• Title/Summary/Keyword: New disease

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Expression of Peroxiredoxin and Thioredoxin in Human Lung Cancer and Paired Normal Lung (인체의 폐암과 정상 폐조직에서 Peroxiredoxin 및 Thioredoxin의 발현 양상)

  • Kim, Young Sun;Park, Joo Hun;Lee, Hye Lim;Shim, Jin Young;Choi, Young In;Oh, Yoon Jung;Shin, Seung Soo;Choi, Young Hwa;Park, Kwang Joo;Park, Rae Woong;Hwang, Sung Chul
    • Tuberculosis and Respiratory Diseases
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    • v.59 no.2
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    • pp.142-150
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    • 2005
  • Background : Continuous growth stimulation by various factors, as well as chronic oxidative stress, may co-exist in many solid tumors, such as lung cancer. A new family of antioxidant proteins, the peroxiredoxins (Prxs), have been implicated in the regulation of many cellular processes, including cell proliferation, differentiation and apoptosis. However, a real pathophysiological significance of Prx proteins, especially in lung disease, has not been sufficiently defined. Therefore, this study was conducted to investigate the distribution and expression of various Prx isoforms in lung cancer and other pulmonary conditions. Method : Patients diagnosed with lung cancer, and who underwent surgery at the Ajou Medical Center, were enrolled. The expressions of Prxs, Thioredoxin (Trx) and Thioredoxin reductase (TR) were analyzed using proteomic techniques and the subcellular localization of Prx proteins was studied using immunohistochemistry on normal mouse lung tissue. Result : Immunohistochemical staining has shown the isoforms of Prx I, II, III and V are predominantly expressed in bronchial and alveolar lining epithelia, as well as in the alveolar macrophages of the normal mouse lung. The isoforms of Prx I and III, and thioredoxin were also found to be over-expressed in the lung cancer tissues compared to their paired normal lung controls. There was also an increased amount of the oxidized form of Prx I, as well as a putative truncated form of Prx III, in the lung cancer samples when analyzed using 2-dimensional electrophoresis. In addition, a 43 kDa intermediate molecular weight protein band, and other high molecular weight bands of over 20 kDa, recognized by the anti-Prx I antibody, were present in the tissue extracts of lung cancer patients on 1-Dimensional electrophoresis, which require further investigation. Conclusion : The over-expressions of Prx I and III, and Trx in human lung cancer tissue, as well as their possible chaperoning function, may represent an attempt by tumor cells to adjust to their microenvironment in a manner advantageous to their survival and proliferation, while maintaining their malignant potential.

Epidemiological Study of Air Pollution and Its Effects on Health of Urban Population (서울시(市) 대기오염(大氣汚染)이 시민보건(市民保健)에 미치는 영향(影響)에 관(關)한 조사연구(調査硏究))

  • Chung, Kyou-Chull
    • Journal of Preventive Medicine and Public Health
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    • v.2 no.1
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    • pp.5-22
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    • 1969
  • The urban population of our country is rapidly increasing due to many factors of social structure, and sociologists are predicting that the increase rate of the urban population will be over 50% in 1980's. Above all, the population of the capital city of Seoul, is at present more than four millions. Such centring of people in cities, together with the improvement of the standards of living, caused rapid increase in the amount of fuel consumption, and this consumption of fuels became one of the primary sources of the air pollution in cities. Moreover, the heavy traffic, construction of many tall buildings, and the increasing number of new factories due to the industrial development-all these are contributing to make the matter of air pollution worse and worse in the Metropolitan, whose geographical location is quite unfavorable considered from the view point of air pollution. Most homes in Seoul use briquet as fuel, while oils are used in tall buildings. The CO, $SO_2$, and smoke that come from burning of these fuels are a great threat to the health of the urban population. With the purpose of examining the influence of air pollution upon the public health, written inquiries were made upon respiratory diseases, and the carboxyhemoglobin saturation in the blood was measured to determine whether the air pollution may affect the health of the urban population. Method of Health Examination (1) Investigation of Respiratory Diseases Patients' records were examined to figure out the monthly ambulance rate of respiratory patients to the total number of patients treated. On the other hand, by using the questionnaire form approved by the Medical Research Council's Committee on Research into Chronic Bronchitis, investigators interviewed the examinees and inquired into the respiratory symptoms. (2) Measuring of Carboxyhemoglobin Saturation From the ear lobe of the examinees, with the use of the melangeur for the white blood cell counting, blood was taken, and after diluting it ten times with 0.1% $Na{2}CO_{3}$, again diulting it 20 times with 0.5% $Na_{2}\;CO_{3}$, its absorbancy was measured. The following results are obtained from the investigation. (1) It was found out that 7.7% of the total patients under treatment were suffering from upper respiratory infection, acute or chronic bronchitis, bronchial asthma, pulmonary emphysema and bronchiectasis. Of them all, patients with upper respiratory infection numbered the greatest with 4.8% and patients with acute or chronic bronchitis the next with 2.1%, and their monthly ambulance rate was high from December to February during the winter, and from April to May and from September to October during the changeable seasons. (2) The daily ambulance rate of respiratory patients, it was revealed, had a close connection with the concentration of $SO_2$ and CO in the air. (3) It was found out that men were more subject to respiratory disease than women, and both men and women were more liable to the diseases with the advancing of age. (4) People living at Choong-ku with the heavy traffic and in the industrial zones of Yeungdungpo had high frequency of respiratory symptoms. (5) Considered from the view point of occupations, high frequency was found among those without job, with jobs unknown, merchants and intdustrial workers, whose social status was rather low and traffic policemen who were always exposed to the exhaust gas of cars. As for women, the frequency was detected in the order of those from high to low, housewives who were exposed to briquet gas, women with jobs unknown, women without jobs, whose social status was low. (6) Ex-smokers rather than smokers, of both sexes, had higher frequency. As for men, heavy smokers had high frequency, while in women light smokers had rather high frequency which was presumed to be due to their average old age. (7) Men's average of carboxyhemoglobin saturation was 9.48%, while women's was 11.3%, higher than men's. (p<0.05). Age meant no difference in the case of men, but as for women, the saturation was remarkably high between the ages from 20 to 60. (8) No regional difference was detected in the carboxyhemoglobin saturation. (9) The carboxyhemoglobin saturation was found, in the case of men, in the order of office workers, traffic policemen, students, the unemployed, merchants and industrial workers, drivers; and as for women, the order was housewives, office workers, merchants and industrial workers. (10) No significant correlation was found between the carboxyhemoglobin saturation and the concentration of CO detected in kitchens, or between the carhoxyhemoglobin saturation and the passing of time after exposure to briquet gas. No difference of carboxyhemoglobin saturation was detected between smokers and non-smokers, and the degrees of smoking; only, significant negative correlation was found between the passing of time after smoking and the carboxyhemoglobin saturation. It is ture that air pollution causes or aggravates the respiratory diseases, increases the carboxyhemoglobin saturation in the blood, but what seems to be more hazardous to the health is the air polluted by the briquet gas in the kitchens and on-dol rooms rather than the atmospheric air pollution.

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Development of Work-related Musculoskeletal Disorder Questionnaire Using Receiver Operating Characteristic Analysis (Receiver Operating Characteristic 분석법을 이용한 업무관련성 근골격계질환 설문지 개발)

  • Kwon, Ho-Jang;Ju, Yeong-Su;Cho, Soo-Hun;Kang, Dae-Hee;Sung, Joo-Hon;Choi, Seong-Woo;Choi, Jae-Wook;Kim, Jae-Young;Kim, Don-Gyu;Kim, Jai-Yong
    • Journal of Preventive Medicine and Public Health
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    • v.32 no.3
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    • pp.361-373
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    • 1999
  • Objectives: Receive Operating Characteristic(ROC) curve with the area under the ROC curve(AUC) is one of the most popular indicator to evaluate the criterion validity of the measurement tool. This study was conducted to develop a standardized questionnaire to discriminate workers at high-risk of work-related musculoskeletal disorders using ROC analysis. Methods: The diagnostic results determined by rehabilitation medicine specialists in 370 persons(89 shipyard CAD workers, 113 telephone directory assistant operators, 79 women with occupation, and 89 housewives) were compared with participant's own replies to 'the questionnair on the worker's subjective physical symptoms'(Kwon, 1996). The AUC's from four models with different methods in item selection and weighting were compared with each other. These 4 models were applied to 225 persons, working in an assembly line of motor vehicle, for the purpose of AUC reliability test. Results: In a weighted model with 11 items, the AUC was 0.8155 in the primary study population, and 0.8026 in the secondary study population(p=0.3780). It was superior in the aspects of discriminability, reliability and convenience. A new questionnaire of musculoskeletal disorder could be constructed by this model. Conclusion: A more valid questionnaire with a small number of items and the quantitative weight scores useful for the relative comparisons are the main results of this study. While the absolute reference value applicable to the wide range of populations was not estimated, the basic intent of this study, developing a surveillance fool through quantitative validation of the measures, would serve for the systematic disease prevention activities.

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The Evaluation of Midwifery Program Through the Midwifery Leadership Training Program (조산수습과정 지도자 강습회를 통한 조산교육 평가조사연구)

  • 이경혜
    • Journal of Korean Academy of Nursing
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    • v.11 no.2
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    • pp.23-32
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    • 1981
  • The purpose of the study was to evaluate the educational content which had been given by midwifery training program. It was hoped that this result would help. It was sponsored by com-munity health worker plan effective health education. College of Nursing Ewha Womans University and The Korean Nurses Academic Society during the November 19 thru 24, 1979. It was carried out on July through on September 1980, and involved 22 community health workers. The results were as follows: 1. Most of the community health workers came from Seoul & Pusan areas and have been working at the hospitals. There were 31.82% of Head Nurses, 27.2% of Staff Nurses, 22.73% Nurse Supervisons, 13.6% of Nurse Directors and 4.5% of educational coordinator for Nurses. These participant had nurse-midwifery lincences by 63.64%. None of there had just midwifery lincences. 2, Age structures of the study population shows 31.82% of whom are.26-30 years and 22.73% of whom are 36. 40 years of age. This shown that seniority proportion is higher than the younger. There are 31.82% of 1-5 years, 27.27% of 6-10 year and 11-15 years, respectively by work career. 3. There are 54.55% of the institutions have opened their own midwifery training course for their nursing staff members. Because of lack of the facilities, shortage of instructors, and problems of administrative process. 4. According to the institution which opened for midwifery training courses, the participant was responsible for “midwifery”“Infant care”“MCH”“practice of midwifery”“Nursing adjustment”and“F. P.”5. During the midwifery couse, there were 8 institution who used the textbook and 4 institution who did not. Least of there referned to content matinals which was given by the sponsored. 6. There are 7 insititues who kept their training courses with other professional helps such as physicians., professiors and nurses. Some problems are pointed out by respondents such as“conflict with residents”“poor suportive administration”and“lake of manpower”. 8. The participant showed that they learned new knowledge as trends during this programs for there quality work so it need (one or twice times) a year. But they suggested that it needed more emphasis on the“maternal health care”and“role of the nurse-midwifery”. 9. The analysis of the results are as follows within the 6 areas which are given by the sponsored: There are highest ranks between“basic theory & family planning”“role of midwifery & nursing practice”. In the prenatal care the highest rank ware related to“health risk”on“idenify of risk symtoms”. In the health care areas which related to delivery, the responsers were related to“general conditions”or“high risk criteria”. In the health care area which related to high risk maternity care. In the neonatal health care, the highest rank was related to”health assessment of normal infant”. In the infant health care the responses was related to“abnormal symptoms”and“risk symptoms”. Actually, the participants show that they are more interested in“role of midwifery”“health assessment”and “high risk maternity care”are which emphasised on health promotion, health maintenance & disease preventive. 1) The midwifery training program need higher education for midwifery on a regular basis. 2) Within the open institution of midwifery training program, the nurses must be supported by their own institution and administry of social welfare must give systematic support. Also non-open institution must be open very soon. 3) All health workers including the residents & other workers, must cooperate for their phased common good of impovement of the maternity health. 4) Administration agonies & education institutions must provide the curriculum facilitis and administration systems which are needed for training of nurse-midwifery.

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Effect of Short Term Treatment with Different Dosage of Inhaled Flucatisone Propionate on Basal Cortisol Concentration (단기간 Fluticasone Propionate 투여 용량에 따른 가저 코르티솔 농도의 변화)

  • Kim, Hyun-Jung;Kim, Hyoung-Sik;Lee, Hong;Moon, Sung-Gi;Lim, Seok-Tae;Park, Ji-Hyun;Lee, Heung-Bum;Lee, Yong-Chul;Rhee, Yang-Keun
    • Tuberculosis and Respiratory Diseases
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    • v.44 no.5
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    • pp.1063-1071
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    • 1997
  • Backgroung : The efficacy of oral corticosteroids in the treatment of chronic asthma is undisputed, but their long-term use is associated with adverse side-effects, including supression of the hypothalamic-pituitary adrenal axis function, osteoporosis, weight gain, hypertension and impaired glucose tolerance. The introduction of inhaled corticosteroids in the early 1970's represented a significant therapeutic advance in the management of asthma, since these compounds combined high topical potency with low systemic activity. Fluticasone propionate is a new topically active synthetic glucocorticosteroid that combinds a high degree of efficacy with negligible systemic bioavailability. This study was perfomed to determine the effect of inhaled fluticasone propionate on the adreocortical supression in patients with bronchial asthma or chronic obstructive pulmonary disease. Method : The adrenocortical function was assessed by measurement of plasma cortisol concentration at 8 o'clock in morning and free cortisol in 24 hour urine collection at interval. Absolutely, no steroid was taken during pretreatment period of 10days. There after each subject inhaled fluticasone aerosol, in daily doses of 500 or 1000micrograms for 12days. The dose was delivered by metered dose inhaler(MDI). Results : The serum cortisol and 24hour urinary free cortisol were not decreased during the treatment period in patients with inhaled fluticasone propionate in daily doses of 500 micrograms. In contrast, serum cortisol was significantly decreased on 9th and 12th day(p less than 0.05). And, 24hour urinary free cortisol was also significantly decreased on 3rd and 12th day of treatement period(p less than 0.05) in patients with inhaled fluticasone in daily doses of 1000 micrograms. Conclusion : These results suggested that endogenous cortisol secretion was not supressed after short-term inhalation of fluticasone in daily dose of 500 micrograms, but in daily dose of 1000 micrograms, the endogenous cortisol secretion was supressed.

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Effect of bronchial artery embolization in the management of massive hemoptysis : factors influencing rebleeding (대량객혈 환자에서 기관지 동맥색전술의 효과 : 색전술후 재발의 원인과 예측인자)

  • Kim, Byeong Cheol;Kim, Jeong Mee;Kim, Yeon Soo;Kim, Seong Min;Choi, Wan Young;Lee, Kyeong Sang;Yang, Suck Cheol;Yoon, Ho Joo;Shin, Dong Ho;Park, Sung Soo;Lee, Jung Hee;Kim, Chang Soo;Seo, Heung Suk
    • Tuberculosis and Respiratory Diseases
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    • v.43 no.4
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    • pp.590-599
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    • 1996
  • Background : Bronchial artery embolization has been established as an effective means to control hemoptysis, especially in patients with decreased pulmonary function and those with advanced chronic obstructive pulmonary disease. We evaluated the effect of arterial embolization in immediate control of massive hemoptysis and investigated the clinical and angiographic characteristics and the course of patients with reccurrent hemoptysis after initial succeseful embolization. Another purpose of this study was to find predictive that cause rebleeding after bronchial artery embolization. Method : We reviewed 47 cases that underwent bronchial artery embolization for the management of massive hemoptysis, retrospectively. We analyzed angiographic findings in all cases before bronchial artery embolization and also reviewed the angiographic findings of patients that underwent additional bronchial artery embolization for the control of reccurrent hemoptysis to find the clauses of rebleeding. Results : 1) Underlying causes of hemoptysis were pulmonary tuberculosis(n=35), bronchiectasis(n=5), aspergilloma(n=2), lung cancer(n=2), pulmonary A-V malformation(n=1), and unknown cases(n=2). 2) Overal immediate success rate was 94%(n=44), an6 recurrence rate was 40%(n=19). 3) The prognostic factors such as bilaterality, systemic-pulmonary artery shunt, multiple feeding arteries and degree of neovascularity were not statistically correlated with rebleeding tendency (p value>0.05). 4) At additional bronchial artery embolization, Revealed recannalization of previous embolized arteries were 14/18cases(78%) and the presence of new deeding arteries was 8/18cases(44%). 5) The complications(31cases, 66%) such as fever, chest pain, cough, voiding difficulty, paralytic ileus, motor and sensory change of lower extremity, atelectasis and splenic infarction were occured. Conclusion : Recannalization of previous embolized arteries is the major cause of recurrence after bronchial artery embolization. Despite high recurrence rate of hemoptysis, bronchial artery embolization for management of massive hemoptysis is a effective and saute procedure in immediate bleeding control.

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Manganese and Iron Interaction: a Mechanism of Manganese-Induced Parkinsonism

  • Zheng, Wei
    • Proceedings of the Korea Environmental Mutagen Society Conference
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    • 2003.10a
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    • pp.34-63
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    • 2003
  • Occupational and environmental exposure to manganese continue to represent a realistic public health problem in both developed and developing countries. Increased utility of MMT as a replacement for lead in gasoline creates a new source of environmental exposure to manganese. It is, therefore, imperative that further attention be directed at molecular neurotoxicology of manganese. A Need for a more complete understanding of manganese functions both in health and disease, and for a better defined role of manganese in iron metabolism is well substantiated. The in-depth studies in this area should provide novel information on the potential public health risk associated with manganese exposure. It will also explore novel mechanism(s) of manganese-induced neurotoxicity from the angle of Mn-Fe interaction at both systemic and cellular levels. More importantly, the result of these studies will offer clues to the etiology of IPD and its associated abnormal iron and energy metabolism. To achieve these goals, however, a number of outstanding questions remain to be resolved. First, one must understand what species of manganese in the biological matrices plays critical role in the induction of neurotoxicity, Mn(II) or Mn(III)? In our own studies with aconitase, Cpx-I, and Cpx-II, manganese was added to the buffers as the divalent salt, i.e., $MnCl_2$. While it is quite reasonable to suggest that the effect on aconitase and/or Cpx-I activites was associated with the divalent species of manganese, the experimental design does not preclude the possibility that a manganese species of higher oxidation state, such as Mn(III), is required for the induction of these effects. The ionic radius of Mn(III) is 65 ppm, which is similar to the ionic size to Fe(III) (65 ppm at the high spin state) in aconitase (Nieboer and Fletcher, 1996; Sneed et al., 1953). Thus it is plausible that the higher oxidation state of manganese optimally fits into the geometric space of aconitase, serving as the active species in this enzymatic reaction. In the current literature, most of the studies on manganese toxicity have used Mn(II) as $MnCl_2$ rather than Mn(III). The obvious advantage of Mn(II) is its good water solubility, which allows effortless preparation in either in vivo or in vitro investigation, whereas almost all of the Mn(III) salt products on the comparison between two valent manganese species nearly infeasible. Thus a more intimate collaboration with physiochemists to develop a better way to study Mn(III) species in biological matrices is pressingly needed. Second, In spite of the special affinity of manganese for mitochondria and its similar chemical properties to iron, there is a sound reason to postulate that manganese may act as an iron surrogate in certain iron-requiring enzymes. It is, therefore, imperative to design the physiochemical studies to determine whether manganese can indeed exchange with iron in proteins, and to understand how manganese interacts with tertiary structure of proteins. The studies on binding properties (such as affinity constant, dissociation parameter, etc.) of manganese and iron to key enzymes associated with iron and energy regulation would add additional information to our knowledge of Mn-Fe neurotoxicity. Third, manganese exposure, either in vivo or in vitro, promotes cellular overload of iron. It is still unclear, however, how exactly manganese interacts with cellular iron regulatory processes and what is the mechanism underlying this cellular iron overload. As discussed above, the binding of IRP-I to TfR mRNA leads to the expression of TfR, thereby increasing cellular iron uptake. The sequence encoding TfR mRNA, in particular IRE fragments, has been well-documented in literature. It is therefore possible to use molecular technique to elaborate whether manganese cytotoxicity influences the mRNA expression of iron regulatory proteins and how manganese exposure alters the binding activity of IPRs to TfR mRNA. Finally, the current manganese investigation has largely focused on the issues ranging from disposition/toxicity study to the characterization of clinical symptoms. Much less has been done regarding the risk assessment of environmenta/occupational exposure. One of the unsolved, pressing puzzles is the lack of reliable biomarker(s) for manganese-induced neurologic lesions in long-term, low-level exposure situation. Lack of such a diagnostic means renders it impossible to assess the human health risk and long-term social impact associated with potentially elevated manganese in environment. The biochemical interaction between manganese and iron, particularly the ensuing subtle changes of certain relevant proteins, provides the opportunity to identify and develop such a specific biomarker for manganese-induced neuronal damage. By learning the molecular mechanism of cytotoxicity, one will be able to find a better way for prediction and treatment of manganese-initiated neurodegenerative diseases.

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Hybrid Two-Dimensional Proton Spectroscopic Imaging of Pediatric Brain: Clinical Application (소아 뇌에서의 혼성 이차원 양성자자기공명분광법의 임상적 응용)

  • Sung Won Youn;Sang Kwon Lee;Yongmin Chang;No Hyuck Park;Jong Min Lee
    • Investigative Magnetic Resonance Imaging
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    • v.6 no.1
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    • pp.64-72
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    • 2002
  • Purpose : To introduce and demonstrate the advantages of the new hybrid two-dimensional (2D) proton spectroscopic imaging (SI) over the single voxel spectroscopy (SVS) and conventional 2D SI in the clinical application of spectroscopy for pediatric cerebral disease. Materials and Methods : Eighty-one hybrid 2D proton spectroscopic imaging was performed in 79 children (36 normal infants and children, 10 with hypoxic-ischemic injury, 20 with toxic-metabolic encephalopathy, seven with brain tumor, three with meningoencephalitis, one with neurofibromatosis, one with Sturge-Weber syndrome and one with lissencephaly) ranging in age from the third day of life to 15 years. In adult volunteers (n=5), all three techniques including hybrid 2D proton SI, SVS using PRESS sequence, and conventional 2D proton SI were performed. Both hybrid 2D proton SI and SVS using PRESS sequence were performed in clinical cases (n=). All measurements were performed with a 1.5-T scanner using standard head quadrature coil. The 16$\times$16 phase encoding steps were set on variable field of view (FOV) depending on the size of the brain. The hybrid volume of interest inside FOV was set as $75{\times}75{\times}15{\;}\textrm{mm}^3$ or smaller to get rid of unwanted fat signal. Point-resolved spectroscopy (TR/TE=1,500 msec/135 or 270msec) was employed with standard chemical shift selective saturation (CHESSI pulses for water suppression. The acquisition time and spectral quality of hybrid 2D proton SI were compared with those of SVS and conventional 2D proton SI. Results : The hybrid 2D proton SI was successfully conducted upon all patients.

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Evaluation of Late Blight Resistance and Agronomic Characteristics of Short-day Adapted Potato Germplasm (단일적응 감자 유전자원들의 역병저항성 및 주요 농업형질 평가)

  • Park, Young-Eun;Cho, Hyun-Mook;Cho, Ji-Hong;Cho, Kwang-Soo;Kim, Hyun-Jun;Landeo, Juan
    • Horticultural Science & Technology
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    • v.29 no.5
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    • pp.474-481
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    • 2011
  • Potato late blight caused by the fungus Phytophthora infestans is one of the most vital diseases damaging the potato plant. It is for this reason that breeding potato cultivars resistant to late blight is now becoming a major concern around the world. The B3C1 clones has been introduced by the Highland Agriculture Research Center, RDA. The clones which came from International Potato Center in 2005 have a durable resistance to late blight. The clones were bred under a short-day condition in Peru. However, there was still no report on the adaptability of these clones to the long-day condition in Korea. Therefore, this study was conducted to evaluate the late blight resistance and major agronomic characteristics of B3C1 clones under Korea's long-day condition. This study was also done to generate genetic resources for developing new varieties resistant to late blight. In this study it was found out that in naturally infested field with P. infestans, AUDPC (area under disease progress curve) values of all B3C1 clones were significantly lower than those of the control varieties, 'Superior', 'Atlantic', and 'Haryeong'. It was found out that B3C1 clones had a high level of resistance to late blight and that they could be used as genetic resources to breed potato varieties with late blight resistance. However, several undesirable characteristics such as extremely late maturity, excessive growth of stems and stolons, and production of tubers that cannot easily be removed from the stolons were also observed. Among the twenty B3C1 clones, two clones, LB-8 (CIP393077.159) and LB-11 (CIP393371.159), were selected for cultivating at the highland area of Korea. Two B3C1 clones were crossed with Korean breeding lines and clonal selection for the progenies is still in progress.

Microtubule-damaging Chemotherapeutic Agent-mediated Mitotic Arrest and Apoptosis Induction in Tumor Cells (미세소관-손상 항암제 처리에 의한 세포주기의 정지 및 에폽토시스 유도)

  • Jun, Do Youn;Kim, Young Ho
    • Journal of Life Science
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    • v.26 no.3
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    • pp.376-386
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    • 2016
  • Apoptosis induction has been proposed as an efficient mechanism by which malignant tumor cells can be removed following chemotherapy. The intrinsic mitochondria-dependent apoptotic pathway is frequently implicated in chemotherapy-induced tumor cell apoptosis. Since DNA-damaging agent (DDA)-induced apoptosis is mainly regulated by the tumor suppressor protein p53, and since more than half of clinical cancers possess inactive p53 mutants, microtubule-damaging agents (MDAs), of which apoptotic effect is mainly exerted via p53-independent routes, can be promising choice for cancer chemotherapy. Recently, we found that the apoptotic signaling pathway induced by MDAs (nocodazole, 17α-estradiol, or 2-methoxyestradiol) commonly proceeded through mitotic spindle defect-mediated prometaphase arrest, prolonged Cdk1 activation, and subsequent phosphorylation of Bcl-2, Mcl-1, and Bim in human acute leukemia Jurkat T cells. These microtubule damage-mediated alterations could render the cellular context susceptible to the onset of mitochondria-dependent apoptosis by triggering Bak activation, Δψm loss, and resultant caspase cascade activation. In contrast, when the MDA-induced Bak activation was inhibited by overexpression of anti-apoptotic Bcl-2 family proteins (Bcl-2 or Bcl-xL), the cells in prometaphase arrest failed to induce apoptosis, and instead underwent mitotic slippage and endoreduplication cycle, leading to formation of populations with 8N and 16N DNA content. These data indicate that cellular apoptogenic mechanism is critical for preventing polyploid formation following MDA treatment. Since the formation of polyploid cells, which are genetically unstable, may cause acquisition of therapy resistance and disease relapse, there is a growing interest in developing new combination chemotherapies to prevent polyploidization in tumors after MDA treatment.