Discovery of urinary metabolomic biomarkers for early detection of acute kidney injury

Won, A Jin,Kim, Siwon,Kim, Yoon Gyoon,Kim, Kyu-Bong,Choi, Wahn Soo,Kacew, Sam,Kim, Kyeong Seok,Jung, Jee H.,Lee, Byung Mu,Kim, Suhkmann,Kim, Hyung Sik The Royal Society of Chemistry 2016 Molecular bioSystems Vol.12 No.1

<P>The discovery of new biomarkers for early detection of drug-induced acute kidney injury (AKI) is clinically important. In this study, sensitive metabolomic biomarkers identified in the urine of rats were used to detect cisplatin-induced AKI. Cisplatin (10 mg kg(-1), i.p.) was administered to Sprague-Dawley rats, which were subsequently euthanized after 1, 3 or 5 days. In cisplatin-treated rats, mild histopathological alterations were noted at day 1, and these changes were severe at days 3 and 5. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly increased at days 3 and 5. The levels of new urinary protein-based biomarkers, including kidney injury molecule-1 (KIM-1), glutathione S-transferase-alpha (GST-alpha), tissue inhibitor of metalloproteinase-1 (TIMP-1), vascular endothelial growth factor (VEGF), calbindin, clusterin, neutrophil, neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin, were significantly elevated at days 3 and 5. Among urinary metabolites, trigonelline and 3-indoxylsulfate (3-IS) levels were significantly decreased in urine collected from cisplatin-treated rats prior to histological kidney damage. However, carbon tetrachloride (CCl4), a hepatotoxicant, did not affect these urinary biomarkers. Trigonelline is closely associated with GSH depletion and results in insufficient antioxidant capacity against cisplatin-induced AKI. The predominant cisplatin-induced AKI marker appeared to be reduced in urinary 3-IS levels. Because 3-IS is predominantly excreted via active secretion in proximal tubules, a decrease is indicative of tubular damage. Further, urinary excretion of 3-IS levels was markedly reduced in patients with AKI compared to normal subjects. The area under the curve receiver operating characteristics (AUC-ROC) for 3-IS was higher than for SCr, BUN, lactate dehydrogenase (LDH), total protein, and glucose. Therefore, low urinary or high serum 3-IS levels may be more useful for early detection of AKI than conventional biomarkers.</P>

선인장 양심실 보조장치의 설계 및 임상적용을 위한 평가

민병구,박찬영,최재순,이혁수,황창모,김삼성,윤걸중,김종원,선경,이경갑,정종태,김원곤 제주대학교 인공심장이식연구소 2001 인공심장 연구 Vol.2 No.1

현재 개발되고 있는 맥동형 이식형 인공심장은 완전이식형 인공심장과 좌심실보조장치 뿐이다. 좌심실보조장치를 장착한 환자의 10~15%가 우심실의 보조를 필요로하고 완전이식형 인공심장의 장착을 위해서는 자연심장을 제거해야하는 상황에서 이식형 양심실보조장치에 대한 필요성이 대두되고 있다. 본 연구진은 완전이식형 인공심장으로 개발된 한국형 인공심장을 개선하여 양심 실 보조장치를 개발하였다. 양심실보조장치는 이동형 작동기식 미케니즘을 이용하고 있으며 에너지 변환장치와 감속기로 구성된 작동기와 혈액주머니, 그리고 내장형 제어기로 구성되어 있다. 선인장 펌프로 명명된 KAH350은 캐뉼라의 연결을 위한 커넥터를 포함하여 길이 177mm, 폭 164mm, 높이 67 이고 무게 780g이며 최대 심박출량은 5L/min 이다. 양심실보조장치로 개발된 선인장펌프는 좌심실보조장치로도 응용이 가능하다. 이식적합성과 생체적합성을 평가하기 위하여 좌심실보조장치로 5회, 양싱실보조장치로 6회의 동물실험을 수행하였다. 각각 최장 28일간 생존하였으며 11회의 동물실험중 장치의 결함에 의한 것이 3회 있었는데 이들은 모두 전자장치의 결함과 방수처리문제였다. 현재 이식적합성과 일박출량을 향상시킨 KAH400모델이 개발중이다. The types of pulsatile implantable artificial hearts that are on the way of development and have been developed are totally implantable artificial heart and implantable left ventricular assist device (LVAD). Approximately 10% to 15% of all patients Implanted with wearable VADs have required right heart support with another device. And it is reluctant to patient who should remove his or her own heart to be implanted with total artificial heart. These situations drive the development of implantable bi-ventricular assist device (BVAD). The Korean BVAD was develophed by modifying the moving actuator type Korean artificial heart. This electro-mechanical BVAD comprises actuator including energy converter and reduction gear train, blood sacs, and internal motor and energy controllers. The KAH350 which is named as 'Cactus Pump' is 177mm in length, 164mm in width, and 67mm in thickness including connectors and nuts. The weight and maximum cardiac output of Cactus Pump is 780g and 5L/min, respectively. The Cactus Pump that was developed as BVAD could be used as LVAD by attaching compliance caps on the 2 ports of one ventricle. The animal experiments were undergone 5 times for LVAD, and 6 times for BVAD. The best records were 28 days survival in both applications. There were 3 times of device failure and they were all associated with electrical connection and hermetic sealing. The KAH400 that has improved anatomical fitting characterisitcs and stroke volume is on development.

Interleukin-2가 Mouse 자궁내막의 Acid Phosphatase 활성에 미치는 영향

김원규,신규철,정호삼,이규식 한양대학교 의과대학 1989 한양의대 학술지 Vol.9 No.2

Interleukin-2, a kind of lymphokine produced by the T-lymphocyte stimulated by antigen or mitogen, has been studied intensively with the development of immuno-oncology and chemoimmunotherapy of the malignancy. Interleukin-2 is known to exert on antitumor effect by stimulating the proliferation of helper and cytotoxic T lymphocytes, augmenting the cytolytic activities of the cytotoxic T lymphocyte and differentiating a precursor cell into a lymphokine-activated killer cell in vivo. Though interleukin-2 suppresses the metastasis of the malignant tumor into the adjacent organs, it develops many side effects including fever, chills, malaise, mental confusion, diarrhea, vomiting and oliguria. Interleukin-2 also causes pulmonary, hepatic and renal toxicities and, especially, increase of capillary permeability with weight gain, pulmonary edema and ascites. In this experiment, the author studied the effect of interleukin-2 on the mouse endometrium, observing histochemically the changes in the activity of acid phosphatase following the estrous cycle. Female, DDY strain, weighing 20gm and exhibiting normal estrous cycle, were used as experimental animals. The estrous cycle was recognized by the vaginal smear. The experimental animals were treated with 2 million units of interleukin-2/0.2ml per Kg of body weight and with 0.2ml of normal saline per Kg of body weight in the control groups for 5 days. And animals were sacrificed 5th day after administration of interleukin-2. The specimens obtained from the corpus uteri were fixed in 10% neutral buffered formalin solution for 24 hours at 4℃ and sliced at 14μm thickness in a frozen cryostat. The activity of acid phosphatase was observed by the Gomori's method for histochemical study. The result obtained was as follows: The acid phosphatase activity was increased at estrus and decreased at diestrus in interleukin-2 treated group. There was, however, no marked differences in acid phosphatase activity of the proestrus and metestrus between control and interleukin-2 treated groups. Consequently, it was suggested that interleukin-2 develop the changes of the acid phosphatase of the endometrium of the mouse.

CS gas가 흰쥐 폐장내 Laminin 분포에 미치는 영향

김대영,정호삼,김원규,백두진 한양대학교 의과대학 1999 한양의대 학술지 Vol.19 No.1

It is known that laminin, a basement membrane-related glycoprotein, was present diffusely in the extracellular matrix throughout the mesenchyme in the developing lung tissues. In a recent study, we established that laminin plays an important role in the morphogenesis of embryonic mouse lung. This study was undertaken to localization of laminin in the alveoli and alveolar septa of lung after CS gas exposure to experimental animals, rats(Sprague-Dawley strain), weighing 150 ∼ 200 gm. The experimental rats were sacrificed on 12 hour, day 1, day 2, day 3, day 5 and day 7 after CS gas exposure, respectively. The specimens of lung were prepared for laminin immunoreactions. All of specimens for immunoreactions were observed with light microscope. The results obtained were as follows. 1. A few mononuclear cells were diffused into alveolar septa of lung, on 12 hour after CS gas exposure. Immunoreaction of laminin in extracellular matrix and basement membrane showed moderate positive reactions. 2. Lymphoid tissues in the alveolar septa were expanded and the numerous alveoli were collapsed or disappeared. Laminin-immunoreaction in this tissues showed moderate reactions on day 2 and day 3 after CS gas exposure. 3. On day 5, day 7 after CS gas exposure, lymphoid tissues in the alveolar septa were mostly disappeared. Intact alveoli were seen. Strong laminin immunoreaction were observed on the surface and interstitium of alveolar septa. It suggested that CS gas exposure to rat may induce the increase of laminin in the alveoli of lung after tissue failure.

Adriamycin이 백서 자궁경부 상피세포층과 근육층의 인산염 분해효소의 활성에 미치는 영향

김원규,정호삼 漢陽大學校 環境科學硏究所 1994 環境科學論文集 Vol.15 No.-

Adriamycin은 Streptomyces peucetius var. caesius에서 추출한 항균성 항암제로서 세포내의 핵산과 결합하여 핵산 및 단백질의 합성을 억제하므로 종양세포의 증식을 억제하는 화학요법제이다. 그러나 adriamycin을 암환자에 투여하면 종양세포 뿐 아니라 정상세포에도 손상을 초래하여 여러가지 부작용을 일으키므로 저자는 adriamycin을 백서에 투여하면 자궁경부세포의 단백질 합성이 억제되어 인산염 분해효소의 활성에도 변화가 야기될 것으로 사료되어 자궁경부에서 acid phophatase, alkaline phosphatase 및 adenosine triphosphatase 활성의 변화를 조직화학적으로 추구하였다. 실험동물은 체중 200gm 내외의 Wistar계 자성 백서를 질도말법으로 발정주기을 확인하고 백서 체중 ㎏당 5㎎의 adriamycin을 5일간 복강내에 주사하였으며, 희생시키기 직전 다시 발정주기을 확인한 후 경동맥사혈로 희생하고 개복하여 자궁경부를 적출하였다. 적출한 자궁경부는 4℃에서 10% 중성 formalin에 24시간 고정한 후 동결절편제작기로 두께 6㎛의 동결절편을 제작하여 acid phosphatase 와 alkaline phosphatase 활성은 Gomori 법으로 adenosine triphosphatase 활성은 Wachstein-Meisel 법으로 효소활성을 관찰하여 다음과 같은 결과를 얻었다. 1. Acid phosphatase 활성은 adriamycin 투여군 백서 자궁경부의 상피세포층에서는 모든 발정주기에서 약한 양성반응을 나타내었으며, 근육층에서는 발정기에서 강한 양성반응을, 발정후기에서 중등도의 양성반응을 나타내었다. 2. Alkaline phosphatase 활성은 adriamycin 투여군 백서 자궁경부의 상피세포층세서는 모든 발정주기에서 약한 양성반응을 나타내었고, 근육층에서는 발정기 및 발정간기에서 약한 양성반응을 나타내었다. 3. Adenosine triphosphatase 활성은 adriamycin 투여군 백서 자궁경부의 상피세포층세서는 발정전기, 발정기 및 발정간기에서 음성반응을 나타내었고, 근육층에서는 발정후기 및 발정간기에서 약한 양성반응을 나타내었다. 이상의 결과을 종합한 바 백서에 adriamycin을 투여하면 자궁경부의 상피세포와 근육세포에 독성으로 작용하여 인산염 분해효소의 활성에 이상이 초래되는 것으로 사료된다. It is well known that adriamycin, an anthracycline antibiotics which is isolated from Streptomyces peucetius var. caesius, inhibits DNA and RNA synthesis and exhibits significant antitumor activity against various tumors. Although adriamycin is very effective against tumor cell proliferation, it may also damage the normal cells of the body and develop the toxic effects during treatment of cancer patients. In this experiment, the author has studied the effect of adriamycin on the rat uterine cervix, observing the changes in the activities of acid phosphatase, alkaline phosphatase and adenosine triphosphatase in the uterine cervix. Fourty female Wistar strain rats, weighing about 200gm and exhibiting normal estrous cycle, were used as experimental animals. After recognization of estrous cycle by means of vaginal smear, the animals of experimental group and control group were injected with 5㎎/㎏ of adriamycin diluted in 0.2ml of distilled water and 0.2ml of normal saline for 5 days, respectively. On the 5th day after administration of adriamycin and normal saline the experimental animals were sacrificed. The obtained cervix uteri was fixed in 10% neutral formalin solution(pH 7.2) for 24 hours at 4℃ and then frozen sections, 6㎛ in thickness, were made with cryostat. The activities of acid and alkaline phosphatase were observed by Gomori's method and the activity of adenosine triphosphatase by Wachstein and Meisel's method. All preparations were observed under light microscope. The results obtained were as follow : 1. Activities of acid phosphatase in the epithelial layer of the uterine cervix of adriamycin treated rat were revealed weakly positive activity at proestrus, estrus, metestrus and diestrus, whereas activities of acid phosphatase in the muscular layer were shown strongly positive activity at estrus and moderately positive activity at metestrus. 2. Activities of alkaline phosphatase in the epithelial layar of the uterine cervix of adriamycin treated rat were revealed weakly positive activity at proestrus, estrus, metestrus and diestrus, whereas activities of alkaline phosphatase in the muscular layer were shown weakly positive activity at estrus and diestrus. 3. Activites of adenosine triphosphatase in the epithelial layer of the uterine cervix of adriamycin treated rat were shown negative activity at proestrus, estrus and diestrus, whereas activites of adenosine triphosphatase in the muscular layer were shown weakly positive activity at metestrus and diestrus. It is consequently suggested that the changes of activites of phosphatase would be resulted from cytotoxic effect of adriamycin on the epithelial and muscular cells in rat uterine cervix.

디지털 및 일반 측방두부규격방사선사진에서 측정 방법에 따른 계측치의 비교

김미자,허경회,이원진,허민석,이삼선,이진구,안병근,최순철 대한구강악안면방사선학회 2005 Imaging Science in Dentistry Vol.35 No.1

Purpose : To compare cephalometric measurement between measuring methods in digital and conventional lateral cephalometric radiograph. Materials and Methods : Twenty digital and conventional lateral cephalometric radiographs were selected. In digital group, cephalometric measurements were performed manually using hardcopies and automatically using VCeph^(TM) program on the monitor. In conventional group, the same measurements were performed manually on conventional films, and for automatic measurement conventional films were digitized by scanner. All measurements were performed twice by 4 observers, and 24 cephalometric variables were calculated and the time spent for each measurement was recorded. The differences in measurements data and the time spent for each measurement were compared within each group. Intra-observer and inter-observer comparisons were performed. Results : In both groups, no statistically significant difference between manual and automatic measurements was observed and most of the variables didn’t show statistically significant differences between methods. The observer with less experience tended to show statistically significant differences of measurements between methods, and differences from other observers. The differences of measurements between methods in digital group were lesser than those of conventional group with statistical significance in 8 variables out of 24. With automatic method and in digital group, the spent time was shorter. Conclusion : With direct digital radiograph, automatic method using manually idenitified landmarks can be preferable in cephalometric analysis.

사용자를 위한 소프트웨어 재사용 검색 시스템 구현에 관한 연구

김성원,김영렬,서삼준 안양대학교 자연과학연구소 1997 自然科學硏究 Vol.4 No.-

재상용 가능한 소프트웨어 부품들을 분류 및 검색하여 재사용하는 방법들이 많이 제안되어 있으나 이들의 부품들을 검색하여 재사용 하기에 쉬운 일은 아니다. 특히 객체지향을 기반으로하는 소프트웨어들이 대다수를 이루고 있기 때문에 객체지향 개념이 부족한 사용자나, 전문가가 아닌 일반적인 사용자들에게는 더욱 그러하다. 본 논문에서는 기존의 재사용 가능한 소프트웨어 부품들을 사용자가 분류 선택하여 요구하는 장소에 보다 쉽게 다양하게 저장할 수 있도록 하였고, 저장소에 있는 부품들을 보다 쉽게 검색하여 요구에 맞는 형태로 수정, 합성 및 재구축할 수 있는 시스템으로 MRRS 재사용 검색 시스템을 윈도우95 환경에서 델파이로 구현했다. Several reuse methods that classify and check reusable software components have been suggested, however they were not easy to process. Since most of current softwares are based on the object-oriented concepts, users who are not experts and do not have enough knowledge about the object-oriented concepts can not reuse them efficiently. This paper suggests that a new reuse method that is easier to classify and select the reusable software components and to store them in the required place with various way. The system MRRS reuse retrieval system that can modify, compose and build the components in th Repository as a suitable form was implemented with Delphi under Window 95 operating system.

의원성 사고로 발생한 타액선염 : 증례보고

김현우,허경회,이원진,허민석,이삼선,최순철 대한구강악안면방사선학회 2004 Imaging Science in Dentistry Vol.34 No.2

A case of sialadenitis is presented in a patient with painful swelling of the right mouth floor. The condition was caused by trauma on the right mouth floor during dental treatment, which had happened 15 days before admission. On aspiration, mucous secretion was found and ultrasonography showed obstruction of duct. Histopathological studies and surgical investigation established a definite diagnosis of obstructive sialadenitis caused by ductal laceration. As surgical treatment sialodochoplasty was selected. The case and relevant considerations are discussed.

흰쥐 입천장발생중 laminin의 발현에 관한 연구

김원규,황우열,윤지희,백두진,정호삼 대한췌담도연구회 2000 대한췌담도연구회지 Vol.5 No.3

Retinoic Acid가 흰쥐 태자 혀조직의 분화와 Laminin 합성에 미치는 영향에 대한 연구

김혜주,정호삼,서윤경,백두진,김원규,윤지희,이방헌 대한췌담도연구회 2000 대한췌담도연구회지 Vol.5 No.4