Glycaemic variability affects ischaemia-induced angiogenesis in diabetic mice

2011 ◽  
Vol 121 (12) ◽  
pp. 555-564 ◽  
Author(s):  
Federico Biscetti ◽  
Dario Pitocco ◽  
Giuseppe Straface ◽  
Francesco Zaccardi ◽  
Raimondo de Cristofaro ◽  
...  
Keyword(s):  
Murine Model ◽  
Basal Insulin ◽  
Vascular Complications ◽  
Diabetic Mice ◽  
Glycaemic Variability ◽  
Ischaemic Injury ◽  
Once Daily ◽  
Glucose Levels ◽  
Diabetic Vascular Complications ◽  
Significant Difference

The aim of the present study was to investigate the role of GV (glycaemic variability) in diabetic vascular complications and to explore the molecular pathways modulated by glycaemic ‘swings’. We developed a murine model. A total of 30 diabetic mice received once daily basal insulin administration plus two oral boluses of glucose solution (GV group, named ‘V’) and 30 diabetic mice received once daily basal insulin plus two oral boluses of saline solution (stable hyperglycaemia group, named ‘S’) for a period of 30 days. Glycaemia was measured eight times daily to detect GV. Finally, postischaemic vascularization, induced by hindlimb ischaemia 30 days after diabetes onset, was evaluated. We found that GV was significantly different between S and V groups, whereas no significant difference in the mean glycaemic values was detected. Laser Doppler perfusion imaging and histological analyses revealed that the ischaemia-induced angiogenesis was significantly impaired in V mice compared with S group, after ischaemic injury. In addition, immunostaining and Western blot analyses revealed that impaired angiogenic response in V mice occurred in association with reduced VEGF (vascular endothelial growth factor) production and decreased eNOS (endothelial nitric oxide synthase) and Akt (also called protein kinase B) phosphorylation. In conclusion, we describe a murine model of GV. GV causes an impairment of ischaemia-induced angiogenesis in diabetes, likely to be independent of changes in average blood glucose levels, and this impaired collateral vessel formation is associated with an alteration of the VEGF pathway.

scholarly journals Drug-Herb Interaction between Metformin and Momordica charantia in Diabetic Mice

2019 ◽  
Vol 3 (2) ◽  
pp. 81
Author(s):  
Asri Dwi Endah Dewi Pramesthi ◽  
Mirhansyah Ardana ◽  
Niken Indriyanti
Keyword(s):  
Fruit Juice ◽  
Negative Control ◽  
Momordica Charantia ◽  
Bitter Gourd ◽  
Diabetic Mice ◽  
Once Daily ◽  
Glucose Lowering ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Significant Difference

Background: Bitter gourd has various metabolites, such as momordicosides, polypeptide-P, v-insulin, charantin, and vicine that have antidiabetic effect. It has synergistically effect while combined with oral diabetic drugs, such as metformin as glucose lowering agent. The aim of this study is to investigate the interaction of bitter gourd fruit juice and metformin as glucose lowering agent in mice.Materials and Methods: Alloxan-induced diabetic mice were treated with bitter gourd fruit juice, metformin, and the combination of those two for 21 days. Glucose level was checked on first and last day of treatment.Results: Furthermore, blood glucose levels measurement showed no significant difference between groups compared with negative control, which was p>0.05. The stomach of groups that treated with metformin and bitter gourd fruit juice histopathologically showed no significant differences.Conclusion: The use of bitter gourd once daily together with metformin is a better choice, while twice daily might induce hypoglycemia and mice death. There is no interaction between them on lowering blood glucose.Keywords: metformin, Momordica charantia, diabetes mellitus

Macrovascular Disease in Diabetes: Is the Mouse a Suitable Model?

2012 ◽  
Vol 120 (04) ◽  
pp. 194-196 ◽  
Author(s):  
O. Müller ◽  
H. Katus ◽  
J. Backs
Keyword(s):  
Animal Models ◽  
Mouse Models ◽  
Knockout Mice ◽  
Vascular Complications ◽  
Macrovascular Disease ◽  
Suitable Model ◽  
Diabetic Mice ◽  
Advantages And Disadvantages ◽  
Diabetic Vascular Complications

AbstractTo elucidate the pathogenesis of macrovascular disease in diabetes, animal models are widely used. Diabetic mice are of particular interest because they can be crossed to knockout mice lacking specific genes that are under consideration to contribute to diabetic vascular complications. However, the mouse is relative resistant to develop atherosclerosis. Therefore, we review some commonly used mouse models and discuss their advantages and disadvantages.

Abstract MP250: Reduction In Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator (arnt) Mediates Vascular Dysfunction In Mice With Type 2 Diabetes Mellitus

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Tu Nguyen ◽  
Kaichao Pan ◽  
Maura Knapp ◽  
Mei Zheng ◽  
Nikola Sladojevic ◽  
...  
Keyword(s):  
Cell Viability ◽  
High Glucose ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Tube Formation ◽  
Diabetic Mice ◽  
Aryl Hydrocarbon ◽  
Diabetic Vascular Complications ◽  
High Fat Chow

Background: Endothelial dysfunction, especially at the microvasculature level, is one of the most deleterious events in diabetes. ARNT is a transcription factor that functions as a master regulator of glucose homeostasis, but its role in diabetic vascular complications is poorly understood. Results and method: We found a reduction in ARNT expression in microvascular endothelial cells (MVECs) derived from type 2 diabetic mice (db/db). Thus, we generated an inducible, EC-specific ARNT-knockout mutation ( Arnt ΔEC, ERT2) to address the hypothesis that aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes. We show here that loss of ARNT in the endothelium mimics diabetic phenotypes, such as impairs blood flow recovery after hindlimb ischemia, delays wound healing, and exacerbates infiltration of pro-inflammatory neutrophils after myocardial infarction. Interestedly, the degree of these impairments in the KO mice was more remarkable in diabetic animals induced with high-fat chow. In addition, the siRNA-mediated knockdown of ARNT activity reduced tube formation and cell viability measurements in HUVECs cultured under high-glucose conditions. The Arnt ΔEC, ERT2 mutation also reduced measures of cell viability while increasing the production of reactive oxygen species (ROS) in MVECs isolated from mouse skeletal muscle, and the viability of Arnt ΔEC, ERT2 MVECs under high-glucose concentrations increased when the cells were treated with a ROS inhibitor. Conclusion: Collectively, these observations suggest that declines in endothelial ARNT expression contribute to the suppressed angiogenic phenotype in diabetic mice and that the cytoprotective effect of ARNT expression in ECs is at least partially mediated by declines in ROS production. Endothelial ARNT might be a critical mediator of endothelial function and could serve as a therapeutic target for diabetic complications.

scholarly journals The sympathoadrenal system in diabetics with different patterns of the disease and its late complications

1994 ◽  
Vol 40 (6) ◽  
pp. 13-14 ◽  
Author(s):  
K. M. Chanclrashekar-Reddy ◽  
M. I. Balabolkin ◽  
L. D. Stoilov
Keyword(s):  
Diabetic Neuropathy ◽  
Diabetic Complications ◽  
Plasma Concentrations ◽  
Vascular Complications ◽  
Late Complications ◽  
Dependent Diabetes Mellitus ◽  
Sympathoadrenal System ◽  
Glucose Levels ◽  
Diabetic Vascular Complications ◽  
Group 2

Blood plasma concentrations of noradrenaline, dopamine, serotonin and their metabolites (DOPAC, HVA) were measured in 28 patients with insulin-dependent and 32 with noninsulin-dependent diabetes mellitus (IDDM and NIDDM, respectively). The patients were divided into 4 groups. Group 1 were 15 patients without late diabetic complications, group 2 were 15 subjects with diabetic neuropathy, group 3 were patients with neuropathy and retinopathy (n=16), and group 4 were 14 patients with neuropathy, retinopathy, and nephropathy. The results showed an increase of serotonin levels in IDDM patients w. those with NIDDM, a positive correlation between serotonin and blood glucose levels in IDDM, increased concentration of dopamine and reduced plasma level of noradrenaline in patients with diabetic neuropathy vs. those without late diabetic complications. Plasma levels of dopamine were decreased in all the patients microvascular involvement. The findings indicate the development of changes in the sympathoadrenal system of patients with late diabetic vascular complications.

scholarly journals Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial

2021 ◽  
Author(s):  
Harpreet S. Bajaj ◽  
Richard M. Bergenstal ◽  
Andreas Christoffersen ◽  
Melanie J. Davies ◽  
Amoolya Gowda ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Glargine ◽  
Basal Insulin ◽  
Oral Glucose ◽  
Loading Dose ◽  
Phase 2 ◽  
Once Daily ◽  
Daily Insulin ◽  
Significant Difference

<b>OBJECTIVE</b><br><b></b><p><b> </b>Insulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine U100 (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and ≥1 oral glucose-lowering medication.</p> <p><b>RESEARCH DESIGN AND METHODS</b><br> This multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal-insulin-treated (total daily dose 10–50 U) people with type 2 diabetes (HbA<sub>1c</sub> 7.0–10.0% [53.0–13.3 mmol/mo]) to icodec with an initial 100% loading dose (where only the first dose was doubled; icodec LD), icodec with no loading dose (icodec NLD) or IGlar U100 for 16 weeks. Primary endpoint was percent time in <a>range (TIR; 3.9–10.0 mmol/L [70–180 mg/dL]) </a>during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary endpoints included HbA<sub>1c</sub>,<sub> </sub>adverse events (AEs) and hypoglycemia. </p> <p><b>RESULTS</b><br> Estimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; <i>n</i> = 54), 66.0% (icodec NLD; <i>n</i> = 50) and 65.0% (IGlar U100; <i>n</i> = 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points, 95% CI 1.8 to 13.9%). Mean HbA<sub>1c</sub> reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% ([54.4 mmol/mol] icodec LD) and 7.4% ([57.6 mmol/mol] icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable.<br> <br> </p> <p><b>CONCLUSIONS</b><br> Switching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to once-weekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.</p>

scholarly journals ERK-containing microparticles from a diabetic mouse induce endothelial dysfunction

2019 ◽  
Vol 241 (3) ◽  
pp. 221-233 ◽  
Author(s):  
Kumiko Taguchi ◽  
Haruka Narimatsu ◽  
Takayuki Matsumoto ◽  
Tsuneo Kobayashi
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Complications ◽  
Diabetic Mouse ◽  
Diabetic Rats ◽  
Enzyme Linked Immunosorbent Assay ◽  
Diabetic Mice ◽  
Diabetic Vascular Complications ◽  
Underlying Mechanisms

Endothelial dysfunction is a hallmark of diabetic vascular complications. Microparticles (MPs) are small vesicles shed from the surface of blood and vascular cells that act as stimuli and during apoptosis. Circulating MPs of diabetic rats have been shown to induce endothelial dysfunction. However, the underlying mechanisms require further study. In this study, we investigated how MPs from diabetic mice affect endothelial function. MPs were collected from streptozotocin-induced diabetic mice and Institute of Cancer Research (ICR) mice as controls. The levels of MPs were assessed and characterized by flow cytometry, enzyme-linked immunosorbent assay and dot blotting. Normal mice aortas were incubated with MPs and expressions of enzymes and vascular relaxation were analyzed. We found that (1) circulating MPs level increased in diabetic mice; (2) MPs impaired endothelial-dependent relaxation in mice aorta, but diabetic mice-derived MPs (diabetes mellitus (DM) MPs) were easier to attach to the endothelial cells than were control MPs; (3) DM MPs had more extracellular signal-regulated kinase (ERK)1/2 than did control mice-derived MPs, and they induced ERK1/2 activation in mice aortas; (4) DM MPs decreased endothelial nitric oxide synthase (eNOS) in mice aortas, and eNOS was emitted from endothelial cells to blood in the shape of endothelial MPs. DM MPs significantly altered endothelial function by activation of ERK1/2, which might provide a therapeutic target for diabetic vascular complications.

Structure-function analysis of the antioxidant properties of haptoglobin

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3693-3698 ◽  
Author(s):  
Meira Melamed-Frank ◽  
Orit Lache ◽  
Benjamin I. Enav ◽  
Tal Szafranek ◽  
Nina S. Levy ◽  
...  
Keyword(s):  
Function Analysis ◽  
Antioxidant Properties ◽  
Vascular Complications ◽  
Differential Susceptibility ◽  
Allelic Polymorphism ◽  
Biochemical Basis ◽  
Diabetic Vascular Complications ◽  
Rational Development ◽  
Significant Difference

Abstract Haptoglobin serves as an antioxidant by virtue of its ability to prevent hemoglobin-driven oxidative tissue damage. It was recently demonstrated that an allelic polymorphism in the haptoglobin gene is predictive of the risk for numerous microvascular and macrovascular diabetic complications. Because these complications are attributed in large part to an increase in oxidative stress, a study was conducted to determine whether the different protein products of the 2 haptoglobin alleles differed in the antioxidant protection they provided. A statistically significant difference was found in the antioxidant capacity of purified haptoglobin protein produced from the 2 different alleles, consistent with the hypothesis that differences in genetically determined antioxidant status may explain differential susceptibility to diabetic vascular complications. These differences may be amplified in the vessel wall because of differences in the sieving capacity of the haptoglobin types. Therefore, an attempt was made to identify the minimal haptoglobin sequences necessary to inhibit oxidation by hemoglobin in vitro, and 2 independent haptoglobin peptides that function in this fashion as efficiently as native haptoglobin were identified. Identification of the biochemical basis for differences among haptoglobin types may lead to the rational development of new pharmacologic agents, such as the mini-haptoglobin described here, to avert the development of diabetic vascular complications.

Reduction in Primary Nonfunction of Syngeneic Islet Transplants with Nordihydroguaiaretic Acid, a Lipoxygenase Inhibitor

2001 ◽  
Vol 10 (3) ◽  
pp. 255-262 ◽  
Author(s):  
Brend Ray-Sea Hsu ◽  
Jyuhn-Huarng Juang ◽  
Shin-Huei Fu ◽  
Chien-Hung Kuo ◽  
Wen-Tsoung Lu
Keyword(s):  
Blood Glucose ◽  
Nordihydroguaiaretic Acid ◽  
Insulin Content ◽  
Diabetic Mice ◽  
Lipoxygenase Inhibitor ◽  
Glucose Levels ◽  
Primary Nonfunction ◽  
Blood Glucose Levels ◽  
Significant Difference ◽  
Islet Transplants

To study the effectiveness of a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), in the reduction of primary nonfunction, an insufficient number of syngeneic islets were transplanted underneath the renal capsule with NDGA administered daily for 4 weeks. After transplantation of the 150 islets, the decrement of blood glucose levels was significantly faster in the mice that had received NDGA than in the mice that had received no drug at all or dimethyl sulfoxide (DMSO) (p < 0.005, p < 0.05). The mean duration of temporary posttransplant hyperglycemia was 22.3 ± 3.2 (n = 10), 35.9 ± 2.3 (n = 14), and 33.7 ± 4.1 (n = 6) days for the respective groups. The diabetic mice that received 300 islets had their blood glucose levels decrease faster than those that received 150 islets (19.7 ± 1.6 vs. 35.9 ± 2.3 days, n = 14, p < 0.0001). There was no significant difference in the blood glucose reducing effect between the mice that received 150 islets with NDGA and the mice that received 300 islets [22.3 ± 3.2 (n = 10) vs. 19.7 ± 1.6 (n = 14) days, p > 0.05]. The insulin content of the graft from the mice treated with 150 islets and NDGA (3.02 ± 0.24 μg, n = 4) was higher than that from the mice that received 150 islets but no treatment (1.10 ± 0.26 μg, n = 15, p < 0.005) or that had been treated with DMSO (1.21 ± 0.30 μg, n = 4, p < 0.05). The insulin content of the pancreas remnant had no significant differences among the three groups. The net glucose-stimulated insulin secretion was 0.82 ± 0.14 vs. 0.20 ± 0.10 μIU/islet × 60 min (n = 8, p < 0.005) and 0.59 ± 0.08 vs. 0.04 ± 0.02 μIU/islet × 60 min (n = 8, p < 0.0001) for islets cultured without NDGA vs. with NDGA at 1 and 2 weeks, respectively. However, the insulin content of the cultured islets was similar between the two groups for up to 2 weeks of incubation (at 1 week: 0.71 ± 0.01 vs. 0.67 ± 0.04 ng/islet, n = 8, p > 0.05; at 2 weeks: 0.71 ± 0.02 vs. 0.80 ± 0.07 ng/islet, n = 8, p > 0.05). Serum leukotriene B4 (LTB4) concentrations before and between the fifth and seventh days after transplantation were determined. For diabetic mice that received 150 islets, serum LTB4 levels were 25,835 ± 3,335 and 27,631 ± 3,136 pg/ml (n = 4, p > 0.05). For diabetic mice that received 150 islets and NDGA, the corresponding figures were 22,401 ± 2,706 pg/ml and 27,530 ± 2,190 pg/ml (n = 8, p > 0.05). The graft histology revealed viable islet cells and networks of close vascular structures around the islets and did not reveal microscopic differences among the samples of all four groups. In conclusion, our data revealed that daily administration of NDGA for 4 weeks enhanced isoislet engraftment and preserved three times more mass of the islet beta cells in the isografts. This result indicates that NDGA reduces primary nonfunction of islet syngeneic grafts in diabetic mice.

scholarly journals Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial

2021 ◽  
Author(s):  
Harpreet S. Bajaj ◽  
Richard M. Bergenstal ◽  
Andreas Christoffersen ◽  
Melanie J. Davies ◽  
Amoolya Gowda ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Glargine ◽  
Basal Insulin ◽  
Oral Glucose ◽  
Loading Dose ◽  
Phase 2 ◽  
Once Daily ◽  
Daily Insulin ◽  
Significant Difference

<b>OBJECTIVE</b><br><b></b><p><b> </b>Insulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine U100 (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and ≥1 oral glucose-lowering medication.</p> <p><b>RESEARCH DESIGN AND METHODS</b><br> This multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal-insulin-treated (total daily dose 10–50 U) people with type 2 diabetes (HbA<sub>1c</sub> 7.0–10.0% [53.0–13.3 mmol/mo]) to icodec with an initial 100% loading dose (where only the first dose was doubled; icodec LD), icodec with no loading dose (icodec NLD) or IGlar U100 for 16 weeks. Primary endpoint was percent time in <a>range (TIR; 3.9–10.0 mmol/L [70–180 mg/dL]) </a>during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary endpoints included HbA<sub>1c</sub>,<sub> </sub>adverse events (AEs) and hypoglycemia. </p> <p><b>RESULTS</b><br> Estimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; <i>n</i> = 54), 66.0% (icodec NLD; <i>n</i> = 50) and 65.0% (IGlar U100; <i>n</i> = 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points, 95% CI 1.8 to 13.9%). Mean HbA<sub>1c</sub> reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% ([54.4 mmol/mol] icodec LD) and 7.4% ([57.6 mmol/mol] icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable.<br> <br> </p> <p><b>CONCLUSIONS</b><br> Switching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to once-weekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.</p>

scholarly journals Switching to Once-Weekly Insulin Icodec Versus Once-Daily Insulin Glargine U100 in Type 2 Diabetes Inadequately Controlled on Daily Basal Insulin: A Phase 2 Randomized Controlled Trial

2021 ◽  
Author(s):  
Harpreet S. Bajaj ◽  
Richard M. Bergenstal ◽  
Andreas Christoffersen ◽  
Melanie J. Davies ◽  
Amoolya Gowda ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Glargine ◽  
Basal Insulin ◽  
Oral Glucose ◽  
Loading Dose ◽  
Phase 2 ◽  
Once Daily ◽  
Daily Insulin ◽  
Significant Difference

<b>OBJECTIVE</b><br><b></b><p><b> </b>Insulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine U100 (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and ≥1 oral glucose-lowering medication.</p> <p><b>RESEARCH DESIGN AND METHODS</b><br> This multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal-insulin-treated (total daily dose 10–50 U) people with type 2 diabetes (HbA<sub>1c</sub> 7.0–10.0% [53.0–13.3 mmol/mo]) to icodec with an initial 100% loading dose (where only the first dose was doubled; icodec LD), icodec with no loading dose (icodec NLD) or IGlar U100 for 16 weeks. Primary endpoint was percent time in <a>range (TIR; 3.9–10.0 mmol/L [70–180 mg/dL]) </a>during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary endpoints included HbA<sub>1c</sub>,<sub> </sub>adverse events (AEs) and hypoglycemia. </p> <p><b>RESULTS</b><br> Estimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; <i>n</i> = 54), 66.0% (icodec NLD; <i>n</i> = 50) and 65.0% (IGlar U100; <i>n</i> = 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points, 95% CI 1.8 to 13.9%). Mean HbA<sub>1c</sub> reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% ([54.4 mmol/mol] icodec LD) and 7.4% ([57.6 mmol/mol] icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable.<br> <br> </p> <p><b>CONCLUSIONS</b><br> Switching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to once-weekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.</p>

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