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1.  Chordoma in the Tail of a Ferret 
Laboratory Animal Research  2011;27(1):53-57.
A chordoma is an uncommon tumor that originates from the remnants of the notochord and most commonly involves the cranial and caudal regions of the axial skeleton. Chordoma has been described in laboratory animals such as dogs, rats, minks, and ferrets. This report describes a case of a chordoma in the tail of a ferret. Grossly, a grayish-white, expansile, subcutaneous soft-tissue mass was observed in the tail. Histopathologically, the mass was a loosely placed, nodular, unencapsulated neoplasm within the dermis. In the mass, tumor lobules were intermingled with fibrous tissues. Fibrous tissues contained abundant extracellular basophilic material that was consistent with mucin. The tumor was composed of a close pack of adipocyte-like vacuolated cells (physaliferous cells). The cells were centrally or eccentrically located round nuclei and eosinophilic cytoplasm with large vacuoles. Immunohistologically, neoplastic cells were positive for vimentin and S-100 protein. Based on histopathologic findings and special staining characteristics, this case was diagnosed as chordoma.
PMCID: PMC3145987  PMID: 21826161
Chordoma; ferret; physaliferous cells; pathology
2.  Incidence and Risk Factors of Subsequent Hip Fractures in Korea: Multicenter Study 
Journal of Korean Medical Science  2014;29(7):992-994.
This study analyzes the incidence of subsequent hip fractures and its risk factors in the northwestern region of Korea. We analyzed hip fracture patients who visited any of the 5 teaching hospitals in the Bucheon and Incheon area from January 2000 to December 2010. Medical records were reviewed and presence of subsequent hip fractures, alcohol history, marital status, live in solitude, dementia, dizziness, American society of anesthesiologists score, osteoporosis treatment after fracture, body mass index (BMI) and initial bone mineral density were analyzed. The average follow-up period was 12 months (range 1-130 months). A total of 2,546 patients (women 1,770, men 776) who had experienced hip fractures were included. Of these, subsequent hip fractures were found in 233 patients (9.2%) (women 187, men 46). Mean age at the time of the first fracture was 79.2 yr old (range 50-100 yr). The average interval between the first fracture and the subsequent hip fractures was 30.2 months (range 4 days-154 months). In this large-scale, retrospective, multicenter study, overall incidence of subsequent hip fractures is 9.2%. Independent risk factors of subsequent fracture are women, BMI<22 kg/m2, and being unmarried.
PMCID: PMC4101789  PMID: 25045233
Subsequent Hip Fractures; Risk Factors; Incidence
3.  Relationships between Dietary Habits and Allostatic Load Index in Metabolic Syndrome Patients 
Korean Journal of Family Medicine  2013;34(5):334-346.
Allostatic load (AL) measures overall physiological wear and tear on one's body, as a preclinical marker of pathophysiologic processes that precede the onset of disease. We studied the association of dietary habits with AL.
Consecutive patients visiting a tertiary hospital Health Promotion Center from September 2009 to February 2010, older than 20 years with metabolic syndrome were selected for study (n = 204). By multivariable linear regression analysis, we investigated the association of various dietary habits evaluated by questionnaires.
In male, multivariable linear regression showed a significant negative association between fat preference and AL with BMI ≥ 30 (1st quartile [Q] vs. 2Q: β = -3.71; 95% confidence interval [CI], -6.26 to -1.16), a significant negative association between salt preference and AL with BMI 25-30 (β = -1.36; 95% CI, -2.46 to -0.26), a negative association between appetite control and AL with BMI < 25 (1Q vs. 3Q: β = -1.54; 95% CI, -3.00 to -0.096), a significant positive association between appetite control and AL with BMI 25-30 (1Q vs. 3Q: β = 1.30; 95% CI, 0.12 to 2.48), and a significant positive association between eating in response to food cues and AL in males with BMI 25-30 (1Q vs. 4Q: β = 1.09; 95% CI, 0.020 to 2.15).
Our results suggest that metabolic syndrome patients should be discouraged from eating fat and eating in response to food cues, and should be educated about nutrition and balanced diet.
PMCID: PMC3791341  PMID: 24106586
Allostasis; Metabolic Syndrome; Food Habits; Food Preferences
4.  A population-based case-crossover study of polyethylene glycol use and acute renal failure risk in the elderly 
AIM: To evaluate the possibility of an association between polyethylene glycol (PEG) and acute renal failure (ARF) in elderly patients using a health insurance claims database.
METHODS: We conducted a population-based case-crossover study using information obtained from Korean Health Insurance Review and Assessment Service (HIRA) claims from January 1, 2005 to December 31, 2005 (Seoul, Korea). The study population consisted of elderly patients who received PEG prior to experiencing their first ARF-related hospitalization from April 1, 2005 to December 31, 2005. For each patient, one case and two control periods were matched. PEG use in a 2- or 4-wk window period prior to hospitalization for ARF was compared with PEG use in two earlier 2- or 4-wk control window periods. Conditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% CI, adjusting for concomitant uses of diuretics, angiotensin converting enzyme inhibitors, non-steroidal anti-inflammatory drugs, antibiotics, anti-cancer drugs, and contrast media.
RESULTS: Within the HIRA database which contained 1 093 262 elderly patients, 1156 hospitalized ARF cases were identified. Among these cases, PEG was prescribed to 17 (1.5%) patients before hospitalization. The adjusted ORs when applying the 2- and 4-wk window periods were 0.4 (95% CI: 0.03-5.24) and 2.1 (95% CI: 0.16-27.78), respectively.
CONCLUSION: No increased risk of ARF was found in elderly PEG users. However, based on the limited number of study subjects, further analysis should be performed to confirm these results.
PMCID: PMC3040338  PMID: 21350715
Polyethylene glycol; Acute renal failure; Adverse drug reaction; Health insurance claims database; Case-crossover
5.  Activation of CD147 with Cyclophilin A Induces the Expression of IFITM1 through ERK and PI3K in THP-1 Cells 
Mediators of Inflammation  2010;2010:821940.
CD147, as a receptor for Cyclophilins, is a multifunctional transmembrane glycoprotein. In order to identify genes that are induced by activation of CD147, THP-1 cells were stimulated with Cyclophilin A and differentially expressed genes were detected using PCR-based analysis. Interferon-induced transmembrane 1 (IFITM1) was detected to be induced and it was confirmed by RT-PCR and Western blot analysis. CD147-induced expression of IFITM1 was blocked by inhibitors of ERK, PI3K, or NF-κB, but not by inhibitors of p38, JNK, or PKC. IFITM1 appears to mediate inflammatory activation of THP-1 cells since cross-linking of IFITM1 with specific monoclonal antibody against it induced the expression of proinflammatory mediators such as IL-8 and MMP-9. These data indicate that IFITM1 is one of the pro-inflammatory mediators that are induced by signaling initiated by the activation of CD147 in macrophages and activation of ERK, PI3K, and NF-κB is required for the expression of IFITM1.
PMCID: PMC2935166  PMID: 20847954
6.  Preclinical Efficacy and Mechanisms of Mesenchymal Stem Cells in Animal Models of Autoimmune Diseases 
Immune Network  2014;14(2):81-88.
Mesenchymal stem cells (MSCs) are present in diverse tissues and organs, including bone marrow, umbilical cord, adipose tissue, and placenta. MSCs can expand easily in vitro and have regenerative stem cell properties and potent immunoregulatory activity. They inhibit the functions of dendritic cells, B cells, and T cells, but enhance those of regulatory T cells by producing immunoregulatory molecules such as transforming growth factor-β, hepatic growth factors, prostaglandin E2, interleukin-10, indolamine 2,3-dioxygenase, nitric oxide, heme oxygenase-1, and human leukocyte antigen-G. These properties make MSCs promising therapeutic candidates for the treatment of autoimmune diseases. Here, we review the preclinical studies of MSCs in animal models for systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, and experimental autoimmune encephalomyelitis, and summarize the underlying immunoregulatory mechanisms.
PMCID: PMC4022782  PMID: 24851097
Mesenchymal stem cells; Immunoregulation; Autoimmune diseases
7.  mTOR Inhibition Ameliorates Cognitive and Affective Deficits Caused by Disc1 Knockdown in Adult-Born Dentate Granule Neurons 
Neuron  2013;77(4):647-654.
Abnormalities during brain development are thought to cause psychiatric illness and other neurodevelopmental disorders. However, developmental processes such as neurogenesis continue in restricted brain regions of adults, and disruptions of these processes could contribute to the phenotypes of neurodevelopmental disorders. As previously reported, we show that Disc1 knockdown specifically in adult-born dentate gyrus (DG) neurons results in increased mTOR signaling, hyper-excitability and neuronal structure deficits. Disc1 knockdown also resulted in pronounced cognitive and affective deficits, which could be reversed when the affected DG neurons were inactivated. Importantly, reversing increases in mTOR signaling with an FDA approved inhibitor, both prevented and treated these behavioral deficits, even when associated structural deficits were not reversed. Our findings suggest that a component of the affective and cognitive phenotypes in neurodevelopmental disorders may be caused by disruptions in adult-born neurons. Consequently, treatments directed at this cell population may have a significant impact on these phenotypes.
PMCID: PMC3586374  PMID: 23439118
8.  Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis 
Cell stem cell  2013;12(2):215-223.
Adult neurogenesis, a process of generating mature neurons from adult neural stem cells, proceeds concurrently with ongoing neuronal circuit activity and is modulated by various physiological and pathological stimuli. The niche mechanism underlying activity-dependent regulation of sequential steps of adult neurogenesis remains largely unknown. Here we report that neuronal activity decreases the expression of secreted frizzled-related protein 3 (sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Sfrp3 deletion activates quiescent radial neural stem cells and promotes newborn neuron maturation, dendritic growth and spine formation in the adult mouse hippocampus. Furthermore, sfrp3 reduction is essential for activity-induced adult neural progenitor proliferation and acceleration of new neuron development. Our study identifies sFRP3 as an inhibitory niche factor from local mature dentate granule neurons that regulates multiple phases of adult hippocampal neurogenesis and suggests a novel activity-dependent mechanism governing adult neurogenesis via acute release of tonic inhibition.
PMCID: PMC3569732  PMID: 23395446
9.  Levothyroxine Dose and Fracture Risk According to the Osteoporosis Status in Elderly Women 
To evaluate the association between fracture risk and levothyroxine use in elderly women with hypothyroidism, according to previous osteoporosis history.
We conducted a cohort study from the Korean Health Insurance Review and Assessment Service claims database from January 2005 to June 2006. The study population comprised women aged ≥65 years who had been diagnosed with hypothyroidism and prescribed levothyroxine monotherapy. We excluded patients who met any of the following criteria: previous fracture history, hyperthyroidism, thyroid cancer, or pituitary disorder; low levothyroxine adherence; or a follow-up period <90 days. We categorized the daily levothyroxine doses into 4 groups: ≤50 µg/d, 51 to 100 µg/d, 101 to 150 µg/d, and >150 µg/d. The hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with the Cox proportional hazard model, and subgroup analyses were performed according to the osteoporosis history and osteoporosis-specific drug prescription status.
Among 11 155 cohort participants, 35.6% had previous histories of osteoporosis. The adjusted HR of fracture for the >150 µg/d group, compared with the 51 to 100 µg/d group, was 1.56 (95% CI, 1.03 to 2.37) in osteoporosis subgroup. In the highly probable osteoporosis subgroup, restricted to patients who were concurrently prescribed osteoporosis-specific drugs, the adjusted HR of fracture for the >150 µg/d group, compared with the 51 to 100 µg/d group, was 1.93 (95% CI, 1.14 to 3.26).
While further studies are needed, physicians should be concerned about potential levothyroxine overtreatment in elderly osteoporosis patients.
PMCID: PMC3930806  PMID: 24570805
Thyroxine; Fractures; Cohort studies; Aged; Osteoporosis
10.  Comparison of the Safety of Seven Iodinated Contrast Media 
Journal of Korean Medical Science  2013;28(12):1703-1710.
We aimed to determine the characteristic adverse events (AEs) of iodinated contrast media (IOCM) and to compare the safety profiles of different IOCM. This study used the database of AEs reports submitted by healthcare professionals from 15 Regional Pharmacovigilance Centers between June 24, 2009 and December 31, 2010 in Korea. All reports of IOCM, including iopromide, iohexol, iopamidol, iomeprol, ioversol, iobitridol and iodixanol, were analyzed. Safety profiles were compared between different IOCM at the system organ level using the proportional reporting ratio (PRR) and 95% confidence interval (95% CI). Among a total of 48,261 reports, 6,524 (13.5%) reports were related to the use of IOCM. Iopromide (45.5%), iohexol (16.9%), iopamidol (14.3%) and iomeprol (10.3%) were identified as frequently reported media. 'Platelet, bleeding & clotting disorders' (PRR, 29.6; 95%CI, 1.9-472.6) and 'urinary system disorders' (PRR, 22.3; 95% CI, 17.1-29.1) were more frequently reported for iodixanol than the other IOCM. In conclusion, the frequency of AEs by organ class was significantly different between individual media. These differences among different IOCM should be considered when selecting a medium among various IOCM and when monitoring patients during and after its use to ensure optimum usage and patient safety.
PMCID: PMC3857363  PMID: 24339697
Contrast Media; Adverse Drug Reaction Reporting Systems; Patient Safety
11.  PPARγ modulates vascular smooth muscle cell phenotype via a protein kinase G-dependent pathway and reduces neointimal hyperplasia after vascular injury 
Vascular smooth muscle cells (VSMCs) undergo phenotypic changes in response to vascular injury such as angioplasty. Protein kinase G (PKG) has an important role in the process of VSMC phenotype switching. In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, could modulate VSMC phenotype through the PKG pathway to reduce neointimal hyperplasia after angioplasty. In vitro experiments showed that rosiglitazone inhibited the phenotype change of VSMCs from a contractile to a synthetic form. The platelet-derived growth factor (PDGF)-induced reduction of PKG level was reversed by rosiglitazone treatment, resulting in increased PKG activity. This increased activity of PKG resulted in phosphorylation of vasodilator-stimulated phosphoprotein at serine 239, leading to inhibited proliferation of VSMCs. Interestingly, rosiglitazone did not change the level of nitric oxide (NO) or cyclic guanosine monophosphate (cGMP), which are upstream of PKG, suggesting that rosiglitazone influences PKG itself. Chromatin immunoprecipitation assays for the PKG promoter showed that the activation of PKG by rosiglitazone was mediated by the increased binding of Sp1 on the promoter region of PKG. In vivo experiments showed that rosiglitazone significantly inhibited neointimal formation after balloon injury. Immunohistochemistry staining for calponin and thrombospondin showed that this effect of rosiglitazone was mediated by modulating VSMC phenotype. Our findings demonstrate that rosiglitazone is a potent modulator of VSMC phenotype, which is regulated by PKG. This activation of PKG by rosiglitazone results in reduced neointimal hyperplasia after angioplasty. These results provide important mechanistic insight into the cardiovascular-protective effect of PPARγ.
PMCID: PMC3849568  PMID: 24287871
cGMP-dependent protein kinase; Rosiglitazone; Smooth muscle cells
12.  Satisfaction and Difficulties of Korean Family Medicine Resident Training Faculty 
Korean Journal of Family Medicine  2013;34(5):357-363.
Practitioners of family medicine are essential to primary care practices in Korea. Resident training staffs in Korean family medicine departments have a crucial role in producing well-trained family physicians. This study assesses the aspects of satisfaction and difficulties of Korean family medicine resident training staffs.
We surveyed the resident training staffs of various Korean family medicine departments using an online survey tool. The survey used in this study was modified from previously used questionnaires. Respondents rated items using a five-point Likert scale and a 0-10 visual analogue scale.
The response rate was 43.9% (122/278). The mean satisfaction score with regard to current family medicine residency programs was 7.59 out of 10. Resident training staffs found the administrative aspects of their role to be the most difficult. There were considerable differences in the reported difficulties of resident training according to the differing characteristics of each staff member, including age, sex, type of hospital, number of staff members, role as chief, and duration of staff. Most respondents (91.9%) cited a need for faculty development programs.
Korean family medicine resident training staffs need faculty development programs for the improvement of resident training. For the strengthening of core competencies among resident training staffs, faculty development programs or courses should be designed and implemented in Korea.
PMCID: PMC3791343  PMID: 24106588
Faculty Development; Survey; Family Medicine Teacher; Faculty Developmental Program
13.  Altered Levels of Sphingosine and Sphinganine in Psoriatic Epidermis 
Annals of Dermatology  2013;25(3):321-326.
Ceramides are the main lipid component of the stratum corneum and are a structurally heterogeneous and complex group of sphingolipids of which sphingoid bases are the basic structural constituents. Altered levels of sphingoid bases have been reported in skin conditions that involve dryness and barrier disruption, including atopic dermatitis.
The purpose of this study was to investigate the altered levels of sphingoid bases in psoriatic epidermis and their relationship with the clinical severity of the psoriasis.
Samples from the lesional and non-lesional epidermis were obtained from eight psoriasis patients. Levels of sphingosine and sphinganine were analyzed by high-performance liquid chromatography. The expression of ceramide synthase and ceramidase proteins, which are related to sphingosine and sphinganine metabolism, were measured using Western blot analysis.
Levels of sphingosine and sphinganine in the lesional epidermis were significantly higher than those in the non-lesional epidermis. Although there was no altered ceramide synthase and ceramidase, there was a highly significant positive correlation between the % change of ceramidase, the degradative enzyme of ceramide into sphingosine, and the Psoriasis Area Severity Index (PASI) score.
The levels of sphingosine and sphinganine were significantly increased in psoriatic epidermis and the % change of ceramidase was positively correlated with the clinical severity of psoriasis.
PMCID: PMC3756197  PMID: 24003275
Ceramidases; Dihydroceramide desaturase; Psoriasis; Sphinganine; Sphingosine
14.  Vascular Calcifying Progenitor Cells Possess Bidirectional Differentiation Potentials 
PLoS Biology  2013;11(4):e1001534.
Calcifying progenitor cells in blood vessels have the potential to differentiate into cells that either promote calcium accumulation or reverse accumulation, and treatment with PPAR? can shift the direction of this differentiation.
Vascular calcification is an advanced feature of atherosclerosis for which no effective therapy is available. To investigate the modulation or reversal of calcification, we identified calcifying progenitor cells and investigated their calcifying/decalcifying potentials. Cells from the aortas of mice were sorted into four groups using Sca-1 and PDGFRα markers. Sca-1+ (Sca-1+/PDGFRα+ and Sca-1+/PDGFRα−) progenitor cells exhibited greater osteoblastic differentiation potentials than Sca-1− (Sca-1−/PDGFRα+ and Sca-1−/PDGFRα−) progenitor cells. Among Sca-1+ progenitor populations, Sca-1+/PDGFRα− cells possessed bidirectional differentiation potentials towards both osteoblastic and osteoclastic lineages, whereas Sca-1+/PDGFRα+ cells differentiated into an osteoblastic lineage unidirectionally. When treated with a peroxisome proliferator activated receptor γ (PPARγ) agonist, Sca-1+/PDGFRα− cells preferentially differentiated into osteoclast-like cells. Sca-1+ progenitor cells in the artery originated from the bone marrow (BM) and could be clonally expanded. Vessel-resident BM-derived Sca-1+ calcifying progenitor cells displayed nonhematopoietic, mesenchymal characteristics. To evaluate the modulation of in vivo calcification, we established models of ectopic and atherosclerotic calcification. Computed tomography indicated that Sca-1+ progenitor cells increased the volume and calcium scores of ectopic calcification. However, Sca-1+/PDGFRα− cells treated with a PPARγ agonist decreased bone formation 2-fold compared with untreated cells. Systemic infusion of Sca-1+/PDGFRα− cells into Apoe−/− mice increased the severity of calcified atherosclerotic plaques. However, Sca-1+/PDGFRα− cells in which PPARγ was activated displayed markedly decreased plaque severity. Immunofluorescent staining indicated that Sca-1+/PDGFRα− cells mainly expressed osteocalcin; however, activation of PPARγ triggered receptor activator for nuclear factor-κB (RANK) expression, indicating their bidirectional fate in vivo. These findings suggest that a subtype of BM-derived and vessel-resident progenitor cells offer a therapeutic target for the prevention of vascular calcification and that PPARγ activation may be an option to reverse calcification.
Author Summary
Atherosclerosis involves hardening of the arteries and can lead to heart disease. Calcium accumulation in blood vessels contributes to this process, and this process is regulated by cells that promote calcium accumulation (osteoblasts) and cells that reverse the accumulation (osteoclasts). In this study, we show that vascular calcifying progenitor cells in the blood vessel have the potential to become either osteoblasts or osteoclasts, and that a drug can push these cells towards becoming osteoclasts instead of osteoblasts. Progenitor cells that express both Sca-1 and PDGFRα cell surface proteins were more committed to differentiate into osteoblasts, while cells that only expressed Sca-1 could differentiate into osteoblasts or osteoclasts in a bidirectional manner. Moreover, treatment with a PPARγ agonist could shift the direction of differentiation of Sca-1+/PDGFRα− progenitor cells toward osteoclast-like cells, whereas it cannot influence the fates of Sca-1+/PDGFRα+ progenitors. These results offer new therapeutic targets for reversing calcium accumulation in blood vessels.
PMCID: PMC3621676  PMID: 23585735
15.  Interplay between DISC1 and GABA Signaling Regulates Neurogenesis in Mice and Risk for Schizophrenia 
Cell  2012;148(5):1051-1064.
How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization, or maternal deprivation stress, restores DISC1-dependent dendritic regulation through mTOR pathway during early postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.
PMCID: PMC3294278  PMID: 22385968
16.  Phosphorescent nanoparticles for quantitative measurements of oxygen profiles in vitro and in vivo 
Biomaterials  2012;33(9):2710-2722.
We present the development and characterization of nanoparticles loaded with a custom phosphor; we exploit these nanoparticles to perform quantitative measurements of the concentration of oxygen within three-dimensional (3-D) tissue cultures in vitro and blood vessels in vivo. We synthesized a customized ruthenium (Ru)-phosphor and incorporated it into polymeric nanoparticles via self-assembly. We demonstrate that the encapsulated phosphor is non-toxic with and without illumination. We evaluated two distinct modes of employing the phosphorescent nanoparticles for the measurement of concentrations of oxygen: 1) in vitro, in a 3-D microfluidic tumor model via ratiometric measurements of intensity with an oxygen-insensitive fluorophore as a reference, and 2) in vivo, in mouse vasculature using measurements of phosphorescence lifetime. With both methods, we demonstrated micrometer-scale resolution and absolute calibration to the dissolved oxygen concentration. Based on the ease and customizability of the synthesis of the nanoparticles and the flexibility of their application, these oxygen-sensing polymeric nanoparticles will find a natural home in a range of biological applications, benefiting studies of physiological as well as pathological processes in which oxygen availability and concentration play a critical role.
PMCID: PMC3412373  PMID: 22240511
Nanoparticle; Oxygen–sensing; Ruthenium phosphor; Poly(urethane acrylate nonionomer)(PUAN); Tissue engineering; Vascular oxygen concentration
17.  Entamoeba histolytica Induces Cell Death of HT29 Colonic Epithelial Cells via NOX1-Derived ROS 
Entamoeba histolytica, which causes amoebic colitis and occasionally liver abscess in humans, is able to induce host cell death. However, signaling mechanisms of colon cell death induced by E. histolytica are not fully elucidated. In this study, we investigated the signaling role of NOX in cell death of HT29 colonic epithelial cells induced by E. histolytica. Incubation of HT29 cells with amoebic trophozoites resulted in DNA fragmentation that is a hallmark of apoptotic cell death. In addition, E. histolytica generate intracellular reactive oxygen species (ROS) in a contact-dependent manner. Inhibition of intracellular ROS level with treatment with DPI, an inhibitor of NADPH oxidases (NOXs), decreased Entamoeba-induced ROS generation and cell death in HT29 cells. However, pan-caspase inhibitor did not affect E. histolytica-induced HT29 cell death. In HT29 cells, catalytic subunit NOX1 and regulatory subunit Rac1 for NOX1 activation were highly expressed. We next investigated whether NADPH oxidase 1 (NOX1)-derived ROS is closely associated with HT29 cell death induced by E. histolytica. Suppression of Rac1 by siRNA significantly inhibited Entamoeba-induced cell death. Moreover, knockdown of NOX1 by siRNA, effectively inhibited E. histolytica-triggered DNA fragmentation in HT29 cells. These results suggest that NOX1-derived ROS is required for apoptotic cell death in HT29 colon epithelial cells induced by E. histolytica.
PMCID: PMC3587751  PMID: 23467460
Entamoeba histolytica; host cell death; HT29 colon epithelial cell; reactive oxygen species (ROS); NADPH oxidase 1 (NOX1)
18.  Inhibition of Human Pancreatic Tumor Growth by Cytokine-Induced Killer Cells in Nude Mouse Xenograft Model 
Immune Network  2012;12(6):247-252.
Pancreatic cancer is the fourth commonest cause of cancer-related deaths in the world. However, no adequate therapy for pancreatic cancer has yet been found. In this study, the antitumor activity of cytokine-induced killer (CIK) cells against the human pancreatic cancer was evaluated in vitro and in vivo. Human peripheral blood mononuclear cells were cultured with IL-2-containing medium in anti-CD3 for 14 days. The resulting populations of CIK cells comprised 94% CD3+, 4% CD3-CD56+, 41% CD3+CD56+, 11% CD4+, and 73% CD8+. This heterogeneous cell population was called cytokine-induced killer (CIK) cells. At an effector-target cell ratio of 100:1, CIK cells destroyed 51% of AsPC-1 human pancreatic cancer cells, as measured by the 51Cr-release assay. In addition, CIK cells at doses of 3 and 10 million cells per mouse inhibited 42% and 70% of AsPC-1 tumor growth in nude mouse xenograft assays, respectively. This study suggests that CIK cells may be used as an adoptive immunotherapy for pancreatic cancer patients.
PMCID: PMC3566419  PMID: 23396819
Pancreatic cancer; Adoptive immunotherapy; Cytokine-induced killer cells
19.  Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia 
Neuron  2011;72(4):559-571.
Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.
PMCID: PMC3222865  PMID: 22099459
20.  Utilization of evidence-based treatment in elderly patients with chronic heart failure: using Korean Health Insurance claims database 
Chronic heart failure accounts for a great deal of the morbidity and mortality in the aging population. Evidence-based treatments include angiotensin-2 receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACE-I), beta-blockers, and aldosterone antagonists. Underutilization of these treatments in heart failure patients were frequently reported, which could lead to increase morbidity and mortality. The aim of this study was to evaluate the utilization of evidence-based treatments and their related factors for elderly patients with chronic heart failure.
This is retrospective observational study using the Korean National Health Insurance claims database. We identified prescription of evidence based treatment to elderly patients who had been hospitalized for chronic heart failure between January 1, 2005, and June 30, 2006.
Among the 28,922 elderly patients with chronic heart failure, beta-blockers were prescribed to 31.5%, and ACE-I or ARBs were prescribed to 54.7% of the total population. Multivariable logistic regression analyses revealed that the prescription from outpatient clinic (prevalent ratio, 4.02, 95% CI 3.31–4.72), specialty of the healthcare providers (prevalent ratio, 1.26, 95% CI, 1.12–1.54), residence in urban (prevalent ratio, 1.37, 95% CI, 1.23–1.52) and admission to tertiary hospital (prevalent ratio, 2.07, 95% CI, 1.85–2.31) were important factors associated with treatment underutilization. Patients not given evidence-based treatment were more likely to experience dementia, reside in rural areas, and have less-specialized healthcare providers and were less likely to have coexisting cardiovascular diseases or concomitant medications than patients in the evidence-based treatment group.
Healthcare system factors, such as hospital type, healthcare provider factors, such as specialty, and patient factors, such as comorbid cardiovascular disease, systemic disease with concomitant medications, together influence the underutilization of evidence-based pharmacologic treatment for patients with heart failure.
PMCID: PMC3468388  PMID: 22849621
Congestive heart failure; Drug utilization evaluation; Elderly; Type 2 angiotensin receptor antagonists; Angiotensin-converting enzyme antagonists; Beta-adrenergic blockers
21.  Magnetic Bionanoparticle Enhances Homing of Endothelial Progenitor Cells in Mouse Hindlimb Ischemia 
Korean Circulation Journal  2012;42(6):390-396.
Background and Objectives
Poor homing efficiency is one of the major limitations of current stem cell therapy. Magnetic bionanoparticles (MPs) obtained from Magnetospirillum sp. AMB-1 have a lipid bilayer membrane and ferromagnetic properties. We evaluated a novel priming strategy using MPs to enhance the homing of transplanted progenitor cells to target tissue.
Materials and Methods
Effects of MP on proliferation, viability, and migration of late human endothelial progenitor cells (EPCs) were examined in vitro. Additionally, effects of MP on gene and protein expression related to survival and adhesion were evaluated. Homing and angiogenic efficiency of MP transferred late EPCs was evaluated in nude mouse hindlimb ischemia model.
Below threshold concentration, MP transfer did not influence proliferation or survival of late EPCs, but enhanced migration and trans-endothelial migration of late EPCs toward magnet. Below threshold concentration, MP transfer did not influence gene and protein expression related to survival. In the mouse hindlimb ischemia model, late EPCs treated with high dose MP (5 ug/mL) showed enhanced homing of injected late EPCs in the ischemic limb by magnet, compared to low dose MP (1 ug/mL) treated late EPCs. In addition, high dose MP transferred EPC showed significantly better improvement of perfusion in ischemic limb compared to untreated EPC.
MP transfer with magnet application can be a promising novel strategy to enhance homing efficacy and outcomes of current stem cell therapy.
PMCID: PMC3390424  PMID: 22787469
Nanoparticles; Stem cells; Ischemia
22.  Postsynaptic TRPC1 Function Contributes to BDNF-Induced Synaptic Potentiation at the Developing Neuromuscular Junction 
Brain-derived neurotrophic factor (BDNF) induces synaptic potentiation at both neuromuscular junctions (NMJs) and synapses of the central nervous system through a Ca2+-dependent pathway. The molecular mechanism underlying BDNF-induced synaptic potentiation, especially the regulation of Ca2+ dynamics, is not well understood. Using the Xenopus NMJ in culture as a model system, we show that pharmacological inhibition or morpholino-mediated knockdown of Xenopus TRPC1 (XTRPC1) significantly attenuated the BDNF-induced potentiation of the frequency of spontaneous synaptic responses at the NMJ. Functionally, XTRPC1 was required specifically in postsynaptic myocytes for BDNF-induced Ca2+ elevation and full synaptic potentiation at the NMJ, suggesting a previously under-appreciated postsynaptic function of Ca2+ signaling in neurotrophin-induced synaptic plasticity, in addition to its well-established role at presynaptic sites. Mechanistically, blockade of the p75 neurotrophin receptor abolished BDNF-induced postsynaptic Ca2+ elevation and restricted BDNF-induced synaptic potentiation, while knockdown of the TrkB receptor in postsynaptic myocytes had no effect. Our study suggests that BDNF-induced synaptic potentiation involves coordinated presynaptic and postsynaptic responses and identifies TRPC1 as a molecular mediator for postsynaptic Ca2+ elevation required for BDNF-induced synaptic plasticity.
PMCID: PMC3213207  PMID: 21994391
23.  Self-assembled nanoplatform for targeted delivery of chemotherapy agents via affinity-regulated molecular interactions 
Biomaterials  2010;31(30):7766-7775.
Site-specific delivery of drugs while minimizing unwanted distribution has been one of the pursued goals in cancer therapy. In this endeavor, we have developed targeted polymeric nanoparticles called amphiphilic urethane acrylate nonionomer (UAN) for encapsulation of diverse water-insoluble drugs and diagnostic agents, as well as for simple and reproducible surface conjugation of targeting ligands. Using monoclonal antibodies or lymphocyte function-associated antigen-1 (LFA-1) I domain engineered for varying affinities to intercellular adhesion molecule (ICAM)-1, we were able to deliver UAN nanoparticles to human cancer cells with the efficiency dependent on the strength of the molecular interactions and the degree of ICAM-1 expression on cell surface. Compared to non-specific uptake of free drugs, targeted delivery of UAN nanoparticles carrying equal amount of drugs produced more potent cytotoxicity. Notably, without the targeting ligands attached, UAN nanoparticles were largely precluded from non-specific uptake by the cells, resulting in much lower toxicity. The versatility of our UAN nanoparticles in both payload encapsulation and presentation of targeting ligands may facilitate developing a robust platform for evaluating various combinations of cancer drugs and molecular interactions toward developing effective cancer therapy formulations.
PMCID: PMC2925180  PMID: 20667589
self-assembled nanoparticle; targeted nanoplatform; adhesion molecule; tumor targeting; drug delivery; payload encapsulation
24.  Implementation of a Videoconferencing System between Multiple Family Medicine Departments 
Korean Journal of Family Medicine  2011;32(5):311-316.
Attending conferences is important for doctors and residents in family medicine. Nevertheless, departments of family medicine at many hospitals find it difficult to hold regular conferences. Holding joint videoconferences between Family Medicine Departments of several hospitals through a videoconferencing system could solve this problem. Therefore, Family Medicine Departments of Seoul National University Hospital, Seoul National University Bundang Hospital, and Kangwon National University Hospital decided to hold regular joint videoconferences via a videoconferencing system. Eighty-one joint videoconferences were held from April 1 to October 29, 2010. PowerPoint slideshows were transferred to the other two locations in the same resolution as presenter's monitor. Image and voice of the speaker were transferred in real time and in acceptable quality. Joint videoconferences are feasible, satisfactory and useful for medical education, especially when individual family medicine departments are small and lack resources to hold face-to-face conferences. We expect that more family medicine departments will choose to participate in implementing similar joint videoconferencing systems in the future.
PMCID: PMC3383138  PMID: 22745869
Videoconference; Medical Education; Family Medicine
25.  Calpains are Involved in Entamoeba histolytica-Induced Death of HT-29 Colonic Epithelial Cells 
Entamoeba histolytica is an enteric tissue-invading protozoan parasite that can cause amebic colitis and liver abscess in humans. E. histolytica has the capability to kill colon epithelial cells in vitro; however, information regarding the role of calpain in colon cell death induced by ameba is limited. In this study, we investigated whether calpains are involved in the E. histolytica-induced cell death of HT-29 colonic epithelial cells. When HT-29 cells were co-incubated with E. histolytica, the propidium iodide stained dead cells markedly increased compared to that in HT-29 cells incubated with medium alone. This pro-death effect induced by ameba was effectively blocked by pretreatment of HT-29 cells with the calpain inhibitor, calpeptin. Moreover, knockdown of m- and µ-calpain by siRNA significantly reduced E. histolytica-induced HT-29 cell death. These results suggest that m- and µ-calpain may be involved in colon epithelial cell death induced by E. histolytica.
PMCID: PMC3121076  PMID: 21738275
Entamoeba histolytica; host cell death; calpain; HT-29 colon epithelial cells

Results 1-25 (41)