Effect of Nanoparticle with VEGF in Mouse Ischemic Hindlimb Model

Purpose: Vascular endothelial growth factor (VEGF) is one of the factors regulating angiogenesis. For angiogenesis, the local concentration of VEGF has to be maintained. Because of its short half-life, VEGF has been conjugated with nanoparticles. Some nanoparticles, such as poly (lactic-co-glycolic acid (PLGA)) or polyethylenimine (PEI) are commonly used in this field, but have weak points such as faster release than expected and cell toxicity. We investigated the effect of core/shell nanoparticles including lecithin lipid cores in the ischemic hindlimb model. Methods: Mice were anesthetized and a region of the common femoral artery and vein was ligated and excised. Hindlimb ischemic mice (n=28) were divided randomly into four groups: Control group (normal saline, n=7), mouse VEGF group (mVEGF, n=7), nanoparticle including mVEGF group (N-mVEGF, n=7), and nanoparticle/hydrogel mouse VEGF group (NH-mVEGF, n=7). The drug was injected postoperatively into the thigh muscle of the ischemic limb. Perfusion, capillary number and H&E stain were assessed 28 d after treatment. Results: The capillary number increased in N-mVEGF and mVEGF group (P=0.026). Improvements of ischemic limb perfusion were inferior in N-mVEGF, NH-mVEGF groups (P=0.006) compared to other groups. Mice received N-mVEGF, NH-mVEGF treatment showed significant inflammation in the H&E staining. Conclusion: Sustained VEGF delivery via core/shell nanoparticle with lecithin core did not show improved perfusion rate despite an increase in capillary number. Furthermore, vacuolization and induction of inflammation requiring a different composition of nanoparticle should be tested. 말초 동맥 질환의 유병률은 3∼10%이고 70세 이상에선 15∼20%로 현재처럼 고령 인구가 증가할수록 환자수는 더욱 늘어날 전망이다.(1) 이들 중 병변의 위치에 따라 수술적 치료가 도움이 될 수도 있지만 혈관의 수술적 재건을 위해 필요한 자가 혈관의 한계로 제한되는 경우가 있으며,(2) 이 경우 혈관 신생은 증상 개선을 위한 또 하나의 치료 방법이 될 수 있다. 혈관 신생은 지난 30년 동안 심근경색, 상처 치유 지연, 신경병증, 망막병증, 이식 실패 등에서 병리학적으로 호전시킬 수 있는 치료 방법으로 고려되고 있다.(3-5) 혈관을 신생시키는 방법 중 vascular endothelial growth factor (VEGF)는 in vivo 실험에서 여러 차례 혈관 신생 효과를 입증했지만 정맥 투여 시 몇 가지 부작용을 보였다.(6) 더욱이 인체를 대상으로 시행된 VIVA 연구에서는 recombinant human VEGF의 정맥 투여는 위약 대조군과 비교 했을 때 통계학적으로 차이가 없었다.(7) 이 실험의 참여자 중 일부에서는 정맥을 통한 전신 투여로 비특이적인 혈관 신생과 고혈압, 부종 등의 부작용을 보였다.(8-10)그러므로 VEGF의 최적의 치료 효과를 얻기 위해서는 정맥을 통한 전신 투여 보다는 국소적이면서 지속적인 분비가 필요할 것이며 이를 위해 새로운 형태의 약물전달체계가 요구 된다.(11) 나노입자(nanoparticle)에 VEGF를 결합하면 약물이 서방형으로 수일에서 수주간 분비되어 지속적으로 근위부위에 혈관 신생을 자극할 것이다.(12,13) 나노입자는 미세분자(micromolecule)보다 더 효과적으로 세포에 의 해 섭취되며 손상 부위에 직접 투여가 가능하다.(14) 현재 다양한 종류의 나노입자가 연구되고 있으며 이 중 lecithin lipid core를 가진 core/shell 나노입자는 in vitro 실험에서 VEGF와 안정적으로 결합하여 지속적으로 VEGF를 방출하였다.(11)이 연구는 VEGF를 함유하고 있는 core/shell nanoparticle 를 이용하여 쥐의 허혈성 사지(ischemic limb)에서 치료 효과의 가능성을 보고자 하였다.본 연구는 교육과학기술부의 지원으로 이루어졌음(과제번호: 800-20080766).Choi WI, 2010, ACTA BIOMATER, V6, P2666, DOI 10.1016/j.actbio.2010.01.029Yang Z, 2009, VASC PHARMACOL, V51, P268, DOI 10.1016/j.vph.2009.07.001Hall H, 2007, CURR PHARM DESIGN, V13, P3597SURI SS, 2007, J OCCUP MED TOXICOL, V2, P16Oh KS, 2006, BIOMACROMOLECULES, V7, P2362, DOI 10.1021/bm060362kBussolati B, 2006, ANTIOXID REDOX SIGN, V8, P1153Hirsch AT, 2006, CIRCULATION, V113, pE463, DOI 10.1161/CIRCULATIONAHA.106.174526Jeon O, 2006, BIOMATERIALS, V27, P1598, DOI 10.1016/j.biomaterials.2005.08.030Dai CY, 2005, COLLOID SURFACE B, V41, P117, DOI 10.1016/j.colsurfb.2004.10.032Robertson D, 2004, J COLLOID INTERF SCI, V270, P187, DOI 10.1016/j.jcis.2003.09.013Zisch AH, 2003, CARDIOVASC PATHOL, V12, P295, DOI 10.1016/S1054-8807(03)00089-9Simons M, 2003, NAT REV DRUG DISCOV, V2, P863, DOI 10.1038/nrd1226Stern M, 2003, GENE THER, V10, P1282, DOI 10.1038/sj.gt.3301994Sinha VR, 2003, J CONTROL RELEASE, V90, P261, DOI 10.1016/S0168-3659(03)00194-9Henry TD, 2003, CIRCULATION, V107, P1359, DOI 10.1161/01.CIR.0000061911.47710.8AMartin A, 2003, MED RES REV, V23, P117, DOI 10.1002/med.10024Panyam J, 2002, FASEB J, V16Yang RH, 2002, HYPERTENSION, V39, P815Qaum T, 2001, INVEST OPHTH VIS SCI, V42, P2408Benns JM, 2001, J DRUG TARGET, V9, P123Murphy WL, 2000, BIOMATERIALS, V21, P2521Ferrara N, 1999, NAT MED, V5, P1359Godbey WT, 1999, J BIOMED MATER RES, V45, P268Ware JA, 1997, NAT MED, V3, P158Abdallah B, 1996, HUM GENE THER, V7, P1947FOLKMAN J, 1993, C R ACAD SCI 3, V316, P909RATNER BD, 1976, ACS SYM SER, V31, P1

Optimized Tacrolimus Therapy in the Early Stage after Renal Transplantation

Purpose: Immunosuppressive regimen based on reduced-dose Tacrolimus (TAC) is widely accepted in the field of renal transplantation. However, optimal targetsfor TAC whole blood trough concentrations during the early period after kidney transplantation remain uncertain. Methods: A total of 184 consecutive adult renal transplant recipients with triple immunosuppression (TAC/Mycophenolate/corticosteroid) were included in this study. According to the trough level of TAC at day 7 after transplantation, patients were classified as low TAC concentration (LT, 15 ng/ml, n=24) groups. Rate of acute rejection, graft function and side effects of TAC within 1 yr after transplantation were evaluated. Results: There was no difference in trough concentrations of TAC at 2 weeks, 1 month, 3 months, 6 months and 12 months after transplantation among the three groups. Significantly higher incidence of acute rejection within 2 weeks after transplantation was observed in LT group compared with IT and HT groups (17.4%, 5.6% and 4.8%, respectively, P=0.037). HT patients showed significantly better estimated glomerular filtration rates until 6 months after transplantation than IT and LT patients (75.5 +/- 24.8 vs. 63.8 +/- 12.8 and 64.3 +/- 15.2 ml/min at 6 months, P=0.03). There was no significant difference in TAC toxicity in terms of post-transplant diabetes and renal toxicity. Conclusion: Short-term high TAC exposure immediately after kidney transplantation may provide lower incidence of acute rejection and better restoration of graft function compared with low or intermediate TAC exposure. 지난 20여 년 간 장기이식 후의 면역억제요법에 많은 변화가 있었다. Tacrolimus (TAC)는 cyclosporine에 비해 단위 mg당 100배에 이르는 더욱 강력한 면역억제효과를 보이며 신장이식 후 급성 거부반응의 발생률을 유의하게 감소시키고 이식신의 기능 역시 더 좋은 것으로 알려져 현재 장기이식 후의 면역억제요법에서 가장 흔하게 사용되고 있다.(1-3) 실제 2006년의 보고에서 미국에서는 장기이식 후 유지 면역억제치료 중인 신장이식 환자 중 67%가 TAC를 쓰고 있다.(4) 신장, 간 및 골수이식 환자에서 시행된 약물역동학 연구들은 TAC의 혈중 최저농도(trough level)가 혈중 약물농도곡선하면적(area under the concentration-time curve)과 밀접한 상관관계가 있음을 보여주었고,(5,6) 따라서 TAC의 혈중 최저농도를 측정함으로써 적절한 약물 노출(drug exposure) 여부를 평가할 수 있다. 최근 TAC의 혈중 최저치 농도가 이식 후 급성거부반응의 발생과 유의한 관계가 있다는 보고가 있으나,(7,8) 아직까지 어느 수준으로 농도를 유지하는 것이 급성 거부반응과 약물 부작용의 발생을 예방하는 데 가장 적정한 것인가에 관한 명확한 연구보고는 없는 실정이다. 또한 급성 거부반응은 신장 이식편 손실의 가장 중요한 원인인 만성 거부반응(chronic rejection)의 발생에 주요한 위험 인자로 알려져 있으므로(9,10) 이러한 연구는 더욱 중요하다 할 수 있다. 따라서 본 연구에서는 신장이식 환자에서 일차 면역억제제로 TAC를 사용했던 환자에서 이식 후 초기의 TAC 혈중최저농도와 급성 거부반응 발생의 관련성 및 이식신의 기능에 대한 효과를 살펴보고 이식 후 초기의 적절한 TAC 혈중 최저농도를 확인하고자 하였다.본 과제는 한국노바티스(주)의 지원으로 이루어졌음(#0620051860).Borobia AM, 2009, THER DRUG MONIT, V31, P436Il Min S, 2009, NEPHROL DIAL TRANSPL, V24, P2584, DOI 10.1093/ndt/gfp192Opelz G, 2009, TRANSPLANTATION, V87, P795, DOI 10.1097/TP.0b013e318199c1c7Ekberg H, 2007, NEW ENGL J MED, V357, P2562Chang SH, 2007, TRANSPLANTATION, V84, P611, DOI 10.1097/01.tp.0000280553.23898.efSamaniego M, 2006, NAT CLIN PRACT NEPHR, V2, P688, DOI 10.1038/ncpneph0343MEIERKRIESCHE LIS, 2006, AM J TRANSPLANT, V6, P1111Webster AC, 2005, BRIT MED J, V331, P810, DOI 10.1136/bmj.38569.471007.AEGaspari F, 2004, AM J TRANSPLANT, V4, P1826, DOI 10.1111/j.1600-6143.2004.00579.xKuypers DRJ, 2004, CLIN PHARMACOL THER, V75, P434, DOI 10.1016/j.clpt.2003.12.009Pascual M, 2002, NEW ENGL J MED, V346, P580Kaplan B, 2002, THER DRUG MONIT, V24, P36Staatz C, 2001, NEPHROL DIAL TRANSPL, V16, P1905Racusen LC, 1999, KIDNEY INT, V55, P713Undre NA, 1999, TRANSPLANT P, V31, P296JUSKO WJ, 1995, THER DRUG MONIT, V17, P596IHARA H, 1995, INT J UROL, V2, P151LINDHOLM A, 1993, TRANSPLANTATION, V56, P307RANDHAWA PS, 1993, AM J SURG PATHOL, V17, P60

Acute Arterial Thromboembolism of Upper Extremity

Purpose: Acute, ischemia of the arm is uncommon compared with events in the leg and much less attention has been paid to the management of acute arterial thromboembolism of the upper extremities. The aim of this study was to evaluate the clinical aspects and treatment outcomes of acute upper extremity thromboembolism. Methods: From January 2007 to March 2010, seven patients underwent the management of upper extremity thromboembolism in three Seoul National University (SNU)-affiliated hospitals. We retrospectively reviewed the medical records. Results: The mean age was 64.6 years (range 48 similar to 93 years) and 4 patients (57.1%) were female. Distribution of the thromboembolism were 4 in brachial, 1 in axillary plus brachial, 1 in ulnar and radial, and 1 in axillary artery, respectively. Time from symptom onset to presentation was 3.5 days (range 1 similar to 10 days). Primary treatment modality were Fogarty catheter embolectomy in 3 cases, bypass surgery in 1 case, and urokinase thrombolysis in 2 cases. A patient without symptoms was treated conservatively. Patients receiving primary thrombolytic therapy underwent surgical approach due to recurred thromboembolism during admission. In our 11.2 months of mean follow-up, there was recurrence but 1 patient died from cerebral infarction after 1.5 year of discharge. Conclusion: In this study, functional outcome of acute upper extremity ischemia following appropriate treatments was excellent. Key features of treatment are shortening the time interval of diagnosis to primary treatment, proper anticoagulation, and treatment of underlying conditions. Larger-volume, long-term results and meta-analysis of upper extremity thromboembolism are required to establish standardized treatment in Korea. 급성 상지 동맥 혈전색전증은 드문 질환이며 하지 동맥혈전색전증에 비하여 1/4 정도의 낮은 빈도로 발생한다고 보고되고 있다.(1)상지 통증이나 창백, 맥박소실, 감각 이상, 마비 등의 급성 동맥폐색의 전형적인 증상을 호소하게 되며, 확진이 되면 빠른 시간 내에 중재적 시술 또는 수술을 필요로 하는 외과적 응급 질환이다. 그러나, 상지 동맥 혈전색전증은 발생 빈도가 낮기 때문에 환자가 내원하여 증상을 호소하는 초기 진료 단계에서 이 질환의 감별진단을 내리기가 쉽지 않고, 이로 인해 적절한 진단 방법의 선택이나 치료가 지연될 수 있다.(2)국내에서는 증례 보고 형식의 일부 보고만 있어 왔고,(3)외국에서도 수술적 또는 중재적 치료 이후의 장기적인 생존율이나 재발에 대한 연구가 이루어진 바가 거의 없는 실정이다. 저자들은 3개 병원 외과에서 경험한 급성 상지 동맥 혈전색전증에 대한 증례들의 임상양상, 치료 및 결과를 분석하여 향후 치료 지침을 확립하는데 도움이 되고자 본 연구를 시행하였다.Magishi K, 2010, ANN THORAC CARDIOVAS, V16, P31Edwards NM, 2009, CLIN J SPORT MED, V19, P331Rutherford RB, 2009, SEMIN VASC SURG, V22, P5, DOI 10.1053/j.semvascsurg.2008.12.003O`Connell JB, 2009, SEMIN VASC SURG, V22, P10, DOI 10.1053/j.semvascsurg.2008.12.004POUSIOS D, 2009, INTERACT CARDIOVASC, V9, P532Ueberrueck T, 2007, J CARDIOVASC SURG, V48, P181Karapolat S, 2006, SURG TODAY, V36, P416, DOI 10.1007/s00595-005-3156-7Licht PB, 2004, EUR J VASC ENDOVASC, V28, P508, DOI 10.1016/j.ejvs.2004.08.007Go AS, 2003, JAMA-J AM MED ASSOC, V290, P2685KIM KH, 2003, J KOREAN SOC VASC SU, V19, P139Hernandez-Richter T, 2001, LANGENBECK ARCH SURG, V386, P261KOYAMA T, 2000, JPN J VASC SURG, V9, P479Eyers P, 1998, BRIT J SURG, V85, P1340MARTINET O, 1994, HELV CHIR ACTA, V60, P875BERGQVIST D, 1983, WORLD J SURG, V7, P786KAIRALUOMA MI, 1976, ANN CHIR GYNAECOL FE, V65, P163FOGARTY TJ, 1971, AM J SURG, V122, P231

Differentiated Muscle-derived Stem Cells Attenuate Intimal Hyperplasia after Carotid Balloon Injury in Rat

Purpose: Although progenitor cells may contribute to intimal hyperplasia (IH) after arterial injury, positive contribution of IH is variable with type of injury or cells. This study was designed to examine whether differentiated muscle derived stem cells (MDSC) attenuate IH in rat. Methods: MDSCs were retrieved using preplate techniques from rat calf muscle and MDSCs (preplate 6th culture fraction, pp6) were exposed to VEGF (50 ng/ml) for endothelial differentiation prior to injection. Male rats were divided into two groups (cell treated vs. control) and underwent carotid balloon injury with 2-Fr catheter. The virus containing Green fluorescent protein (GFP) gene was transfected into cells for monitoring. Cells (5x10(6)) were indwelled into carotid artery for 30 minutes after injury and then blood flow was restored. Arteries were harvested at various intervals (1, 2 and 4 weeks) after injury. The intima to media thickness ratio (IMTR) was calculated with morphometric analysis. Results: Endothelial surface markers such as VE-CADHERIN were strongly expressed on differentiated MDSCs. At 4 weeks after injury, IH was predominantly observed in control group compared to cell treated group. The intensity of OFF was strongly observed at 1 week and declined at 4 weeks in carotid artery wall at MDSC group. CD31(+) endothelial cells were observed at MDSC group compared to control. The mean IMTR in cell treated groups were significantly lower than control at 2 weeks (P=0.005) and 4 weeks (P <= 0.001). Conclusion: Our study demonstrates that MDSCs therapy promotes re-endothelialization and leads to attenuation of IH after balloon injury in rat. 동맥 폐색질환 환자들에서 시행되는 많은 동맥 우회술 혹은 혈관 내 치료들이 초기의 우수한 성공률에도 불구하고 장기간 추적관찰 시 재협착 혹은 폐색을 흔히 보인다. 주요한 폐색원인으로 알려진 내막 증식증 내막손상 후 혈관 평활근 세포의 내막이동 및 증식과 결체조직의 침착으로 혈관내강의 협착이 초래되어 발생하며 상기 치료들의 실패요인으로 이해되었다.(1) 그러나 최근에 혈관전구세포의 발견 및 관련된 많은 연구를 통해서 내막 증식증을 초래하는 병태생리 개념이 새롭게 대두되었다. 즉 혈중, 조직, 혹은 골수 내에 존재하는 전구세포들이 혈관손상부위로 원격 이동하여 내막증식을 초래하는 주 세포원이라는 주장이 제기되고 있다. 그러나 전구세포들에 의한 내막증식연구는 손상모델에 따라서 혹은 전구세포들의 종류에 따라서 내막 증식의 억제 혹은 촉진 등의 다양한 결과를 나타내고 있다.(2) 저자들은 근육 내 존재하는 줄기세포를 내피세포로의 유도 후 백서 경동맥 손상부위에 투여하여 내막증식억 제 여부를 분석하고 그 기전을 규명하고자 본 연구를 시행하였다.이 논문은 2006년 정부의 재원으로 한국학술진흥재단의 지원을 받아 수행된 연구임(KFR-2006-331-E00155).Tsai S, 2009, J VASC SURG, V49, P502, DOI 10.1016/j.jvs.2008.07.060Okada M, 2008, J AM COLL CARDIOL, V52, P1869, DOI 10.1016/j.jacc.2008.07.064HUARD J, 2008, J MUSCULOSKELET NEU, V8, P337WANG CH, 2008, SS, V28, P54NA BG, 2008, J KOREAN SOC VASC SU, V24, P155Kang HJ, 2004, LANCET, V363, P751KONG D, 2004, SS, V109, P1769TANAKA K, 2003, SS, V93, P783GRIESE DP, 2003, SS, V108, P2710Qu-Petersen ZQ, 2002, J CELL BIOL, V157, P851, DOI 10.1083/jcb.200108150SATA M, 2002, SS, V8, P403WALTER DH, 2002, SS, V105, P3017Tomanek RJ, 2000, ANAT REC, V261, P126Huss R, 2000, STEM CELLS, V18, P252Asahara T, 1997, SCIENCE, V275, P964FINGERLE J, 1990, SS, V10, P1082CLOWES AW, 1989, J CARDIOVASC PHARM, V14, pS12

Campaign for the optimal treatment of varicose veins: welcoming the declaration of the Code of Ethics issued by the Korean Society for Phlebology

Background: Varicose veins (VV) is a common chronic venous disorder that is often left untreated due to its minor symptoms. However, recent developments in minimal invasive surgery has resulted in a rapid increase of VV treatment cases. Unfortunately, there have been some ethical issues regarding the high cost of intervention and non-professional treatment administered for VV at some private clinics. Current Concepts: Most endovenous therapies for VV are not reimbursed by the national health insurance but are only covered by personal health insurance plans in Korea. Rapid increase in the coverage costs for VV treatment has led to conflicts between the insurance companies and doctors in several cases. Recently, the Korean Society for Phlebology declared the Code of Ethics to support evidence-based treatment and warn against unethical practices related to interventions for VV. Discussion and Conclusion: The Korean Society for Vascular Surgery and Korean Society for Phlebology have just launched a campaign for the optimal treatment of VV on their YouTube channel, which shares accurate information regarding VV treatment to inform patients and doctors. To strengthen doctor-patient relationship and to avoid falling prey to unethical practitioners, it is critical to educate and update patients and healthcare service providers regarding the options available for VV treatment.N

Evaluation of Multiple Regional Climate Models for Summer Extremes of Temperature and Precipitation over East Asia

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Attribution of the local Hadley cell widening in the Southern Hemisphere

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Multi-model attribution of Hadley Cell widening

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An Integrated Approach toward Strategic Information Systems Planning Methodologies

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Attribution of Recent Arctic Sea Ice Melting to Human Influence

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