• Tuberculosis and Respiratory Diseases
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• v.42 no.6
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• pp.813-822
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• 1995

Background: Bronchial hyperresponsiveness and abnormal response such as a loss of distensibility are pathophysiologic characteristics if bronchial asthma. The only means of direct in vivo measurement of airway size had been a tantalium bronchography, until high-resolution computed tomography(HRCT) enabled to measure noninvasively two dimensional airway area more accurately and reliably. Method: To investigate airway area responses to bronchial provocation with methacholine and evaluate the major sites of bronchial constriction in patients with bronchial asthma. We examined HRCT scans in five patients with bronchial asthma who had significant bronchoconstriction(20% or more decrease in $FEV_1$) using CT scanner(5,000T CT, Shimadzu Co, Japan) before and in 3~5 min. after methacholine inhalation. Airways which were matched by parenchymal anatomic landmarks in each patient before and after methacholine inhalation were measured using film scanner(TZ-3X scanner; Truvel Co. Chatsworth CA, USA) and a semiautomated region growing method. Results: 1) We identified 9 to 12 airways in each patient which were matched by parenchymal anatomic landmarks before and after methacholine inhalation. 2) Airway responses to methacholine are quite different even in a patient. 3) The constriction of small airways(average diameter <2 mm; area < $3.14mm^2$) was 48.7%(8.3; SEM, n=43), being more prominant than that of large airways(average diameter >2 mm; area > $3.14mm^2$), 53.8% (4.4;SEM, n=10), but not significantly different(p>0.05). 4) There was no significant difference in the degree of constriction between upper(44.3% +5.8; mean + SEM, n=30) and lower lung regions(56.7% +4.5, n=23). Conclusions: Thus airway responses to methacholine bronchoprovocation is quite variable in a patient with bronchial asthma and has no typical pattern in patients with bronchial asthma.

• The Korean Journal of Nuclear Medicine
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• v.37 no.4
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• pp.235-244
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• 2003

Purpose: Attention deficit hyperactivity disorder (ADHD) has been known as psychiatric disorder in childhood associated with dopamine dysregulation. In present study, we investigated changes in dopamine transporter (DAT) density of the basal ganglias using I-123 N-(3-iodopropen-2-yl) -2-carbomethoxy-3beta-(4-chlorophenyl) tropane [I-123 IPT] SPECT in children with ADHD before and after methylphenidate treatment. Materials and Method: Nine drug-naive children with ADHD and seven normal children were included in the study. We peformed brain SPECT two hours after the intravenous administration of I-123 IPT and made both quantitative and qualitative analyses using the obtained SPECT data, which were reconstructed for the assessment of soecific/nonspecific DAT binding ratios in the basal ganglia. All children with ADHD reperformed [123I]IPT SPECT after treatment with methylphenidate(0.7mg/kg/d) during about 8 weeks. SPECT data reconstructed for the assessment of specific/nonspecific DAT binding ratio of the basal ganglia were compared between before and after treatment methylphenidate. We investigated correlation between the change of ADHD symptom severity assessed with ADHD rating scale-IV and specific/nonspecific DAT binding ratio of basal ganglia. Results: Children with ADHD had a significantly greater specificinonspecific DAT binding ratio of the basal ganglia comparing to normal children(Right : z = 2.057, p = 0.041 : Left : z : 2.096, p = 0.032). Under treatment with methylphenidate in all children with ADHD, specificinonspecific DAT binding ratio of both basal ganglia decreased significantly greater than before treatment with methylphenidate (Right : t = 3.239, p = 0.018 ; Left : t = 3.133, p = 0.020). However, no significant correlation between the change of ADHD symptom severity scores and specific/nonspecific DAT binding ratio of the basal ganglia were found. Conclusions: These findings support the complex dysregulation of the dopaminergic neurotransmitter system in children with ADHD.

• Tuberculosis and Respiratory Diseases
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• v.44 no.4
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• pp.729-741
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• 1997

Background : We have recently reported that airway epithelial cells can produce RANTES and IL-8 in response to the stimulation of tubercle bacilli suggesting a certain role of airway epithelial cells in the pathogenesis of pulmonary tuberculosis. The pathogenesis of tuberculosis is determined by several factors including phagocytosis, immunological response of host, and virulence of tubercle bacilli. Interestingly, there have been reports suggesting that difference in immunological response of host according to the virulence of tubercle bacilli may be related with the pathogenesis of tuberculosis. We, therefore, studied the expressions and productions of RANTES and IL-8 in airway epithelial cells in response to tubercle bacilli(H37Rv, virulent strain and H37Ra, avirulent strain), in order to elucidate the possible pathophysiology of pulmonary tuberculosis. Methods : Peripheral blood monocytes were isolated from normal volunteers. Peripheral blood monocytes (PBM) were stimulated with LPS($10{\mu}g/ml$), H37Rv, or H37Ra($5{\times}10^5$ bacilli/well) along with normal control for 24 hours. A549 cells were stimulated with supernatants of cultured PBM for 24 hours. ELISA kit was used for the measurement of $TNF{\alpha}$ and IL-$1{\beta}$ production in supernatants of cultured PBM and for the measurement of RANTES and IL-8 in supernatants of cultured A549 cells. Northern blot analysis was used for the measurement of RANTES and IL-8 mRNA expression in cultured A549 cells. Results : $TNF{\alpha}$ and IL-$1{\beta}$ productions were increased in cultured PBM stimulated with LPS or tubercle bacilli(H37Rv or H37Ra) compared with the control. There was, however, no difference in $TNF{\alpha}$ and IL-$1{\beta}$ production between cultured PBM stimulated with H37Rv and H37Ra. RANTES and IL-8 expressions and productions were also increased in cultured A549 cells stimulated with LPS or tubercle bacilli compared with the control. RANTES and IL-8 mRNA expressions were significantly increased in cultured A549 cells stimulated with H37Ra-conditioned media(CM) compared with A549 cells stimulated with H37Rv-CM (p<0.05). However, there was no difference in RANTES and IL-8 productions between A549 cells stimulated with H37Rv-CM and H37Ra-CM. Conclusion : Airway epithelial cells can produce the potent chemokines such as RANTES and IL-8, in response to the stimulation of tubercle bacilli. These results suggest that airway epithelial cells may play a certain role in the pathogenesis of pulmonary tuberculosis. However, the role of airway epithelial cells in the pathogenesis of tuberculosis according to the virulence of tubercle bacilli was not clear in this study.

• Nuclear Medicine and Molecular Imaging
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• v.41 no.1
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• pp.9-15
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• 2007

Purpose: Repetitive transcranial magnetic stimulation (rTMS) has recently been clinically applied in the treatment of drug resistant depressed patients. There are mixed findings about the efficacy of rTMS on depression. Furthermore, the influence of rTMS on the physiology of the brain is not clear. We prospectively evaluated changes of regional cerebral blood flow (rCBF) between pre- and post-rTMS treatment in patients with drug resistant depression. Materials and Methods: Twelve patients with drug-resistant depression (7 male, 5 female; age range: $19{\sim}52$ years; mean age: $29.3{\pm}9.3$ years) were given rTMS on right prefrontal lobe with low frequency (1 Hz) and on left prefrontal lobe with high frequency (20 Hz), with 20-minute-duration each day for 3 weeks. Tc-99m ECD brain perfusion SPECT was obtained before and after rTMS treatment. The changes of cerebral perfusion were analyzed using statistical parametric mapping (SPM; t=3.14, uncorrected p<0.01, voxel=100). Results: Following areas showed significant increase in rCBF after 3 weeks rTMS treatment: the cingulate gyrus, fusiform gyrus of right temporal lobe, precuneus, and left lateral globus pallidus. Significant decrement was noted in: the precental and middle frontal gyrus of right frontal lobe, and fusiform gyrus of left occipital lobe. Conclusion: Low-frequency rTMS on the right prefrontal cortex and high-frequency rTMS on the left prefrontal cortex for 3 weeks as an add-on regimen have increased and decreased rCBF in the specific brain regions in drug-resistant depressed patients. Further analyses correlating clinical characteristics and treatment paradigm with functional imaging data may be helpful in clarifying the pathophysiology of drug-resistant depressed patients.

• Tuberculosis and Respiratory Diseases
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• v.45 no.6
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• pp.1236-1251
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• 1998

Background : TNF-$\alpha$ appears to be a central mediator of the host response to sepsis. While TNF-$\alpha$ is mainly considered a proinflammatory cytokine, it can also act as a direct cytotoxic cytokine. However, there are not so many studies about the relationship bet ween TNF-$\alpha$ level and lung injury severity in ALI, particularly regarding the case of ALI caused by direct lung injury such as diffuse pulmonary infection. Recently, a natural defense mechanism, known as the stress response or the heat shock response, has been reported in cellular or tissue injury reaction. There are a number of reports examining the protective role of pre-induced heat stress proteins on subsequent LPS-induced TNF-$\alpha$ release from monocyte or macrophage and also on subsequent LPS-induced ALI in animals. However it is not well established whether the stress protein synthesis such as HSP can be induced from rat alveolar macrophages by in vitro or in vivo LPS stimulation. Methods : We measured the level of TNF-$\alpha$, the percentage of inflammatory cells in bronchoalveolar lavage fluid, protein synthesis in alveolar macrophages isolated from rats at 1, 2, 3, 4, 6, 12, and 24 hours after intratracheal LPS instillation. We performed histologic examination and also obtained histologic lung injury index score in lungs from other rats at 1, 2, 3, 4, 6, 12, 24 h after intratracheal LPS instillation. Isolated non-stimulated macrophages were incubated for 2 h with different concentration of LPS (0, 1, 10, 100 ng/ml, 1, or 10 ${\mu}g/ml$). Other non-stimulated macrophages were exposed at $43^{\circ}C$ for 15 min, then returned to at $37^{\circ}C$ in 5% CO2-95% for 1 hour, and then incubated for 2 h with LPS (0, 1, 10, 100ng/ml, 1, or 10 ${\mu}g/ml$). Results : TNF-$\alpha$ levels began to increase significantly at 1 h, reached a peak at 3 h (P<0.0001), began to decrease at 6 h, and returned to control level at 12 h after LPS instillation. The percentage of inflammatory cells (neutrophils and alveolar macrophages) began to change significantly at 2 h, reached a peak at 6 h, began to recover but still showed significant change at 12 h, and showed insignificant change at 24 h after LPS instillation compared with the normal control. After LPS instillation, the score of histologic lung injury index reached a maximum value at 6 h and remained steady for 24 hours. 35 kDa protein band was newly synthesized in alveolar macrophage from 1 hour on for 24 hours after LPS instillation. Inducible heat stress protein 72 was not found in any alveolar macrophages obtained from rats after LPS instillation. TNF-$\alpha$ levels in supernatants of LPS-stimulated macro phages were significantly higher than those of non-stimulated macrophages(p<0.05). Following LPS stimulation, TNF-$\alpha$ levels in supernatants were significantly lower after heat treatment than in those without heat treatment (p<0.05). The inducible heat stress protein 72 was not found at any concentrations of LPS stimulation. Whereas the 35 kDa protein band was exclusively found at dose of LPS of 10 ${\mu}g/ml$. Conclusion : TNF-$\alpha$ has a direct or indirect close relationship with lung injury severity in acute lung injury or acute respiratory distress syndrome. In vivo and in vitro LPS stimulation dose not induce heat stress protein 72 in alveolar macrophages. It is likely that 35 kDa protein, synthesized by alveolar macrophage after LPS instillation, does not have a defense role in acute lung injury.

• Tuberculosis and Respiratory Diseases
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• v.59 no.3
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• pp.286-297
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• 2005

Background : Non-small cell lung cancer (NSCLC) is a common cause of cancer-related death in North America and Korea, with an overall 5-year survival rate of between 4 and 14%. The TNM staging system is the best prognostic index for operable NSCLC . However, epidermal growth factor receptor (EGFR), matrix metalloproteinase-9(MMP-9), and C-erbB-2 have all been implicated in the pathogenesis of NSCLC and might provide prognostic information. Methods : Immunohistochemical staining of 81 specimens from a resected primary non-small cell lung cancer was evaluated in order to determine the role of the biological markers on NSCLC . Immunohistochemical staining for EGFR, MMP-9, and C-erbB-2 was performed on paraffin-embedded tissue sections to observe the expression pattern according to the pathologic type and surgical staging. The correlations between the expression of each biological marker and the survival time was determined. Results : When positive immunohistochemical staining was defined as the extent area>20%(more than Grade 2), the positive rates for EGFR, MMP-9, and C-erbB-2 staining were 71.6%, 44.3%, and 24.1% of the 81 patients, respectively. The positive rates of EGFR and MMP-9 stain for NSCLC according to the surgical stages I, II, and IIIa were 75.0% and 41.7%, 66.7% and 47.6%, and 76.9% and 46.2%, respectively. The median survival time of the EGFR(-) group, 71.8 months, was significantly longer than that of the EGFR(+) group, 33.5 months.(p=0.018, Kaplan-Meier Method, log-rank test).. The MMP-9(+) group had a shorter median survival time than the MMP-9(-) group, 35.0 and 65.3 months, respectively (p=0.2). The co-expression of EGFR and MMP-9 was associated with a worse prognosis with a median survival time of 26.9 months, when compared with the 77 months for both negative-expression groups (p=0.0023). There were no significant differences between the C-erbB-2(+) and C-erbB-2 (-) groups. Conclusion : In NSCLC, the expression of EGFR might be a prognostic factor, and the co-expression of EGFR and MMP-9 was found to be associated with a poor prognosis. However, C-erbB-2 expression had no prognostic significance.

• Tuberculosis and Respiratory Diseases
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• v.44 no.4
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• pp.822-835
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• 1997

Background : There have been many in vitro evidences that interleukin-4(IL-4) might be the most important cytokine inducing IgE synthesis from B-cells, and interferon-gamma(IFN-$\gamma$) might be a main cytokine antagonizing IL-4-mediated IgE synthesis. Recently some reports demonstrated that IFN-$\gamma$ might be used as a new therapeutic modality in some allergic diseases with high serum IgE level, such as atopic dermatitis or bronchial asthma. To evaluate the in vivo effect of IFN-$\gamma$ in bronchial asthma we tried a clinical study. Methods : Fifty bronchial asthmatics(serum IgE level over 200 IU/ml) who did not respond to inhaled or systemic corticosteroid treatment, and 17 healthy nonsmoking volunteers were included in this study. The CD 23 expressions of peripheral B-cells, the IL-4 activities of peripheral T-cells, the serum soluble CD23(sCD23) levels, and the superoxide anion(${O_2}^-$) generations by peripheral PMN were compared between bronchial asthmatics and normal subjects. The IL-4 activities of peripheral T-cells were analyzed by T-cell supernatant (T-sup)-induced CD23 expression from tonsil B-cells. In bronchial asthmatics the serum IgE levels and histamine $PC_{20}$ in addition to the above parameters were also compared before and after IFN-$\gamma$ treatment. IFN-$\gamma$ was administered subcutaneously with a weekly dose of 30,000 IU per kilogram of body weight for 4 weeks. Results : The ${O_2}^-$ generations by peripheral PMNs in bronchial asthmatics were higher than normal subjects($8.23{\pm}0.94$ vs $5.00{\pm}0.68\;nmol/1{\times}10^6$ cells, P<0.05), and significantly decreased after IFN-$\gamma$ treatment compared to initial values($3.69{\pm}0.88$ vs $8.61{\pm}1.53\;nmol/1{\times}10^6$ cells, P<0.05). CD23 expression of peripheral B-cells in bronchial asthmatics was higher than normal subjects($47.47{\pm}2.96%$, vs $31.62{\pm}1.92%$, P<0.05), but showed no significant change after IFN-$\gamma$ treatment. The serum sCD23 levels in bronchial asthmatics were slightly higher than normal subjects($191.04{\pm}23.3\;U/ml$ vs $162.85{\pm}4.85\;U/ml$), and 11(64.7%) of 17 patients showed a decreasing pattern in their serum sCD23 levels after IFN-$\gamma$ treatment. However the means of serum sCD23 levels were not different before and after IFN-$\gamma$ treatment. The IL-4 activities of peripheral T-cells in bronchial asthmatics were slightly higher than normal subjects($22.48{\pm}6.81%$ vs $18.90{\pm}2.43%$), and slightly increased after IFN-$\gamma$ treatment($27.90{\pm}2.56%$). Nine(60%) of 15 patients showed a decreasing pattern in their serum IgE levels after IFN-$\gamma$ treatment. And the levels of serum IgE were significantly decreased after IFN-$\gamma$ treatment compared to initial values ($658.67{\pm}120.84\;IU/ml$ vs $1394.32{\pm}314.42\;IU/ml$, P<0.05). Ten(83.3%) of 12 patients showed an improving pattern in bronchial hyperresponsiveness after IFN-$\gamma$ treatment, and the means of histamine $PC_{20}$ were significantly increased after IFN-$\gamma$ treatment compared to initial values ($1.22{\pm}0.29mg/ml$ vs $0.69{\pm}0.17mg/ml$, P<0.05). Conclusion : Our results suggest that IFN-$\gamma$ may be useful as well as safety in the treatment of bronchial asthmatics with high serum IgE level and that in vivo effects of IFN-$\gamma$ may be different from its in vitro effects on the regulations of IgE synthesis or the respiratory burst of PMN.