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Inhibition of Neointima Formation and Migration of Vascular Smooth Muscle Cells by Anti-vascular Endothelial Growth Factor Receptor-1 (Flt-4) Peptide in Diabetic Rats (당뇨병 쥐에서 혈관내피 성장인자 수용체-1 차단 펩타이드를 이용한 신내막 형성과 혈관평활근세포 이동의 억제)

  • Jo, Min-Seop;Yoo, Ki-Dong;Park, Chan-Beom;Cho, Deog-Gon;Cho, Kue-Do;Jin, Ung;Moon, Kun-Woong;Kim, Chul-Min;Wang, Young-Pil;Lee, Sun-Hee
    • Journal of Chest Surgery
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    • v.40 no.4 s.273
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    • pp.264-272
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    • 2007
  • Background: Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis, including stimulating the proliferation and migration of vascular smooth muscle cells (VSMCs). It has been known that diabetes is associated with accelerated cellular proliferation via VEGF, as compared to that under a normal glucose concentration. We investigated the effects of selective blockade of a VEGF receptor by using anti-Flt-1 peptide on the formation and hyperplasia of the neointima in balloon injured-carotid arteries of OLETF rats and also on the in vitro VSMCS' migration under high glucose conditions. Material and Method: The balloon-injury method was employed to induce neointima formation by VEGF. For f4 days beginning 2 days before the ballon injury, placebo or vascular endothelial growth factor receptor-1 (VEGFR-1) specific peptide (anti-Flt-1 peptide), was injected at a dose of 0.5mg/kg daily into the OLETF rats. At 14 days after balloon injury, the neointimal proliferation and vascular luminal stenosis were measured, and cellular proliferation was assessed by counting the proliferative cell nuclear antigen (PCNA) stained cells. To analyze the effect of VEGF and anti-Flt-1 peptide on the migration of VSMCs under a high glucose condition, transwell assay with a matrigel filter was performed. And finally, to determine the underlying mechanism of the effect of anti-Flt-1 peptide on the VEGF-induced VSMC migration in vitro, the expression of matrix metalloproteinase (MMP) was observed by performing reverse transcription-polymerase chain reaction (RT-PCR). Result: Both the neointimal area and luminal stenosis associated with neointimal proliferation were significantly decreased in the anti-Flt-1 peptide injected rats, ($0.15{\pm}0.04 mm^2$ and $ 36.03{\pm}3.78%$ compared to $0.24{\pm}0.03mm^2\;and\;61.85{\pm}5.11%$, respectively, in the placebo-injected rats (p<0.01, respectively). The ratio of PCNA(+) cells to the entire neointimal cells was also significantly decreased from $52.82{\pm}4.20%\;to\;38.11{\pm}6.89%$, by the injected anti-Flt-1 peptide (p<0.05). On the VSMC migration assay, anti-Flt-1 peptide significantly reduced the VEGF-induced VMSC migration by about 40% (p<0.01). Consistent with the effect of anti-Flt-1 peptide on VSMC migration, it also obviously attenuated the induction of the MMP-3 and MMP-9 mRNA expressions via VEGF in the VSMCS. Conclusion: Anti-Flt-1 peptide inhibits the formation and hyperplasia of the neointima in a balloon-injured carotid artery model of OLETF rats. Anti-Flt-1 peptide also inhibits the VSMCs' migration and the expressions of MMP-3 and MMP-9 mRNA induced by VEGF under a high glucose condition. Therefore, these results suggest that specific blockade of VEGFR-1 by anti-Flt-1 peptide may have therapeutic potential against the arterial stenosis of diabetes mellitus patients or that occurring under a high glucose condition.

Study on the Short-Term Hemodynamic Effects of Experimental Cardiomyoplasty in Heart Failure Model (심부전 모델에서 실험적 심근성형술의 단기 혈역학적 효과에 관한 연구)

  • Jeong, Yoon-Seop;Youm, Wook;Lee, Chang-Ha;Kim, Wook-Seong;Lee, Young-Tak;Kim, Won-Gon
    • Journal of Chest Surgery
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    • v.32 no.3
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    • pp.224-236
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    • 1999
  • Background: To evaluate the short-term effect of dynamic cardiomyoplasty on circulatory function and detect the related factors that can affect it, experimental cardiomyoplasties were performed under the state of normal cardiac function and heart failure. Material and Method: A total of 10 mongrel dogs weighing 20 to 30kg were divided arbitrarily into two groups. Five dogs of group A underwent cardiomyoplasty with latissimus dorsi(LD) muscle mobilization followed by a 2-week vascular delay and 6-week muscle training. Then, hemodynamic studies were conducted. In group B, doxorubicin was given to 5 dogs in an IV dose of 1 mg/kg once a week for 8 weeks to induce chronic heart failure, and simultaneous muscle training was given for preconditioning during this period. Then, cardiomyoplasties were performed and hemodynamic studies were conducted immediately after these cardiomyoplasties in group B. Result: In group A, under the state of normal cardiac function, only mean right atrial pressure significantly increased with the pacer-on(p<0.05) and the left ventricular hemodynamic parameters did not change significantly. However, with pacer-on in group B, cardiac output(CO), rate of left ventricular pressure development(dp/dt), stroke volume(SV), and left ventricular stroke work(SW) increased by 16.7${\pm}$7.2%, 9.3${\pm}$3.2%, 16.8${\pm}$8.6%, and 23.1${\pm}$9.7%, respectively, whereas left ventricular end-diastole pressure(LVEDP) and mean pulmonary capillary wedge pressure(mPCWP) decreased by 32.1${\pm}$4.6% and 17.7${\pm}$9.1%, respectively(p<0.05). In group A, imipramine was infused at the rate of 7.5mg/kg/hour for 34${\pm}$2.6 minutes to induce acute heart failure, which resulted in the reduction of cardiac output by 17.5${\pm}$2.7%, systolic left ventricular pressure by 15.8${\pm}$2.5% and the elevation of left ventricular end-diastole pressure by 54.3${\pm}$15.2%(p<0.05). With pacer-on under this state of acute heart failu e, CO, dp/dt, SV, and SW increased by 4.5${\pm}$1.8% and 3.1${\pm}$1.1%, 5.7${\pm}$3.6%, and 6.9${\pm}$4.4%, respectively, whereas LVEDP decreased by 11.7${\pm}$4.7%(p<0.05). Comparing CO, dp/dt, SV, SW and LVEDP that changed significantly with pacer-on, both under the state of acute and chronic heart failure, augmentation widths of these left ventricular hemodynamic parameters were significantly larger under the state of chronic heart failure(group B) than acute heart failure(group A)(p<0.05). On gross inspection, variable degrees of adhesion and inflammation were present in all 5 dogs of group A, including 2 dogs that showed no muscle contraction. No adhesion and inflammation were, however, present in all 5 dogs of group B, which showed vivid muscle contractions. Considering these differences in gross findings along with the following premise that the acute heart failure state was not statistically different from the chronic one in terms of left ventricular parameters(p>0.05), the larger augmentation effect seen in group B is presumed to be mainly attributed to the viability and contractility of the LD muscle. Conclusion: These results indicate that the positive circulatory augmentation effect of cardiomyoplasty is apparent only under the state of heart failure and the preservation of muscle contractility is important to maximize this effect.

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Postoperstive Chemoradiotherapy in Locally Advanced Rectal Cancer (국소 진행된 직장암에서 수술 후 화학방사선요법)

  • Chai, Gyu-Young;Kang, Ki-Mun;Choi, Sang-Gyeong
    • Radiation Oncology Journal
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    • v.20 no.3
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    • pp.221-227
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    • 2002
  • Purpose : To evaluate the role of postoperative chemoradiotherapy in locally advanced rectal cancer, we retrospectively analyzed the treatment results of patients treated by curative surgical resection and postoperative chemoradiotherapy. Materials and Methods : From April 1989 through December 1998, 119 patients were treated with curative surgery and postoperative chemoradiotherapy for rectal carcinoma in Gyeongsang National University Hospital. Patient age ranged from 32 to 73 years, with a median age of 56 years. Low anterior resection was peformed in 59 patients, and abdominoperineal resection in 60. Forty-three patients were AJCC stage II and 76 were stage III. Radiation was delivered with 6 MV X rays using either AP-PA two fields, AP-PA both lateral four fields, or PA both lateral three fields. Total radiation dose ranged from 40 Gy to 56 Gy. In 73 patients, bolus infusions of 5-FU $(400\;mg/m^2)$ were given during the first and fourth weeks of radiotherapy. After completion of radiotherapy, an additional four to six cycles of 5-FU were given. Oral 5-FU (Furtulone) was given for nine months in 46 patients. Results : Forty $(33.7\%)$ of the 119 patients showed treatment failure. Local failure occurred in 16 $(13.5\%)$ patients, 1 $(2.3\%)$ of 43 stage II patients and 15 $(19.7\%)$ of 76 stage III patients. Distant failure occurred in 31 $(26.1\%)$ patients, among whom 5 $(11.6\%)$ were stage II and 26 $(34.2\%)$ were stage III. Five-year actuarial survival was $56.2\%$ overall, $71.1\%$ in stage II patients and $49.1\%$ in stage III patients (p=0.0008). Five-year disease free survival was $53.3\%$ overall, $68.1\%$ in stage II and $45.8\%$ in stage III (p=0.0006). Multivariate analysis showed that T stage and N stage were significant prognostic factors for five year survival, and that T stage, N stage, and preoperative CEA value were significant prognostic factors for five year disease free survival. Bowel complication occurred in 22 patients, and was treated surgically in 15 $(12.6\%)$, and conservatively in 7 $(5.9\%)$. Conclusion : Postoperative chemoradiotherapy was confirmed to be an effective modality for local control of rectal cancer, but the distant failure rate remained high. More effective modalities should be investigated to lower the distant failure rate.

Correlates of Subjective Well-being in Korean Culture (한국문화에서 주관안녕에 영향을 미치는 사회심리 요인들)

  • Hahn, Doug-Woong
    • Korean Journal of Culture and Social Issue
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    • v.12 no.5_spc
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    • pp.45-79
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    • 2006
  • The purpose of this paper was to review the results of the subjective well-being(swb) studies performed by Hahn and coworkers in Korean culture. As the correlates of swb, we dealt with demographic/individual difference variables, intrapersonal variables, interpersonal process variables, and Korean cultural variables. We proposed that the components of swb were consisted of quality of life(cognitive swb) and overall happy feelings about one's own life(emotional swb). It was also assumed that a measure of total swb could be calculated by summated mean of cognitive swb and emotional swb measures. The data of the swb studies were analyzed and interpreted according to the above three measures of swb. The results of a nationwide survey(Hahn, 2004) from age of 19 to 75 years ald(n=2,230) showed significant simple correlation coefficients between the following demographic/individual difference variables and swb: Gender difference in swb was found(total swb r=.08, p<.001; life satisfaction r=.10, p<.001; overall emotional swb r=.05, p<.05). Men were happier than women in terms of all three measures of swb. It was also found that women appeared to experience greater positive and negative emotions. Correlation between age and emotional swb(r=.09, p<.001) was significant, but life satisfaction was not significant(r=.04, n.s). Correlations between economic status and swb were also significant(total swb r =.23, p<.001; life satisfaction r=.15 p<.001; overall emotional swb r=.15, p<.001l). Although existence of father was negatively related to emotional swb(r=-.05, p<.05), the existence of mother was not related to any of swb measures. Similarly existence of brothers was related positively to overall emotional swb, but existence of sisters was not. Though existence of son was not related to swb, daughter contributed negatively to swb(total swb -.12, p<.01; life satisfaction -.09, p<.05; emotional swb r=-.12, p<.01). We assumed that family member-in-Iaw also contributed to swb because the extended dose social networks were important in Korean culture. The results showed that the following family member-in-law variables were related to swb: Parents-in-law(total swb r=.11, p<.01; life satisfaction r=.10, p<.01; emotional swb r=.10, p<.01), father-in-law(total swb r=.11, p<.01; life satisfaction r=.11, p<.01; emotional swb r=.06, n.s). The result suggested that especially father-in-law contributed to swb through financial and social support. Correlations between emotional experiences in everyday life and swb were also presented. The range of correlation coefficients between the positive emotion measures and swb were r=.30~.48(p<.001) when the above two measures obtained at same time. But the range decreased to r=.19~32(p<.001) when the swb measure was obtained 9 month later longitudinally. Intercorrelations between positive emotional experience; and life satisfaction were r=.37~58(p<.001) when two measures were obtained at same time. We also examined the effects of the intrapersonal cognitive responses to the most stressful life event upon swb. The results of nationwide survey(n=1,021) showed that self-disclosure(total swb r=.09, p<.010; life satisfaction r=.10, p<.01; emotional swb r=.07, p<.01), rumination(total swb r=-.17, p<.001), thought avoidance(total swb r=.12, p<.001; life satisfaction r=-.08; emotional swb r=-.12, p<.001) and suppression(total swb r=-.13, p<.001; life satisfaction r=-.08, p<.05: emotional swb r=-.13, p<.001) contributed to swb. It was also suggested that mismatch between self-guide and regulatory focus contributed negatively to emotional swb. It was also found that social comparison motives and fulfillment of the motives contributed to swb. The results of a survey research(n=363 college students) revealed that the higher the general social comparison motive, the lower the swb(total swb r=-.15, P<.01: life satisfaction r=-.17. p<.01; emotional swb r=-.10, p<.05). It was also found that satisfaction level of self-evalution motive contributed positively to swb(total swb r=-.14. p<.01: life satisfaction r=-.12, p<.05; emotional swb r=.15, p<.001). Both of self-improvement motive(r=.13, p<.05) and satisfaction level of self-improvement motive(r=.12, p<.05) contributed positively to emotional swb, respectively. The above results suggested that swb was depended upon the interaction effect of social comparison motive; and level of fulfillment of the motives. We also reported the significant multiple predictors of swb in a sample of age from 60years to 89years olds. The results of multiple regression analysis showed that the significant multiple predictors of swb were past illness(β=.174, p<.001), economic status(β=.418, p<.001), marital satisfaction(β=.0841, p<.001), satisfaction of offsprins(β=.065, p<.01), expectation level of social support from offsprings(β=-.049, p<.001), and negative emotions(β=-.454. p<.001) among 16 social psychological factors. It was also found that swb was an important multiple predictors of physical health. This finding was replicated in a longitudinal study. Both of positive and negative emotional experiences were significant multiple predictors of physical health one year later. The results of the discriminant analysis showed both of total swb and positive emotional experiences contributed to discriminate the happy and healthy olds from unhappy and unhealthy olds. We paper also examined the effects of the nonnative social behaviors upon swb in Korean culture. The main hypotheses of the study(Hahn, 2006, in press) was that the important nonnative behaviors would influence on swb through both of the mediation processes of adjustment to social relationships and psychological stress. The survey data were collected from 2,129 adults age of 19 to 75, from 7 regional areas in Korea. The results of the study revealed that almost all of correlation coefficients between 15 normative social behaviors and the above three criteria w-ere significant. The fitness test results of the covariance structural equation model showed that all of the fitness indices were satisfactory (GFI=.974, AGFI=.909, NNFI=.922, NFI=.973, CFI=.974. RMR=.049, RMSEA=.073). The results of the analysis revealed that the following five path coeffi6ents from behaviors to social adjustment were significant; behavior tor family and family members(t=5.87, p<.001), courteous behavior(t=4.39, p<.001), faithful behavior (t=2.15. p<.05). collectivistic behavior(t=8.31, p<.001). Seven path coefficients from the normative behaviors to psychological stress were significant; behavior for family and family members (t=-4.63, p<.001), faithful behavior(t=-3.86, p<.001). suppression of emotional expression(t=3.99, p<.001), trustworthy and dependable behavior(t=-2.21, p<.05), collectivistic behavior(t=3.72, p<.001), effortful and diligent behavior(t=2.94, p<.001), husbandry and saving behavior(t=3.40, p<.001). The above results suggested that four normative behaviors among seven behaviors contributed negatively to psychological stress in current Korean society. The results abo confirmed the hypothesized paths from social adjustment (t=10.40, p<.001) to swb and from psychological stress(t=-19.74, p<.001) to swb. The important results of the study were discussed in terms of the Confucian traditions and recent social changes in Korean culture. Finally limitations of this review paper were discussed and the suggestions for the future study were also proposed.