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Time course of nitric oxide production and epithelial dysfunction during ischemia/reperfusion of the feline small intestine. 猫小肠缺血/再灌注过程中一氧化氮生成和上皮功能障碍的时间过程。
Pub Date : 1994-03-01
S Kanwar, B L Tepperman, D Payne, L R Sutherland, P Kubes

The objective of this study was to correlate nitric oxide production with time of reperfusion of the post-ischemic feline small intestine. Epithelial permeability, quantitated as blood-to-lumen clearance of 51Cr-EDTA, following 1 hr of ischemia and 4 hr of reperfusion of the small intestine, increased approximately 10-fold. This increase was further augmented by L-NAME infusion between 60 and 120 min but not at 240 min. Ca(2+)-dependent nitric oxide synthase activity was reduced by approximately 50% at 3 and 4 hr of reperfusion, whereas Ca(2+)-independent nitric oxide synthase activity was undetectable throughout the experiment. Administration of L-arginine at the start of reperfusion attenuated the reperfusion-induced epithelial barrier dysfunction for the first 120 min but not at 180 or 240 min. Continuous infusion of a nitric oxide donor (CAS 754) following 1 hr of reperfusion reduced epithelial permeability at 4 hr of reperfusion. In conclusion, a reduction in nitric oxide production was observed with time of reperfusion, possibly due to reduced nitric oxide synthase levels.

本研究的目的是将一氧化氮的产生与缺血后猫小肠再灌注时间联系起来。小肠缺血1小时和再灌注4小时后,上皮通透性(以51Cr-EDTA的血腔清除率来量化)增加了约10倍。在60至120分钟内,L-NAME输注进一步增强了这种增加,但在240分钟时则没有。Ca(2+)依赖性一氧化氮合酶活性在再灌注3和4小时时降低了约50%,而在整个实验中未检测到Ca(2+)非依赖性一氧化氮合酶活性。在再灌注开始时给予l -精氨酸可在前120分钟减弱再灌注诱导的上皮屏障功能障碍,但在180或240分钟时则没有。在再灌注1小时后持续输注一氧化氮供体(CAS 754)可在再灌注4小时时降低上皮通透性。总之,随着再灌注时间的延长,一氧化氮的产生减少,可能是由于一氧化氮合酶水平的降低。
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引用次数: 0
Increased sinusoidal efflux of reduced and oxidized glutathione in rats with endotoxin/D-galactosamine hepatitis. 内毒素/ d -半乳糖胺肝炎大鼠还原性和氧化性谷胱甘肽的正弦外排增加。
Pub Date : 1994-03-01
K Irita, H Okabe, A Koga, K Kurosawa, K Tagawa, M Yamakawa, J Yoshitake, S Takahashi

The changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the plasma as well as in the liver were investigated in rats with endotoxin hepatitis. Hepatitis was induced by intraperitoneal co-administration of small doses of Escherichia coli endotoxin and D-galactosamine. In the liver, the concentration of GSH decreased and that of GSSG increased 12 hr later. In the plasma taken from the right atrium, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased, as it did in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic, suprarenal inferior vena cava from those of the suprahepatic inferior vena cava. The efflux started to increase as early as 2-4 hr after the injection of the toxins. In contrast, a leakage of alanine aminotransferase, an elongation of prothrombin time, an inhibition of starvation ketosis, and an increase in serum concentration of total bilirubin were detected as late as 6-8 hr after the injection. We conclude that endotoxin/D-galactosamine hepatitis induced an increase in plasma concentrations of GSH as well as GSSG by increasing the efflux of these peptides from the liver, and that changes in plasma glutathione status might be useful and sensitive markers for liver damage.

研究了内毒素肝炎大鼠血浆和肝脏中还原性谷胱甘肽(GSH)和氧化性谷胱甘肽(GSSG)浓度的变化。腹腔注射小剂量大肠杆菌内毒素和d -半乳糖胺诱导肝炎。肝脏GSH浓度在12小时后下降,GSSG浓度升高。右心房血浆中GSH和GSSG浓度均升高。血浆中GSH/GSSG比值下降,肝脏中也是如此。通过从肝上下腔静脉中减去肝下、肾上下腔静脉血浆中GSH和GSSG的浓度,计算肝脏的净正弦流出量。早在注射毒素后2-4小时,外排开始增加。相反,在注射后6-8小时检测到丙氨酸转氨酶渗漏、凝血酶原时间延长、饥饿酮症抑制和血清总胆红素浓度升高。我们得出结论,内毒素/ d -半乳糖胺肝炎通过增加GSH和GSSG肽从肝脏的外排而引起血浆GSH和GSSG浓度的增加,血浆谷胱甘肽状态的变化可能是肝损伤的有用和敏感的标志物。
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引用次数: 0
In vivo effect of methylprednisolone on lipopolysaccharide-induced superoxide production by pulmonary and circulating blood neutrophils in rats. 甲基强的松龙对大鼠肺和循环血液中性粒细胞脂多糖诱导的超氧化物产生的体内影响。
Pub Date : 1994-03-01
C Tsuji, S Shioya

The effect of methylprednisolone on superoxide production by pulmonary and circulating blood neutrophils was investigated in rats after the intravenous injection of lipopolysaccharide. Superoxide production by both types of neutrophils was increased by lipopolysaccharide injection, and pretreatment with methylprednisolone inhibited this increase. The inhibitory effect of methylprednisolone on pulmonary neutrophils was greater than that on circulating blood neutrophils. Methylprednisolone also prevented the increase in pulmonary vascular permeability induced by lipopolysaccharide, but failed to inhibit intrapulmonary neutrophil accumulation. These results suggest that the suppression of superoxide production may be one mechanism by which methylprednisolone prevents endotoxin-induced lung damage.

研究了甲基强的松龙对大鼠静脉注射脂多糖后肺和循环血液中性粒细胞产生超氧化物的影响。脂多糖注射增加了两种中性粒细胞的超氧化物产生,甲基强的松龙预处理抑制了这种增加。甲基强的松龙对肺中性粒细胞的抑制作用大于对循环血液中性粒细胞的抑制作用。甲基强的松龙也能阻止脂多糖诱导的肺血管通透性增加,但不能抑制肺内中性粒细胞的积累。这些结果表明,抑制超氧化物的产生可能是甲基强的松龙预防内毒素诱导的肺损伤的一种机制。
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引用次数: 0
Elevations in circulating calcitonin gene-related peptide correlate with hemodynamic deterioration during endotoxic shock in pigs. 循环降钙素基因相关肽的升高与猪内毒素休克期间血流动力学恶化相关。
Pub Date : 1994-03-01
W A Arden, R R Fiscus, X Wang, L Yang, R Maley, M Nielsen, S Lanzo, D R Gross

Calcitonin gene-related peptide (CGRP) is a potent vasodilatory neuropeptide, which may play a role in vascular dysfunction during septic shock. Sixteen pigs (25-50 kg) were anesthetized with ketamine and isoflurane in O2, and administered 100 micrograms/kg Escherichia coli lipopolysaccharide i.v. (LPS; n = 8) or saline vehicle (n = 8). Pigs were instrumented for hemodynamic determinations and blood sampling for CGRP assay (pg/ml) from the portal vein (PV) and the pulmonary (PA) and carotid (CA) arteries. Blood samples were collected into EDTA and aprotinin before (baseline) and at 60, 120, and 180 min after LPS administration. LPS caused significant deterioration in indices of hemodynamic function and a significant increase in plasma CGRP concentration at all sampling sites by 120 min (P < 0.01). No significant difference between sampling sites was recorded at any time. Plasma CGRP concentrations displayed significant negative correlations with mean arterial pressure, cardiac index, and left ventricular stroke work. These data confirm our previous findings of CGRP elevations in endotoxemic rats, and indicate that 1) LPS is a potent stimulus for the systemic release of CGRP, 2) increasing plasma CGRP concentrations temporally correlates with cardiovascular deterioration during LPS shock, and 3) there is little evidence that the portal circulation is a major source of circulating CGRP levels during LPS shock. Vasoactive neuropeptides, such as CGRP, may interact with other documented mediators of vascular dysfunction in the pathogenesis of septic shock.

降钙素基因相关肽(CGRP)是一种有效的血管舒张神经肽,可能在感染性休克时血管功能障碍中起作用。用氯胺酮和异氟醚麻醉16头猪(25-50 kg),并静脉注射100微克/千克大肠杆菌脂多糖(LPS;n = 8)或生理盐水载体(n = 8)。分别从门静脉(PV)、肺动脉(PA)和颈动脉(CA)取血进行血流动力学测定和CGRP测定(pg/ml)。在给药前(基线)和给药后60min、120min和180min采集血液样本检测EDTA和抑肽酶。LPS使血流动力学指标明显恶化,各采样点血浆CGRP浓度显著升高(P < 0.01)。在任何时候,采样点之间都没有记录到显著差异。血浆CGRP浓度与平均动脉压、心脏指数和左室卒中功呈显著负相关。这些数据证实了我们之前关于内毒素大鼠CGRP升高的发现,并表明1)LPS是CGRP全身释放的有力刺激,2)血浆CGRP浓度升高与LPS休克期间心血管恶化有时间相关性,3)很少有证据表明门静脉循环是LPS休克期间循环CGRP水平的主要来源。血管活性神经肽,如CGRP,可能在感染性休克的发病机制中与其他血管功能障碍介质相互作用。
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引用次数: 0
In vivo effect of methylprednisolone on lipopolysaccharide-induced superoxide production by pulmonary and circulating blood neutrophils in rats. 甲基强的松龙对大鼠肺和循环血液中性粒细胞脂多糖诱导的超氧化物产生的体内影响。
Pub Date : 1994-03-01 DOI: 10.11501/3083092
C. Tsuji, S. Shioya
The effect of methylprednisolone on superoxide production by pulmonary and circulating blood neutrophils was investigated in rats after the intravenous injection of lipopolysaccharide. Superoxide production by both types of neutrophils was increased by lipopolysaccharide injection, and pretreatment with methylprednisolone inhibited this increase. The inhibitory effect of methylprednisolone on pulmonary neutrophils was greater than that on circulating blood neutrophils. Methylprednisolone also prevented the increase in pulmonary vascular permeability induced by lipopolysaccharide, but failed to inhibit intrapulmonary neutrophil accumulation. These results suggest that the suppression of superoxide production may be one mechanism by which methylprednisolone prevents endotoxin-induced lung damage.
研究了甲基强的松龙对大鼠静脉注射脂多糖后肺和循环血液中性粒细胞产生超氧化物的影响。脂多糖注射增加了两种中性粒细胞的超氧化物产生,甲基强的松龙预处理抑制了这种增加。甲基强的松龙对肺中性粒细胞的抑制作用大于对循环血液中性粒细胞的抑制作用。甲基强的松龙也能阻止脂多糖诱导的肺血管通透性增加,但不能抑制肺内中性粒细胞的积累。这些结果表明,抑制超氧化物的产生可能是甲基强的松龙预防内毒素诱导的肺损伤的一种机制。
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引用次数: 7
Protection of mice from mortality caused by living and heat-killed bacteria by SDZ MRL 953. SDZ mrl953对活菌和热杀菌致小鼠死亡的保护作用。
Pub Date : 1994-03-01
E Schütze, J Hildebrandt, E Liehl, C Lam

Protective effects of SDZ MRL 953, a monosaccharidic lipid A analog with a reduced toxicity, were investigated in models of experimental septic shock caused by injections of LPS, and inoculations of heat-killed or live bacteria. Female B6D2F1 mice were challenged with a combination of galactosamine (800 mg/kg) plus various doses of heat-killed isolates of Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, and Staphylococcus aureus or LPS from Salmonella abortus equi. In some experiments, isolates of living bacteria at sublethal inocula were also combined with galactosamine. More than 90% of the animals died within 24 hr when the challenge was performed either simultaneously with or up to 4 hr after an intraperitoneal administration of galactosamine. No death was observed when galactosamine was omitted or administered after the microbial or LPS challenge. Pretreatment of the animals with SDZ MRL 953 (1-10 mg/kg) rendered the animals resistant to the lethal effects of both bacterial and LPS challenge in a time- and dose-dependent manner. The levels of TNF-alpha in control mice rose to greater than 600 pg/ml 2 hr postbacterial or LPS challenge, but were below detection in animals pretreated with SDZ MRL 953. Protection against both the infection and the toxicity of heat-killed bacteria or LPS was also achieved when murine anti-TNF-alpha monoclonal antibody was administered prophylactically. Together, these data suggest that SDZ MRL 953 enhances the resistance of mice against the toxicity of heat-killed gram-negative bacteria and S. aureus, and attenuates host responses to living bacteria which may lead to irreversible shock and death.

研究了单糖脂质a类似物SDZ MRL 953对实验性脓毒性休克的保护作用,并对注射LPS和接种热杀菌或活菌进行了研究。雌性B6D2F1小鼠被半乳糖胺(800 mg/kg)加不同剂量的大肠杆菌、铜绿假单胞菌、鼠伤寒沙门菌和金黄色葡萄球菌热杀菌株或产马沙门菌LPS联合攻击。在一些实验中,亚致死接种的活菌分离株也与半乳糖胺联合使用。超过90%的动物在注射半乳糖胺的同时或腹腔注射半乳糖胺后4小时内死亡。当省略半乳糖胺或在微生物或LPS挑战后给予半乳糖胺时,未观察到死亡。用SDZ MRL 953 (1-10 mg/kg)预处理动物,使动物对细菌和LPS的致死效应具有时间和剂量依赖性。对照组小鼠的tnf - α水平在细菌或LPS攻击后2小时上升至大于600 pg/ml,但在SDZ MRL 953预处理的动物中低于检测水平。当小鼠抗tnf - α单克隆抗体被预防性给予时,对热杀细菌或LPS的感染和毒性也有保护作用。总之,这些数据表明,SDZ MRL 953增强了小鼠对热杀革兰氏阴性菌和金黄色葡萄球菌毒性的抗性,并减弱了宿主对活细菌的反应,这种反应可能导致不可逆的休克和死亡。
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引用次数: 0
Modification of vasopressin microvascular responses by endotoxin, endothelin, and nitric oxide. 内毒素、内皮素和一氧化氮对血管加压素微血管反应的影响。
Pub Date : 1994-02-01
C H Baker, E T Sutton

The sensitivity of rat cremaster muscle arterioles to topically applied arginine vasopressin (AVP) is greatly increased by endotoxin (ENDT) [1]. The hypothesis is that the increase in vasoconstrictor sensitivity is in part due to modification of the AVP responses by endothelial compounds such as nitric oxide (NO) and endothelin. Reactivity of left cremaster muscle microvessels of pentobarbital anesthetized Sprague-Dawley rats was measured using videomicroscopy. Femoral arterial pressure as well as second and third order arteriolar (A2 and A3) vasoconstrictor threshold responses were determined for topical AVP (10(-15)-10(-6) M). These measurements were repeated in the presence of ENDT (6 mg/kg) alone and in the presence of the NO synthase inhibitor L-NAME (N omega-nitro-L-arginine methyl ester; 1 mg/kg) and ENDT (group 1). The control threshold (M)(-log) for arteriolar constriction by AVP was 9.4 +/- 0.7. After ENDT the threshold decreased significantly (P < 0.05) to 13.8 +/- 0.5, but returned to 9.0 +/- 0.5 after i.v. injected L-NAME. Acetylcholine (ACh) injected i.a. during AVP constriction significantly increased diameters at control and after ENDT, but not after L-NAME. In group 2 the AVP threshold was determined at control, after L-NAME plus hydroquinone (HQ), and at 30, 90, and 120 min post-ENDT in the presence of L-NAME + HQ. The AVP threshold at control was 9.0 +/- 0.3, after L-NAME 9.0 +/- 0.6, and after HQ 8.0 +/- 0.7. After L-NAME + HQ, the threshold was significantly increased to 7.3 +/- 0.2. After ENDT, in the presence of both antagonists, the threshold remained elevated at 7.4 +/- 0.2.(ABSTRACT TRUNCATED AT 250 WORDS)

内毒素(endotoxin, ENDT)可使大鼠胸肌小动脉对局部应用精氨酸抗利尿激素(AVP)的敏感性大大增加[1]。假设血管收缩剂敏感性的增加部分是由于一氧化氮(NO)和内皮素等内皮化合物改变了AVP反应。用视频显微镜观察戊巴比妥麻醉大鼠左胸肌微血管的反应性。测定了局部AVP (10(-15)-10(-6) M)的股动脉压以及二级和三级动脉(A2和A3)血管收缩阈值反应。这些测量在单独使用ENDT (6 mg/kg)和NO合成酶抑制剂L-NAME (N - omega-硝基- l -精氨酸甲酯;1 mg/kg)和ENDT(1组)。AVP引起小动脉收缩的控制阈值(M)(-log)为9.4 +/- 0.7。ENDT后阈值显著降低(P < 0.05),为13.8 +/- 0.5,静脉注射L-NAME后恢复到9.0 +/- 0.5。乙酰胆碱(ACh)在AVP收缩期间内注射可显著增加对照组和ENDT后的内径,但在L-NAME后无显著增加。在第2组中,分别在对照组、L-NAME +对苯二酚(HQ)后以及在L-NAME + HQ存在下的endt后30min、90min和120min测定AVP阈值。对照组AVP阈值为9.0 +/- 0.3,L-NAME组为9.0 +/- 0.6,HQ组为8.0 +/- 0.7。L-NAME + HQ后,阈值显著提高至7.3 +/- 0.2。ENDT后,在两种拮抗剂存在的情况下,阈值保持在7.4 +/- 0.2。(摘要删节250字)
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引用次数: 0
Effect of glucocorticoid receptor (GR) blockade on endotoxemia in rats. 糖皮质激素受体阻断对大鼠内毒素血症的影响。
Pub Date : 1994-02-01
J Fan, X Q Gong, J Wu, Y F Zhang, R B Xu

To study the clinical significance of the decrease of glucocorticoid receptor (GR) in stress and shock, GR was blocked about 80% by mifepristone (RU38486), and the effects of the blockade on the pathological changes of endotoxemia were studied in rats. The results revealed that GR blockade may exacerbate the pathological and pathophysiological changes of endotoxemia: (1) the more rapid drop in arterial blood pressure, (2) the more severe pathological changes involving multiple organs, especially the lung and small intestine, (3) the increase of leukocyte adherence in venules and more pronounced rheological changes in the mesenteric microcirculation, and (4) the striking elevation of serum acid phosphatase (ACP), phospholipase A2 (PLA2) activity, and lipoperoxide (LPO). The changes of serum ACP, PLA2, and LPO in the rats with 80% GR blockade were more marked than in those with 50% GR blockade. Based on these findings, we propose that the decrease in GR during stress and shock might be a contributing factor in the pathogenesis of shock and multiple organ failure (MOF). The possible mechanisms of the above noted findings are discussed.

为了研究应激和休克时糖皮质激素受体(GR)降低的临床意义,我们用米非司酮(RU38486)阻断约80%的GR,并研究阻断对内毒素血症大鼠病理改变的影响。结果显示,GR阻断可加重内毒素血症的病理和病理生理变化:(1)动脉血压下降越快,(2)涉及多器官的病理改变越严重,特别是肺和小肠,(3)小静脉中白细胞粘附性增加,肠系膜微循环流变学改变更明显,(4)血清酸性磷酸酶(ACP)、磷脂酶A2 (PLA2)活性和脂过氧化物(LPO)显著升高。80% GR阻断组大鼠血清ACP、PLA2、LPO的变化明显高于50% GR阻断组。基于这些发现,我们提出应激和休克期间GR的降低可能是休克和多器官衰竭(MOF)发病的一个因素。讨论了上述发现的可能机制。
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引用次数: 0
Hydrazine sulfate selectively modulates the TNF response to endotoxin in mouse macrophages. 硫酸肼选择性调节小鼠巨噬细胞对内毒素的TNF反应。
Pub Date : 1994-02-01
F Jia, D C Morrison, R Silverstein
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引用次数: 0
Efficacy of a recombinant endotoxin neutralizing protein in rabbits with Escherichia coli sepsis. 重组内毒素中和蛋白对家兔大肠杆菌败血症的治疗效果。
Pub Date : 1994-02-01
R Saladino, C Garcia, C Thompson, B Hammer, J Parsonnet, T Novitsky, G Siber, G Fleisher

Gram-negative bacterial sepsis is associated with endotoxemia and a high mortality rate. In previous studies, we demonstrated the therapeutic benefit of an anti-lipopolysaccharide factor isolated from amebocytes of Limulus polyphemus, and of a recombinant version of this protein, termed endotoxin neutralizing protein (ENP), in rabbits challenged with purified lipopolysaccharides. To assess the benefit of ENP in treating a live bacterial infection, we established a rabbit model of Escherichia coli (E. coli) peritonitis and bacteremia with high mortality despite gentamicin treatment. Twenty-four pairs of New Zealand white rabbits were challenged intraperitoneally (IP) with E. coli O18ac K1 in 5% porcine mucin (mean bacteria per dose = 2.5 x 10(8)). The animals were treated with intravenous (i.v.) gentamicin (2.5 mg/kg), and with either ENP (5 mg/kg) or saline i.v. at 1 hr after E. coli challenge. All rabbits were bacteremic 1 hr after challenge (geometric mean 4.1 +/- 1.2 x 10(4) cfu/mL). Peak geometric mean serum endotoxin (2.62 v 10.54 EU/mL, P = .013) and tumor necrosis factor (TNF) (2540 v 6438 TNF units/mL, P = .046) concentrations were lower in ENP-treated animals as compared to control animals. Seven of 24 animals treated with ENP survived 24 hr compared with 4 of 24 controls (Kaplan-Meier analysis, P = .19). However, in the subgroup of 13 paired animals in whom bacteremia was eliminated by gentamicin treatment, 5 of 13 ENP-treated animals survived 24 hr, compared with 1 of 13 controls (Kaplan-Meier analysis, P = .032).(ABSTRACT TRUNCATED AT 250 WORDS)

革兰氏阴性细菌性败血症与内毒素血症和高死亡率有关。在之前的研究中,我们证明了从多足鲎变形细胞中分离的抗脂多糖因子,以及该蛋白的重组版本,称为内毒素中和蛋白(ENP),在纯化脂多糖刺激的兔子中具有治疗作用。为了评估ENP治疗活细菌感染的益处,我们建立了一种大肠杆菌腹膜炎和菌血症的兔子模型,尽管庆大霉素治疗,但死亡率很高。24对新西兰大白兔腹腔注射含5%猪黏液的大肠杆菌O18ac K1(每剂量平均细菌数= 2.5 × 10(8))。小鼠在大肠杆菌攻毒后1小时静脉注射庆大霉素(2.5 mg/kg)和ENP (5 mg/kg)或生理盐水。所有家兔在攻毒后1小时呈菌血症(几何平均值4.1 +/- 1.2 × 10(4) cfu/mL)。enp处理动物的峰值几何平均血清内毒素(2.62 v 10.54 EU/mL, P = 0.013)和肿瘤坏死因子(TNF) (2540 v 6438 TNF单位/mL, P = 0.046)浓度低于对照动物。24只接受ENP治疗的动物中有7只存活了24小时,而24只对照组中有4只存活了24小时(Kaplan-Meier分析,P = .19)。然而,在庆大霉素治疗消除菌血症的13只配对动物亚组中,13只接受enp治疗的动物中有5只存活了24小时,而13只对照组中有1只存活了24小时(Kaplan-Meier分析,P = 0.032)。(摘要删节250字)
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引用次数: 0
期刊
Circulatory shock
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