OGS PRESIDENT'S MESSAGE

In the last President's message I briefly mentioned the 3rd World Glaucoma Congress to be held in Boston. I would like to spend a little more time encouraging you to attend. The meeting will take place at the Hynes Convention Center from July 8th to 11th. Over 70 glaucoma societies from around the world will be represented at what promises to be the biggest glaucoma meeting ever organized. The Optometric Glaucoma Society is proud to have the status as one of the 14 "regional" societies of the World Glaucoma Association, the organization responsible for the World Glaucoma Congress. We are well represented within the WGA and our members are amongst the Congress faculty. The OGS will be hosting a special symposium on the morning of the 8th July, and has arranged for COPE approval of courses throughout the congress. Please visit the website http://www.worldglaucoma.org/WGC2009/ and explore the vast array of symposia, basic and clinical courses, debates and clinical rounds that are planned. The OGS are also planning a social event on the evening of the 8th July following the opening reception. Optometry is a welcomed participant of the World Glaucoma Congress. It is important that we participate. There are few better cities in North America than Boston in July. The Gala Evening is being held on Friday, July 10th, at the Boston Public Library. I encourage you to take this opportunity to experience what promises to be an exceptional meeting, both the education and the ambience. Early, reduced registration is open until April 30th. I look forward to seeing you at the World Glaucoma Congress, 2009. It promises to be the highlight of the year for all things glaucoma, make sure you don't miss out.

John Flanagan PhD, MCOptom, FAAO
President, Optometric Glaucoma Society
jgflanag@quark.uwaterloo.ca

Welcome to the Optometric Glaucoma Society Electronic Journal. This first issue of 2009 focuses on a significant question that we hope will interest clinicians and scientists alike: what factors may have a role in the cause of primary open angle glaucoma (POAG)?

As a chronic non-infectious disease, it has long been recognised that (in most patients at least) POAG is multifactorial. This is readily obvious from the diversity of possible clinical presentations. As such, there are many theories regarding pathogenesis. This feature issue of the EJ contains review articles that discuss evidence for three specific questions related to causality. Each review is authored by a research group with specialist interest in these specific subject areas with the aim of updating you on the latest theories on the following questions; (1) What causes IOP elevation in glaucoma? (2) What is the role of vascular factors in the cause of glaucoma? (3) Do the biomechanics of the optic nerve head and sclera increase susceptibility to glaucoma?

Understanding causes of disease is one of the foundations upon which better care in the future may be built. Knowledge stimulates research and development of new 'tools' that could have a future use in clinical care. Such tools can take a variety of forms, from new treatments, through to improvements in tests and determination of the most informative clinical outcome measures. They may also show us how to best assay the effectiveness of treatment, or monitor disease status. Knowledge of causality may also inform clinical strategies to better identify currently healthy individuals who are at greatest risk of disease.

Future developments aside, clinicians' improved understanding of causality can greatly improve patient care. Poll data presented in this issue suggest that a majority of clinicians already explain the causes of glaucoma to most of their patients. Because increased involvement in their care is known to improve patients' adherence to their treatment, up-to-date appreciation of disease processes will enable us all to continue this active engagement with our patients and further encourage their participation, maximising the chances of successful treatment.

Paul GD Spry, PhD, BSc, MCOptom DipGlauc
Editor-in-Chief
paul.spry@ubht.nhs.uk

Summary
• There is no direct link between blood flow and glaucoma.
• The retina and the ONH autoregulate to a wide range of ocular perfusion pressure.
• The vascular endothelium derived vasoconstricting and vasodilating factors affect retinal blood flow.
• Over the last few years, retinal vascular reactivity (change in hemodynamic parameters due to provocative stimuli) has been widely studied using a variety of provocations.
• Assessment of the vascular reactivity of the ONH will provide greater understanding of the pathophysiology of POAG.
• Under normal conditions, the retinal and the ONH vessels respond by an increase in diameter, velocity and blood flow to hypercapnia and a decrease in all the hemodynamic parameters in response to hyperoxia.
• A lowering of IOP improves ocular perfusion pressure.
• There is no equivocal evidence that any current IOP-lowering topical medications have a direct vasoactive effect.
• Vascular dysregulation may be a factor in the development of POAG.
• Untreated POAG and patients with treated progressive disease have been shown to have abnormal vascular reactivity when compared to normal controls.
• Clinically practical tests of ocular vascular reactivity are required.

Introduction
There are various theories as to the pathogenesis of POAG, including the traditional concepts of biomechanical and vascular related stress. However, it is generally recognised that glaucoma is typically caused by a combination of different factors, such that it is the ability to maintain perfusion to an individual optic nerve that determines the clinical presentation, no matter what the biomechanical and vascular stresses. This brief review will concentrate on current concepts of vascular factors associated with the onset of POAG.

Over the past three decades, epidemiological and experimental evidence has suggested that impaired ocular blood flow and/or vascular dysregulation are important risk factors in the pathogenesis of POAG (1-6). Studies suggest that ischemia-promoting vascular factors may contribute to glaucomatous damage, including vasospasm or inappropriate vasoconstriction (7), altered ocular perfusion pressure (8,9) and general vascular disorders such as systemic hypotension, including nocturnal dips in blood pressure, which result in deleterious effects on optic nerve perfusion (10,11). The role of vasospasm in the pathogenesis of glaucoma has received particular attention (4,12-15).

To understand the potential for a vascular aetiology in POAG, it is important to be aware of the complex blood supply to the optic nerve. The retina receives its blood supply through the common carotid artery, internal carotid artery and ophthalmic artery (OA) with the central retinal artery (CRA) supplying the inner retina (16) and the posterior ciliary arteries (PCAs) supplying the choroid (17). The short PCAs (SPCA) supply the posterior choroid and the long PCAs supply the anterior choroid, ciliary body and iris. The ONH is stratified into 4 layers. At the level of the superficial nerve fibre layer the ONH is predominantly supplied by the inner retinal circulation and, in part, by the SPCAs in the temporal region (8,10). The prelaminar region receives its blood supply from the peripapillary choroid and from the SPCAs. The lamina cribrosa (LC) is supplied exclusively, and rather surprisingly, by the SPCAs (Figure 1) and the retrolaminar region is nourished by both the pial vessels and small branches from the CRA (10,18-20). The venous drainage of the ONH is primarily through the central retinal vein (10,16,21).

Under normal conditions, change in intraocular pressure (IOP) and blood pressure (BP) are autoregulated by the retinal vessels. Abnormal autoregulation has been proposed in patients with POAG (22-24). Retinal, peripapillary and ONH capillary blood flow (25-28) have been shown to be decreased in patients with POAG, along with peripapillary capillary atrophy (29,30). A decrease in blood flow may even play a role in the reduction of axoplasmic flow along the retinal ganglion cell axons.

Autoregulation is defined as the ability of a tissue to maintain constant blood flow despite changes in perfusion pressure. The retina lacks autonomic innervation and blood flow is principally regulated by a myogenically driven, negative feedback mechanism. In most tissues, arterioles are thought to be the major site for regulation of blood flow to the downstream capillary bed (10,31,32). However, the pericytes in retinal capillaries also regulate flow to a lesser extent at a local level (31,33-36).

Regulation of blood flow in the ONH and retina is not only achieved through myogenic mechanisms but also via metabolically-driven mechanisms. Regulation of flow to metabolic stimuli is determined, for example, by the local concentration of for example, glucose, O₂, CO₂ or K+ (10,32,37). The vascular endothelium lines the lumen of arterioles and is enveloped in vascular smooth muscle cells (16,38). The endothelium regulates blood flow by producing vasoactive substances termed Endothelial Derived Constricting Factors (EDCF) and Endothelial Derived Relaxing Factors (EDRF). Among the various dilating and constricting factors, nitric oxide (NO, an EDRF) and endothelin-1 (ET-1, an EDCF) are thought to be the major signalling factors determining vascular tone in the retina. ET-1 is a potent vasoconstrictor. Plasma levels of ET-1 have been reported to be elevated in POAG, especially NTG, when compared to normal subjects. NO also plays a pivotal role in maintaining vascular tone by promoting vasodilation. Vascular tone reflects the balance of opposing locally produced EDRFs and EDCFs, primarily NO and ET-1, respectively (39). NO and ET-1 each act via negative feedback mechanisms to limit the action of the other but this mechanism is thought to be affected in diseases characterized by endothelial dysfunction. Endothelial dysfunction manifests as an inadequate vasodilatory response following stimulation of EDRF. Endothelial dysfunction may reflect impaired NO availability and/or excess ET-1. ET-1 may also contribute to endothelial dysfunction indirectly through the inhibition of NO bioavailability. However, it is not possible to assess the level of NO because of its short half life, although the level of cyclic guanosine monophosphate (cGMP) in the plasma has been used as an indirect measure of NO expression. It has been reported that plasma cGMP levels are reduced in patients with POAG compared to age-matched controls. An overall imbalance in ET-1 and NO production has been proposed in glaucoma, in particular in POAG, and this disturbance has been suggested to trigger a series of events that lead to dysregulation of ONH perfusion, and the apoptotic loss of retinal ganglion cells and glaucomatous optic neuropathy (23,31,37,40-49).

Figure 1: High definition OCT image (Spectralis HRA-OCT, Heidelberg Engineering) through a normal optic nerve, showing a short posterior ciliary artery (SPCA) piercing through the sclera and approaching the lamina cribrosa. The SPCAs provide the exclusive blood supply to the lamina cribrosa. Note the surprisingly large vessel diameter in this young, healthy subject.

The change in hemodynamic parameters in response to provocation such as CO₂ (50-53), O₂ (47,54-56) or light flicker (62-66) in the absence of a change in perfusion pressure is often referred to as vascular reactivity, particularly in the cerebral blood flow literature. Vascular reactivity is an increasingly important clinical concept in understanding the pathophysiology of glaucoma. The impact of arterial gas provocation on aspects of retinal hemodynamics has been investigated in both animals and humans. CO₂ is a potent vasodilator while O₂ is a vasoconstrictor. Hypercapnia is the increase in the partial pressure of CO₂ (pCO₂) in the arterial blood supply and can be indirectly measured from the peak concentration of CO₂ during expiration, termed end-tidal CO₂ (ETCO₂). Hypercapnia also induces hyperventilation, which leads to an unpredictable change in the arterial partial pressure of O₂. As a result, any measured response to a hypercapnic stimulus without consideration of end-tidal O₂ levels results in a poorly standardised methodology, due to the inter-individual variability of the hyperventilatory response and the resulting change in arterial O₂. Recent studies have demonstrated differences of the retinal vascular reactivity response in patients with POAG when compared to age-matched controls using hypercapnic provocation but many are complicated by the impact of concomitant hyperventilation and confounding change in the arterial O₂.

An increase in blood pressure leads to vasoconstriction of arterioles, and vice versa, and thereby maintains blood flow and this is termed myogenic autoregulation. It occurs secondarily to the activation of stretch activated ion channels in vascular smooth muscle cells that, in turn, allow calcium ions to enter the smooth muscle cell to induce contraction (31,67-72). Hormonal factors also participate in the regulation of blood flow by the signalling of blood vessel smooth muscle cells, endothelial cells and also pericytes (32,38). In particular, the rennin-angiotensin system activates angiotensin I (AT-I) to form angiotensin II (AT-II) by the action of angiotensin converting enzyme (ACE) (73,74). Additional neurogenic factors have been proposed but are not definitively established in the control of human retinal blood flow (75).

The retina and the ONH autoregulate up to an IOP of 30-40mmHg in normal subjects (76-79) and choroidal blood vessels autoregulate during an ocular perfusion pressure (OPP) increase of up to 40% (80). There is increasing evidence that vascular dysregulation, or disturbance in autoregulation, is also an important factor in the pathogenesis of POAG (12,23,48,81-84).

Several studies of POAG have investigated homeostatic levels of ocular blood flow and the response of the retinal, choroidal and ONH vasculature to various myogenic and metabolic provocations. These studies have provided some basic understanding of the possible vascular abnormalities associated with POAG including an association with an imbalance of vasoactive substances such as ET-1 (85,86). Recent developments in blood flow measurement techniques have made the absolute quantification of hemodynamic parameters possible (87). The majority of studies have suggested a decrease in blood flow and a decrease in ONH perfusion in patients with POAG, including NTG. The assessment of retinal and ONH vascular regulation provides additional information about ocular physiology. Importantly, we now know that vascular regulation can be abnormal even when homeostatic retinal blood flow is within normal limits. The ONH blood flow response to myogenic provocation has been studied using various hemodynamic measurement techniques. Using laser Doppler flowmetry, the blood flow in the ONH did not show a significant change in normal controls or patients with NTG after 3 weeks wash-out of topical medications, to a 28% increase in perfusion pressure during exercise 40. However, there was an increase of vascular resistance to the alteration in OPP in the NTG group, that likely indicates an autoregulatory disturbance (40). A similar result was found in a study that measured change in choroidal pulsation and ONH blood flow in response to a 20mmHg increase in OPP, in patients with POAG (88). Similarly, altered autoregulation has been proposed when measured in response to changes in IOP in patients with POAG (89). A short term increase in IOP has been shown to cause a reduced regulatory change in retinal arteriolar and venular diameter (90). Studies on the diurnal characteristics of untreated POAG have proposed that mean ocular perfusion pressure is an early and independent risk factor for the development of POAG (9). It was also shown that there was dysfunctional autoregulation in sectors of the ONH in response to diurnal fluctuation in blood pressure and intra-ocular pressure. In untreated early glaucoma and age matched controls, the mean optic nerve blood flow was autoregulated in response to diurnal fluctuation of the ocular perfusion pressure. However, it was found that the autoregulatory mechanism in the untreated glaucoma group was not consistent across the entire nerve head as there were locations, mostly in the temporal sector of the ONH that demonstrated dysfunctional autoregulation during the day, suggesting that regional susceptibility of the nerve head may predict glaucomatous optic nerve damage.

An exciting new development in vascular reactivity research is the development of an automated gas flow controller (Respiract TM, Thronhill Scientific Inc) that enables the precise and independent manipulation of end-tidal CO₂ and end-tidal O₂ thereby facilitating the production of a standardised gas provocation, including a normoxic hypercapnic stimulus. Recent research from our own lab has used this technique and found that arteriolar vascular reactivity to normoxic hypercapnia was reduced in untreated POAG and also in patients with progressive POAG, when compared to healthy controls. However, there was no difference in baseline arteriolar hemodynamics across groups. In addition, plasma ET-1 levels were demonstrated to be lower in untreated POAG, both at baseline and during normoxic hypercapnia.

There is much still to discover on the role of abnormal blood flow as a factor in glaucoma pathogenesis and many important questions remain unanswered. In particular, there is a need to develop clinically practical tests for the assessment of vascular reactivity. In addition, the relationship between systemic biochemical markers of endothelial function and functional markers of retinal and ONH vascular reactivity, assuming one exists, needs to be defined. However we are optimistic that continued developments in diagnostic imaging and techniques for controlled physiological provocation, will soon realize such aspirations.

John G Flanagan PhD, MCOptom, FAAO,

Subha T Venkataraman BOptom, FAAO,

Chris Hudson PhD, MCOptom, FAAO,
School of Optometry, University of Waterloo and Department of Ophthalmology and Vision Sciences,
University of Toronto.

*(This review is a precise of an article submitted for publication)

Further Reading
1. The glaucomas. Vol I & II. Eds: Ritch R., Shields M.B., Krupin T. St.Louis: Mosby; 1996.
2. Hayreh SS. Blood flow in the optic nerve head and factors that may influence it. Prog.Retin.Eye Res. 2001;20:595-624.
3. Cioffi GA, Granstam E, Alm A. Ocular circulation. P. Kaufman and A. Alm. In Adler's physiology of the eye. Elsevier; 2002. 747-784 pp.
4. Mackenzie PJ, Cioffi GA. Vascular anatomy of the optic nerve head. Can.J.Ophthalmol. 2008;43:308-312.
5. Grieshaber MC, Mozaffarieh M, Flammer J. What is the link between vascular dysregulation and glaucoma? Surv.Ophthalmol. 2007;52:S144-54.
6. Flammer J, Mozaffarieh M. Autoregulation, a balancing act between supply and demand. Can.J.Ophthalmol. 2008;43:317-321.

For a complete reference list to this article, click here.

ETIOLOGY OF IOP ELEVATION IN PRIMARY OPEN ANGLE GLAUCOMA

Ask any clinician or basic scientist who has studied aqueous outflow for many years "What is the etiology of IOP elevation in POAG?" Each will have their pet theory but each will also tell you that we do not know. This review is thus a summary of existing clues rather than a direct answer to the question, "Where does aqueous outflow resistance reside and how is it generated?" We simply do not know. Equally important, we do not know whether the added resistance that elevates intraocular pressure (IOP) in primary open angle glaucoma (POAG) is due to more resistance in the same location as that in which the resistance of the normal eye is found, or an additional resistance that is added downstream in the glaucomatous eye.

In this regard it is important to recall the corollary to Kirchhoff's law that resistances placed in series are additive.

Only recently has evidence arisen that the added resistance of the POAG eye might lie, at least in part, in a location other than that which appears to harbor most of the resistance in the normal eye. In this review, we will consider some of the principal theories of outflow resistance, concluding with recent data implicating an added resistance in a previously unappreciated location.

OUTFLOW vs RESISTANCE
Knowing where aqueous leaves the eye is quite different from knowing where the resistance to outflow resides or how it is generated. We know that aqueous humor leaves the human eye by two principal pathways. The major outflow pathway is through the trabecular meshwork, into Schlemm's canal (SC) and external collector channels, ultimately reaching the venous blood of the episclera. The other pathway is the uveoscleral pathway, which leads through the interstices of the ciliary muscle to the supraciliary and suprachoroidal space to leave the eye. Most current data suggests that uveoscleral outflow contributes little more than 10% of total outflow in the normal eye, notwithstanding our ability to enhance outflow via this pathway in glaucoma using prostanoids (1,2). As such, this review will only consider resistances in the major outflow pathway, beginning with the trabecular meshwork.

Figure 1a: Scanning electron micrograph. This sagittal section traverses the trabecular meshwork (TM), the juxtacanalicular region (JCT), Schlemm's canal (SC) and one of the external collector channels (asterisks) that leads from Schlemm's canal to the episcleral venous system. (From Freddo T. Chapter 3. Ocular anatomy and physiology related to aqueous production and outflow. In: Primary Care of the Glaucomas. Lewis T, Fingeret M, eds, Appleton and Lange, 1993. With kind permission of The McGraw-Hill Companies Inc.)

Figure 1b: Scanning electron micrograph shows the uveal face of the trabecular meshwork. The intersecting trabecular beams are covered by a uniform, thin layer of endothelial cells, surrounding an avascular core of collagen and elastin. The larger open spaces seen at the surface get progressively smaller in deeper layers. (From TF Freddo, MM Patterson, DR Scott, and DL Epstein. Influence of mercurial sulfhydryl agents on aqueous outflow pathways in enucleated eyes. Invest Ophthalmol. Vis. Sci. 1984; 25:278-285. With kind permission of copyright holder, the Association for Research in Vision and Opthalmology.)

In the absence of a pumping mechanism, the flow of fluid through a porous tissue such as the trabecular meshwork is driven passively by gradients in osmotic and/or hydrostatic pressures. Because there is no osmotic difference between aqueous and the blood into which it flows (3), we are left with hydrostatic pressure as the dominant force. So, it is the pressure difference (P) between the IOP in the anterior chamber and that in the episcleral veins (P = 5 mmHg) that drives aqueous humor through this system. The ratio of this pressure difference to that of aqueous flow (assuming a typical flow rate (Q) of 2µl/min) equals the flow resistance (R).

R=P/Q
The inverse of the outflow resistance is known as the outflow facility (C_tm).
C_tm = Q/(P_i - P_e)
where P_i equals IOP and P_e equals episcleral venous pressure.

WHERE DOES NORMAL OUTFLOW RESISTANCE RESIDE?
Enroute to SC, aqueous humor leaving the anterior chamber enters the trabecular meshwork, a nonvascularized tissue that is separated on anatomical grounds into the uveal meshwork, the deeper corneoscleral meshwork and the still deeper juxtacanalicular connective tissue (JCT). The uveal and corneoscleral meshwork are configured as intersecting beams of collagen and elastin in their cores, with an enveloping layer of thin endothelial cells. The open spaces between the beams become progressively smaller as aqueous moves through these tissues towards SC (Figure 1). By contrast, the juxtacanalicular tissue (JCT), just internal to SC is an open connective tissue matrix with fibroblast-like cells in a collagen and elastin matrix (4) (Figure 2).

Figure 2: Transmission electron micrograph shows juxtacanlicular region (JCT) of the trabecular meshwork and inner wall of Schlemm's canal (SC). The JCT region exhibits an open matrix including collagen (C) and elastin. The fibroblast-like cells of the region extend slender connections to the endothelial cells lining Schlemm's canal (arrows). (From Freddo T. Chapter 3. Ocular anatomy and physiology related to aqueous production and outflow. In: Primary Care of the Glaucomas. Lewis T, Fingeret M, eds, Appleton and Lange, 1993. With kind permission of The McGraw-Hill Companies Inc.)

The Uveal and Corneoscleral Meshwork.
Early studies of Bárány (5) showed that perfusion of enucleated bovine eyes with hyaluronidase reduced outflow resistance. From these studies the authors concluded that the glycosaminoglycan substrate for this enzyme, hyaluronan or hyaluronic acid, was the principal resistive material in the outflow pathways and presumed that it was distributed in the "open-spaces" between the trabecular beams of the uveal and corneoscleral meshwork. Only four years later, McEwen (6) showed that there is negligible flow resistance in the uveal and corneoscleral meshwork. Nonetheless, for many years, the notion that glycosaminoglycans (GAGs) were the resistive material in the outflow pathway persisted. More recently, immunohistochemical studies have demonstrated the absence of GAGs in the "open-spaces" of the meshwork (7,8) and intracameral injection of purified testicular hyaluronidase in living monkey eyes failed to produce either a reduction in IOP or a change in outflow facility (9). Most glaucoma investigators now agree that virtually none of the resistance to outflow resides in the uveal or corneoscleral meshwork of the normal eye.

The Juxtacanalicular Region (JCT).
The tortuous and much smaller "open-spaces" for flow within the JCT have made this region an attractive candidate as the tissue that generates the bulk of outflow resistance. But, hydrodynamic analyses have failed to support this view. (10-12). In a particularly innovative approach, Mäepea and Bill (13) passed a micropressure sensor through the inner wall of SC and into the meshwork, to measure the point at which the pressure drop occurred. They found that the pressure drop occurred within 14 µm of the inner wall of SC, a position that should correspond to a point within the JCT. These findings notwithstanding, calculations of hydraulic conductivity in the JCT, using measurements of "open space" from electron micrographs, show a JCT that is simply too porous to account for the outflow resistance of the normal eye. (10-12,14-17). Indeed, even using the challenging technique of quick-freeze/deep-etch (QF/DE) to obtain a more fully preserved extracellular matrix in the JCT, too much open space remained for the JCT to account for even normal outflow resistance (18).

An important caveat of this work is that even the QF/DE technique results in collapse of most of the glycosaminoglycans (GAGs). If these GAGs were not collapsed, the question remains whether measurements of "open-space" in such images (if they could be obtained) would finally give us a calculated hydraulic conductivity that would allow us to attribute most of the outflow resistance to the JCT.

Schlemm's Canal.
The inner wall of SC is composed of endothelial cells, joined by tight junctions that simplify in complexity and tightness as IOP is raised. (19) The endothelium of the inner wall encounters a direction of flow toward the lumen of the canal, similar to that seen in post-capillary venules and lymphatics. (20). There are a couple of specific features that distinguish the behavior of the inner wall from the behavior of post-capillary venues and lymphatics. When the inner wall is chemically fixed for microscopic examination while under conditions of flow, large blebs are seen along the inner wall, which are termed giant vacuoles (4). We know that the size and number of these vacuoles increases with IOP (21,22). Similar structures are also found in the choroid plexus of the brain where cerebrospinal fluid is reabsorbed (23).

In addition to giant vacuoles, the inner wall endothelium of SC exhibits two types of pores. Some occur at the border between adjacent endothelial cells ("B" pores) and others are found away from the cell borders ("I" intracellular pores) (24) (Figure 3). The issue of whether one or both of these pores might be artifactual remains undetermined. One theory is that B pores might correspond to areas in which intercellular tight junctions have been focally interrupted, creating a paracellular pathway for aqueous to enter SC (19,25).

Figure 3: Scanning electron micrograph showing pores within the inner wall of Schlemm's canal as viewed from inside the lumen of Schlemm's canal. Left, an intracellular or I-pore (I) and an artifactual pore with ragged edge (A); right, an intercellular or B-pore (B) (From Ethier CR, Coloma FM, Sit AJ, Johnson M. Two pore types in the inner-wall endothelium of Schlemm's canal. Invest Ophthalmol Vis Sci. 1998; 39:2041-2048. With kind permission of copyright holder, the Association for Research in Vision and Opthalmology.)

If pores were the "bottleneck" that creates resistance in the outflow pathway one might expect to find their numbers to be inversely related to resistance. In fact, Allingham, et al. (1992) found that the density of pores in the inner wall was inversely correlated with resistance under conditions of perfusion at constant pressure and variable flow. But when these studies were repeated under conditions of constant flow with variable pressure, no such relationship was found. (24,27,28). This leaves uncertain whether pores might be a source of resistance in the normal eye. But importantly, in both studies, regardless of perfusion conditions, glaucomatous eyes exhibited fewer pores than normal eyes (28). Could it be that a change in the capacity of the endothelium to produce pores in response to changes in pressure and flow could create an added resistance?

THE FUNNELING EFFECT
There is evidence to support the notion that pores and the JCT may interact in a way that would not be predicted from anatomy alone. Based upon fluid dynamic modeling, even if pores and vacuoles contribute minimal resistance themselves, they could force fluid to flow in limited patterns to reach them. This phenomenon has been referred to as the "funneling effect". This model predicts that with flow headed for a small population of pores, only a limited portion of the JCT is realistically available for flow, thus increasing resistance (29) (Figure 4).

Figure 4: Schematic representation of the flow pattern predicted by the "funneling" hypothesis as aqueous moves through the JCT region towards the limited population of pores in the inner wall of Schlemm's canal. (From Overby D, Gong H, Qiu, G., Freddo T.F., Johnson, M. . "The mechanism of increasing outflow facility during washout in the bovine eye." Invest Ophthalmol Vis Sci. 2002; 43: 3455-3464. With kind permission of copyright holder, the Association for Research in Vision and Ophthalmology.)

External Collector Channels.
Because the external collector channels are tens of microns in diameter, calculations indicate that these vessels should have negligible flow resistance (30-33). Still, smooth muscle cells have been found within the walls of these vessels at their point of origin, raising the issue of whether they can be regulated at these points in a way that could increase resistance by contracting (34). Moreover, several investigators have perfused enucleated eyes following 360 degree trabeculotomy, which should eliminate all resistance internal to the collector channels. Results consistently show that only 75% of resistance is eliminated (35). More study in this area is needed because it suggests that total resistance, even in the normal eye, is the result of more than one resistance coupled in series.

WHAT CAUSES THE ADDED RESISTANCE IN POAG AND WHERE IS IT?
Speculating on the source of added resistance in POAG is daunting, especially when one begins with uncertainty as to the source(s) and location(s) of the resistance in the normal eye. While there is general presumption that the resistance of the normal eye resides within the JCT and/or inner wall of SC, or some dynamic combination of both, this does not guarantee that the additional resistance found in the eye with glaucoma is the result of higher resistance in the same location(s). As mentioned earlier, resistances in series are additive. Thus it is possible that a resistance could be created in the glaucomatous eye that does not exist at all in the normal eye. Based upon the discussion above, a host of candidates present for consideration, either singly or in combination.

Extracellular Matrix, Sheath-derived plaques and the Cribriform Plexus.
It has long been noted that there is a progressive accumulation of extracellular matrix in the JCT region with age. Much of this material, at least in POAG, is associated with the sheaths of the elastic fibers of the cribriform plexus (36). Notwithstanding this progressive accumulation of material, available data do not appear to support the notion that this added material is sufficient in amount to have any hydrodynamic consequences (16,37). It is important to note here that this conclusion is based upon the assumption that the microscopically discernable open space in these specimens truly reflects the open space present in-vivo.

The cribriform plexus mentioned above is the system of tendons from the smooth muscle cells of the longitudinal bundle of the ciliary muscle extending into the meshwork and applying tension to the JCT region and directly to the inner wall (38). We know that as IOP increases, SC collapses (39,40) and in doing so additional resistance is created (41,42). Preventing collapse of SC is likely the mechanism whereby muscarinic agents, such as pilocarpine, act to decrease outflow resistance (14). These agents cause the longitudinal fibers of the ciliary muscle to contract, thus pulling on the cribriform plexus and tethering the wall of SC open in the face of pressure increases. In this way, the canal remains open and normal resistance is maintained. (38,43). Could it be that the documented increase in "sheath-like material" compromises the ability of the cribriform plexus to contract, and therefore to hold the canal open in the absence of the stronger pull of a muscarinic agent such as pilocarpine?

Contractility and Matrix Interactions.
Even if the source and location of the added resistance in POAG remain unknown, interventions that reduce resistance and therefore reduce intraocular pressure can provide us with clues.

Y-27632 is a protein kinase inhibitor selective for Rho associated kinase (ROCK) (44-46). ROCK regulates the phosphorylation of the regulatory myosin light chain (MLC) to promote actomyosin-driven cell contractility. By inhibiting ROCK with Y-27632, MLC phosphorylation is decreased (47,48), resulting in cell relaxation and disassembly of actin stress fibers and focal adhesions in many cell types (49), Included among these cell types are human trabecular meshwork (TM) and SC endothelial cells in-vitro (49,50). Relaxation of stress fiber and focal adhesions would be expected to facilitate aqueous outflow.

H-7, a serine–threonine kinase inhibitor, also induces relaxation of cells in the trabecular meshwork. It is hypothesized that H-7-induced cellular relaxation in the TM may be partially related to its ability to inhibit Rho kinase (51).

Another group of cell/matrix active agents, latrunculins, also alter outflow resistance. Latrunculins disrupt cellular F-actin filaments (52,53). The two most common latrunculins, latrunculin (LAT)-A and -B, cause reversible dose- and incubation time-dependent destruction of actin bundles and associated proteins in cultured trabecular meshwork cells. (52-57). These agents also increase outflow facility in live monkeys, presumably by disrupting the actin cytoskeleton in meshwork cells, leading to relaxation of the meshwork and/or alteration of cell–cell and cell–extracellular matrix adherens junctions (55,58).

It is of interest that the effects of these various agents are to produce changes in the meshwork that are strikingly similar to those resulting from a phenomenon called the wash-out effect (59). When eyes of all species but humans are perfused, the resistance to outflow decreases with the volume of fluid (60). The structural correlate for this increase in facility appears to be similar to that reported following intervention with these various agents. Common features include expansion of the subendothelial JCT matrix and distention of the inner wall of SC. Such changes were reported following Y-27632 perfusion in porcine and bovine eyes (49), H-7 (61) and latrunculin-B (62) in monkeys, and these changes are morphologically similar to the "matrix-matrix" type of inner wall/JCT separation previously shown to correlate with increasing outflow facility during "washout" in bovine eyes (59,63). Combining these results it would appear that inner wall/JCT separation appears to be a critical change underlying both drug-induced and washout-induced increases in outflow facility (59,63). What is unclear from these studies is whether these agents are pointing us toward "the" source of resistance or "a" source of resistance in the normal eye and the eye with POAG.

DOWNSTREAM EFFECTS?
It is clear that most of the research in the area of trabecular outflow resistance, at least in the normal eye, is now focused squarely on the JCT and inner wall of SC, either separately or in combination. And yet, despite decades of research, we remain at a loss to convincingly identify morphological differences in the outflow pathway that would seem to account for the change in intraocular pressure between normal eyes and those with early or moderate glaucoma, using existing methods. Logically, there are several possible explanations. One is that we simply have not yet found the right methods that will give us a "true picture" of the open-spaces in the meshwork and the extent to which the spaces open to flow are reduced in glaucoma. But another possibility is that a site that offers little or no resistance in the normal eye, becomes an added resistance in glaucoma because resistances in series are additive!

Figure 5: At 7 mmHg, the aqueous plexus (AP) is more open compared to the tissue perfused at higher pressures. At 15mmHg, there is focal herniation (arrows) of the inner wall and JCT at the collector channel (CC) ostium. At 30 and 45mmHg more dramatic herniations of the inner wall and JCT into the collector channel ostia were found. (From Battista, S.A., Lu Z., Hofmann, S., Freddo, T.F., Overby, D.R., Gong, H. "Acute IOP elevation reduces the available area for aqueous humor outflow and induces meshwork herniations into collector channels of bovine eyes". Invest. Ophthalmol. Vis. Sci. 2008, 49:5346-52. With kind permission of copyright holder, the Association for Research in Vision and Opthalmology.)

A recent line of evidence by Gong, Freddo and Zhang (64), points to the possibility that the normally low resistance openings from SC into the external collector channels may become occluded in glaucomatous eyes. They have documented that as pressure is elevated, areas of the inner wall of SC progressively collapse and the attached portions of the JCT that face the openings of the external collector channels herniate into the openings. In normal eyes, as pressure is reduced, these herniations withdraw from the openings, relieving them of this partial occlusion (65) (Figure 5). Of particular interest, however, when enucleated eyes from patients with POAG were examined, seemingly permanent herniations into the openings of the collector channels were found, even at a pressure of zero. This line of investigation has opened up the possibility that glaucoma could be the result of a series of events, affecting resistance at more than one site along the outflow pathway.

SUMMARY
Candidates for the site or sites of outflow resistance in the normal eye are being narrowed but the mechanisms that regulate outflow facility remain elusive. The same remains true for the added resistance in glaucoma, but recent studies suggest that both trabecular and non-trabecular elements of the outflow pathway deserve consideration as we continue to unravel this elusive mystery.


Thomas F. Freddo, OD, PhD, DSc(hc), FAAO,
School of Optometry, University of Waterloo,
Waterloo, Ontario, Canada

Haiyan Gong, MD, PhD
Boston University School of Medicine,
Boston, MA

Supported by: National Glaucoma Research, a program of the American Health Assistance Foundation, NIH EY-09699, The Massachusetts Lions Eye Research Fund, Inc., The University of Waterloo, School of Optometry.

For a complete reference list to this article click here.

Lowering intraocular pressure (IOP) remains the only proven method of preventing the onset and progression of glaucomatous vision loss, yet the role of IOP in the neuropathy remains controversial. This arises, in part, from the clinical observation that significant numbers of patients with epidemiologically normal levels of IOP develop glaucoma (e.g. normotensive glaucoma), whereas other individuals with elevated IOP may show no signs of the disease over extended periods. In this text we present why the study of ocular biomechanics is relevant in elucidating the role of IOP and individual sensitivity to IOP. We concentrate on some of the concepts which we believe are central to understanding the role of the sclera on the mechanics of the lamina cribrosa (LC).

IOP is the load exerted by the intraocular fluids on the tissues that contain them, and is, by definition, a mechanical entity. Therefore, while glaucoma is most certainly a multifactorial disease, we believe that it is natural to hypothesize that biomechanics plays a role in the development and progression of the neuropathy. The optic nerve head (ONH) is of particular interest from a biomechanical perspective, because it is a weak spot within an otherwise strong corneo-scleral shell. Also, most evidence suggests that damage to the retinal ganglion cell axons within the LC is the principal pathophysiology underlying glaucomatous vision loss and ONH cupping.

In the biomechanical paradigm of glaucomatous optic neuropathy, the susceptibility of a particular patient's ONH to IOP insult is a function of both the acute and long-term biomechanical response of the constituent tissues to elevated IOP and the resulting mechanical, ischemic and cellular events driven by that response. Eyes with a particular combination of connective tissue geometry, stiffness and blood supply may be more susceptible to damage at normal levels of IOP, whereas others may have a combination of these factors that can withstand prolonged periods of relatively high levels of IOP. One of the challenges of ocular biomechanics is identifying the particular combinations that render an eye more or less susceptible to the effects of elevated IOP.

Before discussing ocular biomechanics further, it is worth mentioning some terms and concepts from mechanics: Strain is a measure of the local deformation of a material or tissue, and is usually expressed as the percentage change in length of the original geometry (e.g. a wire that was originally 10 mm long that has been stretched an additional 1 mm, exhibits 10% strain). Stress is a measure of the load applied to, transmitted through, or carried by a material or tissue. For example, the action of IOP on the inner eye wall induces forces (stress) that may deform (strain) the sclera. Note that mechanical stress is not synonymous with the notions of stress typically used in physiologic or metabolic contexts (e.g. ischemic or oxidative stress).

Stress and strain (i.e. force and deformation) in a material are related to each other through the material's mechanical properties. These mechanical properties, often called the material properties, can be thought of as the stiffness or compliance intrinsic to the material. Hence, under load, a stiff tissue might be under high stress, but exhibit low strain, whereas an equal shape made of compliant tissue might undergo high strains, even at low levels of stress.

The sclera is the stiffest tissue in the posterior pole of the eye, and is therefore the main load bearing component. Other tissues, such as the retina, choroid and optic nerve, are much more compliant, meaning that under IOP these tissues may undergo large strains while still not carrying substantial loads. These soft tissues depend on the stiffer sclera for support and are essentially shielded by the sclera from loads that would otherwise strain them excessively. The LC is likely somewhere in between the soft tissues and the sclera, because the laminar beams are composed of stiff connective tissues similar to that of the sclera, yet it is very porous (LC connective tissue volume fraction is approximately one third) (1). The mechanical response of the LC to elevated IOP is thus expected to be complex from a purely material perspective. Unfortunately there are further complications.

Figure 1. Example of how the factors governing scleral mechanics may combine and interact to affect lamina cribrosa biomechanics. The graph shows computed tensile strains in the prelaminar neural tissues versus scleral shell thickness for two different scleral mechanical properties, a compliant sclera (upper curve) and a stiff sclera (lower curve). The plot shows a strong interaction between the two variables. Specifically, when the sclera is compliant, increased shell thickness leads to reduced strains, whereas when the sclera is stiff, changes in shell thickness have virtually no effect on the predicted strains. Conversely, the effects of an increase in stiffness (the distance between the two lines) are larger in eyes with thin scleral shells (left side) than in eyes with thick shells (right side). Adapted from 2

The mechanical response of tissue also depends on its geometric characteristics—the amount of material and its geometry (Figure 1). The same load induces smaller deformations (lower strains) in a thick bar than in a thin one, assuming both bars are made of the same material. It is useful to define structural stiffness, which incorporates both the mechanical properties and geometry into a composite measure of a structure's resistance to deformation.

Mechanically, the posterior pole of the eye responds to IOP elevations as a system whose structural stiffness depends on the geometry and mechanical properties of the sclera and LC, and to a lesser extent the other tissues. Hence, two eyes exposed to identical IOPs may exhibit very different strain and stress fields due to differences in their structural stiffness (Figure 2). From the perspective of the LC its mechanical response to IOP is linked to that of the peripapillary sclera because the sclera transmits load to the laminar structure at its insertion into the scleral canal wall. Therefore, the structural stiffness of the peripapillary sclera has a significant influence on IOP-related laminar deformation.

Figure 2. En-face views of 3D biomechanical models of the posterior sclera and ONH. The colors represent the magnitude of stresses induced by elevated IOP. The plot on the left shows the stress in an idealized model with a circular canal in a perfectly spherical scleral shell of uniform thickness. The plot on the right shows the stress in a model with an elliptical scleral canal in a scleral shell with a more anatomically realistic shape and thickness. The thickness of the peripapillary sclera and the size and shape of the scleral canal influence the magnitude and distribution of the stress. In both cases, the stresses concentrate around the scleral canal, but the more realistic model on the right shows stress that varies substantially around the canal and that can extend further out into the sclera. For clarity, only the scleral tissue stress is shown. Adapted from 9

Computational models have been used to study the factors that determine scleral response to IOP (2,3). Not surprisingly, these models suggest that the response of the sclera depends on its mechanical properties and certain aspects of its geometry (mainly thickness and the globe size). But these studies also suggest that the factors determining the scleral response interact with one another, meaning that the effects of one factor depend on the level of another. This means that anticipating how the factors combine to determine the scleral structural stiffness is not necessarily trivial.

The models suggest that a structurally compliant sclera allows the scleral canal to expand during an acute IOP elevation, tautening the lamina within the canal and "pulling" it anteriorly. In contrast, a stiffer sclera allows minimal expansion of the canal. IOP acting directly on the anterior laminar surface "pushes" the lamina in the posterior direction (Figure 3). The resultant deformation of the lamina for a given change in IOP is therefore governed by its own structural stiffness, by the extent to which the scleral canal expands and rotates, pulling the lamina taut and bending or twisting it—an indirect action of IOP, and by the extent to which the lamina itself is deformed posteriorly—a direct action of IOP. The net result of the superposition of these effects is that it is possible for the anterior-to-posterior deformation of the LC to be negligible, while the LC is subjected to substantial strain and stress. In the case of a stiff sclera it is also possible that IOP induces negligible canal expansion but substantial anterior-to-posterior deformation of the lamina.

Figure 3. Diagram showing how the mechanical response of the sclera can influence laminar biomechanics. In the case of a compliant sclera (left), IOP induces large scleral deformations that result in a large scleral canal expansion that pulls the contained lamina taut, despite the direct posterior force of IOP on the laminar surface. Conversely, a stiff sclera deforms very little when exposed to IOP (right), with a correspondingly small scleral canal expansion and little stretching of the contained lamina, thus allowing the lamina to be displaced posteriorly by the direct action of IOP on its surface. Note that the structural stiffness of the lamina itself will also play a role in its deformation. Adapted from 9

The question arises—what type of laminar deformation, and its associated modes of stress and strain are "worse" for axons? Could the manner in which the lamina deforms be an indicator of individual susceptibility? The answers to these questions are unknown. Computational modeling is providing insight, but definitive answers will not be possible until new imaging technologies are developed. However, it is still likely that the mode of deformation per se will be less important for maintenance of healthy axons than will be the particulars of laminar stress and strain.

Classical structural engineering analysis seeks to identify stresses and strains within a structure to determine possible modes and regions of failure. However, the long-term nature of the development of glaucoma suggests that this may not be the most adequate approach in ocular biomechanics as it relates to glaucoma. A biomechanical view of the ONH must also seek to understand how the stress and strain borne by the sclera and lamina are related to cellular responses and the resulting tissue remodeling. Such relationships have been observed in other tissues; tendon, cartilage, arteries and bone are known to regulate tissue composition and structure through cellular activity based on the stress and strain environment in vivo (4-6). Recent studies suggest that the eye is not an exception. LC astrocytes have been shown to respond to mechanical stimulation that likely leads to changes in the extracellular matrix (4,6). The lamina and sclera from glaucomatous eyes have distinctly different tissue composition and mechanical properties than those from normal eyes (7,8). Hence, while biomechanics likely plays a prominent role in the pathophysiology of glaucoma, much work remains to elucidate the mechanisms through which it acts, the other factors with which it interacts, and the changes in the ocular tissues that it engenders.

J. Crawford Downs
Michael Roberts
Ocular Biomechanics Laboratory, Devers Eye Institute,
Legacy Health System, Portland, OR

Ian Sigal
Ocular Biomechanics Laboratory, Devers Eye Institute,
Legacy Health System, Portland, OR
Department of Biomedical Engineering, Tulane University, New Orleans, LA

Support: NIH-BRIN/INBRE Grant P20 RR16456 from NCRR

References
1. Roberts MD, Grau V, Grimm J, Reynaud J, Bellezza A, Burgoyne CF, Downs JC. Remodeling of the Connective Tissue Microarchitecture of the Lamina Cribrosa Occurs Early in Experimental Glaucoma in the Monkey Eye. Invest Ophthalmol Vis Sci 2008.
2. Sigal IA. Interactions between geometry and mechanical properties on the optic nerve head. Invest Ophthalmol Vis Sci In Press.
3. Sigal IA, Flanagan JG, Ethier CR. Factors influencing optic nerve head biomechanics. Invest Ophthalmol Vis Sci 2005;46(11):4189-99.
4. Hernandez MR. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res 2000;19(3):297-321.
5. Kirwan RP, Fenerty CH, Crean J, Wordinger RJ, Clark AF, O'Brien CJ. Influence of cyclical mechanical strain on extracellular matrix gene expression in human lamina cribrosa cells in vitro. Mol Vis 2005;11:798-810.
6. Pena JD, Agapova O, Gabelt BT, Levin LA, Lucarelli MJ, Kaufman PL, Hernandez MR. Increased elastin expression in astrocytes of the lamina cribrosa in response to elevated intraocular pressure. Invest Ophthalmol Vis Sci 2001;42(10):2303-14.
7. Downs JC, Suh JK, Thomas KA, Bellezza AJ, Hart RT, Burgoyne CF. Viscoelastic material properties of the peripapillary sclera in normal and early-glaucoma monkey eyes. Invest Ophthalmol Vis Sci 2005;46(2):540-6.
8. Quigley HA, Dorman-Pease ME, Brown AE. Quantitative study of collagen and elastin of the optic nerve head and sclera in human and experimental monkey glaucoma. Curr Eye Res 1991;10(9):877-88.
9. Sigal IA, Roberts MD, Girard M, Burgoyne CF, Downs J. Biomechanical changes of the optic disc. In: Levin LA, Albert DM, eds. Ocular disease: mechanisms and management. New York: Elsevier, In Press 2009.

NEWS

Recognition of World Glaucoma Day on Capitol Hill
To recognize the second annual World Glaucoma Day (WGD) on March 12, the Association for Eye and Vision Research (AEVR) sponsored a March 10 Capitol Hill briefing to educate Members of Congress and their staff. The event was timely, as the Senate was passing the Fiscal Year (FY) 2009 Omnibus appropriations bill, which increases National Eye Institute (NEI) funding by $21.4 million over FY2008. That annual spending increase, coupled with the $175 million in two-year funding for NEI research from the American Recovery and Reinvestment Act of 2009, means nearly $200 million more for vision research.

In introducing the briefing, AEVR Executive Director James Jorkasky read from a March 6 statement issued by the NEI for WGD in which its Director Paul Sieving, M.D., Ph.D., noted that NEI currently spends $65 million in support of 168 glaucoma studies, including the newly initiated NEI Glaucoma Human genetics collaBORation, known as NEIGHBOR, through which seven U.S. research teams will lead genetic studies of the disease.

The featured speakers included Murray Fingeret, O.D., F.A.A.O., (Brooklyn/St. Albans Campus, Department of Veterans Administration New York Harbor Health Care System, Exec VP, OGS), who spoke about the incidence and burden of the disease, and Rohit Varma, M.D., M.P.H., (Doheny Eye Institute, University of Southern California), who spoke about research and treatments. Both speakers had participated in a March13-14, 2008, joint NEI/Food and Drug Administration (FDA) Glaucoma Endpoints meeting at which researchers acknowledged that glaucoma is a complex, neurodegenerative disease in which detectable changes within the eye may not progress linearly or in concert with functional changes, that is, vision loss.

Left to right: The speakers, Rohit Varma and Murray Fingeret are seen with Cong. John Boozman (R-AR).

World Glaucoma Congress 2009
The Optometric Glaucoma Society and the World Glaucoma Association would like to invite optometrists to attend the 2009 World Glaucoma Congress (WGC), to be held in Boston, MA from July 8-11th. Clinicians and scientists from around the world will come together to discuss and learn about glaucoma. The world's experts will be present in a forum only seen every other year. This is the first time the WGC is being held in North America, and should provide a great learning environment for all ODs. Click here for information about the meeting.

 

 

POLL RESULTS FROM PREVIOUS ISSUE

The results of our most recent Live Poll are finalized and presented. It is encouraging to note that 82% of respondents always explain to newly diagnosed glaucoma patients the cause of their condition. Clinicians and scientists will recognize that our current best understanding of the cause of glaucoma will continue to evolve.

The responses to the question of the largest contributor to the cause of primary open angle glaucoma (POAG) were much more varied. Forty percent believe the principle causative factor to be either deficiency of the vascular supply to the optic nerve (11%) or specifically the susceptibility of the optic nerve to damage (29%). Fifty-one percent of respondents believe the main contributing factor of POAG varied between individuals. This diversity of responses is not surprising given the complicated processes that are involved. This information is encapsulated in this edition by our review articles.

This is a promising time for patients with glaucoma and better understanding of pathogenesis means that this is an exciting time for clinicians and scientists. Stay tuned!

John McSoley, OD

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Editor in Chief Paul Spry PhD MCOptom Associate Editors Brad Fortune, OD, PhD Shaban Demirel, BScOptom, PhD Algis Vingrys BScOptom, PhD

Editorial Board Douglas Anderson MD Paul Artes PhD MCOptom Dick Bennett OD Murray Fingeret, OD Ron Harwerth, PhD Chris Johnson, PhD Tony Litwak, OD John McSoley, OD Ron Melton, OD Bruce Onofrey, OD, RPh Leo Semes, OD Randall Thomas, OD Thom Zimmerman, MD, PhD   Art/Production Director Joe Morris

 

To subscribe to the OGS Journal, CLICK HERE! The e-newsletter is offered free to clinicians and scientists, through an unrestricted educational grant from

 

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