Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats

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Object. The mechanisms of brain edema formation following spontaneous intracerebral hemorrhage (ICH) are not well understood. In previous studies, no significant edema formation has been found 24 hours after infusion of packed red blood cells (RBCs) into the brain of a rat or pig; however, there is evidence that hemoglobin can be neurotoxic. In this study, the authors reexamined the role of RBCs and hemoglobin in edema formation after ICH.

Methods. The experiments involved infusion of whole blood, packed RBCs, lysed RBCs, rat hemoglobin, or thrombin into the right basal ganglia of Sprague—Dawley rats. The animals were killed at different time points and brain water and ion contents were measured. The results showed that lysed autologous erythrocytes, but not packed erythrocytes, produced marked brain edema 24 hours after infusion and that this edema formation could be mimicked by hemoglobin infusion. Although infusion of packed RBCs did not produce dramatic brain edema during the first 2 days, it did induce a marked increase in brain water content 3 days postinfusion. Edema formation following thrombin infusion peaked at 24 to 48 hours. This is earlier than the peak in edema formation that follows ICH, suggesting that there is a delayed, nonthrombin-mediated, edemogenic component of ICH.

Conclusions. These results demonstrate that RBCs play a potentially important role in delayed edema development after ICH and that RBC lysis and hemoglobin toxicity may be useful targets for therapeutic intervention.

Edema found in the perihematoma zone is one of the most important factors causing secondary brain injury after intracerebral hemorrhage (ICH). The mechanisms involved in brain edema formation following ICH still have to be fully elucidated. Investigations have indicated that mass effect, ischemia, neurotoxicity, and blood-brain barrier disruption may all be involved in edema formation.19,30,35 Recent studies have indicated that clot retraction and plasma proteins induce brain edema as early as one hour after ICH.29,30 Thrombin and the coagulation cascade also appear to play a major role in early (24-hour) edema formation following ICH, with edema formation being markedly reduced by thrombin inhibitors.10–13 In contrast, injection of red blood cells (RBCs) into brain fails to induce edema formation by 24 hours.12,34 However, the possible role of RBCs in the induction of brain edema needs to be evaluated carefully. There is evidence that hemoglobin can cause brain injury. Reports have shown that hemoglobin can inhibit Na+/K+ adenosine triphosphatase (ATPase) activity,24 generate the toxic hydroxyl radical,20 stimulate peroxidation of central nervous system lipids,5 and cause neuronal death.8,22

In this study, we have reexamined the roles of RBCs and hemoglobin in brain edema formation following ICH by examining the effects of autologous packed RBCs, lysed RBCs, and rat hemoglobin on brain water content and by comparing the time course of edema formation after thrombin injection to that found previously with ICH.

Materials and Methods

Animal Preparation

The protocol for these animal studies was approved by the University Committee on the Use and Care of Animals. One hundred seventeen adult male Sprague—Dawley rats, each weighing between 300 and 450 g, were allowed food and water ad libitum before and after surgery. The rats were anesthetized with an intraperitoneal injection of pentobarbital (40 mg/kg). After anesthesia was achieved, a polyethylene catheter (PE-50) was inserted into the right femoral artery for continuous blood pressure monitoring. Arterial blood was obtained for analysis of blood gas levels, arterial pH, hematocrit value, blood glucose concentration, and as a source of erythrocytes for intracerebral injection. Body temperature was maintained at 37.5°C by using a feedback-controlled heating pad.

Intracerebral Infusion

Before intracerebral infusion, the rat was positioned in a stereotactic frame and the scalp was incised along the sagittal midline by using a sterile technique. A cranial burr hole (1 mm) was drilled near the right coronal suture 4 mm lateral to the midline. A 26-gauge needle was inserted stereotactically into the right basal ganglia (coordinates: 0.2 mm anterior, 5.5 mm ventral, and 4 mm lateral to the bregma). Whole blood, packed RBCs, lysed RBCs, or other solutions were infused using a microinfusion pump into the right basal ganglia. After infusion, the needle was removed and the skin incisions were closed with sutures. The animal was allowed to recover.

Experimental Groups

This study was divided into five parts. In the first four parts, the roles of whole blood, lysed RBCs, hemoglobin, and packed erythrocytes in brain edema formation were assessed. In the fifth part, we examined the time course of brain edema formation following infusion of 5 U rat thrombin.

Part 1. In this portion of the study five groups of rats (five animals in each group) were used. Whole autologous blood (100 µl) was injected into the right caudate nucleus of each rat. The animals were killed at 1, 2, 3, 5, or 7 days.

Part 2. Three groups (five rats each) were used in this portion of the experiment. The first group underwent a sham operation that consisted of needle insertion without infusion. The rats in the second group were each infused with 30 µl of autologous packed RBCs. Packed RBCs (hematocrit level 87 ± 1%) were obtained by centrifuging unclotted blood. The plasma and buffy coat were discarded. The RBCs were washed with five volumes of saline three times. A 30-µl infusion of lysed autologous RBCs was used for the rats in the third group. The washed RBCs were lysed by freezing the cells in liquid nitrogen for 5 minutes followed by thawing at 37°C. The rats were killed 24 hours after RBC infusion.

Part 3. Three groups of animals were used in this part of the study. The first group (six rats) received 20 µl saline. The second and third groups (six rats each) received 20 µl rat hemoglobin at a concentration of either 150 mg/ml or 300 mg/ml. The normal concentration of hemoglobin in RBCs is approximately 300 mg/ml. Because native hemoglobin is readily oxidized in air, this hemoglobin is predominantly methemoglobin, as stipulated by the manufacturer in its 1997 catalogue. All the animals were decapitated 24 hours after infusion.

Part 4. In five groups of rats (five or six animals in each group), 50 µl of packed RBCs were injected into the right basal ganglia. The animals were decapitated at 1, 2, 3, 5, or 7 days to assess edema formation.

Part 5. In this portion of the study, six groups of rats (five or six rats each) were studied. Each rat received an infusion of 60 µl of rat thrombin (5 U). The rats were killed at 4, 12, 24, 48, 72, or 168 hours.

Brain Water, Sodium, and Potassium Contents

After deep pentobarbital anesthesia (80 mg/kg injected peritoneally) had been induced, the rats were killed by decapitation. The brains were removed immediately and, 4 mm from the frontal pole, a 3-mm-thick coronal brain slice was cut. The slice was divided into four samples, ipsilateral and contralateral basal ganglia and ipsilateral and contralateral cortex. Tissue samples were weighed using an electronic analytical balance calculated to the nearest 0.1 mg to obtain the wet weight (WW). The tissue was dried in a gravity oven set at 100°C for more than 24 hours to determine the dry weight (DW). Tissue water contents (%) were calculated as follows: (WW − DW)/WW × 100.

The dehydrated brain samples were digested in 1 ml of 1 N nitric acid for 1 week. The sodium and potassium ion contents in this solution were measured using flame photometry. Ion contents were expressed in microequivalents per gram of dehydrated brain tissue (µEq/g DW).

Statistical Analysis

Data from different animal groups were analyzed using analysis of variance with a Scheffé F-test post hoc test, except for the response to different doses of hemoglobin, in which case a Dunnett's post hoc test was used. Differences were considered significant at probability values less than 0.05. All values in the text are given as the mean ± standard error of the mean (SEM).

Sources of Supplies and Equipment

The animals, which were obtained from Charles River Laboratories (Portage, MI), were positioned in a stereotactic frame purchased from Kopf Instruments (Tujunga, CA). The microinfusion pump used in the experiments was manufactured by Harvard Apparatus, Inc. (South Natick, MA). The rat hemoglobin and thrombin were obtained from Sigma Chemical Co. (St. Louis, MO). The electronic analytical balance (model AE 100) used to weigh tissue samples was obtained from Mettler Instrument Co. (Highstown, NJ) and the flame photometry system (model IL 943) from Instrumentation Laboratory, Inc. (Lexington, MA).

Results

Physiological parameters were recorded just before infusion of the whole blood, RBCs, hemoglobin, thrombin, or saline (Table 1). There were no significant differences among groups used in each part of the experiment. The mean values for levels of blood gases, blood pH, mean arterial blood pressure, hematocrit, and blood glucose were within normal ranges.

TABLE 1

Physiological parameters in 117 rats before intracerebral infusion*

VariableExperiment Parts
12345 
MABP (mm Hg)112 ± 10 110 ± 12 107 ± 8 108 ± 11 109 ± 7 
pH7.43 ± 0.02 7.43 ± 0.04 7.43 ± 0.02 7.43 ± 0.02 7.44 ± 0.02 
PaO2 (mm Hg)80.0 ± 4.4 82.1 ± 3.4 81.9 ± 4.7 82.1 ± 5.1 85.3 ± 6.5 
PaCO2 (mm Hg)43.2 ± 4.5 45.8 ± 3.8 45.7 ± 3.0 46.4 ± 3.0 46.3 ± 3.2 
hematocrit (%)41.4 ± 2.6 41.2 ± 1.4 41.1 ± 1.2 40.9 ± 1.0 40.1 ± 1.5 
glucose (mg%)122.2 ± 20 134 ± 20 136 ± 13 131 ± 16 127 ± 13 

Values are expressed as the mean ± standard deviation. Abbreviation: MABP = mean arterial blood pressure.

Time Course of Edema Formation Following Whole Blood Infusion

Figure 1A shows the time course of brain water content at 1, 2, 3, 5, and 7 days after a 100-µl whole blood infusion. Although marked brain edema was observed on the 1st day after whole blood infusion, the peak increase in brain water content in the ipsilateral cortex and basal ganglia was at 3 days.

Fig. 1.
Fig. 1.

Graphs showing brain water content at 1, 2, 3, 5, and 7 days after infusion of whole blood or packed RBCs. A: After infusion of 100 µl whole blood. B: After infusion of 50 µl packed RBCs. Values are expressed as the mean ± SEM in five or six rats. #p < 0.01.

Brain Water Content Following Lysed and Packed RBC Infusion

Lysed RBCs, but not packed RBCs, produced marked brain edema in the ipsilateral basal ganglia and cortex 24 hours after infusion (Fig. 2). Brain water content in the lysed RBC group was increased significantly in the ipsilateral basal ganglia compared with the packed RBC group (83.2 ± 0.5% and 78.4 ± 0.3%, respectively). The edema formation after lysed RBC infusion was associated with an ipsilateral accumulation of sodium and loss of potassium (Fig. 3).

Fig. 2.
Fig. 2.

Bar graph showing brain water content 24 hours after sham operation or infusion of 30 µl of either packed or lysed RBCs. Values are expressed as the mean ± SEM in five rats. *p < 0.05 compared with the sham-operated and packed RBC groups. #p < 0.01 compared with the sham-operated and packed RBC groups.

Fig. 3.
Fig. 3.

Bar graph depicting brain sodium (A) and potassium ion (B) contents 24 hours after sham operation or a 30-µl infusion of either packed or lysed RBCs. Values are expressed as the mean ± SEM. *p < 0.05 compared with the sham-operated and packed RBC groups. #p < 0.01 compared with the sham-operated and packed RBC groups.

Brain Water Content Following Hemoglobin Infusion

Intracerebral infusion of rat hemoglobin produced a dose-dependent increase in brain water content at 24 hours (Fig. 4). The increase in brain water content was associated with an accumulation of brain sodium and loss of brain potassium (Table 2).

Fig. 4.
Fig. 4.

Bar graph depicting water content at 24 hours after infusion of 20 µl hemoglobin (Hb) or saline. Values are expressed as the mean ± SEM. *p < 0.05 compared with 150-mg/ml hemoglobin group. #p < 0.01 compared with the saline group.

TABLE 2

Brain tissue sodium and potassium ion contents 24 hours after a 20-µl hemoglobin or saline infusion*

Group & RegionSodium Ion (µEq/g DW)Potassium Ion (µEq/g DW)
ipsilat hemisphere
 saline186 ± 2425 ± 4
 hemoglobin (150 mg/ml)240 ± 6423 ± 3
 hemoglobin (300 mg/ml)362 ± 46339 ± 29
contralat hemisphere
 saline177 ± 2432 ± 2
 hemoglobin (150 mg/ml)188 ± 2446 ± 4
 hemoglobin (300 mg/ml)183 ± 3444 ± 7

Values are expressed as the mean ± SEM in six rats.

p < 0.05 compared with the saline and hemoglobin (150 mg/ml) groups.

Time Course of Edema Formation Following Packed RBC Infusion

Figure 1B shows the time course of brain water content at 1, 2, 3, 5, and 7 days after injection of 50 µl packed RBCs. On the 1st day after infusion, no marked brain edema was observed. There was a peak increase in brain water content in the ipsilateral cortex and basal ganglia 3 days after RBC infusion. At 5 to 7 days, ipsilateral brain water content returned to the level of the contralateral tissue. Figure 5 shows the time course of sodium accumulation (Fig. 5A) and potassium loss (Fig. 5B) after infusion of packed RBCs. Again, the peak change in both sodium and potassium was on the 3rd day.

Fig. 5.
Fig. 5.

Graphs showing brain sodium (A) and potassium (B) ion contents 1, 2, 3, 5, and 7 days after infusion of 50 µl packed RBCs. Values are expressed as the mean ± SEM in five or six rats. *p < 0.05 compared with the contralateral side. #p < 0.01 compared with the contralateral side.

Time Course of Edema Formation Following Thrombin Infusion

Figure 6 shows the time course of brain water content after infusion of rat thrombin (5 U). Edema formation started as early as 4 hours after thrombin infusion. The peak in edema was at 24 to 48 hours. Although water content began to decrease after 48 hours, at 7 days it was still higher than that on the contralateral side.

Fig. 6.
Fig. 6.

Graph displaying water content 4, 12, 24, 48, 72, and 168 hours after infusion of rat thrombin (5 U). Values are expressed as the mean ± SEM in five or six rats. *p < 0.001 compared with the contralateral side.

Discussion

This study demonstrates that intracerebral infusion of lysed RBCs results in marked brain edema formation by 24 hours. This edema formation appears to be mediated by hemoglobin because intracerebral infusion of rat hemoglobin at concentrations found in RBCs also resulted in marked increases in brain water content. Studies also indicate that hemoglobin may have other deleterious effects on the brain. Intracortical hemoglobin injection in rats produced chronic focal spike activity, cavity lesions, and gliosis at injection sites.23 Hemoglobin inhibits Na+/K+ ATPase activity in brain homogenates24 and induces depolarization in hippocampal CA1 neurons.36 Regan and Panter22 found brief exposures (1–2 hours) to hemoglobin were not toxic, but exposure of neuronal cell cultures to hemoglobin for 1 day produced concentration-dependent neuronal death.

Although we found that lysed RBCs and hemoglobin induced edema formation, this did not necessarily imply that the RBCs in an intracerebral hematoma contribute to edema formation. In an intracerebral hematoma, RBC lysis and hemoglobin release might occur gradually over a period of time and the brain hemoglobin concentrations might not reach toxic levels. Therefore, we examined the time course of brain water content following injection of packed RBCs into the caudate nucleus. As previously, we found no edema formation 24 hours postinjection.12,34 However, there was marked edema after 3 days, which resolved by 5 days. This delayed edema formation is in accordance with studies in which delayed RBC lysis and hemoglobin release have been found after cerebral hemorrhage. Hemoglobin concentrations reach their peak on the 2nd day after blood injection into the subarachnoid space in the dog and then gradually disappear.15 Hemoglobin release from lysis of RBCs in human intracranial hemorrhage increases during the first few days.31 By using histochemical methods, hemoglobin and heme can be observed in the perihematoma zone 24 hours after whole blood injection in the rabbit.9 The reason for this delayed RBC lysis appears to be either depletion of intracellular energy reserves7 or activation of a complement system and formation of membrane attack complex.21

A comparison of edema formation produced by ICH and thrombin infusion also suggests there may be delayed edema formation from RBC lysis and hemoglobin release in ICH. Data from this laboratory35 and from others4,18,26,27 indicate the amount of edema found in the perihematoma zone after ICH reaches a peak between Day 3 and Day 7. Our present results also show that the peak of edema formation after whole blood infusion is on Day 3 (Fig. 1A). In contrast, edema formation after thrombin injection peaks at 1 to 2 days. Delayed edema formation from RBCs, peaking at 3 days, might explain the difference between the ICH and thrombin data.

The deleterious effects of hemoglobin may derive from the hemoglobin itself or its breakdown products. For example, Gutteridge5 found that hemoglobin activates lipid peroxidation through two different phases. The first phase is induced by the hemoglobin itself, which can be inhibited by haptoglobin. Haptoglobins are glycoproteins that form stable complexes with hemoglobin. The second phase is stimulated by iron, one of the hemoglobin breakdown products, and is inhibited by the iron chelator desferrioxamine, and an iron-binding protein, transferrin.

The adverse effects of hemoglobin vary with its chemical form. Oxyhemoglobin is a spasminogen that has been implicated in cerebral vasospasm.14 In ICH, however, Bradley2 only found oxyhemoglobin in the hematoma for the first few hours following hemorrhage. Thus, it is unlikely that oxyhemoglobin plays a role in ICH-induced edema formation, a suggestion supported by the fact that ICH does not produce marked reductions in cerebral blood flow in the rat35 and intracerebral infusion of essentially methemoglobin can mimic the effects of RBCs on edema formation.

The heme from hemoglobin is broken down by heme oxygenase in the brain into iron, carbon monoxide, and biliverdin.16,17 Carbon monoxide is a free radical that may cause tissue damage analogous to nitric oxide—mediated damage.28 Iron can also stimulate the formation of free radicals leading to neuronal damage. Ferrous and ferric iron are able to react with lipid hydroperoxides to produce alkoxy and peroxy radicals and cause brain damage.25 Cortical injection of iron causes focal epileptiform paroxysmal discharges6 and neuronal damage.33 Anderson and Means1 found iron salts inhibit spinal cord Na+/K+ ATPase in vivo, an effect blocked by antioxidants, whereas Willmore and Rubin32 found that subpial FeCl2 injection induces focal brain edema and malonaldehyde formation. Roles for iron, free radicals, and lipid peroxidation in hemoglobin-induced brain injury are supported by findings that the inhibition of brain Na+/K+ ATPase activity by hemoglobin can be blocked by desferrioxamine mesylate, an iron chelator,24 whereas hemoglobin-induced toxicity in neuronal cell cultures is blocked by the 21-aminosteroid U74500A, the antioxidant Trolox, and desferrioxamine.22

In conclusion, edema formation after ICH appears to involve several phases. These include a very early phase (first several hours) involving hydrostatic pressure and clot retraction,3,30 a second phase (1st day) involving the clotting cascade and thrombin production,10–12 and a third phase (approximately Day 3 in the rat) involving RBC lysis and hemoglobin-induced toxicity. Because of the delay in onset, this third phase may be more amenable to therapeutic intervention either by altering RBC lysis or limiting hemoglobin-induced toxicity.

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This study was supported by Grant No. NS-17760 from the National Institutes of Health.

Article Information

Address reprint requests to: Guohua Xi, M.D., R5605 Kresge I, University of Michigan, Ann Arbor, Michigan 48109–0532. email: guohuaxi@umich.edu.

© AANS, except where prohibited by US copyright law."

Headings

Figures

  • View in gallery

    Graphs showing brain water content at 1, 2, 3, 5, and 7 days after infusion of whole blood or packed RBCs. A: After infusion of 100 µl whole blood. B: After infusion of 50 µl packed RBCs. Values are expressed as the mean ± SEM in five or six rats. #p < 0.01.

  • View in gallery

    Bar graph showing brain water content 24 hours after sham operation or infusion of 30 µl of either packed or lysed RBCs. Values are expressed as the mean ± SEM in five rats. *p < 0.05 compared with the sham-operated and packed RBC groups. #p < 0.01 compared with the sham-operated and packed RBC groups.

  • View in gallery

    Bar graph depicting brain sodium (A) and potassium ion (B) contents 24 hours after sham operation or a 30-µl infusion of either packed or lysed RBCs. Values are expressed as the mean ± SEM. *p < 0.05 compared with the sham-operated and packed RBC groups. #p < 0.01 compared with the sham-operated and packed RBC groups.

  • View in gallery

    Bar graph depicting water content at 24 hours after infusion of 20 µl hemoglobin (Hb) or saline. Values are expressed as the mean ± SEM. *p < 0.05 compared with 150-mg/ml hemoglobin group. #p < 0.01 compared with the saline group.

  • View in gallery

    Graphs showing brain sodium (A) and potassium (B) ion contents 1, 2, 3, 5, and 7 days after infusion of 50 µl packed RBCs. Values are expressed as the mean ± SEM in five or six rats. *p < 0.05 compared with the contralateral side. #p < 0.01 compared with the contralateral side.

  • View in gallery

    Graph displaying water content 4, 12, 24, 48, 72, and 168 hours after infusion of rat thrombin (5 U). Values are expressed as the mean ± SEM in five or six rats. *p < 0.001 compared with the contralateral side.

References

1.

Anderson DKMeans ED: Lipid peroxidation in spinal cord: FeCl2 induction and protection with antioxidants. Neurochem Pathol 1:24926419832 induction and protection with antioxidants. Neurochem Pathol 1:

2.

Bradley WG Jr: MR appearance of hemorrhage in the brain. Radiology 189:15261993Bradley WG Jr: MR appearance of hemorrhage in the brain. Radiology 189:

3.

Brott TBroderick JBarsan Wet al: Hyper-acute clot retraction in spontaneous intracerebral hemorrhage. Stroke 23:1411992 (Abstract)Stroke 23:

4.

Enzmann DRBritt RHLyons BEet al: Natural history of experimental intracerebral hemorrhage: sonography, computed tomography and neuropathology. AJNR 2:5175261981AJNR 2:

5.

Gutteridge JMC: The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation. Biochim Biophys Acta 917:2192231987Gutteridge JMC: The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation. Biochim Biophys Acta 917:

6.

Hammond EJRamsay REVillarreal HJet al: Effects of intracortical injection of blood and blood components on the electrocorticogram. Epilepsia 21:3141980Epilepsia 21:

7.

Kase CSCaplan LR: Intracerebral Hemorrhage. Boston: Butterworth-Heinemann1994Intracerebral Hemorrhage.

8.

Koenig MLMeyerhoff JL: Neurotoxicity resulting from prolonged exposure to hemoglobin. Soc Neurosci Abstr 23:19351997 (Abstract)Soc Neurosci Abstr 23:

9.

Koeppen AHDickson ACMcEvoy JA: The cellular reactions to experimental intracerebral hemorrhage. J Neurol Sci 134 (Suppl):1021121995J Neurol Sci 134 (Suppl):

10.

Lee KRBetz ALKeep RFet al: Intracerebral infusion of thrombin as a cause of brain edema. J Neurosurg 83:104510501995J Neurosurg 83:

11.

Lee KRBetz ALKim Set al: The role of the coagulation cascade in brain edema formation after intracerebral hemorrhage. Acta Neurochir 138:3964011996Acta Neurochir 138:

12.

Lee KRColon GPBetz ALet al: Edema from intracerebral hemorrhage: the role of thrombin. J Neurosurg 84:91961996J Neurosurg 84:

13.

Lee KRKawai NKim Set al: Mechanisms of edema formation after intracerebral hemorrhage: effects of thrombin on cerebral blood flow, blood-brain barrier permeability, and cell survival in a rat model. J Neurosurg 86:2722781997J Neurosurg 86:

14.

Macdonald RLWeir BKA: A review of hemoglobin and the pathogenesis of cerebral vasospasm. Stroke 22:9719821991Stroke 22:

15.

Marlet JMBarreto Fonseca JP: Experimental determination of time of intracranial hemorrhage by spectrophotometric analysis of cerebrospinal fluid. J Forensic Sci 27:8808881982J Forensic Sci 27:

16.

Matz PTurner CWeinstein PRet al: Heme-oxygenase-1 induction in glia throughout rat brain following experimental subarachnoid hemorrhage. Brain Res 713:2112221996Brain Res 713:

17.

Matz PGWeinstein PRSharp FR: Heme oxygenase-1 and heat shock protein 70 induction in glia and neurons throughout rat brain after experimental intracerebral hemorrhage. Neurosurgery 40:1521621997Neurosurgery 40:

18.

Mun-Bryce SKroh FOWhite Jet al: Brain lactate and pH dissociation in edema: 1H and 31P-NMR in collagenase-induced hemorrhage in rats. Am J Physiol 265:R697R70219931H and 31P-NMR in collagenase-induced hemorrhage in rats. Am J Physiol 265:

19.

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