• Tuberculosis and Respiratory Diseases
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• v.54 no.4
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• pp.459-466
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• 2003

Mycobacterium kansasii is the second most common cause of nontuberculous mycobacterial pulmonary disease in Western countries and Japan. The clinical and radiological features of pulmonary disease caused by M. kansasii usually resemble those of pulmonary tuberculosis including cavitary infiltrates with an upper lobe predilection. It is also now apparent that patients with M. kansasii pulmonary disease can present with noncavitary nodular bronchiectatic infiltrates similar to lung diseases of M. avium complex. With rifampin-containing regimens, treatment success rates are almost 100%. Timely diagnosis before the development of extensive disease and effective overall treatment strategies are very important to ensure that patients receive the appropriate medications for a sufficiently long period of time. To our knowledge, there has been no Korean case report of M. kansasii pulmonary disease in the immunocompetent patient until now. We report three cases of M. kansasii pulmonary disease in immunocompetent adult patients.

• Tuberculosis and Respiratory Diseases
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• v.45 no.6
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• pp.1123-1142
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• 1998

Background : The frequency of MOTT has risen as the prevalence of tuberculosis has been declining. Our country has been also. The most of MOTT was resistant to the major anti-tuberculous drugs. Method : To compare clinical characteristics and frequencies of MDR tuberculosis with MOTT, the author studied 65 patients showing AFB culture positive with sputum. The data were collected from 176 patients who had been admitted at the National Masan Tuberculosis Hospital from May to June, 1997 to April, 1998. Result : The frequency of MDR tuberculosis was 43.1% and that of MOTT was 9.2%. Among 65 isolated mycobacteria, 3 cases were M. intracellulare. 2 cases were M. fortuitum, and 1 case was unidentified MOTT. The most frequent age group in 65 culture positive patients was 4th decade and the mean age was 44. The mean age was 61 in MOTT and 42 in M. tuberculosis and had significant difference(p<0.01). The numbers with past history of treatment were 2.3 in MDR tuberculosis and 1.7 in non-MDR tuberculosis and had significant difference(p<0.05). At the time of admission, the most frequent regimen for the treatment of MDR tuberculosis was 24 months regimen(85.7%) with the 2nd line anti-tuberculosis drugs. For non-MDR tuberculosis, 9 or 12 months regimen (72.9%) with the 1st line anti-tuberculosis drugs and had significant difference (p<0.01). At the time of admission, the symptom of weight loss was shown in 84.7% of M. tuberculosis and 50.0% in MOTT and there was significant difference(p<0.05) between them. All of the MOTT were identified to be resistant against INH and PAS. Drug resistance rates to INH, OFX(p<0.01) and PAS(p<0.05) in MOTT were higher than in MDR. All of three M. intracellulare strains were resistant to INH, RFP, PAS and OFX. All of two M. fortuitum strains were resistant to most anti-tuberculosis drugs. And the other MOTT was resistant to INH, EMB and PAS. Conclusion : MOTT was more common in elderly patients than M. tuberculosis. MOTT cases should be considered to be the probability of multiple drug resistance and treatment failure during the 1st treatment because they showed more resistance to anti-tuberculosis drugs than M. tuberculosis cases. Therefore, there should be more careful investigations for clinical characteristics, natural history of disease, and efficient management for MOTT.

• Tuberculosis and Respiratory Diseases
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• v.44 no.5
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• pp.975-991
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• 1997

Background : Many patients with isoniazid and rifampin-resistant pulmonary tuberculosis have organisms that are also resistant to other first-line drugs. Despite of aggressive retreatment chemotherapy, the results are often unsuccessful, with a failure rate approaching 40%. Recently, there has been a revival of resectional surgery for the treatment of multidrug-resistant pulmonary tuberculosis. Methods : A retrospective analyses of the case records and radiographic findings were done. Between January 1991 and December 1995, 14 human immunodeficiency virus (HIV)-seronegative patients with multidrug-resistant pulmonary tuberculosis were selected for resection to supplement chemotherapy. All patients had organisms resistant to many of the first-line drugs, including both isoniazid and rifampin. Results : Despite of aggressive therapy for median duration of 9.5 months, 12 of the 14 patients (86%) were still sputum smear and/or culture positive at the time of surgery. The disease was generally extensive. Although main lesions of the disease including thick-walled cavities were localized in one lung, lesser amounts of contralateral disease were demonstrated in 10 of 14 (71%). Types of surgery performed were pneumonectomy including extrapleural pneumonectomy in six patients, lobectomy or lobectomy plus in six patients, and segmentectomy in two patients. The resected lung appeared to have poor function ; preoperative perfusion lung scan showed only 4.8% of the total perfusion to the resected portion of the lung. There were no operative deaths. Two patients had major postoperative complications including empyema with bronchopleural fistula and prolonged air leak, respectively. Of the 14 patients, 13 (93%) remained sputum-culture-negative for M. tuberculosis for a median duration of 23 months and one remained continuously sputum smear and culture positive for M. tuberculosis. Conclusion : On the basis of comparison with historical controls, adjunctive resectional surgery appears to play a significant beneficial role in the management of patients with multidrug-resistant pulmonary tuberculosis if the disease is localized and there are adequate reserve in pulmonary function.

• Tuberculosis and Respiratory Diseases
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• v.53 no.1
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• pp.17-26
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• 2002

Background : The detection and early elimination of the causes for acute respiratory distress syndrome(ARDS) at the initial stage can result in a more favorable prognosis. Miliary tuberculosis as a cause of the ARDS is quite rare. A diagnosis of miliary tuberculosis is difficult due to the diversity of radiological patterns and non-specific clinical finfings, and low sensitivity of sputum examinations for acid-fast bacilli(AFBs). An analysis of the clinical data is the first step in diagnosing these unusual, rare cases. Materials and Methods : In this study the clinical features, laboratory data, radiological findings and diagnostic methods were analyzed in 9 cases with an initial presentation of ARDS due to miliary tuberculosis. The ARDS was defined by the definition of the American-Europian consensus conference 1992. Results : The mean age of the patients was $67{\pm}18$ years (F:M=7:2). The chief complaints were dyspnea(5/9), coughing (3/9) and fever(5/9). On a physical examination, fine or coarse crackles were noted(6/9). The ARDS developed on average 6.7 days after the initial respiratory symptoms. The mean $PaO_2/FiO_2$ of the patients was $133.5{\pm}53.4$, the number of cases with a WBC<5000/$mm^3$ was 4 out of 9 cases. A platelet count<70,000/$mm^3$ was observed in 2 out of 9 cases, and the serum albumin level was $2.6{\pm}0.6$ g/dL. The initial simple chest PA showed ground glass appearances and consolidation in all cases, However, the miliary nodular densities were observed in only 4 out of the 9 cases. HRCT revealed alveolar densities and a consolidation in 5 out of 6 cases, and miliary nodules in 5 out of 6 cases, The diagnosis of tuberculosis was made by a liver biopsy (4/4, 100% sensitivity), a bone marrow biopsy (1/2, 50% sensitivity), and an open lung biopsy (1/1), the sputum AFB was positive in only 2 out of 9 cases. The patient was treated with INH, RFP, EMB, PZA, and steroids. The survival rate was 55.5%. Conclusion : Miliary tuberculosis should be considered as one of the causes for ARDS in areas where there is a high prevalence of tuberculosis. The chief complaints of the patients on admission are dyspnea, fever and coughing without any specific riskfactors. A liver biopsy is particularly useful in ARDS patients with mechanical ventilation to determine the causes of the ARDS if miliary tuberculosis is suspected as being the underlying disease.

• Tuberculosis and Respiratory Diseases
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• v.48 no.6
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• pp.853-869
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• 2000

Background : Following several decades of decline, the incidence of tuberculosis has recent1y begun to increase in many countries of this the control of this disease has been impeded by the emergence of multi-drug resistant tuberculosis (MDR-TB). The development of rapid diagnostic methods and effective new drugs are needed to control MDR-TB. One of the new drugs for MDR-TB is rifabutin (RBU) which has been known to be effective in some patients with MDR-TB. A few reports showed that some types of mutations of the rpoB gene, which were known to be present in 96-98% of rifampicin-resistant M. tuberculosis, were associated with the rifampicin-resistant but RBU-susceptible phenotype. This study was performed to investigate the correlation between RBU susceptibility and the patterns of rpoB gene mutations in Korean MDR-TB. Methods : Sixty-five clinical isolates of multi-drug resistant Mycobacterium tuberculosis, gathered from patients who visited the Asan Medical Center from July 1997 to June 1999, were investigated. Clinical responses to rifabutin-containing regimen were evaluated. An RBU susceptibility test and sequencing analysis of rpoB gene were performed, and the results were analyzed to confirm which mutations correlated with RBU-susceptible MDR-TB. Results : Fifty-three of 56 (95%) clinical isolates of MDR-TB had 60 mutations of the rpoB gene. The most frequent mutations were found at codon 531 (43%), and two mutations were combined in seven clinical isolates. Five of 53 (10%) clinical isolates showed the RBU-susceptible phenotype, and in them the characteristic patterns of point mutations were found at codon 509, 516, and 526. Conclusion : The frequency and pattern of mutations of the rpoB gene of Korean MDR-TB isolates were similar to those in western countries, where the prevalence of tuberculosis is low, but some show RBU-susceptible phenotypes. RBU-susceptible MDR-TB isolates showed the characteristic pattern of mutations of the rpoB gene which could be used to rapidly diagnose RBU susceptibility.

• Tuberculosis and Respiratory Diseases
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• v.49 no.6
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• pp.676-683
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• 2000

Background : Surgery may have a role when medical treatment alone is not successful in patients with multidrug resistant (MDR) pulmonary tuberculosis (PTB). To document the role of resection in MDR PTB, we analyzed 4 years of our experience. Methods : A retrospective review was performed on thirteen patients that underwent pulmonary resection for MDR PTB between May 1996 and February 2000. All patients had organisms resistant to many of the first-line drugs including isoniazid (INH) and rifampicin (RFP). Results : The thirteen patients were $37.5{\pm}12.4$ years old (mean${\pm}$S.D.)(M : F=5:8), and their sputum was culture positive even with adequate medication for prolonged periods ($109.7{\pm}132.0$ months), resistant to 2-8 drugs including isoniazid and rifampin. All patients had localized lesion(s) and most (92.3%) had cavities. At least 3 sensitive anti-TB medications were started before surgery in all patients according to the drug sensitivity test. The preoperative $FEV_1$ was $2.37{\pm}0.83$ L. Lobectomy was performed in 11 patients and pleuropneumonectomy in two. Postoperative mortality did not occur, but pneumonia occurred as a complication in one (7.7%). After $41.5{\pm}58.9$ days (range 1~150 days) follow up, negative conversion of sputum culture was achieved in all patients within 5 months. Only one patient (7.7%) recurred 32 months after lung resection. Conclusion : When medical treatment alone is not successful, surgical resection can be a good treatment option in patients with localized MDR PTB.

• Tuberculosis and Respiratory Diseases
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• v.59 no.2
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• pp.179-185
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• 2005

Background : To evaluate the clinical efficacy of pulmonary resection combined with first-line antituberculous drug therapy in patients with well-localized, cavities-containing pulmonary multidrug-resistant tuberculosis (MDR-TB). Method : From February 1998, seventeen patients with well-localized, cavities-containing pulmonary MDR-TB were enrolled and followed prospectively up to December 2004. After radical pulmonary resection, the patients were treated with antituberculous drugs comprising of isoniazid (H), rifampin (R), pyrazinamide (Z), ethambutol (E), and streptomycin (S) (3HERZS/3HERS/6HER). Results : All recovered isolates of M. tuberculosis were resistant to both isoniazid and rifampin, and to a mean of 4.8 antituberculous drugs (range, 2 to 7 drugs). Surgical procedures included lobectomy (13 patients), lobectomy plus segmentectomy (3 patients), and pneumonectomy (1 patient). The median time for postoperative sputum smear and culture conversion was 2 days (range, 1 to 23 days). Fifteen (94%) patients had durable cures (mean follow-up period, 39.0 months). One patient failed to convert her sputum and was successfully switched to second-line therapy; one patient developed active disease again almost 7 years later, likely due to re-infection with a new M. tuberculosis strain. Conclusion : Radical resection combined with administration of first-line antituberculous agents was effective in patients with well-localized, cavities-containing pulmonary MDR-TB.

• Molecules and Cells
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• v.38 no.2
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• pp.138-144
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• 2015

Raloxifene is a selective estrogen receptor modulator (SERM) that binds to the estrogen receptor (ER), and exhibits potent anti-tumor and autophagy-inducing effects in breast cancer cells. However, the mechanism of raloxifene-induced cell death and autophagy is not well-established. So, we analyzed mechanism underlying death and autophagy induced by raloxifene in MCF-7 breast cancer cells. Treatment with raloxifene significantly induced death in MCF-7 cells. Raloxifene accumulated GFP-LC3 puncta and increased the level of autophagic marker proteins, such as LC3-II, BECN1, and ATG12-ATG5 conjugates, indicating activated autophagy. Raloxifene also increased autophagic flux indicators, the cleavage of GFP from GFP-LC3 and only red fluorescence-positive puncta in mRFP-GFP-LC3-expressing cells. An autophagy inhibitor, 3-methyladenine (3-MA), suppressed the level of LC3-II and blocked the formation of GFP-LC3 puncta. Moreover, siRNA targeting BECN1 markedly reversed cell death and the level of LC3-II increased by raloxifene. Besides, raloxifene-induced cell death was not related to cleavage of caspases-7, -9, and PARP. These results indicate that raloxifene activates autophagy-dependent cell death but not apoptosis. Interestingly, raloxifene decreased the level of intracellular adenosine triphosphate (ATP) and activated the AMPK/ULK1 pathway. However it was not suppressed the AKT/mTOR pathway. Addition of ATP decreased the phosphorylation of AMPK as well as the accumulation of LC3-II, finally attenuating raloxifene-induced cell death. Our current study demonstrates that raloxifene induces autophagy via the activation of AMPK by sensing decreases in ATP, and that the overactivation of autophagy promotes cell death and thereby mediates the anti-cancer effects of raloxifene in breast cancer cells.

• Journal of Life Science
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• v.17 no.2 s.82
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• pp.198-203
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• 2007

DNA transfection is a powerful tool for studying gene functions. The $Ca^{2+}$-phosphate precipitation remains one of the most popular and cost-effective transfection techniques. Mature neurons are more resistant to transfection than young ones and most other cell types, and easy to die if microenvironment changes. Here, we report a transfection protocol for mature neurons. The critical modifications are inclusion of glial cells in culture and careful control of $Ca^{2+}$-phosphate precipitation under microscope. Cerebral glial cells were grown until ${\sim}70-80%$ confluence in DMEM/10% horse serum, which was thereafter replaced with serum-free Neurobasal/Ara-C, and 319 hippocampal neurons were plated onto the glial layer Formation of fine $DNA/Ca^{2+}$-phosphate precipitates was induced using Clontech $CalPhos^{TM}$ Mammalian Transfection Kit, and the size ($0.5-1\;{\mu}m$ in diameter) and density(about 10 particles/$100\;{\mu}m^2$) were carefully controlled by the time of incubation in the medium. This modified protocol can be reliably applied for transfection of mature neurons that are maintained longer than two weeks in vitro, resulting in 10-15 healthy transfected neurons per a well of 24-well plates. The efficacy of the protocol was verified by punctate expression of $pEGFP-CaMKII{\alpha}$, a synaptic protein, and diffuse expression of pDsRed2. Our protocol provides a reliable method for transfection of mature neurons in vitro.

• Clinical and Experimental Pediatrics
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• v.52 no.1
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• pp.61-67
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• 2009

Purpose : The rate of drug-resistant tuberculosis (DR-TB) in children is an indicator of the effectiveness of TB control programs in the community. This study aimed to assess the prevalence of DR-TB in children and evaluate TB management. Methods : Between January 1999 and July 2007, drug susceptibility tests for anti-TB drugs were employed for patients aged less than 19 years with culture-positive TB. Results : A total of 607 cases (16.6%) were resistant to at least one anti-TB drug as follows: isoniazid (INH; 13.8%), rifampin (8.9%), pyrazinamide (4.2%), streptomycin (3.7%), ethambutol (EMB; 5.9%), and para-aminosalicylic acid (PAS; 1.9%). Multidrug-resistant (MDR) TB was found in 276 cases (7.6%); extensive drug resistant (XDR) TB, in 5 cases (0.2%). The rate of resistance to at least one anti-TB drug in children aged >15 years (16.1%) was significantly lower than that in children aged <15 years (20.5%) (P=0.016). The rate of resistance to at least one anti-TB drug and multidrug-resistance in this survey decreased significantly (P<0.001) as compared to the previous survey (1987-1995). The rate of resistance to INH, EMB, and PAS also significantly decreased (P<0.05). Conclusion : The rate of DR-TB in children in Korea has decreased over time; however, it remains higher than that in other countries. MDR-TB and XDR-TB are the emerging problems in Korean children. Therefore, the selection of effective drugs through drug susceptibility tests and evaluating risk factors of resistant TB is essential to successful therapy and a decreased incidence of DR-TB.