from January, 2000 to June, 2001. TLH has been described in much of the recent literature. We analyzed 300 cases of TLH to evaluate the clinical data such as distribution of age, parity, clinical indication, previous operation history, type of surgery, operation time, weight of uterus, Hb change of post-operation first day and the complications of using this technique. The mean age of patients was 41.3. The mean parity of patients was 2.6. The clinical indications for TLH were myoma (72.3%), adenomyosis (11.3%), PID (5.3%), CIS (4%) and others (5.7%). The most previous operation was bilateral tubal ligation. Others were cesarean section, appendectomy. The most concomitant procedure with TLH was posterior colpoperineorrhaphy. Salpingo-oophorectomy and appendectomy were also carried out concomitantly. The mean operation time was 124 minutes. The mean weight of the uterus was 230 gm. The mean Hb change post-operation on the 1st day was 1.3g/dL. The complications of TLH were bleeding to need blood transfusion, ureteral injury and bladder injury. Thus this technique can be safely performed by skilled laparoscopists for properly selected patients but there is a need for prospective studies for comparision with various laparoscopic hysterctomies.

Comparisons of Food Preference and Nutrient Intake of Students of Elementary School and Middle School Providing School Food Service in Nam Jeju Gun

The purpose of this study was to investigate differences of food preference and nutrient intake of students between elementary school and middle school in the same area and to provide data for better school food service. The subjects were 486 students, third to sixth grade of 3 elementary schools and first to second grade of 1 middle school in Nam jeju gun, Jeju, and the survey was conducted during June 1999. Food preference was assessed using questionnaires and 24-hour food intake was assessed using dietary record method. Data of weight and height were obtained from annual physical examination conducted at schools in May 1999. All the variables were compared among 3 groups in each gender: third and fourth grade elementary school(ES3,4), fifth and sixth grade elementary school(ES5,6), and first and second grade middle school(MS1,2). The results were summarized as follows. The average height, weight and BMI for the 3th grade boys in elementary schools met the national averages, but those of the others are below the national averages. Although general pattern of food preference looked similar among groups, food preference scores were significantly different among groups in 38 kinds foods for boys, and 27 kinds of foods for girls. MS1,2 group showed significantly lower food preference scores for most of foods as compared to those of ES3,4 and ES5,6 in both genders. Students of higher grade took more starch foods such as instant noodle, stewed rice cake and snacks. Average energy intakes of all the groups except MS1,2 girls were lower than recommended dietary allowances(RDA), and average intakes of protein, vitamins B1 and C met RDA, but the other nutrients were taken less than RDA and especially the intakes of iron, calcium and vitamins B2 were poor. Most of nutrients taken by school food service meal provided a major proportion of intakes. In conclusion, students of middle school were more particular about their foods served at school food service and marked lower food preference score than elementary school children and more conscious about their weight and appearance. These points should be reflected in planning food service menu at middle school.