Diabetes & Metabolism Journal

Volume 29(5); September 2005

Review

Review of Insulin Signaling Network.: Hyun Shik Son; Korean Diabetes J. 2005;29(5):383-392. Published online September 1, 2005

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Abstract PDF: No abstract available.

Original Articles

Oxidative Stress of INS-1 Cell, HIT-T15 Cell and Rat Islet Cell as a Mechanism of Glucose Toxicity.: Mi Jung Eun, Kyu Chang Won, Jun Sung Moon, Sun Jung Mun, Ji Eun Lee, Ji Sung Yoon, Kyung Ah Chun, Ihn Ho Cho, Hyoung Woo Lee; Korean Diabetes J. 2005;29(5):393-400. Published online September 1, 2005

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Abstract PDF: BACKGOUND: Chronic hyperglycemia is the proximate cause of many complications of diabetes. The beta cells in type 2 diabetes are also adversely affected by chronic hyperglycemia, with this relentless deterioration in cell function, due to constant exposure to supraphysiologic concentrations of glucose, is termed glucose toxicity; however, the mechanism of glucose toxicity is uncertain. The purpose of this study was to determine whether prolonged exposure of pancreatic islets to supraphysiologic glucose concentration disrupts the intracellular balance between reactive oxygen species(ROS) and antioxidant enzyme; thereby, causing defective insulin secretion. METHODS: HIT-T15 cells were treated with H2O2(20, 50 and 100micrometer) directly added to the culture media, and then intracellular peroxide and insulin mRNA were then measured. The effects of H2O2 on the total peroxide level and insulin secretion were also examined. Isolated pancreatic islet cells from Wistar and 2 beta cell lines (INS-1, HIT-T15) were cultured in either a glucose or ribose (5.6, 11.1, 22.2, 30 and 50mM) containing culture media for 72hours. The intracellular peroxide was measured using flow cytometry and glucose stimulated insulin secretion(GSIS). RESULTS: The intracellular peroxide levels due to H2O2 in HIT-T15 cells were higher with a high concentration of H2O2, and the insulin mRNA in HIT-T15 cells decreased when the cells are treated with a high concentration H2O2. The insulin mRNA of the HIT-T15 cells cultured in a high concentration of ribose was lower than of those cultured in a low concentration of glucose. INS-1, HIT-T15 and rat islet cells, cultured for 72 hours, had progressively greater peroxide levels with higher concentrations of both glucose and ribose. The GSIS in the cells cultured in high concentrations of both glucose and ribose were decreased. CONCLUSION: These results suggest only one potential central mechanism for glucose toxicity in beta cells, this being the formation of excess ROS.

Ascochlorin Derivative, AS-6, Inhibits TNF-alpha-Induced fractalkine, MCP-1 and VCAM-1 Expression in Rat Aortic Smooth Muscle Cells.: Young Yun Jang, Sang Yoon Kim, Nam Keong Kim, Mi Kyung Kim, Hee Kyoung Kim, Hye Soon Kim, Chang Wook Nam, Seong Yeol Ryu, Sung Il Nam, Keun Gyu Park; Korean Diabetes J. 2005;29(5):401-408. Published online September 1, 2005

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Abstract PDF: BACKGOUND: Inflammation is one of the key mechanisms in the development and progression of atherosclerosis. Accumulating evidence suggests that peroxisome proliferators- activated receptorgamma(PPARgamma) plays an important role in the prevention of arterial inflammation and the formation of atherogenesis. This study was designed to evaluate whether the new synthetic PPARgamma, ascochlorin-6(AS-6) has anti-inflammatory and anti-atherogenic effects in primary cultured rat vascular smooth muscle cells(VSMCs). METHODS: Rat VSMCs were isolated and cultured. Northern and Western blot analyses were performed to evaluate the effects of AS-6 on the expressions of tumor necrosis factor (TNF)-alpha-stimulated fractalkine, monocyte chemoattractant protein(MCP)-1 and vascular cell adhesion molecule (VCAM)-1 in VSMCs. A gel shift assay was performed to examine the mechanism by which AS-6 inhibits the expressions of fractalkine, MCP-1 and VCAM-1. RESULTS: TNF-alpha markedly induced the expressions of fractalkine, MCP-1 and VCAM-1 in primary cultured VSMCs. AS-6 inhibited the expressions of TNF-alpha-stimulated fractalkine, MCP-1 and VCAM-1 in primary cultured VSMCs. The result of the gel shift assay suggested the inhibitory effects of AS-6 on the expressions of TNF-alpha-stimulated fractalkine, MCP-1 and VCAM-1 were mediated through a nuclear factor kappaB associated pathway. CONCLUSION: The present study shows that AS-6 has anti-inflammatory effects on VSMCs, suggesting the possibility for the use of AS-6 for prevention of the development and progression of atherosclerosis.

Alpha-Lipoic acid Inhibits TNF-alpha-Induced Fractalkine Expression in Rat aortic Smooth Muscle Cells.: Keun Gyu Park, Hye Soon Kim, Seong Yeol Ryu, Chang Wook Nam, Byung Kyu Chae, Eui Dal Jung, Jung Guk Kim, Bo Wan Kim, In Kyu Lee; Korean Diabetes J. 2005;29(5):409-417. Published online September 1, 2005

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Abstract PDF: BACKGOUND: The induction of vascular inflammation via the proinflammatory cytokine/ nuclear factor (NF)-kappaB pathway is one of the key mechanisms in the development and progression of atherosclerosis. Accumulating evidence suggests a recently identified chemokine, fractalkine, is involved in arterial inflammation and atherogenesis; however, few studies have examined the effects of pharmacological agents on this process. The purposes of this study were to determine if alpha-lipoic acid (ALA) inhibits the expression of tumor necrosis factor (TNF)-alpha-stimulated fractalkine in vascular smooth muscle cells(VSMCs). METHODS: Rat VSMCs were isolated and cultured. Northern and Western blot analyses were performed to evaluate the effects of ALA on the expression of TNF-alpha-stimulated fractalkine in VSMCs. A gel shift assay was performed to examine the mechanism by which ALA inhibits the expression of fractalkine. RESULTS: TNF-alpha markedly induced the expression of fractalkine in primary cultured VSMCs. ALA inhibited the expression of TNF-alpha-stimulated fractalkine in cultured VSMCs. The result of the gel shift assay suggested the inhibitory effects of AS-6 on the expression of TNF-alpha-stimulated fractalkine were mediated via the NF-kappaB pathway. CONCLUSION: This study has shown that ALA has anti-inflammatory effects on VSMCs, which are mediated by the inhibitoin, at least in part, of the NF-kappaB dependent inflammatory signal-stimulated expression of fractalkine. Our data suggest the possibility that antioxidants, such as ALA, inhibit the NF-kappaB pathway, which may be used to prevent the development and progression of atherosclerosis.

Cell Cycle Progression of Vascular Smooth Muscle cell Through Modulation of p38 MAPK and GSK-3beta Activities Under High Glucose Condition.: Yang Ho Kang, In Ju Kim, Yong Ki Kim, Seok Man Son; Korean Diabetes J. 2005;29(5):418-431. Published online September 1, 2005

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Abstract PDF: BACKGOUND: Macroangiopathy, with atherosclerosis, is the leading cause of mortality and morbidity in diabetic patients. Vascular smooth muscle cells play a crucial role in atherosclerosis, as they proliferate, migrate and express genes that encode inducible growth factors. However, the mechanisms induced by hyperglycemia that accelerate the proliferative change of vascular smooth muscle cells in diabetes remain unclear. This study was aimed at clarifying the respective roles of hyperglycemia in the acceleration of vascular complications in diabetes, examine the effects of hyperglycemia on vascular smooth muscle cell proliferation and the possible underlying mechanisms, including cell cycle progression. METHODS: Primary cultured rat aortic RASMs were exposed to normal glucose(5 mmol/L D-glucose), high glucose(30 mmol/L D-glucose) or an osmotic control (5mmol/L D-glucose plus 24.5 mmol/L mannitol) for 72 hours. The effect of high glucose on cell proliferation was determined by assessing the cell count and BrdU incorporation. Proteins involved in the cell proliferation pathway (PDK1, Akt/PKB, p42/44 MAPK, p38 MAPK, GSK-3beta) and those in cell cycle progression (cdk4, cyclin D, cdk2, cyclin E and ppRb phosphorylation) were determined by Western blot analysis. cdk4 kinase and PKC activity assays were also performed. RESULTS: A high level of glucose increased both the cell count(P<0.01) and BrdU incorporation(P<0.01). The PDK1, Akt/PKB and p42/44 MAPK activities were not significantly increased. A high level of glucose significantly increased the activities of p38 MAPK (P<0.01) and GSK-3beta(P<0.05) and the expressions of cdk4, cyclin D and ppRb phosphorylation. The cdk4 (P<0.01) and PKC (P<0.05) activities were also significantly increased. The inhibition of protein kinase C with GF109203X markedly reduced the phosphorylations of p38 MAPK and GSK-3betaand the expressions of cdk4 and cyclin D. In addition, pretreatment with GF109203X decreased the cell number in response to a high glucose level. CONCLUSION: These findings suggest that a high level of glucose increases vascular smooth muscle cell proliferation, with the possible mechanism further increases the G1 to S phase cell cycle progression via the activation of PKC, p38 MAPK and GSK-3beta.

Increasing Trends of Metabolic Syndrome in Korea -Based on Korean National Health and Nutrition Examination Surveys-.: Soo Lim, Eun Jung Lee, Bo Kyeong Koo, Sung Il Cho, Kyong Soo Park, Hak Chul Jang, Seong Yeon Kim, Hong Kyu Lee; Korean Diabetes J. 2005;29(5):432-439. Published online September 1, 2005

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Abstract PDF: BACKGOUND: The number of individuals with metabolic syndrome is increasing in Asian as well as in Western countries. The aim of this study was to compare the prevalence and patterns of metabolic syndrome as determined by the 1998 and 2001 Korean National Health and Nutrition Examination Surveys(KNHANES). METHODS: A total of 6,907 and 4,536 Koreans aged over 20 years participated in the KNHANES in 1998 and 2001, respectively. A stratified multistage probability sampling design and weighting adjustments were made to obtain a representative Korean population. The working definition of the National Cholesterol Education Program-Adult Treatment Panel III was used to define metabolic syndrome. The International Obesity Task Force criteria for the Asian-Pacific population were used to determine waist circumference criteria. RESULTS: The age-adjusted prevalence of metabolic syndrome significantly increased from 22.5 to 24.1% between 1998 and 2001(P<0.01). Of the five components composing metabolic syndrome, low HDL-cholesterolemia showed the highest increase(32.6%) over this period, followed by hypertriglyceridemia and abdominal obesity, with 15.9% and 4.3% increases, respectively. In contrast, the number of subjects with high blood pressure or elevated fasting glucose levels were reduced(37.1-->33.1% and 18.9-->15.4%, respectively, both P<0.01). CONCLUSION: Dyslipidemia and abdominal obesity were primarily responsible for the increase in metabolic syndrome in Korea over the period 1998 to 2001. Changes to diet patterns and a reduction in physical activity are likely to have contributed to the rapid increase in metabolic syndrome in Korea; therefore, national strategies will be needed to counteract this increase.

Polymorphisms of Kir6.2 Gene are Associated with Type 2 Diabetes and Blood Pressure in the Korean Population.: Bo Kyeong Koo, Hong Il Kim, Eu Jin Lee, Young Min Cho, Hyoung Doo Shin, Hak Chul Jang, Hong Kyu Lee, Kyong Soo Park; Korean Diabetes J. 2005;29(5):440-450. Published online September 1, 2005

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Abstract PDF: BACKGOUND: ATP-sensitive potassium channels are a heterooctamer of SUR1 and Kir6.2, which are key components in the insulin secretory mechanism. Whether common variants in the Kir6.2 gene are associated with type 2 diabetes and/or its associated phenotypes was investigated. METHODS: The Kir6.2 gene was sequenced in 24Korean DNA samples to identify common polymorphisms (frequency > 0.05). The common variants found among these samples were genotyped in a larger population including type 2 diabetic patients and nondiabetic subjects. RESULTS: Thirteen single nucleotide polymorphisms and one insertion/deletion polymorphism were identified in the Kir6.2 gene, with six common variants(g.-1709A>T, g.-1525T>C, g.67G >A [E23K], g.570C>T [A190A], g.1009A>G [1337V], and g.1388C>T) genotyped in 761 type 2 diabetic patients and 675 nondiabetic subjects. Four individual polymorphisms(g.-1525T > C, g.67G>A, g.1009A>G and g.1388C>T) appeared to be associated with type 2 diabetes (age, sex and BMI-adjusted odds ratio[OR]=0.751[0.584-0.967] in the recessive model on g-1525T>C, 1.193 [1.020-1.394] in the additive model in g.67G>A, 1.195 [1.022-1.399] in the additive model on g.1009A>G, 0.835 [0.717-0.973] in the additive model in g.1388C >T). The haplotype "ATACGC" in the Kir6.2 gene, composed of rare allele in the g.67 and g.1009, was also associated with a higher prevalence of type 2 diabetes (age, sex, and BMI- adjusted OR = 1.256 [1.067-1.479], P for logistic regression = 0.006). In addition g.67G>A and g.1009A >G in the KCNJ11 were strongly associated with a high systolic blood pressure. CONCLUSION: Polymorphisms in the Kir6.2 gene are associated with type 2 diabetes and blood pressure in the Korean population.

Association of Haplotype Combinations of Calpain-10 Gene Polymorphisms and the Metabolic Syndrome in Type 2 Diabetes.: Eun Seok Kang, Hye Joo Kim, Sung Min Myoung, Yumie Rhee, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Moonsuk Nam; Korean Diabetes J. 2005;29(5):451-459. Published online September 1, 2005

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Abstract PDF: OBJECTIVE: Patients with metabolic syndrome are at increased risk of developing cardiovascular disease. The combinations of the haplotype created by the alleles of three single nucleotide polymorphisms (SNPs): SNP-43, SNP-19, and SNP-63 of the Calpain 10 gene (CAPN10), have been reported to be associated with the risk of type 2 diabetes (T2DM) in many populations. The aim of this study was to examine the association of the CAPN10 polymorphisms with metabolic syndrome in Korean patients with T2DM. METHODS: Overall, 382 T2DM patients were enrolled in this study. All the subjects were genotyped according to CAPN10 SNP-43, SNP-19 and SNP-63. The restriction fragment length polymorphism method was used for the three SNPs. The baseline presence of the components of metabolic syndrome was determined. RESULTS: 265 (69.4 %) patients were found to have metabolic syndrome. Patients with the 111/121 haplotype combination showed a higher risk of hypertension than the other haplotype combinations (OR=2.334, P=0.010) and also had a significantly higher risk of having metabolic syndrome (OR=1.927, P=0.042). CONCLUSION: The results of this study suggest a role of the novel 111/121 haplotype combination created by the CAPN10 SNPs -43, -19 and -63 in the susceptibility to metabolic syndrome of T2DM patients.

The Association Between White Blood Cell Count and Metabolic Syndrome in Korean Type 2 Diabetes Mellitus.: Wan Sub Shim, Hae Jin Kim, Soo Kyung Kim, Shin Ae Kang, Eun Seok Kang, Yu Mie Rhee, Chul Woo Ahn, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Bong Soo Cha; Korean Diabetes J. 2005;29(5):460-468. Published online September 1, 2005

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Abstract PDF: BACKGOUND: Type 2 diabetes and metabolic syndrome are associated with an increased risk of cardiovascular disease, and inflammation is also closely associated with cardiovascular disease. The white blood cell count, which is a marker of systemic inflammation, has been found to correlated with the risk of cardiovascular disease. The aim of this study was to evaluate the association between metabolic syndrome and the WBC count in type 2 diabetic patients. METHODS: 606 patients (males 318, females 288, BMI 25.6+/-3.2 kg/m2 and duration of diabetes 4.8+/-5.9year) were enrolled. The WBC and differential counts, anthropometry, blood pressure, fasting glucose, insulin and lipid profiles were measured. RESULTS: According to the quartiles of the WBC count, the number of components of metabolic syndrome and percentage of patients with metabolic syndrome were increased in the highest WBC count quartile. The WBC, neutrophil, lymphocyte, monocyte and eosinophil counts increased with increasing number of components of metabolic syndrome, but not that of the basophil count. The WBC, neutrophil, lymphocyte, monocyte and eosinophil counts were higher in patients with metabolic syndrome than in those without. The WBC count was found to be positively correlated with the waist circumference(gamma=0.090), systolic blood pressure(gamma=0.090), diastolic blood pressure(gamma=0.104), triglyceride(gamma=0.252), insulin(gamma=0.168) and HOMAIR(gamma=0.170), but negatively with high-density lipoprotein cholesterol(gamma= -0.167)(P<0.05, respectively). CONCLUSION: Chronic inflammation, as indicated by a higher than normal WBC count, may increased with the increasing number of components of metabolic syndrome.

Association Between Impaired Vascular Endothelial Function and High Sensitivity C-reactive Protein, a Chronic Inflammatory Marker, in Patients with Type 2 Diabetes Mellitus.: Jang Yel Shin, Mi Young Lee, Jang Hyun Koh, Jang Young Kim, Young Goo Shin, Choon Hee Chung; Korean Diabetes J. 2005;29(5):469-478. Published online September 1, 2005

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Abstract PDF: BACKGOUND: Eighty percents of diabetes-related mortalities are due to atherosclerotic vascular complications. The accelerated atherosclerosis in type 2 diabetic patients is partly due to the increased incidences of cardiovascular risk factors, such as hypertension, obesity, dyslipidemia, insulin resistance and oxidative stress. Endothelial dysfunction is known as an early marker of cardiovascular disease and a predictor of cardiovascular events. The flow mediated dilation (FMD) of the brachial artery has been documented as being reduced in type 2 diabetic patients. Inflammatory markers, such as C-reactive protein(CRP) and interleukin-6(IL-6), are associated with the risk of cardiovascular disease. Endothelial dysfunction has a direct correlation with the levels of CRP, which are elevated in patients with diabetes compared with non-diabetic subjects. In this study, the FMD in diabetic and non-diabetic subjects were compared, and the association of cardiovascular risk factors and endothelial function examined in type 2 diabetic patients. METHODS: 57 consecutive diabetic subjects and 29 non-diabetic subjects, aged 35 to 69(54.0+/-1.0 years), without proven macrovascular complications, were enrolled in this study. Cardiovascular risk factors, such as body weight, height, waist and hip circumference, fasting plasma glucose and insulin levels, lipid profiles, inflammatory and coagulation markers were measured. The FMD of the brachial artery and the intima-media thickness(IMT) of the carotid artery were determined using high-resolution B-mode ultrasound. RESULTS: The FMD values were significantly lower in the diabetic compared with the non-diabetic subjects(7.6+/-0.2% vs. 8.9+/-0.4%, P=0.004). The homocysteine levels were significantly higher in the diabetic than non-diabetic subjects(12.4+/-0.4micromol/L vs. 9.5+/-0.6micromol/L, P<0.0001). In diabetic subjects, the FMD was shown to be significantly negatively correlated with high sensitivity C-reactive protein(hsCRP)(P=0.006), fibrinogen(P=0.024) and homocysteine (P=0.038). A multiple regression analysis, after adjusted for age, sex, body mass index(BMI), hypertension, and smoking, showed that hsCRP(beta=-0.424, P=0.002) and fibrinogen(beta=-0.324, P=0.025) had significant inverse association with the FMD in diabetic subjects. CONCLUSION: Diabetic subjects have an impaired endothelial function compared with the non-diabetic subjects, and the vascular endothelial function has a significant negative correlation with hsCRP and fibrinogen. These findings suggest that hsCRP might be an independent predictor of endothelial dysfunction and atherosclerosis, and chronic inflammation might play a pivotal role in the impairment of the endothelial function in diabetic patients.

Evaluation of Physical Capacity and Proper Calculation Method of Exercise Intensity based on Measured Maximal Heart Rate in Korean Type 2 Diabetics.: Keun Hee An, Kyung Ah Han, Kyung Wan Min; Korean Diabetes J. 2005;29(5):479-485. Published online September 1, 2005

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Abstract PDF: BACKGROUND
Prescription of aerobic exercise for type 2 diabetics in clinical practice is frequently based on exercise intensity at percent heart rate max(60

Randomized Controlled Trial

The Effects of Aerobic Training Versus Resistance Training in Non-obese Type 2 Diabetics.: Keun Hee An, Kyung Wan Min, Kyung Ah Han; Korean Diabetes J. 2005;29(5):486-494. Published online September 1, 2005

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Abstract PDF: BACKGOUND: The purpose of this study was to explore the influence of the low intensity resistance exercise training and aerobic exercise training on body composition, physical fitness, and metabolic profiles in non-obese type 2 diabetic patients. METHODS: Participants(N:26) had been randomly assigned to resistance exercise(resistance, N:10), aerobic exercise(aerobic, N:9) and control group(control, N:7). Resistance exercise was carried out at 15~20RM(1RM 60%) and aerobic exercise was carried out at anaerobic threshold(AT). Each exercise group was scheduled to implement the training for twelve weeks, two times per day and five days per week. RESULTS: Body mass index, waist to hip ratio, %fat, FBS, PP2, HbA1c and low-density lipoprotein cholesterol(LDL-C) were significantly decreased after the training period in resistance and aerobic exercise group. Strength endurance, agility and flexibility were significantly improved after the training period in resistance and aerobic exercise groups. There were significant differences in BMI, percent fat, FBS, PP2, METs and HR at anaerobic threshold after the training period in aerobic and control groups. Total cholesterol was significantly decreased after the training period in aerobic exercise groups. Load, heart rate and METs at AT significantly increased after the training period in aerobic group. High-density lipoprotein cholesterol(HDL-C) and balance significantly increased after the training period in resistance group. There were significant differences in strength endurance and agility between two exercise groups and control group. CONCLUSION: This study suggested circuit type resistance exercise might have nearly comparable effects on weight control, body composition, blood glucose control and improvement of insulin resistance in non-obese type 2diabetic patients.

Case Report

A case of Rhino-Orbital Mucormycosis in Newly Diagnosed type 1 Diabetic patient.: Jae Min Lee, Kyu Yuop Hwang, Gi Young Choi, Hyo Jung Nam, Dong Hyun Seo, Sun Hyun Park, Jun hwa Hong, Hyun Jin Kim, Kang Seo Park; Korean Diabetes J. 2005;29(5):495-499. Published online September 1, 2005

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Abstract PDF: Rhino-orbital mucormycosis was a rare, but mostly fatal fungal infection, usually found in poorly controlled diabetics or other immunocompromised hosts. This fungal infection begins from the nose, and rapidly spreads to the paranasal sinus (PNS), orbits and central nervous system(CNS), and finally extends to the entire organ. Early diagnosis and treatment is the only way to increase the survival rate. Herein Is reported We experienced a case of rhino-orbital mucormycosis, with type 1 diabetes mellitus, which was confirmed by a maxillary sinus biopsy. A 38-year-old male had been frequently treated for tonsillitis, but with no history of diabetes mellitus. He was admitted with mental change, accompanied by a fever, facial tenderness and swelling, with progressive visual acuity loss. During admission, CT and MRI of the in orbital area were performed. A biopsy in of the nasal cavity was also performed, and the mucormycosis was diagnosed through the pathological finding. The patient was treated with intravenous amphotericn B and an endoscopic antrostomy.

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