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Endothelialneutrophil interactions duringischemia and reperfusion injury: basic

mechanisms of hyperbaric oxygen

J. A. Buras and W. R. Reenstra

Department of Biology and Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute at Northeastern University, Boston, MA 02115, USA

Ischemia/reperfusion injury plays a central role in the development of tissue injury during multiple central nervous system diseases including acute stroke. Neutrophil adhesion to the endothelium indicates a major component of ischemia/reperfusion pathophysiology, and may be a target for therapeutic intervention. Hyperbaric oxygen has been documented to reduce ischemia/reperfusion injury in a number of different experimental models and in a single human randomized clinical trial. One mechanism responsible for the beneficial effect of hyperbaric oxygen in treatment of ischemia/reperfusion injury involves suppression of neutrophil endothelial adhesion. This review intends to describe the current basic mechanisms responsible for hyperbaric oxygen-mediated inhibition of neutrophilendothelial interactions following ischemia/reperfusion injury. [Neurol Res 2007; 29: 127131]

Keywords: Hyperbaric oxygen; ischemia reperfusion injury; adhesion molecule; nitric oxide;endothelium; neutrophil

ISCHEMIA REPERFUSION INJURY OVERVIEWIschemia/reperfusion (I/R) injury indicates a signicantcause of neurological illness in the setting of severaldisease states, including acute stroke, spinal cord injuryand decompression illness 15 . I/R injury is initiated byan acute interruption of blood ow to distal tissues,inducing metabolic compromise through limitation of available metabolic substrates such as oxygen andglucose. This metabolic disturbance elicits protectivecellular stress responses; however, longstanding depri-vation of substrate may result in cell death within theischemic tissue core. Restoration of blood ow mayallow reperfusion of previously ischemic tissue and maycause further injury to surrounding tissue known as theischemic penumbra 6 . The secondary reduction in bloodow and subsequent extension of cellular injury denethe concept of the no re-ow potion of reperfusioninjury1 .

I/R injury in the central nervous system (CNS) may bemediated by several factors responsible for no re-owin the penumbra at the microvascular level 7 , includingalteration in local capillary permeability and endothe-lial function810 , platelet activation and coagulopa-thy8,11 , and leukocyte adhesion 12,13 . The importanceof leukocyte adhesion and the cell adhesion molecules

(CAMs) that mediate adhesion have been demonstratedin several models of cerebral I/R injury1417 .

Hyperbaric oxygen (HBO 2 ) has been used success-fully in the treatment of I/R injury in both experimentaland clinical settings 18,19 . The mechanisms of benetmay relate to effects on preservation of cellularenergetics, reduction in lipid peroxidation and inhibi-tion of leukocyte adhesion 18 . This review focuses on thebasic mechanisms of how HBO 2 limits adhesion of polymorphonuclear leukocytes (PMNs) to endothelialcells (ECs).

NEUTROPHILENDOTHELIAL CELL ADHESIONThe adhesion of PMNs to the endothelium is a well-regulated process with respect to both temporal andspatial characteristics. PMNs normally traverse themicrovasculature powered by the force of ow. Thexed attachment of PMNs to the endothelium over-comes the normal force of ow through the reduction of ow inherent in the ischemic event, coupled with theinteraction of protein receptors with appropriate ligandsthat are expressed on the surfaces of both the PMN andthe EC. Members of this receptorligand class arereferred to as CAMs. Once the PMN has rmly adheredto the endothelium, it is free to traverse the endothelialcell barrier into the distal tissue matrix through theprocess of diapedesis. Diapedesis is dependent onboth interaction of CAMs, guiding the PMN to inter-

endothelial gaps, and chemokines (protein and lipidmolecules), forming a chemotactic gradient attractingthe PMN to its ultimate distal tissue destination.

Correspondence and reprint requests to: Jon A. Buras, MD, PhD,Department of Biology and Department of Pharmaceutical Sciences,New England Inflammation and Tissue Protection Institute at NortheasternUniversity, 134 Mugar Building, 360 Huntington Avenue, Boston, MA02115, USA. [[email protected]] Accepted for publication 4 April 2006.

# 2007 W. S. Maney & Son Ltd Neurological Research, 2007, Volume 29, March 12710.1179/016164107X174147


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The CNS has a vascular tissue compartment barrierthat is considerably less permeable than many otherareas of the microcirculation due to inter-endothelialtight junctions and a substantial basal lamina 7 . Despitesuch a distinct microvascular structure, PMN trafckinguses mechanisms similar to other microvasculaturebeds and occurs predominantly at the post-capillaryvenule endothelium where CAMs are the most highlyexpressed 20 .

The process of PMN trafcking from the microvascu-lature to distal tissues is often described as a three-stepprocess involving rolling, rm adhesion and diaped-esis21 . Rolling, so called due to the appearance of thePMN during videomicroscopy, occurs when the PMNmakes multiple non-sustained contacts with theendothelium. In this state, the PMN is loosely tetheredto the EC surface by forces that transiently overcome theshear force of ow. Rolling is mediated by expression of the CAM P-selectin in response to inammation andischemia 22 . P-selectin is responsible for rapid PMNEC

interaction as it is a pre-made glycoprotein stored withinthe WeibelPalade bodies of endothelial cells and thesecretory a-granules of platelets. Cellular activationinduces release of these granules to the endothelialsurface within 15 minutes of middle cerebral artery(MCA) occlusion, exposing P-selectin to its major ligandP-selectin glycoprotein ligand-1 (PSGL-1) present onPMNs2325 .

Endothelial activation due to ischemia triggers expres-sion of other CAMs such as E-selectin and intercellularadhesion molecule-1 (ICAM-1) through transcriptionand translation. The requirement for new gene expres-

sion accounts for the temporal delay in E-selectin andICAM-1 appearance relative to P-selectin. In a rodentmodel of MCA occlusion, E-selectin production is noted2 hours following ischemia and exhibits peak expres-sion at hours 6 and 12 (Ref. 24). ICAM-1 expression isnoted 4 hours following MCA I/R injury in the rodent13 .E-selectin and ICAM-1 bind to their PMN ligands SLex / PSGL-1/CD44 and CD11b/18, respectively, strengthen-ing the bond between the PMN and EC leading to rmadhesion of the PMN on the EC surface2628 . Followingrm adhesion, the PMN migrates through EC gap junc-tions via the homotypic interactions between platelet

endothelial cell adhesion molecule (PECAM), presenton the PMN and localized at the EC junctions. PECAM-1 independent diapedesis has been reported; however,this alternative mechanism remains uncharacterized 29 .

The cross-talk between PMN and EC during adhesionand transmigration indicates a complex process thatmay be underappreciated. Interaction of the PMNECadhesion molecules leads to bidirectional signalingevents within each cell type, resulting in cellularactivation that further promotes adhesion. Interactionof L-selectin and P-selectin with their respective ligandsresults in increased avidity of the CD11/18 for ICAM-1(Refs. 3032). Engagement of the E-selectin receptoralso leads to phosphorylation of p38 mitogen-activatedprotein kinase and up-regulation of the CD11/18complex on the PMN 33,34 .

Using in vivo models of cerebral ischemia, interrup-tion of the PMNEC interaction has proven benecial.Interruption of the rolling process by P-selectin block-ade by antibody or in P-selectin genetically decientmice results in protection from cerebral infarction 17 .Antibodies inhibiting CD18 have reduced cerebralinfarct volumes in baboons 12 . Further, CD18 geneticallydecient mice were protected from cerebral ischemiaand reperfusion, but not permanent ischemia

15

.Similarly, anti-ICAM-1 antibodies have reduced post-ischemic brain injury in rodents 35 . Mice geneticallydecient for ICAM-1 have demonstrated smaller infarctvolumes than wild-type mice; however, the number of PMNs recruited to the brain did not differ betweengroups16,36 . These in vivo ndings highlight theimportance of the PMNEC interaction in the develop-ment of cerebral I/R injury and provide one mechanismby which HBO 2 might be benecial during acutecerebral I/R injury.

ANTI-ADHESIVE MECHANISMS OF HBO2 IN I/RINJURYEarly studies on the protective mechanisms of HBO 2during I/R injury were performed in a rodent skeletalmuscle ap model 37 . In these studies, HBO2 treatmentwas noted to reduce the adhesion of PMN to injuredendothelium by real-time videomicroscopy in vivo .Subsequent studies in a rat model of MCA-mediated I/Rinjury have shown that HBO 2 limits cerebral infarctvolume and PMN sequestration 38 . Based on thesendings, it is possible that HBO 2 exerts its benecialeffects through interruption of the PMNEC adhesionmechanism.

HBO2 and PMN adhesionThe rst studies evaluating the mechanisms of HBO 2and PMN adhesion were conducted using a model of carbon monoxide (CO) poisoning 4,39 . CO poisoningwas considered to indicate a form of I/R injury as a resultof transient cellular ischemia and regional CNS hypo-tension with subsequent reperfusion upon CO removal 4 .The transient application of CO in this setting resultsin several biochemical changes similar to end-artery

occlusion I/R injury models including lipid peroxida-tion, conversion of xanthine dehydrogenase to xanthineoxidase and intracerebral PMN sequestration 4 . In rats,HBO2 was capable of reducing intracerebral PMNaccumulation following CO poisoning in a dose-dependent manner with the greatest inhibition at 3atmospheres absolute (ATA) 39 . Using an in vitro systemof CD18-mediated PMN adherence to nylon columns,HBO2 was capable of preventing PMN adhesion 39 . Thisstudy was the rst to implicate a specic adhesionmolecule, CD18, in the anti-adhesive mechanism of HBO2 therapy. The effect of HBO2 on adhesion was notirreversible, as demonstrated through restoration of HBO2 -treated PMNs adhesion to nylon following PMNstimulation with phorbol 12-myristate 13-acetate(PMA)39 . Furthermore, in vivo studies demonstrated that

Endothelialneutrophil interactions during ischemia and reperfusion injury: J. A. Buras and W. R. Reenstra

128 Neurological Research, 2007, Volume 29, March


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HBO2 did not prevent CD18-dependent PMN recruit-ment following glycogen-induced peritonitis 39 .

Subsequent biochemical studies demonstrated thatthe effect of HBO2 on CD18 function was mediated byPMN generated cyclic guanosine monophosphate(cGMP)

40

. PMN derived from HBO2 -treated ratsdemonstrated reduced adhesion to nylon which wasreversible following treatment with PMA, 8-bromo-cGMP (a cGMP analog) or dithiothreitol 40 . Furtherexperiments using human PMNs demonstrated thatHBO2 inhibits the production of cGMP by the mem-brane-bound form of guanylate cyclase and does notinterfere with the free cytosolic guanylate cyclase 41 . Theexact mechanism of how cGMP alters CD11/18 func-tion is unclear; however, it may relate to the subsequentactivities of G-proteins or cGMP-dependent proteinkinase activity which may regulate interaction of the

cytoskeleton and b 2 integrins as recently suggested42,43

.Nitric oxide (NO) has been implicated in the regu-lation of cell adhesion and vascular inammation 44 . NOis a short-lived free radical gas produced by threedistinct enzymes, nitric oxide synthase (NOS) I, II andIII44 . NO has been implicated as both an anti-adhesiveand anti-inammatory molecule and also as a proin-ammatory molecule as it indicates a precursor to thepotentially damaging radical peroxynitrite 44 . The ulti-mate effect of NO in promoting tissue protection ordamage depends upon its concentration and the pre-sence of oxidative stress which may promote peroxyni-trite formation44 .

Recently, NO has been implicated in the HBO 2 -mediated suppression of PMN adhesion 45 . Rats wereexposed to HBO 2 in the presence or absence of a

general NOS inhibitor NG-nitro-L-arginine methyl ester(L-NAME). PMN adhesion to nylon was reduced follow-ing HBO2 treatment; however, inhibition of NO syn-thesis by L-NAME reversed the anti-adhesive effect of HBO2 42 . It is possible that the NO effect mediated byHBO2 involves the membrane bound form of guanylatecyclase. Exogenous NO is capable of reducing cGMPproduction from stimulated PMN membrane boundguanylate cylcase 45 . Furthermore, PMN adherence maybe reduced by NO in a dose-dependent manner 45 .These observations suggest that HBO 2 might alter theadhesive function of PMN CD11/18 by altering NOproduction and resulting in reduced production of cGMP from the membrane bound form of guanylatecyclase. The source of NO responsible for mediatingthis hypothetical mechanism of HBO 2 is not known atpresent. Previous studies have suggested that HBO 2 may

increase production of NO from NOS I as determinedby direct measurements taken beside the abdominalaorta in rats46 . Measurement of NO production in thecerebral cortex during HBO 2 exposure also appears tooriginate from NOS I, not NOS III, as determined usingNOS knockout mice 47 . The HBO2 -induced elevation of NO production was dependent on the presence of oxidative stress as antioxidants were able to reverse theeffect46 . Also, the effect of HBO2 was associated withincreasing inux of intracellular calcium and activity of the heat shock protein Hsp90 (Ref. 46). The exact roleof HBO2 regulation of NOS during I/R injury is moredifcult to determine. Previous in vitro studies haveshown that HBO 2 may increase the production of functional NOS III protein48 . Most recently, preliminarywork in a muscle ap I/R injury model has demonstrated

Figure 1: Unifying mechanisms of HBO 2 in I/R injury. HBO2 affects both PMN andEC components required for rolling and adhesion of PMN to the endothelium. Theeffects of HBO2 may be traced to generation of NO affecting: (1) cGMP productionand CD11/18 function in the PMN; (2) cell surface expression of P-selectin, localalteration of microvascular blood ow and CAM expression through potential down-regulation of NF-kB activation


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19 Bouachour G, Cronier P, Gouello JP, et al. Hyperbaric oxygentherapy in the management of crush injuries: A randomizeddouble-blind placebo-controlled clinical trial. J Trauma 1996; 41:333339

20 del Zoppo GJ, Schmid-Schonbein GW, Mori E, et al.Polymorphonuclear leukocytes occlude capillaries followingmiddle cerebral artery occlusion and reperfusion in baboons.Stroke 1991; 22: 12761283

21 Xu H, Gonzalo JA, St Pierre Y, et al. Leukocytosis and resistanceto septic shock in intercellular adhesion molecule 1-deficient

mice. J Exp Med 1994; 180: 9510922 Patel KD, Zimmerman GA, Prescott SM, et al. Oxygen radicalsinduce human endothelial cells to express GMP-140 and bindneutrophils. J Cell Biol 1991; 112 : 749759

23 Moore KL, Varki A, McEver RP. GMP-140 binds to a glycoproteinreceptor on human neutrophils: Evidence for a lectin-likeinteraction. J Cell Biol 1991; 112 : 491499

24 Zhang R, Chopp M, Zhang Z, et al. The expression of P- and E-selectins in three models of middle cerebral artery occlusion. Brain Res 1998; 785: 207214

25 Vandendries ER, Furie BC, Furie B. Role of P-selectin and PSGL-1in coagulation and thrombosis. Thromb Haemost 2004; 92: 459466

26 Walz G, Aruffo A, Kolanus W, et al. Recognition by ELAM-1 of thesialyl-Lex determinant on myeloid and tumor cells. Science 1990;

250: 1132113527 Zou X, Shinde Patil VR, Dagia NM, et al. PSGL-1 derived fromhuman neutrophils is a high-efficiency ligand for endothelium-expressed E-selectin under flow. Am J Physiol Cell Physiol 2005;289: C415C424

28 Katayama Y, Hidalgo A, Chang J, et al. CD44 is a physiological E-selectin ligand on neutrophils. J Exp Med 2005; 201 : 11831189

29 Schenkel AR, Chew TW, Muller WA. Platelet endothelial celladhesion molecule deficiency or blockade significantly reducesleukocyte emigration in a majority of mouse strains. J Immunol 2004; 173 : 64036408

30 Simon SI, Burns AR, Taylor AD, et al. L-selectin (CD62L) cross-linking signals neutrophil adhesive functions via the Mac-1(CD11b/CD18) beta 2-integrin. J Immunol 1995; 155: 15021514

31 Blanks JE, Moll T, Eytner R, et al. Stimulation of P-selectin

glycoprotein ligand-1 on mouse neutrophils activates beta 2-integrin mediated cell attachment to ICAM-1. Eur J Immunol 1998;28: 433443

32 Green CE, Pearson DN, Camphausen RT, et al. Shear-dependentcapping of L-selectin and P-selectin glycoprotein ligand 1 by E-selectin signals activation of high-avidity beta2-integrin onneutrophils. J Immunol 2004; 172: 77807790

33 Simon SI, Hu Y, Vestweber D, et al. Neutrophil tethering onE-selectin activates beta 2 integrin binding to ICAM-1 through amitogen-activated protein kinase signal transduction pathway. J Immunol 2000; 164: 43484358

34 Hentzen E, McDonough D, McIntire L, et al. Hydrodynamic shearand tethering through E-selectin signals phosphorylation of p38MAP kinase and adhesion of human neutrophils. Ann Biomed Eng 2002; 30: 9871001

35 Matsuoka A, Shitara T, Okamoto M, et al. Transient deafness withiopamidol following angiography. Acta Otolaryngol Suppl 1994;514: 7880

36 Kitagawa K, Matsumoto M, Mabuchi T, et al. Deficiency of intercellular adhesion molecule 1 attenuates microcirculatorydisturbance and infarction size in focal cerebral ischemia. J Cereb Blood Flow Metab 1998; 18: 13361345

37 Zamboni WA, Roth AC, Russell RC, et al. Morphologic analysis of the microcirculation during reperfusion of ischemic skeletalmuscle and the effect of hyperbaric oxygen. Plast Reconstr Surg 1993; 91: 11101123

38 Atochin DN, Fisher D, Thom SR, et al. [Hyperbaric oxygeninhibits neutrophil infiltration and reduces postischemic braininjury in rats]. Ross Fiziol Zh Im I M Sechenova 2001; 87: 11181125

39 Thom SR. Functional inhibition of leukocyte B2 integrins byhyperbaric oxygen in carbon monoxide-mediated brain injury inrats. Toxicol Appl Pharmacol 1993; 123: 248256

40 Chen Q, Banick PD, Thom SR. Functional inhibition of ratpolymorphonuclear leukocyte B2 integrins by hyperbaric oxygenis associated with impaired cGMP synthesis. J Pharmacol Exp Ther 1996; 276: 929933

41 Thom SR, Mendiguren I, Hardy K, et al. Inhibition of humanneutrophil beta2-integrin-dependent adherence by hyperbaric O 2 .Am J Physiol 1997; 272: C770C777

42 Thom SR. Effects of hyperoxia on neutrophil adhesion. UnderseaHyperb Med 2004; 31: 123131

43 Wyatt TA, Lincoln TM, Pryzwansky KB. Regulation of humanneutrophil degranulation by LY-83583 and L-arginine: Role of cGMP-dependent protein kinase. Am J Physiol 1993; 265: C201C111

44 Walford GA, Moussignac RL, Scribner AW, et al. Hypoxiapotentiates nitric oxide-mediated apoptosis in endothelial cellsvia peroxynitrite-induced activation of mitochondria-dependentand -independent pathways. J Biol Chem 2004; 279 : 44254432

45 Banick PD, Chen Q, Xu YA, et al. Nitric oxide inhibits neutrophilbeta 2 integrin function by inhibiting membrane-associated cyclicGMP synthesis. J Cell Physiol 1997; 172 : 1224

46 Thom SR, Fisher D, Zhang J,et al. Stimulation of perivascular nitricoxide synthesis by oxygen. Am J Physiol Heart Circ Physiol 2003;284 : H1230H1239

47 Thom SR, Buerk DG. Nitric oxide synthesis in brain is stimulatedby oxygen. Adv Exp Med Biol 2003; 510 : 133137

48 Buras JA, Stahl GL, Svoboda KK, et al. Hyperbaric oxygendownregulates ICAM-1 expression induced by hypoxia andhypoglycemia: The role of NOS. Am J Physiol Cell Physiol 2000;278: C292C302

49 Baynosa RC, Naig AL, Murphy PS, et al. The effect of hyperbaricoxygen on NOS activity and transcription in ischemia reperfusioninjury. Present at Surgical Forum, American College of Surgeons ,2004, New Orleans, LA, USA

50 Bowman CM, Butler EN, Vatter AE, et al. Hyperoxia injuriesendothelial cells in culture and causes increased neutrophiladherence. Chest 1983; 83: S33S35

51 Shinomiya N, Suzuki S, Hashimoto A, et al. Effect of hyperbaricoxygen on intercellular adhesion molecule-1 (ICAM-1) expressionin murine lung. Aviat Space Environ Med 1998; 69: 17

52 Hong JP, Kwon H, Chung YK, et al. The effect of hyperbaricoxygen on ischemia-reperfusion injury: An experimental study in arat musculocutaneous flap. Ann Plast Surg 2003; 51: 478487


Neurological Research, 2007, Volume 29, March 131
http://www.ingentaconnect.com/content/external-references?article=0022-5282(1996)41L.333[aid=2509343]http://www.ingentaconnect.com/content/external-references?article=0022-5282(1996)41L.333[aid=2509343]http://www.ingentaconnect.com/content/external-references?article=0022-5282(1996)41L.333[aid=2509343]http://www.ingentaconnect.com/content/external-references?article=0022-5282(1996)41L.333[aid=2509343]http://www.ingentaconnect.com/content/external-references?article=0022-5282(1996)41L.333[aid=2509343]http://www.ingentaconnect.com/content/external-references?article=0039-2499(1991)22L.1276[aid=2263407]http://www.ingentaconnect.com/content/external-references?article=0039-2499(1991)22L.1276[aid=2263407]http://www.ingentaconnect.com/content/external-references?article=0039-2499(1991)22L.1276[aid=2263407]http://www.ingentaconnect.com/content/external-references?article=0039-2499(1991)22L.1276[aid=2263407]http://www.ingentaconnect.com/content/external-references?article=0022-1007(1994)180L.95[aid=2514306]http://www.ingentaconnect.com/content/external-references?article=0022-1007(1994)180L.95[aid=2514306]http://www.ingentaconnect.com/content/external-references?article=0022-1007(1994)180L.95[aid=2514306]http://www.ingentaconnect.com/content/external-references?article=0022-1007(1994)180L.95[aid=2514306]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.749[aid=1953776]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.749[aid=1953776]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.749[aid=1953776]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.749[aid=1953776]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.491[aid=7754782]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.491[aid=7754782]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.491[aid=7754782]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.491[aid=7754782]http://www.ingentaconnect.com/content/external-references?article=0006-8993(1998)785L.207[aid=2263288]http://www.ingentaconnect.com/content/external-references?article=0006-8993(1998)785L.207[aid=2263288]http://www.ingentaconnect.com/content/external-references?article=0006-8993(1998)785L.207[aid=2263288]http://www.ingentaconnect.com/content/external-references?article=0006-8993(1998)785L.207[aid=2263288]http://www.ingentaconnect.com/content/external-references?article=0006-8993(1998)785L.207[aid=2263288]http://www.ingentaconnect.com/content/external-references?article=0340-6245(2004)92L.459[aid=7754781]http://www.ingentaconnect.com/content/external-references?article=0340-6245(2004)92L.459[aid=7754781]http://www.ingentaconnect.com/content/external-references?article=0340-6245(2004)92L.459[aid=7754781]http://www.ingentaconnect.com/content/external-references?article=0340-6245(2004)92L.459[aid=7754781]http://www.ingentaconnect.com/content/external-references?article=0036-8075(1990)250L.1132[aid=406715]http://www.ingentaconnect.com/content/external-references?article=0036-8075(1990)250L.1132[aid=406715]http://www.ingentaconnect.com/content/external-references?article=0036-8075(1990)250L.1132[aid=406715]http://www.ingentaconnect.com/content/external-references?article=0036-8075(1990)250L.1132[aid=406715]http://www.ingentaconnect.com/content/external-references?article=0022-1007(2005)201L.1183[aid=7403949]http://www.ingentaconnect.com/content/external-references?article=0022-1007(2005)201L.1183[aid=7403949]http://www.ingentaconnect.com/content/external-references?article=0022-1007(2005)201L.1183[aid=7403949]http://www.ingentaconnect.com/content/external-references?article=0022-1007(2005)201L.1183[aid=7403949]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)173L.6403[aid=7754780]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)173L.6403[aid=7754780]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)173L.6403[aid=7754780]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)173L.6403[aid=7754780]http://www.ingentaconnect.com/content/external-references?article=0022-1767(1995)155L.1502[aid=2609524]http://www.ingentaconnect.com/content/external-references?article=0022-1767(1995)155L.1502[aid=2609524]http://www.ingentaconnect.com/content/external-references?article=0022-1767(1995)155L.1502[aid=2609524]http://www.ingentaconnect.com/content/external-references?article=0022-1767(1995)155L.1502[aid=2609524]http://www.ingentaconnect.com/content/external-references?article=0014-2980(1998)28L.433[aid=2619364]http://www.ingentaconnect.com/content/external-references?article=0014-2980(1998)28L.433[aid=2619364]http://www.ingentaconnect.com/content/external-references?article=0014-2980(1998)28L.433[aid=2619364]http://www.ingentaconnect.com/content/external-references?article=0014-2980(1998)28L.433[aid=2619364]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)172L.7780[aid=7754779]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)172L.7780[aid=7754779]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)172L.7780[aid=7754779]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)172L.7780[aid=7754779]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2000)164L.4348[aid=7050845]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2000)164L.4348[aid=7050845]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2000)164L.4348[aid=7050845]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2000)164L.4348[aid=7050845]http://www.ingentaconnect.com/content/external-references?article=0090-6964(2002)30L.987[aid=7754778]http://www.ingentaconnect.com/content/external-references?article=0090-6964(2002)30L.987[aid=7754778]http://www.ingentaconnect.com/content/external-references?article=0090-6964(2002)30L.987[aid=7754778]http://www.ingentaconnect.com/content/external-references?article=0090-6964(2002)30L.987[aid=7754778]http://www.ingentaconnect.com/content/external-references?article=0271-678X(1998)18L.1336[aid=6440534]http://www.ingentaconnect.com/content/external-references?article=0271-678X(1998)18L.1336[aid=6440534]http://www.ingentaconnect.com/content/external-references?article=0271-678X(1998)18L.1336[aid=6440534]http://www.ingentaconnect.com/content/external-references?article=0271-678X(1998)18L.1336[aid=6440534]http://www.ingentaconnect.com/content/external-references?article=0271-678X(1998)18L.1336[aid=6440534]http://www.ingentaconnect.com/content/external-references?article=0032-1052(1993)91L.1110[aid=1952659]http://www.ingentaconnect.com/content/external-references?article=0032-1052(1993)91L.1110[aid=1952659]http://www.ingentaconnect.com/content/external-references?article=0032-1052(1993)91L.1110[aid=1952659]http://www.ingentaconnect.com/content/external-references?article=0032-1052(1993)91L.1110[aid=1952659]http://www.ingentaconnect.com/content/external-references?article=0869-8139(2001)87L.1118[aid=6515349]http://www.ingentaconnect.com/content/external-references?article=0869-8139(2001)87L.1118[aid=6515349]http://www.ingentaconnect.com/content/external-references?article=0869-8139(2001)87L.1118[aid=6515349]http://www.ingentaconnect.com/content/external-references?article=0869-8139(2001)87L.1118[aid=6515349]http://www.ingentaconnect.com/content/external-references?article=0041-008x(1993)123L.248[aid=1952660]http://www.ingentaconnect.com/content/external-references?article=0041-008x(1993)123L.248[aid=1952660]http://www.ingentaconnect.com/content/external-references?article=0041-008x(1993)123L.248[aid=1952660]http://www.ingentaconnect.com/content/external-references?article=0041-008x(1993)123L.248[aid=1952660]http://www.ingentaconnect.com/content/external-references?article=0022-3565(1996)276L.929[aid=3270416]http://www.ingentaconnect.com/content/external-references?article=0022-3565(1996)276L.929[aid=3270416]http://www.ingentaconnect.com/content/external-references?article=0022-3565(1996)276L.929[aid=3270416]http://www.ingentaconnect.com/content/external-references?article=0022-3565(1996)276L.929[aid=3270416]http://www.ingentaconnect.com/content/external-references?article=1066-2936(2004)31L.123[aid=7754776]http://www.ingentaconnect.com/content/external-references?article=1066-2936(2004)31L.123[aid=7754776]http://www.ingentaconnect.com/content/external-references?article=1066-2936(2004)31L.123[aid=7754776]http://www.ingentaconnect.com/content/external-references?article=1066-2936(2004)31L.123[aid=7754776]http://www.ingentaconnect.com/content/external-references?article=1066-2936(2004)31L.123[aid=7754776]http://www.ingentaconnect.com/content/external-references?article=0021-9258(2004)279L.4425[aid=7754775]http://www.ingentaconnect.com/content/external-references?article=0021-9258(2004)279L.4425[aid=7754775]http://www.ingentaconnect.com/content/external-references?article=0021-9258(2004)279L.4425[aid=7754775]http://www.ingentaconnect.com/content/external-references?article=0021-9258(2004)279L.4425[aid=7754775]http://www.ingentaconnect.com/content/external-references?article=0021-9541(1997)172L.12[aid=7754774]http://www.ingentaconnect.com/content/external-references?article=0021-9541(1997)172L.12[aid=7754774]http://www.ingentaconnect.com/content/external-references?article=0021-9541(1997)172L.12[aid=7754774]http://www.ingentaconnect.com/content/external-references?article=0021-9541(1997)172L.12[aid=7754774]http://www.ingentaconnect.com/content/external-references?article=0065-2598(2003)510L.133[aid=7754773]http://www.ingentaconnect.com/content/external-references?article=0065-2598(2003)510L.133[aid=7754773]http://www.ingentaconnect.com/content/external-references?article=0065-2598(2003)510L.133[aid=7754773]http://www.ingentaconnect.com/content/external-references?article=0065-2598(2003)510L.133[aid=7754773]http://www.ingentaconnect.com/content/external-references?article=0095-6562(1998)69L.1[aid=5700561]http://www.ingentaconnect.com/content/external-references?article=0095-6562(1998)69L.1[aid=5700561]http://www.ingentaconnect.com/content/external-references?article=0095-6562(1998)69L.1[aid=5700561]http://www.ingentaconnect.com/content/external-references?article=0095-6562(1998)69L.1[aid=5700561]http://www.ingentaconnect.com/content/external-references?article=0148-7043(2003)51L.478[aid=7754772]http://www.ingentaconnect.com/content/external-references?article=0148-7043(2003)51L.478[aid=7754772]http://www.ingentaconnect.com/content/external-references?article=0148-7043(2003)51L.478[aid=7754772]http://www.ingentaconnect.com/content/external-references?article=0148-7043(2003)51L.478[aid=7754772]http://www.ingentaconnect.com/content/external-references?article=0036-8075(1990)250L.1132[aid=406715]http://www.ingentaconnect.com/content/external-references?article=0036-8075(1990)250L.1132[aid=406715]http://www.ingentaconnect.com/content/external-references?article=0340-6245(2004)92L.459[aid=7754781]http://www.ingentaconnect.com/content/external-references?article=0006-8993(1998)785L.207[aid=2263288]http://www.ingentaconnect.com/content/external-references?article=0006-8993(1998)785L.207[aid=2263288]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.491[aid=7754782]http://www.ingentaconnect.com/content/external-references?article=0021-9525(1991)112L.749[aid=1953776]http://www.ingentaconnect.com/content/external-references?article=0022-1007(1994)180L.95[aid=2514306]http://www.ingentaconnect.com/content/external-references?article=0039-2499(1991)22L.1276[aid=2263407]http://www.ingentaconnect.com/content/external-references?article=0022-5282(1996)41L.333[aid=2509343]http://www.ingentaconnect.com/content/external-references?article=0022-5282(1996)41L.333[aid=2509343]http://www.ingentaconnect.com/content/external-references?article=0022-1767(1995)155L.1502[aid=2609524]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)173L.6403[aid=7754780]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)173L.6403[aid=7754780]http://www.ingentaconnect.com/content/external-references?article=0022-1007(2005)201L.1183[aid=7403949]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2004)172L.7780[aid=7754779]http://www.ingentaconnect.com/content/external-references?article=0014-2980(1998)28L.433[aid=2619364]http://www.ingentaconnect.com/content/external-references?article=0014-2980(1998)28L.433[aid=2619364]http://www.ingentaconnect.com/content/external-references?article=0022-1767(2000)164L.4348[aid=7050845]http://www.ingentaconnect.com/content/external-references?article=0021-9258(2004)279L.4425[aid=7754775]http://www.ingentaconnect.com/content/external-references?article=1066-2936(2004)31L.123[aid=7754776]http://www.ingentaconnect.com/content/external-references?article=1066-2936(2004)31L.123[aid=7754776]http://www.ingentaconnect.com/content/external-references?article=0022-3565(1996)276L.929[aid=3270416]http://www.ingentaconnect.com/content/external-references?article=0022-3565(1996)276L.929[aid=3270416]http://www.ingentaconnect.com/content/external-references?article=0041-008x(1993)123L.248[aid=1952660]http://www.ingentaconnect.com/content/external-references?article=0869-8139(2001)87L.1118[aid=6515349]http://www.ingentaconnect.com/content/external-references?article=0032-1052(1993)91L.1110[aid=1952659]http://www.ingentaconnect.com/content/external-references?article=0032-1052(1993)91L.1110[aid=1952659]http://www.ingentaconnect.com/content/external-references?article=0271-678X(1998)18L.1336[aid=6440534]http://www.ingentaconnect.com/content/external-references?article=0271-678X(1998)18L.1336[aid=6440534]http://www.ingentaconnect.com/content/external-references?article=0090-6964(2002)30L.987[aid=7754778]http://www.ingentaconnect.com/content/external-references?article=0090-6964(2002)30L.987[aid=7754778]http://www.ingentaconnect.com/content/external-references?article=0148-7043(2003)51L.478[aid=7754772]http://www.ingentaconnect.com/content/external-references?article=0095-6562(1998)69L.1[aid=5700561]http://www.ingentaconnect.com/content/external-references?article=0065-2598(2003)510L.133[aid=7754773]http://www.ingentaconnect.com/content/external-references?article=0021-9541(1997)172L.12[aid=7754774]

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