• Tuberculosis and Respiratory Diseases
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• v.57 no.3
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• pp.226-233
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• 2004

Background : Interferon-gamma (IFN-${\gamma}$) is a critical cytokine in the defense against a Mycobacterium tuberculosis infection. Even though IFN-${\gamma}$ has occasionally been used in the treatment of refractory multidrug-resistant tuberculosis (MDR-TB) with some promising results, there is still some controversy regarding the therapeutic efficacy of IFN-${\gamma}$. This study was performed to examine the effect of subcutaneous IFN-${\gamma}$ in the treatment of MDR-TB patients. Methods : Six patients with refractory MDR-TB were enrolled in this study. Two million IU of IFN-${\gamma}$ was administered subcutaneously three times a week with the concomitant administration of antituberculous drugs for at least for 28 weeks. During the IFN-${\gamma}$ therapy, the sputum smear and culture, radiological and clinical evaluations were performed every 4 weeks throughout the study period. Results : The mean age of the 6 patients was 37 years (ranges, 15-61 years). The drug susceptibility test to standard antituberculous drugs revealed resistance to an average of 6.8 (${\pm}1.2$) agents including isoniazid and rifampicin. An average of 10.8 (${\pm}1.3$) antituberculous drugs were prescribed before IFN-${\gamma}$ therapy. The culture became negative in 2 patients (33%) after initiating IFN-${\gamma}$ therapy; one at 8 weeks, and the other at 24 weeks. Finally, after stopping the IFN-${\gamma}$ therapy after 28 weeks, the culture became positive again in the two patients who were culture-negative. The other 4 patients who failed in the culture conversion are still on antituberculous treatment except for one who died of tuberculosis. Conclusion : Even though 28 weeks of subcutaneous IFN-${\gamma}$ therapy in combination with antituberculous drugs was successful in inducing the culture-negative conversion in some patients with refractory MDR-TB, the culture became positive again after stopping the IFN-${\gamma}$ therapy. This suggests that subcutaneous IFN-${\gamma}$ therapy may have suppressive effect on tuberculosis only during the IFN-${\gamma}$ therapy period in some patients. Further studies will be needed to determine the optimum dose, the administration route, the duration of therapy, and the predicting factors of the response to adjuvant IFN-${\gamma}$ therapy.

• Tuberculosis and Respiratory Diseases
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• v.59 no.3
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• pp.257-265
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• 2005

Background : Rifabutin (ansamycin) is a spiro-piperidyl rifamycin, which is highly active against Mycobacterium tuberculosis. It has been found that some clinical isolates of tubercle bacilli that are resistant to rifampicin are susceptible to rifabutin, with some patients with multi-drug resistant pulmonary tuberculosis having shown favorable clinical and bacteriological responses to the rifabutin. This study was conducted to find the proportion of rifabutin-susceptible strains among rifampicin-resistant isolates from Korean MDR-TB patients, and investigate the presence of specific rpoB mutations, which may confer resistance to rifampicin, but not to rifabutin. Methods : 201 rifampicin-resistant and 50 pan-susceptible M. tuberculosis isolates were randomly selected for this study. The isolates were retested at rifampicin and rifabutin concentrations of 0, 20, 40 and $80{\mu}g/ml$, respectively. The isolates that grew at and/or over a rifabutin concentration of $20{\mu}g/ml$ were judged rifabutin-resistant. The rpoB gene was extracted from the isolates, and then amplified for direct sequencing to investigate specific rpoB mutations that conferred rifabutin- susceptibility but rifampicin-resistance. Results : Out of the 201 rifampicin-resistant M. tuberculosis, 41 strains (20.4%) were susceptible to rifabutin using the absolute concentration method on Lowenstein-Jensen media. The rpoB mutation types that showed susceptibility to rifabutin were Leu511Pro, Ser512Arg, Gln513Glu, Asp516Ala, Asp516Gly, Asp516Val, Asp516Tyr, Ser522Leu, His526Asn, His526Leu, His526Cys, Arg529Pro and Leu533Pro. A reverse hybridization technique was able to detect 92.5% of the rifabutin-susceptible isolates, with a specificity of 96.1% among 195 M. tuberculosis isolates with the rpoB mutation. Conclusions : Around 20% of the rifampicin-resistant isolates in Korea showed susceptibility to rifabutin, which was associated with some specific mutations of rpoB. Rifabutin could be used for the treatment of MDR-TB patients, especially when drug susceptibility testing reveals susceptibility to rifabutin.

• Tuberculosis and Respiratory Diseases
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• v.62 no.6
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• pp.492-498
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• 2007

Background: Several lines of evidence suggest that a host's genetic factors influence the outcome of exposure to Mycobacterium tuberculosis. The aim of this study was to determine whether polymorphism in NRAMP1 (natural resistance associated macrophage protein 1) gene is associated with the susceptibility or resistance to tuberculosis infection for patients with drug-sensitive pulmonary tuberculosis (DS-TB) and multi-drug resistant pulmonary tuberculosis (MDR-TB). Methods: Eight genetic polymorphisms of the NRAMP1 gene were investigated in patients suffering with DS-TB (n=100) or MDR-TB (n=102), and in healthy normal controls (NC, n=96). The genetic polymorphisms of NRAMP1 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The frequency of D543N A/G heterogygotes was significantly higher in the DS-TB subjects than the NCs (OR=2.10, 95% CI: 1.00 to 4.41, p=0.049). The frequency of 823C/T T/C heterozygotes was significantly higher in the DS-TB subjects (OR=2.79, 95% CI: 1.11 to 7.04, p=0.029) and the MDR-TB subject (OR=3.30, 95% CI 1.33 to 8.18, p=0.010) than in the NCs. However, the frequency of these genotypes was not different between the DS-TB and MDR-TB subjects. Conclusion: A significant association was found between NRAMP1 823 C/T polymorphism and pulmonary tuberculosis. This result suggests that NRAMP1 polymorphism may be involved in the development of pulmonary tuberculosis in Koreans.

• Tuberculosis and Respiratory Diseases
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• v.50 no.2
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• pp.205-212
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• 2001

Background : The information on nasal transport and the metabolism of peptides have been obtained from pharmacokinetic investigations in experimental animals. However, there are no transport and metabolic studies of human nasal epithelial cells. In this study, the permeability characteristics and the metabolic properties of in vitro human nasal cell monolayers were investigated. Material and Methods : Normal human inferior nasal conchal tissue samples were obtained from patients undergoing endoscopic nasal cavitary surgery. The specimens were cultured in a transwell using an air-liquid Interface (ALI) culture, and the transepithelial electrical resistance (TEER) value of the blank filter and confluent cell monolayers were measured. To determine the % leakage of mannitol, $4{\mu}mol%$ $^{14}C$-labelled mannitol was added and the % leakage was measured every 10 minute for 1 hour. Result : Human nasal epithelial cells in the primary culture grew to a confluent monolayer within 7 days and expressed microvilli. The tight junction between the cells was confirmed by transmission electron microscopy. The TEER value of the blank filter, fifth day and seventh day reached $108.5\;ohm.cm^2$, $141\;ohm.cm^2$ and $177.5\;ohm.cm^2$, respectively. Transcellular % leakage of the $^{14}$-mannitol at 10, 20, 30, 40, 50 and 60 minutes was $35.67{\pm}5.43$, $34.42{\pm}5.60$, $32.75{\pm}5.71$, $31.76{\pm}4.22$, $30.96{\pm}3.49$ and $29.60{\pm}3.68\;%$, respectively. Conclusion : The human nasal epithelial monolayer using ALI culture techniques is suitable for a transcellular permeability study. The data suggests that human nasal epithelial cells In an ALI culture technique shows some promise for a nasal transport and metabolism study.

• Tuberculosis and Respiratory Diseases
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• v.62 no.1
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• pp.33-42
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• 2007

Background: Heme oxygenase-1 (HO-1) is known to modulates the cellular functions, including cell proliferation and apoptosis. It is known that a high level of HO-1 expression is found in many tumors, and HO-1 plays an important role in rapid tumor growth on account of its antioxidant and antiapoptotic effects. Cisplatin is a widely used anti-cancer agent for the treatment of lung cancer. However, the development of resistance to cisplatin is a major obstacle to its use in clinical treatment. We previously demonstrated that inhibiting HO-1 expression through the transcriptional activation of Nrf2 induces apoptosis in A549 cells. The aim of this study was to determine of the inhibiting HO-1 enhance the chemosensitivity of A549 cells to cisplatin. Materials and Methods: The human lung cancer cell line, A549, was treated cisplatin, and the cell viability was measured by a MTT assay. The change in HO-1, Nrf2, and MAPK expression after the cisplatin treatment was examined by Western blotting. HO-1 inhibition was suppressed by ZnPP, which is a specific pharmacologic inhibitor of HO activity, and small interfering RNA (siRNA). Flow cytometry analysis and Western blot were performed in to determine the level of apoptosis. The level of hydrogen peroxide ($H_2O_2$) generation was monitored fluoimetrically using 2',7'-dichlorofluorescein diacetate. Results: The A549 cells showed more resistance to the cisplatin treatment than the other cell lines examined, whereas cisplatin increased the expression of HO-1 and Nrf2, as well as the phosphorylation of MAPK in a time-dependent fashion. Inhibitors of the MAPK pathway blocked the induction of HO-1 and Nrf2 by the cisplatin treatment in A549 cells. In addition, the cisplatin-treated A549 cells transfected with dither the HO-1 small interfering RNA (siRNA) or ZnPP, specific HO-1 inhibitor, showed in a more significantly decrease in viability than the cisplatin-only-treated group. The combination treatment of ZnPP and cisplatin caused in a marked increase in the ROS generation and a decrease in the HO-1 expression. Conclusion: Cisplatin increases the expression of HO-1, probably through the MAPK-Nrf2 pathway, and the inhibition of HO-1 enhances the chemosensitivity of A549 cells to cisplatin.

• Tuberculosis and Respiratory Diseases
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• v.47 no.6
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• pp.735-746
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• 1999

Background: As the prevalence of nontuberculous mycobacteriosis has been increasing rapidly, there has been recent advance in diagnostic methods and drug therapies for disease. Although the incidence of pulmonary disease caused by nontuberculous mycobacteria(NTM) has been increasing in Korea since 1990, detailed clinical description about the disease were very few. In this study we described the clinical manifestations, radiologic findings, and therapeutic outcomes of nontuberculous mycobacterial pulmonary disease. Methods: Medical records and radiologic findings were retrospectively reviewed in 27 patients who were fulfilled the diagnostic criteria of ATS guideline for NTM pulmonary disease between January of 1990 and August of 1998 in Seoul National University Hospital(SNUH). Results: Of the 27 patients, 15 were male. The mean age was 51.5 yr($\pm$11.9). Twenty patients(74.1%) had preexisting pulmonary diseases. Among them, 19 patients had previous pulmonary tuberculosis. Sixteen patients(59.2%) had cavitary lesions and the majority showed slow progression over 1 yr during follow up period on radiography. Susceptibility test to standard antituberculous drugs showed 100% resistance to INH, 72.2% to RMP, 81.5% to EMB, 92.6% to PZA. The average resistance rate to 2nd-line antituberculous drugs was 66.1%. Among twenty-one patients(77.8%) who received drug therapy over 6 months, 11 subjects were improved and 10 subjects were aggravated. Of six subjects(22.2%) without therapy, 5 patients were aggravated. Presence of cavity and less than 3 sensitive drugs in the regimen were indicators for adverse outcome. Conclusion : The nontuberculous mycobacterial pulmonary diseases in our hospital developed predominantly in older patients with preexistent pulmonary disease. The results of antituberculous drug therapy has been frustrating and disappointing. To improve treatment response, different susceptibility tests and drug regimens for different species of NTM should be performed. Also, diagnostic and therapeutic guidelines of Korea should be made in the recent future.

• Tuberculosis and Respiratory Diseases
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• v.44 no.3
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• pp.470-478
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• 1997

Background : Phagocytosis is probably the first step for mycobacteria to be virulent in host because virulent strains are more readily phagocytosed by macrophage than attenuated strains. According to the traditional concept, multi-drug resistant strains have been regarded as less virulent. However, this concept has been challenged, since recent studies(reported) showed that the degree of virulence and drug-resistance is not related. The purpose of this study is to evaluate whether the phagocytic activity of M.tuberculosis by peripheral blood mononuclear cells(PBMC) is different according to drug-resistance or host factor. To evaluate this, we estimated the difference of phagocytic activity of drug-resistant and drug-sensitive M.tuberculosis and also estimated the phagocytic activity of PBMC from intractable tuberculosis patients and healthy controls. Methods : PBMC from ten intractable tuberculosis patients and twelve healthy control, and three different strains of heat-killed M.tuberculosis, ie, ADS(all drug sensitive), MDR(multi-drug resistant), and ADR(all drug resistant) were used. After incubation of various strains of M.tuberculosis with PBMC, the phagocytic activity was evaluated by estimating proportion of PBMC which have phagocytosed M.tuberculosis. Results : Drug-resistant strains of M.tuberculosis were phagocytosed easily than drug sensitive strains(Percentage of PBMC phagocytosed M.tuberculosis in healthy control : ADS : $32.3{\pm}2.9%$, ADR : $49.6{\pm}3.4%$, p = 0.0022, Percentage of PBMC phagocytosed M.tuberculosis in intractable tuberculosis patients : ADS : $34.9{\pm}3.6%$, ADR : $50.7{\pm}4.5%$, p = 0.0069). However, there was no difference in phagocytic activity of PBMC from healthy control and intractable tuberculosis patients. Conclusion : Drug-resistant strains of M.tuberculosis were phagocytosed easily than drug sensitive strains and host factors does not seems to influence the phagocytosis of M.tuberculosis.

• Tuberculosis and Respiratory Diseases
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• v.49 no.6
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• pp.684-690
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• 2000

Background : The most common cause of treatment failure of pulmonary tuberculosis is early stoppage of treatment or irregular medication. The most important aspect of a retreatment is regular medication provided over a long period. Inadequate treatment may cause drug resistance and prolong the duration of chemotherapy. This study analyzed the risk factors of pulmonary tuberculosis patients, who failed in retreatment, and to use the results as basic data in the management of intractable tuberculosis patients with improving the rate of retreatment success. Methods : We performed a retroactive study of 62 pulmonary tuberculosis patients in retreatment at National Mokpo Tuberculosis Hospital from Jan. 1994 to Dec. 1995. The patients were separated into two groups: group I was retreatment failure and group II was retreatrnent success. For the analysis of risk factors in retreatment failure, we compared the difference between the two groups and tested the confidence limit about results of the results by independent t-test, ${\chi}^2$ test and Fisher's exact test. Results : The treatment failure rate of retreatment patients was 13(21%), and treatment success 49(79%). No significant difference (p>0.05)in age, sex, number of treatment, irregular rate of treatment, extent of the disease & cavitary lesion on the chest X-ray, number of resistance drugs, number of used drugs to medication, number of sensitive bactericidal drugs to medication, rate of sensitive drugs to medication and resisiance to INH & RFP had not significant difference. was found. However, the number of treatment was $2.4{\pm}0.8$ in group I and $1.6{\pm}0.9$ in group II, and had showing a significant difference(p<0.05) between the two groups. Conclusion : The risk factor of retreatment failure was more irregular previous treatment the irregularity of the previous treatment. For reducing the retreatment failure of pulmonary tuberculosis, greater efforts are needed more need to be done to prevent failure of first treatment.

• Tuberculosis and Respiratory Diseases
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• v.48 no.5
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• pp.766-772
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• 2000

Background : Pressure rise time (PRT) is the time in which the ventilator aclieves the set airway pressure in pressure-targeted modes, such as pressure control ventilation (PCV). With varying PRT, in principle, the peak inspiratory flow rate of the ventilator also varies. And if PRT is set to a shorter duration, the effective duration of target pressure level would be prolonged, which in turn would increase inspiratory tidal volume(Vti) and mean airway pressure (Pmean). We also postulated that the increase in Vti with shortening of PRT may relate inversely to the patients' basal airway resistance. Methods : In 13 paralyzed patients on PCV (pressure control 18$\pm$9.5 cm $H_2O$ $FIO_2\;0.6\pm0.3$, PEEP 5$\pm$3 cm $H_2O$, f 20/min, I : E1 : 2) with Servo 300 (Siemens-Elema, Solna, Sweden) from various causes of respiratory failure, PRT of 10 %, 5 % and 0 % were randomly applied. At 30 min of each PRT trial, peak inspiratory flow (PIF, L/sec), Vti (ml), Pmean (cm $H_2O$) and ABGA were determined. Results : At PRT 10%, 5%, and 0%, PIF were 0.69$\pm$0.13, 0.77$\pm$0.19, 0.83$\pm$0.22, respectively (p<0.001). Vti were 425$\pm$94, 439$\pm$101, 456$\pm$106, respectively (p<0.001), and Pmean were 11.2$\pm$3.7, 12.0$\pm$3.7, 12.5$\pm$3.8, respectively (p<0.001). pH were 7.40$\pm$0.08, 7.40$\pm$0.92, 7.41$\pm$0.96, respectively (p=0.00) ; $PaCO_2$ (mm Hg) were 47.4$\pm$15.8, 47.2 $\pm$15.7, 44.6$\pm$16.2, respectively (p=0.004) ; $PAO_2-PaO_2$ (mm Hg) were 220$\pm$98, 224$\pm$95, 227$\pm$94, respectively (p=0.004) ; and $V_n/V_T$ as determined by ($PaCO_2-P_E-CO_2$)/$PaCO_2$ were 0.67$\pm$0.07, 0.67$\pm$0.08, 0.66$\pm$0.08, respectively (p=0.007). The correlation between airway resistance and change of Vti from PRT 10% to 0% were r= -0.243 (p=0.498). Conclusion : Shortening of pressure rise timee during PCV was associated with increased tidal volume, increased mean airway pressure and lower $PaCO_2$.

• Tuberculosis and Respiratory Diseases
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• v.48 no.2
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• pp.210-222
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• 2000

Background: Endothelin(ET) is the most potent vasoconstrictor and bronchoconstrictor. The plasma ET-1 level is elevated in patients with acute pulmonary thromboembolism(APTE). This finding suggest that ET-1 may be an important mediator in the cardiopulmonary derangement of APTE. But whether ET-1 is a pathogenic mediator or a simple marker of APTE is not known. The role of ET-1 in the pathogenesis of cardiopulmonary dysfunction in APTE(delete) was investigated through an evaluation of the effects of $ET_A$-receptor antagonist on APTE. The increase in local levels of preproET-1 mRNA and ET-1 peptide in the embolized lung was also demonstrated. Methods: In a canine autologous blood clot pulmonary embolism model, $ET_A$-receptor antagonist(10 mg/kg intravenously, n=6) was administered one hour after the onset of the embolism. Hemodynamic measurements, blood gas tensions and plasma levels of ET-1 immunoreactivity in this treatment group were compared with those in the control group(n=5). After the experiment., preproET-1 mRNA expression(using Northern blot analysis) and the distribution of ET-1(by immunohistochemical analysis) in the lung tissues were examined. Results: The increases in pulmonary arterial pressure and pulmonary vascular resistance of the treatment group were less than those of the control group. Decrease in cardiac output was also less in the treatment group. Complications such as systemic arterial hypotension and hypoxemia did not occur with the administration of $ET_A$-receptor antagonist The plasma level of ET-1 like(ED: what does 'like' mean?) immunoreactivity was increased after embolization in both groups but was significantly higher in the treatment group. The preproET-1 mRNA and ET-1 peptide expressions were increased in the embolized lung. Conclusion: ET-1 synthesis increases with embolization in the lung and may plays play an important role in the pathophysiology of cardiopulmonary derangement of APTE. Furthermore, $ET_A$-receptor antagonist attenuates cardiopulmonary alterations seen in APTE, suggesting a potential benefit of this therapy.