혈청학적 결핵 진단법의 유용성에 관한 연구

학위논문 (박사) -- 서울대학교 대학원 : 의과대학 의학과, 2021. 2. 국윤호.Background: Tuberculosis remains a major public health problem. Conventional tests are inadequate to distinguish between active tuberculosis (ATB) and latent tuberculosis infection (LTBI). Serological tests offer the potential to improve diagnosis of tuberculosis (TB). This study aimed to investigate new biomarkers in the diagnosis of TB. Methods: Antibody responses to Mycobacterium tuberculosis antigens (Mycobacterium tuberculosis chorismate mutase (TBCM), antigen 85B (Ag85B), early secreted antigen‐6 (ESAT-6), and culture filtrate protein‐10 (CFP-10)) and macrophage migration inhibitory factor (MIF) were measured in groups of 65 ATB, 53 LTBI, and 62 non-infected (NI) individuals. Enzyme-linked immunosorbent assay was used to measure levels of IgG and IgA from sera of study participants. The QuantiFERON-TB Gold In-Tube assay was used to diagnose LTBI. Results: IgG levels against TBCM were significantly higher in LTBI than NI subjects. IgG and IgA levels against Ag85B and IgG levels against CFP-10 were significantly higher in ATB, followed by LTBI, and then NI. When the ATB group was subdivided, IgG levels against Ag85B and CFP-10 were significantly higher in each subgroup compared with those in LTBI and NI groups. Positive correlation trends between interferon-gamma (IFN-γ) and IgG levels against Ag85B, TBCM, and CFP-10 and IgA levels against Ag85B in LTBI and NI subjects were observed. Age- and sex-adjusted models showed that IgG against TBCM and CFP-10 was independently related to LTBI diagnosis, and IgG against Ag85B was independently related to the diagnosis of ATB and could distinguish between LTBI and ATB. The level of IgA against MIF was significantly lower in LTBI and ATB patients than in NI individuals and was significantly related to LTBI diagnosis, ATB, and the discrimination between LTBI and ATB. The level of IgG against MIF was significantly lower in LTBI patients than in NI individuals and was significantly related to LTBI diagnosis. Levels of IgA against MIF were significantly lower in AFB-negative TB, minimal TB, and new patients of the ATB group than in the NI group. Both IgA and IgG levels against MIF showed significant negative correlations with IFN-γ levels induced in QFT-GIT test. Conclusion: Overall, IgG antibody responses to TBCM, Ag85B, and CFP-10 can discriminate among ATB, LTBI, and NI groups. Also, results suggest the possibility of using IgA antibody responses to MIF in the diagnosis of LTBI and ATB.배경: 공공 보건의 중대한 문제인 결핵을 효과적으로 관리하기 위해서는 조기 진단이 필수적이지만, 기존 검사법들은 검사 시간, 비용, 정확성 및 재현성을 포함한 많은 제한점이 있다. 혈청학적 검사는 기존 방법의 한계를 개선할 수 있는 잠재력을 제공하므로, 본 연구에서는 혈청학적 결핵 진단에 유용한 새로운 지표들을 개발하고자 하였다. 방법: 결핵균 항원 (TBCM, Ag85B, ESAT-6, CFP-10) 및 대식세포이동저지인자 (macrophage migration inhibitory factor, MIF)에 대한 항체 반응을 65 명의 활동성 결핵, 53 명의 잠복 결핵 및 62 명의 비감염 군에서 측정하였다. 효소결합면역흡착검사를 사용하여 연구 참가자의 혈청에서 IgG 및 IgA 수준을 측정하였다. 잠복 결핵 진단에는 QuantiFERON-TB Gold In-Tube 검사를 사용하였다. 결과: TBCM에 대한 IgG 수준은 비감염군에 비해 잠복 결핵군에서 유의하게 높았다. Ag85B에 대한 IgG 및 IgA 수준과 CFP-10에 대한 IgG 수준은 활동성 결핵 군에서 가장 높았고, 다음으로 잠복 결핵, 비감염군 순이었다. 활동성 결핵군을 객담 항산균 도말 검사 결과, 영상학적 중증도 및 결핵 치료 과거력에 따라 세분화하였을 때, Ag85B 및 CFP-10에 대한 IgG 수준은 잠복 결핵군 및 비감염군에 비하여 활동성 결핵군의 각 하위 군에서 유의하게 높았다. Ag85B, TBCM 및 CFP-10에 대한 IgG 수준과 Ag85B에 대한 IgA 수준은 잠복 결핵 및 비감염군에서 IFN-γ 수준과 유의한 양의 상관 관계를 보였다. 연령 및 성별을 보정한 모델에서 TBCM 및 CFP-10에 대한 IgG는 잠복 결핵 진단과 독립적으로 유의한 연관성을 보였으며, Ag85B에 대한 IgG는 활동성 결핵 진단 및 잠복결핵과 활동성 결핵의 감별진단과 독립적인 연관성을 보였다. MIF에 대한 IgA 수준은 비감염군보다 잠복 결핵 및 활동성 결핵군에서 유의하게 낮았으며, 잠복 결핵 진단, 활동성 결핵 진단 및 잠복결핵과 활동성 결핵의 감별진단과 유의한 연관성을 보였다. MIF에 대한 IgG 수준은 비감염군보다 잠복 결핵군에서 유의하게 낮았으며 잠복 결핵 진단과 유의한 연관성이 있었다. MIF에 대한 IgA 수준은 항산균 도말 음성 활동성 결핵, 영상학적 경증 활동성 결핵 및 결핵 신환자에서 각각 비감염군에 비하여 유의하게 낮았다. MIF에 대한 IgA 및 IgG 수준은 IFN-γ 수준과 유의한 음의 상관 관계를 나타내었다. 결론: TBCM, Ag85B 및 CFP-10에 대한 IgG 항체 반응은 활동성 결핵, 잠복 결핵 및 비감염 군을 유의하게 구분하였으며, MIF에 대한 IgA 항체 반응은 잠복 결핵 및 활동성 결핵의 진단과 유의한 연관성을 보여 결핵의 새로운 혈청학적 진단법 개발을 위한 활용 가능성을 보여준다.Chapter 1. General Introduction 1 Chapter 2 7 Diagnostic potential of IgG and IgA responses to Mycobacterium tuberculosis antigens for discrimination among active tuberculosis, latent tuberculosis infection, and non‐infected individuals Introduction...........................................................................8 Material and Methods..........................................................13 Results.................................................................................18 Discussion............................................................................65 Conclusion............................................................................71 Chapter 3 72 Usefulness of IgA and IgG Responses to Macrophage Migration Inhibitory Factor for Diagnosing Tuberculosis Introduction.........................................................................73 Material and Methods..........................................................77 Results.................................................................................81 Discussion..........................................................................100 Conclusion.........................................................................104 Bibliography 105 Abstract in Korean 119Docto

최고경영자의 성별과 이사회의 구성이 최고경영자의 초임에 미치는 영향

학위논문(석사)--서울대학교 대학원 :경영대학 경영학과,2019. 8. 조승아.우리 사회에서 여성지도자가 남성 지도자보다 능력과 역량이 저평가 되고 있다는 것이 일반적인 사실이지만, 이와 같은 남녀의 차이가 기업 최고경영진들의 보수에서도 발견되는지는 학계의 의견이 분분하다. 따라서, 본 연구가 새로 임명된 최고경영자의 초봉을 비교 분석해 본 결과 여성 최고경영자가 남성 최고경영자에 비해 유의미하게 적은 보수를 받는 것을 발견했다. 그 뿐만 아니라, 기업의 사외이사 비율이 증가함에 따라 여성 최고경영자의 초봉은 증가하고, 남성 최고경영자의 초봉은 감소하는 현상을 보였는데, 이로써 사외이사 비율 증가가 남녀간의 보수의 차이를 축소 시키는 것을 알 수 있었다. 하지만 본 연구의 예측과는 달리, 사외이사 내 여성의 비율을 최고경영자의 성별과 초봉간의 차이를 줄이는데 상호작용 효과를 주기 못하는 것으로 나타났다.Despite the general consensus that female leaders are undervalued than their male counterparts, research on gender gap in executive compensation has yielded mixed results. Using data on the first pay of newly appointed CEOs, I show that new female CEOs tend to receive a significantly lesser amount of first pay than new male CEOs. Moreover, I find that the proportion of independent directors in corporate boards reduces this tendency both by increasing the first pay of new female CEOs and by decreasing the first pay of new male CEOs. Contrary to my expectation, however, the proportion of female directors in corporate boards has no interaction effects between new CEO gender and the amount of first pay.Chapter 1. Introduction 1 Chapter 2. Theory and Hypotheses 5 2.1. Gender Discrimination in Leadership Positions 5 2.2. The Moderating Role of Independent Director Ratio 7 2.3. The Moderating Role of Female Director Ratio 9 Chapter 3. Data and Methods 11 Chapter 4. Results 12 Chapter 5. Conclusion 15 References 17 Abstract in Korean 24Maste

홍삼박 첨가 크래커의 이화학적 특성 및 관능적 기호도

학위논문(석사)--서울대학교 대학원 :생활과학대학 식품영양학과,2019. 8. 황금택.홍삼을 추출하고 남은 부산물인 홍삼박은 대부분이 폐기되고 있다. 그러나 홍삼박에는 진세노사이드 및 식이섬유와 같은 유용성분들이 남아 있으며, 이를 활용할 수 있는 연구가 요구되고 있다. 홍삼박을 활용하기 위하여 식빵, 머핀 등의 베이킹 제품에 첨가하는 연구가 진행되었으나, 이는 열에 의한 홍삼박의 주요 유용성분들의 변화를 고려하지 않았다는 한계가 있다. 이에 본 연구에서는 홍삼박을 크래커에 첨가하여 온도와 시간을 달리하여 구워, 베이킹 조건에 따른 홍삼박 유용 성분의 변화를 분석하고자 하였다. 또한 크래커에 홍삼박 첨가량을 달리하였을 때, 홍삼박의 첨가량이 크래커에 미치는 이화학적 및 관능적 특성을 분석하여 유용 성분이 보다 많이 함유되어 있고 관능적 기호도가 높은 크래커를 만들고자 하였다. 10%의 밀가루를 홍삼박으로 대체한 크래커를 다양한 온도와 시간 조건(120℃-60분, 170℃-15, 20, 25분, 220℃-10분)에서 구워 베이킹 조건에 따른 홍삼박의 진세노사이드, 식이섬유, 향미 성분의 변화를 분석한 후 베이킹 조건을 설정하였다. 설정한 베이킹 조건에서 홍삼박의 첨가량(밀가루의 0, 5, 10, 15, 20%를 홍삼박으로 대체)을 달리하여 홍삼박 첨가량에 따른 일반 성분, 식이섬유, 진세노사이드, 색도, 물성, 관능 특성을 분석하였다. 진세노사이드 Rb1, Rg1, Rg3의 합과 수용성 식이섬유 함량은 120℃에서 60분 동안의 베이킹 조건에서 구운 홍삼박 크래커에서 유의적으로 높았다. 홍삼박의 주요 향미 성분인 ginsinsene, -panasinsene, -elemene, -gurjunene, ledene는 베이킹을 하였을 때 유의적으로 증가하였으며, 특히 120℃에서 60분 동안 베이킹할 때 가장 많이 증가하였다. 이 결과를 통하여 실험에 이용한 베이킹 조건들 중 120℃에서 60분 동안 베이킹할 때 홍삼박의 유용성분을 이용하기에 적합하다고 판단하였다. 120℃에서 60분 동안으로 설정된 베이킹 조건에서 홍삼박 첨가량을 달리하여 크래커를 제조하였을 때, 홍삼박 첨가량이 증가함에 따라 수분은 감소한 반면, 조단백, 조회분, 식이섬유, 진세노사이드는 증가하였다. 명도는 홍삼박이 증가함에 따라 감소하였으며, 적색도는 홍삼박 첨가량이 증가함에 따라 함께 증가하였다. 경도는 홍삼박 첨가량이 증가함에 따라 높아지는 경향을 나타냈다. 관능 평가 결과, 밀가루의 5%를 홍삼박으로 대체한 크래커가 맛에 대한 기호도는 가장 높았으며, 외관, 색, 향, 조직감, 전체적인 기호도에 있어서는 홍삼박을 첨가하지 않은 크래커와 유의적인 차이를 보이지 않았다. 결과적으로 홍삼박의 주요 유용성분을 고려하였을 때 본 연구에서 사용한 베이킹 조건 중, 저온 장시간(120℃에서 60분 동안)이 베이킹 조건으로 적합하며, 적당량의 홍삼박을 베이킹 제품에 첨가할 때 영양적인 면뿐만 아니라, 관능적인 특성 또한 향상시킬 수 있을 것이라고 판단한다.Red ginseng marc (RGM), a by-product from ginseng industry, still contains bioactive compounds such as ginsenosides and dietary fibers. The objective of this study was to investigate effects of baking conditions and formulations on physicochemical and sensory characteristics of crackers in which RGM was incorporated. Proximate composition, ginsenosides, dietary fibers, aroma compounds, color, texture, and sensory characteristics were analyzed. The sum of ginsenoside Rb1, Rg1 and Rg3, dietary fibers, and major aroma compounds were the highest in the crackers baked at 120 C for 60 min. The crackers with 5% replacement of wheat flour with RGM scored the highest in taste and overall acceptability. The results suggest that low temperature-long time may be a suitable baking condition to utilize RGM in baking products and a proper amount of RGM may improve not only nutritional quality but also sensory properties.CONTENTS ABSTRACT I CONTENTS III LIST OF TABLES V LIST OF FIGURES VI INTRODUCTION 1 MATERIALS AND METHODS 3 1. Chemicals 3 2. Materials 3 3. Preparation of crackers 4 4. Proximate composition 6 5. Analysis of ginsenosides 6 6. Analysis of dietary fibers 7 7. Analysis of aroma compounds 8 8. Analysis of color 9 9. Analysis of texture 9 10. Sensory evaluations 9 11. Statistical analysis 12 RESULTS AND DISCUSSION 13 1. Proximate composition of wheat flour and RGM 13 2. Effect of baking conditions on the crackers containing RGM 13 2.1. Effect on ginsenoside composition 13 2.2. Effect on dietary fibers 19 2.3. Effect on aroma compounds 21 3. Effect of different RGM replacement levels on physicochemical and sensory characteristics of crackers 23 3.1. Proximate composition and dietary fiber contents 23 3.2. Ginsenoside content 23 3.3. Color 26 3.4. Texture 26 3.5. Sensory acceptability 29 CONCLUSION 31 REFERENCES 32 국문초록 38Maste

99mTc-MSA와 염료 접합체를 사용한 감시림프절 맵핑용 다중모드영상제의 개발

학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과, 2019. 2. 정재민.Purpose: Sentinel lymph node (SLN) is the first regional lymph node (LN) existing nearest to the primary tumor. The detection of SLN in breast cancer and melanoma patients is important to evaluate tumor staging or to establish therapeutic decision-making. Blue dyes, radiotracers, combination of a radiotracer and blue dye method and radiolabeled blue dyes have been clinically used for SLN detection. However, these methods still have some limitations. Here, the aim for this study was to develop a SLN mapping agent using 99mTc-labeled mannosylated human serum albumin (MSA) and dyes. Various dyes were tested by in vitro experiments such as binding efficiency with MSA, size exclusion liquid chromatography with HPLC and fluorescent screening. The selected dye, naphthol blue black (NBB) which showed the highest binding efficiency with MSA, was tested regarding its ability for SLN mapping by visual investigation, fluorescence imaging, and single photon emission computed tomography (SPECT)/computed tomography (CT). Methods: Visible screening was performed using 8 different dyes. Each 1 mM dye solution was prepared by dissolving 1 μmol of dye in 1 mL of distilled water (DW) and the solution was serially diluted from 0.25 to 0.001 mM with DW. The color of the prepared solutions was compared by visual inspection. To determine values of MSA-dye conjugates, UV-VIS-NIR spectrum assay was conducted and optical density (OD) was measured by Varioskan Flash screening mode at 350-850 nm. Binding efficiencies between MSA and various dyes were measured by thin-layer chromatography at 10, 30 min, 1, 2, 6, and 24 h after incubation. TLC plates were scanned by Fujifilm LAS 3000 and the spots were quantified by multi-gauge 3.0. HPLC was used to distinguish the size between before and after dye and MSA conjugation. Fluorescence imaging was performed at 420-780 nm excitation and 520-845 nm emission to find out the wavelength band which exhibits strong fluorescence for MSA-dye conjugates. To evaluate the ability of MSA-NBB conjugate for SLN mapping, MSA-NBB conjugate or only NBB was injected to a same male BALB/c mice and visible and fluorescence images were obtained at 10, 30 min, 1, and 2 h post-injection. For SPECT/CT imaging, MSA-NBB conjugate was labeled with 99mTc and the conjugate complex was subcutaneously injected into the left footpad of the mouse. SPECT/CT images were obtained at 10, 30 min, 1, and 2 h after injection. Results: All dyes that were used in visible screening showed a clear color at 0.25 mM. As dilution, some dyes were difficult to identify color of the solution and NBB, PBVF, NY, BR and EB showed most visible at low concentration at 0.004 mM. In order to compare each of MSA-dye conjugates by a quantified value, values were calculated by Beer-Lambert Law using OD values at peak wavelength. MSA-PBVF conjugate demonstrated the highest value of 141,481 M−1·cm−1, followed by MSA-EB conjugate (99259.3), MSA-ICG conjugate (87037.0) and MSA-NBB conjugate (62222.2). Size exclusion HPLC confirmed that MSA-dye conjugates was formed as a monomer. All the prepared MSA-dye conjugates was stable for 24 h and no other aggregates were found in the chromatogram. TLC results showed that binding efficiencies of all dyes were increased depending on the concentration of MSA and the reaction time. Especially, NBB had the highest binding affinity with MSA among all the tested dyes requiring the least amount of MSA (2.5 mg) and the short reaction time (10 min). Binding ratio was calculated that 0.7 of NBB was bound with 1.0 of MSA. Based on these results, NBB was selected for the in vivo application. Fluorescence of MSA-NBB conjugate was detected at excitation 600 nm, emission 670 nm and fluorescence of unbound dyes or MSA was not detected at the same range. In visible image, MSA-NBB conjugate accumulated more in the popliteal lymph node that NBB alone at all the investigational time. The fluorescence of MSA-NBB conjugate and NBB alone were accumulated in the popliteal LN at 10 min at 4.48±0.34 and 4.24±0.18 flux (108 p/s), respectively. While the fluorescence of MSA-NBB conjugate in the popliteal LN was maintained for 2 h (4.81±1.24 flux (108 p/s)), the fluorescence of NBB alone rapidly decreased (2.61±0.46 flux (108 p/s)). MSA-NBB conjugate showed about two-fold higher popliteal LN uptake as compared with NBB alone from 30 min to 2 h after footpad injection. In SPECT/CT images, 99mTc-MSA-NBB conjugate was highly accumulated in the popliteal and inguinal LN. The SUVmean value of 99mTc-MSA-NBB conjugate in the popliteal and inguinal LN was 13.08±2.33 and 3.00±1.64 at 10 min and 17.83±5.85 and 4.99±3.44 at 2 h, respectively. SPECT/CT results showed that the popliteal LN uptake of 99mTc-MSA-NBB conjugate was about 3.5-fold higher than inguinal LN uptake at all time points. Conclusion: In this study, 99mTc-MSA-NBB conjugate was developed as a multimodal SLN mapping agent for direct visualization, fluorescence and SPECT/CT. The ability of 99mTc-MSA-NBB conjugate for accumulation in SLN was assessed by evaluating the popliteal LN uptake which is closest to the foot pad by visual monitoring, fluorescence imaging, and SPECT/CT. The results demonstrated that 99mTc-MSA-NBB conjugate binds quickly to SLN and accumulates in SLN until 2 h after footpad injection. Based on these results, 99mTc-MSA-NBB conjugate has a great potential as an SLN mapping agent for clinical use.목적: 감시림프절은 원발성 종양으로부터 가장 가까이에 위치한 림프절이다. 유방암환자, 흑색종 암환자에서 감시림프절을 검출하는 것은 종양 병기를 평가하고, 수술 중 치료 결정을 하는데 중요한 역할을 한다. 현재 임상에서 청색 염료, 방사성 추적자, 방사성 추적자와 청색 염료 방법의 조합 그리고 방사성 동위원소가 표지된 청색 염료가 감시림프절 검출에 이용되고 있다. 그러나 이러한 방법에는 각각 한계가 있었다. 본 연구의 목표는 99mTc이 표지된 MSA와 염료를 사용한 감시림프절 맵핑 영상제를 개발하는 것이었다. MSA와의 결합효율, 사이즈 배제 크로마토그래피를 이용한 고성능액체크로마토그래피 실험, 형광 모니터링과 같은 시험관 실험을 통해 다양한 염료를 테스트하였다. 그 중 MSA와 가장 높은 결합 효율을 보인 NBB가 선택되었고, 육안 검사, 형광 이미징 그리고 단일 광자 방출 컴퓨터 단층 촬영/컴퓨터 단층 촬영 (SPECT/CT)을 통해 감시림프절 맵핑 성능을 평가하였다. 방법: 육안검사는 8개의 염료를 사용하여 수행되었다. 1 mM의 염료 용액은 1 µmol의 염료를 1 mL의 증류수에 녹여 준비하였고, 증류수를 이용하여 0.25 mM에서 0.001 mM까지 연속 희석하였다. 준비된 염료 용액의 색상은 육안검사를 통해 비교되었다. MSA-염료 접합체의 분자흡광계수 (ε)를 구하기 위해, UV-VIS-NIR 스펙트럼 분석을 수행하였고 흡광도 (OD)는 350-850 nm의 Varioskan flash screening mode에서 측정되었다. MSA와 다양한 염료간의 결합 효율은 반응 10분, 30분, 1시간, 2시간, 6시간 그리고 24시간 후 박층크로마토그래피를 통해 측정되었다. 박층크로마토그래피 플레이트는 Fujifilm LAS 3000를 이용하여 스캔하였고, multi-gauge 3.0를 이용하여 정량평가 하였다. 염료와 MSA 접합 전후의 크기를 확인하기 위하여 고성능액체크로마토그래피를 실행하였다. MSA-염료 접합체가 강한 형광 신호를 나타내는 파장대를 찾기 위해, 여기 420-780 nm, 방출 520-845 nm에서 형광 이미징 실험을 수행하였다. 감시림프절 맵핑을 위한 MSA-NBB 접합체의 성능을 평가하기 위해, MSA-NBB 접합체 혹은 NBB를 수컷 BALB/c 마우스 (총 12마리)에 투여 후 10분, 30분, 1시간 그리고 2시간에 육안 사진과 형광 이미지를 얻었다. SPECT/CT를 얻기 위해, MSA-NBB 접합체를 99mTc으로 표지 하였고, 마우스(총 3마리) 좌측 발바닥에 피하 주사하였다. 약품 투여 10분, 30분, 1시간, 2시간 후 SPECT/CT를 얻었다. 결과: 육안 검사에서 모든 염료가 0.25 mM에서 명확한 색을 나타냈다. 희석된 일부 염료는 용액의 색을 확인하기 어려웠고, NBB, PBVF, NY, BR 그리고 EB는 0.004 mM의 낮은 농도에서도 잘 보였다. MSA-염료 접합체 각각을 정량화된 값으로 비교하기 위해, 흡광도 (OD)와 Beer-Lambert Law를 이용하여 분자흡광계수 ()를 계산하였다. MSA-PBVF 접합체는 141,481 M−1·cm−1로 가장 높은 분자흡광계수를 나타내었으며, MSA-EB 접합체 (99259.3), MSA-ICG 접합체 (87037.0) 그리고 MSA-NBB 접합체 (62222.2)가 뒤를 이었다. 사이즈 배제 고성능액체크로마토그래피를 통해 MSA-염료 접합체가 단량체로 존재한다는 것을 확인하였다. 크로마토그램에서 준비된 모든 MSA-염료 접합체는 24시간 동안 안정하였고, 다른 응집체는 발견되지 않았다. 박층크로마토그래피결과는 MSA 농도와 결합 반응 시간이 증가됨에 따라 모든 염료와 MSA간의 결합 효율이 증가함을 보여주었다. 특히, 테스트된 모든 염료 중 NBB가 가장 적은 양의 MSA (2.5 mg)와 짧은 시간 (10분)내에 가장 높은 결합 친화력을 보였다. 결합 비율(mol/mol)은 NBB 0.7이 MSA 1과 결합된 것으로 계산되었다. 이러한 결과를 바탕으로, 생체 내 적용 실험을 위해 NBB가 선택되었다. MSA-NBB 접합체의 형광 신호는 여기 600 nm, 방출 670 nm에서 검출되었으며, 결합되지 않은 염료와 MSA의 형광 신호는 동일한 파장에서 검출되지 않았다. 육안검사에서, MSA-NBB 접합체가 NBB 단독으로 투여하였을 때 보다 모든 시간대에서 더 많은 슬와림프절 축적을 나타냈다. 약품 투여 10분 후 슬와림프절에 축적된 MSA-NBB 접합체와 NBB의 형광 세기는 각각 4.48±0.34 그리고 4.24±0.18 flux (108 p/s)이었다. 약품 투여 2시간 후 MSA-NBB 접합체의 슬와림프절 축적(4.81±1.24 flux (108 p/s))은 유지되었으나, NBB의 형광 세기는 빠르게 감소 (2.61±0.46 flux (108 p/s))하였다. 약품 투여 30분에서 2시간까지 MSA-NBB 접합체는 NBB 단독으로 투여하였을 때 보다 약 2배 높은 슬와림프절 축적을 보였다. SPECT/CT에서, 99mTc-MSA-NBB 접합체는 슬와림프절과 서혜부림프절에 높은 섭취를 보였다. 약품 투여 10분 후 슬와림프절과 서혜부림프절 각각에 섭취된 99mTc-MSA-NBB 접합체의 SUVmean은 13.08±2.33, 3.00±1.64이었고, 약품 투여 2시간 후에는 17.83±5.85, 4.99±3.44이었다. SPECT/CT 결과를 통해, 모든 시간대에서 99mTc-MSA-NBB 접합체의 슬와림프절 축적이 서혜부림프절 축적보다 약 3.5배 높음을 확인하였다. 결론: 본 연구에서, 99mTc-MSA-NBB 접합체는 육안 검사, 형광 이미지 및 SPECT/CT를 위한 다중모드 감시림프절 맵핑 영상제로 개발되었다. 우리는 육안검사, 형광 이미지 그리고 SPECT/CT를 통해, 발바닥으로부터 가장 가까이에 위치한 슬와림프절 축적을 평가함으로써 99mTc-MSA-NBB 접합체의 감시림프절 축적 능력을 평가하였다. 결과는 99mTc-MSA-NBB 접합체가 감시림프절에 빠르게 결합하고, 약품투여 2시간 후까지 감시림프절에 축적됨을 보여 주었다. 이러한 결과를 바탕으로, 99mTc-MSA-NBB 접합체가 임상에서 감시림프절 맵핑을 위해 사용될 가능성이 있음을 확인하였다.ABSTRACT ----------------------------------------------------------------------------------2 LIST OF FIGURES AND TABLES ----------------------------------------------------9 LIST OF ABBREVIATIONS -----------------------------------------------------------11 INTRODUCTION ------------------------------------------------------------------------14 MATERIALS AND METHODS -------------------------------------------------------19 Preparation of MSA and kits for 99mTc labeling ----------------------------------20 In vitro visibility test of dyes ----------------------------------------------------------21 Absorption spectra and molar absorption coefficient () of MSA-dye conjugates ---------------------------------------------------------------------------------------------22 In vitro measurements for the binding efficiencies of dyes with MSA ----------22 Size exclusion HPLC before and after MSA and dye conjugation --------------25 Electrophoresis for the binding mechanism study of MSA and dyes ------------25 In vitro fluorescence monitoring of MSA-dye conjugates-------------------------26 In vivo visible and fluorescence experiments of MSA-NBB conjugate for the detection of SLN ------------------------------------------------------------------------29 Preparation for 99mTc-MSA-NBB conjugate ----------------------------------------29 Analysis of SPECT/CT ----------------------------------------------------------------30 Stability test of 99mTc-MSA-NBB conjugate in in vivo ---------------------------31 RESULTS -----------------------------------------------------------------------------------33 In vitro visibility test of dyes ----------------------------------------------------------33 Absorption spectra and molar absorption coefficient () of MSA-dye conjugates ---------------------------------------------------------------------------------------------35 In vitro measurements for the binding efficiencies of dyes with MSA ----------39 Size exclusion HPLC before and after MSA and dye conjugation----------------44 Electrophoresis for the binding mechanism study of MSA and dyes ------------48 In vitro fluorescence monitoring of MSA-dye conjugates ------------------------50 In vivo visible and fluorescence experiments of MSA-NBB conjugate for the detection of SLN------------------------------------------------------------------------52 Preparation for 99mTc-MSA-NBB conjugate ----------------------------------------56 Analysis of SPECT/CT ----------------------------------------------------------------61 Stability test of 99mTc-MSA-NBB conjugate in in vivo ---------------------------63 DISCUSSION ------------------------------------------------------------------------------65 CONCLUSION ----------------------------------------------------------------------------73 REFERENCES ----------------------------------------------------------------------------74 국문초록 ------------------------------------------------------------------------------------82Docto

Unplanned conversion during minimally invasive liver resection for hepatocellular carcinoma: risk factors and surgical outcomes

Purpose: Unplanned conversion is sometimes necessary during minimally invasive liver resection (MILR) of hepatocellular carcinoma (HCC). The aims of this study were to compare surgical outcomes of planned MILR and unplanned conversion and to investigate the risk factors after unplanned conversion. Methods: We retrospectively analyzed 286 patients who underwent MILR with HCC from January 2006 to December 2017. All patients were divided into a MILR group and an unplanned conversion group. The clinicopathologic characteristics and outcomes were compared between the 2 groups. In addition, surgical outcomes in the conversion group were compared with the planned open surgery group (n = 505). Risk factors for unplanned conversion were analyzed. Results: Of the 286 patients who underwent MILR, 18 patients (6.7%) had unplanned conversion during surgery. The unplanned conversion group showed statistically more blood loss, higher transfusion rate and postoperative complication rate, and longer hospital stay compared to the MILR group, whereas no such difference was observed in comparison with the planned open surgery group. There were no significant differences in overall and disease-free survival among 3 groups. The right-sided sectionectomy (right anterior and posterior sectionectomy), central bisectionectomy and tumor size were risk factors of unplanned conversion. Conclusion: Unplanned conversion during MILR for HCC was associated with poor perioperative outcomes, but it did not affect long-term oncologic outcomes in our study. In addition, when planning right-sided sectionectomy or central bisectionectomy for a large tumor (more than 5 cm), we should recommend open surgery or MILR with an informed consent for unplanned open conversions.ope

eHealth Literacy Instruments: Systematic Review of Measurement Properties

Background: The internet is now a major source of health information. With the growth of internet users, eHealth literacy has emerged as a new concept for digital health care. Therefore, health professionals need to consider the eHealth literacy of consumers when providing care utilizing digital health technologies. Objective: This study aimed to identify currently available eHealth literacy instruments and evaluate their measurement properties to provide robust evidence to researchers and clinicians who are selecting an eHealth literacy instrument. Methods: We conducted a systematic review and meta-analysis of self-reported eHealth literacy instruments by applying the updated COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) methodology. Results: This study included 7 instruments from 41 articles describing 57 psychometric studies, as identified in 4 databases (PubMed, CINAHL, Embase, and PsycInfo). No eHealth literacy instrument provided evidence for all measurement properties. The eHealth literacy scale (eHEALS) was originally developed with a single-factor structure under the definition of eHealth literacy before the rise of social media and the mobile web. That instrument was evaluated in 18 different languages and 26 countries, involving diverse populations. However, various other factor structures were exhibited: 7 types of two-factor structures, 3 types of three-factor structures, and 1 bifactor structure. The transactional eHealth literacy instrument (TeHLI) was developed to reflect the broader concept of eHealth literacy and was demonstrated to have a sufficient low-quality and very low-quality evidence for content validity (relevance, comprehensiveness, and comprehensibility) and sufficient high-quality evidence for structural validity and internal consistency; however, that instrument has rarely been evaluated. Conclusions: The eHealth literacy scale was the most frequently investigated instrument. However, it is strongly recommended that the instrument's content be updated to reflect recent advancements in digital health technologies. In addition, the transactional eHealth literacy instrument needs improvements in content validity and further psychometric studies to increase the credibility of its synthesized evidence.ope

파골세포 이동과 골흡수에 대한 CCL19 및 CCL21 케모카인의 역할

학위논문 (박사)-- 서울대학교 대학원 : 치의과학과, 2017. 2. 김홍희.OBJECTIVE: Bone resorption is a severe problem in inflammatory diseases such as periodontitis and rheumatoid arthritis (RA). Osteoclasts are responsible for bone resorption and CCL19 and CCL21 act as chemokines for several cell types. The purpose of this study was to investigate the role of CCL19 and CCL21 in bone resorption by osteoclasts. METHODS: The levels of CCL19, CCL21 and CCR7 in RA and osteoarthritis patient samples were measured using ELISA. Data deposited to gene expression omnibus was also analyzed. The expression levels of these molecules and differentiation markers of osteoclasts were measured by real time polymerase chain reaction (PCR), western blotting or flow cytometry. Osteoclast differentiation was evaluated by tartate-resistant acid phosphatase staining and osteoclast migration was assessed with transwell assay and Oris migration assay kits. Resorption activity was performed with calcium phosphate-coated dishes or dentin slices, which were analyzed by von Kossa staining or confocal microscopy, respectively. Involvement of CCR7 was demonstrated with the small interference RNA system and contribution of GTPase Rho was investigated by the Rho pull-down assay. Collagen transplantation model was used to examine the in vivo effects of these chemokines. RESULTS: The expression levels of CCL19, CCL21 and CCR7 were higher in RA patient samples compared to OA or normal samples. Bone marrow macrophages and osteoclasts expressed more CCR7 in response to the stimulation of TNF, IL-1 and LPS. CCL19 and CCL21 promoted the migration and resorption activity of both bone marrow macrophages and osteoclasts. Knock-down of CCR7 significantly reduced the CCL19- and CCL21-induced migration. Moreover, CCL19 and CCL21 stimulated small GTPase Rho and its downstream molecule, ROCK. Rho inhibitors suppressed both the migration and resorption activity of BMMs and osteoclasts. It demonstrates that the increase of migration and bone resorption by CCL19 and CCL21 was mediated by the CCR7/Rho axis. Collagen transplantation study showed that CCL19 and CCL21 can promote bone resorption in vivo. CONCLUSION: This study indicates that under inflammatory conditions, osteoclast precursors increase the CCR7 expression. CCL19 and CCL21 are up-regulated in RA patients and enhance the osteoclast migration and resorption activity, resulting in severe bone destruction. This study suggests that neutralizing antibody for CCL19 and CCL21 or CCR7 knock-down are potential therapeutic strategies for periodontitis and RA.I. Introduction 1 1. Roles of osteoblasts and osteoclasts in bone remodeling 1 2. Rheumatoid arithritis and osteoclasts 5 3. Osteoclast migration and bone resorption 8 4. Roles of CCL19/CCL21 and CCR7 in rheumatoid arithritis 13 5. Purpose of this study 17 II. Materials and Methods 19 1. Reagents 19 2. Bone marrow-derived macrophage (BMM) generation 19 3. Osteoclast differentiation 20 4. Enzyme-linked immunosorbent assay (ELISA) 20 5. Quantification of mRNA 21 6. Western blotting analysis 21 7. TRAP staining 22 8. Cytotoxicity assay 22 9. Flow cytometry 23 10. Small interference RNA transfection 23 11. Cell migration assay 24 12. Rho pull-down assay 25 13. von Kossa staining 25 14. Dentin resorption and confocal microscopy 25 15. Confocal fluorescence microscopy 26 16. In vivo mouse calvariae resorption assay 26 17. Statistical analysis 27 18. Institutional Review Board (IRB) 27 III. Results 28 1. Increased expression of CCR7 increased in synovial macrophages of RA patients 28 2. Expression levels of CCL19, CCL21 and CCR7 increased in synovial tissues of RA patients 31 3. Increased mRNA expression level of CCR7 in response to inflammatory stimuli 34 4. Increased protein expression level of CCR7 in response to inflammatory stimuli 37 5. Effects of CCL19 and CCL21 on osteoclast differentiation 40 6. Regulation of osteoclast migration activity by CCL19 and CCL21 44 7. CCL19 and CCL21 increase osteoclast migration through CCR7 47 8. CCL19 and CCL21 increase osteoclast resorption activity 49 9. CCL19 and CCL21 increase osteoclast actin ring density 53 10. CCL19 and CCL21 stimulate osteoclasts via Rho 55 11. Rho inhibitors suppress CCL19- and CCL21-induced osteoclast migration and resorption activity 58 12. CCL19 and CCL21 increase mouse calvariae resorption 61 13. LPS accentuates the CCL19-induced calvariae resorption 64 IV. Discussion 66 V. References 75 국문초록 89Docto

Dynamic Voltage Drop Estimation of PDN Using Elmore Metric

학위논문 (석사) -- 서울대학교 대학원 : 공과대학 전기·정보공학부, 2021. 2. 김재하.Elmore metric 으로 간소화한 파워 네트워크 시스템과 회로 동작을 모사한 PWL(삼각파형) 입력 전류를 이용해 동적 과도 전압 강하를 예측한다. 전력 무결성 검증을 위한 보편적으로 이용되는 full-chip 시뮬레이션 파워 네트워크와 하위 회로를 분할하여 관찰한다. 시스템에 해당하는 mesh 구조의 파워 네트워크에서 노드 간 전달 함수를 1차로 근사하고, 하위 회로에서의 스위칭 동작을 반영한 과도 전류(transient current) 를 PWL 형태로 모사한다. 이 두 근사 모델을 이용해 동적 과도 전압을 exponential 형태로 표현한다. 이때 유도된 수식은 중첩(superposition) 형태로 병렬 연산으로 연산의 효율을 극대화한다. 과도 전압 강하의 하한 범위 또한 수식적으로 풀어내어, 추정 값을 보다 pessimistic 하게 관찰할 수 있다. Y-∆ 변환을 이용해 mesh 구조의 파워 네트워크에서 저항 행렬이 갖는 diagonally-dominant 속성을 보이고, 이를 활용해 전압 강하의 하한 범위를 유도하였다. IBM/ISCAS benchmark 를 이용해 SPICE 시뮬레이션 대비 최대 속도 이득 7.75 배에서 rms 오차 1% 이하의 정확도를 얻어 제안한 방법론의 효용성을 검증하였다. 또한 과도 전압 강하를 개선하기 위한 디커플링 커패시터 삽입 혹은 파워 패드 위치 조정 등을 빠르게 테스트하는데 이용할 수 있다.Dynamic transient voltage drops predicted using the simplified power network system by Elmore metric and PWL(triangular waveform) input current reflecting circuits switching activities. For power integrity verification, instead of the commonly used full-chip simulation, we divide the power network and sub-circuits. The transfer function of mesh structure power network is approximated by first order and transient current reflecting the switching operation is approximated in PWL form. Using these two approximate models, the dynamic transient voltage is expressed in exponential form. The derived equation maximizes efficiency through parallel operation with superposition type expression. The lower bound also be derived to observe the estimated value more pessimistically. The diagonally-dominant characteristics of the resistance matrix in mesh-structured power network are shown using Y-∆ transformation. With benchmark, the proposed methodology has a speed-gain of up to 7.75 times and an accuracy of less than 1% rms error at 7.75 times compared to SPICE simulation. It can also be used to quickly test the insertion of decoupling capacitor or adjustment of the power pad position to improve transient voltage drop.제１장 서 론 제１절 연구의 배경 제２절 논문의 구성 제２장 배경 이론 제１절 정적/동적 전압 강하 제２절 동적 전압 강하 검출 방법론 종류 제３절 Elmore Delay 소개 및 전제 조건 제３장 제안하는 과도 전압 강하 검출 방법론 제１절 PDN 모델 및 MNA 형식 제２절 동적 과도 전압 강하 수식 유도 제１항 용어 정의 제２항 단위 계단 함수(unit step function) 입력 전류에 대한 출력 전압 강하 추정 제３항 PWL(삼각파형) 입력 전류에 대한 출력 전압 강하 추정 제３절 Worst-case 추정을 위한 하한 범위 수식 유도 제４장 방법론 적용 결과 제１절 Tool Flow 소개 제２절 Iteration Approach 제３절 Toy Example 결과 제４절 IBM Benchmark 결과 제１항 예제 구성 제２항 방법론 적용 결과 제５절 ISCAS Benchmark 결과 제１항 Iteration approach 제２항 예제 소개 및 방법론 적용 결과 제６절 Possible Explorations / Applications 제１항 Decoupling Capacitor Insertion 제２항 Location of Power Pad 제５장 결 론Maste

Periodontal outcome of buccally impacted maxillary canines after orthodontic traction following closed eruption technique

치의학과/석사The aim of this investigation was to evaluate the periodontal status of the buccally impacted maxillary canines after orthodontic traction following closed eruption technique by clinical and radiographic methods and to investigate pre-treatment orthodontic variables affecting the periodontal changes. 54 patients (21 males and 33 females) having one maxillary canine in a buccally impacted position was choosed (impaction group) and a contralateral canine in a normal position served as a control group. Probing depth, bone probing depth, keratinized gingiva width, attached gingiva width, clinical crown length, distance from cemento-enamel junction (CEJ) to alveolar crest (AC) and bone support were measured at 1.4 months after the end of treatment. The following results were observed.1. Probing depth on midbuccal and mesiolingual sides was significant increased in the impaction group (mean difference 0.20 mm, 0.25 mm, respectively, P <0.05). Bone probing depth on mesiolingual and distolingual sides was increased in the impaction group than the control group (mean difference 0.24 mm, 0.48 mm, respectively, P < 0.05).2. The attached gingiva width was significant shorter in the impaction group compared to the control group (mean difference 0.62 mm,P < 0.01). The buccal clinical crown length was longer on the impaction group than the control group (mean difference 1.12 mm, P < 0.001).3. The distance from CEJ to AC was significant longer in the impaction group on mesial and distal sides compared to the control group (mean difference 0.89 mm, 0.82 mm, P < 0.001). There were significant smaller bone supports at mesial and distal sides in impaction group compared to control group (mean difference 7.30%, 8.80%, P < 0.001).4. If the impacted canine was localized at the more mesial angulation (to the horizontal) and the deeper from occlusal plane at the beginning of treatment, the distance from CEJ to AC on distal side was increased significantly at the end of treatment (P < 0.01). These results revealed that forced eruption of the maxillary impacted canine after orthodontic traction following closed eruption technique, resulted in significant gingival recession on the buccal side and alveolar bone loss on the interproximal sides. Initial intraosseous position and the inclination of impacted canine were related with the periodontal changes.ope

Career Guidance at Higher Education Level in Korea

본 연구의 목적은 대학 내 지도서비스의 1차 수혜자인 대학생의 진로개발역량이 함양될 수 있는 진로지도 방안을 모색하고, 궁극적으로는 최종수혜자인 기업과 국가가 대학에서 양성된 인적자원을 효과적으로 활용하여 그 경쟁력을 확보할 수 있는 대학 내 진로지도 방안을 제안하는 것이다.The Research aims at presenting a new career guidance service that could systematically support career development competency among all university students from freshmen all the way up to seniors. It has been pointed out that career guidance services provided by 161 universities in Korea are too focused on "recruitment" rather than "holistic student's career development". This problem causes the lack of continuity and professionalism in the area of career guidance service at higher educational level. However, fundamentally, those problems are integrated such as failures of career guidance at the levels of elementary to high schools, lack of communications and coordination between universities and companies, and undue emphasis on short term performances in the process of career guidance service in reality. The case has also been made for the strong need for university students to raise career competency that would allow them to effectively cope with possible unemployment after graduation . The experience of the "unemployment" comes on the heels of graduation can decisively weaken a sense of economic independence and a positive role they could play in society. Therefore, the role of career guidance service has been noted that it needs to help harmonize students' career plans with the human resources needs of companies the ultimate beneficiaries of such service. This situation has provided a context in which the Research has been launched, with the following four questions: First, what institutions are there that provide career service in universities and what are their roles? Second, what is the demanding needs form universities, companies and students on the issues of career guidance service respectively? Third, what is the best delivery structure of integrated career guidance service among instituties? Fourth, what is the best way for realization those suggestions on career guidance service in Korea? Chapter 2 classifies the services provided by the 161 universities into on-line and off-line career guidance services in trying to answer the first question. Chapter 3 surveys needs among students, career guidance professionals in universities and companies through questionnaires, conference calls and interviews, correspondingly. The questionnaires found that 60.9% of the students asked have never received on-campus career development service. Most of those who have received career guidance services are juniors and seniors (74.5%). Also found was that most of the experiences in career development service were from recruitment-oriented one-time events such as special lectures and seminars. Both the suppliers and beneficiaries of university career guidance service were found to demand, first and foremost, that career guidance institutions be strengthened in terms of personnel and finance. Following such demand was the request for putting in place systematic career development programs. Chapter 4 is a case study of career guidance service in U.S. universities concerning how it is structured and provided as well as how it develops and applies competency-oriented career development strategies. Chapter 4 also identifies four implications that it has for Korea. First, there is a need for cooperation between career guidance service and various other university-based institutions on campus. Second, career service needs to be specialized so that it can be provided at the faculty or department level. Third, the focus of career guidance service should shift from one-off events to continuous and synergistic approaches. Fourth, a blueprint for career guidance service should contain a roadmap that addresses each grade specifically. Career guidance service should also be an enabler that empowers students to set up and manage their own career goals. Chapter 5 recommends ways for better career guidance service in universities through the following 4 research questions:...연구요약 I. 서론 1 1. 연구의 필요성 및 목적 1 2. 연구의 내용 및 방법 9 3. 용어 정의 15 II. 대학의 진로지도 17 1. 4년제 일반대학의 진로지도 유형화 17 2. On-line 진로지도 20 3. Off-line 진로지도 24 III. 대학 내 진로지도 요구 분석 33 1. 대학생의 진로지도 요구 33 2. 대학 및 기업의 진로지도 요구 56 IV . 미국 대학의 진로지도 사례 61 1. 대학 내 진로지도 유형 63 2. 대학 내 진로지도 주요 내용 69 3. 역량중심의 진로개발전략 및 활용 81 4. 우리나라 진로지도에 주는 시사점 90 V . 대학의 효율적인 진로지도 방안 93 1. 대학 내 진로지도의 최종 성과 94 2. 대학 내 진로지도의 내용체계 96 3. 대학 내 진로지도 전달을 위한 체제 103 4. 대학 내 효율적인 진로지도의 성공 조건 108 참 고 문 헌 117 ABSTRA CT 121 부 록 12