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1.  Intravenous Recombinant Tissue Plasminogen Activator Thrombolysis in a Patient with Acute Ischemic Stroke Secondary to Aortic Dissection 
Acute ischemic stroke secondary to aortic dissection (AoD) is challenging in the era of thrombolysis owing to the diagnostic difficulty within a narrow time window and the high risk of complications.
Case Report
A 64-year-old woman with middle cerebral artery occlusion syndrome admitted to the emergency room within intravenous recombinant tissue plasminogen activator (rt-PA) time window. Her neurological symptoms improved during thrombolysis, but chest and abdominal pain developed. Repeated history-taking, physical examination, and imaging studies led to the timely diagnosis and surgical treatment of AoD, which produced a successful outcome.
Clinical suspicion is invaluable for the diagnosis of this rare cause of stroke. Considering the stroke mechanism and complications, the risks of thrombolysis might outweigh its benefits.
PMCID: PMC2686889  PMID: 19513335
aortic dissection; ischemic stroke; thrombolysis; recombinant tissue plasminogen activator
2.  Ruptured Popliteal Cyst Diagnosed by Ultrasound Before Evaluation for Deep Vein Thrombosis 
Annals of Rehabilitation Medicine  2014;38(6):843-846.
Most popliteal cysts are asymptomatic. However, cysts may rupture, resulting in pain and swelling of the leg that could also arise from other diseases, including deep vein thrombosis, lymphedema, cellulitis, and tear of a muscle or tendon. Therefore, it is difficult to diagnose a ruptured popliteal cyst based on only a patient's history and physical examination. Musculoskeletal ultrasound has been regarded as a diagnostic tool for ruptured popliteal cyst. Here, we describe a patient who was rapidly diagnosed as ruptured popliteal cyst by ultrasonography. Therefore, ultrasound could be used to distinguish a ruptured popliteal cyst from other diseases in patients with painful swollen legs before evaluation for deep vein thrombosis.
PMCID: PMC4280382  PMID: 25566485
Calf pain; Complicated popliteal cyst; Ultrasonography
3.  Ultra-Low-Dose Chest CT in Patients with Neutropenic Fever and Hematologic Malignancy: Image Quality and Its Diagnostic Performance 
The aim of this study was to evaluate the image quality of ultra-low-dose computed tomography (ULDCT) and its diagnostic performance in making a specific diagnosis of pneumonia in febrile neutropenic patients with hematological malignancy.
Materials and Methods
ULDCT was performed prospectively in 207 febrile neutropenic patients with hematological malignancy. Three observers independently recorded the presence of lung parenchymal abnormality, and also indicated the cause of the lung parenchymal abnormality between infectious and noninfectious causes. If infectious pneumonia was considered the cause of lung abnormalities, they noted the two most appropriate diagnoses among four infectious conditions, including fungal, bacterial, viral, and Pneumocystis pneumonia. Sensitivity for correct diagnoses and receiver operating characteristic (ROC) curve analysis for evaluation of diagnostic accuracy were calculated. Interobserver agreements were determined using intraclass correlation coefficient.
Of 207 patients, 139 (67%) had pneumonia, 12 had noninfectious lung disease, and 56 had no remarkable chest computed tomography (CT) (20 with extrathoracic fever focus and 36 with no specific disease). Mean radiation expose dose of ULDCT was 0.60±0.15 mSv. Each observer regarded low-dose CT scans as unacceptable in only four (1.9%), one (0.5%), and three (1.5%) cases of ULDCTs. Sensitivity and area under the ROC curve in making a specific pneumonia diagnosis were 63.0%, 0.65 for reader 1; 63.0%, 0.61 for reader 2; and 65.0%, 0.62 for reader 3; respectively
ULDCT, with a sub-mSv radiation dose and acceptable image quality, provides ready and reasonably acceptable diagnostic information for pulmonary infection in febrile neutropenic patients with hematologic malignancy
PMCID: PMC4206072  PMID: 25308150
Hematologic neoplasms; Febrile neutropenia; Pulmonary infection; Ultra-low-dose CT
4.  Small-Group Counseling in a Modified Tinnitus Retraining Therapy for Chronic Tinnitus 
The authors have treated chronic tinnitus patients using a combination of a simplified tinnitus retraining therapy (TRT) and medications, which we called modified TRT. In this clinical setting, we have attempted small-group counseling to find a time-effective equivalent of individual counseling. The aim of the present study was to evaluate the effectiveness of small-group counseling by comparing the treatment outcomes between individual and small-group counseling.
The patients who had distressing chronic tinnitus with normal hearing or mild hearing loss were included. The subjects were placed into the small-group (group 1:4) or the individual (group 1:1) counseling group, and underwent a modified TRT composed of a single session of directive counseling and ambient sound stimulation. In addition, alprazolam (0.25 mg) and ginkgo biloba extract (80 mg) were administered orally to the subjects for 3 months. The 3- and 6- month outcomes were assessed using the follow-up rates and tinnitus severity scores: awareness, tinnitus handicap inventory (THI), loudness, annoyance, and effect on life. The treatment responses were classified as improvement, no changes, and worsening.
Of the total 149 patients (77 in group 1:1; 72 in group 1:4), 104 patients completed the protocol at 3 months, and 55 patients at 6 months. The follow-up rates were similar in both groups. Over the period of 6 months, all scores declined significantly except the loudness score at 3 months in both groups. Treatment responses showed no between-group differences. The success rate based on THI was 70% in group 1:1, and 64% in group 1:4 at 6 months.
The small-group counseling of our modified TRT was comparable to the individual counseling for tinnitus relief. We suggest that this protocol can be implemented effectively in any crowded otolaryngology clinics.
PMCID: PMC3863669  PMID: 24353860
Tinnitus; Tinnitus retraining therapy; Directive counseling; Benzodiazepines
5.  Invasive Pulmonary Aspergillosis after Influenza A Infection in an Immunocompetent Patient 
Invasive aspergillosis has emerged as a major cause of life-threatening infections in immunocompromised patients. Recently, patients with chronic obstructive pulmonary disease, who have been receiving corticosteroids for a long period, and immunocompetent patients in the intensive care unit have been identified as nontraditional hosts at risk for invasive aspergillosis. Here, we report a case of invasive pulmonary aspergillosis after influenza in an immunocompetent patient. The patient's symptoms were nonspecific, and the patient was unresponsive to treatments for pulmonary bacterial infection. Bronchoscopy revealed mucosa hyperemia, and wide, raised and cream-colored plaques throughout the trachea and both the main bronchi. Histologic examination revealed aspergillosis. The patient recovered quickly when treated systemically with voriconazole, although the reported mortality rates for aspergillosis are extremely high. This study showed that invasive aspergillosis should be considered in immunocompetent patients who are unresponsive to antibiotic treatments; further, early extensive use of all available diagnostic tools, especially bronchoscopy, is mandatory.
PMCID: PMC3884115  PMID: 24416058
Invasive Pulmonary Aspergillosis; Influenza A Virus; Immunocompetence
6.  Genetic and Clinical Characteristics of Korean Patients with Isolated Hypoparathyroidism: From the Korean Hypopara Registry Study 
Journal of Korean Medical Science  2013;28(10):1489-1495.
Isolated hypoparathyroidism (IH) shows heterogeneous phenotypes and can be caused by defects in a variety of genes. The goal of our study was to determine the clinical features and to analyze gene mutations in a large cohort of Korean patients with sporadic or familial IH. We recruited 23 patients. They showed a broad range of onset age and various values of biochemical data. Whole exome sequencing was performed on two affected cases and one unaffected individual in a family. All coding exons and exon-intron borders of GCMB, CASR, and prepro-PTH were sequenced using PCR-amplified DNA. In one family who underwent the whole exome sequencing analysis, approximately 300 single nucleotide changes emerged as candidates for genetic alteration. Among them, we identified a functional mutation in exon 2 of GCMB (C106R) in two affected cases. Besides, heterozygous gain-of-function mutations in the CASR gene were found in other subjects; D410E and P221L. We also found one single nucleotide polymorphism (SNP) in the prepro-PTH gene, five SNPs in the CASR gene, and four SNPs in the GCMB gene. The current study represents a variety of biochemical phenotypes in IH patients with the molecular genetic diagnosis of IH.
PMCID: PMC3792604  PMID: 24133354
CASR; GCMB; Hypocalcemia; Hypoparathyroidism; Prepro-PTH
7.  Clinical Factors Affecting Discrepant Correlation Between Asthma Control Test Score and Pulmonary Function 
The Asthma Control Test (ACT) score is widely used in asthma clinics, particularly with the recent emphasis on achievement and maintenance of optimal asthma control. However, this self-assessment score does not always correspond with lung function parameters, leading to uncertainty about each patient's control status; therefore, we investigated the clinical characteristics that are associated with discrepant correlation between the ACT score and pulmonary function. The 252 adult asthmatic subjects were divided into 5 groups according to their changes in FEV1% predicted values and ACT scores between 2 consecutive visits three months apart. The data were retrospectively reviewed and several clinical variables were compared. Elderly, non-eosinophilic, non-atopic asthma patients were more likely to show paradoxical changes of pulmonary function and ACT score. Female patients were prone to report exaggerated changes of ACT score compared with baseline lung function and changes in FEV1 levels. This group was using more medications for rhinosinusitis. Male patients seemed less sensitive to changes in lung function. From these findings, we conclude that when assessing asthma control status, physicians should carefully consider patient age, gender, atopy status, blood eosinophil levels, and comorbidities along with their ACT scores and pulmonary function test results.
PMCID: PMC4274474  PMID: 25553267
Asthma; asthma control test; pulmonary function test
8.  Circadian phase-dependent effect of nitric oxide on L-type voltage-gated calcium channels in avian cone photoreceptors 
Journal of neurochemistry  2013;127(3):314-328.
Nitric oxide (NO) plays an important role in phase-shifting of circadian neuronal activities in the suprachiasmatic nucleus and circadian behavior activity rhythms. In the retina, NO production is increased in a light-dependent manner. While endogenous circadian oscillators in retinal photoreceptors regulate their physiological states, it is not clear whether NO also participates in the circadian regulation of photoreceptors. In the present study, we demonstrate that NO is involved in the circadian phase-dependent regulation of L-type voltage-gated calcium channels (L-VGCCs). In chick cone photoreceptors, the L-VGCCα1 subunit expression and the maximal L-VGCC currents are higher at night, and both Ras-MAPK (mitogen-activated protein kinase)-Erk (extracellular-signal-regulated kinase) and Ras-phosphatidylinositol 3 kinase (PI3K)-protein kinase B (Akt) are part of the circadian output pathways regulating L-VGCCs. The NO-cGMP-protein kinase G (PKG) pathway decreases L-VGCCα1 subunit expression and L-VGCC currents at night, but not during the day, and exogenous NO donor or cGMP decreases the phosphorylation of Erk and Akt at night. The protein expression of neural NO synthase (nNOS) is also under circadian control, with both nNOS and NO production being higher during the day. Taken together, NO/cGMP/PKG signaling is involved as part of the circadian output pathway to regulate L-VGCCs in cone photoreceptors.
PMCID: PMC4112736  PMID: 23895452
retina; photoreceptor; circadian; ion channel; signaling; cone
9.  Osteochondral Lesion of the Bilateral Femoral Heads in a Young Athletic Patient 
Korean Journal of Radiology  2014;15(6):792-796.
Osteochondral lesions of the femoral head are uncommon and few studies have reported their imaging findings. Since joints are at risk of early degeneration after osteochondral damage, timely recognition is important. Osteochondral lesions of femoral head may often be necessary to differentiate from avascular necrosis. Here, we report a case of osteochondral lesions on bilateral femoral heads. This lesion manifested as subchondral cysts in initial radiographs, which led to further evaluation by computed tomography arthrography and magnetic resonance imaging, which revealed overlying cartilage defects.
PMCID: PMC4248635  PMID: 25469091
Osteochondral lesion; Femoral head; Athlete; Arthrography
10.  Innovative three-dimensional (3D) eco-TiO2 photocatalysts for practical environmental and bio-medical applications 
Scientific Reports  2014;4:6740.
It is known that water purified by conventional TiO2 photocatalysts may not be safe enough for drinking, due to the toxicity by tiny existence of TiO2 nanoparticles after water treatment. We herein demonstrate a facile design of a three-dimensional (3D) TiO2 photocatalyst structure with which both the efficiency of purification and the safety level of the final purified water can be improved and ensured, respectively. The structure, consisting of 3D sulfur-doped TiO2 microtubes in nanotubes (eco-TiO2), is suitable for both environmental and bio-medical applications. Investigation of its formation mechanism reveals that anodic aluminum oxide (AAO), owing to a spatial constraint, causes a simple, nanoparticles-to-nanotubes structural rearrangement as a template for nanotube growth. It is found that eco-TiO2 can be activated under visible-light irradiation by non-metal (sulfur; S) doping, after which it shows visible-light photocatalytic activities over a range of solar energy. Importantly, an in vitro cytotoxicity test of well-purified water by eco-TiO2 confirms that eco-TiO2 satisfies the key human safety conditions.
PMCID: PMC4206844  PMID: 25338845
11.  Evidence of complex formation between FADD and c-FLIP death effector domains for the death inducing signaling complex 
BMB Reports  2014;47(9):488-493.
Adaptor protein FADD forms the death inducing signaling complex (DISC) by recruiting the initiating caspases-8 and -10 through homotypic death effector domain (DED) interactions. Cellular FLICE-inhibitory protein (c-FLIP) is an inhibitor of death ligand-induced apoptosis downstream of death receptors, and FADD competes with procaspase-8/10 for recruitment for DISC. However, the mechanism of action of FADD and c-FLIP proteins remain poorly understood at the molecular level. In this study, we provide evidence indicating that the death effector domain (DED) of FADD interacts directly with the death effector domain of human c-FLIP. In addition, we use homology modeling to develop a molecular docking model of FADD and c-FLIP proteins. We also find that four structure-based mutants (E80A, L84A, K169A and Y171A) of c-FLIP DEDs disturb the interaction with FADD DED, and that these mutations lower the stability of the c-FLIP DED. [BMB Reports 2014; 47(9): 488-493]
PMCID: PMC4206723  PMID: 24355299
c-FLIP; Death effector domain; FADD; Interaction; Structure-based mutations
12.  Metabolic syndrome as an indicator of high cardiovascular risk in patients with diabetes: Analyses based on Korea National Health and Nutrition Examination Survey (KNHANES) 2008 
Patients with either diabetes mellitus (DM) or metabolic syndrome (MS) are recognized as a high risk group for cardiovascular disease (CVD). Several studies have demonstrated the clinical value of MS for predicting additional CVD risk in the DM population, although the clinical significance remains debatable.
We used the Korea National Health and Nutrition Examination Survey (KNHANES) 2008, which is the national representative database. We classified the KNHANES subjects based on MS and glucose tolerance status, and compared clinical characteristics and future CVD risk among the subgroups.
A total of 796 of the 4314 subjects were diagnosed with MS. Their clinical characteristics were significantly different from patients without MS. Prevalence of DM was 9.5% in subjects with MS, but only 1.1% in subjects without MS. In addition, there was no MS in 30.9% of total DM patients who were enrolled in this study. For the normal and impaired fasting glucose subgroups, the prevalence of moderate (5–10%) and high (>10%) CVD risk was significantly higher in patients with MS than in patients without MS (p < 0.001). However, in the DM subgroup, even after multiple adjustments, there were no differences in clinical characteristics or in the prevalence of moderate to high CVD risk according to MS status. That said, LDL cholesterol in the DM group without MS was significantly higher than in the DM group with MS (p = 0.010).
The efficacy of MS as a screening tool for high CVD risk may be limited in DM patients, and conventional risk factors such as LDL may be more important.
Electronic supplementary material
The online version of this article (doi:10.1186/1758-5996-6-98) contains supplementary material, which is available to authorized users.
PMCID: PMC4176586  PMID: 25264460
Metabolic syndrome; Syndrome X; Cardiovascular disease; Framingham risk score; Diabetes mellitus; DM; Dyslipidemia; Cholesterol; KNHANES; Korea
13.  Symptomatic aggravation after corticosteroid pulse therapy in definite sporadic Creutzfeldt-Jakob disease with the feature of Hashimoto’s encephalopathy 
BMC Neurology  2014;14(1):179.
Creutzfeldt-Jakob disease and Hashimoto’s encephalopathy often show similar clinical presentation. Among Creutzfeldt-Jakob disease mimics, Hashimoto’s encephalopathy is particularly important as it is treatable with corticosteroids. Thus, in cases of middle-aged woman diagnosed with probable Creutzfeldt-Jakob disease and who exhibit high titers of antithyroid antibodies, corticosteroid pulse therapy is typically performed with expectations of near complete recovery from Hashimoto’s encephalopathy. Herein, we provide the first case report that exhibited a negative effect of corticosteroid pulse therapy for a patient with Creutzfeldt-Jakob disease with features of Hashimoto’s encephalopathy.
Case presentation
We report a case of 59-year-old Asian woman with blurred vision, dysarthria, myoclonus, and rapidly progressive dementia. Cerebrospinal fluid showed 14-3-3 protein positive. Electroencephalogram showed periodic sharp waves (1.5 Hz) at the bilateral frontal or occipital areas. Magnetic resonance imaging showed high signal intensities at the bilateral cerebral cortex, caudate nucleus, and putamen. The patient was diagnosed with probable Creutzfeldt-Jakob disease. However, serum analysis showed a high titer of antithyroid antibodies. We started corticosteroid pulse therapy with subsequent aggravation of seizure activity including generalized myoclonus, epilepsia parialis continua, and ballistic dyskinesia, which was effectively treated with clonazepam.
We provide evidence of a case of Creutzfeldt-Jakob disease that exhibited clinical deterioration after corticosteroid therapy. Although histopathological confirmation with brain biopsy is not easily available in Creutzfeldt-Jakob disease patients, selective initiation of corticosteroid pulse therapy should be considered in cases of uncertain diagnosis for differentiation with Hashimoto’s encephalopathy.
PMCID: PMC4172833  PMID: 25196053
Creutzfeldt-Jakob disease; Hashimoto’s encephalopathy; Corticosteroid; Seizure
14.  Effects of Korean Red Ginseng on Hearing and Blood Glucose Levels in Steroid Therapy for Sudden Sensorineural Hearing Loss 
Korean red ginseng (KRG) has hypoglycemic, antioxidant, antithrombotic, and other beneficial effects in human. The present study evaluate the therapeutic effects of KRG on hearing recovery and glucocorticoid-induced hyperglycemia in patients with idiopathic sudden sensorineural hearing loss (SSNHL) undergoing systemic steroid therapy.
The patients were divided into 2 groups: the steroid, and the combination of steroid and red ginseng. Pure tone averages (PTA) were assessed at the first visit and 2-month follow-up. All patients underwent fasting blood glucose analyses just before and on the fifth day of treatment. Both groups were treated with a 10-day course of oral methylprednisolone at tapering doses starting from a daily dose of 48 mg. To the combination group, KRG extract was administered by mouth at a daily dose of 3 g for 20 days in addition to methylprednisolone. Hearing gain was calculated comparing the initial PTA and PTA at 2 months' follow-up. Treatment responses were classified according to Siegel's criteria.
Pretreatment conditions were similar between the steroid (n=37) and combination groups (n=36). At 2 months after the treatment, PTA improved significantly in both groups, but there was no significant difference in the mean hearing gain & recovery rate. The non-diabetic subjects in the steroid group (n=27) exhibited a 24% increase in the mean blood glucose level during the systemic steroid therapy, while those in the combination group (n=34) showed no changes.
Although the KRG did not provide greater therapeutic effects on hearing recovery, we suggest that red ginseng can be a useful adjuvant to the current steroid therapy to normalize glucocorticoid-induced hyperglycemia in non-diabetic patients during the treatment of SSNHL.
PMCID: PMC4135151  PMID: 25177431
Korean red ginseng; Sudden sensorineural hearing loss; Steroids; Glucose; Hyperglycemia
15.  Minor Criteria of Infectious Disease Society of America/American Thoracic Society for Severe Community-Acquired Pneumonia Can Predict Delayed Treatment Response 
Journal of Korean Medical Science  2012;27(8):907-913.
The purpose of this study was to investigate the clinical aspects of patients satisfying the Infectious Disease Society of America/American Thoracic Society (IDSA/ATS) minor severity criteria, focusing on their treatment response to empirical antibiotics. In total, 381 community-acquired pneumonia (CAP) patients who did not require mechanical ventilation or vasopressors at admission were enrolled, and 50 (13.1%) satisfied the minor severity criteria (i.e. , minor severe CAP [minor-SCAP]). The rates of new complication events and clinical treatment failure were significantly higher in the minor-SCAP group than in the control group (30.0% vs 2.1%, P < 0.001, and 42.0% vs 10.6%, P < 0.001, respectively), and the time to reach clinical stability was longer in the minor-SCAP group (8 days vs 3 days, P < 0.001). In a multivariate model, minor severity criteria (≥ 3) were significantly associated with treatment failure (odds ratio, 2.838; 95% confidence interval, 1.216 to 6.626), and for predicting treatment failure the value of the area under the receiver operating characteristic curve for minor criteria was 0.731, similar to other established scoring methods. The IDSA/ATS minor severity criteria can predict delayed treatment response and clinical treatment failure.
PMCID: PMC3410239  PMID: 22876058
Minor Criteria; Pneumonia; Severe; Treatment Response
16.  Chicken Embryos as a Potential New Model for Early Onset Type I Diabetes 
Journal of Diabetes Research  2014;2014:354094.
Diabetic retinopathy (DR) is the leading cause of blindness among the American working population. The purpose of this study is to establish a new diabetic animal model using a cone-dominant avian species to address the distorted color vision and altered cone pathway responses in prediabetic and early diabetic patients. Chicken embryos were injected with either streptozotocin (STZ), high concentration of glucose (high-glucose), or vehicle at embryonic day 11. Cataracts occurred in varying degrees in both STZ- and high glucose-induced diabetic chick embryos at E18. Streptozotocin-diabetic chicken embryos had decreased levels of blood insulin, glucose transporter 4 (Glut4), and phosphorylated protein kinase B (pAKT). In STZ-injected E20 embryos, the ERG amplitudes of both a- and b-waves were significantly decreased, the implicit time of the a-wave was delayed, while that of the b-wave was significantly increased. Photoreceptors cultured from STZ-injected E18 embryos had a significant decrease in L-type voltage-gated calcium channel (L-VGCC) currents, which was reflected in the decreased level of L-VGCCα1D subunit in the STZ-diabetic retinas. Through these independent lines of evidence, STZ-injection was able to induce pathological conditions in the chicken embryonic retina, and it is promising to use chickens as a potential new animal model for type I diabetes.
PMCID: PMC4122024  PMID: 25133191
17.  Carnosic Acid Inhibits the Epithelial-Mesenchymal Transition in B16F10 Melanoma Cells: A Possible Mechanism for the Inhibition of Cell Migration 
Carnosic acid is a natural benzenediol abietane diterpene found in rosemary and exhibits anti-inflammatory, antioxidant, and anti-carcinogenic activities. In this study, we evaluated the effects of carnosic acid on the metastatic characteristics of B16F10 melanoma cells. When B16F10 cells were cultured in an in vitro Transwell system, carnosic acid inhibited cell migration in a dose-dependent manner. Carnosic acid suppressed the adhesion of B16F10 cells, as well as the secretion of matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, urokinase plasminogen activator (uPA), and vascular cell adhesion molecule (VCAM)-1. Interestingly, secretion of TIMP-2 increased significantly in B16F10 cells treated with 10 μmol/L carnosic acid. Additionally, carnosic acid suppressed the mesenchymal markers snail, slug, vimentin, and N-cadherin and induced epithelial marker E-cadherin. Furthermore, carnosic acid suppressed phosphorylation of Src, FAK, and AKT. These results indicate that inhibition of the epithelial-mesenchymal transition may be important for the carnosic acid-induced inhibition of B16F10 cell migration.
PMCID: PMC4139869  PMID: 25036034
carnosic acid; melanoma; migration; epithelial-mesenchymal transition
18.  Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice 
Hepatology (Baltimore, Md.)  2011;53(4):1373-1382.
Activation of innate immunity (natural killer cell/interferon-γ: NK cell/IFN-γ) has been shown to play an important role in anti-viral and anti-tumor defenses as well as anti-fibrogenesis. However, little is known about the regulation of innate immunity during chronic liver injury. Here, we compared the functions of NK cells in early and advanced liver fibrosis induced by a 2-week or a 10 week-carbon tetrachloride (CCl4) challenge, respectively. Injection of poly I:C or IFN-γ induced NK cell activation and NK cell killing of hepatic stellate cells (HSCs) in the 2-week CCl4 model. Such activation was diminished in the 10-week CCl4 model. Consistent with these findings, the inhibitory effect of poly I:C and IFN-γ on liver fibrosis was markedly reduced in the 10-week vs. the 2-week CCl4 model. In vitro co-culture experiments demonstrated that 4-day cultured (early-activated) HSCs induce NK cell activation via an NKG2D-retinoic acid-induced early gene 1 (RAE1)-dependent mechanism. Such activation was reduced when co-cultured with 8-day cultured (intermediately-activated) HSCs due to the production of transforming growth factor-β (TGF-β) by HSCs. Moreover, early-activated HSCs were sensitive, while intermediately-activated HSCs were resistant to IFN-γ mediated inhibition of cell proliferation, likely due to elevated expression of suppressor of cytokine signaling 1 (SOCS1). Disruption of the SOCS1 gene restored the IFN-γ inhibition of cell proliferation in intermediately-activated HSCs. Production of retinol metabolites by HSCs contributed to SOCS1 induction and subsequently inhibited IFN-γ signaling and functioning, while production of TGF-β by HSCs inhibited NK cell function and cytotoxicity against HSCs.
The anti-fibrogenic effects of NK cell/IFN-γ are suppressed during advanced liver injury, which is likely due to the increased production of TGF-β and expression of SOCS1 in intermediately-activated HSCs.
PMCID: PMC3079530  PMID: 21480338
hepatic stellate cell; STAT1; SOCS1; TGF-β; retinol
19.  Anti-carcinogenic effects of non-polar components containing licochalcone A in roasted licorice root 
Nutrition Research and Practice  2014;8(3):257-266.
Licorice has been shown to possess cancer chemopreventive effects. However, glycyrrhizin, a major component in licorice, was found to interfere with steroid metabolism and cause edema and hypertension. The roasting process of licorice modifies the chemical composition and converts glycyrrhizin to glycyrrhetinic acid. The purpose of this study was to examine the anti-carcinogenic effects of the ethanol extract of roasted licorice (EERL) and to identify the active compound in EERL.
Ethanol and aqueous extracts of roasted and un-roasted licorice were prepared. The active fraction was separated from the methylene chloride (MC)-soluble fraction of EERL and the structure of the purified compound was determined by nuclear magnetic resonance spectroscopy. The anti-carcinogenic effects of licorice extracts and licochalcone A was evaluated using a MTT assay, Western blot, flow cytometry, and two-stage skin carcinogenesis model.
EERL was determined to be more potent and efficacious than the ethanol extract of un-roasted licorice in inhibiting the growth of DU145 and MLL prostate cancer cells, as well as HT-29 colon cancer cells. The aqueous extracts of un-roasted and roasted licorice showed minimal effects on cell growth. EERL potently inhibited growth of MCF-7 and MDA-MB-231 breast, B16-F10 melanoma, and A375 and A2058 skin cancer cells, whereas EERL slightly stimulated the growth of normal IEC-6 intestinal epithelial cells and CCD118SK fibroblasts. The MC-soluble fraction was more efficacious than EERL in inhibiting DU145 cell growth. Licochalcone A was isolated from the MC fraction and identified as the active compound of EERL. Both EERL and licochalcone A induced apoptosis of DU145 cells. EERL potently inhibited chemically-induced skin papilloma formation in mice.
Non-polar compounds in EERL exert potent anti-carcinogenic effects, and that roasted rather than un-roasted licorice should be favored as a cancer preventive agent, whether being used as an additive to food or medicine preparations.
PMCID: PMC4058558
Roasted licorice roots; apoptosis; licochalcone A; cancer
20.  Effect of Exercise Intensity on Unfolded Protein Response in Skeletal Muscle of Rat 
Endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and mitochondrial biogenesis were assessed following varying intensities of exercise training. The animals were randomly assigned to receive either low- (LIT, n=7) or high intensity training (HIT, n=7), or were assigned to a control group (n=7). Over 5 weeks, the animals in the LIT were exercised on a treadmill with a 10° incline for 60 min at a speed of 20 m/min group, and in the HIT group at a speed of 34 m/min for 5 days a week. No statistically significant differences were found in the body weight, plasma triglyceride, and total cholesterol levels across the three groups, but fasting glucose and insulin levels were significantly lower in the exercise-trained groups. Additionally, no statistically significant differences were observed in the levels of PERK phosphorylation in skeletal muscles between the three groups. However, compared to the control and LIT groups, the level of BiP was lower in the HIT group. Compared to the control group, the levels of ATF4 in skeletal muscles and CHOP were significantly lower in the HIT group. The HIT group also showed increased PGC-1α mRNA expression in comparison with the control group. Furthermore, both of the trained groups showed higher levels of mitochondrial UCP3 than the control group. In summary, we found that a 5-week high-intensity exercise training routine resulted in increased mitochondrial biogenesis and decreased ER stress and apoptotic signaling in the skeletal muscle tissue of rats.
PMCID: PMC4071173  PMID: 24976760
ER stress; Exercise; Mitochondria; Skeletal muscle; Unfolded protein responses
21.  Workers' Compensation for Occupational Respiratory Diseases 
Journal of Korean Medical Science  2014;29(Suppl):S47-S51.
The respiratory system is one of the most important body systems particularly from the viewpoint of occupational medicine because it is the major route of occupational exposure. In 2013, there were significant changes in the specific criteria for the recognition of occupational diseases, which were established by the Enforcement Decree of the Industrial Accident Compensation Insurance Act (IACIA). In this article, the authors deal with the former criteria, implications of the revision, and changes in the specific criteria in Korea by focusing on the 2013 amendment to the IACIA. Before the 2013 amendment to the IACIA, occupational respiratory disease was not a category because the previous criteria were based on specific hazardous agents and their health effects. Workers as well as clinicians were not familiar with the agent-based criteria. To improve these criteria, a system-based structure was added. Through these changes, in the current criteria, 33 types of agents and 11 types of respiratory diseases are listed under diseases of the respiratory system. In the current criteria, there are no concrete guidelines for evaluating work-relatedness, such as estimating the exposure level, latent period, and detailed examination methods. The results of further studies can support the formulation of detailed criteria.
Graphical Abstract
PMCID: PMC4085175  PMID: 25006324
Respiratory Tract Diseases; Occupational Diseases; Workers' Compensation; Korea
22.  COPD Patients with Exertional Desaturation Are at a Higher Risk of Rapid Decline in Lung Function 
Yonsei Medical Journal  2014;55(3):732-738.
A recent study demonstrated that exertional desaturation is a predictor of rapid decline in lung function in patients with chronic obstructive pulmonary disease (COPD); however, the study was limited by its method used to detect exertional desaturation. The main purpose of this study was to explore whether exertional desaturation assessed using nadir oxygen saturation (SpO2) during the 6-minute walk test (6MWT) can predict rapid lung function decline in patients with COPD.
Materials and Methods
A retrospective analysis was performed on 57 patients with moderate to very severe COPD who underwent the 6MWT. Exertional desaturation was defined as a nadir SpO2 of <90% during the 6MWT. Rapid decline was defined as an annual rate of decline in forced expiratory volume in 1 second (FEV1) ≥50 mL. Patients were divided into rapid decliner (n=26) and non-rapid decliner (n=31) groups.
A statistically significant difference in exertional desaturation was observed between rapid decliners and non-rapid decliners (17 vs. 8, p=0.003). No differences were found between the groups for age, smoking status, BODE index, and FEV1. Multivariate analysis showed that exertional desaturation was a significant independent predictor of rapid decline in patients with COPD (relative risk, 6.8; 95% CI, 1.8 to 25.4; p=0.004).
This study supports that exertional desaturation is a predictor of rapid lung function decline in male patients with COPD.
PMCID: PMC3990067  PMID: 24719141
Chronic obstructive pulmonary disease; exercise; hypoxemia; lung function
23.  Efficient Delivery of Plasmid DNA Using Cholesterol-Based Cationic Lipids Containing Polyamines and Ether Linkages 
Cationic liposomes are broadly used as non-viral vectors to deliver genetic materials that can be used to treat various diseases including cancer. To circumvent problems associated with cationic liposome-mediated delivery systems such as low transfection efficiency and serum-induced inhibition, cholesterol-based cationic lipids have been synthesized that resist the effects of serum. The introduction of an ether-type linkage and extension of the aminopropyl head group on the cholesterol backbone increased the transfection efficiency and DNA binding affinity compared to a carbamoyl-type linkage and a mono aminopropyl head group, respectively. Under optimal conditions, each liposome formulation showed higher transfection efficiency in AGS and Huh-7 cells than commercially available cationic liposomes, particularly in the presence of serum. The following molecular structures were found to have a positive effect on transfection properties: (i) extended aminopropyl head groups for a strong binding affinity to plasmid DNA; (ii) an ether linkage that favors electrostatic binding to plasmid DNA; and (iii) a cholesterol backbone for serum resistance.
PMCID: PMC4057673  PMID: 24786091
cholesterol; cationic lipids; cyanoethylation; transfection; gene delivery; macropinocytosis
24.  Inhibition of Inducible Nitric Oxide Synthase Attenuates Monosodium Urate-induced Inflammation in Mice 
The present study elucidated the effect of the selective inducible nitric oxide synthase (iNOS) inhibitor N6-(1-iminoethyl)-L-lysine (L-NIL) on monosodium urate (MSU) crystal-induced inflammation and edema in mice feet. L-NIL (5 or 10 mg/kg/day) was administered intraperitoneally 4 h before injection of MSU (4 mg) into the soles of mice hindlimb feet. Twenty-four hours after MSU injection, foot thickness was increased by 160% and L-NIL pretreatment reduced food pad swelling in a dose dependent manner. Pretreatment of 10 mg/kg/day L-NIL significantly suppressed the foot pad swelling by MSU. Plasma level of nitric oxide (NO) metabolites and gene expression and protein level of iNOS in feet were increased by MSU, which was suppressed by L-NIL pretreatment. Similar pattern of change was observed in nitrotyrosine level. MSU increased the gene expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β and L-NIL pretreatment suppressed MSU-induced cytokines expression. The mRNA levels of superoxide dismutase and glutathione peroxidase1 were increased by MSU and L-NIL pretreatment normalized the gene expression. Phosphorylation of extracellular signal-regulated kinase 1/2 and p38 was increased by MSU, which was suppressed by L-NIL pretreatment. The mRNA levels of iNOS, TNF-α, and IL-1β were increased by MSU in human dermal fibroblasts, C2C12 myoblasts, and human fetal osteoblasts in vitro, which was attenuated by L-NIL in a dose dependent manner. This study shows that L-NIL inhibits MSU-induced inflammation and edema in mice feet suggesting that iNOS might be involved in MSU-induced inflammation.
PMCID: PMC3282224  PMID: 22359474
Uric acid; Gout; iNOS
25.  Photoluminescent carbon nanotags from harmful cyanobacteria for drug delivery and imaging in cancer cells 
Scientific Reports  2014;4:4665.
Using a simple method of mass production of green carbon nanotags (G-tags) from harmful cyanobacteria, we developed an advanced and efficient imaging platform for the purpose of anticancer therapy. Approximately 100 grams of G-tags per 100 kilograms of harmful cyanobacteria were prepared using our eco-friendly approach. The G-tags possess high solubility, excellent photostability, and low cytotoxicity (<1.5 mg/mL for 24 h). Moreover, doxorubicin-conjugated G-tags (T-tags; >0.1 mg/mL) induced death in cancer cells (HepG2 and MCF-7) in-vitro at a higher rate than that of only G-tags while in-vivo mice experiment showed enhanced anticancer efficacy by T-tags at 0.01 mg/mL, indicating that the loaded doxorubicin retains its pharmaceutical activity. The cancer cell uptake and intracellular location of the G- and T-tags were observed. The results indicate that these multifunctional T-tags can deliver doxorubicin to the targeted cancer cells and sense the delivery of doxorubicin by activating the fluorescence of G-tags.
PMCID: PMC3983594  PMID: 24721805

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