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Hydrogen sulphide as a novel therapy to ameliorate cyclosporine nephrotoxicity Gwyn Lee, MRCS, BMBS, BA (Hons),* Sarah A. Hosgood, PhD, BSc, Meeta S. Patel, BSc (Hons), MSc, and Michael L. Nicholson, MD, DSc, FRCS Department of Infection, Immunity and Inflammation, Transplant Group, The University of Leicester, Leicester General Hospital, Leicester, United Kingdom
article info
abstract
Article history:
Background: Calcineurin inhibitors have significant nephrotoxic side effects, which can
Received 21 October 2014
exacerbate ischemiaereperfusion injury in renal transplantation. Novel therapeutic agents
Received in revised form
such as hydrogen sulphide (H2S) may reduce these harmful effects. This study investigated
24 February 2015
the effects of H2S on cyclosporine (CsA) induced nephrotoxicity.
Accepted 26 February 2015
Materials and methods: Porcine kidneys were subjected to 15 min of warm ischemia and 2 h
Available online 17 March 2015
of static cold storage. They were reperfused for 3 h with oxygenated normothermic autologous whole blood on an isolated organ reperfusion apparatus. Kidneys were treated
Keywords:
with CsA during reperfusion (n ¼ 6) or cyclosporine and 0.25 mmol/L of H2S infused 10 min
Ischemiaereperfusion injury
before and 20 min after reperfusion (n ¼ 6). These were compared with untreated controls
Kidney
(n ¼ 7).
Cyclosporine
Results: CsA caused a significant reduction in renal blood flow during reperfusion, which
Hydrogen sulphide
was reversed by H2S (area under the curve renal blood flow CsA 257 93 versus control 477 206 versus CsA þ H2S 478 271 mL/min/100 g.h; P ¼ 0.024). Urine output was higher after 2 h of reperfusion in the CsA þ H2S group (CsA þ H2S 305 218 versus CsA 78 180 versus control 210 45 mL; P ¼ 0.034). CsA treatment was associated with an increase in tubular injury, which was not reversed by H2S (area under the curve fractional excretion of sodium, control 77 53 versus CsA 100 61 versus CsA þ H2S 111 57%.h; P ¼ 0.003). Histologic evaluation showed significant vacuolation and glomerular shrinkage in the CsA group. These were significantly reduced by H2S (P ¼ 0.005, 0.002). Conclusions: H2S reversed the vasoconstriction changes associated with CsA treatment during reperfusion. ª 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Cyclosporine (CsA) is widely used as maintenance immunosuppression after kidney transplantation [1] and remains the archetype of this crucial class of immunosuppressant drugs. Calcineurin inhibition downregulates interleukin (IL) 2 secretion and signal transduction. This in turn reduces the
activation and proliferation of T-helper cells, a leukocyte subset crucial for cell-mediated rejection. The benefits of CsA as an effective immunosuppressant are countered by the nephrotoxic sequence, which occurs after its administration. It begins with initially reversible renal and systemic vasoconstriction [1] but also causes an endothelin-mediated dysregulation of afferent and efferent glomerular arteriolar tone. This interferes
* Corresponding author. Department of Infection, Immunity and Inflammation, Transplant Group, The University of Leicester, Leicester General Hospital, Gwendolen Rd, LE5 4PW, Leicester, United Kingdom. Tel.: þ44 0116 252 2951; fax: þ44 0116 252 5030. E-mail address:
[email protected] (G. Lee). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2015.02.061
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with tubuloglomerular feedback, which in turn reduces glomerular filtration rate (GFR) [2]. Eventually this process culminates in interstitial fibrosis and tubular atrophy, the final common pathway of chronic allograft nephropathy [3]. Reperfusion injury associated with organ transplantation is unavoidable; it initiates immunogenic inflammation, oxidative damage, cell edema, and lysis. There is a refractory medullary vasoconstriction that follows renal reperfusion injury and this leads to a disproportionate ischemic insult, which contributes to tubular injury, cortical necrosis, and subsequent fibrosis. The vasoconstriction caused by CsA is central to the severity of its nephrotoxicity during reperfusion [4,5]. It may be possible to counteract the nephrotoxic effects of CsA during reperfusion with the coadministration of another therapy. Hydrogen sulphide (H2S) is well known as a toxic foul smelling product of putrefaction; however, it has recently been characterized as an endogenous biologically active gaseous signaling molecule, or gasotransmitter [6,7]. It is synthesized from amino acid substrates by enzymes including cystathionine b-synthase and cystathionine g-lyase, although it is 3-mercaptopyruvate sulfurtransferase, which predominates in the kidney [8]. The exact mechanisms by which these enzymes are regulated are yet to be described, but redox signaling and product inhibition are thought to play a role [9]. H2S has a number of effects that are beneficial in renal reperfusion injury [10]. These include antithrombotic [11], anti-inflammatory, antioxidant, and antiapoptotic properties but it is the ability of H2S to vasodilate [8] that is most likely to counteract the effects of CsA in renal reperfusion injury. The aim of this study was to investigate the immediate effects of CsA and coadministration of H2S in a porcine ex vivo transplant reperfusion injury model.
2.
Materials and methods
Experiments were conducted so as to comply with the Home Office Animals (Scientific Procedures) Act 1986. Under the Schedule 1 method, female large white pigs (60e70 kg) were euthanized by electrocution and exsanguination. Females were selected for ease of husbandry. The blood was collected from a neck incision into a sterilized bottle containing 25,000 U of heparin (Leo Laboratories, Dublin, Republic of Ireland). Immediately postmortem, the abdomen was opened in the midline and the retroperitoneal space exposed. Kidneys were harvested and subjected to a standard period of 15 min of warm ischemia in the abdominal cavity and then immersed in iced Soltran preservation solution (Baxter, Newbury, United Kingdom). They were flushed with 500 mL of Soltran at 100 cm H2O pressure. Kidneys were stored for 2 h on ice and then reperfused on an isolated organ perfusion system for 3 h (Fig. 1A).
reperfused in an identical way to the treatment groups but without the addition of CsA or H2S.
2.2.
To achieve a therapeutic level of 250e300 ng.mL1 of CsA, 0.5 mL (25 mg) of the Sandimmune injection (Novartis Pharmaceuticals Ltd, Basel, Switzerland) was dispersed in 100 mL of normal saline to give a 0.25 mg.mL1 solution. One milliliter of this was added to the reperfusate (1 L) 15 min before reperfusion of the kidney. Prereperfusion CsA levels were then determined for each kidney by the automated Siemens (Camberley, United Kingdom) Xpand Dimension CsA method. This is a spectrophotometric enzyme-linked antibody assay which uses magnetic beads coated with CsA to bind to and then remove unligated CsA antibody [12].
2.3.
Hydrogen sulphide
Sodium sulfide ([Na2S]; SigmaeAldrich, St Louis, MO) was used as the H2S donor. Immediately before the experiment, 0.25 mmol/L of Na2S was dissolved in 60 mL of Ringer lactate (Baxter) and infused into the venous reservoir of the isolated organ perfusion system for 10 min before and 20 min after initiation of reperfusion.
2.4.
Reperfusion
The organ perfusion apparatus was based on a paediatric cardiopulmonary bypass system (Bio-Console 550; Medtronic, Watford, United Kingdom) as previously described [13]. The system was primed with equal parts of whole blood and Ringer’s lactate. This was allowed to equilibrate to 38 C and achieve maximal oxygenation. One thousand micromoles of creatinine (SigmaeAldrich) was added as was 375 mg cefuroxime (Flynn Pharmaceuticals, Stevenage, United Kingdom) and nutrients (Synthamin; Baxter, Deerfield IL). To prepare kidneys for ex vivo normothermic perfusion, the renal artery and ureter were cannulated with trimmed silastic urethral catheters. The arterial feed was inserted into the arterial cannula. During reperfusion, a normothermic oxygenated blood-based perfusate was pumped into the renal artery at set mean arterial pressure of 80 mm Hg, an optimal pressure determined from previous work [14]. The mean arterial pressure remains constant throughout reperfusion allowing the kidney to regulate its own blood flow according to the level of intrarenal resistance (IRR; Fig. 1B). Urine produced during reperfusion was carried to a urinometer and measured hourly. Nutrients, glucose, and bicarbonate (Polyfusor; Fresenius Kabi, Runcorn, UK) were continuously infused by peristaltic pumps, and Ringer lactate was replenished to the reservoir to make up losses as urine and evaporation.
2.5. 2.1.
Cyclosporine
Data collection
Experimental design
Kidneys were divided into three groups as follows: control (n ¼ 7), CsA (n ¼ 6) or cyclosporine þ hydrogen sulphide (CsA þ H2S, n ¼ 6). Kidneys in the control group were
Blood samples were taken before reperfusion and at 1, 2, and 3 h for biochemical analysis. Arterial and venous blood gas and acid and/or base parameters were also determined at 1 and 3 h. Renal blood flow (RBF) was measured and IRR
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Fig. 1 e (A) Experimental design. Kidneys were subject to 15-min warm ischemia followed by 2 h of cold storage. After preservation, they were reperfused on an isolated perfusion system for 3 h. (B). Isolated organ perfusion system with the main components highlighted. (Color version of the figure is available online.)
derived throughout reperfusion. Biopsies were taken before and after reperfusion. Urine output was measured at 1, 2, and 3 h and sent for biochemical analysis. Fractional excretion of sodium (FexNa) and creatinine clearance was calculated from urinary and serum measurements at 1, 2, and 3 h. A post reperfusion sample of urine was snap-frozen in liquid nitrogen for later determination of biomarkers using enzyme-linked immunosorbent assay (ELISA) as per the manufacturer’s instructions as follows: endothelin (ET)-1 (ELISA kit; Enzo Life Sciences, Exeter, United Kingdom), IL-6 (ELISA kit; R&D Systems, Abingdon, United Kingdom), IL-1b 6 (R&D Systems), and neutrophil-associated lipocalin (NGAL) 6 (ELISA kit; Pathway Diagnostics, Dorking, United Kingdom).
2.6.
Histopathologic examination
Wedge biopsies were taken before and after reperfusion. Biopsies were fixed in 10% formal saline, dehydrated, and embedded in paraffin wax. A section of 4 mm was cut and stained with hematoxylin and eosin for evaluation under light microscopy (400). Sections were scored over 10 fields assessing changes in four morphologic variables; tubular dilatation, tubular debris, vacuolation, interstitial edema, and glomerular shrinkage. A trained assessor blinded to the experimental group scored samples from 0e3 according to the level of damage; 0 ¼ normal, 1 ¼ mild, 2 ¼ moderate, and 3 ¼ severe morphologic changes.
2.7.
Statistical analysis
Reperfusion data are presented as median interquartile range. They were compared using analysis of variance (ANOVA) if normally distributed or KruskaleWallis ANOVA otherwise. Area under the curve (AUC) was calculated. Histopathologic data are presented as the mean standard deviation. They were compared using KruskaleWallis ANOVA with Dunn multiple comparisons. GraphPad (PRISM version 6 software) was used to perform these calculations and analyses. Statistical significance was established at P < 0.050.
3.
Results
3.1.
CsA levels
CsA levels were equivalent in both groups (CsA 215 24.5 versus CsA þ H2S 209 140 ng.mL1; P ¼ 0.79, ManneWhitney U-test).
3.2.
Hemodynamic data
AUC RBF was significantly lower in kidneys treated with CsA compared with that of control and kidneys treated with CsA þ H2S (CsA: 257 93 versus control: 477 206 versus CsA þ H2S: 478 271 mL.min1.100 g1; P ¼ 0.024; ANOVA). RBF was maintained at a constant low level throughout
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(Fig. 4A). There was no significant difference in AUC creatinine among the groups (control: 1650 410 versus CsA: 2025 375 versus CsA þ H2S: 1662 711, P ¼ 0.68; ANOVA). AUC creatinine clearance was numerically lower in the CsA group (control: 8.9 6.3 versus CsA: 5.5 8.0 versus CsA þ H2S: 14 12, P ¼ 0.16; ANOVA). Creatinine clearance at 2 h was numerically higher in the CsA þ H2S group than CsA (CsA þ H2S: 9.1 8.4 versus CsA: 3.2 3.9 versus control: 5.2 3.4, P ¼ 0.11; ANOVA; Fig. 4B). Fig. 2 e Graph showing RBF versus time for porcine kidneys subject to 15 min warm and 2 h cold ischemia. They were reperfused with a normothermic oxygenated blood-based solution for 3 h on an isolated organ reperfusion apparatus. Control (n [ 7) and either CsA (n [ 6) or CsA D H2S (n [ 6). Results are presented as median ± interquartile range.
reperfusion in the CsA group. In the control and the CsA þ H2S groups, RBF increased over the first 120 min. Thereafter, there was a decrease in the RBF in the CsA þ H2S group but it remained constant in the control group (Fig. 2). AUC IRR was significantly lower in the CsA þ H2S group compared with that in the control group (CsA þ H2S: 4.0 2.1 versus control 8.9 5.7 mm Hg min1.100 g1.h; P ¼ 0.027; ANOVA). There was no statistically significant difference in levels of oxygen consumption between the three groups at 1 and 3 h after reperfusion; however, levels were numerically higher in the CsA þ H2S group than those in the CsA group (P ¼ 0.22, 0.14, respectively; Fig. 3). Levels improved significantly in the control group after 3 h of reperfusion but remained constant in the CsA and CsA þ H2S groups (P ¼ 0.007, 0.157, and 0.161, respectively; Fig. 3).
3.3.
Functional data
Urine output was significantly higher 2 h after reperfusion in the CsA þ H2S group compared with that in the CsA group (values þ data). There was no significant difference in the total urine output between the three groups (control: 635 65 versus CsA: 225 574 versus CsA þ H2S: 700 437 mL; P ¼ 0.11); however, levels were numerically lower in the CsA group. Serum creatinine fell during reperfusion in all three groups
Fig. 3 e Levels of oxygen consumption at 1 and 3 h of reperfusion. Control (n [ 7) and either CsA (n [ 6) or CsA D H2S (n [ 6). Results are presented as median ± interquartile range.
3.4.
Tubular injury
FexNa fell during reperfusion in the control group but rose during the third hour in both CsA and the CsA þ H2S groups. AUC FexNa was significantly higher in the CsA þ H2S group compared with that in the control group but not in the CsA group (CsA þ H2S: 110.5 56.8 versus control: 77.4 53.1 versus CsA: 100.2 61.4%.h; P ¼ 0.0034; ANOVA). Urinary concentration of IL-6 at 3 h was significantly higher in the CsA þ H2S group than the control group (P ¼ 0.024), there was no difference between control and CsA. ET-1 and NGAL at 3 h were equivalent in all three groups. (P ¼ 0.33, 0.95; ANOVA). IL-1b was not detected (Fig. 5AeD).
3.5.
Histopathologic scores
In the control and CsA groups, reperfusion caused significant increases in tubular dilatation, vacuolation, and interstitial edema (P < 0.05). In the control group, there was also a significant increase in glomerular shrinkage (P < 0.05). In the CsA þ H2S group, there was a significant increase in vacuolation, interstitial edema, and glomerular shrinkage (P < 0.05) and a decrease in tubular debris (P < 0.05). In the reperfusion biopsies, CsA þ H2S showed reduced vacuolation and glomerular shrinkage compared with those in CsA-treated kidneys (P ¼ 0.005, 0.002; Table; Fig. 6AeD).
4.
Discussion
This study provides evidence that exogenously administered H2S can reverse some of the vasoconstrictive effects of CsA during reperfusion. CsA is known to cause renal and systemic vasoconstriction by stimulating secretion of ET-1, increasing the evolution of reactive oxygen species, and by decreasing production of nitric oxide [1,15,16]. Experimental evidence has also shown that it causes differential vasoconstrictive effects on afferent arterioles [20]. There is radiologic evidence that CsA reduces perfusion of transplanted human kidneys within 1 h of administration [17]. Our findings confirm that CsA causes a direct and immediate reduction in RBF. It is clear that calcineurin inhibitors (CNI) such as CsA can aggravate renal reperfusion injury and their administration is often delayed until an adequate level of renal function is maintained after transplantation. Their long-term use causes chronic allograft nephropathy, which reduces graft survival. CsA remains in wide use; however, newer CNI such as tacrolimus are now more commonly used in the United Kingdom.
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Fig. 4 e Graphs showing results for porcine kidneys subject to 15-min warm and 2-h cold ischemia. They were reperfused with a normothermic oxygenated blood-based solution for 3 h on an isolated organ reperfusion apparatus. Control (n [ 7) and either CsA (n [ 6) or CsA D H2S (n [ 6). Results are presented as median ± interquartile range. (A) Serum creatinine versus time. (B) Creatinine clearance versus time.
CNIs can have other advantageous effects during reperfusion injury. Opening of the mitochondrial permeability transition pore in response to the ischemiaereperfusion insult is a potent proapoptotic signal. CsA inhibits mitochondrial permeability transition pore opening [18], protecting against reperfusion injury [19]. Nonetheless, therapies that may ameliorate the nephrotoxic effect of CNIs during the critical phase of reperfusion injury and possibly prolong graft life warrant investigation before clinical evaluation can begin. Previous isolated studies have investigated anti-inflammatory agents [20], phosphodiesterase inhibitors [21,22], a derivative of erythropoietin [23], and an aldosterone receptor antagonist
to reduce some of the effects of CsA-induced renal reperfusion injury [24]. H2S was chosen to counteract the effects of CsA in this present study because of its diverse properties. H2S has a central role in cellular signaling in renal, cardiac neuronal, and vascular tissues [25], and there are numerous studies showing beneficial effects in renal reperfusion injury [26,27]. Furthermore, it has been shown to counteract the profound global vasoconstriction associated with renal reperfusion injury in a large animal model [28]. H2S has a half-life measured in minutes and acts by several mechanisms. It is an endothelium-dependent relaxing factor and can also act
Fig. 5 e Graph showing 3-h urinary levels of biomarkers from three groups of porcine kidneys subject to 15 min warm and 2-h cold ischemia. They were reperfused with a normothermic oxygenated blood-based solution for 3 h on an isolated organ reperfusion apparatus. Control (n [ 7) and either CsA (n [ 6) or CsA D H2S (n [ 6). Results are presented as median ± interquartile range. (A) IL-6 (outliers in the control and CsA D H2S removed; *P [ 0.024); ANOVA, (B) ET-1, (C) NGAL, and (D) IL-1b.
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Table e The results of histopathologic examination of samples from porcine kidneys subject to 15-min warm and 2-h cold ischemia. Morphological variable
Control Before
Tubular dilatation Vacuolation Tubular debris Interstitial edema Glomerular shrinkage
1.1 0.3 1.5 1.5 1.5
0.69 0.44 0.70 0.79 0.78
CsA þ H2S
CsA After
1.6 2.5 1.7 2.5 1.8
Before *
0.82 0.70* 0.70 0.56* 0.53*
1.4 0.5 1.1 1.3 1.6
0.55 0.27 0.43 0.66 0.56
After 1.9 2.7 1.2 2.0 1.5
Before *
0.71 0.50* 0.50 0.58* 0.81x
1.7 1.0 1.6 1.4 0.92
0.59 0.55 0.64 0.55 0.46
After 1.6 2.3 1.2 2.1 1.3
0.64 0.74*y 0.43*z 0.68*x 0.46*x
They were reperfused with a normothermic oxygenated blood-based solution for 3 h on an isolated organ reperfusion apparatus. Control (n ¼ 7) and either CsA (n ¼ 6) or CsA þ H2S (n ¼ 6). Results are presented as mean standard deviation. Wedge biopsies were taken before and after reperfusion. Biopsies were fixed in 10% formal saline, dehydrated, and embedded in paraffin wax. Section of 4 mm was cut and stained with hematoxylin and eosin for evaluation under light microscopy (400). Sections were scored over 10 fields assessing changes in four morphologic variables; tubular dilatation, tubular debris, vacuolation, interstitial edema, and glomerular shrinkage. A trained assessor blinded to the experimental group scored samples from 0e3 according to the level of damage; 0 ¼ normal, 1 ¼ mild, 2 ¼ moderate, and 3 ¼ severe morphologic changes. * P < 0.050 comparing before and after reperfusion biopsies. Comparing after reperfusion biopsies are given in the following: y P < 0.050 CsA versus CsA þ H2S. z P < 0.050 control versus CsA and control versus CsA and CsA þ H2S. xP < 0.050 control versus CsA þ H2S.
directly to activate adenosine triphosphate sensitive Kþ channels (KATP), hyperpolarising the membrane and thus causing relaxation of smooth muscle. It may also prevent medullary ischemia [29] and has been shown to inhibit secretion and signaling of profibrotic factors [30e32]. Therefore, its coadministration with CsA may have long-term beneficial effects. The dose of H2S was chosen on the basis of previous work [28], whereas CsA was added to achieve levels in the reperfusate that were comparable with human trough levels in renal transplantation [33].
We chose Na2S as a H2S donor infused over 30 min, for ease, for quantifiability and cost-effectiveness [28,34]. We found an immediate and enduring vasoconstrictive effect of CsA and a powerful but transient vasodilatory effect of H2S. The histology showed marked ischemic changes after reperfusion in CsA-treated kidneys. However, this was substantially less in those treated with H2S suggesting that there is less ischemic injury, possibly due to its vasodilatory effect. Nonetheless, we found no improvement in renal function. There was a higher level of diuresis in kidneys treated with
Fig. 6 e Histology sections stained with hematoxylin and eosin 3400. (A) Severe tubular dilatation, moderate interstitial edema, and mild vacuolation. (B) Moderate tubular debris. (C) Severe vacuolation and moderate tubular dilatation. (D) Severe glomerular shrinkage. (Color version of the figure is available online.)
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H2S, but this did not enhance the level of function. Several biomarkers of inflammation and tubular injury were used to determine the level of injury. IL-6 has proinflammatory properties and levels increase during injury; however, it has also been shown to be reparative [35]. The increased levels of IL-6 in the CsA- and H2S-treated kidneys may therefore represent enhanced cellular repair processes. Levels of IL-1ß were not detectable, and levels of NGAL and ET-1 showed a similar level of injury among the groups. This ex vivo reperfusion model allows the measurement of perfusion characteristics that can be used to assess hemodynamic, metabolic, and renal processes in the intact kidney. It is limited to a short reperfusion phase and although the porcine kidney has many similarities to the humans, there is significant biological variation in the level of function between the kidneys. Larger groups sizes may be needed to reduce the amount of variability. The short reperfusion phase is also limited. With the degree of ischemic injury used in this study, it is perhaps unsurprising to find no significant difference in the level of renal function in this early reperfusion phase. All kidneys showed a marked reduction in renal function. Transplantation of treated kidneys would allow us to look further into the longer term effects of H2S. Na2S has a short shelf-life and therefore alternative donors that provide a more sustained effect could be investigated. D cysteine has been shown to replenish molecular stores of H2S in the kidney [36]. L cysteine from which H2S is usually synthesized has been shown to increase intracellular concentrations of H2S [25]. Sulfur-containing amino acids are more stable and less toxic than inorganic sulfides and so represent good potential H2S donors. Allicin, an active component of garlic, has H2S-mediated vasoactivity [37], and finally there are sulfur derivatives of drugs such as NOSH aspirin and sulfur diclofenac [38] that have shown benefits as H2S donors. Therefore, the application of H2S as a therapeutic agent is achievable and practical in clinical renal transplantation.
5.
Conclusions
H2S reversed the vasoconstriction associated with CsA treatment during reperfusion.
Acknowledgment Authors’ contribution: Mr Keyur K Shah participated in the data collection for one of the experimental groups. G.L., S.A.H., and M.L.N. contributed substantially to the conception and design of the study and revised the article critically for important intellectual content. G.L. and M.S.P. did the acquisition of data and drafted the article. G.L., S.A.H., and M.S.P. did the analysis and interpretation of data. G.L., S.A.H., M.S.P., and M.L.N. gave final approval of the version to be submitted. M.L.N. was central to the conception and design of the study.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in the article.
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