Vascular wall reactivity in conductance and resistance arteries: differential effects of insulin resistance

1998 ◽  
Vol 76 (1) ◽  
pp. 72-76 ◽  
Author(s):  
Sheila F O'Brien ◽  
Joyce D McKendrick ◽  
Marek W Radomski ◽  
Sandra T Davidge ◽  
James C Russell
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Vascular Disease ◽  
Vascular Wall ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Resistance Arteries ◽  
Resistance Vessels ◽  
Increased Risk ◽  
Obese Rats

Insulin resistance is associated with an increased risk of cardiovascular disease that is probably related to abnormalities of vascular wall function. The JCR:LA-cp rat is a unique animal model of human vascular disease that exhibits a profound insulin resistance, vasculopathy, and cardiovascular disease, and allows study of the relationships between insulin resistance and vascular function. Conductance and resistance arteries serve different functions, thus vascular disease may affect these types of artery differently. Concentration-response curves to norepinephrine, phenylephrine, and acetylcholine were studied in conductance vessels (aortic rings) and resistance vessels (mesenteric arteries) from 12-week-old male obese and lean JCR:LA-cp rats. The aortic rings and mesenteric arteries from obese rats showed increased maximal response to phenylephrine compared with those from lean rats, whereas only the mesenteric arteries from obese rats showed increased maximal response to norepinephrine. In aortic rings, relaxation to acetylcholine was similar for both genotypes, but the mesenteric arteries of obese rats showed impaired relaxation to acetylcholine. We conclude that the sensitivity to vasoconstriction is enhanced in aortic rings and mesenteric arteries of obese male JCR:LA-cp rats, but endothelial function is impaired only in the mesenteric resistance arteries of these animals. Hence functional aberrations in the obese, insulin-resistant state are more pronounced in mesenteric resistance arteries than in a major conductance artery.Key words: insulin resistance, arterial contraction and relaxation, resistance vessels, JCR:LA-cp rat, smooth muscle cells,endothelium.

Vascular wall dysfunction in JCR:LA-cp rats: effects of age and insulin resistance

1999 ◽  
Vol 277 (5) ◽  
pp. C987-C993 ◽  
Author(s):  
Sheila F. O'brien ◽  
James C. Russell ◽  
Sandra T. Davidge
Keyword(s):  
Insulin Resistance ◽  
Vascular Dysfunction ◽  
Vascular Wall ◽  
Vascular Relaxation ◽  
Resistance Arteries ◽  
High Potassium ◽  
Insulin Resistant ◽  
Vasoconstrictor Response ◽  
Obese Rats ◽  
Oxide Synthase

We tested the hypothesis that aging and insulin resistance interact to increase vascular dysfunction by comparing the function of isolated mesenteric resistance arteries in obese, insulin-resistant JCR:LA-cp rats and lean, insulin-sensitive rats of the same strain at 3, 6, 9, and 12 mo of age. The peak constrictor responses to norepinephrine, phenylephrine, and high potassium were elevated in arteries from obese rats. Responses to these agents increased with age in both obese and lean rats. An eicosanoid constrictor contributed substantially to vasoconstriction in the arteries from both lean and obese animals. Inhibition of nitric oxide synthase increased the vasoconstrictor response to norepinephrine in both obese and lean rats. This effect increased with age in lean rats only. Vascular relaxation in response to acetylcholine and sodium nitroprusside was impaired in the obese rats and did not alter with age. The results suggest that obese JCR:LA-cp rats have enhanced maximal constriction, which originates in the arterial smooth muscle and increases with age. There is evidence that the ability of the arteries to compensate for the enhanced contractility is impaired in obese rats, particularly with advanced age.

Modulation of vasomotion in resistance arteries of JCR:LA-cp rats: a model of insulin resistance

1999 ◽  
Vol 77 (1) ◽  
pp. 71-74 ◽  
Author(s):  
Sheila F O'Brien ◽  
James C Russell ◽  
Sandra T Davidge
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Nitric Oxide Synthase Inhibitor ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Prostaglandin H ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Obesity and insulin resistance are strongly associated with an increased risk of vascular disease. Vasomotion is the cyclic variation in the diameter of arteries and is a general feature of the vasculature that may have important physiological consequences. We tested the hypothesis that obesity - insulin resistance is associated with abnormal vasomotion by comparing obese, insulin-resistant JCR:LA-cp rats, known to develop vasculopathy, atherosclerosis, and ischemic lesions of the heart, with lean insulin-sensitive animals from the same strain. Vasomotion was assessed using isolated mesenteric arteries on a myograph system after preconstriction to 50% of maximal constriction with norepinephrine. The amplitude of vasomotion was enhanced by the presence of meclofenamate, a prostaglandin H synthase inhibitor, and was diminished by NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Removal of the endothelium essentially abolished vasomotion, and meclofenamate had no effect on de-endothelialized arteries. Frequency was not altered by either L-NAME or meclofenamate. Although pharmacological inhibition of nitric oxide and eicosanoid production clearly altered vasomotion, there was no difference in the amplitude or frequency of vasomotion in arteries from obese rats compared with lean rats. These results indicate that the endothelium plays a central role in modulating vasomotion, involving both enhancing and inhibiting effects, and that vasomotion is similar between obese, insulin-resistant and lean, insulin-sensitive rats.Key words: insulin resistance, vasomotion, resistance arteries, JCR:LA-cp rats.

Dietary obesity in the rat induces endothelial dysfunction without causing insulin resistance: a possible role for triacylglycerols

2001 ◽  
Vol 101 (5) ◽  
pp. 499-506 ◽  
Author(s):  
Ebrahim K. NADERALI ◽  
Michael J. BROWN ◽  
Lucy C. PICKAVANCE ◽  
John P.H. WILDING ◽  
Patrick J. DOYLE ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Endothelial Dysfunction ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Fat Pad ◽  
Metabolic Disturbances ◽  
Response Curves ◽  
No Donor ◽  
Obese Rats

Impaired arterial vasorelaxation, due primarily to endothelial dysfunction, is associated with obesity. To clarify the relationship with insulin resistance and other metabolic disturbances, we studied endothelial-dependent and -independent vascular responses in rats with dietary-induced obesity. Dietary-obese rats had significantly higher body weights (10-32%; P < 0.001) and fat-pad masses (220-280%; P < 0.001) than lean controls, together with raised plasma levels of triacylglycerols (15-80%; P < 0.001), non-esterified fatty acids (13-38%; P < 0.05) and leptin (85-180%; P < 0.001). However, measures of insulin sensitivity (including the hyperinsulinaemic-euglycaemic clamp in a parallel experiment) were comparable with those in controls. Contractions induced in mesenteric arteries by noradrenaline (0.5-8μmol/l) were comparable in lean and obese groups, but vasorelaxation in noradrenaline-preconstricted arteries was markedly reduced in dietary-obese rats of both sexes. Concentration-response curves to endothelium-dependent vasorelaxants (acetylcholine, A23187 and insulin) showed significant reductions in maximal relaxation (20-95% less than in leans; P < 0.001) and significant rightward shifts in EC40 (concentration giving 40% of maximal response) (P < 0.01). Relaxation in response to the direct NO donor, sodium nitroprusside, showed a lesser impairment (12%; P < 0.01) in dietary-obese rats. Maximal relaxation to acetylcholine was correlated inversely in both sexes with fat-pad mass (r2 = 0.37, P < 0.05) and plasma triacylglycerols (r2 = 0.51, P < 0.01), and with leptin in males only (r2 = 0.35, P < 0.05). Independent determinants of acetylcholine-induced relaxation were fat mass and plasma triacylglycerols; plasma insulin and insulin sensitivity had no effect. Dietary-induced obesity severely impaired arterial relaxation in both sexes, particularly at the endothelial level. This is not attributable to insulin resistance, but may be related to moderate hypertriglyceridaemia.

scholarly journals Influence of methyltestosterone postmenopausal therapy on plasma lipids, inflammatory factors, glucose metabolism and visceral fat: a randomized study

2006 ◽  
Vol 154 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Lenora M Camarate S M Leão ◽  
Mônica Peres C Duarte ◽  
Dalva Margareth B Silva ◽  
Paulo Roberto V Bahia ◽  
Cláudia Medina Coeli ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Postmenopausal Women ◽  
Fat Mass ◽  
Visceral Fat ◽  
Increased Risk

Background: There has been a growing interest in treating postmenopausal women with androgens. However, hyperandrogenemia in females has been associated with increased risk of cardiovascular disease. Objective: We aimed to assess the effects of androgen replacement on cardiovascular risk factors. Design: Thirty-seven postmenopausal women aged 42–62 years that had undergone hysterectomy were prospectively enrolled in a double-blind protocol to receive, for 12 months, percutaneous estradiol (E2) (1 mg/day) combined with either methyltestosterone (MT) (1.25 mg/day) or placebo. Methods: Along with treatment, we evaluated serum E2, testosterone, sex hormone-binding globulin (SHBG), free androgen index, lipids, fibrinogen, and C-reactive protein; glucose tolerance; insulin resistance; blood pressure; body-mass index; and visceral and subcutaneous abdominal fat mass as assessed by computed tomography. Results: A significant reduction in SHBG (P < 0.001) and increase in free testosterone index (P < 0.05; Repeated measures analysis of variance) were seen in the MT group. Total cholesterol, triglycerides, fibrinogen, and systolic and diastolic blood pressure were significantly lowered to a similar extent by both regimens, but high-density lipoprotein cholesterol decreased only in the androgen group. MT-treated women showed a modest rise in body weight and gained visceral fat mass relative to the other group (P < 0.05), but there were no significant detrimental effects on fasting insulin levels and insulin resistance. Conclusion: This study suggests that the combination of low-dose oral MT and percutaneous E2, for 1 year, does not result in expressive increase of cardiovascular risk factors. This regimen can be recommended for symptomatic postmenopausal women, although it seems prudent to perform baseline and follow-up lipid profile and assessment of body composition, especially in those at high risk of cardiovascular disease.

scholarly journals The Role of Endothelial Dysfunction in the Pathogenesis of Vascular Complications of Diabetes Mellitus - A High Priority Area of Investigation

2015 ◽  
Vol 22 (1) ◽  
pp. 61-66 ◽  
Author(s):  
Rodica Teodora Străchinariu
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Vascular Complications ◽  
Noninvasive Methods ◽  
Cardiovascular Damage ◽  
Vasoactive Substances ◽  
Organ Systems ◽  
Increased Risk

Abstract Endothelium, the inner layer of the vasculature, represents the interface between blood and organ systems and it is active in the process of contraction and relaxation of vascular smooth muscle and in functions like secretion of vasoactive substances. Endothelial dysfunction is an important cause of cardiovascular disease. The function of the endothelium can be assessed by invasive and noninvasive methods. Endothelial cells produce vasoactive substances like endothelium derived relaxing factor, prostacyclin, nitric oxide, and endothelium derived hyperpolarizing factor. Diabetes mellitus is associated with an increased risk of cardiovascular diseases. Hyperglycemia leads to cardiovascular damage through different pathways, including the polyol and hexosamine pathways, generation of advanced glycation end products, and activation of protein kinase C. Together with hyperglycemia induced mitochondrial dysfunction and endoplasmic reticulum stress, all these can promote the accumulation of reactive oxygen species. The oxidative stress induced by hyperglycemia promotes endothelial dysfunction with an important role in micro and macro vascular disease. Insulin-resistance could be independently predictive of cardiovascular disease. Life style modification and pharmacotherapy could possibly ameliorate the effect of insulin resistance

scholarly journals The Role of Fetuin-A in Disease Processes Prevalent in Postmenopausal Women (El papel de la fetuina A en los procesos de enfermedad prevalentes en mujeres posmenopáusicas)

Retos ◽  
2015 ◽  
pp. 172-179
Author(s):  
Annie A. Bane ◽  
Peter W. Grandjean
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Postmenopausal Women ◽  
Abdominal Fat ◽  
Mineral Density ◽  
Fetuin A ◽  
Increased Risk ◽  
Resistencia A La Insulina ◽  
Low Levels

The purpose of this review is to summarize the role of fetuin-A in disease processes prevalent in postmenopausal women and synthesize effective interventions in obtaining healthy fetuin-A levels. A review of databases for articles related to fetuin-A and diseases associated with postmenopausal women was conducted. Articles were limited to full-text access, published in English since 1944. High fetuin-A levels are closely associated with decreased bone mineral density, increased cardiovascular disease risks, impairment of insulin signaling and disruption of adipocyte functioning. Postmenopausal women have increased risk of osteoporosis, cardiovascular disease, insulin-resistance, intra-abdominal fat accumulation and vascular calcification. Low-levels of fetuin-A have been shown to be protective against the latter. The role of fetuin-A is multi-factorial and the mechanisms in which it is involved in each of these processes are vast. The present body of literature is inconsistent in defining high versus low levels of fetuin-A and their association with healthy-matched controls. The diseases associated with high levels of fetuin-A mimic diseases most prevalent in postmenopausal women. In addition, there is no research, to date, exploring fetuin-A levels in postmenopausal women and the associations it may or may not have in related diseases.Key words: fetuin-A; Alpha2-Heremans-Schmid glycoprotein; cardiovascular disease; and elderly, insulin-resistance, intra-abdominal fat, metabolic syndrome, exercise, weight-loss, calorie restriction and postmenopausal.Resumen. El propósito de esta revisión es sintetizar el papel de la fetuina A en los procesos de enfermedad prevalentes en mujeres posmenopáusicas y resumir las intervenciones efectivas que permiten obtener niveles saludables de fetuina A. Para ello, se revisaron bases de datos con artículos relacionados con fetuina A y las enfermedades asociadas con mujeres posmenopáusicas. La búsqueda de artículos se limitó a aquellos de texto completo publicados en el idioma inglés desde el año 1944. Se encontró que altos niveles de fetuina A están íntimamente relacionados con una reducción de la densidad mineral ósea, un aumento en el riesgo de enfermedad cardiovascular, deterioro de la señalización de la insulina y la alteración del funcionamiento de los adipocitos. Las mujeres posmenopáusicas tienen un mayor riesgo de osteoporosis, enfermedad cardiovascular, resistencia a la insulina, acumulación de grasa intra abdominal y calcificación vascular. Se ha demostrado que niveles bajos de fetuina A son protectores contra esta última condición. El papel de fetuina A es multifactorial y los mecanismos en los que está involucrado en cada uno de estos procesos son muy amplios. El estado actual de la literatura no es consistente en la definición de niveles de fetuina A altos versus bajos y su asociación con controles sanos. Las enfermedades asociadas con altos niveles de fetuina A asemejan las enfermedades más prevalentes en mujeres posmenopáusicas. Además, no existen investigaciones, hasta la fecha, en las que se   exploren los niveles de fetuina A en mujeres posmenopáusicas y las asociaciones que puede o no puede tener en las enfermedades relacionadas.Palabras claves: fetuina A, glicoproteína Alpha2-Heremans-Schmid, enfermedad cardiovascular, adulto mayor, resistencia a la insulina, grasa intra abdominal, síndrome metabólico, ejercicio, pérdida de peso, restricción calórica, posmenopausia.

scholarly journals Relationship between endothelial dysfunction and development of complications of metabolic syndrome

2018 ◽  
Vol 99 (5) ◽  
pp. 784-791
Author(s):  
A G Mustafaeva
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Endothelial Dysfunction ◽  
Smooth Muscles ◽  
Circulatory System ◽  
Vascular Wall ◽  
Vascular Walls ◽  
Increased Risk ◽  
Normal Tone ◽  
Almost All

The article presents the analysis of literature data on the pathogenetic role of endothelial dysfunction (ED) in the development of complications of metabolic syndrome (MS). There are two main signs of MS development - abdominal obesity (AO) and primary insulin resistance (IR). IR and concomitant hyperinsulinemia have both direct and indirect atherogenic effects on vascular walls, lead to the development of dyslipidemia, a number of hormonal and metabolic disorders, activation of the sympathoadrenal system, ie, are the basis of almost all components of MS. Despite the high margin of safety of the circulatory system, there comes a time when, due to frequent vasoconstrictor effects thickening of the walls of resistive vessels occurs to limit local perfusion. The thickening of the walls of arteries develops, that is, the modeling of the vascular wall occurs, leading to an increase of the total peripheral vascular resistance with normal tone of smooth muscles. Currently, the concept of ED is formulated as a key link of insulin resistance and atherogenesis in MS. Methods for studying endothelial function have been created and are introduced into clinical practice. New approaches to directed correction of endothelial dysfunction are being developed. Prospective studies have shown that the degree of endothelial dysfunction may be important in predicting cardiovascular events in patients with or without identified vascular disease. Probably, ED may also be related to the pathogenesis of diabetes mellitus type 2 (DM2). Since all components of MS can have an adverse effect on endothelium, ED can be an extremely common phenomenon in patients with metabolic syndrome and can act as a predictor of increased risk of cardiovascular diseases and DM2 in this population.

scholarly journals Osteopontin in Vascular Disease

2019 ◽  
Vol 39 (4) ◽  
pp. 613-622 ◽  
Author(s):  
Zoe Shin Yee Lok ◽  
Alicia N. Lyle
Keyword(s):  
Cardiovascular Disease ◽  
Vascular Disease ◽  
Strong Predictor ◽  
Healing Process ◽  
Major Adverse Cardiovascular Event ◽  
Adverse Cardiovascular Event ◽  
Acute Response ◽  
Increased Risk ◽  
Traditional Risk Factors

Inflammatory cytokines are necessary for an acute response to injury and the progressive healing process. However, when this acute response does not resolve and becomes chronic, the same proteins that once promoted healing then contribute to chronic inflammatory pathologies, such as atherosclerosis. OPN (Osteopontin) is a secreted matricellular cytokine that signals through integrin and CD44 receptors, is highly upregulated in acute and chronic inflammatory settings, and has been implicated in physiological and pathophysiologic processes. Evidence from the literature suggests that OPN may fit within the Goldilocks paradigm with respect to cardiovascular disease, where acute increases are protective, attenuate vascular calcification, and promote postischemic neovascularization. In contrast, chronic increases in OPN are clinically associated with an increased risk for a major adverse cardiovascular event, and OPN expression is a strong predictor of cardiovascular disease independent of traditional risk factors. With the recent finding that humans express multiple OPN isoforms as the result of alternative splicing and that these isoforms have distinct biologic functions, future studies are required to determine what OPN isoform(s) are expressed in the setting of vascular disease and what role each of these isoforms plays in vascular disease progression. This review aims to discuss our current understanding of the role(s) of OPN in vascular disease pathologies using evidence from in vitro, animal, and clinical studies. Where possible, we discuss what is known about OPN isoform expression and our understanding of OPN isoform contributions to cardiovascular disease pathologies.

scholarly journals Vascular function in rats with adenine-induced chronic renal failure

2012 ◽  
Vol 302 (12) ◽  
pp. R1426-R1435 ◽  
Author(s):  
Lisa Nguy ◽  
Holger Nilsson ◽  
Jaana Lundgren ◽  
Maria E. Johansson ◽  
Tom Teerlink ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Vascular Function ◽  
Ex Vivo ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Severe Renal Failure ◽  
Stress Markers

The aim of the present study was to characterize the function of resistance arteries, and the aorta, in rats with adenine-induced chronic renal failure (A-CRF). Sprague-Dawley rats were randomized to chow with or without adenine supplementation. After 6–10 wk, mesenteric arteries and thoracic aortas were analyzed ex vivo by wire myography. Plasma creatinine concentrations were elevated twofold at 2 wk, and eight-fold at the time of death in A-CRF animals. Ambulatory systolic and diastolic blood pressures measured by radiotelemetry were significantly elevated in A-CRF animals from week 3 and onward. At death, A-CRF animals had anemia, hyperphosphatemia, hyperparathyroidism, and elevated plasma levels of asymmetric dimethylarginine and oxidative stress markers. There were no significant differences between groups in the sensitivity, or maximal response, to ACh, sodium nitroprusside (SNP), norepinephrine, or phenylephrine in either mesenteric arteries or aortas. However, in A-CRF animals, the rate of aortic relaxation was significantly reduced following washout of KCl (both in intact and endothelium-denuded aorta) and in response to ACh and SNP. Also the rate of contraction in response to KCl was significantly reduced in A-CRF animals both in mesenteric arteries and aortas. The media of A-CRF aortas was thickened and showed focal areas of fragmented elastic lamellae and disorganized smooth muscle cells. No vascular calcifications could be detected. These results indicate that severe renal failure for a duration of less than 10 wk in this model primarily affects the aorta and mainly slows the rate of relaxation.

scholarly journals Genetic and Metabolite Variability in One-Carbon Metabolism Applied to an Insulin Resistance Model in Patients With Schizophrenia Receiving Atypical Antipsychotics

2021 ◽  
Vol 12 ◽  
Author(s):  
Kristen M. Ward ◽  
Kyle Burghardt ◽  
A. Zarina Kraal ◽  
Andrew Jaeger ◽  
Larisa Yeomans ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Carbon Metabolism ◽  
Carrier Status ◽  
Diabetes Diagnosis ◽  
Model Assessment ◽  
Least Squares Regression ◽  
Increased Risk ◽  
Homeostatic Model Assessment ◽  
One Carbon Metabolism

Background: Patients with schizophrenia are at high risk of pre-mature mortality due to cardiovascular disease (CVD). Our group has completed studies in pharmacogenomics and metabolomics that have independently identified perturbations in one-carbon metabolism as associated with risk factors for CVD in this patient population. Therefore, this study aimed to use genetic and metabolomic data to determine the relationship between folate pharmacogenomics, one-carbon metabolites, and insulin resistance as measured using the homeostatic model assessment for insulin resistance (HOMA-IR) as a marker of CVD.Methods: Participants in this pilot analysis were on a stable atypical antipsychotic regimen for at least 6 months, with no diabetes diagnosis or use of antidiabetic medications. Participant samples were genotyped for MTHFR variants rs1801131 (MTHFR A1298C) and rs1801133 (MTHFR C677T). Serum metabolite concentrations were obtained with NMR. A least squares regression model was used to predict log(HOMA-IR) values based on the following independent variables: serum glutamate, glycine, betaine, serine, and threonine concentrations, and carrier status of the variant alleles for the selected genotypes.Results: A total of 67 participants were included, with a median age of 47 years old (IQR 42–52), 39% were female, and the median BMI was 30.3 (IQR 26.3–37.1). Overall, the model demonstrated an ability to predict log(HOMA-IR) values with an adjusted R2 of 0.44 and a p-value of &lt; 0.001. Glutamate, threonine, and carrier status of the MTHFR 1298 C or MTHFR 677 T allele were positively correlated with log(HOMA-IR), whereas glycine, serine, and betaine concentrations trended inversely with log(HOMA-IR). All factors included in this final model were considered as having a possible effect on predicting log(HOMA-IR) as measured with a p-value &lt; 0.1.Conclusions: Presence of pharmacogenomic variants that decrease the functional capacity of the MTHFR enzyme are associated with increased risk for cardiovascular disease, as measured in this instance by log(HOMA-IR). Furthermore, serine, glycine, and betaine concentrations trended inversely with HOMA-IR, suggesting that increased presence of methyl-donating groups is associated with lower measures of insulin resistance. Ultimately, these results will need to be replicated in a significantly larger population.

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