Biomedical subjects
Publications and source records attributed to H C Kim.
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Previously we reported that immunostimulated astrocytes were highly vulnerable to glucose deprivation. The augmented death was mimicked by the peroxynitrite (ONOO )-producing reagent 3-morpholinosydnonimine (SIN-1). Here we show that glucose deprivation and ONOO- synergistically deplete intracellular reduced glutathione (GSH) and augment the death of astrocytes via formation of cyclosporin A-sensitive mitochondrial permeability transition (MPT) pore. Astrocytic GSH levels were only slightly decreased by glucose deprivation or SIN-1 (200 microM) alone. In contrast, a rapid and large depletion of GSH was observed in glucose-deprived/ SIN-1-treated astrocytes. The depletion of GSH occurred before a significant release of lactate dehydrogenase (a marker of cell death). Superoxide dismutase and ONOO-scavengers completely blocked the augmented death, indicating that the reaction of nitric oxide with superoxide to form ONOO was implicated. Furthermore, nitrotyrosine immunoreactivity (a marker of ONOO-) was markedly enhanced in glucose-deprived/SIN-1 -treated astrocytes. Mitochondrial transmembrane potential (MTP) was synergistically decreased in glucose-deprived/SIN-1-treated astrocytes. The glutathione synthase inhibitor L-buthionine-(S,R)-sulfoximine markedly decreased the MTP and increased lactate dehydrogenase (LDH) releases in SIN-1-treated astrocytes. Cyclosporin A, an MPT pore blocker, completely prevented the MTP depolarization as well as the enhanced LDH releases in glucose-deprived/SIN-1-treated astrocytes.
We have developed a centrifugal blood pump with thick impeller blades (60% of pitch) to obtain a small tip clearance. An unshrouded impeller with 6 backward curved thick blades was used to reduce the dead zone between the shroud and upper casing. A streamline angle in volute was uniform in circumferential direction by continuity and angular momentum conservation. To prove the effectiveness of small tip clearance, performance and hemolysis tests were conducted on pumps with a tip clearance of 0.5, 1.5, and 2.0 mm at exit with the blade thickness of 60% of pitch, and with that of 1.0, 2.0, and 2.5 mm at exit with the thickness of 40% of pitch. The results showed that the smaller the tip clearance, the better the hydrodynamic and hemolytic performance. The best result was seen in the pump with tip clearance of 0.5 mm with a blade thickness of 60% of pitch. These results suggest that a centrifugal pump with thick blades and a small tip clearance can be a promising alternative as a cardiopulmonary bypass pump.
During advanced renal failure, and particularly in patients with end-stage renal disease, proteins are carbamylated as a result of a reaction with cyanate. If the carbamylation of proteins adversely alters their biologic activities and structures, then urea must be viewed as an uremic toxin, rather than a surrogate. Therefore, we studied in this paper the role of cyanate as a hemolytic factor of erythrocytes to explain anemia observed in patients with high blood urea levels due to inadequate dialysis. Cyanate was added to make the final concentration 150, 300 and 600 nmol to each test tube containing the final concentration of 140 x 10(6) with human erythrocytes per mL of phosphate buffered saline solution. And they were incubated at 37 degrees C for 24, 48 and 72 hours. The extent of hemolysis and carbamylation was monitored. The levels of hemolysis and carbamylated erythrocytes increased as the time of exposure to cyanate increased from 24 hours to 72 hours. Furthermore, those increased as cyanate concentration in the incubation media rose from 150 nmol to 600 nmol. Cyanate can induce hemolysis by carbamylation of erythrocytes. Urea, through cyanate, may contribute to hemolysis. If one extrapolates these results to patients with end-stage renal disease, it may help explain one of the reasons for the anemia in patients with high levels of BUN due to inadequate dialysis.
The authors report two cases of non-Hodgkin's lymphoma that were evaluated not only by conventional staging work-up but also additional Tc-99m MDP bone scans and fluorine-18 fluorodeoxyglucose (F-18 FDG) coincidence detection (CoDe) positron emission tomographic (PET) imaging. There were discordant results between the Tc-99m MDP bone scans and F-18 FDG CoDe PET. In the first case, the bone marrow biopsy was positive, and F-18 FDG CoDe PET was consistent with a malignancy, but the findings of the Tc-99m MDP bone scintiscan were negative. In the second case, the bone marrow biopsy was negative, but F-18 FDG CoDe PET revealed focal skeletal involvement, which improved markedly on the follow-up study after chemotherapy. If skeletal involvement has a focal distribution and is confined to the marrow cavity, both bone marrow biopsy and bone scintigraphy can be falsely negative. In this situation, F-18 FDG PET is useful and revealing.
PURPOSE: The authors evaluated the utility of F-18 fluorodeoxyglucose (FDG) coincidence detection (CoDe) positron emission tomography (PET) for staging, post-treatment evaluation, and follow-up assessment of patients with malignant lymphomas. MATERIALS AND METHODS: Fifty-eight patients with histologically proved malignant lymphomas (4 Hodgkin's disease, 54 non-Hodgkin's lymphoma) underwent CoDe PET using F-18 FDG. CoDe PET was performed using a dual-head gamma camera equipped with coincidence detection circuitry. Of the 87 CoDe PET studies, 26 were performed for staging, 38 for post-treatment evaluation, and 23 for follow-up evaluation of recurrence. The entire trunk, from the cervical to the inguinal regions, or selected regions were scanned with the patient in the supine position. No attenuation correction was made and reconstruction was performed using filtered back-projection rather than iterative reconstruction. CoDe PET findings were compared with corresponding results of computed tomographic (CT) and magnetic resonance imaging (MRI), tissue biopsy, or clinical follow-up. RESULTS: For staging, 52 sites were positive on CoDe PET or CT-MRI. CoDe PET detected 49 sites (94%), and CT-MRI showed 47 sites (90%). CoDe PET detected five more lymphomatous lesions and missed three lesions. For post-treatment evaluation, CoDe PET showed a positive predictive value of 100% and a negative predictive value of 83%, but the validated cases numbered only 11. For follow-up for recurrence, CoDe PET had a negative predictive value of 90%, but frequent false-positive findings were noted in the head and neck region as a result of underlying inflammatory changes. CONCLUSIONS: For staging, FDG CoDe PET alone without attenuation correction is not sensitive enough to be used as an independent imaging method, especially for small abdominal lesions. However, it appears to be an accurate method for assessing residual disease and for patient follow-up.
INTRODUCTION: Germline mutations in E-cadherin (CDH1) have been reported in families with early onset, diffuse gastric cancer. More recently, mutations in CDH1 have been described in colorectal cancer cell lines. AIMS: We have investigated if germline mutations in CDH1 occur among different groups of Korean gastric and colorectal cancer patients, with and without a positive family history. METHODS: We studied 131 patients and 168 normal controls (88 Korean and 80 non-Korean). Patients were divided into five groups: group I, 20 gastric cancer patients with a family history; group II, 26 colorectal cancer patients with a family history of gastric cancer (those from familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) kindred were excluded); group III, 16 HNPCC patients without identified germline mutations in hMLH1 and hMSH2; group IV, 35 gastric cancer patients without a family history; and group V, 34 colorectal cancer patients without a family history. Polymerase chain reaction, single strand conformational polymorphism analysis, direct sequencing, and genotyping for identified variants were performed. RESULTS: Several germline changes in CDH1 were found. In addition to previously described polymorphisms, we found three novel changes, two of which were missense changes (T340A and L599V). T340A was present in one patient in group III and one in group V. L599V was present in one patient in group II, in two in group III, and in one in group IV. T340A was not found in normal controls while L599V was present in two of 88 Korean controls. Patients with these variants may appear to have a tendency to early onset cancer with a positive family history, although differences in frequencies did not reach statistical significance. Genotyping results suggest that these variants might have a common origin, particularly T340A. CONCLUSION: We have described two new missense germline variants in CDH1 in various groups of Korean gastrointestinal cancer patients. Further work is required to assess if these variants increase the risk of gastrointestinal cancer.
The effects of poly vinyl alcohol (PVA)/Chitosan/Fibroin (PCF)-blended sponge on wound healing in rats were investigated. We excised the skin of a rat, including the dermis, approximately 2 x 2 cm in size. The wound was covered with PCF-blended spongy sheets. The spongy sheets absorbed the exudate, and gained flexibility and softness. Histopathological inspection of the wound 12 d later showed an increase of vascular ingrowth and the absence of inflammatory cells. Regeneration of the skin around the wound was faster than that of the control. We also tested wound healing effects of PVA, Chitosan and Fibroin, alone or in various combinations. Wound healing was accelerated in the order of PCF-blended sponge>Chitosan/Fibroin (CF)-blended sponge>Fibroin (F) sponge > PVA/Chitosan-blended sponge (PC) > Chitosan (C) sponge.
Isolated splenic metastasis arising from colorectal carcinoma is very rare and there has been only 6 cases reported in the English literature. A new case is presented, and its possible pathogenesis was considered with previously reported cases. A 65-year-old male patient had received a right hemicolectomy for ascending colon cancer 36 months earlier. He was followed up regularly with serial measurement of serum carcinoembryonic antigen (CEA). Rising serum CEA was discovered from 33 months postoperatively and CT revealed an isolated splenic metastasis. He therefore underwent splenectomy, which was proven to be a metastatic adenocarcinoma with similar histological feature to the original tumor. As all reported cases showed elevated serum CEA at the time of metastasis, isolated splenic metastasis might be associated with CEA in regard to its biological functions of immunosuppression and adhesion.
Gastric adenocarcinoma is one of the most common malignancies in the world, and yet little is known about its molecular process of development and progression. Recent studies have suggested that ingestion of nonsteroid anti-inflammatory drugs reduces the risk of colon cancer, presumably by inhibiting the cyclooxygenase (COX) enzyme. COX-2, one isoform of the COX enzyme, is the rate-limiting enzyme in prostaglandin synthesis, and the function of this enzyme is thought to relate to inflammatory processes and carcinogenesis. To understand the role of COX enzyme in gastric cancer, we measured COX-2 expression in 104 human gastric carcinoma tissues by immunohistochemical analysis. We obtained tissue specimens from 104 surgically resected gastric adenocarcinoma patients. We performed immunohistochemical stain for human COX-2 with polyclonal antibody in gastric carcinoma. After curative resection and extensive lymph node dissection, all patients received adjuvant chemotherapy containing 5-fluorouracil. Expression of COX-2 showed cytoplasmic staining, not only in cancer cells but also in precancerous lesions such as metaplastic and adenomatous cells. We confirmed up-regulation of COX-2 in gastric cancer tissues compared with normal paired mucosa using Western blot analysis. There was no correlation between clinicopathological characteristics of gastric cancer patients and intensity of COX-2 protein expression. This study indicates that COX-2 protein over-expression may contribute to an early event of gastric cancer development, and it further suggests that selective inhibition of COX-2 may provide a chemopreventive effect against gastric carcinogenesis.
Since 1993, more than 2,000 cases of vivax malaria have occurred in the Republic of Korea in an epidemic that ended nearly 20 malaria-free years. Most malaria has occurred in the northwestern part of the country, mainly affecting Korean military personnel. As a part of an operational surveillance effort, we sampled mosquitoes in and near the Demilitarized Zone (Paju County, Kyonggi Province) during the last 2 wk of July in 1996 and from May 15 to September 10 in 1997. The 1st year, landing collections were done at 5 different sites; the 2nd year, carbon-dioxide-baited light traps at 5 sites, larval collections in 10 adjacent fields, and landing collections at 1 site in the Demilitarized Zone were performed weekly. Of 17 species collected, Anopheles sinensis was consistently the most abundant mosquito, comprising 79-96% of mosquitoes. The diel pattern of biting by An. sinensis varied by location and season, with the majority of individuals biting late at night during warm weather (>20 degrees C) and early at night during cool weather. In contrast, Aedes vexans nipponii (the 2nd most abundant species) bit in the greatest numbers at the same time all season, from 2000 to 2300 h. Among the correlates with abundance of An. sinensis were average nighttime temperature 2 wk previous to the night in question, wind late at night (negatively correlated), and apparent size of the moon (negatively correlated). The data showed that the exact number of An. sinensis biting could not be estimated from numbers collected in carbon-dioxide-baited light traps. On the other hand, a threshold of 15 An. sinensis per trap night corresponded (88% accuracy) to a threshold of 12 mosquitoes biting 2 adjacent collectors per night. Larval collections were also significantly correlated with landing collections, despite inexact sampling methods and separation of the larval habitat from the site where landing collections were performed. Operational entomology assets using nighttime temperature records, carbon-dioxide-baited light traps, and larval collections should be able to target their efforts in Korea more efficiently.
We have developed a centrifugal blood pump with a magnetically suspended impeller to reduce the hemolysis level for long-term use. The main advance we have made was simplifying the traditional 5 axes controlled magnetic bearing system, since the total device should ultimately be small enough to implant into a human body. A simplified magnetic bearing system with only 3 actively controlled axes was designed to levitate the impeller. The state equations of the magnetic bearing plant were established using Lagrange's methods, and using the results, a linear quadratic optimal controller was designed to regulate the position of the impeller. Flow rate and differential pressure of 5L/min and 300 mmHg, respectively at a motor speed of 2750 rpm was achieved from a mock circulation setup. These results show satisfactory performance as a cardiopulmonary bypass device. The lowering of pumping efficiency as the clearance between the impeller and pump housing increased was negligible. Thus for power efficiency, the smallest gap not leading to a hemolysis level rise can be determined as a feasible operation clearance.
We describe the first reported case in Korea of a woman with a D--/ D-- phenotype, a high-titer anti-Hr0, and the successful delivery of her newborn. The mother had a history of spontaneous abortion and artificial termination. In her third pregnancy, a live infant was delivered, but died of severe hemolytic disease of the newborn due to anti- Hr0 in spite of intensive medical intervention. In her fourth pregnancy, at 22 weeks gestation, the titer of anti- Hr0 was 1024, fetal cells were direct antiglobulin test positive and the blood type was group O, D+ (CDe). We performed plasma exchanges in the mother; however, the titer of antibody rebounded to its initial level after the third plasma exchange. At 26 weeks gestation, cord blood Hb decreased to 7.1 g/dL and three intrauterine transfusions were performed using the mother's washed red blood cells (RBCs). At 34 weeks gestation, a live baby was delivered by cesarean section. The infant was hydropic with hyperbilirubinemia and severe anemia. However, after two exchange transfusions using the washed RBCs of the mother's sister, who was also D--/D--, laboratory and clinical findings returned to normal.
Multiple dose administration of methamphetamine (MA) results in long-lasting toxic effects in the nigrostriatal dopaminergic system. These effects are considered to be primarily due to oxidative damage mediated by increased production of hydrogen peroxide or other reactive oxygen species in the dopaminergic system. The present study was designed to determine the protective effects of dietary antioxidant selenium on MA-induced neurotoxicity in the nigrostriatal dopaminergic system. Male C57BL/6J mice were fed either selenium-deficient (< 0.01 ppm Se) or selenium-replete (0.2 ppm Se) diets for 90 days. MA treatment decreased the dopamine (DA) levels in the striatum and substantia nigra (SN) of both Se-replete and Se-deficient animals. However, in Se-replete animals, this DA depletion was significantly attenuated in both the striatum and SN. A novel observation is that MA administration resulted in increased activity of Cu,Zn-SOD in the brains of both Se-deficient and Se-replete animals. However, MA administration to Se-deficient animals exhibited a higher Cu,Zn-SOD activity in the nigrostriatal system than the control animals. Elevated malondialdehyde (MDA) levels in the striatum and SN were also observed in Se-deficient MA-treated animals. Se repletion significantly increased the glutathione peroxidase (GPx) activity and the ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) in the MA-treated animals. In conclusion, we have shown that dietary Se attenuated methamphetamine neurotoxicity and that this protection involves GPx-mediated antioxidant mechanisms. Even though Cu,Zn-SOD activity was significantly elevated by MA treatment, the role of this enzyme in MA-mediated neurotoxicity is not yet clear.
The abrupt elevation in the levels of cyclooxygenase or lipoxygenase metabolites of arachidonic acid during cerebral ischemia contributes to neuronal injury. Recently, evidence has accumulated that both excitotoxic and apoptotic features can coexist in ischemia models in vitro and in vivo. In this study, we evaluated whether phenidone, an inhibitor of both cyclooxygenase and lipoxygenase, can provide protection against excitotoxin- or ischemia-induced neurotoxicity, including the staurosporine apoptosis model, in mouse cortical cultures. We examined the protective effect of phenidone against free radical injuries induced by arachidonic acid, hydrogen peroxide, xanthine/xanthine oxidase, Fe2+/ascorbic acid. Pre- and post-treatment with phenidone (300 microM for 24 h) moderately attenuated the neuronal injury induced by 50 microM kainate and oxygen/glucose deprivation (45 min) by 33% and 50%, respectively. It had no effect on NMDA induced injury (150 microM for 5 min). The maximum dose of phenidone (300 microM) reduced the oxidative injury induced by arachidonic acid (71% inhibition), hydrogen peroxide (95% inhibition), xanthine/xanthine oxidase (57% inhibition), and Fe2+/ascorbic acid (99% inhibition) neurotoxicity. Phenidone (300 microM) decreased staurosporine (100 nM)-induced apoptosis to 30%. These results suggest that phenidone may contribute to neuronal survival by modulating oxidative stress, which is involved in the excitotoxic and apoptotic processes occurring under ischemic conditions.
Fifteen to twenty-five percent of sporadic colorectal carcinomas are replication error (RER) positive. Because the frequency of mutations in the mismatch repair genes (hMLH1 and hMSH2) is low in these tumors, we have investigated the role of mutational inactivation, methylation of the promoter region, and loss of heterozygosity (LOH) as a possible explanation for the mutator phenotype of RER+ colorectal cancer cell lines. Genomic DNA was extracted from a panel of 49 human colorectal cancer cell lines. The RER status was determined by amplification of BAT-26. All exons of hMLH1 and hMSH2 were amplified with the PCR and screened by using single-strand conformational polymorphism and direct sequencing. The methylation status was ascertained by methylation-specific PCR after bisulfite modification of DNA. Western blotting for hMLH1 was performed on methylated cell lines before and after the addition of the demethylating agent 5-azacytidine. LOH was sought by GENESCAN analysis of amplified CA repeat markers and indirectly by determining the number of homozygotes in the cell lines and human random controls. Twelve cell lines from ten tumors (24%) were RER+. Hypermethylation of the hMLH1 promoter occurred in five of ten (50%) RER+ tumors, whereas three of thirty-two (6%) RER tumors showed partial methylation. None of the fully methylated cell lines expressed hMLH1, although all reexpressed hMLH1 after treatment with 5-azacytidine. There was no LOH in the RER+ tumors in either hMLH1 or hMSH2. Our results suggest that mutations of hMLH1 together with hypermethylation of the promoter region, but not LOH, are the cause of the mutator phenotype in the majority (70%) of RER+ tumors.