관동화 유래 세스퀴테르펜 화합물에 의한 Nrf2 활성화 매개 신경보호 및 항건선 효능 연구

학위논문 (박사)-- 서울대학교 대학원 : 약학대학 약학과, 2019. 2. 김영식.Oxidative stress plays a key role in neurodegenerative diseases, such as Alzheimers and Parkinsons disease. It is responsible for the dysfunction or death of neuronal cells that contribute to disease pathogenesis. Skin is the major target of oxidative stress, as it is continuously exposed to exogenous stressors, such as UV radiation and other environmental stresses producing reactive oxygen species. Thus, an efficient antioxidative strategy stimulating an endogenous defense mechanism is important for treatment of neurodegenerative diseases and psoriasis, a chronic inflammatory skin disease. Pharmacological activation of Nrf2, a master regulator of the antioxidant response, can be a beneficial therapeutic strategy. The present study demonstrates that 7β-(3′-ethyl-cis-crotonoyloxy)-1α-(2′-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN) and tussilagonone (TGN), sesquiterpenoids isolated from the medicinal plant Tussilago farfara, are potent, naturally occurring Nrf2 activators. Furthermore, the underlying mechanisms of Nrf2-mediated neuroprotection by ECN and amelioration of psoriatic features by TGN were investigated. Phytochemicals are potent antioxidants and act as activators of Nrf2 inducing phase II detoxification enzymes and cytoprotective genes. Terpenoids, including sesquiterpenoids, activate Nrf2 through the Michael reaction of reactive cysteine residues on the Keap1 protein. Because of this common feature, various terpenoids have been reported to possess protective effects. However, Nrf2-mediated pharmacological activities of ECN and TGN have yet to be elucidated. The objective of this study was to i) assess the potency of ECN and TGN as Nrf2 activators and ii) investigate the molecular mechanisms underlying neuroprotective activities of ECN and anti-psoriatic properties of TGN both in vitro and in vivo. ECN had a protective effect against oxidative stress-induced cell damage. ECN up-regulated Nrf2 and heme oxygenase-1 (HO-1) expression in PC12 cells at the transcriptional level and induced phosphorylation of Akt for Nrf2 activation. Knockdown of Nrf2 by small interfering RNA (siRNA) abrogated the protective effects of ECN, indicating that a neuroprotective effect of ECN against oxidative stress is mediated by Nrf2/HO-1 signaling. In a 6-OHDA-induced mouse model of Parkinsons disease, administration of ECN ameliorated motor impairments and dopaminergic neuronal damage. TGN showed HO-1-mediated anti-inflammatory properties in macrophages and reduced the expression of inflammatory mediators in a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation mouse model. Furthermore, TGN inhibited NF-kB and STAT3 activation, leading to attenuation of psoriasis-related inflammatory genes and hyperproliferation of keratinocytes. It was identified that inhibition of NF-κB and STAT3 by TGN is mediated through Nrf2 activation. Topical TGN treatment ameliorated imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice. Moreover, TGN reduced inflammatory immune genes and epidermal hyperproliferation in IMQ-induced skin homogenates. Taken together, these results suggest that ECN and TGN, as potent Nrf2 activators, could be attractive therapeutic candidates for the neuroprotection or treatment of neurodegenerative diseases and psoriasis.산화 스트레스는 알츠하이머 및 파킨슨 병과 같은 신경 퇴행성 질환에서 병의 발병 기전에 기여하는 신경 세포의 기능 장애 또는 사멸을 초래하여, 주요한 병인으로 작용한다. 피부는 자외선 및 활성 산소종 (ROS)을 생성하는 외인성 스트레스 요인에 지속적으로 노출되므로 산화 스트레스의 주된 표적이 되는 신체 기관이다. 따라서, 체내 항산화 방어 기작을 활성화시키는 것은 신경 퇴행성 질환 및 만성 염증성 피부 질환인 건선의 치료에 있어 효과적인 전략이 될 수 있으며 항산화 반응의 주 조절자인 Nrf2의 약리학적 활성화가 주요 표적이 될 수 있다. 본 연구에서는 약용식물 관동화의 세스퀴테르펜 화합물인 ECN과 TGN이 강력한 Nrf2 활성화 물질임을 밝혔다. 또한, ECN과 TGN을 대상으로 신경보호 및 항건선 효능과 관련 작용 기전을 규명하였고, 동물 모델을 이용하여 생체 내 효능을 확인하였다. 식물 유래 생리활성 물질을 일컫는 파이토케미컬 (Phytochemical)은 강력한 항산화 물질로 해독 효소 및 세포 보호 단백질의 발현을 유도하는 Nrf2의 활성화제 역할을 하는 것으로 주목받고 있다. 세스퀴테르펜을 포함하는 테르페노이드 계열 화합물은 Keap1 단백질에 존재하는 반응성 시스테인 잔기의 마이클 반응을 통해 Nrf2를 활성화시킬 수 있다. 이러한 특징으로 인해 다양한 테르페노이드가 보호 효과를 갖는 것으로 보고되어있다. 그러나, ECN 및 TGN의 Nrf2 매개 약리학적 활성은 아직 밝혀지지 않았다. 본 연구의 목적은 1) Nrf2 활성화 물질로서의 ECN 및 TGN의 효능을 평가하고, 2) ECN의 신경 보호 활성 및 TGN의 항건선 효능에 대한 분자 기전을 밝히고 동물 모델을 이용하여 생체 내 반응을 확인하고자 하였다. ECN은 산화 스트레스에 의해 유발된 세포 손상에 대한 보호 효과를 나타내었다. 또한, PC12 세포에서 Nrf2 및 heme oxygenase-1 (HO-1) 발현을 상향 조절하고 Nrf2 활성화의 상위 기전으로 Akt의 인산화를 유도하였다. Nrf2유전자의 하향 조절은 ECN에 의한 보호 효과를 억제시킨 결과를 통해, 산화 스트레스에 대한 ECN의 신경 보호 효과가 Nrf2 / HO-1 신호 전달을 매개로 한다는 것을 밝혔다. 6-OHDA 유발 파킨슨병 동물 모델에서, ECN의 투여는 운동 장애 및 도파민성 신경 손상을 완화시켰다. TGN은 대식세포에서 HO-1 매개 염증 저항성을 나타냈고 12-O-tetradecanoylphorbol-13-acetate (TPA)로 유도한 급성 피부 염증 쥐 모델에서 염증 매개 단백질의 발현을 감소시켰다. 또한 TGN은 NF-kB 및 STAT3 활성화를 억제하여 건선 관련 염증 인자들의 발현 및 각질 세포의 과다 증식을 감소시켰다. 이와 같은 TGN에 의한 NF-kB 및 STAT3의 억제는 Nrf2 활성화를 통해 매개됨이 확인되었다. TGN의 국소처리는 쥐에서 이미퀴모드 유발 건선성 피부 염증을 개선시켰다. 또한 TGN은 쥐의 피부 조직에서 염증성 면역 유전자의 발현과 표피 과다 증식을 억제하였다. 본 연구 결과들을 종합하여 볼 때, 관동화 유래 세스퀴테르펜 화합물ECN과 TGN은 강력한 Nrf2 활성화 물질로 작용하며, Nrf2 활성화를 매개로 하여 신경보호와 관련된 퇴행성 질환 및 건선의 예방 또는 치료 소재로서 가치 있을 것으로 기대된다. 이는 향후 관동화 유래 천연물 신약 개발에 있어 기초가 되는 중요한 연구로 사료된다.I. INTRODUCTION 1 1. Neurodegenerative diseases 2 1.1. Parkinsons disease 6 1.2. Phytochemicals for neuroprotection 10 2. Psoriasis 13 2.1. Inflammation 18 2.2. Psoriasis treatment 21 3. Nuclear factor erythroid 2-related factor 2 (Nrf2) 24 3.1. Activation of the Nrf2 pathway for neuroprotection 26 3.2. The role of Nrf2 in skin 27 4. Tussilago farfara L. 28 II. STATE OF THE PROBLEM 31 III. RESULTS AND DISCUSSION 34 1. Neuroprotection against 6-OHDA toxicity in PC12 cells and mice through the Nrf2 pathway by ECN 35 1.1. ECN exerts protective effects against H2O2- or 6-OHDA-induced injury in PC12 cells 35 1.2. ECN up-regulates Nrf2 and HO-1 expression in PC12 cells at the transcriptional level 37 1.3. ECN-induced HO-1 expression is mediated through activation of Nrf2/ARE signaling 39 1.4. ECN may directly modify thiols of Keap1 for Nrf2 activation 41 1.5. ECN induces phosphorylation of Akt for Nrf2 activation 43 1.6. Neuroprotective effect of ECN against oxidative stress is mediated by Nrf2/HO-1 signaling 45 1.7. ECN ameliorates 6-OHDA-induced motor impairments 47 1.8. ECN prevents 6-OHDA-induced dopaminergic neuronal damage in the ST and SN of the mouse brain 49 1.9. Discussion 51 2. Amelioration of psoriasis-like skin lesions in keratinocytes and mice through Nrf2 activation by TGN 56 2.1. Heme oxygenase-1-mediated anti-inflammatory effects of TGN on macrophages and 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation in mice 56 2.1.1. TGN induces HO-1 expression in RAW 264.7 macrophages at the transcriptional level 56 2.1.2. TGN increases Nrf2 protein expression at the translational level in RAW 264.7 cells 60 2.1.3. TGN-induced HO-1 expression is mediated through activation of Nrf2 62 2.1.4. TGN inhibits the production of NO and PGE2 as well as the expression of iNOS, COX-2, TNF-α and IL-6 in LPS-stimulated RAW 264.7 cells 64 2.1.5. TGN suppresses LPS-stimulated activation of NF-κB 67 2.1.6. HO-1 mediates the inhibitory effect of TGN on LPS-induced inflammatory responses 69 2.1.7. TGN inhibits TPA-induced iNOS and COX-2 expression in HaCaT cells and mouse skin 72 2.1.8. Discussion 75 2.2. TGN ameliorates psoriatic features in keratinocytes and an imiquimod-induced psoriasis-like dermatitis in mice mediated through Nrf2 activation 80 2.2.1. TGN inhibits TNF-α-induced NF-κB activation and the expression of psoriasis-related pro-inflammatory genes in keratinocytes 80 2.2.2. TGN suppresses IL-6-induced STAT3 activation and keratinocyte proliferation 83 2.2.3. TGN activates Nrf2/ARE signaling pathway 86 2.2.4. Inhibition of NF-κB and STAT3 by TGN is mediated through Nrf2 activation 89 2.2.5. Topical TGN treatment ameliorates IMQ-induced psoriasis-like skin inflammation in mice 91 2.2.6. TGN reduces inflammatory immune genes and epidermal hyperproliferation in IMQ-induced psoriasis-like skin 96 2.2.7. Discussion 103 IV. CONCLUSION 108 V. EXPERIMENTAL SECTION 111 1. Materials 112 1.1. ECN 112 1.2. Isolation and identification of TGN 112 1.3. Preparation of TGN 113 1.4. Chemicals and reagents 113 1.5. Cell culture 114 1.6. Animals 115 1.6.1. 6-OHDA-induced mouse model of PD 115 1.6.2. TPA-induced skin inflammation in mice 116 1.6.3. IMQ-induced psoriasis-like dermatitis model in mice 116 2. Methods 116 2.1. Measurement of cell viability 116 2.2. Western blot analysis 117 2.3. Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) 118 2.4. Luciferase assay 120 2.5. Transient transfection of small interfering RNA 120 2.6. Measurement of ROS accumulation 120 2.7. Measurement of NO, PGE2 production and cell viability 121 2.8. NF-κB SEAP reporter gene assay 122 2.9. Isolation and culture of murine primary epidermal keratinocytes 122 2.10. Chromatin Immunoprecipitation (ChIP) 123 2.11. Animal study 124 2.11.1. 6-OHDA-induced mouse model of PD 124 2.11.1.1. Surgery procedure 124 2.11.1.2. Drug administration 125 2.11.1.3. Rotarod test 125 2.11.1.4. APO-induced rotation test 126 2.11.1.5. Immunohistochemistry 126 2.11.2. TPA-induced skin inflammation in mice 127 2.11.3. IMQ-induced psoriasis-like dermatitis model in mice 128 2.11.3.1. Treatments 128 2.11.3.2. Scoring severity of skin inflammation 129 2.11.3.3. Histology and immunohistochemistry 129 2.12. Statistical analysis 130 REFERENCES 131 ABSTRACT IN KOREAN 152Docto

Use of Topical Rapamycin as Maintenance Treatment after a Single Session of Fractionated CO2 Laser Ablation: A Method to Enhance Percutaneous Drug Delivery

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder with an incidence of approximately 1 in 5,000 to 10,000 live births. TSC has various clinical manifestations such as multiple hamartomas in systemic organs, including the skin. Angiofibromas are the most common skin lesions in patients with TSC. Although benign, angiofibromas develop in childhood and puberty, and can be psychosocially disfiguring for patients. Skin lesions in TSC, specifically angiofibromas, have no significant risk of malignant transformation after puberty; thus, they require no treatment if not prominent. However, the presentation of TSC is important owing to its impact on patient cosmesis. Surgical treatment and laser therapy are the mainstream treatments for angiofibromas. Although the evidence is limited, topical mammalian target of rapamycin inhibitors such as sirolimus (rapamycin) are effective in facial angiofibroma treatment. We describe an adult patient with an angiofibroma who had an excellent response to treatment with topical rapamycin after a single session of carbon dioxide (CO2) laser ablation. The patient showed no sign of relapse or recurring lesions for a year. CO2 laser ablation may serve as a new paradigm of treatment for angiofibromas in TSC. Since the selection of laser devices can be limited for some institutions, we suggest a rather basic but highly effective approach for angiofibroma treatment that can be generally applied with the classic CO2 device.ope

Posttraumatic Growth Measures in Breast Cancer Survivors: A Systematic Review

Purpose: The objective of this study was to identify and evaluate the measures used for assessment of posttraumatic growth (PTG) for women survivors with breast cancer and to evaluate the psychometric properties of each instrument. Methods: A systematic review was conducted to identify measurement instruments used for assessment of PTG using electronic databases such as KoreaMed, DBpia, PubMed, Embase, PsycINFO, CINAHL, and Cochrane Library. Studied published both in Korean and/or English were included for the analysis. Studies were examined by two independent reviewers and eighty-nine studies met the inclusion criteria. The selection of the eighty-nine studies was evaluated on methodological and psychometric properties including validity and reliability of the instruments. Results: Three instruments were identified in the review of the eighty-nine studies. The three instruments were identified as 1) Posttraumatic Growth Inventory (PTGI), 2) Benefit Finding Scale, and 3) Positive Meaning Scale. The PTGI was the most frequently reported instrument used in the review. The majority of the reported studies were used translation and back-translation, but some of the studies did not report translation methods. Most studies (71.9%) reported reliability, but only 29.2% studies reported validity of the instruments used in the study. Conclusion: This study was conducted to provide an evidence for selection and development of measurement instruments of PTG for breast cancer survivors.ope

이차원 전이금속 칼코겐 화합물의 음이온 공공 자리에서의 수소 발생 반응에 대한 계산 연구

학위논문 (박사)-- 서울대학교 대학원 공과대학 재료공학부, 2017. 8. 한승우.Hydrogen is a strong contender for a next-generation clean energy source that may replace the current fossil fuels. However, the low-cost and clean production of hydrogen source is a critical issue. In this regard, the hydrogen production by splitting water, the abundant resource on earth, may resolve many of these problems, particularly if it is driven by the solar energy. To split water using solar energy or electricity, catalysts are necessary to reduce the large overpotential during the hydrogen and oxygen evolution. For several decades, Pt is known to be the best catalyst for hydrogen evolution reaction in water splitting, but the material is very expensive and so might not be suitable for large scale applications. As such, numerous studies searched for alternative catalysts that have potential to replace Pt. Especially, transition metal dichalcogenides (TMDs) are receiving much attention as a new class of two-dimensional catalysts for hydrogen evolution reaction (HER). Despite extensive efforts to find highly efficient catalytic TMD systems, strong candidates to replace Pt have not been suggested yet. In TMD catalysts such as MoS2, edges are believed to be the active sites, but their limited density is a problem. Recently, it was found that the basal plane of MoS2 can also be active for HER by introducing sulfur vacancies in addition to strain.1 Herein, we try to identify the mechanism of HER on sulfur vacancy sites by means of kinetic Monte Carlo simulation using the energetics of first-principles calculations. We find that HER at sulfur vacancy site of MoS2 are dominated by the Volmer-Heyrovsky mechanism, and the vacancy site can be electrically charged, thereby lowering the energy barrier of rate-limiting Heyrovsky step. In addition, when a tensile strain is applied to MoS2, it leads to reaction paths with lower energy barriers in more negatively charged states. We also try to find new defective TMD catalyst for HER by means of computational screening based on the density functional theory. We explore the HER efficiencies of basal planes and anion vacancy sites for various TMD materials by using the hydrogen binding free energy as the descriptor for the HER efficiency. We find hydrogen binding energy is varied by the concentration of vacancy and discover good TMD candidates which are expected to show high HER performance in proper vacancy concentrations. We suggest ZrSe2 and ZrTe2 for low vacancy concentration, and MoSe2, MoTe2, WSe2, ReTe2, MoS2 and ReSe2 when intermediate or high concentration of vacancy is accessible. We expect that these materials could compete with Pt as HER catalyst even without strain engineering. In addition, through multiple linear regression, we identify that the formation energies and the electronic structures of anion vacancies strongly affect the hydrogen adsorption energy.1. Introduction 1 1.1 Hydrogen as a next-generation clean energy source 1 1.2 2D materials as novel catalysts for water splitting 2 1.3 TMD materials for HER 4 1.4 Anion vacancy as a HER active site in TMDs 5 1.5 Goal of the dissertation 7 2. Theoretical backgrounds and methods 8 2.1 Density functional theory (DFT) 8 2.1.1 Hohenberg and Kohn theorem 8 2.1.2 Kohn-Sham equation 9 2.1.3 Exchange-correlation energy 10 2.2 Gibbs free energy 12 2.2.1 Gibbs free energy of intermediates of HER on VS in MoS2 12 3. Mechanism of HER on VS in MoS2 13 3.1 Introduction: Mechanisms of HER 13 3.1.1. HER on VS in MoS2 13 3.2 Theoretical approaches for HER on VS 16 3.2.1. Multiscale simulation 16 3.2.2 HERa stepwise chemical reaction 16 3.2.3 Transition state theory 18 3.2.4 Possible intermediate states of sulfur vacancy in the MoS2 during HER 20 3.2.5 Definition of relative energies of intermediate states 21 3.2.6 Reaction energy and kinetic barrier 23 3.2.7 State transition diagrams of intermediate and transition states 25 3.2.8 Algorithm of KMC 29 3.2.7.1 Rate of event 32 3.2.7.1.1 Reaction barrier 32 3.2.7.1.2 Pre-exponential factors of rates 35 3.3 Result and discussion 38 3.3.1 State change over time and turnover frequency 38 3.3.2 Reaction mechanism 41 3.3.3 Bias dependence 43 3.3.4 Simple model 48 3.3.5 Strain effect 49 3.4 Summary: Mechanisms of HER 55 4. Screening active anion vacancy sites of various TMDs for HER 56 4.1 Introduction: Screening HER catalyst 56 4.2 Computational screening of stable TMDs for HER 59 4.2.1 Computational detail 59 4.2.2 Screening for HER on 40 stable TMD phases 59 4.2.3 Anion vacancy formation 63 4.2.4 Hydrogen adsorption free energy 65 4.2.5 Hydrogen adsorption on TMD basal plane 66 4.2.6 Hydrogen coverage on vacancies of high concentration 67 4.2.6.1 Equilibrium coverage model 67 4.2.6.2 dependence of hydrogen adsorption energy on θ_H 67 4.2.7 Establishing volcano curve 70 4.3 Result and discussion 73 4.3.1 Candidate basal planes of TMD 73 4.3.2 Anion vacancy in TMDs 73 4.3.2.1 Anion vacancy formation energies in TMDs 73 4.3.2.2 Electronic structures of TMDs with anion vacancy 76 4.3.3 Hydrogen adsorption on anion vacancy site in TMD 78 4.3.3.1 Distribution of hydrogen adsorption energies on basal planes and anion vacancy sites 82 4.3.3.2 Candidate TMDs with anion vacancy as an active site 84 4.3.3.3 Classification of candidate TMDs with anion vacancy 86 4.3.3.4 Key physical quantities that affect hydrogen adsorption energy 89 4.4 Conclusion: Screening HER catalyst 92 4.5 Summary: Screening HER catalyst 93 5. Conclusion 94 Bibliography 96 국문 초록 105Docto

Factors Affecting Clinical Practicum Stress of Nursing Students: Using the Lazarus and Folkman's Stress-Coping Model

PURPOSE: This study was conducted to test a path model for the factors related to undergraduate nursing students' clinical practicum stress, based on Lazarus and Folkman's stress-coping model. METHODS: This study utilized a path analysis design. A total of 235 undergraduate nursing students participated in this study. The variables in the hypothetical path model consisted of clinical practicum, emotional intelligence, self-efficacy, Nun-chi, and nursing professionalism. We tested the fit of the hypothetical path model using SPSS/WIN 23.0 and AMOS 22.0. RESULTS: The final model fit demonstrated a satisfactory statistical acceptance level: goodness-of-fit-index=.98, adjusted goodness-of-fit-index=.91, comparative fit index=.98, normed fit index=.95, Tucker-Lewis index=.92, and root mean square error of approximation=.06. Self-efficacy (β=-.22, p=.003) and Nun-chi behavior (β=-.17, p=.024) were reported as significant factors affecting clinical practicum stress, explaining 10.2% of the variance. Nursing professionalism (β=.20, p=.006) and self-efficacy (β=.45, p<.001) had direct effects on emotional intelligence, explaining 45.9% of the variance. Self-efficacy had indirect effects on Nun-chi understanding (β=.20, p<.001) and Nun-chi behavior (β=.09, p=.005) through emotional intelligence. Nursing professionalism had indirect effects on Nun-chi understanding (β=.09, p=.005) and Nun-chi behavior (β=.09, p=.005) through emotional intelligence. The variables for self-efficacy and nursing professionalism explained 29.1% of the Nun-chi understanding and 18.2% of the Nun-chi behavior, respectively. CONCLUSION: In undergraduate nursing education, it is important to identify and manage factors that affect clinical practicum stress. The findings of this study emphasize the importance of Nun-chi, self-efficacy, emotional intelligence, and nursing professionalism in the development of an educational strategy for undergraduate nursing students.ope

Assessment of deep neural networks for the diagnosis of benign and malignant skin neoplasms in comparison with dermatologists: A retrospective validation study

Background: The diagnostic performance of convolutional neural networks (CNNs) for diagnosing several types of skin neoplasms has been demonstrated as comparable with that of dermatologists using clinical photography. However, the generalizability should be demonstrated using a large-scale external dataset that includes most types of skin neoplasms. In this study, the performance of a neural network algorithm was compared with that of dermatologists in both real-world practice and experimental settings. Methods and findings: To demonstrate generalizability, the skin cancer detection algorithm (https://rcnn.modelderm.com) developed in our previous study was used without modification. We conducted a retrospective study with all single lesion biopsied cases (43 disorders; 40,331 clinical images from 10,426 cases: 1,222 malignant cases and 9,204 benign cases); mean age (standard deviation [SD], 52.1 [18.3]; 4,701 men [45.1%]) were obtained from the Department of Dermatology, Severance Hospital in Seoul, Korea between January 1, 2008 and March 31, 2019. Using the external validation dataset, the predictions of the algorithm were compared with the clinical diagnoses of 65 attending physicians who had recorded the clinical diagnoses with thorough examinations in real-world practice. In addition, the results obtained by the algorithm for the data of randomly selected batches of 30 patients were compared with those obtained by 44 dermatologists in experimental settings; the dermatologists were only provided with multiple images of each lesion, without clinical information. With regard to the determination of malignancy, the area under the curve (AUC) achieved by the algorithm was 0.863 (95% confidence interval [CI] 0.852-0.875), when unprocessed clinical photographs were used. The sensitivity and specificity of the algorithm at the predefined high-specificity threshold were 62.7% (95% CI 59.9-65.1) and 90.0% (95% CI 89.4-90.6), respectively. Furthermore, the sensitivity and specificity of the first clinical impression of 65 attending physicians were 70.2% and 95.6%, respectively, which were superior to those of the algorithm (McNemar test; p < 0.0001). The positive and negative predictive values of the algorithm were 45.4% (CI 43.7-47.3) and 94.8% (CI 94.4-95.2), respectively, whereas those of the first clinical impression were 68.1% and 96.0%, respectively. In the reader test conducted using images corresponding to batches of 30 patients, the sensitivity and specificity of the algorithm at the predefined threshold were 66.9% (95% CI 57.7-76.0) and 87.4% (95% CI 82.5-92.2), respectively. Furthermore, the sensitivity and specificity derived from the first impression of 44 of the participants were 65.8% (95% CI 55.7-75.9) and 85.7% (95% CI 82.4-88.9), respectively, which are values comparable with those of the algorithm (Wilcoxon signed-rank test; p = 0.607 and 0.097). Limitations of this study include the exclusive use of high-quality clinical photographs taken in hospitals and the lack of ethnic diversity in the study population. Conclusions: Our algorithm could diagnose skin tumors with nearly the same accuracy as a dermatologist when the diagnosis was performed solely with photographs. However, as a result of limited data relevancy, the performance was inferior to that of actual medical examination. To achieve more accurate predictive diagnoses, clinical information should be integrated with imaging information.ope

Neuromuscular Characteristics and Physical Function in Participants with Parkinson’s Disease

PURPOSE: This study aimed to investigate the level of physical function, lower body strength, and muscle activation during various types of muscle contraction in participants with and without Parkinson’s disease (PD). METHODS: Twelve participants with PD (mean age=63.17±6.24 years) and 12 age- and sex-matched healthy adults (mean age = 58.67±6.39 years) were recruited. An isokinetic dynamometer was used to measure the length- and velocity-dependent maximum voluntary force and the rate of torque development (RTD) of the knee extensor muscles. Muscle activation of the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) muscles of both legs was examined using surface electromyography. The 6-minute walk test, chair stand test, timed up-and-go test, sit-and-reach test, and back-scratch test were performed to assess physical function. RESULTS: Compared to healthy individuals, participants with PD showed significantly lower maximum voluntary force and RTD (p<.05), performed fewer repetitions in the chair stand test (11.64±1.75 vs. 17.08±2.27, p<.001), were slower in the timed up-and go test (8.36±1.42 vs. 5.65±1.07, p<.001), and walked shorter distances in the 6-minute walk test (424.17±65.97 vs. 539.47±63.18, p<.001). However, activation of the three different muscles during isometric and isokinetic muscle contraction was not different between participants with and without PD. CONCLUSIONS: Preserved muscle activation and significantly lower muscle strength during various types of muscle contractions may suggest lower muscle strength and efficiency. The lower physical function seen in participants with mild PD could be due to disease and low physical activity-related muscle atrophy rather than lower muscle activation.ope

Vegetative Growth and Inflorescence Emergence of Phalaenopsis 'Mantefon' as Affected by Photoperiod, Light Intensity, and Daily Light Integral

학위논문 (석사)-- 서울대학교 대학원 : 농업생명과학대학 식물생산과학부, 2018. 2. 김기선.This study was conducted to deterimne how photoperiod, light intensity, and daily light integral (DLI) influence vegetative growth (Experiment 1) and inflorescence emergence (Experiment 2) in Phalaenopsis. In Experiment 1, five-month-old plants were treated with a combination of three photoperiods [8 (short day, SD), 12 (medium day, MD), and 16 h (long day, LD)] and three light intensities (50, 100, and 200 μmol∙m-2∙s-1), resulting in 7 DLIs ranging from 1.44 to 11.52 mol∙m-2∙d-1. Each light treatment was maintained for 20 weeks at constant 28oC. It was observed that plants grown under longer photoperiod and high light intensity resulted in shorter, wider, and thicker leaves, respectively. Number of new leaves, total leaf area, and shoot and root weights were increased with increasing photoperiod and light intensity. DLI showed higher correlation coefficients with vegetative growth parameters than with photoperiod and light intensity. The regression analysis indicated that increased DLIs promoted vegetative growth. However, it was observed that when DLI reached 11.52 mol∙m-2∙d-1, response slope gradually decreased. In Experiment 2, twelve-month-old plants were used to investigate the effects of photoperiod, light intensity, and DLI on inflorescence emergence. Plants were treated with combinations of three photoperiods [8/16 (day/night, SD), 8+8 (DE10 μmol∙m-2∙s-1 for 8 h extension right after the SD), and 16/8 h (LD)] and three light intensities (75, 150, and 300 μmol∙m-2∙s-1). Each light treatment was maintained for 12 weeks at constant 20oC. Inflorescence emergence percent, the days to emergence, and the number of inflorescences were generally more promoted under LD treatments than SD and DE treatments, indicating that the effect of photoperiod on flower induction of Phalaenopsis was insignificant. Comparing the light intensities, inflorescence emergence was generally promoted as the light intensity was increased. Correlation coefficients of DLIs with days to emergence and number of inflorescences showed the highest values. Regression analysis indicated that as DLI increase from 2 to 17 mol∙m-2∙d-1, the days to inflorescence emergence was shortened by about one month, and average number of the inflorescence was increased more than 2 times. However, they seemed not to be promoted beyond DLI of 12 mol∙m-2∙d-1, suggesting that the DLI reached the maximum (or saturation) point. Thus, inflorescence emergence was promoted with increasing DLI, but the DLI above 12 mol∙m-2∙d-1 was less promotive for inflorescence emergence.INTRODUCTION 1 LITERATURE REVIEW Characteristics of Phalaenopsis 4 Vegetative Growth in Response to Light Intensity and Photoperiod 5 Reproductive Growth in Response to Light Intensity and Photoperiod 6 Growth and Development in Response to Daily Light Integral (DLI) 7 MATERIALS AND METHODS Vegetative Growth (Experiment 1) 9 Inflorescence Emergence (Experiment 2) 11 RESULTS AND DISCUSSION Vegetative Growth (Experiment 1) 13 Inflorescence Emergence (Experiment 2) 30 LITERATURE CITED 48 ABSTRACT IN KOREAN 58Maste

Clinical Efficacy and Tolerance of 1% Nadifloxacin Cream in the Treatment of Mild to Moderate Acne Vulgaris in South Korea

Background: Antimicrobials have been a mainstay of inflammatory acne treatment for more than 30 years. However, antibiotic-resistant propionibacteria had been isolated with increased frequency, and associated with failure to respond to antibiotic therapy. Objective: The aim of this study was to investigate the clinical efficacy and tolerance of 1% nadifloxacin cream. Methods: In the final analysis, 197 patients with mild to moderate facial acne vulgaris were enrolled. The patients were instructed to apply 1% nadifloxacin cream twice daily to the affected skin after washing the face. Following 2 and 4 weeks of treatment, patients were observed for clinical response: number of the acne lesions, Korea acne grading system (KAGS), global improvement, and occurrence of adverse reactions. Results: During 4 weeks of treatment, nadifloxacin caused significant reduction in the number of inflamed papulo-pustular lesions and open/closed comedones. In addition, significant reduction of KAGS was observed. About 96% of patients showed clinical improvement in the overall evaluation of the therapeutic effect by physicians. All reported adverse events were mild. Conclusion: This study shows that 1% nadifloxacin cream can be an effective and safe treatment for mild to moderate acne vulgaris.ope

Impact of Stroke Knowledge, Fear of Recurrence on Health Behavior in patients with ischemic stroke

Purpose: The purpose of this study was to identify the following: knowledge of stroke, fear of recurrence and health behaviors among patients with ischemic stroke. Further, factors influencing health behavior will be described. Methods: Data were collected from 180 patients with ischemic stroke at a general hospital. The study instruments included items about general and health related characteristics, a Stroke Knowledge Scale, a Stroke Fear of Recurrence Scale, and a Health Behavior Scale. Hierarchical regression method was conducted to examine predictors of health behavior. Results: The mean age of the participants was 63.62±11.10 years, and 57.8% of the sample was men. The mean score for stroke knowledge (possible range=0~17) was 14.99±1.76, the mean score for fear of recurrence (possible range=0~32) was 23.16±3.75, and the mean score for health behavior (possible range=20~80) was 54.69±6.46. Stroke knowledge and fear of recurrence were associated with health behavior in patients with ischemic stroke (F=9.98, p<.001, Adjusted R2=.43). Conclusion: The results demonstrated that stroke knowledge and fear of recurrence impacts the health behavior among patients with ischemic stroke. Thus, nursing interventions which focused on fear of recurrence as well as enhancing stroke knowledge could help health behavior in patients with ischemic stroke.ope